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1. Introduction Uterine rupture is an obstetric complication that causes significant maternal and fetal morbidity and mortality. It is associated with prolonged labor, oxytocin induction, and uterine scarring, especially following prior cesarean section [1]. Several reports have indicated that antepartum uterine rupture can occur in an unscarred uterus, but the contributory risk factors have not been identified [2–7]. Here we report a case of spontaneous rupture of an unscarred gravid uterus with favorable fetal outcome at 32 weeks of gestation. 2. Case Presentation A healthy 29-year-old primigravid woman conceived naturally and began receiving prenatal checkups at a private hospital. At week 31, fetal bilateral hydronephrosis was observed, and the subject was referred to Kumamoto University Hospital at 31 weeks + 6 days of gestation for diagnostic studies and proper management. She had no history of trauma, uterine surgery, or intrauterine intervention, or symptoms suggesting the presence of Ehlers-Danlos syndrome in either herself or her family members.

and the subject was referred to Kumamoto University Hospital at 31 weeks + 6 days of gestation for diagnostic studies and proper management. She had no history of trauma, uterine surgery, or intrauterine intervention, or symptoms suggesting the presence of Ehlers-Danlos syndrome in either herself or her family members. Abdominal ultrasonography revealed bilateral hydronephrosis and a small ventricular septal defect in the fetus, but no structural abnormalities of the uterus, though no special attention was paid to the uterine wall. Four days later, the subject suffered from acute right upper quadrant abdominal pain and visited a private hospital. Abdominal ultrasonography revealed an anechoic cystic lesion in the region of her symptoms. A cardiotocogram showed a reassuring fetal heart late pattern with periodical uterine contractions. A drip infusion of ritodrine hydrochloride was administered and the subject was immediately transferred to Kumamoto University Hospital at 32 weeks + 3 days of gestation. On admission, she was not in acute distress. Her abdomen was soft, and a fist-sized elastic soft mass was palpated at the upper right quadrant. Speculum examination revealed a normally positioned cervix and no vaginal bleeding. On digital examination the cervix was tightly closed and uneffaced. Her vital signs were stable, and she had a hemoglobin level of 12.2 g/dL. A cardiotocogram showed fetal tachycardia of 180 bpm with moderate baseline variability and nonperiodic accelerations. Periodic uterine contractions occurred every 6–8 min.

ding. On digital examination the cervix was tightly closed and uneffaced. Her vital signs were stable, and she had a hemoglobin level of 12.2 g/dL. A cardiotocogram showed fetal tachycardia of 180 bpm with moderate baseline variability and nonperiodic accelerations. Periodic uterine contractions occurred every 6–8 min. Abdominal ultrasonography demonstrated a defect in the uterine wall at the right side near the uterine fundus. The amniotic cavity was bulging out of the uterus, corresponding to the palpable mass. The placenta was situated in the fundus and there was no evidence of placental abruption. There was a normal amount of amniotic fluid. Though ultrasonographic findings led us to speculate uterine rupture, her clinical course did not suggest such a life threatening complication. So she underwent magnetic resonance imaging (MRI) examination to check uterine anomalies. MRI confirmed an 8.5-cm diameter extrauterine cyst protruding from the intrauterine amniotic cavity (Figure 1). These findings led us to suspect the possibility of an impending uterine rupture, and we, therefore, performed an emergent cesarean section.

Though ultrasonographic findings led us to speculate uterine rupture, her clinical course did not suggest such a life threatening complication. So she underwent magnetic resonance imaging (MRI) examination to check uterine anomalies. MRI confirmed an 8.5-cm diameter extrauterine cyst protruding from the intrauterine amniotic cavity (Figure 1). These findings led us to suspect the possibility of an impending uterine rupture, and we, therefore, performed an emergent cesarean section. No peritoneal fluid or hemoperitoneum was detected, and the anterior surface of the uterus had a normal appearance. A lower segment cesarean section was performed, and the subject gave birth to a male infant weighing 1,788 g with Apgar scores of 6 at 1 min and 9 at 5 min. The amniotic fluid was clear. A 2-cm diameter uterine perforation was located at the right cornual area, with prolapse of the amniotic sac (Figure 2(a)). There was no bleeding at the perforation. On uterine examination, the perforation was located behind the cornual end of right fallopian tube. The left side of the cornual area was also focally thin, and the cornual ends of both fallopian tubes seemed closer to the midline of the uterus than normal (Figure 2(b)). The cornual areas were repaired with interrupted vicryl sutures. The total blood loss was approximately 500 g without blood transfusion.

opian tube. The left side of the cornual area was also focally thin, and the cornual ends of both fallopian tubes seemed closer to the midline of the uterus than normal (Figure 2(b)). The cornual areas were repaired with interrupted vicryl sutures. The total blood loss was approximately 500 g without blood transfusion. The subject's recovery period was uneventful, and she was discharged on the eighth postoperative day. MRI examination performed 4 months after the cesarean section revealed no uterine deformity, and follow-up hysterosalpingography (HSG) at 8 months showed an arcuate uterus with right tubal occlusion (Figure 3). The infant was diagnosed with bilateral hydronephrosis and ventricular septal defect but did not require surgery and remained in stable condition and was discharged 10 weeks after birth.

The subject's recovery period was uneventful, and she was discharged on the eighth postoperative day. MRI examination performed 4 months after the cesarean section revealed no uterine deformity, and follow-up hysterosalpingography (HSG) at 8 months showed an arcuate uterus with right tubal occlusion (Figure 3). The infant was diagnosed with bilateral hydronephrosis and ventricular septal defect but did not require surgery and remained in stable condition and was discharged 10 weeks after birth. 3. Discussion Rupture of the gravid uterus is an emergency condition causing high fetomaternal mortality and morbidity. In developed countries the prevalence of uterine rupture in pregnant women with previous cesarean section has been reported to be approximately 1%, whereas it is extremely rare in women without a history of cesarean section [8]. Several risk factors may contribute to uterine rupture of the gravid uterus in women with no history of uterine surgery, including intrauterine surgery, multiparity, oxytocin stimulation, placenta accreta, Ehlers-Danlos syndrome, cocaine abuse, in-utero exposure to diethylstilbestrol, uterine anomalies, and obstructed labor, for instance, due to undiagnosed fetopelvic disproportion or malpresentation [1, 7, 9–14]. Because the key factor in uterine rupture during pregnancy is the contraction of the uterine musculature due to labor, careful intrapartum monitoring of uterine activity can lead to the correct diagnosis.

s, and obstructed labor, for instance, due to undiagnosed fetopelvic disproportion or malpresentation [1, 7, 9–14]. Because the key factor in uterine rupture during pregnancy is the contraction of the uterine musculature due to labor, careful intrapartum monitoring of uterine activity can lead to the correct diagnosis. In the English literature there are six reported cases of antepartum uterine rupture of the unscarred uterus in the absence of any identified risk factors [2–7] (Table 1). Half of these cases (3/6) were primigravid women. All cases were associated with symptoms of acute abdomen with prominent hemoperitoneum, occurring primarily in the third trimester. Two-thirds (4/6) of fetuses died before delivery; however, all patients recovered following treatment. The most common rupture sites were the cornual area and the uterine fundus.

id women. All cases were associated with symptoms of acute abdomen with prominent hemoperitoneum, occurring primarily in the third trimester. Two-thirds (4/6) of fetuses died before delivery; however, all patients recovered following treatment. The most common rupture sites were the cornual area and the uterine fundus. In addition to these six cases with acute abdomen, there were two interesting cases of antepartum “silent” uterine rupture whose clinical findings were similar to those in this report [15, 16]. First, the patients were in no acute distress and had no hemoperitoneum. Second, uterine perforations were located at the cornual area. Third, focal loss of myometrial thickness was detected in the counterpart of the ruptured cornual area. In our case, follow-up HSG revealed that the subject had an arcuate uterus, a common congenital uterine anomaly affecting 3.9% of all women [17]. We are not aware of any reports suggesting a correlation between spontaneous uterine rupture and arcuate uterus. Though we cannot definitively identify the mechanisms involved in this case, based on our findings we speculate that Müllerian duct anomalies may have been related to focal weakness of the bilateral cornual uterine myometrium. In conclusion, while spontaneous uterine rupture of the unscarred gravid uterus is extremely rare, it usually occurs in the cornual area. Further studies are needed to determine the etiology of cornual myometrial defects and the relation to Müllerian duct anomalies. Acknowledgment The authors wish to thank the family for agreeing to participate in this investigation.

In conclusion, while spontaneous uterine rupture of the unscarred gravid uterus is extremely rare, it usually occurs in the cornual area. Further studies are needed to determine the etiology of cornual myometrial defects and the relation to Müllerian duct anomalies. Acknowledgment The authors wish to thank the family for agreeing to participate in this investigation. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Magnetic resonance imaging (T2WI, coronal section) of the pelvis revealed a bulging amniotic cavity protruding through the defect in the uterine wall (arrows). Neither peritoneal fluid nor hemoperitoneum was observed. Figure 2 (a) Macroscopic appearance of the uterine fundus before placenta removal. A uterine perforation was located at the right corneal area, and the amniotic sac (∗) was prolapsed. (b) Macroscopic appearance of the uterine fundus after placenta removal. The uterine perforation was focal and located just behind the cornual end of the right fallopian tube. The left cornual area (arrowhead) was focally thin, and the cornual ends of both fallopian tubes (arrows) seemed closer to the midline of uterus than normal. Figure 3 Hysterosalpingography at 8 months after cesarean section revealed mild indentation of the endometrium at the uterine fundus with right tubal occlusion. Table 1 Antepartum uterine rupture in the unscarred uterus with no identified risk factors.

Figure 2 (a) Macroscopic appearance of the uterine fundus before placenta removal. A uterine perforation was located at the right corneal area, and the amniotic sac (∗) was prolapsed. (b) Macroscopic appearance of the uterine fundus after placenta removal. The uterine perforation was focal and located just behind the cornual end of the right fallopian tube. The left cornual area (arrowhead) was focally thin, and the cornual ends of both fallopian tubes (arrows) seemed closer to the midline of uterus than normal. Figure 3 Hysterosalpingography at 8 months after cesarean section revealed mild indentation of the endometrium at the uterine fundus with right tubal occlusion. Table 1 Antepartum uterine rupture in the unscarred uterus with no identified risk factors. Case Age G-P GA Initial presentation Rupture site Fetal outcome Reference 1 20 1-0 37 Abdominal pain Loss of FM Lt. cornual area Stillbirth [2] 2 27 1-0 32 Abdominal pain Nausea Rt. uterosacral area Live birth [3] 3 31 1-0 21∗ Abdominal pain Lt. cornual area Live birth [4] 4 26 3-2 32 Abdominal pain Loss of FM Rt. cornual area~Fundus Stillbirth [5] 5 29 2-1 32 Abdominal pain Loose stool Lower segment~Fundus Stillbirth [6] 6 31 3-2 17 Abdominal pain Fundus Stillbirth [7] G-P; gravida-para, GA; gestational age (weeks), Lt.; left, Rt.; right, FM; fetal movement. *The rupture site was repaired, and the subject underwent cesarean section at 33 weeks gestation due to premature rupture of the amniotic membranes.

1. Introduction Although cases of cardiac metastasis from uterine cervical carcinoma are occasionally recognized, they are rarely detected before death. Here, we present a case of suspected cardiac metastasis from uterine cervical squamous cell carcinoma. Systemic examinations were performed owing to a decrease in the patient's platelet count. Cardiac metastasis was later diagnosed on autopsy. This report describes this case together with the findings from other literatures. 2. Case Presentation The patient was a 27-year-old woman with four previous pregnancies resulting in two births and two abortions. She had no history of appreciable disease. She was diagnosed with class IIIa high-grade squamous intraepithelial lesion by a cervical smear conducted at 14 weeks of pregnancy and diagnosed with squamous cell carcinoma by punch biopsy. She was referred to our hospital at 16 weeks and 6 days of pregnancy for further examination and treatment. No clear macroscopic abnormality was recognized by colposcopy. She was admitted for conization at 18 weeks and 3 days of pregnancy. An exophytic papillary tumor was observed by colposcopy at the time of admission; it may have grown rapidly before admission. We fully explained to the patient and family members that the cancer had advanced and when the baby would be able to survive outside the uterus if the patient continued the pregnancy. The patient and her family desired surgical treatment and termination of the pregnancy. A radical hysterectomy with pelvic lymphadenectomy was conducted at 19 weeks and 0 days of pregnancy (Figure 1).

ncer had advanced and when the baby would be able to survive outside the uterus if the patient continued the pregnancy. The patient and her family desired surgical treatment and termination of the pregnancy. A radical hysterectomy with pelvic lymphadenectomy was conducted at 19 weeks and 0 days of pregnancy (Figure 1). Postoperative pathological diagnosis revealed the following: uterine cervical carcinoma (pT1b1N1MX), squamous cell carcinoma with a keratinizing type, lymph vascular space positive for invasion, vaginal stump negative for invasion, and lymph nodes metastases (right external iliac lymph nodes, right inguinal lymph nodes, and right obturator lymph nodes).

s revealed the following: uterine cervical carcinoma (pT1b1N1MX), squamous cell carcinoma with a keratinizing type, lymph vascular space positive for invasion, vaginal stump negative for invasion, and lymph nodes metastases (right external iliac lymph nodes, right inguinal lymph nodes, and right obturator lymph nodes). Metastasis to the para-aortic lymph nodes was detected on positron emission tomography/computed tomography (PET-CT) performed postoperatively. Additional treatment options were discussed and explained. The patient and her family desired treatment that could be administered by visiting the hospital; therefore, chemotherapy was chosen. Weekly TN therapy (taxol 80 mg/m2, nedaplatin 25 mg/m2, i.v., once weekly) was conducted. Most of the metastases disappeared on PET-CT three months postoperatively and after the completion of nine cycles of chemotherapy. The medical effect of the treatment was judged as PR and chemotherapy was continued. FDG accumulation was noted in the left common iliac lymph nodes on PET-CT six months postoperatively and after the completion of 18 cycles of chemotherapy; this region also showed enlargement on CT. The medical effect of treatment was judged as PD, and chemotherapy was terminated. The treatment method was changed to radiation to the pelvis and para-aortic lymph nodes (whole pelvis: 1.8 Gy/fr, 5 fr/week, and 50.4 Gy; 2 Gy/fr for para-aortic lymph nodes to left common iliac lymph nodes, boosted to 10 Gy, 60.4 Gy in total) and the tumor shrunk. The patient did not desire additional medical treatment such as continued chemotherapy; therefore, we followed up the patient through outpatient visits without treatment.

fr/week, and 50.4 Gy; 2 Gy/fr for para-aortic lymph nodes to left common iliac lymph nodes, boosted to 10 Gy, 60.4 Gy in total) and the tumor shrunk. The patient did not desire additional medical treatment such as continued chemotherapy; therefore, we followed up the patient through outpatient visits without treatment. FDG accumulation was recognized in the para-aortic lymph nodes and both common iliac lymph modes by PET-CT 10 months postoperatively (two months after the completion of radiation treatment). Although the patient had been informed about her condition, she was nearly asymptomatic; she and her family desired to continue follow-up on an outpatient basis.

in the para-aortic lymph nodes and both common iliac lymph modes by PET-CT 10 months postoperatively (two months after the completion of radiation treatment). Although the patient had been informed about her condition, she was nearly asymptomatic; she and her family desired to continue follow-up on an outpatient basis. Thereafter, she continued to undergo routine examinations and blood tests through outpatient visits, and her platelet count decreased. She was asymptomatic and desired follow-up visits. A remarkable decrease in platelet count from 32,000/μL was observed in a blood test 15 months postoperatively (seven months after radiation treatment) (Figure 2). Although we attempted to persuade her to be hospitalized for detailed examination and treatment, she wished to be examined and treated through outpatient visits. Her PET-CT scan showed the FDG accumulations in the para-aortic lymph nodes and both common iliac lymph nodes remained nearly unchanged; however, an accumulation was detected in the left gluteus. Accumulations were detected in mediastinum and hilar lymph nodes as well, and metastases were suspected. Bone marrow examination revealed normal hematopoiesis, but the result was probably because of the idiopathic increase in platelet consumption. Multidetector CT showed a tumor extending from the right atrium to the right cardiac chamber (longest diameter, 10 cm).

hilar lymph nodes as well, and metastases were suspected. Bone marrow examination revealed normal hematopoiesis, but the result was probably because of the idiopathic increase in platelet consumption. Multidetector CT showed a tumor extending from the right atrium to the right cardiac chamber (longest diameter, 10 cm). The cardiovascular internal medicine department concluded that a medical procedure would be difficult. The cardiovascular surgery department was also consulted, and tumor removal by surgery was considered. However, careful judgment as to whether the patient's prognosis could be improved after surgical treatment was necessary. The patient and her family were fully informed about the above information and the possible risks of surgery; they did not desire surgery. Therefore, it was decided she would be followed up continuously. On the 14th day after confirmation of the tumor, she was admitted to the hospital because of generalized weakness and difficulty with oral intake. Her general condition gradually worsened, and she died on the 21st day after confirmation of the tumor (488th day after the onset of initial treatment). Consent was obtained from the family to perform an autopsy. The findings were as follows:  patient: a 28-year-old woman; clinical diagnosis: uterine cervical carcinoma; primary diagnosis:

On the 14th day after confirmation of the tumor, she was admitted to the hospital because of generalized weakness and difficulty with oral intake. Her general condition gradually worsened, and she died on the 21st day after confirmation of the tumor (488th day after the onset of initial treatment). Consent was obtained from the family to perform an autopsy. The findings were as follows:  patient: a 28-year-old woman; clinical diagnosis: uterine cervical carcinoma; primary diagnosis: metastases of uterine cervical carcinoma (squamous cell carcinoma: status after the removal of the uterus, condition after chemoradiation therapy): heart, bilateral lungs, soft structure of the left gluteus, and lymph nodes (para-aortic lymph nodes, para-common iliac artery, and paratrachea); multiple microscopic tumor emboli and hemorrhagic infarctions of bilateral lungs (left: 382 g, right: 426 g). A metastatic tumor (10 × 6 × 5 cm) extending from the right atrium to the pulmonary artery through the right ventricle was recognized; therefore, intracardiac tumor, tumor embolization, and tumor infarction of the lung periphery were thought to be the cause of death (Figures 3 –6). 3. Discussion Cases of cardiac metastasis from uterine cervical carcinoma are very rare; less than 40 of such cases have been reported in the literature (Table 1).

A metastatic tumor (10 × 6 × 5 cm) extending from the right atrium to the pulmonary artery through the right ventricle was recognized; therefore, intracardiac tumor, tumor embolization, and tumor infarction of the lung periphery were thought to be the cause of death (Figures 3 –6). 3. Discussion Cases of cardiac metastasis from uterine cervical carcinoma are very rare; less than 40 of such cases have been reported in the literature (Table 1). Regarding cardiac tumors, metastatic tumors are 40 times more frequent than tumors originating from the cardiac region [1]. According to the autopsy results of cancer patients, the frequency of cardiac metastasis ranges from 1.5% to 21.8% [2, 3]. The primary tumors of cardiac metastases are often malignant melanoma, malignant lymphoma, leukemia, lung cancer, and breast cancer. Cases of gynecological malignancy are relatively infrequent [4, 5] and are rarely diagnosed before death [6]. The prognosis of a metastatic heart tumor is poor; the average life expectancy of patients with this diagnosis is less than six months.

nt melanoma, malignant lymphoma, leukemia, lung cancer, and breast cancer. Cases of gynecological malignancy are relatively infrequent [4, 5] and are rarely diagnosed before death [6]. The prognosis of a metastatic heart tumor is poor; the average life expectancy of patients with this diagnosis is less than six months. We philologically discussed the cases in which cardiac metastases from uterine cervical carcinoma were found before death. Among the symptoms of 37 cases in which cardiac metastases were found before death, there were 30 (81.5%) cases in which chest symptoms were the most prevalent; among them, the following symptoms were common: sensation of dyspnea, 15/30 (50%); dyspnea, 13/30 (43.3%); chest pain, 10/30 (33.3%); and coughing, 6/30 (20.0%). Echocardiography was used for most diagnoses (Table 1). In all, 29% of the cases were thought to be caused by cardiac metastases, and 16% cases developed cardiac tamponade as a clinical condition [4]. When a patient with uterine cervical carcinoma complains of chest symptoms, it is necessary to confirm the findings by echocardiographic examination and determine whether heart enlargement, an intracardiac space-occupying lesion, or pericardial effusion is present. If pericardial effusion, which could cause chest symptoms, is detected, it is necessary to conduct pericardial drainage and a pathological examination of punctual fluid simultaneously.

raphic examination and determine whether heart enlargement, an intracardiac space-occupying lesion, or pericardial effusion is present. If pericardial effusion, which could cause chest symptoms, is detected, it is necessary to conduct pericardial drainage and a pathological examination of punctual fluid simultaneously. In our case, the patient had mild general malaise but only mild symptoms. Therefore, cardiac metastasis from uterine cervical carcinoma was detected through a detailed systemic examination performed because of decreased platelet count. In addition, the following cases were noted in the literature: an abnormality on electrocardiography performed for routine examination for bowel obstruction, a cardiac tumor detected through echocardiography, and a cardiac tumor incidentally detected on gallium scintigraphy performed to confirm the absence of pelvic suppuration as a cause of abdominal pain. As for the immediate cause of death, cases in which tumor emboli of the lungs led to death have been reported, similar to our case [6, 10, 11]. If the emboli had been found and treated earlier, the symptoms could have been alleviated and the patient's prognosis could have been improved. Although treatment focused on palliative care in our case, there have been cases in which open-heart surgery was performed and the patients survived for more than two years. Therefore, open-heart surgery is an option to improve survival [14, 27].

As for the immediate cause of death, cases in which tumor emboli of the lungs led to death have been reported, similar to our case [6, 10, 11]. If the emboli had been found and treated earlier, the symptoms could have been alleviated and the patient's prognosis could have been improved. Although treatment focused on palliative care in our case, there have been cases in which open-heart surgery was performed and the patients survived for more than two years. Therefore, open-heart surgery is an option to improve survival [14, 27]. In cases of advanced uterine cervical carcinoma, in addition to systemic symptoms including chest symptoms, tumor marker increase, platelet count decrease, and hematogenous metastasis, it is useful to perform other tests such as measurement of D-dimer levels, echocardiography, and a detailed examination for cardiac metastasis using multidetector CT to improve the prognosis and alleviate symptoms. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Cervix at operation. The tumor is indicated by the arrow. Figure 2 Tumor markers and platelet counts postoperatively. RH: radical hysterectomy, CT: chemotherapy, weekly TN (taxol 80 mg/m2, nedaplatin 25 mg/m2, i.v., once weekly), RT: radiation therapy whole pelvic 50.4 Gy, para-aortic lymphnode 60.4 Gy, SCC: squamous cell carcinoma-related antigen, and Plt: platelet. Figure 3 Gross aspect of the heart at autopsy, showing the right ventricle containing the mass (arrow).

Figure 2 Tumor markers and platelet counts postoperatively. RH: radical hysterectomy, CT: chemotherapy, weekly TN (taxol 80 mg/m2, nedaplatin 25 mg/m2, i.v., once weekly), RT: radiation therapy whole pelvic 50.4 Gy, para-aortic lymphnode 60.4 Gy, SCC: squamous cell carcinoma-related antigen, and Plt: platelet. Figure 3 Gross aspect of the heart at autopsy, showing the right ventricle containing the mass (arrow). Figure 4 Cross section of the heart, showing tumor involvement of the right ventricle and pulmonary valve. Figure 5 Microscopic view of the tumor, squamous cell carcinoma. Hematoxylin and eosin staining. Magnification ×400. Figure 6 Pathophysiological changes until death. Table 1 Cases of reported antemortem diagnosis of cardiac metastasis from cervical carcinoma. Year Authors Age Stage Symptoms Diagnostic method Prognosis Autopsy References 1967 Dibadj 56 II SOB Autopsy Uncertain Yes [7] 1977 Charles et al. 46 IIIb SOB Biopsy 8 mo+ No [8] 1979 Ritcher and Yon 32 IIb SOB Echocardiogram 15 d Yes [9]

Table 1 Cases of reported antemortem diagnosis of cardiac metastasis from cervical carcinoma. Year Authors Age Stage Symptoms Diagnostic method Prognosis Autopsy References 1967 Dibadj 56 II SOB Autopsy Uncertain Yes [7] 1977 Charles et al. 46 IIIb SOB Biopsy 8 mo+ No [8] 1979 Ritcher and Yon 32 IIb SOB Echocardiogram 15 d Yes [9] 1980 Greenwald et al. 77 IIIb Dyspnea, SOB, and weakness Autopsy 5 d Yes [10] 1981 Krivokapich et al. 32 IIIb Chills, dyspnea, fever, and hemoptysis Echocardiogram and operation NS Yes [11] 1984 Itoh et al. 64 IIb SOB Echocardiogram 10 d Yes [12] 1986 Hands et al. 43 Ib Chest pain, lethargy, and nausea ECG, echocardiogram, and operation 5 mo No [13] 1987 Schaefer et al. 28 NS Edema, SOB, and substernal heaviness Echocardiogram 2 d Yes [14] 1990 Vargas-Barron et al. 55 NS Aphasia and hemiparesis Echocardiogram and operation 3 mo+ No [15] 1990 Malviya et al. 37 IIIb SOB NS 3 mo NS [4] 1990 Malviya et al. 42 IIIb Chest pain, cough, dysplasia, and SOB Biopsy, CT, and echocardiogram 5 d NS [4] 1991 Lustig et al. 36 Ib Chest pain Echocardiogram 1 mo No [16] 1992 Hsu et al. 36 Ib Cough and dyspnea Biopsy and echocardiogram 9 mo NS [17] 1993 Kountz 28 IIb Ileus Biopsy and echocardiogram 3 mo No [18] 1993 Nelson and Rose 51 IV SOB Biopsy and echocardiogram 4 mo No [19] 1993 Nelson and Rose 61 IIIb Cough and dyspnea Biopsy and echocardiogram 12 mo No [19] 1995 Mohammed S et al. 64 IIIb Dyspnea, SOB, and weakness Echocardiogram 3 d Yes [20] 1997 Ando et al. 41 IIb Abdominal pain and dyspnea Biopsy, gallium scintigram, and MRI 5 mo Yes [21] 1997 Batchelor et al. 43 IIb VF Biopsy and echocardiogram 1 y+ No [22] 1997 Batchelor et al. 51 IIb Chest pain and dyspnea Autopsy NS Yes [22] 1997 Batchelor et al. 65 NS NS Autopsy NS Yes [22]

hocardiogram 3 d Yes [20] 1997 Ando et al. 41 IIb Abdominal pain and dyspnea Biopsy, gallium scintigram, and MRI 5 mo Yes [21] 1997 Batchelor et al. 43 IIb VF Biopsy and echocardiogram 1 y+ No [22] 1997 Batchelor et al. 51 IIb Chest pain and dyspnea Autopsy NS Yes [22] 1997 Batchelor et al. 65 NS NS Autopsy NS Yes [22] 1998 Lemus et al. 49 IVb Dyspnea CT and echocardiogram 7 mo No [6]

hocardiogram 3 d Yes [20] 1997 Ando et al. 41 IIb Abdominal pain and dyspnea Biopsy, gallium scintigram, and MRI 5 mo Yes [21] 1997 Batchelor et al. 43 IIb VF Biopsy and echocardiogram 1 y+ No [22] 1997 Batchelor et al. 51 IIb Chest pain and dyspnea Autopsy NS Yes [22] 1997 Batchelor et al. 65 NS NS Autopsy NS Yes [22] 1998 Lemus et al. 49 IVb Dyspnea CT and echocardiogram 7 mo No [6] 1998 Lemus et al. 53 Ib Dyspnea Echocardiogram and MRI 1 mo Yes [6] 1998 Shimotsu et al. 36 Ib Precordial pain Biopsy, CT, ECG, echocardiogram, and MRI NS NS [23] 1999 Senzaki et al. 28 Ib Chest pain and dyspnea Biopsy and echocardiogram Less than 1 mo Yes [5] 2000 Harvey et al. 44 Ib None CT and echocardiogram 8 mo+ No [24] 2001 Iwaki et al. 49 IVb Cough, dyspnea, and fever Biopsy and echocardiogram 2 mo Yes [2] 2004 Inamura et al. 58 Ib1 Chest pain, cough, and dyspnea CT and echocardiogram 4 mo NS [25] 2005 Feys et al. 37 IIIb Cough, fever, SOB, and sweating Echocardiogram and PET/CT 8 mo+ No [26] 2005 Saitoh et al. 68 IIIb Palpitation and SOB Echocardiogram and operation 5 mo NS [3] 2006 Nakao et al. 57 IIIb Chest pain and dyspnea Echocardiogram 2 mo No [27] 2006 Ferraz et al. 63 NS Dyspnea and fatigue Echocardiogram and operation 5 mo+ NS [1] 2007 Borsaru et al. 42 IVb Chest pain and respiratory distress CT, echocardiogram, and operation NS NS [28] 2010 Miller et al. 48 Ib2 Chest pain Biopsy and MRI 8 mo NS [29] 2010 Tomoko et al. 56 Ib2 None CT, echocardiogram, and PET/CT 25 mo No [30] 2013 Byun et al. 32 IIa2 Dyspnea and purpura of extremity CT, echocardiogram, and operation 13 mo NS [31] 2015 Okamoto et al. 27 Ib1 None Multidetector computed tomography 21 d Yes Present case NS: not stated, SOB: shortness of breath, VF: ventricular fibrillation, ECG: electrocardiogram, CT: computed tomography, PET/CT: positron emission computerized tomography, mo: months, and d: days.

1. Introduction Ectopic pregnancies account for 1-2% of all pregnancies, and the rupturing of ectopic pregnancies can cause massive bleeding and maternal mortality [1]. Although the risk of recurrent ectopic pregnancies increases after previous medical and surgical management, it is reduced after salpingectomy [2–4]. Recurrent ectopic pregnancy in a remnant tube after ipsilateral salpingectomy is rare, and less than 20 cases have been reported in the English literature [5–7]. In addition, there has only been one reported case of three surgically managed ipsilateral ectopic pregnancies [8]. We experienced a rare case in which a third ectopic pregnancy occurred in the intact tube after two salpingectomy procedures involving the opposite tube.

ave been reported in the English literature [5–7]. In addition, there has only been one reported case of three surgically managed ipsilateral ectopic pregnancies [8]. We experienced a rare case in which a third ectopic pregnancy occurred in the intact tube after two salpingectomy procedures involving the opposite tube. 2. Case Presentation A 26-year-old gravida 3, para 0 female was referred to our hospital at 6 + 5 weeks of gestation due to a suspicion of left tubal ectopic pregnancy. The patient's medical history included one miscarriage and two ectopic pregnancies in the right tube, which had been surgically treated with right partial salpingectomy 4 years ago and right remnant salpingectomy 2 years ago, respectively. During these two ipsilateral salpingectomy procedures, normal left tubal patency was confirmed by chromotubation using indigo carmine. All of the pregnancies were established via natural conception, and during the first ectopic pregnancy the patient was diagnosed with a Chlamydia trachomatis infection. On admission, she was free from abdominal pain and vaginal discharge. Transvaginal ultrasonography revealed the absence of an intrauterine pregnancy and the presence of a left tubal ectopic pregnancy (a fetus and a fetal heartbeat were detected). The patient exhibited a serum β-human chorionic gonadotropin (hCG) level of 4,000 international units/mL. We fully discussed the surgical options with the patient, whether to perform salpingectomy or salpingotomy, and she selected salpingectomy, even though this would result in the loss of her natural fertility, as she was concerned about the risk of a fourth ectopic pregnancy. Due to the appearance of marked peritoneal irritation, an emergent laparotomy was performed. We found massive hemoperitoneum, and a left tubal isthmus ectopic pregnancy. To prevent any further recurrence, we performed left complete salpingectomy based on the patient's wishes. The clinical diagnosis of tubal ectopic pregnancy was confirmed histologically. The patient's postoperative course was uneventful, and a serum β-hCG test produced a negative result at one postoperative month. The patient gave birth after in vitro fertilization without any problems.

ectomy based on the patient's wishes. The clinical diagnosis of tubal ectopic pregnancy was confirmed histologically. The patient's postoperative course was uneventful, and a serum β-hCG test produced a negative result at one postoperative month. The patient gave birth after in vitro fertilization without any problems. 3. Discussion This report highlights an interesting clinical case of three surgically managed recurrent ectopic pregnancies brought about by natural conception, which were surgically treated with right partial salpingectomy, right resection of the remnant tube, and left total salpingectomy, respectively. The third tubal pregnancy occurred in the intact left tube, the patency of which was confirmed by chromotubation using indigo carmine during the previous two salpingectomy procedures.

re surgically treated with right partial salpingectomy, right resection of the remnant tube, and left total salpingectomy, respectively. The third tubal pregnancy occurred in the intact left tube, the patency of which was confirmed by chromotubation using indigo carmine during the previous two salpingectomy procedures. To the best of our knowledge, this is the first report about a third surgically managed recurrent ectopic pregnancy in an intact tube after two salpingectomy procedures involving the opposite tube. Recurrent ectopic pregnancy in the remnant tube after ipsilateral salpingectomy is exceptionally rare [3–5]; thus, the frequency of serious complications in such cases remains unclear. Furthermore, there has only been one report about three consecutive surgically managed ipsilateral ectopic pregnancies [8]. Three hypotheses regarding the mechanisms responsible for recurrent ectopic pregnancies after ipsilateral salpingectomy have been proposed: contralateral fertilized egg migration across the endometrium to the remnant fallopian tube, contralateral fertilized egg trans-peritoneal passage through the contralateral intact fallopian tube, and recanalization of the tubal remnant [5, 8, 9]. In some cases of recurrent ectopic pregnancy brought about by natural conception after ipsilateral salpingectomy, it might be necessary to preserve the normal contralateral tube, as seen in our case. We confirmed the patency of the normal contralateral tube during the two previous ipsilateral salpingectomy procedures via intraoperative chromotubation. Even in cases involving natural conception, we should consider the risk of a third recurrent ectopic pregnancy in the normal tube.

alateral tube, as seen in our case. We confirmed the patency of the normal contralateral tube during the two previous ipsilateral salpingectomy procedures via intraoperative chromotubation. Even in cases involving natural conception, we should consider the risk of a third recurrent ectopic pregnancy in the normal tube. The optimal management strategy for recurrent ectopic pregnancy was unclear. The risk of recurrent ectopic pregnancy is reported to be fourfold higher in cases involving previous medical or surgical management [10], and the risk of such pregnancies does not differ significantly between medically and surgically treated cases. Total and partial salpingectomy might be selected in cases in which the patient does not want any further children, but salpingotomy might be chosen to preserve future natural fertility, especially in primiparous women. In a large retrospective study, salpingotomy was found to be significantly better at preserving fertility than total salpingectomy, although total salpingectomy carries a lower risk of recurrent ectopic pregnancy [2, 3, 11]. Although complete tubal resection cannot prevent cornual pregnancy, it might reduce the risk of recurrent ectopic pregnancy in the remnant tube. In cases of recurrent ectopic pregnancy, the surgical management strategy should be fully discussed with patient and their family, and appropriate informed consent should be obtained. In the present case, partial salpingectomy was performed the first ectopic pregnancy, which might induce the second recurrent ectopic pregnancy treated by resection of remnant tube, followed by the third recurrent ectopic pregnancy with total salpingectomy.

r family, and appropriate informed consent should be obtained. In the present case, partial salpingectomy was performed the first ectopic pregnancy, which might induce the second recurrent ectopic pregnancy treated by resection of remnant tube, followed by the third recurrent ectopic pregnancy with total salpingectomy. We described the first reported case of a third surgically managed recurrent ectopic pregnancy in an intact tube after two salpingectomy procedures involving the opposite tube. Obstetricians should be aware of the possibility of such rare cases, and the available surgical interventions should be fully discussed with patients when managing recurrent ectopic pregnancies. To avoid the risk of future recurrence in the remnant tube, it might be necessary to perform total salpingectomy rather than partial salpingectomy. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper.

1. Introduction Human Papillomavirus (HPV) is a DNA virus, member of the papillomavirus family, which causes genital warts, precancerous dysplasia, and cervical, anal, and other anogenital and oropharyngeal cancers. HPV infection is the most common sexually transmitted infection with prevalence of up to 80% among sexually active individuals of both sexes [1]. Genital HPV types fall into two categories: low-risk viruses that mainly cause skin lesions (condylomata acuminata) and high-risk viruses that are considered oncogenic. From the first group, the subtypes 6 and 11 account for 90% of all genital warts and from the second, HPV 16 and 18 are responsible for about 70% of cervical cancers [1, 2]. In 2006, a quadrivalent vaccine was licensed containing virus-like particles (VLPs) for HPV types 6, 11, 16, and 18. Later, in 2007, a bivalent vaccine became available offering protection against the subtypes 16 and 18 [3]. Since then, a variety of studies have proved that HPV vaccination is an effective strategy for reducing the impact of HPV-related diseases [4]. This is a case report of a patient with completed HPV vaccination and nevertheless diagnosed with an in situ adenocarcinoma caused by an HPV 16 infection.

btypes 16 and 18 [3]. Since then, a variety of studies have proved that HPV vaccination is an effective strategy for reducing the impact of HPV-related diseases [4]. This is a case report of a patient with completed HPV vaccination and nevertheless diagnosed with an in situ adenocarcinoma caused by an HPV 16 infection. 2. Case Report This is the case of a 30-year-old sexually active nulligravida female presenting with an abnormal Pap test. The patient had a free gynecological and family medical history, she has been smoking since the age of 15 (totally 10 py), and she had completed the HPV vaccination (three doses of the HPV vaccine) 6 years ago, after she became sexually active. There was no known history of STDs reported from her sexual partners (six in total) and she had the same sexual partner for the last 3 years.

he has been smoking since the age of 15 (totally 10 py), and she had completed the HPV vaccination (three doses of the HPV vaccine) 6 years ago, after she became sexually active. There was no known history of STDs reported from her sexual partners (six in total) and she had the same sexual partner for the last 3 years. The patient had been undergoing gynecological assessment by her treating specialist, including clinical examination and Pap test in a private practice, annually, since the age of 20, and all of them had been negative; however, at the age of 29, the Pap test revealed for the first time a low grade squamous intraepithelial lesion (LGSIL). One year later, the patient was referred to the Cervical Pathology Department, Third Department of Obstetrics and Gynecology, General University Hospital “Attikon”, University of Athens; after the clinical and gynecological examination, liquid phase cytological examination and a colposcopy were performed. The cytological assessment revealed a high-grade squamous intraepithelial lesion (HGSIL) and the PCR HPV test (CLART® Human Papillomavirus 2, GENOMICA) was positive for types 16 and 83. The dual staining immunocytochemical evaluation, using the CINtec® cytology double staining (p16/Ki67) kit, revealed p16 and ki-67 positivity.

logical assessment revealed a high-grade squamous intraepithelial lesion (HGSIL) and the PCR HPV test (CLART® Human Papillomavirus 2, GENOMICA) was positive for types 16 and 83. The dual staining immunocytochemical evaluation, using the CINtec® cytology double staining (p16/Ki67) kit, revealed p16 and ki-67 positivity. Because of the extent and the immunocytochemical features of the lesion, and since the colposcopy was inadequate (the transformation zone was type 3 and the squamocolumnar junction was not entirely visible), the patient underwent a type 3 large loop excision of the transformation zone (LLETZ) and a curettage of the endocervix under local anesthesia. The pathological diagnosis from cervical biopsy revealed an in situ adenocarcinoma of the endocervix with negative limits. HPV typing in the biopsy sample confirmed the positivity for HPV 16 and 83 was detected. In addition, there was positive immunostaining of the protein p16 and Ki-67 expression was 30%. After the counseling, the patient decided to preserve her fertility since she wishes to procreate. She was informed about the possible risks and decided to perform a hysterectomy by the completion of her family planning. One year after LLETZ, she remains without evidence of local recurrence or invasive cancer. Written informed consent was obtained by the patient for the publication of this case report.

to procreate. She was informed about the possible risks and decided to perform a hysterectomy by the completion of her family planning. One year after LLETZ, she remains without evidence of local recurrence or invasive cancer. Written informed consent was obtained by the patient for the publication of this case report. 3. Discussion We present a case of cervical adenocarcinoma in situ (AIS) in a 30-year-old female with a positive HPV 16 typing test though fully vaccinated against HPV after the onset of her sexual life. This is a rare incident that is raising many questions about the efficacy and the safety of HPV vaccines. What remains unknown about this case is the time of the infection since the patient's annual Pap smears had been negative. One possible explanation may therefore be the efficacy of the vaccine. Since the two vaccines became available and were included in the National Vaccination Program of many countries including Greece, a variety of studies have been published concerning the impact of the vaccines on the prevalence of HPV 16 and 18 related precancerous lesions, in situ carcinomas, and invasive cancers. Villa et al. [5] in the 5-year follow-up study performed in 2006 indicated that among quadrivalent vaccine recipients there was one case of HPV 16 DNA detection reported at the last visit before loss to follow-up and one case of verifiable persistent infection caused by HPV 18 infection. For this subject, the aforementioned subtype was detected only at months 12 and 18.

rmed in 2006 indicated that among quadrivalent vaccine recipients there was one case of HPV 16 DNA detection reported at the last visit before loss to follow-up and one case of verifiable persistent infection caused by HPV 18 infection. For this subject, the aforementioned subtype was detected only at months 12 and 18. In 2007 the members of the FUTURE II study group [6] published a study based on a combined analysis of four randomized clinical trials. In this study, one case of HPV 16-related CIN3 was reported among vaccine recipients. Yet in this case, the patient was also tested positive for HPV 52. This specific subtype was detected at baseline and in five histology specimens, whereas HPV 16 DNA was detected in one histology specimen only during the diagnosis. Wong et al. [7] presented some interesting data in 2010. Four cases of in situ and microinvasive cervical cancer were reported, identified in the Vaccine Adverse Event Reporting System (VAERS) database from January 1, 2006, through April 9, 2009. As far as the HPV subtype is concerned, three cases were identified as having high-risk HPV types, including one case with HPV 16. Nevertheless, the writers underlined that they did not have information on prevaccination HPV status of the patients in question (other than a single case, who was HPV positive prior to vaccination) and therefore exposure before vaccination could not be excluded.

ing high-risk HPV types, including one case with HPV 16. Nevertheless, the writers underlined that they did not have information on prevaccination HPV status of the patients in question (other than a single case, who was HPV positive prior to vaccination) and therefore exposure before vaccination could not be excluded. In 2012, Szarewski et al. [8] identified five HPV-vaccinated patients with CIN III associated with HPV types 16 (three cases) and 18 (two cases) at the study endpoint. What is interesting about this study is that the women participating were included regardless of their HPV DNA, serological, and cytological status at baseline. For that reason it was possible to evaluate the vaccine efficiency (VE) in both seropositive and seronegative females. As it appears, in women with serological evidence of previous-to-vaccination HPV-16/18 infection, the VE was generally lower than in women who, at baseline, were either HPV DNA negative and seronegative or DNA negative regardless of serological status. In another study by Gertig et al. [9] there are 47 cases of CIN3/AIS reported at the fully vaccinated cohort from which only one refers to adenocarcinoma in situ. In 2015, Apter et al. [10] reported in the PATRICIA trial (Papilloma TRIal against Cancer In young Adults) three cases of CIN1 in the vaccinated cohort and one case of CIN2 in a young woman. However, the patient in question acquired the HPV-16 responsible for development of the lesion before she completed the full three-dose series.

et al. [10] reported in the PATRICIA trial (Papilloma TRIal against Cancer In young Adults) three cases of CIN1 in the vaccinated cohort and one case of CIN2 in a young woman. However, the patient in question acquired the HPV-16 responsible for development of the lesion before she completed the full three-dose series. The aforementioned studies may indicate that the VE may not always be 100%. Therefore, it might be helpful to monitor the immunological response of the patient after the vaccination by controlling the antibodies against the HPV viruses, although the clinical relevance of this test has not been fully established. In conclusion, vaccinated females should not consider themselves totally secure. It is highly recommended that they continue their annual gynecological examination, since the Pap smear and/or HPV typing have been proved an excellent method of secondary prevention. Competing Interests The authors declare that they have no competing interests.

1. Introduction Uterine fibroids are common benign tumors in women. Most women with fibroids are asymptomatic. However, when clinically apparent, women usually experience heavy or prolonged menstrual bleeding or pelvic pressure [1]. Acute complications secondary to fibroids are rare and seldom necessitate immediate surgical intervention. Such complications include thromboembolism, acute pain due to degeneration or torsion of a pedunculated fibroid, acute urinary retention and subsequent renal failure, and acute intra-abdominal blood loss [2]. It is imperative to recognize and diagnose acute complications from fibroids as failure to do so can result in significant morbidity and even mortality. We report herein a case of spontaneous rupture of a degenerated fibroid causing life-threatening blood loss necessitating massive transfusion and emergent surgery.

2]. It is imperative to recognize and diagnose acute complications from fibroids as failure to do so can result in significant morbidity and even mortality. We report herein a case of spontaneous rupture of a degenerated fibroid causing life-threatening blood loss necessitating massive transfusion and emergent surgery. 2. Case A 53-year-old (gravida 2, para 2) perimenopausal African-American woman presented to the emergency department with worsening severe, acute-onset abdominal pain. The patient also reported dizziness and nausea. Her past medical history was significant for hypertension and known uterine fibroids. Vitals were notable for blood pressure 78/50 mm Hg and pulse rate 116 bpm. Examination revealed a 14-week-sized fibroid uterus, a distended abdomen, and diffuse abdominal tenderness with positive rebound and guarding. Hemoglobin concentration was initially 10.6 g/dL. A bedside abdominal sonogram was performed which revealed a large amount of free fluid, extending into Morison's pouch. Computed tomography, obtained by the emergency department prior to consultation, revealed an enlarged uterus with multiple fibroids as well as an 8.8 × 7.3 × 8.3 cm multicystic, partially solid, enhancing structure and moderate ascites (Figure 1). Repeat hemoglobin 2.5 hours later was 7.1 g/dL. Transfusion of 2 units of packed red blood cells was initiated. A ruptured degenerated fibroid was suspected given the patient's known history of fibroids and perimenopausal state, imaging consistent with a degenerating fibroid, and free fluid in the abdomen. However, other gynecologic sources of intra-abdominal bleeding could not be ruled out.

packed red blood cells was initiated. A ruptured degenerated fibroid was suspected given the patient's known history of fibroids and perimenopausal state, imaging consistent with a degenerating fibroid, and free fluid in the abdomen. However, other gynecologic sources of intra-abdominal bleeding could not be ruled out. Given the acute nature of the patient's intra-abdominal bleeding and deteriorating hemodynamic status, she was taken emergently to the operating room for exploratory laparotomy. Prior to induction of anesthesia, the patient's blood pressure nadired at 60/53 and pulse was in the 140's. Vasopressors were started and additional transfusion products were given. Upon entry into the abdomen, approximately 4.5 liters of hemoperitoneum was observed. Intraoperative findings were significant for a ruptured degenerated fundal subserosal fibroid, which was actively bleeding posteriorly (Figure 2). The patient's uterus was fibromatous. Given the severity of the bleeding, the decision was made to perform a total hysterectomy. Additional blood loss from the case was 500 milliliters. In total, she received 6 units of packed red blood cells, 3 units of fresh frozen plasma, 1 unit of platelets, and 5 liters of crystalloid. The patient's postoperative course was uneventful and she was discharged home three days after surgery. Histopathologic review of the specimen revealed multiple fibroids, the largest being 15 cm with extensive ischemic hemorrhagic and hyalinizing degenerative changes.

, 1 unit of platelets, and 5 liters of crystalloid. The patient's postoperative course was uneventful and she was discharged home three days after surgery. Histopathologic review of the specimen revealed multiple fibroids, the largest being 15 cm with extensive ischemic hemorrhagic and hyalinizing degenerative changes. 3. Discussion Although uterine fibroids are very common, they infrequently cause acute complications. The spontaneous rupture of a degenerated fibroid is extremely rare with only around 10 cases reported in the last half decade [3, 4]. Significant bleeding from a ruptured fibroid is even more unusual [5, 6]. This case documents rupture of a degenerated fibroid causing acute hemorrhage requiring a massive blood transfusion.

spontaneous rupture of a degenerated fibroid is extremely rare with only around 10 cases reported in the last half decade [3, 4]. Significant bleeding from a ruptured fibroid is even more unusual [5, 6]. This case documents rupture of a degenerated fibroid causing acute hemorrhage requiring a massive blood transfusion. Intraperitoneal hemorrhage from rupture of a fibroid is usually venous and secondary to an increase in abdominal pressure, which causes rupture of superficial veins. Less often, bleeding can be arterial and associated with hypertension. Trauma causing avulsion of a fibroid, torsion of a pedunculated fibroid, and pregnancy causing venous congestion resulting in vessel rupture are other possible etiologies for intra-abdominal bleeding from a fibroid [2, 4, 6–8]. In our case, the most likely cause was from degeneration of a pedunculated fibroid. This resulted in necrosis and spontaneous perforation of the fibroid's posterior surface and bleeding into the abdomen. Hyaline and red degeneration were noted on pathologic examination of the specimen removed. Hyaline degeneration is the most common degenerative change (63% of cases), whereas red degenerations account for only ~3% of uterine fibroid degenerations. Fibroid degeneration results from excessive growth that exceeds the blood supply or from mechanical compression of feeder vessels [9].

ion of the specimen removed. Hyaline degeneration is the most common degenerative change (63% of cases), whereas red degenerations account for only ~3% of uterine fibroid degenerations. Fibroid degeneration results from excessive growth that exceeds the blood supply or from mechanical compression of feeder vessels [9]. Although the pathogenesis and degeneration of fibroids are incompletely understood, steroid hormones are known to play a role [10]. Fibroids are responsive to estrogen and progesterone, with symptomatic fibroids being uncommon in prepubertal and postmenopausal women [11]. Interestingly, both pregnancy and menopause have been associated with a decrease in size and risk of fibroid formation [12–14]. Although pregnancy causes an increase in estrogen levels and menopause decreases estrogen levels, both conditions are associated with a lack of menstrual cyclicity. Therefore, menstrual cyclicity has also been implicated to be important to maintenance and growth of fibroids. As the patient in this case was perimenopausal, one mechanism for degeneration of her fibroid could be directly related to decreasing levels of estrogen and progesterone in combination with menstrual cyclicity irregularity. Hormonal changes likely affected angiogenesis and vascular blood supply to her large, dominant fibroid, ultimately causing red degeneration.

al, one mechanism for degeneration of her fibroid could be directly related to decreasing levels of estrogen and progesterone in combination with menstrual cyclicity irregularity. Hormonal changes likely affected angiogenesis and vascular blood supply to her large, dominant fibroid, ultimately causing red degeneration. Imaging modalities can aid in diagnosis of hemoperitoneum. However, computed tomography and ultrasound may not be able to delineate the origin of the bleeding [15]. Timely diagnosis and rapid emergent surgical intervention can be life-saving in situations such as the case described. Even though acute hemorrhage from a degenerated fibroid is rare, it should be included on the differential in any women with an acute intra-abdominal bleed and a history of fibroids. Additional Points Spontaneous rupture of a uterine fibroid is rare. Ruptured degenerated fibroid should be included on the differential in the situation of an acute abdomen and massive hemoperitoneum. Prompt diagnosis and management of a ruptured fibroid can be life-saving. Consent Written informed consent was obtained from the patient for publication of this case report. Competing Interests The authors do not have any conflict of interests. Figure 1 Computed tomography of the abdomen and pelvis showing the 8.8 × 7.3 × 8.3 cm degenerated fibroid (arrow) and free fluid in Morison's pouch (arrowhead). Figure 2 Photograph of the specimen removed. Grossly, approximately 15 cm exophytic red degenerated fibroid.

1. Introduction Mullerian adenosarcoma (MA) is a rare tumor with usually low malignancy potential and has been reported to account for 8% of all uterine sarcomas. MAs are composed of two different components: sarcomatous stromal lesions (usually of the endometrial low-grade stromal type) and benign or mildly atypical epithelial elements [1–3]. The presence of one or more of the following criteria results in a diagnosis of MA: a stromal mitotic count of 2 or more mitotic figures/10 HPF, marked stromal cellularity, and mild or moderate nuclear atypia of the stromal cells [4]. The most frequent primary site of MA is the uterine endometrium, but these tumors can also arise (albeit rarely) in uterine cervix, ovary, vagina, and fallopian tubes. Cervical MAs are reported to account for 2% to 9% of all MA cases [2, 4, 5]. Clinical presentation of cervical MAs often resembles either a benign endocervical or endometrial polyp or a pedunculated submucosal leiomyoma protruding through a cervical canal. Cervical MAs are reported to occur in relatively younger women (mean age 27 years), while tumors originating from the uterine endometrium generally present in postmenopausal women (median age 58 years) [4, 6].

endocervical or endometrial polyp or a pedunculated submucosal leiomyoma protruding through a cervical canal. Cervical MAs are reported to occur in relatively younger women (mean age 27 years), while tumors originating from the uterine endometrium generally present in postmenopausal women (median age 58 years) [4, 6]. Due to the rarity of cervical MA, there are limited data concerning its prognosis and management. Therefore, optimal management for the cervical MAs in younger women continues to be explored. Here, we present a case of a woman of reproductive age diagnosed with cervical MA and treated by fertility-preserving surgery; she successfully delivered a child 18 months after receiving the initial treatments.

nd management. Therefore, optimal management for the cervical MAs in younger women continues to be explored. Here, we present a case of a woman of reproductive age diagnosed with cervical MA and treated by fertility-preserving surgery; she successfully delivered a child 18 months after receiving the initial treatments. 2. Case Presentation A 28-year-old healthy nulliparous woman presented with a short history of metrorrhagia of 30-day duration. Previous medical history was unremarkable. Pelvic examination revealed a 4 × 5 cm friable cervical mass with an irregular and hemorrhagic surface that appeared to be protruding through the cervical ostium. Transvaginal ultrasonography showed a normal shape of the uterine corpus and a smooth endometrium. The tumor was resected for biopsy. Macroscopically, the tumor presented as an irregular polypoid mass with granular and papillary surface. Upon microscopic examination, the tumor comprised two components: endocervical glandular lesions without atypia of a phyllodes-like pattern and a periglandular, cambium-like layer of spindle stromal cell condensation with mild nuclear atypia (Figure 1). The mitotic counts were more than two mitotic figures/10 HPF. The mesenchymal lesion showed neither sarcomatous overgrowth nor heterologous elements such as cartilage or rhabdomyosarcoma. The tumor was pathologically diagnosed as Mullerian endocervical heterologous adenosarcoma. MRI of the pelvis showed no residual uterine tumor and significant pelvic lymphadenopathy. Tumor markers such as CA125, CA19-9, and CEA were all within normal ranges. Then, she underwent conization of the uterine cervix to confirm the existence of a residual lesion. Pathological diagnosis of the conization showed mainly normal cervical epithelium with no residual sarcomatous lesion.

t pelvic lymphadenopathy. Tumor markers such as CA125, CA19-9, and CEA were all within normal ranges. Then, she underwent conization of the uterine cervix to confirm the existence of a residual lesion. Pathological diagnosis of the conization showed mainly normal cervical epithelium with no residual sarcomatous lesion. Although she received sufficient explanation and fully understood the risk of recurrent disease, the patient and her husband desired to preserve their fertility. Therefore, she wished to have monthly follow-up visits for careful surveillance to avoid hysterectomy or hormonal therapy. However, 3 months later, she presented recurrent 4 cm polypoid and hemorrhagic irregular tumors filling the vagina from thin stalk (Figure 2). She underwent transcervical resection (TCR) to preserve her fertility. The pathological diagnosis after TCR showed focal sarcomatous remnants without involvement of the tumor stalk and resembled findings from the first biopsy. Endometrial curettage showed no remaining tumor. After continuous and careful monthly follow-up, she successfully conceived naturally and delivered a healthy infant 18 months after surgery. She is alive with no evidence of disease 32 months after TCR.

ent of the tumor stalk and resembled findings from the first biopsy. Endometrial curettage showed no remaining tumor. After continuous and careful monthly follow-up, she successfully conceived naturally and delivered a healthy infant 18 months after surgery. She is alive with no evidence of disease 32 months after TCR. 3. Discussion MAs are a rare tumor variant with low malignancy potential and have been reported to account for 8% of all uterine sarcomas. Typical symptoms of cervical MAs include abnormal genital bleeding accompanied by polypoid lesions protruding through the external cervical os. The initial impression of these tumors resembles benign cervical polyps. Therefore, some cases are initially diagnosed as a benign cervical polyp [7] due to the rare incidence of cervical MAs. A history of recurrent cervical polyps is clinically important when suspecting the possibility of MA. The etiology of MA is still unknown due to the rarity of these tumors. Some literature reported that a history of long-term use of oral contraceptives or tamoxifen might possibly be associated with the development of MA [3, 8–10], although, in our case, the patient had no history of any of these factors. Clement and Scully reported in a series of 100 cases that the recurrence rate after surgery was 23.9% [4].

ted that a history of long-term use of oral contraceptives or tamoxifen might possibly be associated with the development of MA [3, 8–10], although, in our case, the patient had no history of any of these factors. Clement and Scully reported in a series of 100 cases that the recurrence rate after surgery was 23.9% [4]. Unfavorable factors for cervical MAs include sarcomatous overgrowth, necrosis, cytologic atypia, high mitotic rate, heterologous elements, deep myometrial invasion, and extrauterine spread [7, 11]. Of these features, sarcomatous overgrowth and deep myometrial invasion are thought to be the most important adverse prognostic factor [6, 12, 13]. MAs with sarcomatous overgrowth are reported in approximately 33% of uterine corpus MAs and approximately 60% of those cases relapsed [1]. Fortunately, in our case, the patient had no poor prognostic factor. The prognosis of cervical MA is unknown due to its low incidence and the absence of long-term follow-up data. Previous studies have reported that cervical MA seemed to trend towards relatively slow progression. In a series of 100 cases, Clement and Scully reported that the recurrence rate of MA after surgery was 23.9% and that one-third of the recurrences occur after 5 years [4]. Therefore, long-term follow-up longer than 5 years is thought to be necessary for adequate surveillance.

trend towards relatively slow progression. In a series of 100 cases, Clement and Scully reported that the recurrence rate of MA after surgery was 23.9% and that one-third of the recurrences occur after 5 years [4]. Therefore, long-term follow-up longer than 5 years is thought to be necessary for adequate surveillance. There is no consensus on the optimal management of cervical MA. Many authors have recommended total hysterectomy with bilateral salpingo-oophorectomy as a curative treatment. The necessity of lymphadenectomy is unknown due to the low incidence of pelvic (6.5%) and para-aortic (0%) lymph node metastasis [8]. MAs are low-grade neoplasms and are capable of local recurrence after polypectomy or hysterectomy and, much less commonly, distant metastasis. The reported local and distant recurrence rates are 24% and 2%, respectively, after hysterectomy and bilateral salpingo-oophorectomy [4]. Cervical MAs have been reported to occur in relatively younger women (mean age 27 years) [6]. On the other hand, uterine MAs generally present in postmenopausal women (median age 58 years) [4]. In the review by Ramos et al., one-third of patients were younger than 15 years old [13].

MAs are low-grade neoplasms and are capable of local recurrence after polypectomy or hysterectomy and, much less commonly, distant metastasis. The reported local and distant recurrence rates are 24% and 2%, respectively, after hysterectomy and bilateral salpingo-oophorectomy [4]. Cervical MAs have been reported to occur in relatively younger women (mean age 27 years) [6]. On the other hand, uterine MAs generally present in postmenopausal women (median age 58 years) [4]. In the review by Ramos et al., one-third of patients were younger than 15 years old [13]. In many cases, the strategy for the treatment of cervical MA is based on experience with uterine MAs. Therefore, therapeutic options for cervical MA patients who desire to preserve their fertility are still unknown. Until now, there have been only rare cases of women who desire fertility-preserving surgery and undergo successful treatment via local excision [4, 13–15]. These reports suggest that fertility-preserving surgery may be an alternative for patients with pedunculated cervical polypoid tumors with disease-free stalks [5, 16]. However, there is inadequate evidence to support either local resection or ovarian preservation for younger patients.

ent via local excision [4, 13–15]. These reports suggest that fertility-preserving surgery may be an alternative for patients with pedunculated cervical polypoid tumors with disease-free stalks [5, 16]. However, there is inadequate evidence to support either local resection or ovarian preservation for younger patients. To date, there have been only two reports describing successful pregnancies in patients with MA who underwent local resection. Chin et al. reported, that among their 9 patients with cervical MAs, one 17-year-old patient who underwent cervical wedge resection successfully conceived and delivered a healthy infant after surgery and remained disease-free throughout the 204-month follow-up [15]. Zaloudek and Norris reported that, among 35 patients, two teenage girls were treated by wide local excision of cervical adenosarcoma and remained well for the follow-up duration; furthermore, one of them successfully conceived after treatment [14]. To the best of our knowledge, our present patient is likely the third reported case in the English literature. The risk of ovarian metastasis among patients with uterine MA is relatively low, as initial ovarian involvement is reported to be approximately 2% [4, 17]. Thus, Michener and Simon reported that ovarian conservation can probably be safely achieved in carefully selected women with MA who are of reproductive age.

To date, there have been only two reports describing successful pregnancies in patients with MA who underwent local resection. Chin et al. reported, that among their 9 patients with cervical MAs, one 17-year-old patient who underwent cervical wedge resection successfully conceived and delivered a healthy infant after surgery and remained disease-free throughout the 204-month follow-up [15]. Zaloudek and Norris reported that, among 35 patients, two teenage girls were treated by wide local excision of cervical adenosarcoma and remained well for the follow-up duration; furthermore, one of them successfully conceived after treatment [14]. To the best of our knowledge, our present patient is likely the third reported case in the English literature. The risk of ovarian metastasis among patients with uterine MA is relatively low, as initial ovarian involvement is reported to be approximately 2% [4, 17]. Thus, Michener and Simon reported that ovarian conservation can probably be safely achieved in carefully selected women with MA who are of reproductive age. On the other hand, recurrence rates for patients undergoing local resection were reported to be as high as 50% compared to approximately 25% for patients treated by hysterectomy [4]. Fleming et al. reported that, in 12 patients with cervical MA, 5 patients underwent fertility-preserving surgery, 4 patients underwent either D&C or polypectomy, and 1 patient underwent trachelectomy. Among the 5 patients who underwent surgery, recurrence occurred in 4 of them, and the recurrence sites were all in endometrium with a time until recurrence ranging from 3 to 11 years [18].

Figure 1 Perinatal course and fibrinogen infusion therapy in case 2. Table 1 Characteristics of inherited fibrinogen disorders. Afibrinogenemia Hypofibrinogenemia Dysfibrinogenemia Transmission AR AD/AR AD Fibrinogen level (mg/dL) <10 70–100 Lower limit of normal Laboratory PT-APTT-TT PT: normal or prolonged PT-APTT: normal Markedly prolonged APTT: normal Symptoms Umbilical cord bleeding No symptoms Abnormal bleeding after trauma or operation No symptoms Abnormal bleeding after trauma or operation Thrombosis Recurrent abortion Cutaneous bleeding Intracranial bleeding Gastrointestinal bleeding Hypermenorrhea AR; Autosomal recessive, AD; Autosomal dominant, PT; prothrombin time, APTT; actinated partial thromboplastin time, TT; thrombin time. Table 2 Fibrinogen level during pregnancy in case 2. Weeks of gestation Fibrinogen level (mg/dL) 9 109.2 10 109.2 11 114.6 12 125.9 13 115.5 14 120.7 15 112 16 112.9 17 120.7 18 100.6 19 121.8 21 90.5 22 106.8 23 112.9 24 122.8 25 123.9 26 136.5 27 174.4 28 130.5 29 137.8 30 105.5 31 103.7 32 112 33 83.6 34 126.5 35 100.2 36 180.3 Operation day 228.8 POD1 281.4 POD4 274.7 POD7 147.8 POD25 68 POD: postoperative day.

ents underwent fertility-preserving surgery, 4 patients underwent either D&C or polypectomy, and 1 patient underwent trachelectomy. Among the 5 patients who underwent surgery, recurrence occurred in 4 of them, and the recurrence sites were all in endometrium with a time until recurrence ranging from 3 to 11 years [18]. 4. Conclusion Here, we present a patient of reproductive age who was diagnosed with cervical MA and treated by fertility-preserving surgery; this patient successfully delivered a child 18 months after her initial treatment and experienced no recurrent disease. However, previous several case reports demonstrated high recurrence rates for patients undergoing local resection compared to patients treated by hysterectomy. So we should still be cautious as much as possible when offering a patient fertility-preserving surgery, as there has been inadequate evidence to support the use of local resection or ovarian preservation for younger patients. Furthermore, an accumulation of case reports concerning the long-term follow-up and obstetrical outcomes after fertility-preserving surgery is needed to establish optimal management for these patients. Competing Interests All authors declare that there are no competing interests regarding the publication of this paper. Figure 1 (a) Tumor cells with two components: endocervical glandular lesion without atypia of a phyllodes-like pattern and periglandular, spindle stromal cell condensation. (b) Stromal spindle cells with mild nuclear atypia. The mitotic counts were greater than two mitotic figures/10 HPF.

Competing Interests All authors declare that there are no competing interests regarding the publication of this paper. Figure 1 (a) Tumor cells with two components: endocervical glandular lesion without atypia of a phyllodes-like pattern and periglandular, spindle stromal cell condensation. (b) Stromal spindle cells with mild nuclear atypia. The mitotic counts were greater than two mitotic figures/10 HPF. Figure 2 Recurrent polypoid and hemorrhagic irregular tumors filling the vagina and protruding through a cervical canal.

1. Introduction Malignant melanoma (MM) is a common neoplasm of the skin and mucous membranes. Less than 2% of all MMs occur in the female genital tract [1], and the majority of cases of MM in the female genital tract have been reported in the vulva and vagina [2]. Primary MM of the uterine cervix is extremely rare and its associated prognosis is very poor [3]. Radical hysterectomy with lymphadenectomy is selected in operable cases [4], although there is no consensus regarding standard treatment for this disease. Here, we report a case of primary MM of the cervix with multiple disseminated metastases throughout the vaginal wall, treated with radical hysterectomy and total vaginectomy.

ysterectomy with lymphadenectomy is selected in operable cases [4], although there is no consensus regarding standard treatment for this disease. Here, we report a case of primary MM of the cervix with multiple disseminated metastases throughout the vaginal wall, treated with radical hysterectomy and total vaginectomy. 2. Case Presentation A 66-year-old woman presented with postmenopausal bleeding. Gynecologic examination and colposcopic findings revealed a 2 cm polypoid blackish-pigmented tumor in the cervix, and multiple small blackish-pigmented lesions were found throughout the vaginal wall, spreading to the lower third of the vagina (Figure 1). Cervical Pap smear showed MM. MRI and PET/CT did not detect any distant or lymph node metastases. The serum level of 5-SCD, a tumor marker for melanoma, was 5.1 nmol/L (normal level: 1.5～8.0). She underwent radical hysterectomy, bilateral salpingooophorectomy, pelvic lymphadenectomy, and total vaginectomy (Figure 2) without any major complications, and optimal surgery was achieved with no residual tumors. The operative time was 333 min, and blood loss was 1335 mL. Pathological examination of the cervix and vaginal wall demonstrated spindle-shaped tumor cells showing intracytoplasmic melanin and strong reactivity for melan-A (Figure 3). The tumor of the cervix was larger than that of the vagina, and the depth of tumor invasion in the cervix was 7 mm, while the depth of invasion of the vaginal lesions was very shallow. The endometrium, bilateral adnexa, lymph nodes, and vaginal stump were free of tumors. Therefore, the final diagnosis was stage IIIA primary cervical melanoma with dissemination to the vaginal wall according to the International Federation of Gynecology and Obstetrics staging system. She received 6 courses of adjuvant chemotherapy with dacarbazine after surgery, but CT six months later showed multiple lung metastases, and she received 4 courses of anti-PD-1 antibody (nivolumab). However, the level of 5-SCD was elevated to 187.9 nmol/L, and CT showed increased lung and bone metastases. She and her family chose palliative care, and she died 13 months after surgery.

fter surgery, but CT six months later showed multiple lung metastases, and she received 4 courses of anti-PD-1 antibody (nivolumab). However, the level of 5-SCD was elevated to 187.9 nmol/L, and CT showed increased lung and bone metastases. She and her family chose palliative care, and she died 13 months after surgery. 3. Discussion Primary MM of the cervix is a rare entity. The incidence of genital tract melanomas has been reported to be 1.6 cases per 1 million females [5]. Most cases of genital tract melanoma occur in the vulva (76.7%) and vagina (19.8%) and more rarely (3–9%) in the cervix [5, 6]. The peak incidence of patients with primary MM of the cervix occurs between 60 and 70 years, and it is likely to present with vaginal discharge, bleeding, or dyspareunia [3, 7, 8]. The diagnosis is usually based on gynecologic examination, colposcopy, and cervical pathology. Cervical Pap smears usually show round or spindle atypical cells containing melanin pigments [9]. Cervical melanoma originates from the melanocytic cells of the cervix [10]. About half of the melanomas are amelanotic [9], and due to the absence of pigmentation, the diagnosis of amelanotic melanoma may be difficult to distinguish from rhabdomyosarcoma, leiomyosarcoma, mixed Müllerian tumor, adenocarcinoma, and poorly differentiated squamous cell carcinoma. Immunostaining is useful for the diagnosis of MM. Protein S100 is considered sensitive and protein HMB 45 is specific to confirm MM, and it is more useful when the two markers are combined [9].

1. Introduction Benign cystic teratoma of the ovary is the most common type of ovarian neoplasm. By contrast, an immature teratoma is a rare tumor, representing less than 1% of all ovarian teratomas and 1% of all ovarian cancers [1]. Although there are some reports about familial occurrences of ovarian tumors, literature concerning the clinical cases of monozygotic twins is rare. We report the cases of a bilateral and repeated ovarian benign teratoma and an immature teratoma that appeared simultaneously in two monozygotic twins.

om rhabdomyosarcoma, leiomyosarcoma, mixed Müllerian tumor, adenocarcinoma, and poorly differentiated squamous cell carcinoma. Immunostaining is useful for the diagnosis of MM. Protein S100 is considered sensitive and protein HMB 45 is specific to confirm MM, and it is more useful when the two markers are combined [9]. Norris and Taylor [11] proposed four criteria for the diagnosis of primary cervical MM: (1) presence of melanin in the normal cervical epithelium, (2) absence of melanoma elsewhere in the body, (3) demonstration of junctional change in the cervix, and (4) metastases according to the pattern of cervical carcinoma. In this case, the tumor size of the cervix was larger, and the invasion depth of the cervical tumor was deeper than that of the vaginal tumors. Therefore, we conclude that the cervix was the primary site and it disseminated to the vaginal wall.

cervix, and (4) metastases according to the pattern of cervical carcinoma. In this case, the tumor size of the cervix was larger, and the invasion depth of the cervical tumor was deeper than that of the vaginal tumors. Therefore, we conclude that the cervix was the primary site and it disseminated to the vaginal wall. There is no consensus regarding standard management for primary cervical MM due to its rarity. The most common treatment based on the literature is surgery, including radical hysterectomy coupled with pelvic lymphadenectomy for stage I-II disease or pelvic exenteration for advanced cases [4]. In our case, we selected radical hysterectomy with total vaginectomy. In general, MM in female genital tract easily spreads into the rectum, bladder, and urethral tube. Because there was no evidence of extending to these tracts beyond cervical disease on MRI and PET/CT preoperatively, we avoided pelvic exenteration, considering the age of the patient and her quality of life after surgery. According to Pucceddu's review, of 76 primary cervical MM cases, vaginectomy was performed in only two cases [3]. MM is considered a radio-resistant tumor, and radiotherapy has been used as adjuvant or palliative treatment. Chemotherapy was performed using the same protocol for skin melanoma [12]. Dacarbazine as a single agent is the most commonly used drug, with response rates (RR) of about 15–20%. Combination chemotherapy with cisplatin, vinblastine, and dacarbazine led to RR of 20–35%, but this was not more effective than dacarbazine alone for prolonging survival [13]. There is a lack of evidence on the efficacy of postoperative radiation or chemotherapy. Nivolumab (anti-PD-1) was made available in Japan from July 2014, and it is expected to be effective for MM in the female genital tract. The prognosis associated with primary cervical MM is generally poor because its diagnosis is usually made at an advanced stage. According to a recent review, the 5-year survival is 18.8% for stage I, 11.1% for stage II, and 0% for stages III and IV [3]. In our case, we achieved optimal surgery for primary cervical MM without pelvic exenteration. However, the tumor recurred in the lung and rapidly progressed despite treatment with dacarbazine or nivolumab. Further studies are needed in order to propose standard treatment for primary cervical MM.

stages III and IV [3]. In our case, we achieved optimal surgery for primary cervical MM without pelvic exenteration. However, the tumor recurred in the lung and rapidly progressed despite treatment with dacarbazine or nivolumab. Further studies are needed in order to propose standard treatment for primary cervical MM. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Macroscopic findings demonstrated a 2 cm polypoid blackish-pigmented tumor in the cervix (a). Multiple small blackish-pigmented tumors throughout the vaginal wall spreading to the lower third of the vagina (b). Figure 2 Surgical specimens showed a 2 cm polypoid blackish-pigmented tumor in the uterine cervix (a), and multiple small blackish-pigmented tumors throughout the vaginal wall (b). Figure 3 Pathological findings of the cervix revealed spindle-shaped tumor cells showing intracytoplasmic melanin (a) and strong reactivity for melan-A (b). There were similar findings in the vagina (c, d). The invasion depth of the cervical tumor was deeper than that of the vaginal tumors. Magnification: (a) ×400, (b) ×400, (c) ×40, (d) ×100.

1. Introduction Vulvovaginal haematoma (VVH) occurring postpartum is a relatively uncommon complication of labour but can be a cause of serious morbidity and even maternal death [1]. This is because the symptoms could be nonspecific and bleeding is usually concealed, leading to diagnostic difficulties and delayed treatment. Clinically significant haematoma requiring surgical intervention occurs in about 1 in 1000 vaginal deliveries, while estimates from case series report incidences of 1 : 500 to 1 : 12,500 vaginal births [2]. Frequently cited risk factors include nulliparity, prolonged second stage of labour, instrumental delivery, poorly repaired episiotomy and lacerations, delivery of a baby > 4 kg, varicosities of the genital tract, and maternal age > 29 years [3]. Vulvovaginal haematomas classically present a few hours after delivery. The patient is usually restless, complaining of pelvic pain, inability to pass urine or rectal tenesmus. The rare presentation with the urge to “bear down” may confuse the accoucheur who is not conversant with this pathology leading to the possibility of extensive tissue damage and postpartum collapse from hypovolemic shock before an accurate diagnosis is made [4]. We therefore present the case of a nullipara with puerperal VVH that mimicked the “bearing down” efforts of the second stage of labour.

Vulvovaginal haematomas classically present a few hours after delivery. The patient is usually restless, complaining of pelvic pain, inability to pass urine or rectal tenesmus. The rare presentation with the urge to “bear down” may confuse the accoucheur who is not conversant with this pathology leading to the possibility of extensive tissue damage and postpartum collapse from hypovolemic shock before an accurate diagnosis is made [4]. We therefore present the case of a nullipara with puerperal VVH that mimicked the “bearing down” efforts of the second stage of labour. 2. Case Presentation A 26-year-old now Para 1 was referred from a peripheral hospital to the Teaching Hospital because of persistent “bearing down” efforts after a spontaneous vaginal delivery of a live male neonate with birth weight of 3400 gm six (6) hours prior to presentation. The labour had lasted about 9 hours. The birth attendant, having examined the patient again and excluded the possibility of an undiagnosed twin, decided to refer her for expert management. Examination on admission revealed a young lady who was pale, dehydrated, and intermittently straining in response to “the irresistible urge to push.” Her pulse rate was 102 beats/min, regular and of moderate volume with a blood pressure of 120/70 mmHg. The uterus was about 20-week pregnancy size and was well contracted. Pelvic examination revealed a blood-smeared vulva with a tender swelling involving the right labia minus and majus measuring about 4 cm by 4 cm.

h.” Her pulse rate was 102 beats/min, regular and of moderate volume with a blood pressure of 120/70 mmHg. The uterus was about 20-week pregnancy size and was well contracted. Pelvic examination revealed a blood-smeared vulva with a tender swelling involving the right labia minus and majus measuring about 4 cm by 4 cm. A diagnosis of puerperal genital haematoma was made. The plan was to institute conservative management with vaginal pack and analgesics. Intravenous access was established and blood sample was obtained for packed cell volume (PCV) (which was 22%) and grouping and cross-matching of three units of whole blood. The limits of the swelling were ink-marked and observed for one hour to confirm if there would be an enlargement. Progressive expansion of the VVH occurred, necessitating surgical intervention. The intraoperative findings included a huge 12 cm by 10 cm right vulvovaginal haematoma completely occluding the vaginal cavity and stretching the overlying perineal skin (Figures 1 and 2).

hour to confirm if there would be an enlargement. Progressive expansion of the VVH occurred, necessitating surgical intervention. The intraoperative findings included a huge 12 cm by 10 cm right vulvovaginal haematoma completely occluding the vaginal cavity and stretching the overlying perineal skin (Figures 1 and 2). There was no significant bleeding from the vagina. Incision and evacuation of the haematoma and exploration of the cavity were done and 1500 mls of clotted blood was evacuated from the cavity. Haemostasis was achieved with “figure-of-eight” sutures. The space was obliterated with deep sutures and the overlying skin approximated carefully, avoiding injury to the urethra. The vagina was packed with gauze to further assist with haemostasis (Figure 3). She had broad-spectrum antibiotics and transfusion of three units of blood and was discharged home on the third day following a satisfactory postoperative recovery.

the overlying skin approximated carefully, avoiding injury to the urethra. The vagina was packed with gauze to further assist with haemostasis (Figure 3). She had broad-spectrum antibiotics and transfusion of three units of blood and was discharged home on the third day following a satisfactory postoperative recovery. 3. Discussion Puerperal VVH are rare and have not been extensively reported. They are usually unilateral and in most cases develop insidiously, attention being drawn to them when the woman collapses in shock, groans in pain, or complains of “bearing down” pain after vaginal delivery [4]. This is usually due to rupture of the labial branches of the ipsilateral internal pudendal artery [5], which can occur without laceration of the superficial tissue. In about 20% of the cases, radial stretching of the birth canal occurs as the fetus passes through leading to rupture of the blood vessels [6]. Since the subcutaneous tissue in the vagina is quite pliable, haematomas from the concealed bleeding can achieve massive dimensions before expansion ceases [7]. The cases present with a huge vulval swelling that is associated with pain and may progress to occlude the vaginal orifice causing urinary retention and hypovolemic shock. The persistent involuntary urge in this patient to bear down when the VVH was still quite small makes this case a true rarity.

expansion ceases [7]. The cases present with a huge vulval swelling that is associated with pain and may progress to occlude the vaginal orifice causing urinary retention and hypovolemic shock. The persistent involuntary urge in this patient to bear down when the VVH was still quite small makes this case a true rarity. Management options are either conservative or surgical depending on the size and rate of progression of the haematoma. Conservative management was initially instituted in the patient presented because the swelling was less than 5 cm. Other conservative measures employed when the haematoma is <5 cm and static/not rapidly increasing in size include ice packs, pressure dressing, bladder drainage, and analgesics [8]. The visible skin margin of the haematoma could also be marked to establish progression. However, in swellings > 5 cm, the conservative approach was associated with longer hospital stay, increased need for antibiotics and blood transfusion, and greater recourse to surgical intervention [7]. Following evidence of progression or in large haematomas, surgical management should be instituted with the incision made as medially as possible to minimize visible scarring [1]. The presence of any residual bleeding into the haematoma cavity (which was not present in this case) is an indication for the insertion of a drain, which should be left in place for at least 12–24 hours [9]. The repair should be done in such a way as to obliterate the dead space to prevent recollection and abscess formation.

esence of any residual bleeding into the haematoma cavity (which was not present in this case) is an indication for the insertion of a drain, which should be left in place for at least 12–24 hours [9]. The repair should be done in such a way as to obliterate the dead space to prevent recollection and abscess formation. Continuing bleeding should be excluded by close monitoring of the operation site, evaluation of the vital signs, and urinary output. When it occurs, the site should be reexplored and identified bleeders ligated. Sometimes, ligation of the internal iliac artery or even hysterectomy may be necessary [1] or use of angiographic embolization for cases of on-going bleeding not controlled by conventional surgical techniques [10]. To prevent infection, broad-spectrum antibiotics should be given. Good analgesia and close observation are important postoperatively. Prompt resolution of haematoma will improve outcome and result in reduced scarring, postpartum pain, and dyspareunia [11]. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Preoperative VVH. Figure 2 The VVH viewed with patient in the dorsal position (urethral catheter in situ). Figure 3 Evacuated clots, closed dead space.

1. Introduction A supernumerary ovary is one of the rarest conditions of gynecological conditions, in which the structure containing ovarian tissue, such as the primordial follicle, is located at some distance from the normally placed ovary [1]. It occurs in the pelvic area, attached to the uterus, bladder, pelvic wall, retroperitoneum, and omental, mesenteric, and inguinal regions [2]. Tumors or endometriosis originating in the supernumerary ovary is exceedingly rare, with only 16 cases reported in the English literature [3–17]. Here, we present a case of cystic endometriosis with coexisting fibroma originating in a supernumerary ovary in the rectovaginal pouch and describe the differences between this case and rectovaginal endometriosis based on the results of our previous studies [18, 19].

16 cases reported in the English literature [3–17]. Here, we present a case of cystic endometriosis with coexisting fibroma originating in a supernumerary ovary in the rectovaginal pouch and describe the differences between this case and rectovaginal endometriosis based on the results of our previous studies [18, 19]. 2. Case Presentation A 40-year-old 2-multipara female was urgently admitted to Juntendo University Nerima Hospital with a diagnosis of acute abdomen. She had no previous pelvic surgery. Her initial laboratory data revealed a normal range of WBC and CRP and an elevation of CA125 (114 U/mL) and CA19-9 (402 U/mL). We had a diagnosis of the rupture or torsion of the ovarian malignant tumor because of the findings of magnetic resonance imaging revealing the suspicion of hemorrhage within the rectovaginal mass (Figure 1), and an operation was performed by the accommodation of the acute abdomen within one day after admission. During the operation, a small amount of yellowish ascites was pooled in the abdominal cavity. A cystic and solid mass, with a maximal diameter of 90 mm, was present in the rectovaginal region, the mass did not connect to the bilateral ovaries, and the bilateral ovaries and fallopian tubes showed no abnormality (Figure 2). The resection of the mass was performed by the separate resection of the cystic and solid portions, respectively. The resection was smoothly performed without adhesion to the surrounding peritoneum.

did not connect to the bilateral ovaries, and the bilateral ovaries and fallopian tubes showed no abnormality (Figure 2). The resection of the mass was performed by the separate resection of the cystic and solid portions, respectively. The resection was smoothly performed without adhesion to the surrounding peritoneum. After mass fixation by formalin solution, the size of the cystic portion was 35 × 30 mm and that of the solid portion was 50 × 45 × 30 mm. The solid area showed a gray-colored fibrous appearance (Figure 3). Histological examination was performed with the addition of immunostaining of CD10, ER, PgR, alpha-inhibin, desmin, and smooth muscle actin.

alin solution, the size of the cystic portion was 35 × 30 mm and that of the solid portion was 50 × 45 × 30 mm. The solid area showed a gray-colored fibrous appearance (Figure 3). Histological examination was performed with the addition of immunostaining of CD10, ER, PgR, alpha-inhibin, desmin, and smooth muscle actin. Histologically, in the cystic area, variously sized cysts with the lining of endometrial tissue in the cyst wall were present (Figures 4 and 5), which indicated a diagnosis of cystic endometriosis (endometriosis with cystic change). In the larger cysts, a spindle cell layer around the endometrial lining layer of the cyst wall was present (Figure 6(a)). The spindle cells showed positivity for PgR (Figure 6(b)) and week positivity for ER. In the spindle cell layer, the presence of the primordial follicle in a few sites was noted (Figures 6(a), 6(c), and 6(d)). Although the cellularity was lower compared with normal ovarian stroma, the spindle cell layer was considered as ovarian stroma because of the presence of primordial follicles and positivity for both PgR and EM in the spindle cells. In the solid area, spindle cells with bland nuclei and scant cytoplasm were arranged in intersecting bundles admixed with collagen (Figures 7(a) and 7(b)). The hyalinization of collagen bundles was noted at many sites, and calcification was focally present. These findings indicated that the solid part was fibroma.

lls. In the solid area, spindle cells with bland nuclei and scant cytoplasm were arranged in intersecting bundles admixed with collagen (Figures 7(a) and 7(b)). The hyalinization of collagen bundles was noted at many sites, and calcification was focally present. These findings indicated that the solid part was fibroma. Based on the clinical (solid and cystic mass in the rectovaginal region without connection to the normal bilateral ovaries) and histological (coexisting cystic endometrioma and fibroma) findings, the mass was diagnosed as cystic endometrioma with coexisting fibroma originating in a supernumerary ovary in the rectovaginal pouch. This case was approved by the Research Ethics Committee of Juntendo University Nerima Hospital. 3. Discussion Cases of lobulated, accessory, and supernumerary ovary are among the rarest conditions of abnormalities. A lobulated ovary is a normally situated ovary divided by one or several fissures into two or more lobes. An accessory ovary attaches to normal ovarian tissue or a ligament of eutopic ovary [2]. A supernumerary ovary is a similar structure but located at some distance from an eutopic ovary [2]; therefore this tumor was thought to be originated from supernumerary ovary.

ded by one or several fissures into two or more lobes. An accessory ovary attaches to normal ovarian tissue or a ligament of eutopic ovary [2]. A supernumerary ovary is a similar structure but located at some distance from an eutopic ovary [2]; therefore this tumor was thought to be originated from supernumerary ovary. The site and disease in the 17 cases (16 previously reported cases and the present case) with a tumor and/or endometriosis originating in a supernumerary ovary are presented in Table 1. Among the 16 previously reported cases, malignant tumor in 6 cases, benign tumor in 8 cases, and endometrioma in 2 cases occurred, respectively. Five of eight cases of the benign tumor were cystic teratoma, and fibroma, serous cystadenoma, and mucinous adenoma were a case each. (Table 1). Consequently, the present patient is the first reported case of endometrioma with coexisting fibroma originating in a supernumerary ovary.

a in 2 cases occurred, respectively. Five of eight cases of the benign tumor were cystic teratoma, and fibroma, serous cystadenoma, and mucinous adenoma were a case each. (Table 1). Consequently, the present patient is the first reported case of endometrioma with coexisting fibroma originating in a supernumerary ovary. In rectovaginal endometrioma, fibrosis occurred around the endometrial tissues and it extended into fat and connective tissue as well as within the endometrial tissues and finally produced a nodular fibrous mass, while causing clinical symptoms, including obstinate, severe dysmenorrhea, dyspareunia, and chronic pelvic pain [18, 19]. In the process of the disease progression of rectovaginal endometriosis, the dilation of endometrial glands occurred, but cyst formation, which is similar to endometrial cyst, did not occur [18, 19]. This cyst formation of endometriosis, that is, cystic endometrioma, observed in this case, is a characteristic finding, which is a point differing from rectovaginal endometriosis.

ndometriosis, the dilation of endometrial glands occurred, but cyst formation, which is similar to endometrial cyst, did not occur [18, 19]. This cyst formation of endometriosis, that is, cystic endometrioma, observed in this case, is a characteristic finding, which is a point differing from rectovaginal endometriosis. Concerning the diagnosis of this patient, we initially considered rectovaginal endometriosis with coexisting fibroma. However, cystic endometriosis in the rectovaginal pouch was not found in the 195 specimens of the 63 cases with rectovaginal endometriosis in our previous study [18]. So, we performed a detailed examination, including various histochemical stains, and found a few primordial follicles in the area of the cystic endometriosis, which led to the diagnosis of cystic endometriosis originating in a supernumerary ovary. These indicated the necessity of a detailed examination for the presence or absence of the ovarian tissue in cystic endometriosis in the rectovaginal pouch. In rectovaginal endometriosis, fibrosis and smooth muscle metaplasia frequently occurred. So, concerning the pathogenesis of the coexisting fibroma in this case, metaplastic theory may be considered. However, fibroma is the most common ovarian stromal tumor [20], so the consideration of the coexisting fibroma arising from the ovarian stroma in a supernumerary ovary is more reasonable.

a frequently occurred. So, concerning the pathogenesis of the coexisting fibroma in this case, metaplastic theory may be considered. However, fibroma is the most common ovarian stromal tumor [20], so the consideration of the coexisting fibroma arising from the ovarian stroma in a supernumerary ovary is more reasonable. In conclusion, we reported the first case of cystic endometriosis with coexisting fibroma originating in a supernumerary ovary in the rectovaginal pouch. When cystic endometriosis is present in the rectovaginal pouch, our experiences with the present case suggest that the possibility of cystic endometriosis originating in a supernumerary ovary shall be examined. Acknowledgments The authors thank Dr. Masako Suzuki (Clinical Laboratory Department, Iida Hospital) and Dr. Yuko Sasajima (Department of Pathology, Teikyo Medical University, School of Medicine) for advice on the diagnosis of the present case and also Mr. Daniel Mrozek (Medical English Service, Kyoto, Japan) for organizing the English revision of this paper. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 The rectovaginal mass on pelvic MRI (T2-weighted, sagittal line). The mass with multilocular cyst (indicated by C) and solid (indicated by S) components and a maximal diameter of 9 cm locates in the rectovaginal pouch. The uterus is indicated with an arrowhead, and the rectum is indicated with an arrow.

Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 The rectovaginal mass on pelvic MRI (T2-weighted, sagittal line). The mass with multilocular cyst (indicated by C) and solid (indicated by S) components and a maximal diameter of 9 cm locates in the rectovaginal pouch. The uterus is indicated with an arrowhead, and the rectum is indicated with an arrow. Figure 2 View of the rectovaginal pouch during the operation. The cystic and solid mass, indicated by arrows, is present in the rectovaginal pouch and it is located separately from normal bilateral ovaries (R, right ovary; L, left ovary). Figure 3 Gross appearance of the solid part of the rectovaginal mass in the cut section. Note the gray-colored fibrous appearance in the solid part. Figure 4 Loupe image of cystic endometriosis (indicated by CE) and fibroma (indicated by F). HE stain. Figure 5 Endometrial tissue in the cyst wall of cystic endometriosis. HE stain. Figure 6 A primordial follicle in the ovarian stroma. (a) Note the spindle cell layer (indicated by S) around the endometrial tissue (indicated by E) of cystic endometriosis. A primordial follicle (indicated by an arrow) is present in the spindle cell layer. HE stain. (b) Many spindle cells show positivity for PgR immunostain, which indicates that the spindle cell layer is an ovarian stroma. (c) High-power view of primordial follicle. HE stain. (d) Granular cells consisting of primordial follicle show positivity for alpha-inhibin immunostain.

ent in the spindle cell layer. HE stain. (b) Many spindle cells show positivity for PgR immunostain, which indicates that the spindle cell layer is an ovarian stroma. (c) High-power view of primordial follicle. HE stain. (d) Granular cells consisting of primordial follicle show positivity for alpha-inhibin immunostain. Figure 7 Histological appearance of the fibroma. (a) The fibroma (indicated by F) is present adjacent to endometrial tissue (indicated by E) of cystic endometriosis. HE stain. (b) High-power of the fibroma. Note the increase of the admixture of fibroblasts and collagen fibers. HE stain. Table 1 Site and diseases in 17 cases with tumors and/or endometriosis originating in supernumerary ovary.

Figure 7 Histological appearance of the fibroma. (a) The fibroma (indicated by F) is present adjacent to endometrial tissue (indicated by E) of cystic endometriosis. HE stain. (b) High-power of the fibroma. Note the increase of the admixture of fibroblasts and collagen fibers. HE stain. Table 1 Site and diseases in 17 cases with tumors and/or endometriosis originating in supernumerary ovary. Case Authors Year Age Site Diseases 1 Wharton [1] 1947 49 Pelvic Granulosa cell carcinoma 2 Wharton [1] 1947 34 Side of the right ovary Serous cystadenoma 3 Irving and Clement [2] 1967 21 Omentum Cystic teratoma 4 Kriss [3] 1973 23 Omentum Cystic teratoma 5 Hogan et al. [4] 1975 — Omentum Cystic teratoma 6 Printz et al. [5] 1977 48 Left retroperitoneum Mucinous cystadenocarcinoma 7 Huhn [6] 1982 36 Left retroperitoneum Mucinous cystadenoma 8 Roth and Ehrlich [7] 1987 34 Omentum Cystic teratoma 9 Cruikshank and van Drie [8] 1991 — — Adenocarcinoma 10 Mercer et al. [9] 1992 47 Omentum Cystic teratoma 11 El-Gohary et al. [10] 1995 32 Left retroperitoneum Endometrioma 12 Barik et al. [11] 2001 47 Omentum Fibroma, Meig's syndrome 13 Barik et al. [11] 2001 28 On pregnant uterus Endometrioma 14 Besser and Posey [12] 2005 30 Left retroperitoneum Mucinous adenocarcinoma 15 Badawy et al. [13] 2013 64 Retrouterine Serous adenocarcinoma 16 Kamiyama et al. [14] 2013 31 Left retroperitoneum Serous adenocarcinoma 17 Present case 2016 40 Rectovaginal pouch Cystic endometrioma and fibroma

1. Introduction Uterine fibroids affect 20%–30% of older women. Extrauterine fibroids are very unusual and they present with a greater diagnostic dilemma. These are histologically benign tumors and originate from smooth muscle cells, usually from the genitourinary tract (in the vulva, ovaries, urethra, and urinary bladder). Unusual growth patterns and locations can also be seen including disseminated peritoneal leiomyomatosis, benign metastasizing leiomyoma, parasitic leiomyoma, intravenous leiomyomatosis, and retroperitoneal growth. The disseminated leiomyomatosis growth out of subperitoneal mesenchymal stem cells, which undergo metaplasia under the stimulation of hormones, has been widely accepted theory [1]. However, in some cases iatrogenic theory has been proposed where dissemination of uterine tissue particles occurs during electrical morcellation and results in development of disseminated leiomyomatosis. Several cases of parasitic leiomyomas, disseminated peritoneal leiomyomatosis, adenomyosis, and endometriosis following morcellation have been reported recently [1–5]. A synchronous uterine leiomyoma or a previous hysterectomy for removal of a primary uterine tumor may be indicative of the diagnosis in the presence of such a pattern. The most useful modalities for detecting extrauterine leiomyomas are ultrasonography, computed tomography, and magnetic resonance (MR) imaging.

y [1–5]. A synchronous uterine leiomyoma or a previous hysterectomy for removal of a primary uterine tumor may be indicative of the diagnosis in the presence of such a pattern. The most useful modalities for detecting extrauterine leiomyomas are ultrasonography, computed tomography, and magnetic resonance (MR) imaging. 2. Case Report A 29-year-old female patient presented in 2014 with complaints of heaviness and pain in the lower abdomen for the past 3 months. Ultrasound was done outside of our hospital which revealed a large heterogeneously isoechoic mass lesion in the myometrium of fundus displacing and splaying of the endometrial cavity. She underwent laparoscopic myomectomy by morcellation technique for removal of uterine fibroids. Surgical specimen is sent for the histopathological evaluation, which confirmed the leiomyoma.

led a large heterogeneously isoechoic mass lesion in the myometrium of fundus displacing and splaying of the endometrial cavity. She underwent laparoscopic myomectomy by morcellation technique for removal of uterine fibroids. Surgical specimen is sent for the histopathological evaluation, which confirmed the leiomyoma. After one year, she again presented with abdominal pain and underwent ultrasound imaging, which revealed a well-defined oval shaped highly vascular lesion along the anterior abdominal wall in the right hypochondrium. CT angiography was performed for further evaluation, which revealed a well-defined oval shaped highly vascular lesion along the anterior abdominal wall. The blood supply to this lesion was from 10th right intercostal artery and the branch from the right internal mammary artery. In addition, multiple well-defined round to oval homogenously enhancing lesions were also noted in the mesentery in the left iliac fossa and along the superior border of urinary bladder (Figure 1). The patient underwent exploratory laparotomy because of uncertain diagnosis and suspicion of disseminated neoplasm. At laparotomy, tumor in right hypochondrium was found attached to the peritoneum, and the nodular lesions (four in numbers) in the left iliac fossa were found attached to the mesentery. The all lesions were completely removed. Gross appearance of tumors resembled uterine leiomyomas. Histologically, the tumor from the right hypochondrium showed interlacing bundles of spindle cells without mitosis or necrosis, suggestive of leiomyomatosis. Nodular lesions from left iliac fossa showed circumscribed lesions made up interlacing spindle cells, one of the lesion was surrounded by fibro fatty tissue, and one of the nodule showed few dilated cystic spaced by columnar epithelium suggestive of leiomyomatosis with endosalpingiosis.

s, suggestive of leiomyomatosis. Nodular lesions from left iliac fossa showed circumscribed lesions made up interlacing spindle cells, one of the lesion was surrounded by fibro fatty tissue, and one of the nodule showed few dilated cystic spaced by columnar epithelium suggestive of leiomyomatosis with endosalpingiosis. In march 2016, again she presented with abdominal pain from the past 15–20 days. On imaging, she was diagnosed as a case of uterine fibroids and was taken for surgery. During the surgery it was found that the fibroid was extremely vascular and hence the surgery was abandoned and was referred to our hospital for embolization and further treatment. MRI (Figure 2) and CT angiography (Figure 3) were performed to localize the origin and relation with adjacent structure and visualize and locate the feeding vessels and to facilitate embolization better, respectively. The imaging findings revealed a large markedly heterogenous pelvic-abdominal mass in relation to left posterolateral wall of the uterus with vascular supply from upper abdomen via a large vascular pedicle traversing the omentum containing hypertrophied omental branch from the right gastroepiploic artery with a large tortuous vein draining into the superior mesenteric vein. The mass was inseparable from the sigmoid mesocolon, the omentum, and adjacent large gut loops. Because of high vascularity and the unusual blood supply, patient was taken for the embolization of the leiomyoma. Coeliac axis was catheterized followed by gastroduodenal artery (GDA) catheterization. The feeding artery possibly omental branch to the fibroid was identified arising from the right gastroepiploic artery. This feeding artery was superselectively catheterized using Progreat microcatheter and embolized using coils just proximal to the fibroid and at the origin from the gastroepiploic artery (Figure 4). Superior mesenteric artery (SMA) was selectively catheterized; however branches of SMA were not seen to be supplying the fibroid. Thereafter, inferior mesenteric artery (IMA) was selectively catheterized and the feeding branches from it to the fibroid identified and superselectively catheterized. These feeding branches were, however, not embolized in view of supply to sigmoid colon from these branches. Significant reduction in the vascularity to the fibroid was noted on check angiogram. Postembolization surgery was done. The mass was inseparable from the sigmoid colon.

ntified and superselectively catheterized. These feeding branches were, however, not embolized in view of supply to sigmoid colon from these branches. Significant reduction in the vascularity to the fibroid was noted on check angiogram. Postembolization surgery was done. The mass was inseparable from the sigmoid colon. So the large leiomyoma along with the omentum was taken out and partial colectomy was done and sent for histopathological analysis. Histopathological analysis (Figure 5) confirmed the diagnosis of fibroid with tongue like extension of smooth muscle into the subserosal fat of colonic wall and proliferation of smooth muscles into the omentum suggestive of disseminated fibroid. The patient recovered satisfactory in postoperative period and was discharged in next seven days. 3. Discussion Disseminated leiomyomatosis is rare disorder characterized by multiple vascular leiomyomas growing along the submesothelial tissues of the abdominopelvic peritoneum [1]. Laparoscopic myomectomy is recommended as a procedure of choice for patients requiring removal of the fibroids in the young patients. Laparoscopic route has been proved to be safe, efficient, and cost-effective [6]. However, some reports published in recent years have raised the concern that retrieval of tissues by electric morcellation presents a hazard for seeding of fibroid remnants into the peritoneal cavity [7]. Although recurrence rates for uterine leiomyoma range from 22% to 62% [8, 9], recurrence of disseminated leiomyoma is rare.

some reports published in recent years have raised the concern that retrieval of tissues by electric morcellation presents a hazard for seeding of fibroid remnants into the peritoneal cavity [7]. Although recurrence rates for uterine leiomyoma range from 22% to 62% [8, 9], recurrence of disseminated leiomyoma is rare. Because of nonspecific symptoms and atypical radiologic features diagnosis of disseminated fibroid is challenging. On CT scans they are usually observed as well-circumscribed multiple nodules with contrast-enhancement characteristic to that of myometrium or uterine fibroids. However, when necrosis, degeneration, or implantation of endometrial components occurs an enhancement is heterogenous, mimicking peritoneal carcinomatosis. Our case is presenting myometrial tissue with internal cystic areas suggestive of plentiful endometrial glands interspersed between the smooth muscle cells. What is important, these findings imply that there is a risk of dissemination of endometrial cancer or other uterine malignancies if they are not diagnosed before laparoscopic surgery. The superb contrast resolution and multiplanar capabilities of MR imaging make it particularly valuable for characterizing these tumors, which usually show low signal intensity similar to that of smooth muscle on T2-weighted images. Early diagnosis and knowledge of such disease may help the clinician toward timely appropriate management.

resolution and multiplanar capabilities of MR imaging make it particularly valuable for characterizing these tumors, which usually show low signal intensity similar to that of smooth muscle on T2-weighted images. Early diagnosis and knowledge of such disease may help the clinician toward timely appropriate management. Only few cases of recurrent disseminated fibroid after laparoscopic hysterectomy and laparoscopic myomectomy have been reported in the literature [1–5]. Although, the risk of implantation and growth of myometrial tissue left in the abdominal cavity after morcellation can be regarded as very low. As in our case, in 1st time recurrence the fibroid was along the anterior abdominal wall and supplied by 10th intercostal artery and the branch of right internal mammary artery and in second recurrence, the fibroid is in the peritoneal cavity and embedded in the omentum and adherent to the adjacent large gut loops. It was supplied by a large omental branch from the right gastroepiploic artery and branches from inferior mesenteric artery and was draining into the superior mesenteric vein supplying it. In summary, uterine morcellation may result in seeding of myometrial tissue throughout the abdominal cavity that leads to serious morbidity and causes diagnostic dilemma. And the disseminated leiomyomatosis can seek blood supply from any nearby vessel. Although laparoscopic hysterectomy is safe and widely accepted procedure, possibility of such a complication should be kept in mind. Additional Points

In summary, uterine morcellation may result in seeding of myometrial tissue throughout the abdominal cavity that leads to serious morbidity and causes diagnostic dilemma. And the disseminated leiomyomatosis can seek blood supply from any nearby vessel. Although laparoscopic hysterectomy is safe and widely accepted procedure, possibility of such a complication should be kept in mind. Additional Points Learning Points. (i) A synchronous uterine leiomyoma or a previous hysterectomy for removal of a primary uterine tumor may be indicative of the diagnosis. (ii) The superb contrast resolution and multiplanar capabilities of MR imaging make it particularly valuable for characterizing these tumors, which usually show low signal intensity similar to that of smooth muscle on T2-weighted images. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 CT angiography. Axial section through right hypochondrium showed a well-defined oval shaped enhancing mass lesion along the peritoneal surface (a); axial section through the lower abdomen revealed few round well-defined homogenously enhancing soft tissue lesions in the mesentery (red circle in (b) and (c)) and yellow arrow shows a postsurgical changes in the uterus (b); volume rendering image of the right hypochondrium (d) shows the blood supply from right 10th intercoastal artery (thin arrow) and from the branch of right internal mammary artery (curved arrow). Thick arrow represents the mass lesion.

rcle in (b) and (c)) and yellow arrow shows a postsurgical changes in the uterus (b); volume rendering image of the right hypochondrium (d) shows the blood supply from right 10th intercoastal artery (thin arrow) and from the branch of right internal mammary artery (curved arrow). Thick arrow represents the mass lesion. Figure 2 MRI of lower abdomen. Axial (a), coronal (b), and sagittal (c) sections of T2WI through the lower abdomen revealed a large heterogeneous pelvic-abdominal mass lesion in relation to the uterus. The mass appears to be inseparable from the adjacent mesentery and omentum. A tortuous vascular pedicle is also seen in the coronal section (b). Axial section of SWI sequence through the mass lesion showed areas of blooming suggestive of intralesional hemorrhagic foci (d). The mass lesion shows extensive enhancement after administration of gadolinium contrast (e). Figure 3 CT Angiography. Axial scan through the lower abdomen revealed a large heterogenous mass with multiple intralesional vascular channels ((a) and (b)); volume rendering reconstructed images ((c) and (d)) show a hypertrophied vascular channel (omental branch) arising from the right gastroepiploic artery (red arrow on (c)) which is encircled with a draining tributary which is drained into the superior mesenteric vein (yellow arrow on (d)); an angiographic reconstructed image (e) shows a highly vascular mass with multiple intralesional vascular channels (red circle).

branch) arising from the right gastroepiploic artery (red arrow on (c)) which is encircled with a draining tributary which is drained into the superior mesenteric vein (yellow arrow on (d)); an angiographic reconstructed image (e) shows a highly vascular mass with multiple intralesional vascular channels (red circle). Figure 4 Conventional angiography of right gastroepiploic artery. The omental branch of right gastroepiploic artery was embolized using coils at its distal most end ((a) and (b)) and at proximal end ((c) and (d)). Postembolization images ((b) and (d)) showed complete embolization of this artery. Figure 5 Histopathological analysis. Microscopic images of pelvic-abdominal mass (a) show intertwining bundles of smooth muscle cells and microscopic images omentum (b) show multiple irregular but discrete smooth muscle proliferation (leiomyomatous proliferation).

1. Introduction 1.1. Overview of Short Stature, Dwarfism, and Cartilage-Hair Hypoplasia Dwarfism has been defined as individuals with a height less than 148 cm at adulthood [1]. There are over 100 [2] forms of dwarfism that have been documented; however there is limited information surrounding pregnancy, birth, and breastfeeding in this population. The majority of documented experiences focus on anesthetic management [1, 3–6]. Cartilage-hair hypoplasia (CHH) is a rare form of short-limbed dwarfism with an incidence of 1/23,000 births [7]. It is the result of a genetic autosomal recessive pattern of inheritance, from a mutation to the noncoding RNA gene, RMRP [8]. The RMRP mutation disrupts ribosomal processing and progression through the cell cycle in rapidly dividing cells, such as chondrocytes [8], which results in defective cell proliferation [7]. Cartilage deficiency at the metaphyseal ends of bones causes shortening of limbs [8]. Similar disruption to lymphocytes can result in defective proliferation of T lymphocytes, causing features of severe T cell immunodeficiency [8]. Other associated clinical features include sparse hair growth, bone marrow failure, increased risk of Hirschsprung disease, and malignancies [8]. It is a disease of highly variable penetrance with phenotypic differences evident within families.

n of T lymphocytes, causing features of severe T cell immunodeficiency [8]. Other associated clinical features include sparse hair growth, bone marrow failure, increased risk of Hirschsprung disease, and malignancies [8]. It is a disease of highly variable penetrance with phenotypic differences evident within families. There have been few case reports in patients with cartilage-hair hypoplasia and other forms of dwarfism, discussing their clinical manifestations, treatment, and genetic implications; however, pregnancy outcomes in these patients have not been published. A survey of obstetrical and gynecological outcomes in women with chondrodystrophies in 1986 included 3 women with CHH [9]; however details of their pregnancy are unknown. There have been case reports in the literature on the pregnancy outcomes in patients with diastrophic dwarfism [5], achondroplasia [1, 3], pituitary dwarfism [10], spondylometaphyseal dysplasia [4], and osteogenesis imperfecta [11], with a substantial risk of cesarean delivery. Of these, many focused on the anesthetic planning for their cesarean deliveries. Breastfeeding rates or concerns were not mentioned. These patients tended to suffer from respiratory distress towards the end of their pregnancy. A main concern in patients with varying forms of dwarfism is the use of anesthetics, both general and regional dosing can be problematic.

nning for their cesarean deliveries. Breastfeeding rates or concerns were not mentioned. These patients tended to suffer from respiratory distress towards the end of their pregnancy. A main concern in patients with varying forms of dwarfism is the use of anesthetics, both general and regional dosing can be problematic. Pregnancy loss and fetal complications do appear to be increased in maternal dwarfs [12, 13]; however this is not seen in all studies [14]. From the obstetric view, women of short stature are also at increased risk of preterm birth [14] and have been found in multiple studies to have a higher risk of cesarean delivery, often associated with cephalopelvic disproportion [12, 14]. However, in patients with skeletal dysplasias with less disproportion, vaginal deliveries have been noted [14]. It should be noted that what is defined as short stature may differ between ethnic populations. In populations with lower average maternal height, there is proportionately less impact of height on obstetrics [13].

Pregnancy loss and fetal complications do appear to be increased in maternal dwarfs [12, 13]; however this is not seen in all studies [14]. From the obstetric view, women of short stature are also at increased risk of preterm birth [14] and have been found in multiple studies to have a higher risk of cesarean delivery, often associated with cephalopelvic disproportion [12, 14]. However, in patients with skeletal dysplasias with less disproportion, vaginal deliveries have been noted [14]. It should be noted that what is defined as short stature may differ between ethnic populations. In populations with lower average maternal height, there is proportionately less impact of height on obstetrics [13]. 2. Case Report A 32-year-old gravida 3, para 0, was referred at 13 weeks 5 days' gestation to the High-Risk Clinic in June 2015 due to her maternal skeletal dysplasia, cartilage-hair hypoplasia. This diagnosis was established based on clinical findings and confirmed by genetic studies. She is 4 ft 0 in (122 cm) tall and has had eleven surgeries of the spine with Harrington rods placed and 10 inches (25.4 cm) of lower limb lengthening. She had no ongoing musculoskeletal concerns. She has also had bilateral breast implants. Her obstetrical history included a first-trimester miscarriage of a spontaneous pregnancy and an ectopic pregnancy following IVF, treated with methotrexate. This pregnancy occurred spontaneously. She has no history of gastrointestinal manifestations, immunodeficiency, or autoimmune disorders, which can be associated with cartilage-hair hypoplasia; however, she reports a history of sciatica. Informed consent was obtained from the patient in writing this case report.

rexate. This pregnancy occurred spontaneously. She has no history of gastrointestinal manifestations, immunodeficiency, or autoimmune disorders, which can be associated with cartilage-hair hypoplasia; however, she reports a history of sciatica. Informed consent was obtained from the patient in writing this case report. Genetic counseling had been provided to the patient and her unaffected partner prior to conception and he was not found to be a carrier. As a result of her extremely short stature and associated skeletal abnormalities, elective cesarean at term was recommended. Baseline pulmonary function tests were done and a referral to consultation with anesthesia was made during the second trimester. Due to her previous surgeries along the spine, the decision was made for general anesthesia. Cervical length was monitored from 16 weeks' gestation due to increased risk of preterm birth and measured to be 3.5–3.8 cm. Pulmonary function tests were repeated at 31 weeks' gestation and remained normal. Her 20-week anatomy scan showed a persistent right umbilical vein and midline gallbladder, and fetal echo showed a single papillary muscle of the fetal mitral valve. She opted for noninvasive prenatal testing, which was normal.

5–3.8 cm. Pulmonary function tests were repeated at 31 weeks' gestation and remained normal. Her 20-week anatomy scan showed a persistent right umbilical vein and midline gallbladder, and fetal echo showed a single papillary muscle of the fetal mitral valve. She opted for noninvasive prenatal testing, which was normal. Concerns were raised regarding increased intraabdominal pressure and potential difficulties acquiring adequate nutrition, respiratory compromise, preterm birth and intrauterine growth restriction, difficulty in ambulation and instability, and anesthetic management. She experienced some back discomfort and occasional pain in the left hip, which was managed with Tylenol, physiotherapy, and massage. Occupational therapy was also suggested; however the patient had improvement with swimming and therefore did not have this consult. She was also advised on hydration, stretch exercises, and increased dairy intake to help with nocturnal leg cramps. Referral was made for dietician review every 2 weeks to monitor her progress with weight gain and associated symptoms relating to constipation. The lack of evidence regarding ideal body weight and gestational weight gain for people of short stature was discussed. She gained a total of 30 lbs during her pregnancy, which is within the normal weight gain recommended by the Society of Obstetricians and Gynecologists of Canada for women of normal BMI [15]; however, she experienced satiety early on and reported eating slower. Increased fruit and vegetable consumption was recommended, with smaller portions overall. She was on docusate and increased fluid intake was encouraged to improve constipation. Fiber content was not increased to avoid further limiting her hunger and weight gain.

experienced satiety early on and reported eating slower. Increased fruit and vegetable consumption was recommended, with smaller portions overall. She was on docusate and increased fluid intake was encouraged to improve constipation. Fiber content was not increased to avoid further limiting her hunger and weight gain. Because of her desire to breastfeed and the possible associated difficulties due to her short upper limbs, she had a prenatal lactation consultation. It was discovered that her short upper limbs may limit her movement, and she was therefore provided with teaching surrounding laid back positioning, which involves lying back at a 45-degree angle and allowing the baby to use their reflexes to “bob” on and off until finding the breast. The concern regarding reaching the breasts for pumping was addressed by recommending a sports bra with holes cut in it, and using this to keep the breast pump flanges in place. She presented to hospital at 34 weeks 2 days' gestation with fetus in breech position and active labor following spontaneous rupture of membranes. An uncomplicated cesarean was performed with a low segment transverse abdominal incision and general anesthesia followed by an uneventful postoperative recovery. She gave birth to a male infant weighing 2.4 kg. She was discharged 2 days later with support from the hospital breastfeeding clinic. She breastfed for approximately 6 weeks but stopped due to neonatal cow's milk allergy.

sverse abdominal incision and general anesthesia followed by an uneventful postoperative recovery. She gave birth to a male infant weighing 2.4 kg. She was discharged 2 days later with support from the hospital breastfeeding clinic. She breastfed for approximately 6 weeks but stopped due to neonatal cow's milk allergy. 3. Discussion 3.1. Maternal Complications Obstetric and gynecologic complications have been sparsely studied in the population of women with short stature and different forms of dwarfism. Preterm deliveries frequently occur due to maternal respiratory distress [9]. In this case, respiratory disease was not a primary concern; however, pulmonary baseline testing was conducted and shown to be normal. Due to the normal fetus head size in a smaller maternal pelvis [1], this can cause cephalopelvic disproportion and result in dystocia [12]. As a result, elective cesarean deliveries are sometimes recommended, as it was in this case. Short stature has been shown to be an independent risk factor for cesarean delivery [12].

e to the normal fetus head size in a smaller maternal pelvis [1], this can cause cephalopelvic disproportion and result in dystocia [12]. As a result, elective cesarean deliveries are sometimes recommended, as it was in this case. Short stature has been shown to be an independent risk factor for cesarean delivery [12]. During pregnancy and labor, there is the added concern of appropriate pain management, particularly in these patients who have had multiple previous surgeries due to orthopedic problems. Continuous spinal epidural anesthesia has been successfully used during labor in women with scoliosis in previous spinal surgery [5] and people with achondroplastic dwarfism, even in urgent cesarean deliveries. Regional anesthesia may be difficult due to poor landmarks, spinal deformity, and narrowing of the epidural spaces, which increases the risk for dural puncture [5]. With regional anesthesia, neurological complications have not been reported in this cohort of patients [1]; however, since this patient reported a history of sciatica in addition to her history of spinal surgeries, general anesthesia was chosen. General anesthesia has been recommended in some cases [9] but may require postoperative ventilator support [5]. There is insufficient data regarding pain management during the duration of pregnancy, particularly in these patients who may have increased pain secondary to skeletal problems and multiple previous surgeries. Nerve-root compression has also been reported as a complication in the short stature literature [16]; however this patient did not suffer from this difficulty.

ent during the duration of pregnancy, particularly in these patients who may have increased pain secondary to skeletal problems and multiple previous surgeries. Nerve-root compression has also been reported as a complication in the short stature literature [16]; however this patient did not suffer from this difficulty. Referral was made to a dietician during pregnancy to assess the appropriate weight gain, BMI, and nutrition, given her short stature. There is a lack of literature on this topic; however it is postulated that her increasing intraabdominal pressure may have contributed to her constipated bowel movements and pelvic discomfort. 3.2. Fetal Complications Genetic testing was performed and appropriate genetic counseling is important in patients with cartilage-hair hypoplasia, which is an autosomal recessive condition [8]. Many studies have shown the association between maternal short stature with increased risk of premature labor [13] and preterm births [16]. The risk of preterm births appears to be secondary to both spontaneous labor [16] and respiratory distress [5]. Fetal growth in women with dwarfism can encroach on the diaphragm in later stages of pregnancy [1], causing dyspnea and necessitating an earlier date of delivery, often with the use of corticosteroids to optimize fetal lung development.

ppears to be secondary to both spontaneous labor [16] and respiratory distress [5]. Fetal growth in women with dwarfism can encroach on the diaphragm in later stages of pregnancy [1], causing dyspnea and necessitating an earlier date of delivery, often with the use of corticosteroids to optimize fetal lung development. In women with cartilage-hair hypoplasia, the anteroposterior diameter of the pelvic inlet can be shorter, pushing the uterus up so that it becomes an intra-abdominal organ earlier in pregnancy [9]. As a result of this limited ability for uterine expansion in patients with relatively shortened trunks [9], there is potential for intrauterine growth restriction. The birthweight of infants born to women with short stature overall has been found to be about average; however infants of women with cartilage-hair hypoplasia appear to have slightly lower birthweights [9].

ansion in patients with relatively shortened trunks [9], there is potential for intrauterine growth restriction. The birthweight of infants born to women with short stature overall has been found to be about average; however infants of women with cartilage-hair hypoplasia appear to have slightly lower birthweights [9]. 3.3. Postnatal Complications Our primary postnatal concern was the ability to breastfeed given her shorter upper limbs; however, she was able to express immediately after delivery. Data is lacking on breastfeeding in women with dwarfism. Early referral to the breastfeeding clinic was made as a result of the patient's goal to breastfeed for at least 2 years. Here, the benefits of early skin-to-skin and hand expressing were discussed. Although concerns had been raised about finding an appropriate position for breastfeeding according to the limits of her arms' length, this patient breastfed successfully for 6 weeks, stopping not because of her ability to breastfeed but on recommendation from her pediatrician due to the baby being diagnosed with cow's milk protein allergy, a condition whereby cow's milk protein from the mother's diet passes into the breast milk and causes an allergic and gastrointestinal reaction in the neonate [17].

opping not because of her ability to breastfeed but on recommendation from her pediatrician due to the baby being diagnosed with cow's milk protein allergy, a condition whereby cow's milk protein from the mother's diet passes into the breast milk and causes an allergic and gastrointestinal reaction in the neonate [17]. 4. Conclusion Overall, this patient with cartilage-hair hypoplasia had reasonable outcomes. She avoided the major complication of pulmonary dysfunction and had an emergency cesarean delivery in active preterm labor after spontaneous ruptured membranes at 34 weeks. Primary concerns during pregnancy related to respiratory function, preterm birth risk, and appropriate weight gain. She successfully breastfed her infant with the support of the breastfeeding clinic for the first 6 weeks of life, which is especially important in the context of preterm birth. Additional Points

4. Conclusion Overall, this patient with cartilage-hair hypoplasia had reasonable outcomes. She avoided the major complication of pulmonary dysfunction and had an emergency cesarean delivery in active preterm labor after spontaneous ruptured membranes at 34 weeks. Primary concerns during pregnancy related to respiratory function, preterm birth risk, and appropriate weight gain. She successfully breastfed her infant with the support of the breastfeeding clinic for the first 6 weeks of life, which is especially important in the context of preterm birth. Additional Points Teaching Points. (1) The pregnancy and delivery of this patient with cartilage-hair hypoplasia were effectively managed using a multidisciplinary approach. (2) Since patients with dwarfism are at increased risk for preterm birth, which may be secondary to maternal respiratory distress, pulmonary function was monitored during pregnancy. This patient did not have any respiratory complications and spontaneously labored resulting in cesarean delivery at 34 weeks' gestation, possibly secondary to short stature. Monitoring for preterm births and respiratory function is important in this population. (3) Despite having breast surgery and short upper limbs, she was able to breastfeed with the help of a team of lactation consultants. Data on breastfeeding in women with dwarfism is lacking; however, it can be done with the appropriate support. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper.

1. Introduction Peripartum cardiomyopathy (PPCM) is a disease affecting young otherwise healthy women near the end of pregnancy or in the early postpartum months [1]. Although incidence is low, patients with PPCM can experience rapid deterioration leading to heart failure, arrhythmias, and even death [1–3]. Because the presenting symptoms are typically nonspecific, clinicians must have a high index of suspicion to ensure a timely diagnosis and proper management. Here we report the first described case of PPCM presenting as symptomatic bradycardia.

deterioration leading to heart failure, arrhythmias, and even death [1–3]. Because the presenting symptoms are typically nonspecific, clinicians must have a high index of suspicion to ensure a timely diagnosis and proper management. Here we report the first described case of PPCM presenting as symptomatic bradycardia. 2. Case Report A 28-year-old gravida 1 para 1 presented to her local emergency department (ED) on postpartum day 5 for chest heaviness and a “slow heartbeat.” The patient had no significant past medical history, and there was no known family history of cardiac disease or genetic syndromes. There were no complications during pregnancy. The patient delivered a healthy female infant via vacuum-assisted vaginal delivery at 39 2/7 weeks and was discharged home on postpartum day 2. There was no record of intrapartum or postpartum bradycardia during that hospital admission. Initial assessment in the ED revealed a heart rate of 30–40 beats per minute (bpm) and blood pressure (BP) 158/77 mmHg. Atropine 0.5 mg IV was given, causing the patient's heart rate to increase to 80 bpm and systolic blood pressure to rise to 170–180 mmHg. Due to concern for postpartum preeclampsia, labetalol 20 mg IV was administered and a magnesium sulfate infusion was initiated. Computed tomography (CT) of the head showed no acute intracranial event. CT angiography of the chest was negative for pulmonary embolism. Due to concerns regarding the patient's cardiac status, the patient was transferred to our medical center.

l 20 mg IV was administered and a magnesium sulfate infusion was initiated. Computed tomography (CT) of the head showed no acute intracranial event. CT angiography of the chest was negative for pulmonary embolism. Due to concerns regarding the patient's cardiac status, the patient was transferred to our medical center. Upon arrival to our center, the patient was alert and oriented. Oxygen saturation was normal. Mean arterial pressure remained below 50 mmHg and heart rate ranged between 40 and 60 bpm. A dopamine infusion was initiated and the patient's blood pressure improved. She complained of a worsening headache but no lightheadedness, shortness of breath, or chest pain. Physical exam, including cardiac exam, was unremarkable. Routine laboratory tests were normal. Preeclampsia work-up was negative. Troponin T was 0.01 ng/mL (normal < 0.01 ng/mL) and NT-proBNP was 324 pg/mL (normal < 124 pg/mL). Electrocardiogram showed sinus bradycardia but was otherwise unremarkable. Transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction (LVEF) of 35%, numerous wall motion abnormalities and an estimated right ventricular systolic pressure (RVSP) of 46 mmHg. These findings suggested possible ischemia or infarction due to multivessel spontaneous coronary artery dissection (SCAD) or PPCM. Repeat troponin T was elevated at 0.03 ng/mL. Aspirin 325 mg was administered. Coronary angiogram showed a 20% lesion in the mid left anterior descending artery but no SCAD. Optical coherence tomography was also negative for SCAD. Right heart catheterization confirmed the RVSP of 48 mmHg.

ery dissection (SCAD) or PPCM. Repeat troponin T was elevated at 0.03 ng/mL. Aspirin 325 mg was administered. Coronary angiogram showed a 20% lesion in the mid left anterior descending artery but no SCAD. Optical coherence tomography was also negative for SCAD. Right heart catheterization confirmed the RVSP of 48 mmHg. Dopamine infusion was successfully weaned the following day. The patient's only complaint was dyspnea on exertion. Enalapril was initiated. Cardiac MRI performed on hospital day 3 confirmed left ventricular systolic dysfunction with LVEF of 50% and mild basal hypokinesis but no myocardial delayed enhancement to suggest edema, fibrosis or infarction. The patient was discharged home on hospital day four. Given the constellation of symptoms and diagnostic test results, the final diagnosis was PPCM.

confirmed left ventricular systolic dysfunction with LVEF of 50% and mild basal hypokinesis but no myocardial delayed enhancement to suggest edema, fibrosis or infarction. The patient was discharged home on hospital day four. Given the constellation of symptoms and diagnostic test results, the final diagnosis was PPCM. One month after discharge, TTE showed completely normal cardiac structure and function with an LVEF of 63%. The patient reported persistent intermittent bradycardia to 40 bpm mostly during periods of anxiety and in the evenings, without associated dyspnea or chest pain. On 24-hour Holter monitor, her heart rhythm was sinus with occasional sinus arrhythmia and heart rate ranging between 41 and 130 bpm (average, 61 bpm). During a treadmill exercise stress test, the patient achieved 13.0 METS and 113% of predicted functional capacity. ECG showed no signs of ischemia. Heart rate was 89 bpm at baseline, increasing to 173 bpm at peak exercise. Blood pressure was 102/78 mmHg at baseline, increasing to 160/72 mmHg at peak exercise. Enalapril was continued to complete a minimum of 6 months of treatment.

13.0 METS and 113% of predicted functional capacity. ECG showed no signs of ischemia. Heart rate was 89 bpm at baseline, increasing to 173 bpm at peak exercise. Blood pressure was 102/78 mmHg at baseline, increasing to 160/72 mmHg at peak exercise. Enalapril was continued to complete a minimum of 6 months of treatment. 3. Discussion Peripartum cardiomyopathy is defined as cardiac failure occurring in the last month of pregnancy or within 5 months of delivery in the absence of an identifiable cause of heart failure. Additional diagnostic criteria include the absence of heart failure prior to the last month of pregnancy and the evidence of left ventricular systolic dysfunction (depressed shortening fraction or ejection fraction) [1]. In the United States, the incidence of PPCM is 1 in 2,500 to 4,000 live births [3]. Symptoms of PPCM are nonspecific and patients most commonly complain of dyspnea and fatigue. Other presenting symptoms include cough, orthopnea, and pedal edema [1–3]. Because some of these symptoms resemble those of normal pregnancy, diagnosis of PPCM may be delayed. Physical signs are also nonspecific but most commonly include tachycardia, elevated jugular venous pressure, displaced apical impulse, a third heart sound, and a mitral regurgitation murmur [1].

, and pedal edema [1–3]. Because some of these symptoms resemble those of normal pregnancy, diagnosis of PPCM may be delayed. Physical signs are also nonspecific but most commonly include tachycardia, elevated jugular venous pressure, displaced apical impulse, a third heart sound, and a mitral regurgitation murmur [1]. To our knowledge, this is the first reported case of PPCM presenting as symptomatic bradycardia. Typically, the decreased cardiac output observed in PPCM causes an activation of the sympathetic system and a decrease in parasympathetic tone; as a result, tachycardia usually occurs. Although no obvious cause for our patient's bradycardia was identified, our hypothesis is that the bradycardia may have been caused by very high parasympathetic tone. According to some authors, postpartum bradycardia in the absence of PPCM could possibly be genetically related. In a study by Nof et al., 20% of patients presenting with postpartum bradycardia had a mutation of the hyperpolarization-activated nucleotide-gated channel-HCN4, important in the depolarization of the sinus node cells [4]. Other potential causes of bradycardia such as acute myocardial infarction, sick sinus syndrome, infectious causes, exaggerated vagal activity and medications were excluded in this case. Interestingly, the patient continued to experience symptomatic bradycardia more than 2 months following initial presentation, especially at times of increased anxiety.

rdia such as acute myocardial infarction, sick sinus syndrome, infectious causes, exaggerated vagal activity and medications were excluded in this case. Interestingly, the patient continued to experience symptomatic bradycardia more than 2 months following initial presentation, especially at times of increased anxiety. Reporting this case is of great significance to obstetrician-gynecologists and cardiologists in order to improve our knowledge of the possible presentations of PPCM. Although the incidence of PPCM is low, patients can experience rapid deterioration leading to heart failure, arrhythmias, and even death. The reported mortality rates of PPCM vary significantly between studies, but the range typically varies between 9% and 60% [5–11]. In a population-based study, Mielniczuk et al. reported a much lower mortality rate of 2.05%, attributing this improved prognosis to earlier diagnosis and contemporary management of heart failure [7]. This highlights the importance of a timely and systematic approach, including ECG, TTE, cardiac biomarkers, and possible coronary angiography in cases of bradycardia and decreased left ventricular systolic function in the postpartum state in order to decrease maternal morbidity and mortality. Disclosure This case report was presented as an oral communication at the 4th International Congress on Cardiac Problems in Pregnancy (CPP2016), from February 27 to March 1, 2016, in Las Vegas, NV. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper.

1. Introduction Cervical pregnancy (CP) is a rare type of ectopic pregnancy characterized by implantation of a fertilized ovum in the endocervical canal. CP accounts for less than 1% of all ectopic pregnancies [1–3]. Risk factors include endometrial damage after curettage or chronic endometritis, leiomyoma, intrauterine devices, and in vitro fertilization [2, 4, 5]. This type of ectopic pregnancy is highly dangerous because massive hemorrhage can ensue secondary to bleeding from the cervical vessels. Early detection has been improved by ultrasonography. However, even with advanced diagnostic modalities and treatment options, CP remains a life-threatening condition. During the last decade, in an effort to avoid hysterectomy and maintain fertility, a more conservative therapeutic approach has been advocated. This includes chemotherapy with methotrexate, intra-amniotic feticide, dilation and curettage, uterine tamponade, and uterine artery embolization [5, 6]. Usually more than one modality of treatment is necessary [2, 7]. We describe a novel method of cervical tamponade using a silicone double balloon cervical ripening catheter (Cook® Cervical Ripening Balloon, Cook Medical, Bloomington, Indiana) in a patient that presented with acute hemorrhage after conservative management with systemic chemotherapy.

of treatment is necessary [2, 7]. We describe a novel method of cervical tamponade using a silicone double balloon cervical ripening catheter (Cook® Cervical Ripening Balloon, Cook Medical, Bloomington, Indiana) in a patient that presented with acute hemorrhage after conservative management with systemic chemotherapy. 2. Case A 31-year-old gravida 2 para 0 at 7 weeks and 3 days presented to the emergency room with complaints of vaginal bleeding and abdominal cramping that began earlier that morning. On examination, her abdomen was nontender without rebound or guarding. No active bleeding was noted vaginally. Her serum beta human chorionic gonadotrophin (β-hCG) was 18,645 mIU/L. Transvaginal ultrasound revealed a 22 mm gestational sac implanted within the cervical canal with a fetal pole but no fetal cardiac activity. Decision was made to admit patient for systemic multidose methotrexate regimen for conservative management of a cervical pregnancy. Uterine artery embolization was considered but concern arose about long term effects on the patient's future fertility.

the cervical canal with a fetal pole but no fetal cardiac activity. Decision was made to admit patient for systemic multidose methotrexate regimen for conservative management of a cervical pregnancy. Uterine artery embolization was considered but concern arose about long term effects on the patient's future fertility. Methotrexate 85 mg (1 mg/kg) was administered on days 1, 3, 5, and 7. Rescue leucovorin 8.5 mg (0.1 mg/kg) was administered on days 2, 4, 6, and 8. Her β-hCG levels on days 1, 3, 5, and 7 were 18,645 IU/mL, 15,527 IU/mL, 15,099 IU/mL, 12,718 IU/mL, and 10,222 IU/mL, respectively. On hospital day 7, repeat transvaginal ultrasonography showed a collapsing gestational sac with no visible yolk sac or fetal pole. The patient experienced no further vaginal bleeding during admission. The patient was discharged home with plan of having weekly β-hCG measured until levels declined to zero.

respectively. On hospital day 7, repeat transvaginal ultrasonography showed a collapsing gestational sac with no visible yolk sac or fetal pole. The patient experienced no further vaginal bleeding during admission. The patient was discharged home with plan of having weekly β-hCG measured until levels declined to zero. The patient returned to the emergency room two days after discharge with heavy vaginal bleeding. On examination, approximately 300 mL of blood was cleared from the vaginal vault. The vaginal vault was packed with gauze in an attempt to tamponade bleeding so that patient could be safely transported to the operating room for an examination under anesthesia. At the time of the patient's presentation to emergency room, interventional radiology was not readily available to perform uterine artery embolization. After removal of vaginal packing, approximately 500 mL of additional vaginal bleeding was noted. Dilation and suction curettage was performed in order to excise the remaining trophoblast tissue that was readily visualized at the cervical os. After curettage, the patient continued to actively hemorrhage. A silicone double balloon cervical ripening catheter (Cook Cervical Ripening Balloon) was introduced into the cervical canal (Figures 1 and 2). 80 mL of normal saline was inserted in the uterine valve and 60 mL of normal saline inserted in was introduced into the vaginal valve. Upon insufflation, the cervix was compressed between the two balloons of the catheter and hemostasis was rapidly achieved (Figures 3 and 4). Positioning of the Cook Balloon was ascertained by visual inspection and by gentle traction. Gentle traction insured that the uterine balloon of the Cook catheter was securely positioned above the internal os after insufflation. Once the uterine balloon was determined to be in the appropriate place, the vaginal valve was insufflated under direct visualization. Due to the acuity and urgency to stabilize the patient and to minimize bleeding, imaging to document placement could not be performed during the procedure.

nternal os after insufflation. Once the uterine balloon was determined to be in the appropriate place, the vaginal valve was insufflated under direct visualization. Due to the acuity and urgency to stabilize the patient and to minimize bleeding, imaging to document placement could not be performed during the procedure. The patient was observed overnight and reexamined the following morning. No further bleeding was noted and the patient remained hemodynamically stable. The compression balloon was removed without difficulty after 12 hours. The patient received two doses of tranexamic acid (1000 mg) approximately 18 hours apart after removal of Cook Balloon. The patient was discharged the following day in stable condition. β-hCG repeated 24 days after discharge from the hospital was 2 IU/mL. 3. Discussion The early diagnosis of cervical ectopic pregnancy in our patient was made by confirming the following ultrasound criteria: (1) an empty uterine cavity above the level of the internal cervical os (Figure 5), (2) barrel-shaped cervix (Figure 6), (3) gestational sac located below the level of the uterine arteries, and (4) vascularization around the gestational sac demonstrated by Doppler color flow ultrasonography (Figure 7) [7, 8]. Cervical pregnancy can be distinguished from an imminent aborting pregnancy within the cervix by the absence of the “sliding sign” (elicited when mechanical pressure from the ultrasound transducer causes the gestational sac to slide against the endocervical canal in case of imminent abortion but not in an implanted CP) [7].

cal pregnancy can be distinguished from an imminent aborting pregnancy within the cervix by the absence of the “sliding sign” (elicited when mechanical pressure from the ultrasound transducer causes the gestational sac to slide against the endocervical canal in case of imminent abortion but not in an implanted CP) [7]. Although there are no definitive guidelines for the management of cervical pregnancies, a variety of modalities have been proposed [4]. Approaches include curettage combined with Foley balloon tamponade, methotrexate with/without potassium chloride injection, uterine artery embolization, and ligation of cervical branches of uterine arteries. The most commonly reported medical treatments are methotrexate, by either local injection (intra-amniotic or intrafetal) or systemic administration [6, 9, 10]. The outcome of conservative management with methotrexate has been reported to be relatively safe and effective, allowing for uterine preservation in more than 90% of cases treated before 12 weeks of gestation [6, 9, 10].

te, by either local injection (intra-amniotic or intrafetal) or systemic administration [6, 9, 10]. The outcome of conservative management with methotrexate has been reported to be relatively safe and effective, allowing for uterine preservation in more than 90% of cases treated before 12 weeks of gestation [6, 9, 10]. In the case presented, the patient desired to preserve fertility. Inpatient conservative therapy with multidose methotrexate was elected. Although her β-hCG levels declined appropriately over the course of her treatment, she re-presented with profuse bleeding per vagina. In the event of hemorrhage following failed medical therapy or postsuction curettage, mechanical compression or tamponade of the cervix can rapidly restore hemostasis [7, 11]. There are several types of balloon catheters that have been described for cervical compression in the literature [12]. These include the Bakri™ Balloon (Cook Medical, Bloomington, Indiana), Rusch hydrostatic catheter (Teleflex Medical Sdn Bhd, Kamuntung, Malaysia), condom catheters, and Foley catheters [12]. Fylstra describes treatment of cervical pregnancy being achieved successfully in 13 patients by curettage immediately followed by placement of 30 mL balloon Foley catheter for tamponade; tamponade was left in place for 24 hours [13]. The use of Foley balloon has also been cited to prophylactically control bleeding in cervical pregnancies [13, 14]. Similarly, Timor-Tritsch successfully treated cervical and cesarean scar ectopic pregnancies with double balloon catheter [15]. The double balloon catheter provided compression to terminate pregnancy and prevent bleeding. Our case report defers from both Fylstra and Timor-Tritsch in that use of double balloon catheter was to control hemorrhage with tamponade, not to prophylactically prevent hemorrhage nor to treat a live ectopic pregnancy.

15]. The double balloon catheter provided compression to terminate pregnancy and prevent bleeding. Our case report defers from both Fylstra and Timor-Tritsch in that use of double balloon catheter was to control hemorrhage with tamponade, not to prophylactically prevent hemorrhage nor to treat a live ectopic pregnancy. As an alternative to the Foley catheter, in our patient, tamponade and further hemostasis were created with the Cook Balloon by the insufflation of the internal and external balloon, respectively. Although the Cook Balloon is normally used for cervical ripening for induction of labor, its use has been reported for the management of postabortal hemorrhage [12]. Unlike other compression devices such as the Foley balloon, the Cook catheter consists of a double balloon system. This allows for one balloon to be positioned below the internal-external cervical os and the second balloon to be situated above in the internal cervical os (Figure 1). Tamponade with a double balloon cervical ripening catheter has not been previously described to control hemorrhage in CP. The double balloon additionally adjusts to the length of the cervix prior to insufflation allowing for compression from internal to external os (Figure 2). A double balloon catheter, as used in our case, may be considered to control hemorrhage for CP as it was able to quickly create a tamponade by compressing the cervix from the internal to external os.

usts to the length of the cervix prior to insufflation allowing for compression from internal to external os (Figure 2). A double balloon catheter, as used in our case, may be considered to control hemorrhage for CP as it was able to quickly create a tamponade by compressing the cervix from the internal to external os. Tranexamic acid (TXA) in the case presented was used prophylactically to prevent any further event of hemorrhage. Tranexamic acid is a potent antifibrinolytic agent that exerts its effect by competitively blocking lysine binding sites on plasminogen molecules [16]. This prevents the binding of fibrin to plasminogen and therefore impairs fibrinolysis [16]. The use of TXA in cervical pregnancy has limited discussion in literature. However, the use of TXA in postpartum hemorrhage and trauma is a field of evolving study [17]. Clinically, TXA has been shown to decrease the need of blood transfusions, reoperation for bleeding, and mean of transfused units [17]. TXA's use for menorrhagia has shown to reduce mean blood loss, which may suggest a possible link in reducing uterine blood flow [18].

hage and trauma is a field of evolving study [17]. Clinically, TXA has been shown to decrease the need of blood transfusions, reoperation for bleeding, and mean of transfused units [17]. TXA's use for menorrhagia has shown to reduce mean blood loss, which may suggest a possible link in reducing uterine blood flow [18]. 4. Conclusion The case presented delineates the use of conservative management and complications of cervical pregnancy. The use of methotrexate is well documented in literature for the treatment of cervical pregnancy. However, the use of a double balloon cervical ripening catheter (Cook Balloon) to achieve cervical tamponade during hemorrhage has limited citing in literature. In cases where future fertility is of greatest concern, the Cook Balloon may serve as an option for decreasing blood loss. Furthermore, the use of TXA to prevent future hemorrhage and decrease the need for reoperation is a possible consideration when patient's desire to maintain fertility is a major concern. The prophylactic use of TXA is not well established in cervical pregnancies and future studies are needed to demonstrate its effectiveness. Competing Interests The authors have no competing interests to declare. Figure 1 Cook Balloon Inflated with 80 mL saline in the uterine balloon and 60 mL saline in vaginal balloon. Figure 2 Distance between the two balloons can be stretched approximately 5 cm. Figure 3 Placement of balloons in uterus and vagina (picture from package insert).

Competing Interests The authors have no competing interests to declare. Figure 1 Cook Balloon Inflated with 80 mL saline in the uterine balloon and 60 mL saline in vaginal balloon. Figure 2 Distance between the two balloons can be stretched approximately 5 cm. Figure 3 Placement of balloons in uterus and vagina (picture from package insert). Figure 4 Illustration of “sandwich effect” of the two inflated balloons. Note that space between the balloons is stretchable and can accommodate the entire cervix. Figure 5 Empty uterus with gestational sac (GS) in cervix. Figure 6 Gestational sac with yolk sac and fetal pole within the cervix. Figure 7 Vascularization around the gestational sac demonstrated by Doppler color flow.

1. Introduction Takayasu's arteritis (TA), also known as pulseless disease/aortoarteritis/“young female arteritis,” is a rare chronic inflammatory progressive large vessel vasculitis (LVV) of unknown etiology afflicting women of childbearing age [1–4]. It was first described by the Japanese ophthalmologists Mikito Takayasu and Onishi [5]. Its incidence is reported to be 13 cases per million population [1]. It is predominantly seen in the women of Asian origin [6]. It leads to narrowing, occlusion, and aneurysms of systemic and pulmonary arteries in the body, affecting primarily the aorta and its branches [3, 7].

mologists Mikito Takayasu and Onishi [5]. Its incidence is reported to be 13 cases per million population [1]. It is predominantly seen in the women of Asian origin [6]. It leads to narrowing, occlusion, and aneurysms of systemic and pulmonary arteries in the body, affecting primarily the aorta and its branches [3, 7]. Pregnancy as such has no effect on the evolution of the disease;however, its peak incidence is in second and third trimesters. Thus, such patients warrant special attention during the peripartum period owing to the likelihood of development of complications such as hypertension, multiple organ dysfunction, and stenosis hindering regional blood flow leading to restricted intrauterine fetal growth and low birth weight in babies [8–10]. Delay in diagnosis is quite common, so patients often conceive without prior knowledge of having TA, or having initiated specific treatment against it [2]. Ideal management for pregnant patients with this disease still poses a stringent challenge, especially in the light of movement towards multicentric LVV research across the world, coupled with the recent availability of levitating pool of targeted drugs. An interdisciplinary collaboration of obstetricians, cardiologists, rheumatologists, and neurologists is often necessitated for an optimal maternal and fetal prognosis. Taking into consideration the small-scale researches in literature so far on active TA in pregnancy, especially in LMIC countries, here a case is described and literature reviewed to enlighten the obstetricians on fetomaternal outcome and management of this infrequent, but not uncommon clinical entity encountered nowadays.

ng into consideration the small-scale researches in literature so far on active TA in pregnancy, especially in LMIC countries, here a case is described and literature reviewed to enlighten the obstetricians on fetomaternal outcome and management of this infrequent, but not uncommon clinical entity encountered nowadays. 2. Case Report A 25-year-old primigravida was admitted in the hospital as pregnancy with chronic hypertension (not on any antihypertensives), at 36 completed weeks in active labor. She was a known case of active TA on treatment (taking prednisolone 2 mg, aspirin 150 mg, and clopidogrel 75 mg OD.) She was booked and supervised throughout her pregnancy at the same hospital, in liaison with cardiologists. Her past and personal histories were thoroughly reviewed in outpatient department; she had been a bidi smoker since teenage, one-two per day. She had surgical correction of complete stenosis of right common carotid artery (CCA) and right vertebral and subclavian artery by percutaneous stenting of right brachiocephalic (size 7 × 39 mm) and right CCA (size 9 × 30 mm) in some peripheral hospital. She had no history of other comorbidities like IBD and sinusitis. She had an uneventful antenatal and intrapartum period and delivered a healthy neonate weighing 2.8 kg. During her postpartum period, all necessary investigations were done and consultations were taken, and she was discharged on drugs after one week in stable condition, with the advice for regular follow-up and abstinence from smoking. During her subsequent visits, her MRA scan showed markedly attenuated flow in left CCA, for which she was conservatively managed by cardiologist.

were done and consultations were taken, and she was discharged on drugs after one week in stable condition, with the advice for regular follow-up and abstinence from smoking. During her subsequent visits, her MRA scan showed markedly attenuated flow in left CCA, for which she was conservatively managed by cardiologist. One year later, she had an accidental second conception but could not get herself booked for antenatal care anywhere till the third trimester, due to social and financial issues. At her first visit at 34 weeks in the institute, she was admitted for safe confinement for severe fetal growth restriction and neurological sequelae of aortoarteritis in the form of tonic-clonic convulsions (three episodes in last 24 hours before admission). She gave history of myalgias, arthralgias, and fever off and on throughout her pregnancy, despite continued glucorticoid treatment. On admission, her BP was 200/110 in ankle and pulse was 100/min. There was no albuminuria. Per-abdomen examination showed a fundal height corresponding to 26 weeks with faintly audible fetal heart sound. She was put on strict fetomaternal surveillance. After thorough history taking, cardiology, and CTVS references were taken, her anticoagulants were stopped in v/o anticipated termination of pregnancy, and she was started on labetalol 300 mg in divided doses and continuous BP monitoring (noninvasive). A neurology consultation was done, and levetiracetam 1000 mg was started to take care of seizures. All routine antenatal and specific blood investigations (INR, PT, and APTT) were normal. Though CRP was also normal, it was on a higher side of normal range (3 mg/dL). ESR was found to be raised being equal to 33 mm/1st hour. Echocardiography was performed which revealed mild concentric LVH, moderate AR (38 mm diameter), mildly thickened aortic valve leaflets, and ejection fraction 63% (Figure 2). Carotid and vertebral Doppler reported mild stenosis of poststent segment, with 65–70% stenosis of left CCA and ICA, which was suggestive of progressive active TA in the patient (Figure 1). A renal Doppler was also done that was normal. Her obstetric ultrasound with Doppler velocimetry showed a single live growth restricted fetus with oligohydramnios (AFI-5CMS) and severely deranged diastolic flow in umbilical artery (Figure 3).

ICA, which was suggestive of progressive active TA in the patient (Figure 1). A renal Doppler was also done that was normal. Her obstetric ultrasound with Doppler velocimetry showed a single live growth restricted fetus with oligohydramnios (AFI-5CMS) and severely deranged diastolic flow in umbilical artery (Figure 3). The couple were counselled adequately about fetomaternal prognosis and after their informed consent, she was given two doses of betamethasone for lung maturity, following which induction of labor was done with cervigel at 35 weeks two days. Her labor progressed well and she delivered live boy baby weighing 1.2 kgs, who was transferred to nursery, being very low birth weight baby, and discharged after one month. Patient's intrapartum and postpartum period were uneventful and she was discharged on higher dose of prednisolone, amlodac 7.5 mg, and levetiracetam. At the time of this writing, she is convalescing well, with both mother and baby doing fine, and following up periodically with cardiologists, rheumatologists, and gynecologists.

s intrapartum and postpartum period were uneventful and she was discharged on higher dose of prednisolone, amlodac 7.5 mg, and levetiracetam. At the time of this writing, she is convalescing well, with both mother and baby doing fine, and following up periodically with cardiologists, rheumatologists, and gynecologists. 3. Discussion Takayasu's arteritis is a LVV with aortic inflammation leading to proximal occlusion and/or aneurysms of carotid, subclavian, pulmonary, iliac, and renal arteries [3, 18]. Mean age is typically reported between second and third decade of life [19–21]. Its etiology remains primarily idiopathic. Autoimmunity, sex hormones, and genetic (predisposition of the human leukocyte antigen, HLA BW52) factors have often been hypothesized as plausible factors causing it [22]. These factors were conspicuously absent in the case described.

second and third decade of life [19–21]. Its etiology remains primarily idiopathic. Autoimmunity, sex hormones, and genetic (predisposition of the human leukocyte antigen, HLA BW52) factors have often been hypothesized as plausible factors causing it [22]. These factors were conspicuously absent in the case described. Various types of TA have been acknowledged in the past: type I (disease embroiling aortic arch and its branches), type II (lesions constrained to descending thoracic aorta and abdominal aorta), type III (patients with characteristics of types I and II), type IV (involvement of pulmonary artery), and type V (combined features of types IIb and IV) [10]. The above described patient was labeled as type II TA. The disease can also be classified into stages as per the presence of major complications such as hypertension, retinopathy, aneurysms, and aortic insufficiency [23]: stage I (no complications observed), stage IIa (patients having only one of these complications), stage IIb (patients with only one of these complications, but the severe form), and stage III (more than one complication is present). The patient presented here was in stage II, but during pregnancy her hypertension was compensated and her aneurysm had been corrected.

(patients having only one of these complications), stage IIb (patients with only one of these complications, but the severe form), and stage III (more than one complication is present). The patient presented here was in stage II, but during pregnancy her hypertension was compensated and her aneurysm had been corrected. Pregnancy does not interfere with disease progression [1–3]; but TA has several adverse implications on pregnancy like abortions, preeclampsia, IUGR, IUD, and abruption [21, 24, 25], as seen in our case in the form of late-onset IUGR. Etiology of IUGR may be impaired placental blood flow. Incidence of IUGR is high when bilateral renal involvement is present [3]. Gatto et al. reported fetal growth restriction in 51.7% of fetuses in a study in India [21]. More than 60% of patients have some kind of complications and the four most important ones are Takayasu's retinopathy, secondary hypertension, aortic regurgitation, and aneurysm formation. Hypertension is fairly common due to reduction in elasticity and narrowing of the arteries, besides abnormalities in functioning of aortic and carotid baroreceptors function [26]; it should be prudently contained during pregnancy, as severe renovascular hypertension, cardiac involvement, or pulmonary hypertension is associated with poor fetomaternal prognosis like abortion, preterm labor, and low birth weight babies [2]. Blood pressure in such patients should be also measured in the lower extremity to pick up blood pressure discrepancies; like in our case BP recordings in lower extremity were higher than upper extremity. Besides, pulselessness of unilateral or bilateral radial arteries and vascular bruit should be seen in all cases of hypertension. Involvement of abdominal aorta is associated with adverse pregnancy outcomes, which was fortunately absent in the present case. Arterial ultrasound Doppler, quantifying the flow in the uterine arteries, is beneficial in evaluation of fetal well-being and growth in women with TA.

ld be seen in all cases of hypertension. Involvement of abdominal aorta is associated with adverse pregnancy outcomes, which was fortunately absent in the present case. Arterial ultrasound Doppler, quantifying the flow in the uterine arteries, is beneficial in evaluation of fetal well-being and growth in women with TA. Diagnosis is usually based on clinical manifestations, inflammatory markers (acute phase reactants), and arteriography demonstrating aortic stenosis and of its branches. Common features of active TA are fatigue, myalgia, arthralgia, and low-grade fever in initial stages and intermittent claudication, visual defects, and fainting attacks in later stages. Many may be diagnosed after clinical examination, when one or more peripheral pulses are not palpable or blood pressures vary in two limbs. However, computed tomography or magnetic resonance angiography can detect TA even before the development of severe vascular compromise as in our case [27]. Recently, 18 FDG-PET scan has been added as an adjunct imaging modality in the armamentarium of rheumatologists and cardiologists to diagnose LVV, with a pooled sensitivity and specificity of 70.1% and 77.2%, respectively [28]. But this is currently not available in our hospital. However, the gold standard for diagnosis still remains as vessel biopsy [27] which could not be performed in our case. Presence of constitutional symptoms (postsurgical treatment and glucocorticoids), progressive involvement of other branches of aortic arch, raised ESR, and onset of seizures in the patient clinched the diagnosis of active TA in her. Contribution from other specialties is fundamental for detection and treatment of disease complications. In the case presented here the disease was not compensated with drug therapy and lesions in the aortic arch and aortic valve had been partially corrected; but the patient did not have a recent arteriography or angio-MRI of large vessels due to loss to follow-up.

tal for detection and treatment of disease complications. In the case presented here the disease was not compensated with drug therapy and lesions in the aortic arch and aortic valve had been partially corrected; but the patient did not have a recent arteriography or angio-MRI of large vessels due to loss to follow-up. Involvement of large vessels in our case excludes granulomatosis with polyangiitis and Behcet's disease. Another cause of LVV is giant cell arteritis, which was one of the primary differential diagnoses in our case. But younger age, lower values of raised ESR, absence of any new onset headache, visual symptoms, and jaw claudication symptoms favored the diagnosis of TA [29]. Fibromuscular dysplasia is ruled out by the presence of raised ESR in our patient [29]. IgG4 related vasculitis was eliminated by the absence of lymphadenopathy, normal upper abdomen scan, and unresponsiveness of the patient to prednisolone. Management of TA entails an interdisciplinary approach with involvement of obstetricans, anesthesiologists, cardiologists, rheumatologists, and neonatologist in a tertiary care center. The aims are control of inflammation, prevention and treatment of complications like hypertension and revascularization by percutaneous angioplasty, use of endoprosthesis, or surgical correction for occlusive and stenotic lesions.

esiologists, cardiologists, rheumatologists, and neonatologist in a tertiary care center. The aims are control of inflammation, prevention and treatment of complications like hypertension and revascularization by percutaneous angioplasty, use of endoprosthesis, or surgical correction for occlusive and stenotic lesions. Preconception counselling is essential regarding dosage adjustment or cessation of cytotoxic drugs, folic acid supplementation in the periconceptional period, and optimal timing of pregnancy. Pregnancy should be ideally planned in remission phase. There should be an early booking with regular antenatal supervision. Along with routine antenatal visits, serial monitoring of blood pressure, renal function, cardiac status, and preeclamptic screening are vital in such patients. Fetal surveillance including daily fetal kick count, gravidogram, serial fetal biometry, biophysical profile, and fetal Doppler is also imperative as per requirements [30].

utine antenatal visits, serial monitoring of blood pressure, renal function, cardiac status, and preeclamptic screening are vital in such patients. Fetal surveillance including daily fetal kick count, gravidogram, serial fetal biometry, biophysical profile, and fetal Doppler is also imperative as per requirements [30]. Blood pressure monitoring can be challenging in patients with pulseless peripheral arteries. In most cases described in literature, and in the present case, it was possible to use the noninvasive technique [31]. If there is a large difference in blood pressure in upper and lower limbs, one must encourage recording it in both limbs. To evaluate limb perfusion a good alternative is to assess blood pressure in one limb and oximetry in the other; the same was done in the extant case. Antihypertensive drugs and antiplatelets can be started as per need, as was in the present case. TA may respond symptomatically to corticosteroid therapy (first line drugs) at a dose of 1-2 mg/kg/bodyweight for 4 weeks followed by slow tapering. However, chronic use of corticosteroids could lead to suppression of adrenal gland activity with inadequate release of endogenous corticosteroids in moments of stress, such as surgeries [32]. Also immune-suppressors including methotrexate and azathioprine are used.

g/kg/bodyweight for 4 weeks followed by slow tapering. However, chronic use of corticosteroids could lead to suppression of adrenal gland activity with inadequate release of endogenous corticosteroids in moments of stress, such as surgeries [32]. Also immune-suppressors including methotrexate and azathioprine are used. Utilization of immunomodulatory agents like mycophenolate mofetil, infliximab, tocilizumab, leflunomide, and abatacept has gained momentum in recent times for treatment of TA, especially in refractory cases [33, 34]; however their safety in pregnancy has not yet been established. Hence these are generally avoided in pregnancy or used after a meticulous assessment of the risk/benefit ratio for the patient [35, 36]. Vaginal delivery is the preferred mode, and epidural analgesia has been advocated for labor and delivery. In women with hypertension, delivery should be abbreviated by the use of outlet forceps. In women with stages IIb and III, LSCS is preferred to prevent cardiac decompensation due to increased blood volume and blood pressure observed during uterine contractions and increased cardiac output observed during labor. Our patient was hemodynamically stable and was also induced as she belonged to group IIa and she did not have additional supplementary investigation of the abdominal vessels.

nsation due to increased blood volume and blood pressure observed during uterine contractions and increased cardiac output observed during labor. Our patient was hemodynamically stable and was also induced as she belonged to group IIa and she did not have additional supplementary investigation of the abdominal vessels. Patients with metallic valvular prosthesis should be maintained anticoagulated during pregnancy. The choice of medication should take into account the probable due date and reversibility of the method. Heparin should be discontinued 4 to 6 hours before anesthesia, and it can be reversed with protamine if the gravida goes into labor or in case of bleeding. Patients on prophylactic doses of enoxaparin should receive their last dose 12 hours before anesthesia. In the case of therapeutic doses the drug should be discontinued 24 hours before anesthesia. Table 1 shows the clinical presentation, maternal complications, mode of delivery, and fetal/neonatal outcome of recently reported cases, in comparison with the reported case [11–17, 26]. The overall five-year survival rate after diagnosis was 83.1%. Death typically is a consequence of congestive heart failure or cerebrovascular events. The survival is better in patients without a progressive course and in those below 35 years of age. Early diagnosis with proper medical or surgical management is essential for a good prognosis. A high index of clinical suspicion in patients presenting with pulseless peripheral vessels could be kept in mind to optimize the management following a multidisciplinary approach.

ve course and in those below 35 years of age. Early diagnosis with proper medical or surgical management is essential for a good prognosis. A high index of clinical suspicion in patients presenting with pulseless peripheral vessels could be kept in mind to optimize the management following a multidisciplinary approach. 4. Conclusion Pregnancy with TA presents as an onerous medical condition to manage for an obstetrician. Acknowledgments The authors are grateful to their patient, who besides having experienced this rare condition allowed them to evaluate her in detail for a better comprehension of the clinical entity. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Carotid artery Doppler of the patient. Figure 2 Echocardiography of the patient. Figure 3 Obstetric ultrasound of the patient. Table 1 Study Parity Clinical presentation Maternal complications Mode of delivery Fetal outcome Leal et al. (2011) [11] G4P3l3 Precordial squeezing pain Controlled HTN Elective LSCS at 39 weeks 2.7 kgs live baby Rengaraj and Rani (2015) [12] PGR Dyspnea PROM GTCS Outlet forceps 2.4 kgs live baby Nalini and Santa (2015) [13] PGR Oliguria IUGR Uncontrolled hypertension Elective LSCS at 37 weeks 2.4 kgs live baby De Lucena et al. (2008) [14] G3P1L0 Dyspnea Palpitations Intermittent claudication Uncontrolled HTN Elective LSCS at 37 weeks 2.1 kgs Soma-Pillay et al. (2015) [15] G2P1L1 Claudication in LL Compensated HTN Elective LSCS 2.3 kgs

Nalini and Santa (2015) [13] PGR Oliguria IUGR Uncontrolled hypertension Elective LSCS at 37 weeks 2.4 kgs live baby De Lucena et al. (2008) [14] G3P1L0 Dyspnea Palpitations Intermittent claudication Uncontrolled HTN Elective LSCS at 37 weeks 2.1 kgs Soma-Pillay et al. (2015) [15] G2P1L1 Claudication in LL Compensated HTN Elective LSCS 2.3 kgs Satia et al. (2016) [16] G3A2 Exertional dyspnea Palpitations dizziness Dilated cardiomyopathy MTP at 6 weeks Khandelwal and Gandhi (2016) [17] G7P1A5 Blurring of vision Grade IV hypertensive retinopathy Elective LSCS at 37 weeks 2.5 kgs live baby Present report (2017) G2P1L1 Pain in right lower limb Controlled HTN Neurological Sequelae IUGR NVD 1.2 kgs live baby

1. Introduction Fibrinogen is a 340 Da glycoprotein synthesized in the liver, which is involved not only in coagulation but also in maintaining pregnancy. Inherited fibrinogen disorders are divided into two different types: quantitative defects, that is, afibrinogenemia or hypofibrinogenemia, and qualitative defects, that is, dysfibrinogenemia. The prevalence of afibrinogenemia is about 1 in 1 million [1]. Mutations related to these disorders have been detected all over the world. The patient with afibrinogenemia is usually identified at birth by the presence of bleeding from the umbilical cord. However, hypofibrinogenemia and dysfibrinogenemia are usually asymptomatic. Appropriate control of the fibrinogen level is necessary for successful prenatal and peripartum management. It is necessary to maintain the fibrinogen level higher than 100 mg/dL during pregnancy [2, 3]. After the onset of labor, the fibrinogen level must be maintained to higher than 150 mg/dL or 200 mg/dL in case of caesarean section [2, 3]. Here, we report two cases of hypofibrinogenemia with different course during pregnancy. 2. Case Report

1. Introduction Fibrinogen is a 340 Da glycoprotein synthesized in the liver, which is involved not only in coagulation but also in maintaining pregnancy. Inherited fibrinogen disorders are divided into two different types: quantitative defects, that is, afibrinogenemia or hypofibrinogenemia, and qualitative defects, that is, dysfibrinogenemia. The prevalence of afibrinogenemia is about 1 in 1 million [1]. Mutations related to these disorders have been detected all over the world. The patient with afibrinogenemia is usually identified at birth by the presence of bleeding from the umbilical cord. However, hypofibrinogenemia and dysfibrinogenemia are usually asymptomatic. Appropriate control of the fibrinogen level is necessary for successful prenatal and peripartum management. It is necessary to maintain the fibrinogen level higher than 100 mg/dL during pregnancy [2, 3]. After the onset of labor, the fibrinogen level must be maintained to higher than 150 mg/dL or 200 mg/dL in case of caesarean section [2, 3]. Here, we report two cases of hypofibrinogenemia with different course during pregnancy. 2. Case Report Case  1. A 26-year-old (gravida 1, para 1) woman presented with a positive pregnancy test result. She had been diagnosed with hypofibrinogenemia at the age of 23 during blood testing to be a bone-marrow transplantation donor. Her personal and family histories were negative for hemorrhagic or thrombotic episodes. At 25 years of age, the patient delivered a girl at 39 weeks of gestation. Blood tests were performed monthly to check the fibrinogen levels. Since her fibrinogen level increased spontaneously during pregnancy, she did not receive infusion therapy. Her prepregnancy fibrinogen level was 76 mg/dL. During the first trimester, it increased gradually to 119 mg/dL and was more than 300 mg/dL in the third trimester. She was admitted to our hospital with rupture of the membranes at 38 weeks and 2 days' gestation. Her coagulation tests showed a normal prothrombin time (PT) of 12.2 s (normal: 10–13 s), activated partial thromboplastin time (APTT) of 28.0 s (normal: 25–38 s), and fibrinogen concentration of 311 mg/dL (normal: 200–400 mg/dL). After inducing labor with prostaglandin E2, a 3206 g healthy male infant was delivered. His fibrinogen level was 171 mg/dL. Though the total amount of bleeding was 828 mL because of atonic bleeding, uterine contraction improved with intravenous oxytocin injection and no complications occurred during puerperium.

mg/dL). After inducing labor with prostaglandin E2, a 3206 g healthy male infant was delivered. His fibrinogen level was 171 mg/dL. Though the total amount of bleeding was 828 mL because of atonic bleeding, uterine contraction improved with intravenous oxytocin injection and no complications occurred during puerperium. Case  2. A 30-year-old (gravida 3, para 1) woman presented with a positive pregnancy test result. She was diagnosed with hypofibrinogenemia at the age of 25 following an emergency caesarean section with her first pregnancy. She was admitted to the previous hospital to induce labor at 40 weeks and 2 days' gestation, and although there were no complications during labor initially, the patient suddenly developed abnormal vaginal bleeding. Although an emergency caesarean section was performed under general anesthesia, because of suspected placental abruption, no surgical and pathological findings were found to confirm this suspicion. The female infant was healthy with a birth weight of 2120 g. Postpartum hemorrhage (PPH) occurred and the fibrinogen level was 60 mg/dL postoperatively. Immediate transfusion therapy using fresh-frozen plasma (FFP) was administered; this was the only abnormal bleeding episode experienced by the patient. The infant's fibrinogen level was also low, and inherited hypofibrinogenemia was suspected. The patient's history included an artificial abortion at the age of 21 and a spontaneous abortion at 29. She underwent a dilatation and curettage in these two pregnancies at 8 weeks' gestation, with no fibrinogen infusion. She underwent preoperative coagulation tests, only PT and APTT, the first time, and her fibrinogen level was monitored in the perioperative period after she was diagnosed with hypofibrinogenemia the second time. Her fibrinogen level was 66 mg/dL. The surgeries were completed with no complications. The patient's mother received red blood cell (RBC) infusion therapy after delivery; however, there was no other family history of coagulation testing. The patient's two brothers and their families' histories were negative for hemorrhagic and thrombotic episodes. The patient first visited our hospital at 6 weeks' gestation during this pregnancy. Her coagulation tests showed PT of 12.5 s, APTT of 40.1 s, and fibrinogen concentration of 75.9 mg/dL (normal: 200–400 mg/dL). Hematology doctors were consulted, and fibrinogen infusion therapy was started at 7 weeks' gestation.

isodes. The patient first visited our hospital at 6 weeks' gestation during this pregnancy. Her coagulation tests showed PT of 12.5 s, APTT of 40.1 s, and fibrinogen concentration of 75.9 mg/dL (normal: 200–400 mg/dL). Hematology doctors were consulted, and fibrinogen infusion therapy was started at 7 weeks' gestation. The patient's fibrinogen level was monitored weekly during her pregnancy. She received 3 g of fibrinogen weekly to maintain a fibrinogen level higher than 100 mg/dL [2, 3]. Beginning in the third trimester, physiological elevation of fibrinogen allowed extension of the infusion therapy interval to every three weeks. Fetal growth slowed at 27 weeks of gestation, and a diagnosis of fetal growth restriction (FGR) was made. The patient was hospitalized at 31 weeks' gestation to monitor FGR, because the fetal growth worsened: the estimated fetal weight (EFW) below −2.5 Standard Deviation (SD) from the population standard. However, the fetus grew at the same rate (−2.5 SD) as the fetal growth curve during hospitalization. Doppler ultrasound of fetal blood vessels was normal. A selective caesarean section was performed at 36 weeks and 2 days' gestation under general anesthesia to avoid the risk of bleeding on the recommendation of the anesthesiologist [4]. The male infant had Apgar scores of 8 and 10 at 1 and 5 min, respectively, with a birth weight of 1724 g. The patient received 3 g of fibrinogen for 3 consecutive days, 2 days before the surgery, to maintain the fibrinogen level higher than 200 mg/dL in the perioperative period. The fibrinogen level was 228 mg/dL on the day of operation. Total bleeding during the operation was 260 mL. The placenta was hypoplastic, with a weight of 350 g and marginal insertion of the cord. Since fibrinogen level of the infant persisted at 40–50 mg/dL, he was also suspected to have inherited hypofibrinogenemia, as was the case with his sister. The postoperative course was uneventful. One month after delivery, the patient's fibrinogen level decreased to 68 mg/dL.

f 350 g and marginal insertion of the cord. Since fibrinogen level of the infant persisted at 40–50 mg/dL, he was also suspected to have inherited hypofibrinogenemia, as was the case with his sister. The postoperative course was uneventful. One month after delivery, the patient's fibrinogen level decreased to 68 mg/dL. We were unable to get patient consent in case 1; therefore, genetic analysis was only conducted in case 2. Her functional fibrinogen level was 112.0 mg/dL and immunological level was 115.7 mg/dL; therefore, congenital hypofibrinogenemia was suspected. A new mutation (γ278Tyr→His) was identified as leading to hypofibrinogenemia. Inherited fibrinogen disorders are named after the city where the patient lives or after the city in which the patient was evaluated. Therefore, this case was named “Hiroshima I.” The same mutation was also detected in her two children.

cted. A new mutation (γ278Tyr→His) was identified as leading to hypofibrinogenemia. Inherited fibrinogen disorders are named after the city where the patient lives or after the city in which the patient was evaluated. Therefore, this case was named “Hiroshima I.” The same mutation was also detected in her two children. 3. Discussion Inherited fibrinogen disorders are very rare; the number of certified patients was 70 according to the national survey on coagulation disorders 2015 [4]. Inherited fibrinogen disorders are divided into two different types: quantitative defects (i.e., afibrinogenemia or hypofibrinogenemia) and qualitative defects (i.e., dysfibrinogenemia) (Table 1). No complications were observed during the pregnancy in case 1, whereas abnormal bleeding occurred after the caesarean section in case 2. Coagulation tests for congenital hypofibrinogenemia and dysfibrinogenemia are usually normal, with the exception of fibrinogen levels [1]. Two measurement methods (PT-derived method and immunoturbidimetry) are used to distinguish these two conditions. The PT-derived method can detect functional fibrinogen level and immunoturbidimetry can reveal immunologic fibrinogen level [1, 5]. Hypofibrinogenemia shows a low level of fibrinogen in both methods and dysfibrinogenemia only demonstrates low functional assay. The functional and immunological level in case 2 showed a proportional decrease; therefore, congenital hypofibrinogenemia was suspected.

imetry can reveal immunologic fibrinogen level [1, 5]. Hypofibrinogenemia shows a low level of fibrinogen in both methods and dysfibrinogenemia only demonstrates low functional assay. The functional and immunological level in case 2 showed a proportional decrease; therefore, congenital hypofibrinogenemia was suspected. Fibrinogen also plays an important role in adhesion between the placenta and the uterus; therefore, while it is not essential for implantation, it is necessary for maintaining pregnancy. According to some case reports, pregnancy in the patients with afibrinogenemia will result in abortion without fibrinogen infusion therapy by at least 5 weeks' gestation [2, 3]. Moreover, fibrinogen disorders can cause recurrent abortion, subchorionic hematoma, placental abruption, and PPH [2, 3]. It is known that the minimal fibrinogen level for maintaining pregnancy is above 60 mg/dL [2, 3]. As fibrinogen decreases under threatened premature labor or inflammation, it is necessary to maintain the fibrinogen level higher than 100 mg/dL during pregnancy [2, 3]. After the onset of labor, the fibrinogen level must be maintained to higher than 150 mg/dL or 200 mg/dL in case of caesarean section [2, 3]. The fibrinogen level increased spontaneously to higher than 200 mg/dL during pregnancy in case 1; therefore, she did not receive infusion therapy. In case 2, the patient received 3 g of fibrinogen (half-life of 3-4 days) once a week through the second trimester (Figure 1, Table 2). Beginning in the third trimester, the physiological elevation of fibrinogen allowed extension of the infusion therapy interval to every 3 weeks (Figure 1). The fibrinogen level after surgery stayed higher than 150 mg/dL. Fetal growth restriction occurred, the same as with her previous one. Pathology of the placenta revealed no specific information leading to FGR, such as thrombus or infarction. We did not find out the literature showing relationship between FGR and hypofibrinogenemia and fibrinogen infusion therapy. Marginal insertion of the cord might be one of the reasons for FGR in this case.

ous one. Pathology of the placenta revealed no specific information leading to FGR, such as thrombus or infarction. We did not find out the literature showing relationship between FGR and hypofibrinogenemia and fibrinogen infusion therapy. Marginal insertion of the cord might be one of the reasons for FGR in this case. Fibrinogen consists of three polypeptide chains (A2α, Bβ, and γ) encoded by three genes (FGA, FGB, and FGG, resp.) located on the long arm of chromosome 4 [6]. Afibrinogenemia is caused by variations in the FGA, FGB, and FGG genes [7]. Afibrinogenemia is associated with homozygous or compound heterozygous mutation. On the other hand, hypofibrinogenemia is usually related to heterozygous mutation. Mutations causing afibrinogenemia and hypofibrinogenemia in FGA gene are mainly deletions, frameshift, nonsense, or splicing mutations [7]. In contrast, mutations in FBG and FGG include an excess of missense mutation [7]. Genetic analyses have shown the mechanisms regulating the production of fibrinogen. For example, the Matsumoto IV (γ 153 Cys→Arg) mutation affects the proximal A region of the γ D domain resulting in abnormal folding without intrachain disulphide bond [4, 8]. In case 2, genetic analysis revealed a new mutation (γ 278 Tyr→His) named as Hiroshima I on exon 8 in FGG which can affect mRNA splicing or stability or protein synthesis, assembly, and secretion.

on affects the proximal A region of the γ D domain resulting in abnormal folding without intrachain disulphide bond [4, 8]. In case 2, genetic analysis revealed a new mutation (γ 278 Tyr→His) named as Hiroshima I on exon 8 in FGG which can affect mRNA splicing or stability or protein synthesis, assembly, and secretion. We reported two cases of hypofibrinogenemia with different courses during pregnancy. The personal and family history must be checked carefully in case of fibrinogen disorders, as occasionally hereditary abnormalities are found, such as in case 2. For the patients with the fibrinogen disorders, the fibrinogen level must be measured continuously and infusion therapy is essential not only maintaining the pregnancy but also preventing PPH and other complications. Acknowledgments The authors wish to thank Dr. Okumura at the Department of Biomedical Laboratory Sciences, School of Health Sciences, Shinshu University, for genetic analysis. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Perinatal course and fibrinogen infusion therapy in case 2. Table 1 Characteristics of inherited fibrinogen disorders. Afibrinogenemia Hypofibrinogenemia Dysfibrinogenemia Transmission AR AD/AR AD Fibrinogen level (mg/dL) <10 70–100 Lower limit of normal Laboratory PT-APTT-TT PT: normal or prolonged PT-APTT: normal Markedly prolonged APTT: normal

varian cancers [1]. Although there are some reports about familial occurrences of ovarian tumors, literature concerning the clinical cases of monozygotic twins is rare. We report the cases of a bilateral and repeated ovarian benign teratoma and an immature teratoma that appeared simultaneously in two monozygotic twins. 2. Case Presentation 2.1. Case  1 A 12-year-old Japanese girl, gravida 0 para 0, visited our gynecologic outpatient department for mild lower abdominal pain. Her history was noncontributory, and she had no remarkable family history. A pelvic examination was avoided since she was a virgin. A transabdominal ultrasound test detected a large left ovarian cyst, measuring 9.9 cm × 6.6 cm with calcification inside it, with no vascularity. Her uterus and right adnexa were normal. Magnetic resonance imaging (MRI) of the pelvis revealed a left ovarian tumor (9.2 × 7.6 × 7.5 cm in diameter) with high signal intensity that was capsulated with small amount of fluid in the Douglas pouch (Figure 1). The right ovary was normal. Laboratory examination showed that the level of cancer antigen (CA) 125 was 36.8 U/mL (normal range < 35 U/mL), and no other tumor marker levels were elevated. She underwent laparotomy later. She was also diagnosed with left ovarian tumor without rupture and torsion. A left cystectomy was performed, and no surgical complications occurred. Microscopic and histopathological examination of the cystic mass revealed that it was a benign teratoma emerging from the left ovary.

ated. She underwent laparotomy later. She was also diagnosed with left ovarian tumor without rupture and torsion. A left cystectomy was performed, and no surgical complications occurred. Microscopic and histopathological examination of the cystic mass revealed that it was a benign teratoma emerging from the left ovary. After discharge, the patient was followed every third month. Fifteen months after the first surgery, a right ovarian cystic mass was detected with an elevated CA125 level (35.6 U/mL), and she presented to the emergency room because of severe lower abdominal pain with acute onset. A right ovarian cyst with torsion was suspected. She underwent laparotomy again, and right salpingooophorectomy was then performed because of twisted and black-and-blue ovarian findings. The patient recovered well after the surgery, and histological analysis of the ovarian cyst revealed that it was a benign teratoma with infarcted and necrotic tissue. We resumed regular follow-up. Twenty months after the second surgery, a left ovarian cystic tumor (4 cm in size) was detected without any symptoms. Regular pelvic examination was continued, and an enlarged ovarian cystic mass (6.6 cm in size) was diagnosed, with an elevated squamous cell carcinoma (SCC) antigen level (2.0 U/mL; the normal range is less than 1.0 U/mL) on hematological investigation. A third laparotomy was performed, and the left ovarian cystic tumor was resected. The histological diagnosis was a benign teratoma. After 13 months, the patient continued to do well and her blood SCC antigen level was normalized.

n level (2.0 U/mL; the normal range is less than 1.0 U/mL) on hematological investigation. A third laparotomy was performed, and the left ovarian cystic tumor was resected. The histological diagnosis was a benign teratoma. After 13 months, the patient continued to do well and her blood SCC antigen level was normalized. 2.2. Case  2 A 12-year-old Japanese girl, gravida 0 para 0, who was the monozygotic twin sister of the patient in Case  1, visited our gynecologic department for ovarian screening 3 months after the first operation of Case  1. Transrectal echography revealed bilateral ovarian cystic tumors with calcified structures. Tumor marker levels (CA125, SCC, CEA, and CA19-9) were normal. The bilateral ovarian cystic walls were extracted, and normal ovarian tissues were preserved by laparotomy. Pathological analysis of the cyst wall disclosed that there were benign teratomas in both ovaries.

l ovarian cystic tumors with calcified structures. Tumor marker levels (CA125, SCC, CEA, and CA19-9) were normal. The bilateral ovarian cystic walls were extracted, and normal ovarian tissues were preserved by laparotomy. Pathological analysis of the cyst wall disclosed that there were benign teratomas in both ovaries. Sixteen months after the first surgery, bilateral ovarian tumors were detected with echogram and pelvic MRI (right side: 4.4 cm, left side: 8.0 cm in diameter) during her regular check-up (Figure 2). The ovarian tumors were accompanied by a solid part and high echoic part inside. Blood examination of tumor markers revealed a mild, elevated CA125 (37.5 U/mL). Bilateral cystectomy was performed 20 months after the first surgery. Examination of the other pelvic and abdominal organs found no disseminated and metastatic lesions in the surgery. There were no swollen pelvic lymph nodes. The histological diagnosis was an immature teratoma of grade 1 with International Federation of Gynecology and Obstetrics stage I in the right ovary and a benign mature teratoma in the left ovary. The girl's postoperative condition was good, and she was discharged without any complications. An additional surgery and chemotherapy were not planned according to a deliberated discussion with her family.

Federation of Gynecology and Obstetrics stage I in the right ovary and a benign mature teratoma in the left ovary. The girl's postoperative condition was good, and she was discharged without any complications. An additional surgery and chemotherapy were not planned according to a deliberated discussion with her family. After being discharged, she continued to be followed every other month. Four months after the last surgery, a right ovarian cystic mass (4 cm in size) was detected, and it enlarged to 6 cm two months later (Figure 3). The blood CA125 level (32.3 U/mL) was in the normal range. Therefore, a third laparotomy was performed 7 months after the second surgery. The right adnexa, appendix, and greater omentum were resected. Examination of the other pelvic and abdominal organs showed that they did not have disseminated and metastatic lesions. There were no swollen pelvic lymph nodes. The histological diagnosis was an immature teratoma of grade 1 in the right ovary, and metastatic carcinoma was not detected in the other extracted organs (Figures 4 and 5). After 30 months, the patient continued to do well and there was neither tumor recurrence nor pelvic lymphadenopathy. Levels of tumor markers, including CA125, were within normal levels. Approval of the institutional study board and informed consent of these patients were obtained.

After being discharged, she continued to be followed every other month. Four months after the last surgery, a right ovarian cystic mass (4 cm in size) was detected, and it enlarged to 6 cm two months later (Figure 3). The blood CA125 level (32.3 U/mL) was in the normal range. Therefore, a third laparotomy was performed 7 months after the second surgery. The right adnexa, appendix, and greater omentum were resected. Examination of the other pelvic and abdominal organs showed that they did not have disseminated and metastatic lesions. There were no swollen pelvic lymph nodes. The histological diagnosis was an immature teratoma of grade 1 in the right ovary, and metastatic carcinoma was not detected in the other extracted organs (Figures 4 and 5). After 30 months, the patient continued to do well and there was neither tumor recurrence nor pelvic lymphadenopathy. Levels of tumor markers, including CA125, were within normal levels. Approval of the institutional study board and informed consent of these patients were obtained. 3. Discussion Mature cystic teratoma is one of the most common kinds of ovarian tumor, with a frequency of approximately 20% [2]. Torsion of the ovary is a major complication, and rupture of the cyst may also occur. Immature teratoma is a rare tumor, representing less than 1% of all ovarian teratomas, 1% of all ovarian cancers, and 35.6% of malignant ovarian germ cell tumors [1]. They are most common in the first two decades of life [1]. However, data on the management and treatment of immature teratoma are limited because of its rarity. According to a recent study that assessed 27 patients with immature teratoma, 82% had an International Federation of Gynecology and Obstetrics stage I, 11% had stage II, and 7% had stage III disease [3].

s of life [1]. However, data on the management and treatment of immature teratoma are limited because of its rarity. According to a recent study that assessed 27 patients with immature teratoma, 82% had an International Federation of Gynecology and Obstetrics stage I, 11% had stage II, and 7% had stage III disease [3]. Ovarian teratoma is considered an acquired neoplastic disease; therefore, familial incidence has been reported in only a few papers. Only three studies have reported teratoma of the ovary in twins [4–6], only one of which described monozygotic twins [4]. Some previous studies reported endometrioma, borderline tumors, and carcinoma of the ovary in twins, but studies on mature cystic teratomas and immature teratomas are relatively rare.

a few papers. Only three studies have reported teratoma of the ovary in twins [4–6], only one of which described monozygotic twins [4]. Some previous studies reported endometrioma, borderline tumors, and carcinoma of the ovary in twins, but studies on mature cystic teratomas and immature teratomas are relatively rare. Teratoma contains elements of the ectodermal component in most tumors, and the cause has not been identified. There are two main hypotheses for its etiology. The first is based on totipotent cells, which are segregated in the development of the morula. Subsequently, derivates of all germinal cell layers occur, and they are similar to those in the contiguous tissues. The second hypothesis, which is the most accepted theory, supposes that an unknown trigger stimulates asexual development or parthenogenesis [6]. Parthenogenesis mentions development of embryo without the male gamete. Chromosome banding studies and enzyme polymorphisms helped the pathogenic research of gonadal teratomas from 1970s. Linder et al. suggested that benign cystic teratomas of the ovary are derived from parthenogenetically activated ovarian oocytes after meiosis I, but before meiosis II [7, 8]. Additional analysis indicates that the DNA content and karyotype (46,XX) of mature cystic teratomas of the ovary are usually homozygous and it strongly supports Linder's hypothesis of a germ cell origin [9]. Since parthenogenetic activation of meiosis I oocytes takes place in the ovarian follicles, there are probably other factors which contribute to the development and growth of the parthenote. It was shown that these abnormal embryos may develop to form the bizarre messes which consist of a variety of differentiated cell and tissue types, a unique feature of the ovarian teratomas [10].

in the ovarian follicles, there are probably other factors which contribute to the development and growth of the parthenote. It was shown that these abnormal embryos may develop to form the bizarre messes which consist of a variety of differentiated cell and tissue types, a unique feature of the ovarian teratomas [10]. Additionally, a disorder of “genomic imprinting” is considered as an important mechanism in pathogenesis of ovarian teratomas. Genomic imprinting is the phenomenon that the paternal and maternal sets of chromosomes have different functionality in mammals, due to parental-specific epigenetic modification of the genome. Thus, the allelic expression of an imprinted gene depends upon whether it resided in a male or a female in the previous generation. Imprinted expression can also vary between tissues, developmental stages, and species [11]. The presence of genomic imprinting in mammals has considerable medical, societal, and intellectual implications in terms of the clinical management of genetic traits and diseases, the capacity to control human and animal breeding by assisted reproductive technologies, and the progress of biotechnology and postgenomic medical research [12]. According to previous research, parthenogenesis in teratomas of the ovary can be considered as control by genomic imprinting from mother. Thus, although the etiology and mechanism of the simultaneous occurrence of ovarian teratomas in monozygotic twins are not proven, they could be explained by these theories.

ch [12]. According to previous research, parthenogenesis in teratomas of the ovary can be considered as control by genomic imprinting from mother. Thus, although the etiology and mechanism of the simultaneous occurrence of ovarian teratomas in monozygotic twins are not proven, they could be explained by these theories. Some malignant tumors in other regions, such as gastric cancer, breast cancer, or neuroblastoma, have been reported to present simultaneously in monozygotic twins. The etiology of malignant cases has been debated: is the disease a simultaneous occurrence in both twins, or is it because of metastatic spread via placental vascular anastomoses in utero from one twin with a congenital disease to the second twin? By contrast, it is difficult to speculate about metastatic spread in the twins in the present cases, because one had a benign, mature teratoma and the other had a malignant, immature teratoma. Linder and Power have reported that monozygotic twins have a higher chance of malignant suffering than fraternal twins do [7]. According to the latest prospective study of over 80,000 monozygotic twins, 38% of monozygotic twins were diagnosed with the same cancer type, and significant heritability (39%) was observed for ovarian cancers [8]. We continue to closely follow up the patient described in Case  1, considering the chance of genetic risk of malignant presentation.

pective study of over 80,000 monozygotic twins, 38% of monozygotic twins were diagnosed with the same cancer type, and significant heritability (39%) was observed for ovarian cancers [8]. We continue to closely follow up the patient described in Case  1, considering the chance of genetic risk of malignant presentation. Currently, information describing the development of teratoma of the ovary in twins globally is scarce. This is the first clinical report on mature teratoma and immature teratoma of the ovary in two monozygotic twins. Our cases are only a small part of the reports on ovarian mature teratoma and immature teratoma in monozygotic twins, but our report supports future clarification of the molecular mechanism and pathogenesis including the parthenogenesis with genomic imprinting of ovarian teratomas. Acknowledgments The authors thank Dr. Shigetaka Yamazaki, department of pathology, Tokyo Rinkai Hospital, Tokyo, Japan, for the pathological diagnosis of the patients who were studied in this report. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Pelvic magnetic resonance imaging (T2-weighted image) before the first surgery of Case  1. An intrapelvic tumor (9.2 × 7.6 × 7.5 cm in diameter) with high signal intensity is detected. The right ovary is normal. Figure 2 Pelvic magnetic resonance imaging (T2-weighted image) before the second surgery of Case  2. Bilateral ovarian tumors are detected (right side: 4.4 cm, left side: 8.0 cm in diameter).

Figure 1 Pelvic magnetic resonance imaging (T2-weighted image) before the first surgery of Case  1. An intrapelvic tumor (9.2 × 7.6 × 7.5 cm in diameter) with high signal intensity is detected. The right ovary is normal. Figure 2 Pelvic magnetic resonance imaging (T2-weighted image) before the second surgery of Case  2. Bilateral ovarian tumors are detected (right side: 4.4 cm, left side: 8.0 cm in diameter). Figure 3 Pelvic magnetic resonance imaging (T2-weighted image) before the third surgery of Case  2. Right ovarian tumors are detected (multiple cystic, 6.3 × 4.9 cm in diameter). Figure 4 Histological section showing immature teratoma composed of small immature neurogenic cells (hematoxylin and eosin, 100x magnification). Figure 5 Histological section showing the immature teratoma with immature tissue of the bone (asterisk), cartilage (arrow), and islands of adipose tissue (arrowhead) (hematoxylin and eosin, 100x magnification).

1. Introduction Pelvic actinomycosis is a rare indolent disease caused most frequently by Actinomyces israelii, an anaerobic gram positive bacillus that is part of the normal flora of the oropharynx, gastrointestinal tract, and female genital tract [1–5]. The infection is characterized by suppurative and granulomatous inflammation, contiguous spread, and the formation of colonies described macroscopically as sulfur granules [2, 3, 6]. It can become pathogenic when mucosal integrity is compromised or in the presence of a foreign body, like an IUD [2]. Pelvic actinomycosis represents approximately 3% of human actinomycosis infections [1]. A definitive diagnosis requires a positive anaerobic culture or histologic identification of actinomyces sulfur granules. The infection typically manifests as a unilateral tuboovarian abscess but can also present as an ovarian tumor or retroperitoneal mass that mimics a pelvic or intra-abdominal malignancy that requires extensive surgical intervention [6]. For those reasons, the diagnosis is made in most of the cases intraoperatively. The case presented demonstrates that preoperative diagnosis of pelvic actinomycosis can be achieved through CT-guided paracentesis if there is high clinical suspicion and that conservative management with prolonged antibiotics can result in clinical and radiologic resolution.

made in most of the cases intraoperatively. The case presented demonstrates that preoperative diagnosis of pelvic actinomycosis can be achieved through CT-guided paracentesis if there is high clinical suspicion and that conservative management with prolonged antibiotics can result in clinical and radiologic resolution. 2. Case Presentation A 42-year-old Caucasian female, gravida 3 para 1 (1 spontaneous vaginal delivery and 2 elective abortions), was admitted with a 2-month history of diffuse abdominal pain, decreased appetite, nausea, vomiting, abdominal distention, weakness, and a twenty-pound unintentional weight loss. Her history was significant for a twenty-eight-pack-year tobacco use and a copper IUD placed approximately fifteen years earlier. On admission, the patient was found to be cachectic, tachycardic, and tachypneic but afebrile. Her abdomen was moderately distended, tender to palpation throughout but without acute peritoneal signs. It was diffusely tympanic but dull over bilateral lower quadrants, with hypoactive bowel sounds. External genitalia and vagina were normal. Cervix was parous in appearance with two strings visualized from the cervical os; IUD was removed and sent for microbiologic studies. Uterus was difficult to palpate secondary to pain and adnexal tenderness. Adnexa were diffusely tender with bilateral fullness. Rectal exam showed normal tone and normal rectovaginal septum with fullness palpated anteriorly.

wo strings visualized from the cervical os; IUD was removed and sent for microbiologic studies. Uterus was difficult to palpate secondary to pain and adnexal tenderness. Adnexa were diffusely tender with bilateral fullness. Rectal exam showed normal tone and normal rectovaginal septum with fullness palpated anteriorly. The patient's initial laboratory evaluation showed marked leukocytosis (WBC: 29,000), anemia (Hgb: 10.9), hypoalbuminemia (albumin: 2.2), and mildly elevated CA 125 (54). AST/ALT, CEA, and CA 19-9 were normal. No infectious disease was found per evaluation via urine and blood cultures, gonorrhea, chlamydia, vaginitis panel (testing for trichomoniasis, candida, and bacterial vaginosis), tuberculin test, HIV, or hepatitis B and hepatitis C. CT of the abdomen demonstrated marked bowel distention and a complex cystic mass within the left pelvis with enhancing septations measuring 8.2 × 6.7 × 9.8 cm, retroperitoneal lymphadenopathy, and small ascites with peritoneal enhancement. Large distended bowel loops surrounded the heterogeneous lesion peripherally (Figure 1).

e abdomen demonstrated marked bowel distention and a complex cystic mass within the left pelvis with enhancing septations measuring 8.2 × 6.7 × 9.8 cm, retroperitoneal lymphadenopathy, and small ascites with peritoneal enhancement. Large distended bowel loops surrounded the heterogeneous lesion peripherally (Figure 1). Parenteral antibiotics (Meropenem and Vancomycin) were started for coverage of pelvic abscess of unknown etiology with noted improvement in leukocytosis after 72 hours. Nasogastric tube was placed for upper GI decompression and control of emesis for suspected partial small bowel obstruction. Total parenteral nutrition was also started to improve her malnourished state. Gynecologic oncology was consulted and concluded that the likelihood of carcinomatosis was very low based on the patient's age, absence of omental caking or peritoneal implants on CT, and only mildly elevated CA-125. In the presence of a neglected IUD for 15 years with low suspicion for malignancy, actinomycosis was a likely diagnosis. CT-guided diagnostic paracentesis was performed after bowel decompression was achieved with NG tube. Purulent peritoneal fluid was obtained which was negative for malignancy, yet positive for Actinomyces (Figure 2). Copper IUD was removed and culture grew Micromonas micros and Actinomyces (Figure 3).

likely diagnosis. CT-guided diagnostic paracentesis was performed after bowel decompression was achieved with NG tube. Purulent peritoneal fluid was obtained which was negative for malignancy, yet positive for Actinomyces (Figure 2). Copper IUD was removed and culture grew Micromonas micros and Actinomyces (Figure 3). One week after initiation of antibiotic therapy, repeat CT of abdomen and pelvis showed stable to slightly improved fluid collections compared to prior exams. As final laboratory diagnosis was achieved, Vancomycin and Meropenem were discontinued after 8 and 11 days of treatment, respectively. The patient was started on Ampicillin-Sulbactam 3 g IV every 6 hours, which helped control her leukocytosis. On day five of the Ampicillin-Sulbactam, AST and ALT values were 209 and 148, respectively, and patient was diagnosed with transaminitis secondary to the Ampicillin-Sulbactam. The Ampicillin-Sulbactam was discontinued, which improved the transaminitis, and the patient was started on Penicillin 3 million units IV every 4 hours, which was continued for a total of 4 weeks. After 3 weeks of in-hospital management, patient was tolerating regular diet with regular bowel movements and improved pain control. Patient was discharged home with close outpatient follow-up arranged. At her outpatient follow-up four weeks later, she was transitioned to Penicillin 500 mg PO four times daily. Patient continued Penicillin orally for 1 year, during which she was gaining the strength and weight back with assistance of nutrition and occupational therapy professionals.

close outpatient follow-up arranged. At her outpatient follow-up four weeks later, she was transitioned to Penicillin 500 mg PO four times daily. Patient continued Penicillin orally for 1 year, during which she was gaining the strength and weight back with assistance of nutrition and occupational therapy professionals. Repeat CT of abdomen and pelvis 1 year after initiation of treatment demonstrated complete resolution of bowel distention, ascites, and adenopathy; the left adnexal mass had more than 50% size reduction, measuring 3.9 × 3.2 cm (Figure 4). The patient was found to have complete resolution of pain and abdominal distention, as well as 21 lbs weight gain since treatment was initiated. 3. Discussion Pelvic actinomycosis has a characteristic invasion pattern that causes an intense inflammatory reaction with subsequent risk of intestinal obstructions, strictures, and even mass effect leading to ureteral obstruction. Acute surgical intervention is usually performed due to very unspecific clinical presentation with concern for malignancy or acute abdomen. This approach frequently leads to extensive removal of reproductive or gastrointestinal organs with greatly increased morbidity. If actinomycosis is highly suspected or diagnosed preoperatively, delayed surgical intervention after prolonged antibiotic therapy and metabolic support is the preferred approach.

te abdomen. This approach frequently leads to extensive removal of reproductive or gastrointestinal organs with greatly increased morbidity. If actinomycosis is highly suspected or diagnosed preoperatively, delayed surgical intervention after prolonged antibiotic therapy and metabolic support is the preferred approach. Diagnosing pelvic actinomycosis before surgical intervention is extremely uncommon. Although this chronic infection can manifest as tuboovarian abscesses, in many cases it mimics pelvic or intra-abdominal malignancy, cervix carcinoma, or colorectal cancer, leading to surgical intervention in almost all cases [1]. To our knowledge, only four reported cases of pelvic actinomycosis diagnosed preoperatively exist [5–10].

ronic infection can manifest as tuboovarian abscesses, in many cases it mimics pelvic or intra-abdominal malignancy, cervix carcinoma, or colorectal cancer, leading to surgical intervention in almost all cases [1]. To our knowledge, only four reported cases of pelvic actinomycosis diagnosed preoperatively exist [5–10]. In our case, diagnosis was successfully achieved through CT-guided paracentesis instead of the commonly performed surgical approach. The patient was then treated exclusively with noninvasive medical management. We found only six other reports of preoperative diagnosis of pelvic actinomycosis that support exclusive medical management in the absence of a surgical abdomen [5–10]. As long as no acute abdominal signs are present, diagnostic paracentesis should be considered. Although distended bowel loops make it difficult for imaging guided biopsy, nasogastric decompression can assist. Paracentesis becomes a very important diagnostic tool, as in our case, pointing out the causative agent via histologic and microbiologic studies. Additionally, the absence of malignant cells in the peritoneal fluid makes carcinomatosis unlikely. Further evaluation by removal of IUD and pap smear collection can also support the diagnosis. Pap smear is a simple diagnostic aid of greater sensitivity than vaginal cultures, with accuracy of up to 69% [6]. Once diagnosis is confirmed, exclusive medical management with long term use of antibiotics and close follow-up is an acceptable approach which could prevent the need for extensive and risky surgical interventions in patients with pelvic actinomycosis.

sensitivity than vaginal cultures, with accuracy of up to 69% [6]. Once diagnosis is confirmed, exclusive medical management with long term use of antibiotics and close follow-up is an acceptable approach which could prevent the need for extensive and risky surgical interventions in patients with pelvic actinomycosis. Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. Competing Interests The authors declare that there is no conflict of interests. Figure 1 CT of pelvis demonstrating multiloculated abscess and dilated bowel loops. Figure 2 Sulfur granules from peritoneal aspiration, 40x. Figure 3 Sulfur granules from IUD, 40x. Figure 4 CT of pelvis demonstrating reduction of adnexal mass and decompressed bowel loops at 1 year of treatment.

1. Introduction Uterine arteriovenous malformation (AVM) is a rare condition, and although its precise incidence is unknown, most cases of AVM are undiagnosed. Thus, this condition may have a higher incidence than expected [1]. AVM can be congenital or acquired. Acquired AVM is believed to be caused by spontaneous abortion [2], dilation and curettage (D&C) [2, 3], uterine trauma [4], and gestational trophoblastic disease [5]. The reported incidence of AVM has been increasing [6–8]. Although emergency uterine artery embolization (UAE) can be performed to stop the bleeding, some women may require hysterectomy [3, 6, 8]. The effect of UAE on fertility and pregnancy is unclear; therefore, performing UAE for women who wish to conceive remains controversial [9, 10]. Alternatively, some reports have described the spontaneous disappearance of AVM by expectant management [1, 3, 11–15]. Therefore, considering the risks for ovarian insufficiency and placental abnormalities during subsequent pregnancies associated with UAE, we examined whether UAE can be avoided in patients with AVM, particularly in those undergoing fertility treatment. We retrospectively examined patients with AVM who were treated at our department and determined the feasibility of conservative management as a treatment option. Ethical Approval Statement. This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of the Ryukyus on 7 April 2015 (#936). All patients gave informed consent prior to her inclusion in the study.

Alternatively, some reports have described the spontaneous disappearance of AVM by expectant management [1, 3, 11–15]. Therefore, considering the risks for ovarian insufficiency and placental abnormalities during subsequent pregnancies associated with UAE, we examined whether UAE can be avoided in patients with AVM, particularly in those undergoing fertility treatment. We retrospectively examined patients with AVM who were treated at our department and determined the feasibility of conservative management as a treatment option. Ethical Approval Statement. This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of the Ryukyus on 7 April 2015 (#936). All patients gave informed consent prior to her inclusion in the study. 2. Case Presentation Clinical course of the three patients with AVM after miscarriage with conservative management are shown in Table 1. An AVM diagnosis was made using transvaginal ultrasound with grayscale and color and spectral Doppler imaging using the Voluson 3D power Doppler (GE Healthcare, Tokyo, Japan). Each examination comprised a standard grayscale ultrasound of the uterus in both the longitudinal and transverse planes. The endometrial thickness and presence/absence of retained products were recorded. Masses with abundant blood flow in the myometrium were shown as a mosaic color pattern using Doppler imaging. A venous-type flow in the intramural venous plexus, a turbulent aspect in the fistula, and a high-velocity low-resistance flow in the artery branch were observed in patients with AVM (Figure 1). The size of AVM was measured using ultrasonography. Patient 1 received medroxyprogesterone acetate therapy for stage IA endometrial cancer and grade 1 endometrioid adenocarcinoma. Following remission, she underwent in vitro fertilization-embryo transfer (IVF-ET) and became pregnant by freeze-thawed embryo transfer (ET). However, the pregnancy was a blighted ovum, and D&C was performed. Ultrasonography performed 2 weeks later revealed a cyst with a low-level echo and abundant blood flow. A mass measuring 22 × 19 mm in size with abundant blood flow in the myometrium was shown on Doppler imaging as a mosaic color pattern (Figures 1 and 2). As no vaginal bleeding was observed, we opted for conservative management. At diagnosis, the patient's estradiol level was 530 pg/mL, and a functional cyst was observed in the right ovary. Considering that the elevated estradiol level could have affected the growing AVM, a gonadotropin-releasing hormone (GnRH) agonist (900 μg/day Suprecur®; Mochida Pharmaceutical Co., Ltd., Tokyo, Japan) was administered for 4 weeks. Furthermore, methylergometrine maleate was administered for 3 weeks to promote uterine contraction. Four weeks following diagnosis, the patient's estradiol level dropped to 5 pg/mL, the hCG level dropped to 4.9 mIU/mL, and the AVM disappeared (Figure 3).

maceutical Co., Ltd., Tokyo, Japan) was administered for 4 weeks. Furthermore, methylergometrine maleate was administered for 3 weeks to promote uterine contraction. Four weeks following diagnosis, the patient's estradiol level dropped to 5 pg/mL, the hCG level dropped to 4.9 mIU/mL, and the AVM disappeared (Figure 3). Five months after the disappearance of AVM, hysteroscopy revealed no abnormal findings in the uterus. The patient became pregnant by freeze-thawed ET and delivered a healthy infant. Patient 2 also conceived by IVF-ET. However, it resulted in missed abortion, and she underwent D&C. She showed abnormal vessels (10 × 3 mm) in the myometrium on ultrasonography 1 day after D&C. After 1 week, the abnormal vessels had grown to a size of 16 × 6 mm with abundant blood flow, which was shown on Doppler as a mosaic color pattern (Figure 4). No vaginal bleeding was observed. Because her estradiol level was normal (42 pg/mL), no GnRH agonist was administered. Methylergometrine maleate was administered for 3 weeks to promote uterine contraction. Four weeks after D&C, AVM disappeared. The patient is currently undergoing IVF treatment.

olor pattern (Figure 4). No vaginal bleeding was observed. Because her estradiol level was normal (42 pg/mL), no GnRH agonist was administered. Methylergometrine maleate was administered for 3 weeks to promote uterine contraction. Four weeks after D&C, AVM disappeared. The patient is currently undergoing IVF treatment. Patient 3 had become pregnant by IVF-ET but had a missed abortion at 8 weeks of gestation, which ended in a complete abortion without D&C. Ultrasonography performed 1 week later revealed a cyst with a low-level echo (6 × 2 mm) and blood flow in the myometrium. Methylergometrine maleate was administered for 5 days. After 3 weeks, the cyst had grown to 20 × 15 mm with abundant blood flow (Figure 5). No vaginal bleeding was observed. Because the patient's estradiol level was 2,552 pg/mL and multiple functional cysts were observed in the right ovary, a GnRH agonist was administered. Six weeks after complete abortion, AVM disappeared and the patient's estradiol level dropped to 30.2 pg/mL. The patient is currently undergoing IVF treatment. Her hCG level was 294.1 mIU/mL on the day of AVM diagnosis, but it spontaneously decreased to 14.3 mIU/mL.

d in the right ovary, a GnRH agonist was administered. Six weeks after complete abortion, AVM disappeared and the patient's estradiol level dropped to 30.2 pg/mL. The patient is currently undergoing IVF treatment. Her hCG level was 294.1 mIU/mL on the day of AVM diagnosis, but it spontaneously decreased to 14.3 mIU/mL. 3. Discussion Data regarding AVM following miscarriage are limited. Although the number of cases is small, we presented detailed cases of conservative management. Methylergometrine maleate was administered to all three cases to promote uterine contraction. A GnRH agonist was administered to cases 1 and 2 in whom estradiol levels were >300 pg/mL when AVM was diagnosed, which could have affected the growing AVM. In three patients with AVM without vaginal bleeding, the mass spontaneously disappeared without performing UAE. AVM does not always cause massive vaginal bleeding and spontaneously disappears in some patients. Therefore, for women concerned about ovarian insufficiency, particularly those undergoing fertility treatments, performing UAE should be carefully considered.

ing, the mass spontaneously disappeared without performing UAE. AVM does not always cause massive vaginal bleeding and spontaneously disappears in some patients. Therefore, for women concerned about ovarian insufficiency, particularly those undergoing fertility treatments, performing UAE should be carefully considered. Although AVM-induced massive vaginal hemorrhage is considered a rare disease, it is possible that the actual incidence is higher because of cases not being diagnosed [1]. Asymptomatic AVM might spontaneously disappear without diagnosis. These three patients experienced miscarriage following IVF; therefore, we were able to diagnose AVM after performing frequent ultrasound examinations to determine when the next treatment should begin. Thus, in women undergoing fertility treatment, AVM may be diagnosed early, and it may be a mild form that spontaneously regresses. Conversely, women who are not infertile have fewer reasons to undergo ultrasound examination following a miscarriage. In these patients, AVM may be overlooked and may remain undiagnosed.

n. Thus, in women undergoing fertility treatment, AVM may be diagnosed early, and it may be a mild form that spontaneously regresses. Conversely, women who are not infertile have fewer reasons to undergo ultrasound examination following a miscarriage. In these patients, AVM may be overlooked and may remain undiagnosed. Blood flow in the myometrium, verified by color Doppler on day 3 and at 6 weeks following normal delivery, has been reported [16]. Of 93 cases following vaginal delivery, enhanced myometrial vascularity (EMV) with locally increased blood flow in the myometrium at the placental bed was observed in 50.5% on day 3 following delivery. However, EMV was observed in only 3.9% at 6 weeks, and it spontaneously disappeared in most cases. EMV is found in the myometrium at the site of placental attachment and is associated with retained placenta. However, no relationship has been observed between EMV and postpartum bleeding. If EMV is observed without vaginal bleeding, treatment is considered unnecessary [16]. On the basis of these reports, we can infer that a small amount of retained placenta following a normal delivery is related to the abnormal blood flow in the myometrium. AVM has also been suggested to be associated with retained placenta and villi [7]; therefore, it is difficult to distinguish between AVM and EMV that does not require treatment. Hence, we should consider expectant management for AVM without bleeding.

mal delivery is related to the abnormal blood flow in the myometrium. AVM has also been suggested to be associated with retained placenta and villi [7]; therefore, it is difficult to distinguish between AVM and EMV that does not require treatment. Hence, we should consider expectant management for AVM without bleeding. There are many reports of UAE for uterine myoma [17–19]. However, a simple comparison is impossible because metal coils are often used in these cases. Several reports on UAE, used to treat AVM after miscarriage, have described effects on ovarian function and adverse effects on subsequent pregnancies [20]. Inoue reported findings from 211 women who underwent UAE for postpartum hemorrhage [20]. Of the 113 women who underwent postoperative follow-up, amenorrhea developed in seven, Asherman's syndrome in four, endometritis in seven, and uterine necrosis in three. Placenta accreta was observed in five of 30 women (16.7%) who conceived following UAE.

rom 211 women who underwent UAE for postpartum hemorrhage [20]. Of the 113 women who underwent postoperative follow-up, amenorrhea developed in seven, Asherman's syndrome in four, endometritis in seven, and uterine necrosis in three. Placenta accreta was observed in five of 30 women (16.7%) who conceived following UAE. When conservative treatment is selected for AVM, the use of methylergometrine maleate [11, 13] and GnRH agonists [12, 13] has been reported. Methylergometrine maleate is used to reduce AVM blood flow by promoting uterine contraction rather than directly acting on AVM. Estrogen is believed to contribute to vascular endothelial differentiation, and the use of GnRH agonists inhibits estrogen and thus might inhibit AVM progression [13]. GnRH agonist was administered to women with elevated estrogen levels of >300 pg/mL. We made this the cut-off value because it is the average value for the ovulation phase in normal reproductive women. However, it is unclear whether AVM disappearance was because of these agents or if it spontaneously occurred. Other reports have described treatment with follow-up observation only and without the use of drugs [1, 3, 14]. Timmerman prospectively performed expectant management in 30 patients with AVM who were diagnosed by ultrasonography and color Doppler [15]. Eight women required UAE for massive vaginal bleeding; however, in 22 women (73%), AVM spontaneously disappeared. Lee prospectively analyzed 75 patients with AVM and chose to perform UAE only in women who were anemic or hemodynamically unstable because of vaginal bleeding [3]. In 45 women (60%), AVM spontaneously disappeared without UAE. Evaluation by ultrasound and color Doppler showed the strongest association between low peak systolic velocity (cm/s) and the ability to undergo expectant management. Our department did not assess patient blood flow, which is a limitation that we plan to examine in the future. Furthermore, it is difficult to select a cut-off value for conservative management, but masses measuring < 3 cm without genital bleeding should be considered for conservative management.

expectant management. Our department did not assess patient blood flow, which is a limitation that we plan to examine in the future. Furthermore, it is difficult to select a cut-off value for conservative management, but masses measuring < 3 cm without genital bleeding should be considered for conservative management. In cases of AVM for which UAE is performed, early recurrence can develop with choriocarcinoma diagnosed after a subsequent hysterectomy [21]. Therefore, when considering uterine preservation, the possibility of trophoblastic disease should be considered. We observed no abnormal elevation of hCG levels in the three patients; therefore, trophoblastic disease was ruled out. In conclusion, to avoid ovarian insufficiency caused by UAE and potential complications in subsequent pregnancies, we believe that conservative management should be considered as the primary approach in hemodynamically stable patients, particularly in those undergoing fertility treatment. Acknowledgments The authors would like to thank Enago (https://www.enago.jp) for the English language review. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Diagnosis of AVM by Doppler examination (Patient 1). (a) Several arteries were observed in AVM. (b) A turbulent aspect in the fistula. (c) Venous flow in the intramural venous plexus. Figure 2 AVM depicted by ultrasonography using grayscale and color Doppler (Patient 1, mass measuring 22 × 19 mm in size). Figure 3 AVM spontaneously regressed after 6 weeks without UAE (Patient 1).

Figure 1 Diagnosis of AVM by Doppler examination (Patient 1). (a) Several arteries were observed in AVM. (b) A turbulent aspect in the fistula. (c) Venous flow in the intramural venous plexus. Figure 2 AVM depicted by ultrasonography using grayscale and color Doppler (Patient 1, mass measuring 22 × 19 mm in size). Figure 3 AVM spontaneously regressed after 6 weeks without UAE (Patient 1). Figure 4 AVM depicted by ultrasonography using grayscale and color Doppler (Patient 2, mass measuring 16 × 6 mm in size). Figure 5 AVM depicted by ultrasonography using grayscale and color Doppler (Patient 3, mass measuring 20 × 15 mm in size). Table 1 Clinical course of the three patients with AVM after miscarriage with conservative management. Age (y) Conception Surgery after miscarriage Size of AVM (mm) Hemorrhage Estradiol level at AVM diagnosis (pg/mL) hCG level at AVM diagnosis (mIU/mL) Treatment Time of spontaneous regression Pregnancy after regressive AVM 1 37 IVF D&C 22 × 19 (—) 530.0 93.4 Methylergometrine maleate for 3 weeks + GnRHa for 4 weeks 6 weeks after D&C Term delivery 2 41 IVF D&C 16 × 6 (—) 42 32.3 Methylergometrine maleate for 3 weeks 4 weeks after D&C Under IVF treatment 3 41 IVF Spontaneous abortion 20 × 15 (—) 2,552 294.1 Methylergometrine maleate for 5 days + GnRHa for 3 weeks 6 weeks after miscarriage Under IVF treatment

1. Introduction Known as a rare condition, pyometra is considered as the collection of pus in the uterine cavity [1]. Blockage of the cervical canal secondary to benign or malignant cervical or endometrial lesions and outcomes of their treatments, cervicitis, postvaginal surgery, puerperal infection, and congenital cervical anomaly are the main cause of pyometra [2]. Moreover another rare case is spontaneous perforation of pyometra and subsequent diffuse peritonitis with an incidence of about 0.01%–0.05% [1]. There is a high association between pyometra on one hand and malignancies, risk of perforation, and high mortality rate in a way that clinicians get aware of this disease, especially in postmenopaused women presenting with acute abdomen [3]. A woman was reported who has been treated under a clinical diagnosis of diffuse peritonitis caused by spontaneously perforated pyometra without malignancy.

sk of perforation, and high mortality rate in a way that clinicians get aware of this disease, especially in postmenopaused women presenting with acute abdomen [3]. A woman was reported who has been treated under a clinical diagnosis of diffuse peritonitis caused by spontaneously perforated pyometra without malignancy. 2. Case Presentation A 40-year-old woman presented with vaginal bleeding to Gynecology Service. Bleeding had started two days earlier and was getting severe. Bleeding had happened after lifting a heavy box and was associated with abdominal pain. The pain was generalized and was associated with vomiting. She had no past medical history. She was using contraception and also she was a pill user. She had 2 children, both delivered via cesarean. She did not have any evidence of sexually transmitted disease. On presentation, her blood pressure was 90/60, she was tachycardic at 96, and her body temperature was 37.2. On examination uterus was about 8–10 weeks, it was tender in palpation, and cervix had a normal appearance with a heavy bleeding. Her abdomen was generally tender. Differential diagnosis consisted of ectopic pregnancy (EP), abortion, rupture of an ovarian cyst, endometrial cancer, uterine sarcoma, degenerating myoma, pelvic inflammatory disease (PID), and rupture of the cesarean scar.

2. Case Presentation A 40-year-old woman presented with vaginal bleeding to Gynecology Service. Bleeding had started two days earlier and was getting severe. Bleeding had happened after lifting a heavy box and was associated with abdominal pain. The pain was generalized and was associated with vomiting. She had no past medical history. She was using contraception and also she was a pill user. She had 2 children, both delivered via cesarean. She did not have any evidence of sexually transmitted disease. On presentation, her blood pressure was 90/60, she was tachycardic at 96, and her body temperature was 37.2. On examination uterus was about 8–10 weeks, it was tender in palpation, and cervix had a normal appearance with a heavy bleeding. Her abdomen was generally tender. Differential diagnosis consisted of ectopic pregnancy (EP), abortion, rupture of an ovarian cyst, endometrial cancer, uterine sarcoma, degenerating myoma, pelvic inflammatory disease (PID), and rupture of the cesarean scar. Investigations. Due to vaginal bleeding and abdominal pain we first checked Beta-Human Chorionic Gonadotropin (BHCG) for ruling out pregnancy. BHCG was negative. Laboratory investigations revealed hemoglobin of 6.4 g/dL. In the context of severe vaginal bleeding and abdominal pain an urgent abdominal sonography was performed which showed that the endometrium was about 3 mm and there was remarkable free fluid in the abdomen (Figure 1).

or ruling out pregnancy. BHCG was negative. Laboratory investigations revealed hemoglobin of 6.4 g/dL. In the context of severe vaginal bleeding and abdominal pain an urgent abdominal sonography was performed which showed that the endometrium was about 3 mm and there was remarkable free fluid in the abdomen (Figure 1). 3. Approach and Treatment Protocol Considering abdominal pain, low blood pressure, and remarkable free fluid in the abdomen, we began blood transfusion and did laparotomy. We transfused 3 units of packed-cell. There were about 1000 cc blood and clots in the abdomen. There was a longitudinal rupture from fundus up to cervix at the left side of the uterus. Tearing was in full thickness from serosa to endometrium (Figure 2). Previous cesarean scar was intact. The patient did not have any desire for the next pregnancy, so we did hysterectomy and saved both of ovaries. 4. Outcome and Follow-Up After surgery and recovery, the patient was transferred to the ward. After three days, she discharged from hospital with stable vital sign and good status. Uterus pathology revealed no specific findings and only inflammation was seen in investigated tissues which can be in favor of spontaneous rupture of pyometra as the main reason.

and recovery, the patient was transferred to the ward. After three days, she discharged from hospital with stable vital sign and good status. Uterus pathology revealed no specific findings and only inflammation was seen in investigated tissues which can be in favor of spontaneous rupture of pyometra as the main reason. 5. Discussion Uterine rupture is defined as disruption or tear of the myometrium and serosa of uterus [4]. Spontaneous rupture of the uterus is an uncommon condition occurring mainly in elderly postmenopausal females and results when natural drainage of the uterine cavity is compromised. But documented finding in pregnant women and also the occurrence of spontaneous uterus rupture in a nongravid woman are much rarer [5, 6]. Previous cesarean scar or myomectomy, trauma, grand-multiparity, uterine anomaly or injudicious use of oxytocin or prostaglandin, and neglected labor are some of the predisposing factors for uterine rupture during labor [7–9]. Most ruptures occur in women who have had a previous transmyometrial surgical incision, typically for cesarean delivery [10]. In a study of uterine ruptures in Netherlands, the incidence of rupture in unscarred and scarred uteri was 0.7 and 5.1 per 10,000 deliveries, respectively [11]. A study from the United States reported rupture of the unscarred uterus in 4.54 per 100,000 deliveries or about 1 in 22,000 deliveries [10]. The incidence of rupture in both scarred and unscarred uteri has increased during recent decades [12].

and scarred uteri was 0.7 and 5.1 per 10,000 deliveries, respectively [11]. A study from the United States reported rupture of the unscarred uterus in 4.54 per 100,000 deliveries or about 1 in 22,000 deliveries [10]. The incidence of rupture in both scarred and unscarred uteri has increased during recent decades [12]. Vyas et al. reported that multidetector computed tomography (CT) with sagittal and coronal reformatted images may aid preoperative diagnosis of the ruptured pyometra [13]. As a result of reported studies, 33% of patients were diagnosed correctly using CT or magnetic resonance imaging [14, 15]. In this case after lifting a heavy box, rupture of uterus occurred. The occurrence of the rupture is associated with past surgical history of cesarean section. The signs and symptoms of uterine rupture, largely depending on timing, site, and extent of uterine defect, are severe hemorrhage, palpable fetal parts, loss of uterine contractility and rarely blood stained urine, appearance of placenta at vulva, and prolapsing of loops of gut into vagina [16, 17]. Some signs and symptoms are common in patients. Abdominal pain is reported to occur in up to 13–60% of cases, vaginal bleeding in 11–67% of patients, and hemorrhagic shock in up to 46% of patients [18, 19]. Intensive antibiotic therapy is considered important for a favorable outcome because these patients easily develop generalized peritonitis followed by septic shock [20].

Some signs and symptoms are common in patients. Abdominal pain is reported to occur in up to 13–60% of cases, vaginal bleeding in 11–67% of patients, and hemorrhagic shock in up to 46% of patients [18, 19]. Intensive antibiotic therapy is considered important for a favorable outcome because these patients easily develop generalized peritonitis followed by septic shock [20]. The cases of spontaneously type pyometra without associated with malignancy have better prognosis as compared to those cases that are associated with malignancy. This conclusion is based on the fact that 73% of nonmalignant cases had a favorable prognosis for survival [21]. The uterine rupture is most appropriately diagnosed on the basis of standard signs and symptoms. Considering short time available to diagnose uterine rupture, time-consuming diagnostic methods and sophisticated imaging modalities have a limited utility [17]. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. The authors have no proprietary interests in any aspect of this study. No one has been paid during preparing this manuscript. Figure 1 Abdominal ultrasonography view of patient before any treatment protocol. Figure 2 Rupture view of fundus up to cervix at the left side of the uterus in operation room.

1. Introduction Ovarian squamous cell carcinomas are uncommon, with most arising from malignant transformation of a mature cystic teratoma. Only a few appear in pure form [1, 2]. Most patients with ovarian cancer present at an advanced stage and have a poor prognosis. Invasion into the serosal and muscular layer of the sigmoid colon and rectum by advanced ovarian cancer is common, but colorectal perforation is an extremely rare presentation. Although fistulae communicating with the bladder, rectum, and intestine are reported in malignant transformation of mature cystic teratoma [3, 4], perforation by a pure primary ovarian squamous cell carcinoma has not been reported. We present a case of pure primary ovarian squamous cell carcinoma perforating the rectum.

lthough fistulae communicating with the bladder, rectum, and intestine are reported in malignant transformation of mature cystic teratoma [3, 4], perforation by a pure primary ovarian squamous cell carcinoma has not been reported. We present a case of pure primary ovarian squamous cell carcinoma perforating the rectum. 2. Case Report A 50-year-old woman visited a gastroenterology outpatient clinic complaining of rectal bleeding for several days. There was no significant past history. Rectosigmoidoscopy suggested perforation of a pelvic tumor into the proximal part of the rectum. A biopsy specimen showed squamous cell carcinoma. She was then referred to our hospital. She had no fever and no lower abdominal tenderness on physical examination. Gynecological examination revealed a firm, fixed, fist-sized mass in the pouch of Douglas. Transvaginal ultrasonography revealed a 9 cm heterogeneous, solid mass. There was no free fluid. Laboratory findings included a normal blood count and biochemical parameters. Tumor marker values were normal: CA 125, 9 units/mL (normal: 0–65 units/mL); CA 19-9, 26 units/mL (0–40 units/mL); carcinoembryonic antigen, 3 ng/mL (0.4–3.1 ng/mL); and squamous cell carcinoma antigen, 1.5 ng/mL (0–2 ng/mL). Abdominopelvic magnetic resonance imaging indicated a complex mass containing a pocket of air, which appeared to be separate from the uterus and was seen to penetrate the proximal part of the rectum (Figure 1). Computed tomography revealed several slightly enlarged pelvic lymph nodes.

ma antigen, 1.5 ng/mL (0–2 ng/mL). Abdominopelvic magnetic resonance imaging indicated a complex mass containing a pocket of air, which appeared to be separate from the uterus and was seen to penetrate the proximal part of the rectum (Figure 1). Computed tomography revealed several slightly enlarged pelvic lymph nodes. A laparotomy revealed a left ovarian mass adherent to the rectosigmoid colon (Figure 2(a)). The uterus and right adnexa were intact. Except for slight enlargement of pelvic lymph nodes, no signs of infection or other pathology were found in the rest of the abdomen. In order to resect the tumor and fistula tract, we performed an en-bloc resection of the uterus, adnexa, and rectosigmoid colon (Figure 2(b)). Frozen section examination of the specimen suggested ovarian squamous cell carcinoma, and we therefore performed infracolic omentectomy, pelvic and para-aortic lymphadenectomy, and ileostomy. The cytoreduction was complete. Pathological evaluation of the specimen confirmed the diagnosis of pure primary squamous cell carcinoma of the left ovary, secondarily penetrating through the rectal wall into the lumen. The International Federation of Gynecology and Obstetrics (FIGO) classification was stage IIB (Figure 3). There were no metastases to the lymph nodes or omentum. The patient had no postoperative complications and was discharged 18 days after the operation. Adjuvant chemotherapy (carboplatin and paclitaxel) was administered 42 days after the operation, and no recurrence was seen at the 7-month postoperative follow-up.

e 3). There were no metastases to the lymph nodes or omentum. The patient had no postoperative complications and was discharged 18 days after the operation. Adjuvant chemotherapy (carboplatin and paclitaxel) was administered 42 days after the operation, and no recurrence was seen at the 7-month postoperative follow-up. 3. Discussion Primary squamous cell carcinoma of the ovary is a very rare subtype of ovarian cancer, different from malignant transformation of a mature cystic teratoma, which may also contain squamous cells. Cases of ovarian cancer, including malignant transformation of mature cystic teratomas causing fistulae, involving the colon or rectum are extremely rare [4]. Here we describe the first case to be reported of pure primary ovarian squamous cell carcinoma perforating the rectum, which caused a common symptom of rectal bleeding.

f ovarian cancer, including malignant transformation of mature cystic teratomas causing fistulae, involving the colon or rectum are extremely rare [4]. Here we describe the first case to be reported of pure primary ovarian squamous cell carcinoma perforating the rectum, which caused a common symptom of rectal bleeding. Most ovarian squamous cell carcinomas arise from malignant transformation of mature cystic teratomas, but they have also been reported in association with endometriosis and in a pure form [1, 2]. In our patient, the histological diagnosis showed features of invasive squamous cells alone, without a surrounding teratoma containing elements from all three germ layers. One series has been reported of 37 cases of ovarian squamous cell carcinoma, 19 of which were associated with teratoma, seven with endometriosis, and 11 in the pure form [1]. Because few cases of pure squamous cell ovarian carcinoma have been reported, descriptions of the clinical and pathological features are sparse. Of the 11 cases of this entity reported by Pins et al., presentation occurred at a mean age of 56 years (range 27–73 years), with FIGO stages I, II, III, and IV reported in one, four, five, and one patients, respectively. The tumors ranged in size from 6 to 26 cm in greatest diameter and were usually solid with focal necrosis [1]. The prognosis for squamous ovarian carcinoma, independent of type, is poorer than that for ovarian epithelial cancers of all histologic types, according to most reports in the literature [2]. The overall survival of the patients with pure primary ovarian squamous cell carcinoma in the series reported by Pins et al. was not significantly different from that of the 19 patients with malignant teratoma [1]. The stage at diagnosis correlated best with survival but not with age at diagnosis, tumor diameter, or the presence or absence of necrosis. Five-year survival with advanced ovarian squamous cell carcinoma is better for patients with optimal debulking (76%) than that for patients whose surgical result was suboptimal (24.5%). The evidence is very limited, but adjuvant chemotherapy (mostly platinum-based) appeared to prolong survival in patients with stage III and IV disease compared with those who had surgery only [2, 5].

is better for patients with optimal debulking (76%) than that for patients whose surgical result was suboptimal (24.5%). The evidence is very limited, but adjuvant chemotherapy (mostly platinum-based) appeared to prolong survival in patients with stage III and IV disease compared with those who had surgery only [2, 5]. Perforation of ovarian cancer into the large bowel has been reported in only seven cases [6], including two cases of malignant transformation of mature cystic teratomas [3, 4]. Perforation into the rectosigmoid has also been reported with benign ovarian tumors, mainly mature cystic teratomas. In a review of 38 cases of fistulae associated with teratomas, 30 communicated with the urinary bladder and the others with the colon [7]. The exact factor in not clear, but these reports indicate that leakage of cyst fluid caused by torsion, trauma, malignant transformation, infection, or chronic pressure during labor leads to a fistula [8]. Malignant transformation has not always been shown as an essential factor in formation of a fistula [6]. In our case, there were no apparent factors described above, and tumor was not cystic. The exact pathophysiology is unknown, but severe adherence and chronic pressure could have caused the fistula in our case.

[8]. Malignant transformation has not always been shown as an essential factor in formation of a fistula [6]. In our case, there were no apparent factors described above, and tumor was not cystic. The exact pathophysiology is unknown, but severe adherence and chronic pressure could have caused the fistula in our case. Bats et al. reported a case of ovarian carcinoma penetrating the rectosigmoid that was also associated with an abscess [6]. Our patient did not have an abscess, but we agree with their recommended surgical management that allows management of the fistula along with cytoreduction of the tumor [6]. In addition, chemotherapy is necessary because rectal involvement of an ovarian cancer is classified as at least FIGO stage II, although bowel resection or intra-abdominal infection may delay the start of chemotherapy. Such factors could contribute to a poor prognosis, but our patient is fortunate in that her rectal bleeding prompted a rapid diagnosis. The tumor was encapsulated and had not spread elsewhere in the pelvis, nor was significant inflammation present. We were able to perform an en-bloc resection of the tumor and complete debulking, which is a major prognosis factor in ovarian cancer. We were also able to start adjuvant chemotherapy without significant delay.

tumor was encapsulated and had not spread elsewhere in the pelvis, nor was significant inflammation present. We were able to perform an en-bloc resection of the tumor and complete debulking, which is a major prognosis factor in ovarian cancer. We were also able to start adjuvant chemotherapy without significant delay. In conclusion, formation of a fistula by an ovarian cancer is extremely rare, with a few such cases reporting involved malignant transformation of a mature cystic teratoma. Pure primary ovarian squamous cell carcinoma was the cause of perforation in our patient. Rectal bleeding prompted the diagnosis, and timely, complete debulking surgery was performed. Thorough evaluation of a common sign such as rectal bleeding is crucial in determining the correct diagnosis and appropriate treatment. Acknowledgments This study was supported by Grants-in-Aid for Scientific Research (25462555, 25462556, and 26462488) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Japan Society for the Promotion of Science. The authors would like to thank Enago (http://www.enago.jp) for the English language review. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Abdominopelvic magnetic resonance imaging shows a complex mass containing a pocket of air in the pouch of Douglas. Figure 2 (a) At laparotomy, a left ovarian mass (arrow) was found adhering to the rectosigmoid colon. (b) Resected specimen revealing perforation into the rectum.

Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Abdominopelvic magnetic resonance imaging shows a complex mass containing a pocket of air in the pouch of Douglas. Figure 2 (a) At laparotomy, a left ovarian mass (arrow) was found adhering to the rectosigmoid colon. (b) Resected specimen revealing perforation into the rectum. Figure 3 Microphotograph showing a well-differentiated squamous cell carcinoma (hematoxylin-eosin; ×100).

1. Introduction Labor related pneumomediastinum and subcutaneous emphysema is also known as Hamman's syndrome, it is named after the physician who first described pneumomediastinum in association with subcutaneous emphysema during pregnancy in 1945 [1]. We report the case of an uneventful pregnancy in a primigravid parturient, which was complicated in the late second stage of labor by the development of Hamman's syndrome. 2. Case Report A 22-year-old nulliparous, with no medical history, presented to our hospital in established labor after a spontaneous rupture of membranes, at 40 weeks of pregnancy. The first stage of labor lasted for 6 hours. During labor, she refused to receive any form of analgesia. At the end of the second stage of labor which had lasted for 2 hours, the patient began to cough; she also complained of shortness of breath and pain over the chest and the neck regions. Physical examination revealed conscious patient; the blood pressure was 120/90 mmHg, pulse was 96/min, and the oxygen saturation was 98% on 3 L/min of oxygen. The patient had mild dyspnea with breath rate of 24 cycles/minutes. No edema was present and the patient was afebrile; the cardiopulmonary auscultation was normal.

Physical examination revealed conscious patient; the blood pressure was 120/90 mmHg, pulse was 96/min, and the oxygen saturation was 98% on 3 L/min of oxygen. The patient had mild dyspnea with breath rate of 24 cycles/minutes. No edema was present and the patient was afebrile; the cardiopulmonary auscultation was normal. Palpation showed crepitus underneath the skin of the anterior neck and bilateral subclavian regions consistent with subcutaneous emphysema. The patient had not undergone any radiological examination due to the imminent delivery and the stability of the respiratory function. She received oxygen by facial mask and remained stable. 15 minutes later, the labor ended with a vaginal delivery requiring an episiotomy. The patient delivered a healthy, live infant with Apgar score of 10/10 in the first and fifth minute. One hour later, the cripitations extended to the upper anterior chest wall and to the face including the eyelids without any deterioration in respiratory status. A chest X-ray showed pneumomediastinum with subcutaneous emphysema extending to the soft tissue of the axillary region. Computed tomography (Figures 1 and 2) confirmed pneumomediastinum and subcutaneous emphysema extending to the thoracic, cervical, and abdominal regions. It showed also a minimal pneumothorax. There were no anomalies in the pulmonary parenchyma and thoracic great vessels. Routine blood tests and arterial gas were found to be normal.

graphy (Figures 1 and 2) confirmed pneumomediastinum and subcutaneous emphysema extending to the thoracic, cervical, and abdominal regions. It showed also a minimal pneumothorax. There were no anomalies in the pulmonary parenchyma and thoracic great vessels. Routine blood tests and arterial gas were found to be normal. The patient had been followed up for 4 days in hospital, without a specific medication. The symptoms have regressed and chest X-ray showed disappearance of pneumomediastinum. The patient had been discharged home. Regular follow-up showed complete recovery without any sequelae. 3. Discussion The estimated incidences of subcutaneous emphysema and pneumomediastinum in labor and delivery are between 1/2000 and 1/10000 [2]. The pathophysiology involves rupture of marginal alveoli into perivascular tissue planes, with trapping of air into the mediastinum [3]. It is related to the valsalva maneuver during the labor that increases intrathoracic pressure associated with coughing, vomiting, screaming, or pushing in labor. The increased intrathoracic pressure, combined with decreased vascular calibre, establishes a pressure gradient into the vascular sheath, where air can dissect into the mediastinum and from there into the subcutaneous tissues along fascial planes [4]. Spontaneous pneumomediastinum can be seen in situations other than Hamman's syndrome: forceful coughing related to asthmatic bronchospasm or infections, physical activity, and vomiting [5].

vascular sheath, where air can dissect into the mediastinum and from there into the subcutaneous tissues along fascial planes [4]. Spontaneous pneumomediastinum can be seen in situations other than Hamman's syndrome: forceful coughing related to asthmatic bronchospasm or infections, physical activity, and vomiting [5]. Despite being unproved, some suggest that Hamman's syndrome is most likely to occur in a long labor [6]. However, there was no evidence to substantiate this. A large analysis of 187 cases of Hamman's syndrome, with and without evidence of pneumothorax, revealed that 95% of women were primiparous and both first and second stages of labor were of normal duration. Average fetal size was also found to be within normal limits [7]. The onset of symptoms of pregnancy-related pneumomediastinum usually develops during labor; however, clinical appearance is often delayed until the postpartum phase [8]. These symptoms have also been reported in the earlier antepartum period, during hyperemesis or even spontaneously at rest [9]. The symptoms include chest pain, dysphagia, dysphonia, dyspnea, cough, palpitations, anxiety, and hemoptysis [10]. A chest X-ray usually reveals the subcutaneous emphysema, and significant pneumomediastinum or pneumopericardium may be visible. In our case, the patient was primiparous and had regular length of the first and second stages of labor. She delivered with an important pushing effort as she had not any form of analgesia.

The onset of symptoms of pregnancy-related pneumomediastinum usually develops during labor; however, clinical appearance is often delayed until the postpartum phase [8]. These symptoms have also been reported in the earlier antepartum period, during hyperemesis or even spontaneously at rest [9]. The symptoms include chest pain, dysphagia, dysphonia, dyspnea, cough, palpitations, anxiety, and hemoptysis [10]. A chest X-ray usually reveals the subcutaneous emphysema, and significant pneumomediastinum or pneumopericardium may be visible. In our case, the patient was primiparous and had regular length of the first and second stages of labor. She delivered with an important pushing effort as she had not any form of analgesia. Pneumothorax occurs due to a sudden rise in mediastinal pressure with rupture of the parietal mediastinal pleura. It is reported in a third of cases [11]. However, an isolated pneumothorax can occur in patients with predisposing lung disease. The importance of awareness of this condition, which is usually self-limiting, is to be able to distinguish it from other more life-threatening postpartum conditions such as pulmonary embolism, amniotic fluid embolism, aortic dissection, and myocardial infarction [10].

Pneumothorax occurs due to a sudden rise in mediastinal pressure with rupture of the parietal mediastinal pleura. It is reported in a third of cases [11]. However, an isolated pneumothorax can occur in patients with predisposing lung disease. The importance of awareness of this condition, which is usually self-limiting, is to be able to distinguish it from other more life-threatening postpartum conditions such as pulmonary embolism, amniotic fluid embolism, aortic dissection, and myocardial infarction [10]. Hamman's syndrome is a self-limiting condition, rarely complicated, unless there are underlying respiratory diseases. In the absence of pneumothorax that can cause cardiorespiratory collapse, Hamman's syndrome can resolve with bed rest or even with a conservative treatment within 2 weeks [12]. Treatment is supportive and based on administration of oxygen and provision of analgesia. Management includes avoidance of factors likely to exacerbate the condition such as active pushing, the use of nitric oxide and positive pressure ventilation, and attention to the reassurance and comfort of the patient [13]. Regional anaesthesia is preferred for caesarean section, in order to avoid positive pressure ventilation [14]. 4. Conclusion Hamman's syndrome is a rare complication of labor. It is often a benign condition that is treated conservatively and most cases have a self-limiting course. This condition shows the major interest of labor analgesia especially locoregional techniques. Competing Interests The authors declare no conflict of interests.

4. Conclusion Hamman's syndrome is a rare complication of labor. It is often a benign condition that is treated conservatively and most cases have a self-limiting course. This condition shows the major interest of labor analgesia especially locoregional techniques. Competing Interests The authors declare no conflict of interests. Figure 1 Thoracic computed tomography showing pneumomediastinum, subcutaneous emphysema, and minimal pneumothorax. Figure 2 Cervical computed tomography showing extension of subcutaneous emphysema to the cervical region.

1. Introduction Endometriosis was first described by Karl Von Rokitansky in 1860. It is a chronic gynecologic disorder where the functional and morphological endometrial glands and stroma are present outside the uterine cavity [1]. It mainly affects women in reproductive ages. Major sites for extrapelvic endometriosis include the lungs, pleura, kidneys, bladder, omentum, bowel, lymph nodes, and abdominal wall. Abdominal wall endometriosis is one of the most frequent extra pelvic locations, mostly occurring in old surgical scars from obstetrical and gynecological procedures [2]. The great variability of symptoms and clinical presentations as well as the limited knowledge on the disease can lead to diagnosis difficulties and delays that are detrimental to the patient's wellbeing and quality of life. We report the case of a cesarean section scar endometriosis (CSE) managed at the National Reference Center for Reproductive Health in Rabat and highlight the diagnosis steps and therapeutic management.

ase can lead to diagnosis difficulties and delays that are detrimental to the patient's wellbeing and quality of life. We report the case of a cesarean section scar endometriosis (CSE) managed at the National Reference Center for Reproductive Health in Rabat and highlight the diagnosis steps and therapeutic management. 2. Case Presentation A 37-year-old, G3P3, reported the appearance of a subcutaneous abdominal mass, with discreet menstrually related enlargement, pain, and sporadic brown leakage. Personal history revealed that she had undergone three lower segment cesarean sections; the two first ones were planned, respectively, at 39 and 38 weeks of gestational age for narrow pelvic outlet with uneventful postoperative period. The last one was an emergency, performed at 32 weeks for heavy placenta praevia hemorrhage, with positive fetal outcome. The mass appeared 7 months after the last cesarean section.

first ones were planned, respectively, at 39 and 38 weeks of gestational age for narrow pelvic outlet with uneventful postoperative period. The last one was an emergency, performed at 32 weeks for heavy placenta praevia hemorrhage, with positive fetal outcome. The mass appeared 7 months after the last cesarean section. Physical examination performed during her menstruation period found a palpable tender subcutaneous oval mass of 80 × 35 mm, located under the incision scar, with a small 2 mm diameter skin orifice at the center of the mass, producing thick brown leakage when pressuring the skin on both sides of the orifice (Figure 1). Sonography and Doppler examinations of the abdominal wall soft tissue revealed a heterogeneous hypoechoic mass studded with echogenic spots. A few vascular satellite arterial structures were described (Figure 2). A complementary Computed Tomography reported the presence of a thin fistula between the mass and the skin and described its progression through the subcutaneous tissue. The clinical history, physical examination, and imaging features led to the diagnosis of CSE. Surgical wide en bloc excision was performed, ensuring surrounding macroscopic clear margins and including the covering skin and fistula orifice. The mass was surrounded by fibrosis and small extensions through the aponeurosis were found (Figure 3). They were thoroughly removed, and the subsequent defects were repaired after complete excision of the mass, with no need of mesh placement (Figure 4). The histological examination confirmed the presence of clusters of endometrial glands surrounded by endometrial-like stromal cells and haemosiderin-laden macrophages. The postoperative period was uneventful and periodic 6 months check-ups were set, with no recurrence observed during the 24 months following the surgery.

The histological examination confirmed the presence of clusters of endometrial glands surrounded by endometrial-like stromal cells and haemosiderin-laden macrophages. The postoperative period was uneventful and periodic 6 months check-ups were set, with no recurrence observed during the 24 months following the surgery. 3. Discussion Abdominal wall endometriosis is largely related to previous history of surgery [3]. Endometriosis implants developing in the subcutaneous tissue of surgical scars occur most frequently after gynecological and obstetrical procedures, including cesarean sections, hysterectomies, cystectomies, tubal ligations, and amniocenteses [4]. A few cases have been reported after episiotomy but remain far more rare [5, 6], and cases related to surgical scars of appendectomies, umbilical hernioplasties, and laparoscopic trocar tracts have also been described [7, 8]. It is interesting to note that Ideyi et al. and Chatzikokkinou et al. have published spontaneous cases, in absence of previous surgery, highlighting the complex multifactorial physiopathological processes behind the development of endometriosis [9, 10].

s, and laparoscopic trocar tracts have also been described [7, 8]. It is interesting to note that Ideyi et al. and Chatzikokkinou et al. have published spontaneous cases, in absence of previous surgery, highlighting the complex multifactorial physiopathological processes behind the development of endometriosis [9, 10]. According to Nominato et al., cesarean section remains the most common surgical procedure related to the development of abdominal wall scar endometriosis [11]. They published an estimated incidence of 0.2 to 0.45% though it remains difficult to evaluate as most of the literature available is based on case reports and small series. More recently, in a study examining a cohort of 151 patients diagnosed with CSE, Zhang and Liu reported an incidence of 1.96% [12].

metriosis [11]. They published an estimated incidence of 0.2 to 0.45% though it remains difficult to evaluate as most of the literature available is based on case reports and small series. More recently, in a study examining a cohort of 151 patients diagnosed with CSE, Zhang and Liu reported an incidence of 1.96% [12]. The pathogenesis of endometriosis is complex and CSE is believed to be the result of a mechanical iatrogenic implantation, through the direct inoculation of the abdominal fascia and/or subcutaneous tissue with endometrial cells during the surgical intervention, which, stimulated by estrogen, become active and expand [13]. Wang et al. examined the factors contributing to CSE and defined possible causes, including the easy separation and transport of endometrial cells by the amniotic fluid flowing into the pelvic cavity after hysterotomy; the large amount of endometrial cells liberated into the pelvis before hysterotomy closure and that can potentially be trapped in the wound; and the nurturing role of blood and hormones, after inoculation of the cells, allowing them to grow and develop into subcutaneous masses [14]. It is important to highlight that higher incidence is reported after early hysterotomy (end of second or beginning of third trimester), as early decidua seems to have more pluripotential capabilities and can result in enhanced cellular replication producing endometriosis [15]. This was supported by our case, as the patient developed CSE after a cesarean at 32 weeks.

ce is reported after early hysterotomy (end of second or beginning of third trimester), as early decidua seems to have more pluripotential capabilities and can result in enhanced cellular replication producing endometriosis [15]. This was supported by our case, as the patient developed CSE after a cesarean at 32 weeks. The presence of hormone-sensitive tissue under the skin explains the symptoms reported by our patient, including cyclic pain, swelling, and the very evocative blood-like brown leakage during menstruations. Pain—either cyclical or noncyclical—remained the major symptom, reported by more than 80% of patients in the cohorts of Zhang and Liu in China, Uçar et al. in Turkey, and Vellido-Cotelo et al. in Spain [12, 16, 17]. A mass was present at examination of more than 70% of patients in these studies. With regard to imaging, ultrasound is the most accessible, reliable, and cost-effective imaging technique for the diagnosis of CSE according to Hensen et al. [18], allowing—along with clinical examination—a differential diagnosis with incisional hernia, hematoma, abscess, cyst, or lipoma in most cases. In the study of Zhang and Liu, it also revealed deep infiltrations in 26% of patients, which helped guide the surgical excision [12]. Computed Tomography or Magnetic Resonance Imaging can be used in case of diagnosis doubt but they are rarely needed. Uçar et al. found no evidence of pelvic endometriosis associated for the 12 cases of CSE examined in their study [16]. Vellido-Costelo et al. highlighted that there seem to be no linkages between pelvic and scar endometriosis development. In their study, 14% of patients had associated pelvic endometriosis, which corresponds to the incidence in the general population [17].

associated for the 12 cases of CSE examined in their study [16]. Vellido-Costelo et al. highlighted that there seem to be no linkages between pelvic and scar endometriosis development. In their study, 14% of patients had associated pelvic endometriosis, which corresponds to the incidence in the general population [17]. Based on their clinical experience of fine needle aspiration cytology (FNAC) for 9 cases of CSE, Medeiros et al. have argued that it is a quick, cost-effective, and accurate diagnosis tool to include in patients' management [19]. They encouraged the use of this technique to provide a histopathological diagnosis prior to the surgical procedure in cases of uncertainty on the origin of the mass. In the study of Vellido-Cotelo et al., 52% had a FNAC diagnosis before surgery and one of the patients was diagnosed with cancer by this method, which subsequently led to a different therapeutic management [17]. However, the use of this technique is controversial, as some authors have warned against an increased risk of producing new endometriotic implants at the puncture site, as well as viscera injury if the diagnosis is uncertain [6]. In the case of our patient, clinical examination patterns and imaging features were sufficient to suggest the diagnosis of CSE and there was no need to perform FNAC.

arned against an increased risk of producing new endometriotic implants at the puncture site, as well as viscera injury if the diagnosis is uncertain [6]. In the case of our patient, clinical examination patterns and imaging features were sufficient to suggest the diagnosis of CSE and there was no need to perform FNAC. Therapeutic management is essentially based on large surgical excision, with clear margins and reconstruction of damaged tissue. Medical treatment involving hormone suppression has been suggested to relieve clinical symptoms [20] but, according to Al-Jabri, it only gives partial relief and recurrence after the cessation of medication is constant [21]. Recurrence rates after surgery are variable but seem generally low. No recurrence was reported by Uçar et al. for a follow-up period ranging from 12 to 60 months [16]. Horton et al. found a recurrence rate of 4.3% [7], while Zhang and Liu reported a recurrence of 7.8% over an average period of 20 (±16) months [12]. Most authors agreed that surgery is effective in preventing recurrence, as well as conversion to malignancy, which—although quite rare—has been described in a few sporadic cases [22, 23].

und a recurrence rate of 4.3% [7], while Zhang and Liu reported a recurrence of 7.8% over an average period of 20 (±16) months [12]. Most authors agreed that surgery is effective in preventing recurrence, as well as conversion to malignancy, which—although quite rare—has been described in a few sporadic cases [22, 23]. The role of prevention has been explored in several studies. Picod et al. recommended thorough isolation of the surgical incision site and abundant lavage of the pelvic cavity with saline before closure of the wall [24]. Other studies suggested that absence of closure of the parietal and visceral peritoneum may significantly increase the risk of endometriosis in the skin incision scar [25]. Lastly, instrument and needle replacement when suturing more superficial abdominal layers was also advanced, in order to avoid iatrogenic inoculation of endometrial cells [26]. These recommendations were all based on the various physiopathological hypotheses suggested for the constitution of CSE. No studies have explored them and further research is needed to establish effective measures to prevent abdominal wall postsurgical endometriosis. Competing Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Figure 1 Cesarean section scar with subcutaneous mass and orifice with brown leakage. Figure 2 Heterogenous hypoechoic mass at sonography. Figure 3 Surgical exploration showing mass margins and extensions into the fascia layer. Figure 4 Final surgical outcome with mass and skin excision.

1. Introduction Abdominal pregnancy (AP) accounts for 1% of all ectopic pregnancies [1]. It is defined as the total or partial implantation and development of the fertilized egg in the abdominal cavity. This implantation may be primary or secondary to an intraperitoneal abortion of a tubal pregnancy [2]. In sub-Saharan Africa, the high prevalence of sexually transmitted infections (STIs) with subsequent tubal damage may explain the increasing frequency of this pathology [3, 4]. It varies from 1/2256 pregnancies (Congo) to 1/2941 (Nigeria) [3, 5, 6]. In developed countries, AP is rare (1/10000–15000 births); the lowest rate has been reported in Tunisia (1 case/21439) [2]. In Cameroon it rose from 1/10000 deliveries (1995) to 3.3/10000 (2015). Cases diagnosed beyond the fifth month of pregnancy are not rare in low resource settings where AP remains a challenge to the poorly equipped health facilities, leading to high perinatal mortality and maternal morbidity (heavy bleeding, bowel obstruction, and infection) [5, 7–9]. If AP is rare, a term AP with viable foetus in HIV-positive mother is an even rarer phenomenon with very few cases reported in the literature. Though rare, AP is usually associated with high maternal and perinatal morbi-mortality. AP poses serious clinical and imaging challenges. Despite the significant advances in the domain of diagnostic imaging, the likelihood of preoperative diagnosis of AP is still low.

non with very few cases reported in the literature. Though rare, AP is usually associated with high maternal and perinatal morbi-mortality. AP poses serious clinical and imaging challenges. Despite the significant advances in the domain of diagnostic imaging, the likelihood of preoperative diagnosis of AP is still low. The diagnosis during the second half of pregnancy is suspected in front of painful foetal movements. However, ultrasonographic imaging is the mainstay of diagnosis in resource-poor settings, where laparoscopy and/or magnetic resonance imaging (MRI) are inaccessible. MRI specifies the placental relationship with the abdominal organs while laparoscopy is useful during the first trimester [7]. We report a case of viable term AP in a 24-year-old HIV-positive woman discovered incidentally during a laparotomy indicated for a suspected uterine rupture. 2. Case Presentation The patient was a 24-year-old, gravida 2, para 0, with a past surgical history of right salpingectomy indicated for ruptured ectopic pregnancy 2 years prior to admission. She was admitted with a pregnancy of 39 weeks and 4 days for diffuse abdominal pain of sudden onset with no history of abdominal trauma. She was HIV-positive under tritherapy (Tenofovir, Lamivudine, and Nevirapine) for the past 4 years with good clinical and biological improvement.

pregnancy 2 years prior to admission. She was admitted with a pregnancy of 39 weeks and 4 days for diffuse abdominal pain of sudden onset with no history of abdominal trauma. She was HIV-positive under tritherapy (Tenofovir, Lamivudine, and Nevirapine) for the past 4 years with good clinical and biological improvement. She had her menarche at 12, her first sexual intercourse at 16, and 03 sexual partners in her life, and, at 18 years of age, she used combined oral contraceptive drugs. She did two antenatal consultations (ANC) from the 5th month of pregnancy. Antianaemic prevention was done. The pregnancy was marked by recurrent abdominal pain and painful active foetal movements without bowel obstruction or vaginal bleeding. She had 05 documented ultrasounds done by two specialists: gynecologist and radiologist. The first was done at 17th week of gestation. All reported “a singleton viable intrauterine pregnancy with fundal placenta insertion.” Her main complaint on admission was severe diffuse abdominal pain aggravated by the change of position. The patient had reported no prior loss of liquor. On examination, she was conscious with a good general condition. Her blood pressure was 121/83 mmHg, pulse rate at 101 beats per minute, and temperature 37, 6°C. Her conjunctivae were pink, and the cardiovascular and pulmonary exams were unremarkable. The abdomen was distended, deflected to the right, and tender on palpation. There was no uterine contraction. Foetal parts were easily palpable beneath abdominal wall and foetal heart rate (FHR) was 138 beats per minute. On vaginal exam there was no bleeding and the cervix was posteriorly long and closed. The posterior pouch of Douglas was bulging and tender.

he right, and tender on palpation. There was no uterine contraction. Foetal parts were easily palpable beneath abdominal wall and foetal heart rate (FHR) was 138 beats per minute. On vaginal exam there was no bleeding and the cervix was posteriorly long and closed. The posterior pouch of Douglas was bulging and tender. The general practitioner on call took the patient to the theatre for emergency laparotomy with a presumed diagnosis of uterine rupture with live foetus. Findings were as follows: 600 milliliters of clear amniotic fluid in the peritoneal cavity; an enlarged uterus to the size of 16 weeks with no sign of rupture and a live (Apgar scores of 7 and 9 at the 1st and 5th minute, resp.) female foetus in the subhepatic area weighing 3400 grammes without deformities. No maternal digestive organs were attached to the foetal adnexae (Figure 1), and the placenta was solely inserted to the uterine fundus (Figure 2). Initial detachment of the placenta led to massive bleeding and hypovolemic shock (blood pressure falling to 50/30 mmHg). Resuscitation was achieved through fluid replacement with 4000 milliliters' saline, oxygenation, and epinephrine. Blood transfusion was not achieved due to lack of compatible blood. A tourniquet (sterile drips set cord) concomitantly placed on the lower uterine segment significantly reduced bleeding and allowed complete removal of the placenta. Uterine repair was done with three layers of interrupted sutures. The left fallopian tube was macroscopically normal (Figure 3). Estimated blood loss was 2400 milliliters and urine output was normal.

itantly placed on the lower uterine segment significantly reduced bleeding and allowed complete removal of the placenta. Uterine repair was done with three layers of interrupted sutures. The left fallopian tube was macroscopically normal (Figure 3). Estimated blood loss was 2400 milliliters and urine output was normal. Postoperative follow-up was uneventful and the patient was discharged on the ninth postoperative day. She was put on iron therapy for anaemia and was followed up weekly with her baby for six weeks and then monthly for six months. The mother continued with antiretrovirals and the baby was on exclusive breastfeeding and Nevirapine the first six months. The result of the polymerase chain reaction (PCR) test for the detection of HIV at six weeks of age was negative. The mother was counselled on the need for an 18-month intergenesic space and elective caesarean section during next pregnancies. She accepted lactational amenorrhoea method for contraception and pursued with microprogesterone-only pills. 3. Discussion Abdominal pregnancy is extremely rare. Its prevalence is 10 to 25 times higher in blacks than in Caucasians [9]. Its frequency is increasing in Africa because of predisposing factors including low socioeconomic status, making this disease one of the highlights of poverty [2, 10].

Postoperative follow-up was uneventful and the patient was discharged on the ninth postoperative day. She was put on iron therapy for anaemia and was followed up weekly with her baby for six weeks and then monthly for six months. The mother continued with antiretrovirals and the baby was on exclusive breastfeeding and Nevirapine the first six months. The result of the polymerase chain reaction (PCR) test for the detection of HIV at six weeks of age was negative. The mother was counselled on the need for an 18-month intergenesic space and elective caesarean section during next pregnancies. She accepted lactational amenorrhoea method for contraception and pursued with microprogesterone-only pills. 3. Discussion Abdominal pregnancy is extremely rare. Its prevalence is 10 to 25 times higher in blacks than in Caucasians [9]. Its frequency is increasing in Africa because of predisposing factors including low socioeconomic status, making this disease one of the highlights of poverty [2, 10]. The case reported was incidentally discovered at term, despite Antenatal Care (ANC) with serial obstetric echographies. Nassali et al. reported a case of asymptomatic late term AP despite routine ANC demonstrating diagnosis challenge [11, 12]. In a Nigerian series of twenty cases, 55% of AP were not diagnosed before laparotomy [6]. In our case the results of five antenatal echographies made the diagnosis of AP very unlikely on admission.

assali et al. reported a case of asymptomatic late term AP despite routine ANC demonstrating diagnosis challenge [11, 12]. In a Nigerian series of twenty cases, 55% of AP were not diagnosed before laparotomy [6]. In our case the results of five antenatal echographies made the diagnosis of AP very unlikely on admission. In our case, surgery was indicated for uterine rupture with a live foetus. Several authors reported similar incorrect preoperative diagnosis: abscess of the Douglas pouch; paralytic ileus; hemoperitoneum; and bowel obstruction [6, 13]. Sometimes misdiagnosed AP is discovered after a failure of induction of term pregnancies [6, 9, 11]. In our case, intraperitoneal spillage of amniotic fluid (due to spontaneous intra-abdominal rupture of membranes) caused peritoneal irritation that led to the wrong diagnosis of uterine rupture. D'cunha suggested that absence of a well constituted amniotic sac and the presence of free amniotic fluid predispose to peritonitis [14]. The abundance of amniotic fluid is among one of the criteria for good foetal prognosis in abdominal pregnancies and might explain why our foetus was alive without deformities [8, 12, 15]. AP is very rare in HIV infected women. Increased likelihood of Sexual Transmitted Infections in HIV-positive women may predispose them to tubal damage and hence to ectopic pregnancy including abdominal pregnancy [16].

In our case, surgery was indicated for uterine rupture with a live foetus. Several authors reported similar incorrect preoperative diagnosis: abscess of the Douglas pouch; paralytic ileus; hemoperitoneum; and bowel obstruction [6, 13]. Sometimes misdiagnosed AP is discovered after a failure of induction of term pregnancies [6, 9, 11]. In our case, intraperitoneal spillage of amniotic fluid (due to spontaneous intra-abdominal rupture of membranes) caused peritoneal irritation that led to the wrong diagnosis of uterine rupture. D'cunha suggested that absence of a well constituted amniotic sac and the presence of free amniotic fluid predispose to peritonitis [14]. The abundance of amniotic fluid is among one of the criteria for good foetal prognosis in abdominal pregnancies and might explain why our foetus was alive without deformities [8, 12, 15]. AP is very rare in HIV infected women. Increased likelihood of Sexual Transmitted Infections in HIV-positive women may predispose them to tubal damage and hence to ectopic pregnancy including abdominal pregnancy [16]. Risk factors for AP are those for ectopic pregnancy (EP): subfertility, history of EP, genital malformations, hormonal contraception, tubal surgery, multiple sexual partners, and STIs [3, 17]. Our patient presented all these factors except for malformations.

AP is very rare in HIV infected women. Increased likelihood of Sexual Transmitted Infections in HIV-positive women may predispose them to tubal damage and hence to ectopic pregnancy including abdominal pregnancy [16]. Risk factors for AP are those for ectopic pregnancy (EP): subfertility, history of EP, genital malformations, hormonal contraception, tubal surgery, multiple sexual partners, and STIs [3, 17]. Our patient presented all these factors except for malformations. Abdominopelvic pain is the most common symptom [6, 12, 13]. Our patient had abdominal pain throughout the pregnancy. Other digestive disorders include the following: nausea, postprandial vomiting, bowel obstruction, peritonitis, abnormal foetal lie, and easy palpation of foetal parts beneath maternal skin [4, 14, 15]. Abdominal ultrasound is the key paraclinical exam for AP [7, 12]. It visualizes the foetus in the gestational sac out of the uterus, without uterine wall between the foetus and the bladder. It shows the relationship between the placenta and abdominal organs [7]. Unfortunately echography is an operator-dependent exam that could miss the diagnosis of AP like in our case. Magnetic resonance imaging and laparoscopy may also be useful but are not available in our settings [2, 18].

n the foetus and the bladder. It shows the relationship between the placenta and abdominal organs [7]. Unfortunately echography is an operator-dependent exam that could miss the diagnosis of AP like in our case. Magnetic resonance imaging and laparoscopy may also be useful but are not available in our settings [2, 18]. The management of AP is mainly surgical [2]. A conservative approach may be proposed if diagnosis is made after 20 weeks, provided there is a normal foetal assessment, a placenta implantation site distant from the liver and spleen, a clinical stability of the mother, and a hospital based follow-up with proper information about the risks [18]. In our case the diagnosis was made after emergency laparotomy. The therapeutic challenges were as follows: the young age of the patient and nulliparity and past history of right salpingectomy and the HIV infection. The cataclysmic haemorrhage (2, 4 liters) was to be mastered without compromising her obstetric outcome. 4. Conclusion This case illustrates an AP with two specificities: the diagnosis revealed by the intraperitoneal spillage of amniotic fluid simulating peritonitis from uterine rupture and successful control of bleeding with a tourniquet on the lower uterine segment allowing complete removal of the placenta.

The management of AP is mainly surgical [2]. A conservative approach may be proposed if diagnosis is made after 20 weeks, provided there is a normal foetal assessment, a placenta implantation site distant from the liver and spleen, a clinical stability of the mother, and a hospital based follow-up with proper information about the risks [18]. In our case the diagnosis was made after emergency laparotomy. The therapeutic challenges were as follows: the young age of the patient and nulliparity and past history of right salpingectomy and the HIV infection. The cataclysmic haemorrhage (2, 4 liters) was to be mastered without compromising her obstetric outcome. 4. Conclusion This case illustrates an AP with two specificities: the diagnosis revealed by the intraperitoneal spillage of amniotic fluid simulating peritonitis from uterine rupture and successful control of bleeding with a tourniquet on the lower uterine segment allowing complete removal of the placenta. Acknowledgments The authors are grateful to their patient who allowed them to publish personal information and pictures for a better illustration of this case report and also to Drs. Taafo Francis, Atem Bethel Anjong, and Tchuisse Njonta Henri and to Mr. Kuate Gabriel and the nurse and midwife team and the sisters community Daughters of charity. Competing Interests The authors declare that there are no competing interests regarding the publication of this paper. Figure 1 View of the placenta and uterus after extraction of the foetus. Figure 2 Normal uterus with the placenta implanted on the posterofundal surface.

Acknowledgments The authors are grateful to their patient who allowed them to publish personal information and pictures for a better illustration of this case report and also to Drs. Taafo Francis, Atem Bethel Anjong, and Tchuisse Njonta Henri and to Mr. Kuate Gabriel and the nurse and midwife team and the sisters community Daughters of charity. Competing Interests The authors declare that there are no competing interests regarding the publication of this paper. Figure 1 View of the placenta and uterus after extraction of the foetus. Figure 2 Normal uterus with the placenta implanted on the posterofundal surface. Figure 3 Uterus after placenta removal and uterine suture.

1. Introduction Pelvic organ prolapse (POP) is a common condition in the elderly. Effective treatments for POP include surgery. However, in the elderly population, the incidence of malignancy is increased and the risk peaks in the 75–84-year-old population. The incidence of endometrial cancer coexistent with POP varies from 0.2% to 1.2% [1]. The standard treatment for endometrial cancer is surgical treatment including hysterectomy with bilateral salpingo-oophorectomy (BSO) and pelvic and para-aortic lymphadenectomy [2]. In addition, vaginal hysterectomy is an alternative surgical treatment for endometrial cancer concomitant with POP particularly in those with morbid obesity or poor medical status [2, 3]. For adjuvant treatment, radiotherapy is generally used in women with intermediate risk of metastasis or recurrence; however, radiation alone could be considered in some circumstances [4]. To the best of our knowledge, there was no standard treatment for patients with endometrial cancer coexistent with POP. The objective of this case study was to highlight an alternative management of endometrial cancer in association with POP.

The standard treatment for endometrial cancer is surgical treatment including hysterectomy with bilateral salpingo-oophorectomy (BSO) and pelvic and para-aortic lymphadenectomy [2]. In addition, vaginal hysterectomy is an alternative surgical treatment for endometrial cancer concomitant with POP particularly in those with morbid obesity or poor medical status [2, 3]. For adjuvant treatment, radiotherapy is generally used in women with intermediate risk of metastasis or recurrence; however, radiation alone could be considered in some circumstances [4]. To the best of our knowledge, there was no standard treatment for patients with endometrial cancer coexistent with POP. The objective of this case study was to highlight an alternative management of endometrial cancer in association with POP. 2. Case Report An 87-year-old Asian woman, para 7, was referred to our urogynecology clinic with a week of vaginal bleeding and untreated pelvic organ prolapse. She had no previous vaginal bleeding. The patient had a reducible prolapsed uterus for ten years. She denied any forms of treatment. She did not have any other complaints. This patient, ECOG performance status Grade 2, denied any hormonal replacement therapy or underlying medical conditions other than well-controlled hypertension. Her BMI was 17.6 kg/m2. On vaginal examination, it was found that there was POP Stage IV (POP-Q; Aa +3, Ba +5, C +6, Gh 8, Pb 2, TVL 7, Ap +3, Bp +3.5, D −1) (Figure 1), negative standing cough stress test with full bladder (reduced), normal sensation of perineum, weak and brief pelvic floor muscle strength, and good anal sphincter tone. In addition, there were no lesions in her vaginal wall and cervix, a slightly enlarged uterus, and there was no adnexal mass. Rectal examination showed no abnormalities. The endometrial sampling was performed with a curette at the outpatient department.

brief pelvic floor muscle strength, and good anal sphincter tone. In addition, there were no lesions in her vaginal wall and cervix, a slightly enlarged uterus, and there was no adnexal mass. Rectal examination showed no abnormalities. The endometrial sampling was performed with a curette at the outpatient department. Pathologic result from endometrial biopsy reported endometrioid adenocarcinoma, Grade 2. Imaging studies were evaluated. Her chest X-ray did not show any characteristic of metastasis. A computed tomography (CT) scan showed a uterine mass with bilateral ovarian and omental metastasis, clinical Stage IVB. The initial treatment plan was surgical management; however, she developed stroke and deep vein thrombosis of her left leg with pulmonary embolism. Secondary to her multiple medical comorbidities, her treatment plan was reconsidered and to include vaginal hysterectomy with BSO followed by radiation therapy, or radiotherapy alone. At the time, pelvic radiation either with uterine prolapse or with reduced uterus was considered. After discussion in our multidisciplinary oncology team of both possible treatment options, radiotherapy with a palliative aim on her primary tumor without reducing the prolapse was decided upon in order to avoid radiation side effects to adjacent organs. The radiation was performed 15 fractions (4,500 cGy) with external beam radiation 300 cGy per fraction (Figure 2). The simple small-field technique was used with hypofractionated regimen. After radiation was completed, her symptoms recovered and she developed Grade 2 dermatotoxicity (moist desquamation) that resolved within three months. She visited the radiation oncologist again at six months after radiation without symptoms. After discussion with her cousins, the best supportive care was designed to be further management. In addition, a ring with support pessary was placed for treating the POP.

(moist desquamation) that resolved within three months. She visited the radiation oncologist again at six months after radiation without symptoms. After discussion with her cousins, the best supportive care was designed to be further management. In addition, a ring with support pessary was placed for treating the POP. 3. Discussion Uterine malignancy in pelvic organ prolapsed (POP) patients is uncommon, a range of 0.2%–1.2% risk of diagnosing uterine cancer after POP surgery [1]. In POP patients who present with postmenopausal bleeding, endometrial biopsy should be considered to exclude coexisting endometrial cancer [3].

(moist desquamation) that resolved within three months. She visited the radiation oncologist again at six months after radiation without symptoms. After discussion with her cousins, the best supportive care was designed to be further management. In addition, a ring with support pessary was placed for treating the POP. 3. Discussion Uterine malignancy in pelvic organ prolapsed (POP) patients is uncommon, a range of 0.2%–1.2% risk of diagnosing uterine cancer after POP surgery [1]. In POP patients who present with postmenopausal bleeding, endometrial biopsy should be considered to exclude coexisting endometrial cancer [3]. Vaginal hysterectomy is an effective surgical treatment in POP patients. On the other hand, abdominal hysterectomy, complete surgical staging, was the mainstay of treatment for endometrial cancer patient. However, patients with endometrial cancer, particularly with Stage I disease, coexistent uterine prolapse, would best be treated with vaginal hysterectomy with BSO and/or peritoneal cytologic sample vaginally with vaginal repair [1, 3]. In advanced stage uterine cancer in POP patients, no ideal treatment has been proposed. After vaginal surgery, adjuvant treatment may play an important role. Nevertheless, the treatment options and postoperative adjuvant treatments are based on histologic cell type, stage, and risk factors of recurrence. In significantly medically compromised patients, surgical risk/benefit analysis should be evaluated against risk/benefit analysis of radiation therapy alone when guiding therapeutic decision making [2]. Recent publications showed that an average five-year disease-free survival rate in early stage endometrial cancer in medically compromised patients treated with primary radiotherapy and vaginal hysterectomy was 87%–95% and 90%, respectively [2, 4]. Various studies showed radiotherapy as a primary treatment is effective with a higher recurrence rate of 10–15% [4].

ve-year disease-free survival rate in early stage endometrial cancer in medically compromised patients treated with primary radiotherapy and vaginal hysterectomy was 87%–95% and 90%, respectively [2, 4]. Various studies showed radiotherapy as a primary treatment is effective with a higher recurrence rate of 10–15% [4]. Treatment goals for this patient are a very important factor when making management decisions. Previous case reports have been published regarding the management in these cases. For curative aim, surgery should be performed to obtain accurate pathological details and radiation therapy is considered according to risks as normal condition [5]. For palliation, the aim of treatment was improvement of symptoms. The target of radiation was only the symptomatic lesion. Local irradiation to the problematic area with the smaller field was enough to control symptoms, in this case, regardless of the location of the lesion inside or outside of the pelvis. POP with abnormal uterine bleeding requires careful evaluation. Uterine malignancy in POP patients is uncommon and standardized treatment is controversial. Radiotherapy is an alternative management. Competing Interests The authors declare that they have no competing interests. Figure 1 An 87-year-old woman with uterine prolapse Stage IV. Figure 2 Localized small pelvic radiotherapy for endometrial cancer with prolapsed uterus.

1. Introduction Epithelioid leiomyomas of the vagina are extremely rare benign smooth muscle tumors. Usually, smooth muscle tumors of the vagina present with a submucosal growth pattern or a pedunculated growth pattern from the anterior vaginal wall into vaginal cavity [1] (Figure 1). Preoperative determination of the primary organ is difficult when a vaginal tumor presents a pedunculated growth pattern into the pelvic area. Typically, for this condition a complete surgical resection is part of a multimodality treatment, and the determination of the primary organ and a diagnosis of benignancy or malignancy are desirable for informing the method of surgical treatment of the tumor. Here, we report a case of epithelioid leiomyoma in an extremely rare location.

s condition a complete surgical resection is part of a multimodality treatment, and the determination of the primary organ and a diagnosis of benignancy or malignancy are desirable for informing the method of surgical treatment of the tumor. Here, we report a case of epithelioid leiomyoma in an extremely rare location. 2. Case Presentation A 43-year-old primigravida female was admitted to our hospital for a Pap smear test. As an incidental finding, an ultrasonography and transvaginal physical examination combined with a bimanual rectal exam revealed a solid rubbery mass of approximately 8 × 6 cm between the posterior wall of vagina and anterior wall of the rectum with no obvious limits. Laboratory findings revealed that lactate dehydrogenase, CA-125, carcinoembryonic antigen (CEA), and CA19-9 were within normal limits. Radiological analysis with an echography and contrast enhanced computed tomography (CT) and contrast enhanced magnetic resonance imaging (MRI) revealed multiple leiomyoma in the uterus a solid-cystic mass (8 × 6 cm) in the pelvic area. The mass did not extend from the uterus corpus, but the findings were insufficient to determine its origin (Figure 2). On a diffusion-weighted MRI scan, uterine tumors that were a suspected leiomyoma were hypointense, and a pelvic tumor was hyperintense. Sigmoidoscopy showed a mass pressing the anterior wall of the rectum with no mucosal abnormalities. An ultrasound-guided transvaginal needle biopsy was performed. Microscopically, the tumor showed epithelioid short spindle-cell growth without necrosis. Nuclear pleomorphism was mild, and no mitotic activity was detected (Figure 3). The immunohistochemical staining pattern was partially positive for alpha-smooth muscle actin, desmin, and h-caldesmon. The tumor was negative for pan cytokeratin (AE1/AE3), which excluded epithelium and endothelium differentiation. Melanoma markers melanin A and HMB45 were also negative, which excluded diagnosis of a perivascular epithelioid cell tumor or melanoma. CD34 expression was negative, which excluded solitary fibrous tumor. Estrogen and progesterone receptor were both positive. Ki-67 positive cells were less than 5% of the tumor cells. The pathological diagnosis was an epithelioid leiomyoma. To determine the tumor origin, an angiography was performed, revealing tumor feeding from the vaginal artery, but not the inferior mesenteric artery or the uterine artery (Figure 2).

r were both positive. Ki-67 positive cells were less than 5% of the tumor cells. The pathological diagnosis was an epithelioid leiomyoma. To determine the tumor origin, an angiography was performed, revealing tumor feeding from the vaginal artery, but not the inferior mesenteric artery or the uterine artery (Figure 2). Based on this finding, we suspected that the tumor originated from the vagina. An abdominal wide excision of the tumor with a partial vaginectomy, hysterectomy, and bilateral salpingectomy were performed. Upon laparotomy, the uterine was enlarged with multiple myoma. A pelvic mass was connected to the vagina, but not to the rectum (Figure 4). Firstly, after isolating of ureter, hysterectomy and bilateral salpingectomy were performed. The vagina was transected approximately 1 cm below the cervix. The edges of the vagina were picked up with straight clamps. Secondly, The mass and the connected small posterior vaginal wall measuring 2 × 2 cm were excised en bloc. Thirdly, the edges of the vagina were closed. Macroscopically, the mass measured 8 × 6 cm and had well demarcated borders, and a cut surface revealed occasional nodules of white fasciculated tissue (Figure 5). The microscopic findings were the same as those of the noodle biopsy. The tumor involved the vaginal smooth muscle layer and originated from the vaginal wall (Figure 3). Multiple uterine tumors were diagnosed as a leiomyoma; pathological characteristics of these tumors were different from those of the vaginal tumor. The patient was discharged one week after surgery, and since the time of this report no recurrence has been observed for more than 14 months.

m the vaginal wall (Figure 3). Multiple uterine tumors were diagnosed as a leiomyoma; pathological characteristics of these tumors were different from those of the vaginal tumor. The patient was discharged one week after surgery, and since the time of this report no recurrence has been observed for more than 14 months. 3. Discussion Almost all of the smooth muscle tumors of the gynecological organ that have been reported were in the uterus. Vaginal smooth muscle tumors are rare. There are several histological types of vaginal smooth muscle tumors. Tavassoli and Norris reviewed the pathological features of 60 cases of vaginal smooth muscle tumors and found two tumors that were epithelioid leiomyomas [2]. Only these other two cases of vaginal epithelioid leiomyoma have been reported in the English literature. Epithelioid leiomyoma is more commonly observed in the stomach (59–94% [3–5]), in other gastrointestinal tract regions, the mesentery, and the uterus [3, 4]. However, few cases have been reported for the gynecological organ, 16 cases in the vulva [6], and two cases in the vagina [2]. A summary of our review of the literature on the reports of epithelioid leiomyoma of vagina is presented in Table 1. Our report is the third report in the English literature of an epithelioid leiomyoma of the vagina.

been reported for the gynecological organ, 16 cases in the vulva [6], and two cases in the vagina [2]. A summary of our review of the literature on the reports of epithelioid leiomyoma of vagina is presented in Table 1. Our report is the third report in the English literature of an epithelioid leiomyoma of the vagina. The rectum, vaginal canal, uterine, and the Denonvillier fascia (as it contains smooth muscle cells and blood vessels [7]) can all be possible origins of a pelvic smooth muscle tumor. Smooth muscle tumors of the vagina are usually located in the anterior wall [8] and rarely in the lateral wall [9] and fornix [1]. Usually, smooth muscle tumors of the vagina form well-delineated submucosal anterior vaginal wall masses or are vaginally pedunculated (Figure 1). Tavassoli and Norris reported the possibility that smooth muscle tumors of the vagina can also be multiple [2]. In the present rare case, a pedunculated vaginal tumor presented from the anterior vaginal wall, occupying the pelvic cavity; thus, the preoperative determination of the primary organ was difficult (Figure 1). Radiologic (CT or MRI) analysis is mandatory to evaluate a vaginal mass and its relationship to adjacent structures [10]. Although radiological analysis is important, no test provides sufficient sensitivity or specificity to conclusively rule out malignancy, as this determination must be performed based on a histopathological examination [11]. The radiological findings (CT and MRI) of the present case were insufficient to determine the tumor origin.

diological analysis is important, no test provides sufficient sensitivity or specificity to conclusively rule out malignancy, as this determination must be performed based on a histopathological examination [11]. The radiological findings (CT and MRI) of the present case were insufficient to determine the tumor origin. Determination of the primary organ and a benign or malignant diagnosis are desirable to inform the choice of the surgical approach. In our case, the pathological findings were based on an ultrasound-guided transvaginal needle biopsy, which can be safely performed. In addition, we could determine the tumor origin using an angiography. Histopathologically, benign and malignant vaginal smooth muscle tumors are difficult to distinguish. The criteria used for diagnosing uterine and soft tissue smooth muscle tumors are markedly different. Tavassoli and Norris established diagnostic criteria for smooth muscle tumors of the vagina that indicate that any tumor with greater than 5 mitoses per 10 high power fields and moderate to marked atypism should be considered as a leiomyosarcoma [2]. When the morphological diagnosis is difficult, biomarkers, such as p16, p53, and ki-67, can be used to predict the behavior of a tumor [11].

s with various amount of old milk, water, and proteinaceous materials may present as a heterogeneous mass with a pseudo-solid appearance, containing hypoechoic and hyperechoic materials or a complicated cyst-like lesion mimicking breast cancer, but well-defined and distinct margins would suggest a benign lesion [3, 7]. Salvador et al. reported a wavy line separating the mass into hyperechoic and hypoechoic portions or fat-fluid level [9]. Kim et al. reported that, in their series, about 4.6% of breast masses with BI-RADS category 4 on ultrasound in women during breastfeeding period were proven to be galactocele after performing core needle biopsy [3]. In rare instance when galactocele presents as a solid tumor, multiple differential diagnosis including benign fibroadenoma and invasive carcinoma should be considered [3, 10]. In general, an ultrasound-guided fine needle aspiration (FNA) and/or core needle biopsy should be performed if a lesion does not have the typical imaging appearance of galactocele or a benign breast lesion in a lactating woman [2, 11].

tumors of the vagina that indicate that any tumor with greater than 5 mitoses per 10 high power fields and moderate to marked atypism should be considered as a leiomyosarcoma [2]. When the morphological diagnosis is difficult, biomarkers, such as p16, p53, and ki-67, can be used to predict the behavior of a tumor [11]. Complete excision of a tumor with its capsule and a surrounding rim of normal tissue are recommended for patients with a vaginal leiomyoma [12]. Dhaliwal et al. have specifically recommended the removal of the tumor en bloc to avoid any possible recurrence [13]. Although morcellation of the tumor might allow for an easier surgery approach through a vaginal or abdominal route, tumor recurrence is of concern [8]. In Zhao's series, most epithelioid vulvar leiomyoma patients did not show recurrence at 2 years after excision, but three patients showed recurrence 11 months and 1 year and 10 years later [6]. Thus, long-term follow-up is encouraged for patients with vaginal leiomyoma. In conclusion, angiography is useful for determining the origin of a pelvic mass. An ultrasound-guided needle biopsy is a useful and safe method for preoperative diagnosis of an epithelioid leiomyoma of the vagina. Acknowledgments The authors would like to thank Dr. Yasushi Ito for his help with histopathologic considerations and thank Dr. Katsuji Imoto for his help with radiological considerations. Competing Interests The authors declare that they have no competing interests.

In conclusion, angiography is useful for determining the origin of a pelvic mass. An ultrasound-guided needle biopsy is a useful and safe method for preoperative diagnosis of an epithelioid leiomyoma of the vagina. Acknowledgments The authors would like to thank Dr. Yasushi Ito for his help with histopathologic considerations and thank Dr. Katsuji Imoto for his help with radiological considerations. Competing Interests The authors declare that they have no competing interests. Figure 1 (a) A schematic is shown of the typical location of a smooth muscle tumor (T) of the vagina with a submucosal growth pattern or a pedunculated growth pattern from anterior vaginal wall into the vaginal cavity. (b) In the present case, a vaginal tumor (T) presented a pedunculated growth pattern from the posterior vaginal wall into pelvic cavity, occupying the pelvic cavity. Figure 2 (a) Contrast enhanced MRI radiological analysis. A transverse section shows the tumor (T) anteriorly compressing the uterus corpus (U), cervix (C), and vaginal canal (V), posteriorly compressing the rectum (R). (b) Angiography frontal section image showing that the tumor (T) was nourished from the vaginal artery (VA) and the uterus corpus (U). Figure 3 (a) Microscopic findings show the tumor with epithelioid short spindle-cell growth without necrosis. Nuclear pleomorphism is mild. No mitotic activity is present. (b) The tumor involves the vaginal smooth muscle layer and originated (→) from the vaginal wall.

Figure 2 (a) Contrast enhanced MRI radiological analysis. A transverse section shows the tumor (T) anteriorly compressing the uterus corpus (U), cervix (C), and vaginal canal (V), posteriorly compressing the rectum (R). (b) Angiography frontal section image showing that the tumor (T) was nourished from the vaginal artery (VA) and the uterus corpus (U). Figure 3 (a) Microscopic findings show the tumor with epithelioid short spindle-cell growth without necrosis. Nuclear pleomorphism is mild. No mitotic activity is present. (b) The tumor involves the vaginal smooth muscle layer and originated (→) from the vaginal wall. Figure 4 (a) Laparotomy findings. A pelvic tumor (T) was not connected to the uterus (U). (b) Laparotomy findings after an abdominal hysterectomy and a bilateral salpingectomy. A pelvic tumor (T) was connected to the vaginal stump (VS), but not the rectum (R). Figure 5 (a) Macroscopic findings of the tumor with connected vaginal (V) tissue. (b) The cut surface of a tumor shows occasional nodules of white fasciculated tissue. Table 1 A summary of the epithelioid leiomyoma cases of nonuterine gynecological origin. First author, year Age Size (cm) Outcome Our case, 2017 43 8 No recurrence in 14 months Tavassoli, 1979 34 1.2 No recurrence in 14 years Tavassoli, 1979 — — —

1. Introduction Congenital diaphragmatic hernia (CDH) is a serious birth defect that, despite advances in neonatal care, leads to a significant mortality and morbidity during the neonatal period [1, 2]. CDH occurs in 1 in 3000 live births and differential diagnosis includes cystic adenomatous malformation, teratoma, bronchogenic cyst, and extralobar pulmonary sequestration [3]. Technical improvements in early ultrasound examinations have increased the rate of prenatal diagnosis of different congenital anomalies including CDH. A high percentage of CDH is identified during prenatal ultrasound, when the liver and/or the intestines are presented in the chest together with a malpositioned heart. CDH impairs normal lung development, which implies pulmonary hypoplasia determining the fetus outcome [4]. The size of CDH is important in order to assess the risk of neonatal morbidity and mortality. Currently, prenatal MRI studies have been used in the differential diagnosis of echogenic, cystic intrathoracic masses [5]. Fetal echocardiography is essential since cardiac defects are the most common abnormality associated with CDH and it determines a possible early surgery [3]. Fetuses presenting with other malformations, chromosome abnormalities, and/or syndromes together with or including CDH show a lower survival rate than those with isolated CDH [4].

raphy is essential since cardiac defects are the most common abnormality associated with CDH and it determines a possible early surgery [3]. Fetuses presenting with other malformations, chromosome abnormalities, and/or syndromes together with or including CDH show a lower survival rate than those with isolated CDH [4]. The wide variety of genetic abnormalities associated with either isolated or syndromic CDH reflects the heterogeneity of this malformation. Chromosomal abnormalities including aneuploidies, genomic deletions, and duplication are frequently identified in fetuses with nonisolated CDH. Mutations in CDH forms with autosomal recessive, autosomal dominant, or X-linked patterns of inheritance have been identified [6]. However, the high percentage of CDH cases of unknown origin suggests the existence of other nongenetic causes [6]. Here, we report the case of a fetus with isolated CDH diagnosed at 21 weeks of gestation. Ultrasound examination, echocardiography, MRI, and genetic analysis were performed. We discuss the usefulness of these techniques in the diagnosis of a fetus with either isolated or nonisolated CDH.

The wide variety of genetic abnormalities associated with either isolated or syndromic CDH reflects the heterogeneity of this malformation. Chromosomal abnormalities including aneuploidies, genomic deletions, and duplication are frequently identified in fetuses with nonisolated CDH. Mutations in CDH forms with autosomal recessive, autosomal dominant, or X-linked patterns of inheritance have been identified [6]. However, the high percentage of CDH cases of unknown origin suggests the existence of other nongenetic causes [6]. Here, we report the case of a fetus with isolated CDH diagnosed at 21 weeks of gestation. Ultrasound examination, echocardiography, MRI, and genetic analysis were performed. We discuss the usefulness of these techniques in the diagnosis of a fetus with either isolated or nonisolated CDH. 2. Case Presentation A healthy 37-year-old woman was examined at 16 weeks of gestation because of a positive first-trimester screening. There was neither consanguinity nor familial history of genetic disease or miscarriage. The couple previously had a healthy child. Ultrasound scan showed normal fetal biometry, with a biparietal diameter of 36.9 mm, frontooccipital diameter of 45.8 mm, head circumference of 129.8 mm, abdominal perimeter of 104.9 mm, and femur length of 21.4 mm, as well as an estimated fetal weight of 159 g. The patient refused amniocentesis for cytogenetic analysis.

trasound scan showed normal fetal biometry, with a biparietal diameter of 36.9 mm, frontooccipital diameter of 45.8 mm, head circumference of 129.8 mm, abdominal perimeter of 104.9 mm, and femur length of 21.4 mm, as well as an estimated fetal weight of 159 g. The patient refused amniocentesis for cytogenetic analysis. Subsequently, ultrasound scan at 20 + 4 weeks of gestation showed a CDH on the left side (Figure 1). The fetal biometry showed a biparietal diameter of 48.8 mm, frontooccipital diameter of 58.8 mm, head circumference of 172.9 mm, abdominal perimeter of 137.7 mm, femur length of 37.2 mm, and an estimated fetal weight of 353 g. A detailed ultrasound examination showed a full-filled stomach within the chest cavity, mediastinum shift, and dextrocardia. Given those findings, the patient decided to accept amniocentesis for genetic analysis. 2.1. MRI Exam MRI was performed at 21 + 5 weeks of gestation. MRI showed wide left diaphragmatic herniation that included the left hepatic lobe, the stomach, and the spleen as well as the colon and the bowel loops. This extensive hernia caused cardiomediastinal shift and bilateral lung hypoplasia. Volumetric right lung was 1.22 cc, while volumetric left lung was not possible to determine because of extensive lung hypoplasia. 2.2. Cytogenetic and FISH Analysis Two independent amniotic fluid cells cultures were set up. We analyzed 20 metaphases with chromosomal standard GTG banding techniques with a minimum resolution level of 550 bands.

2.1. MRI Exam MRI was performed at 21 + 5 weeks of gestation. MRI showed wide left diaphragmatic herniation that included the left hepatic lobe, the stomach, and the spleen as well as the colon and the bowel loops. This extensive hernia caused cardiomediastinal shift and bilateral lung hypoplasia. Volumetric right lung was 1.22 cc, while volumetric left lung was not possible to determine because of extensive lung hypoplasia. 2.2. Cytogenetic and FISH Analysis Two independent amniotic fluid cells cultures were set up. We analyzed 20 metaphases with chromosomal standard GTG banding techniques with a minimum resolution level of 550 bands. Amniotic fluid cell chromosome preparations hybridized with the LSI MLL Dual Color Break Apart Rearrangement Probe (11q23)kit [Vysis, Downers Grove, IL] were analyzed. This kit consists in a combination of two probes that hybridize in the MLL locus: a proximal LSI MLL Flanking Probe (SpectrumGreen) and a distal MLL Flanking Probe (SpectrumRed). In addition, FISH analysis with the subtelomeric probe D11S1037 (11qter) [Vysis, Downers Grove, IL] was performed on slides with the amniotic fluid cells according to supplier protocols.

bes that hybridize in the MLL locus: a proximal LSI MLL Flanking Probe (SpectrumGreen) and a distal MLL Flanking Probe (SpectrumRed). In addition, FISH analysis with the subtelomeric probe D11S1037 (11qter) [Vysis, Downers Grove, IL] was performed on slides with the amniotic fluid cells according to supplier protocols. Karyotype revealed additional material in 11q (Figure 2). FISH analysis allowed us to identify an extra signal for MLL probes in interphase nuclei. Analysis in the metaphase cells showed an extra signal in the long arm of chromosome 11 (Figure 3). Only cells showing signals for both the proximal LSI MLL Flanking Probe (SpectrumGreen) and the distal MLL Flanking Probe (SpectrumOrange) were scored. FISH analysis with the subtelomeric probe showed a normal FISH pattern. These findings were compatible with tandem duplication of 11q chromosome material. Karyotype formula was established as 46,XX,dup(11)(q13.5q24).ish dup(11)(MLL++,D11S1037+). A cytogenetic study was performed for the parents in order to discard any familial rearrangement. Parental karyotypes resulted to be normal. Taking together the cytogenetic results, together with the ultrasound and MRI findings, the parents decided to terminate the pregnancy at 23 + 4 weeks of gestation. Autopsy confirmed a female fetus presenting with an extensive left side congenital diaphragmatic hernia with left lung hypoplasia.

A cytogenetic study was performed for the parents in order to discard any familial rearrangement. Parental karyotypes resulted to be normal. Taking together the cytogenetic results, together with the ultrasound and MRI findings, the parents decided to terminate the pregnancy at 23 + 4 weeks of gestation. Autopsy confirmed a female fetus presenting with an extensive left side congenital diaphragmatic hernia with left lung hypoplasia. 3. Discussion CDH is most often diagnosed during morphological ultrasound examination performed at the 18th–22nd week of pregnancy. During this stage, ultrasound shows the diaphragm as a fine hypoechogenic structure between the thorax and the abdomen. Experience of ultrasound examiners, gestational age, fetus position, side of the lesion, extension of the alteration, and the existence of additional malformations are aspects that influence the ability to identify prenatally this malformation [7]. Left side CDHs are easier to be identified during ultrasound examination because they affect the stomach, small bowel, and colon. Extensive hernias are associated with cardiomediastinal shift and bilateral lung hypoplasia and consequently with a poor prognosis [4, 8]. Bilateral CDHs are very uncommon and they are associated with a fatal outcome.

o be identified during ultrasound examination because they affect the stomach, small bowel, and colon. Extensive hernias are associated with cardiomediastinal shift and bilateral lung hypoplasia and consequently with a poor prognosis [4, 8]. Bilateral CDHs are very uncommon and they are associated with a fatal outcome. The severity of lung hypoplasia is determined by the lung-to-head ratio (LHR). LHR is the ratio between the lung area contralateral to the hernia obtained at the level of a four-chamber view of the fetal heart in cross-sectional images and the head circumference of the fetus. LHR > 1.4 is associated with a high survival rate, between 1 and 1.4 with a moderate survival rate, and <1 with a very low survival rate. In this case, the fetus showed LHR < 1. The observed-to-expected lung-to-head ratio expressed as percentage (O/E LHR) was 24%, associated as well with a poor prognosis. MRI has been applied for the prenatal diagnosis of this pathology [9]. MRI allows obtaining a high resolution level of the lesion and of the fetal organs and is independent of the fetus position, the side of the lesion, and gestational age. Total fetal lung volume and right and left lung volumes are determined and compared with normal lung volumes for a specific time of gestation. These values can be obtained by either ultrasound or MRI. Volumetric lung measurements are a predictive postnatal outcome factor. In our particular case, since the two main predictions of postnatal outcome rates showed a poor prognosis for the fetus, we offered again a late amniocentesis.

a specific time of gestation. These values can be obtained by either ultrasound or MRI. Volumetric lung measurements are a predictive postnatal outcome factor. In our particular case, since the two main predictions of postnatal outcome rates showed a poor prognosis for the fetus, we offered again a late amniocentesis. Many genetic causes have been identified during prenatal diagnosis of fetal CDH. The most prevalent aneuploidies include trisomy 18 and trisomy 13 [2], as well as sex chromosomes aneuploidies [10–12]. Complete autosomal trisomy in fetal CDH is always associated with additional prenatal morphological abnormalities. Large chromosome deletions and duplication have been also associated with CDH. The most frequent deletion syndrome associated with CDH is the deletion of 8p23.1. This syndrome presents with Central Nervous System (CNS) anomalies, characteristic facies, mental retardation, and autism. This region includes the GATA4 gene implicated in the development of the diaphragm [13]. Other deletion syndromes associated with CDH and heterogeneous malformations included deletions of 15q26.1 [14], 1q41 [15], or 8q23.1 [16].

tral Nervous System (CNS) anomalies, characteristic facies, mental retardation, and autism. This region includes the GATA4 gene implicated in the development of the diaphragm [13]. Other deletion syndromes associated with CDH and heterogeneous malformations included deletions of 15q26.1 [14], 1q41 [15], or 8q23.1 [16]. CDH has been associated as well with partial 11q23.2 duplication too. However, those partial 11q trisomies were associated with other chromosome anomalies resulting from unbalanced translocations, so that those patients showed additionally a partial monosomy in other chromosomes [17, 18]. In the case present here, parental cytogenetic analyses were normal and no other chromosome region was involved. Therefore, we conclude that the duplication 11q observed during prenatal diagnosis was a de novo event. In this situation, recurrence risk might be very low. Different genes located at 11q have been proposed to play a role in the development of CDH [19]. The ROBO4 gene is expressed in the endothelial cells and it is essential for coordinated symmetric and directed sprouting of intersomitic vessels. The CDON gene is implicated in differentiation and transformation of cells in the skeletal muscle lineage. Therefore, the additional copies of these genes may contribute to CDH in patients with duplication of 11q24.2.

al cells and it is essential for coordinated symmetric and directed sprouting of intersomitic vessels. The CDON gene is implicated in differentiation and transformation of cells in the skeletal muscle lineage. Therefore, the additional copies of these genes may contribute to CDH in patients with duplication of 11q24.2. In summary, CDH is a heterogeneous entity. Prenatal diagnosis by ultrasound and MRI will help to evaluate the extensiveness of the malformation and to determine the prognosis and the treatment. It is essential that the genetic specialist should be present when providing the genetic information to the affected family. In fetuses with CDH, a genetic analysis by array CGH combined with a cytogenetic analysis will probably allow detecting the genetic cause of the malformation and hopefully predicting the prognosis. Ethical Approval The study conformed to the tenets of the Declaration of Helsinki and was approved by the “Committee of Ethics and Clinical Procedures” of our institution (Hospital Universitario Virgen del Rocío in Seville). Consent The couple consented to publish all the information regarding their clinical and genetic findings as well as those from their fetus. Competing Interests The results of this manuscript have not been distorted by research funding or competing interests. Authors' Contributions Lutgardo García-Díaz and Javier Sánchez contributed equally. Figure 1 Ultrasound image. Ultrasound image in which we observe stomach and liver in the chest cavity next to four-chamber view of the heart and left lung's volume reduced.

Competing Interests The results of this manuscript have not been distorted by research funding or competing interests. Authors' Contributions Lutgardo García-Díaz and Javier Sánchez contributed equally. Figure 1 Ultrasound image. Ultrasound image in which we observe stomach and liver in the chest cavity next to four-chamber view of the heart and left lung's volume reduced. Figure 2 Karyotype of amniotic fluid cells showing additional material in the long arm of chromosome 11 (black arrow). Figure 3 FISH analysis with MLL probes. Partial metaphase with MLL probes showed two signals in the 11q chromosome. Interphase nuclei showed three signals for MLL probes. White arrows show MLL hybridization pattern.

1. Introduction Complete androgen insensitivity syndrome, formerly known as testicular feminization, was first described in detail in 1953 in a classic report of 82 cases published by Morris [1]. Since this disease is rare, there are no statistics on its actual prevalence in the population; however, it is estimated to occur in around 1 in 20,400 to 1 in 99,100 male infants [2]. The androgens synthesized in the gonads during embryonic life are of vital importance in determining the male phenotype in an embryo with the 46, XY karyotype. Structural changes in the hormone receptor as a consequence of possible mutations in the X chromosome prevent it from functioning, leading to the expression of a female phenotype in an individual with a male karyotype. All the sex characteristics develop completely; however, the internal genitalia are absent, since production of the anti-Müllerian hormone is maintained. Anti-Müllerian hormone is produced by the Sertoli cells; therefore, detection of this hormone in serum suggests the presence of testicles. In the case of complete androgen insensitivity syndrome (CAIS), serum levels are high, while, in other intersex states, levels may be below normal or undetectable. Therefore, measuring anti-Müllerian hormone levels is of key importance in the diagnosis of male pseudohermaphroditism [3, 4].

ts the presence of testicles. In the case of complete androgen insensitivity syndrome (CAIS), serum levels are high, while, in other intersex states, levels may be below normal or undetectable. Therefore, measuring anti-Müllerian hormone levels is of key importance in the diagnosis of male pseudohermaphroditism [3, 4]. The clinical signs that characterize the disease consist of female behavior, complete lack or scarcity of axillary and pubic hair, adequate female breast development, female external genitalia, blind vaginal pouch, absence of internal genitalia, and the presence of gonads with seminiferous tubules; however, spermatogenesis is absent [4, 5]. Individuals with androgen insensitivity syndrome should be submitted to prophylactic gonadectomy due to the risk of developing testicular malignancy. Studies in adults have shown that 50% of testicles containing a carcinoma in situ develop an invasive tumor within five years of diagnosis when left untreated. The question under debate is the ideal moment for surgery [6, 7]. Historically, surgery was performed as soon as possible to avoid uncomfortable psychosexual questions during adolescence or at the beginning of adult life. More recently, surgery at the end of the teenage years or in the early twenties has been preferred; nevertheless, when opting for this management, it should be remembered that the prevalence of carcinoma in situ is between 2 and 5% during puberty [7, 8].

l questions during adolescence or at the beginning of adult life. More recently, surgery at the end of the teenage years or in the early twenties has been preferred; nevertheless, when opting for this management, it should be remembered that the prevalence of carcinoma in situ is between 2 and 5% during puberty [7, 8]. The present report describes the histopathology findings of bilateral Sertoli cell tumors in a patient with androgen insensitivity syndrome receiving care at the Department of Gynecology and Obstetrics, Santa Casa de Misericórdia, Vitória, Espírito Santo, Brazil. The internal review board of the Santa Casa de Misericórdia Hospital approved the procedures involved in this report on April 27, 2016, under reference number CAAE 51407815.2.0000.5065. Written informed consent for the publication of this report and corresponding images was obtained from the patient. 2. Case Report An unmarried, white 22-year-old patient with a female phenotype, living in a small town in the state of Espírito Santo, presented at the gynecology outpatient clinic of the Santa Casa de Misericórdia Hospital on April 25, 2014 reporting primary amenorrhea. She had begun her sexual life at 19 years of age and had never conceived. She reported having been monitored by a multidisciplinary medical team since she was 17 years old.

ito Santo, presented at the gynecology outpatient clinic of the Santa Casa de Misericórdia Hospital on April 25, 2014 reporting primary amenorrhea. She had begun her sexual life at 19 years of age and had never conceived. She reported having been monitored by a multidisciplinary medical team since she was 17 years old. The patient had a history of hypothyroidism and was undergoing treatment with 100 mcg/day of levothyroxine. There was a positive family history of malformation of the genital tract (two aunts with uterine agenesis). The patient was 1.70 meters in height and weighed 52 kg. Physical examination showed her to be in good general health, with good coloring, well-hydrated, acyanotic, and anicteric and with no swelling. She had poorly developed secondary sex characteristics, small breasts and sparse body hair (vulva and axillae). Her cardiovascular and respiratory systems were normal. Abdominal palpation revealed two inguinal masses, both approximately 4.0 cm in size, mobile and painless. Gynecological examination showed a trophic vulva, sparse pubic hair, and no lesions or dyschromia. Pelvic examination revealed a vaginal canal about 7 cm in length with normal elasticity and rugae, no apparent lesions, and blind vaginal pouch. Bimanual palpation revealed absence of the cervix.

The patient had a history of hypothyroidism and was undergoing treatment with 100 mcg/day of levothyroxine. There was a positive family history of malformation of the genital tract (two aunts with uterine agenesis). The patient was 1.70 meters in height and weighed 52 kg. Physical examination showed her to be in good general health, with good coloring, well-hydrated, acyanotic, and anicteric and with no swelling. She had poorly developed secondary sex characteristics, small breasts and sparse body hair (vulva and axillae). Her cardiovascular and respiratory systems were normal. Abdominal palpation revealed two inguinal masses, both approximately 4.0 cm in size, mobile and painless. Gynecological examination showed a trophic vulva, sparse pubic hair, and no lesions or dyschromia. Pelvic examination revealed a vaginal canal about 7 cm in length with normal elasticity and rugae, no apparent lesions, and blind vaginal pouch. Bimanual palpation revealed absence of the cervix. The patient had brought the results of imaging exams. Magnetic resonance imaging (MRI) showed normal bone morphology with normal signal intensity patterns; no uterus and no ovaries; bladder of normal size with regular walls; and partial vaginal canal with the upper segment missing. There was no free fluid in the abdominal cavity. Nodular formations with regular contours and well-defined borders were located at the level of the inguinal canal, bilaterally and symmetrically, measuring around 3.4 × 2.4 × 1.4 on the right side and 3.6 × 2.5 × 1.4 on the left side, with a slight bulging of the corresponding subcutaneous tissue. Clinically, this finding could correspond to ectopic gonads (cryptorchidism). Ultrasound of the urinary tract was normal. Pelvic ultrasonography showed absence of a uterus at the usual site (agenesis). The ovaries were not visualized, and there was no sign of tumors in the ovarian region or in the pelvis. No free fluid was detected in the pelvis. Previous laboratory tests showed FSH 12.0 mIU/mL, LH 52.5 mIU/mL, TSH 1.092 μIU/mL, cortisol 24.27 μg/dL, 17-hydroxyprogesterone 198 ng/dL, estradiol 33 pg/mL, and 8:00 a.m. cortisol 23.99 μg/dL.

isualized, and there was no sign of tumors in the ovarian region or in the pelvis. No free fluid was detected in the pelvis. Previous laboratory tests showed FSH 12.0 mIU/mL, LH 52.5 mIU/mL, TSH 1.092 μIU/mL, cortisol 24.27 μg/dL, 17-hydroxyprogesterone 198 ng/dL, estradiol 33 pg/mL, and 8:00 a.m. cortisol 23.99 μg/dL. G-banded karyotype was performed on a peripheral blood sample, with results showing the 46, XY genotype. The patient was referred to the hospital's Department of Gynecology for bilateral gonadectomy (Figure 1). The procedure was uneventful and the surgical specimens were sent for anatomopathology, with results showing 3 Sertoli cell tumors in the right gonad, the largest tumor measuring 1 cm in diameter and a Sertoli cell tumor measuring 1 cm in diameter in the left gonad (Figure 2). In all cases, the tumors had the same histological pattern and there were no signs of malignancy (Figure 3). The patient is being monitored clinically at the gynecological endocrinology clinic and is currently under hormone replacement therapy with 2 mg of estradiol valerate (Primogyna®, Schering, Brazil). 3. Discussion Androgen insensitivity syndrome is a metabolic disease characterized by complete resistance to the effects of androgens. According to the literature, its prevalence ranges from 1 in 20,400 to 1 in 99,100 male infants and the disorder is associated with X-linked recessive inheritance [1, 3].

The patient is being monitored clinically at the gynecological endocrinology clinic and is currently under hormone replacement therapy with 2 mg of estradiol valerate (Primogyna®, Schering, Brazil). 3. Discussion Androgen insensitivity syndrome is a metabolic disease characterized by complete resistance to the effects of androgens. According to the literature, its prevalence ranges from 1 in 20,400 to 1 in 99,100 male infants and the disorder is associated with X-linked recessive inheritance [1, 3]. Although diagnosis is usually reached after puberty, it is known that 1-2% of the children who present with an inguinal hernia or a palpable lump in this region may have alterations associated with the syndrome [3]. In adolescence, the principal complaint is primary amenorrhea, with androgen insensitivity syndrome being the third most common cause of this alteration [5]. Diagnosis is based on findings of a female phenotype, absence of the upper genital tract, and confirmation of the 46, XY karyotype. The principal complaint of the patient in question was primary amenorrhea, and, at physical examination, two palpable masses were found in both inguinal regions, in addition to clinical signs of androgen resistance.

ngs of a female phenotype, absence of the upper genital tract, and confirmation of the 46, XY karyotype. The principal complaint of the patient in question was primary amenorrhea, and, at physical examination, two palpable masses were found in both inguinal regions, in addition to clinical signs of androgen resistance. Pelvic examination and evaluation of the gonads can be made by supplementary tests such as ultrasonography and MRI, which, according to the review published by Khan and Craig, are the most accurate tests in such cases [6]. Ultrasound is ideal for an initial diagnostic approach, since it is cheap and easily accessible and its sensitivity for detection of the gonads is good. However, MRI is considered the best option, since it provides a more detailed evaluation and can be used to complement ultrasound findings [6]. In the case presented here, both ultrasonography and MRI revealed the fact that the upper genital tract was absent and that the gonads were missing at the usual site. Compared to ultrasonography, MRI provided a more precise definition of the site and size of the ectopic testicles. Neither of the two methods identified any malformation of the urinary tract.

sonography and MRI revealed the fact that the upper genital tract was absent and that the gonads were missing at the usual site. Compared to ultrasonography, MRI provided a more precise definition of the site and size of the ectopic testicles. Neither of the two methods identified any malformation of the urinary tract. The incidence of testicular cancer is higher in developed countries, with the disease affecting 1.5/100,000 inhabitants worldwide. Female patients diagnosed with Morris syndrome may develop gonadal tumors. According to the literature, the risk of these patients developing malignant tumors is distinctly higher than that of the general population [9–11]. Manuel et al. reported that the risk of malignancy is accumulative and increases with age, with the risk in patients of 25 and 50 years of age being 3.6% and 33%, respectively [10]. Nonetheless, the risk of malignancy in childhood remains low, so bilateral prophylactic gonadectomy is recommended only after puberty, since by then the patient will have benefited from the spontaneous development of the secondary sex characteristics and better bone maturation due to gonadal hormone production [12, 13]. The malignant tumors often associated with this syndrome are seminomas and gonadoblastomas, although other histological forms such as teratomas, choriocarcinomas, yolk sac tumors, and embryonal tumors may also be present. Likewise, benign tumors such as adenomas, Leydig cell, and/or Sertoli cell tumors are other possible findings [14–16].

often associated with this syndrome are seminomas and gonadoblastomas, although other histological forms such as teratomas, choriocarcinomas, yolk sac tumors, and embryonal tumors may also be present. Likewise, benign tumors such as adenomas, Leydig cell, and/or Sertoli cell tumors are other possible findings [14–16]. In the case described here, prophylactic gonadectomy was performed after puberty and the histopathology finding of Sertoli cell tumors in both gonads was unusual. The prevalence of this type of benign tumor is low in the population, representing 0.4 to 1.5% of testicular tumors in adults and 4% in children [16, 17]. Treatment is not restricted to just removing the gonads but demands multidisciplinary management in an attempt to minimize the psychological impact, since there is discordance between the individual's 46, XY genotype and female phenotype [18, 19]. Guidance with respect to sexuality and the impossibility of reproduction is also important aspects and cannot be neglected. In this case, the patient received appropriate counseling and had no complaints regarding her sexual life. Bearing this in mind, expectant management was adopted.

pe and female phenotype [18, 19]. Guidance with respect to sexuality and the impossibility of reproduction is also important aspects and cannot be neglected. In this case, the patient received appropriate counseling and had no complaints regarding her sexual life. Bearing this in mind, expectant management was adopted. Following surgery, estrogen replacement therapy is recommended [20]. Some studies show that estrogen is beneficial in maintaining bone mass, preserving secondary sex characteristics, and preventing the symptoms of hypoestrogenism. Adding progesterone to estrogen therapy during hormone replacement therapy is unnecessary, since the patient has no uterus. Although there are doubts regarding the most appropriate dose and route of administration, either natural or synthetic estrogens can be used, either orally or transdermally [20, 21]. Therefore, taking into consideration the questions of compliance and access to the medication, it was decided to use oral estrogens for hormone replacement therapy. Following treatment initiation, the patient remains asymptomatic and is being followed up at the gynecological endocrinology outpatient clinic of the Santa Casa de Misericórdia Hospital in Vitória. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Surgical outcome following bilateral incisions for gonadectomy. Figure 2 Macroscopy: a solid nodule in the testicular parenchyma. Figure 3 Microscopy: Sertoli cell tumor, with Sertoli cell tubules under high magnification (HE staining, magnification 400x).

1. Background Liddle syndrome was first described in 1963 by Liddle et al. [1] and is caused by a rare autosomal dominant gain-of-function mutation in one of the genes for the epithelial sodium channel (ENaC) found in the distal convoluted tubule of the kidney nephron. This mutation results in pathological reabsorption of sodium and water from the tubule and excretion of potassium into the urine which results in hypertension, hypokalemia, metabolic alkalosis, and suppression of renin and aldosterone. The ENaC, sometimes referred to as the amiloride-sensitive epithelial sodium channel, is composed of three homologous subunits: alpha (encoded by the SCNN1A gene), beta (SCNN1B gene), and gamma (SCNN1G gene). Mutations in the beta or gamma subunits have been shown to cause Liddle syndrome (Staub, Warnock).

aldosterone. The ENaC, sometimes referred to as the amiloride-sensitive epithelial sodium channel, is composed of three homologous subunits: alpha (encoded by the SCNN1A gene), beta (SCNN1B gene), and gamma (SCNN1G gene). Mutations in the beta or gamma subunits have been shown to cause Liddle syndrome (Staub, Warnock). Liddle syndrome often presents with the onset of hypertension at a young age, hypokalemia, decreased renin and aldosterone, and a family history consistent with autosomal dominant inheritance. The phenotypic presentation of Liddle syndrome varies somewhat even within families carrying the same mutation and thus hypokalemia is not always present and the degree of hypertension is variable [2, 3]. Inhibitors of the ENaC that are used in the treatment for Liddle syndrome are, namely, two medications: amiloride (preferred in pregnancy, the Food and Drug Administration classifies it as pregnancy category B) and triamterene (generally avoided in pregnancy due to interference with folic acid metabolism, pregnancy category C). Some patients with Liddle syndrome may respond to only triamterene or amiloride depending on their genetic mutation (Warnock). Treatment with these medications typically results in resolution of the hypertension and hypokalemia.

avoided in pregnancy due to interference with folic acid metabolism, pregnancy category C). Some patients with Liddle syndrome may respond to only triamterene or amiloride depending on their genetic mutation (Warnock). Treatment with these medications typically results in resolution of the hypertension and hypokalemia. 2. Case A 27-year-old African American woman, gravida 4, para 2-1-0-3, at 18-week gestation with a history of chronic hypertension with no prenatal care presented to triage with conjunctivitis and was found to have a blood pressure of 183/108 mmHg. She had been diagnosed with chronic hypertension at the age of 13 and had multiple partial workups for her hypertension and several hospital admissions for severely elevated blood pressures. Upon review of her medical records, her hypokalemia dated to the age of 17 at least. She had uncomplicated vaginal deliveries in 2008 and 2010. In 2013, she had an induction of labor and vaginal delivery at 28 weeks for severely elevated blood pressure readings up to 250/120 mmHg. She reported a family history of hypertension in her two brothers, two sisters, her mother, and her 4-year old child. She reported one sibling that was unaffected by hypertension. She reported that most of her family members had onset of their hypertension between the ages of 15 and 30 (Figure 1).

s up to 250/120 mmHg. She reported a family history of hypertension in her two brothers, two sisters, her mother, and her 4-year old child. She reported one sibling that was unaffected by hypertension. She reported that most of her family members had onset of their hypertension between the ages of 15 and 30 (Figure 1). On admission, her serum potassium was 2.6 mMol/L, sodium 140 mMol/L, and creatinine 0.47 mg/dL. Her urine potassium was 15 mMol/L, urine sodium was 112 mMol/L, and urine chloride was 110 mMol/L. She had very low renin and aldosterone which is consistent with Liddle syndrome. Her renin activity was 0.8 ng/mL/hr, aldosterone was <3.0 ng/dL, and Aldosterone/Renin Activity (A/RA) was <3.8. The A/RA ratio was difficult to interpret as the renin level was near the lower limit of the reported range and the aldosterone level was below the reported range. Her serum adrenocorticotropic hormone (ACTH), urine metanephrines, and urine vanillylmandelic acid (VMA) were all within normal range. Her baseline 24 hr urine showed 357 mg of protein. A renal US showed normal echotexture and there was no evidence of hydronephrosis or nephrolithiasis. There was no size discrepancy between the two kidneys. A previous computed tomography scan of the abdomen showed normal appearing kidneys, renal vasculature, and adrenal glands. Her extensive laboratory workup and family history were consistent with the provisional diagnosis of Liddle syndrome as other causes were less likely. To confirm her diagnosis, genetic testing for our patient was sent and confirmed a heterozygous frameshift mutation in the SCNN1B gene (Monogenic Hypertension Evaluation, Athena Diagnostics). The patient was notified multiple times to bring her family members in for evaluation and genetic testing but declined to do so.

To confirm her diagnosis, genetic testing for our patient was sent and confirmed a heterozygous frameshift mutation in the SCNN1B gene (Monogenic Hypertension Evaluation, Athena Diagnostics). The patient was notified multiple times to bring her family members in for evaluation and genetic testing but declined to do so. Initially, she was admitted and her acute hypertension was treated with intravenous hydralazine followed by oral sustained-release nifedipine 30 mg daily and oral labetalol 300 mg twice daily. After her laboratory workup and the provisional diagnosis of Liddle syndrome, she was started on oral amiloride 5 mg daily as an outpatient, which was increased to 5 mg twice daily at 22 weeks of gestation and later to 10 mg in the morning and 5 mg at bedtime. With this amiloride dosing regimen, her serum potassium increased to 3.8 mMol/L without requiring any oral potassium supplementation, but her blood pressure control was still suboptimal. Amiloride was further increased to 10 mg twice daily. Her BP at 24 weeks of gestation was 155/102 mmHg. Unfortunately, the patient was poorly compliant with her amiloride and did not present for any further prenatal care before delivery.

al potassium supplementation, but her blood pressure control was still suboptimal. Amiloride was further increased to 10 mg twice daily. Her BP at 24 weeks of gestation was 155/102 mmHg. Unfortunately, the patient was poorly compliant with her amiloride and did not present for any further prenatal care before delivery. At 37 weeks and 4 days of gestation, she presented to triage in labor and was found to be dilated at 8 centimeters. She had not been taking her amiloride and her blood pressure readings were 186/133 and 212/129 mmHg. Her potassium level was 3.9 mMol/L. Her acute hypertension was controlled with intravenous labetalol. The patient underwent an emergent primary low transverse cesarean section for FHR deceleration. A female infant was born with 1-minute and 5-minute Apgar scores of 8 and 9, respectively, and a weight of 2070 grams (<1% percentile). The umbilical cord arterial pH was 7.20 and the base excess was −6.2. The placental pathology was unremarkable. Postpartum hypertension was treated with oral triamterene 50 mg daily (it was more readily available than amiloride as it was on hospital formulary) and oral labetalol 300 mg three times daily, resulting in BPs in the range of 140–150 s/70–80 s mmHg. She was discharged 3 days after her delivery. She did not follow up for a postoperative or postpartum visit despite frequent reminders. She was treated in the emergency room for a yeast infection 3 months after delivery at which time her blood pressure was 173/111 mmHg, likely secondary to noncompliance with triamterene.

e was discharged 3 days after her delivery. She did not follow up for a postoperative or postpartum visit despite frequent reminders. She was treated in the emergency room for a yeast infection 3 months after delivery at which time her blood pressure was 173/111 mmHg, likely secondary to noncompliance with triamterene. 3. Discussion Amiloride appears to be a safe and effective medication for controlling blood pressure and correcting hypokalemia in pregnant patients with Liddle syndrome. A previous case report of Liddle syndrome diagnosed before pregnancy describes the achievement of optimal blood pressure control with oral amiloride 15 mg daily; however, a cesarean delivery was later performed for uncontrolled hypertension in labor (Caretto). Our patient had a c.1789_1790 base pair duplication of cytosine in codon 597 of the SCNN1B gene (heterozygous frameshift mutation). This is one of the different mutations that can lead to the Liddle syndrome phenotype (Jackson).

, a cesarean delivery was later performed for uncontrolled hypertension in labor (Caretto). Our patient had a c.1789_1790 base pair duplication of cytosine in codon 597 of the SCNN1B gene (heterozygous frameshift mutation). This is one of the different mutations that can lead to the Liddle syndrome phenotype (Jackson). Diuretics in pregnancy are generally avoided due to possible volume depletion and uteroplacental hypoperfusion. This is counterintuitive to the presumption of volume expansion in Liddle syndrome. The clinical presentation does not usually include edema. Liddle syndrome patients behave clinically similar to patients with primary hyperaldosteronism due to the function of their mutation. In primary hyperaldosteronism, it is known that there is initially sodium and water retention that is followed by a spontaneous diuresis called aldosterone escape which lowers the extracellular fluid volume almost toward normal. This occurs due to volume expansion. The mechanisms responsible for the escape include the following: increased secretion of atrial natriuretic peptide ANP, decreased thiazide-sensitive sodium chloride (NaCl) cotransporter in the distal tubule, and pressure natriuresis. It is possible that the same autodiuresis may be involved in Liddle syndrome, and hence diuretics should be avoided [4].

escape include the following: increased secretion of atrial natriuretic peptide ANP, decreased thiazide-sensitive sodium chloride (NaCl) cotransporter in the distal tubule, and pressure natriuresis. It is possible that the same autodiuresis may be involved in Liddle syndrome, and hence diuretics should be avoided [4]. Amiloride is an effective medication in the treatment of Liddle syndrome in pregnancy since it reverses the pathological volume expansion and the excessive sodium reabsorption, thus, mitigating the pathogenesis of hypertension. In rats, the amount of alpha ENaC subunits, the rate-limiting subunit for formation of the ENaC channel, has been shown to increase in late pregnancy (West) which is consistent with an increase in the number of ENaC channels as pregnancy progresses. This is consistent with our clinical experience and that of Caretto's group [5] that increasing doses of amiloride are needed to control BP as gestational age advances due to the presence of more pathological ENaC channels. Amiloride doses of up to 15 mg orally twice a day have been used during pregnancy (Mathen). Titrating amiloride to a target blood pressure of 140–150 s/90–100 s mmHg seems reasonable with a maximum dose of 30 mg daily. Warnock has suggested that, in patients with Liddle syndrome who correct their potassium with ENaC-blocking medication but remain hypertensive, the addition of beta blockers or vasodilators may be beneficial [6]. By the third day after delivery, the blood pressure of the patient described by Caretto et al. had normalized to 125/85 mmHg [5]. In contrast, the blood pressure of the patient in our case remained elevated after delivery, which could be likely due to noncompliance with triamterene. Due to the potential for the number of ENaC channels to change after delivery, the blood pressure medication regimen should be reevaluated after a patient with Liddle syndrome delivers. The safety of both amiloride and triamterene in lactation is unknown; hence close monitoring of the breastfed infant is advised. Pregnant patients with Liddle syndrome may require additional agents to achieve their blood pressure target which could be done by adding a second agent to the first-line medications, the ENaC blockers. There is limited literature on this topic; however, it is well accepted that a poorly controlled blood pressure in pregnancy is a major risk factor for adverse prenatal outcome and hence more medications may be needed [7].

et which could be done by adding a second agent to the first-line medications, the ENaC blockers. There is limited literature on this topic; however, it is well accepted that a poorly controlled blood pressure in pregnancy is a major risk factor for adverse prenatal outcome and hence more medications may be needed [7]. Although only a few cases of Liddle syndrome in pregnancy have been reported, there is an association with both fetal growth restriction and preeclampsia. One case described by Caretto et al. was complicated by fetal growth restriction without preeclampsia or proteinuria [5]. Hayes et al. reported on the anesthetic management of a cesarean hysterectomy for a patient with Liddle syndrome and placenta accreta in her third pregnancy [8]. The case report notes that the woman's two previous deliveries were complicated by fetal growth restriction and preeclampsia. The patient's third pregnancy was complicated by fetal growth restriction but not preeclampsia. Our case was associated with fetal growth restriction less than the 1st percentile at delivery. Our patient had 357 mg protein in a baseline 24 hr urine sample at 18 weeks of gestation and did not develop increased proteinuria in her pregnancy (her urinalysis on the day of delivery was negative for protein). Although diagnosis of preeclampsia in patients with Liddle syndrome can be challenging, standard criteria for diagnosis of chronic hypertension with superimposed preeclampsia should be used.

tion and did not develop increased proteinuria in her pregnancy (her urinalysis on the day of delivery was negative for protein). Although diagnosis of preeclampsia in patients with Liddle syndrome can be challenging, standard criteria for diagnosis of chronic hypertension with superimposed preeclampsia should be used. In summary, a high suspicion for Liddle syndrome in pregnancy should be maintained in cases with uncontrolled hypertension and hypokalemia with a significant family history of the same. Management should involve controlling the acute severe elevation of blood pressure with intravenous hydralazine or labetalol as per standard obstetric protocols, replacing potassium and initiating the oral ENaC blocker (amiloride during pregnancy and either amiloride or triamterene afterward). Due to a 2-month turnaround time for genetic testing, empiric treatment with amiloride is reasonable. Weekly prenatal care appointments should be scheduled during initiation of amiloride to monitor blood pressure and potassium and to titrate the dose along with evaluation of preeclampsia and fetal growth restriction. Finally, encourage first-degree relatives to be evaluated for elevated blood pressure and hypokalemia, including the newborn infant.

ents should be scheduled during initiation of amiloride to monitor blood pressure and potassium and to titrate the dose along with evaluation of preeclampsia and fetal growth restriction. Finally, encourage first-degree relatives to be evaluated for elevated blood pressure and hypokalemia, including the newborn infant. Additional Points (1) Until genetic testing results are available, suspected Liddle syndrome can be diagnosed and treated empirically based on onset of hypertension at a young age often less than 20 years old, hypokalemia, decreased renin and aldosterone, and a family history consistent with autosomal dominant inheritance. (2) In pregnancy, a reasonable starting dose of oral amiloride is 5 to 10 mg total daily as once-a-day dosing or divided for twice-a-day dosing. As gestational age progresses, higher doses of amiloride up to 30 mg daily divided into two doses may be required. It seems reasonable to titrate amiloride to a target blood pressure range of 140–150 s/90–100 s and a potassium greater than 3.5. (3) Amiloride is preferred in pregnancy over triamterene for treatment of Liddle syndrome due to its safety profile in pregnancy. Conflicts of Interest The authors declare no conflicts of interest. Figure 1 Patient's family pedigree.

1. Introduction Abdominal pain, a common complaint during pregnancy, has a broad differential diagnosis which includes spontaneous adrenal hemorrhage (SAH). While autopsy reports reveal that between 0.03 and 1.8% of unselected cases demonstrate adrenal hemorrhage, the incidence among pregnant women is unknown [1]. A high index of suspicion is necessary to diagnose SAH as most patients present with nonspecific symptoms including abdominal or flank pain and fever [2, 3]. Rarely, patients can develop massive retroperitoneal bleeding and present with hemodynamic instability [1, 4, 5]. If bilateral, SAH can lead to adrenal crisis and shock necessitating emergency laparotomy and adrenalectomy [2, 5]. We present two cases of symptomatic SAH in the third trimester of pregnancy with successful conservative management.

op massive retroperitoneal bleeding and present with hemodynamic instability [1, 4, 5]. If bilateral, SAH can lead to adrenal crisis and shock necessitating emergency laparotomy and adrenalectomy [2, 5]. We present two cases of symptomatic SAH in the third trimester of pregnancy with successful conservative management. 2. Case Presentation 2.1. Case #1 A 35-year-old nulliparous patient at 36 weeks of gestation presented to labor and delivery complaining of sudden onset, left sided back pain which radiated anteriorly. She denied any other gastrointestinal or urinary symptoms. The patient had a past medical history significant only for chronic hypertension and a past surgical history of laparoscopic Roux en Y gastric bypass two years priorly. She denied any prior complications related to this surgical history. The pregnancy was further complicated by gestational diabetes class A1. On presentation the patient had a blood pressure of 162/80 and heart rate of 70 beats per minute and was saturating 99% on room air. Initial exam revealed the abdomen to be tender to palpation in left upper quadrant with no guarding and no peritoneal signs. There were no symptoms of labor and fetal status was reassuring.

presentation the patient had a blood pressure of 162/80 and heart rate of 70 beats per minute and was saturating 99% on room air. Initial exam revealed the abdomen to be tender to palpation in left upper quadrant with no guarding and no peritoneal signs. There were no symptoms of labor and fetal status was reassuring. Complete blood count, coagulation studies, liver function tests, amylase, and lipase were all within normal limits with a hemoglobin of 12.4 g/dL. A urinalysis demonstrated rare bacteria and calcium oxalate crystals, but no blood. A renal ultrasound showed no evidence of hydronephrosis, mass, or stone. An obstetrical ultrasound revealed a live singleton fetus with a normal appearing anterior placenta and appropriate fetal growth. Intravenous narcotics were required for adequate pain control. General surgery was consulted given her history of gastric bypass and concern for a possible related complication. A CT scan of the abdomen demonstrated a mildly enlarged left adrenal gland with areas of hyperdensity consistent with acute left adrenal hemorrhage (Figure 1). This was a new finding compared with a CT scan performed one year priorly. The patient denied any history of abdominal trauma or anticoagulation. She was admitted to the Surgical Intensive Care Unit where she was comanaged by Maternal Fetal Medicine and General Surgery. She was monitored with serial hemoglobin assessments and abdominal examinations and remained clinically and hemodynamically stable. She was discharged home at 37 weeks of gestation after a 4-day hospitalization and returned for induction of labor at 39 weeks of gestation due to chronic hypertension and gestational diabetes. The patient had an uncomplicated, spontaneous vaginal delivery of a female neonate weighing 7 pounds and 4 ounces with APGARs of 8 at 1 minute and 9 at 5 minutes. Her postpartum course was uncomplicated and interval imaging study to assess resolution of the adrenal hemorrhage was planned.

sion and gestational diabetes. The patient had an uncomplicated, spontaneous vaginal delivery of a female neonate weighing 7 pounds and 4 ounces with APGARs of 8 at 1 minute and 9 at 5 minutes. Her postpartum course was uncomplicated and interval imaging study to assess resolution of the adrenal hemorrhage was planned. 2.2. Case #2 A 27-year-old multiparous patient presented to labor and delivery at 38 weeks of gestation for evaluation of sudden onset, left upper quadrant pain that radiated to the midline. The patient also reported regular, painful contractions. She had a past medical history significant for nephrolithiasis during her previous pregnancy, bipolar disease, and migraines. Prior surgeries included a diagnostic laparoscopy for chronic pelvic pain, Loop Electrosurgical Excision Procedure, and 2 elective terminations of pregnancy. The patient was a 5-6-cigarette/day smoker. On admission vital signs were within normal limits. Physical examination revealed her abdomen to be soft and minimally tender to palpation. A complete blood count was within normal limits with a hemoglobin of 12.4 g/dL. A urine drug screen was negative and a urinalysis revealed no blood or evidence of infection. Fetal status was reassuring and an obstetric ultrasound revealed no apparent pathology. The patient's pain improved with intravenous narcotics, antacids, and a muscle relaxer and was attributed to a likely musculoskeletal etiology. However, the patient was found to be in spontaneous labor and progressed to deliver a male infant without complication. Intrapartum pain relief was provided via epidural. On the first postpartum day the patient again complained of left sided flank and upper abdominal pain and was presumptively treated for nephrolithiasis, given the clinical presentation and history, with intravenous narcotics and hydration. Despite treatment, the pain worsened and was associated with nausea and two episodes of emesis. A CT scan of the abdomen revealed enlargement and mild heterogeneity of the left adrenal gland with surrounding fat stranding consistent with acute left adrenal hemorrhage. An MRI performed at the request of the attending physician confirmed these findings as seen in Figure 2. She denied any trauma or use of anticoagulants. Total cortisol level was normal at 14.7 ug/dL with a low ACTH of 5.0 pg/mL. The patient was monitored with serial assessments of hemoglobin and remained clinically and hemodynamically stable. Her pain was controlled with intravenous narcotics.

indings as seen in Figure 2. She denied any trauma or use of anticoagulants. Total cortisol level was normal at 14.7 ug/dL with a low ACTH of 5.0 pg/mL. The patient was monitored with serial assessments of hemoglobin and remained clinically and hemodynamically stable. Her pain was controlled with intravenous narcotics. She was discharged on postpartum day 4 with a plan for short interval follow-up. A CT scan performed 8 months later revealed unremarkable adrenal glands with complete resolution of the previously identified hemorrhage. 3. Discussion If unrecognized, adrenal hemorrhage can lead to adrenal crisis, shock, and theoretically death for both mother and fetus and should be considered in the differential diagnosis of abdominal pain in pregnancy [3, 4]. Presenting symptoms are similar to those in nonpregnant patients and include acute onset flank, abdominal or even chest pain, nausea, vomiting, or hypotension [4, 5]. In order to be classified as spontaneous and idiopathic there can be no history of trauma, anticoagulation, tumor, or sepsis [2, 4–6].

pregnancy [3, 4]. Presenting symptoms are similar to those in nonpregnant patients and include acute onset flank, abdominal or even chest pain, nausea, vomiting, or hypotension [4, 5]. In order to be classified as spontaneous and idiopathic there can be no history of trauma, anticoagulation, tumor, or sepsis [2, 4–6]. While the initial abdominal imaging study in pregnancy is typically ultrasound, sonographic findings of adrenal hemorrhage are nonspecific. MRI or CT scan is needed to confirm the diagnosis and to evaluate for potential underlying etiology such as pheochromocytoma or malignant tumor [2]. On MRI, adrenal hemorrhage appears as a heterogeneous mass with enlargement of one or both adrenal glands while a contrast CT scan demonstrates adrenal echogenicity, streaky appearance of the perirenal fat, perinephric hematoma, or a retroperitoneal hematoma in a massive bleed [2, 4]. A follow-up MRI or CT scan is usually recommended to confirm stability or resolution of the hematoma, especially if a conservative approach is adopted. Recommended laboratory evaluations include serial hemoglobin measurements as well as assessment of adrenal function. Work-up should also rule out disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Consideration should be given to inherited and acquired thrombophilias, including antiphospholipid syndrome, as potential etiologies of adrenal vein thrombosis and subsequent hemorrhage [3]. In both of the above reported cases platelet count and coagulation parameters were within normal limits and there was no clinical suspicion for thrombophilia.

to inherited and acquired thrombophilias, including antiphospholipid syndrome, as potential etiologies of adrenal vein thrombosis and subsequent hemorrhage [3]. In both of the above reported cases platelet count and coagulation parameters were within normal limits and there was no clinical suspicion for thrombophilia. Appropriate management of SAH in pregnancy depends on the stability of the patient. Conservative management includes supportive therapy with intravenous fluids, pain control, and serial hemoglobin assessments with blood transfusion and correction of coagulopathy as indicated [3]. Close monitoring of fetal status is warranted. Preterm delivery may be indicated if a patient is unstable, worsening, or if adrenal hemorrhage is associated with severe preeclampsia or eclampsia [2]. In hemodynamically unstable patients with ongoing hemorrhage arterial embolization can be considered, but severely ill patients may warrant emergent adrenalectomy [3, 7]. There is scant literature available on optimal mode of delivery but, in a stable patient, vaginal delivery can be safely undertaken as demonstrated in the reported cases. 4. Conclusion SAH, although rare, is an important consideration when evaluating abdominal and flank pain in pregnancy. Diagnosis requires a high index of suspicion, particularly when more common etiologies of pain are excluded as was demonstrated in the two cases presented in this report. Diagnosis can be made by MRI or CT scan. In a clinically stable pregnant patient with SAH conservative management and vaginal delivery are safe and appropriate.

equires a high index of suspicion, particularly when more common etiologies of pain are excluded as was demonstrated in the two cases presented in this report. Diagnosis can be made by MRI or CT scan. In a clinically stable pregnant patient with SAH conservative management and vaginal delivery are safe and appropriate. Acknowledgments The authors would like to thank Dr. David Ginsburg for obtaining informed consent. Disclosure The abstract for this manuscript was presented at the ACOG annual clinical meeting in Washington DC on May 14–17, 2016. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 CT scan findings with arrow pointing at left adrenal hemorrhage. Figure 2 MRI findings of left adrenal hemorrhage.

1. Introduction Uterine leiomyosarcomas (LMS) are associated with poor prognosis, with an average five-year survival rate of around 40% [1, 2]. Moreover, median overall survival after recurrence is under 12 months [3, 4]. The treatment for unresectable advanced or recurrent uterine LMS is chemotherapy. Standard first-line chemotherapy has been doxorubicin with or without ifosfamide [5]. The response rate of this combination chemotherapy was reported as complete response in 3% to 16% of patients and partial response in 27% to 32% of patients [6, 7]. If the disease does not respond to standard chemotherapy, one agent of interest is pazopanib because of its activity in patients with soft-tissue sarcoma [8]. Pazopanib has been comprehensively defined as a synthetic indazolpyrimidine with activity as a small-molecule vascular endothelial growth factor (VEGF) inhibitor (specifically, as a multitargeted tyrosine kinase inhibitor) against VEGFs 1, 2, and 3 and platelet-derived growth factors. Pazopanib was approved as a second-line treatment after a phase III trial of this drug reported a statistically significant increase in progression-free survival [9, 10]. Pazopanib has been available in Japan for treating soft-tissue sarcoma since 2012. Many tyrosine kinase inhibitors (TKIs) are also used in the treatment of other cancers such as non-small cell lung cancer, chronic myeloid leukemia, renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer. Recently, several reports have demonstrated cases of rapid tumor size increase related to cessation of TKI treatment [11–15].

nhibitors (TKIs) are also used in the treatment of other cancers such as non-small cell lung cancer, chronic myeloid leukemia, renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer. Recently, several reports have demonstrated cases of rapid tumor size increase related to cessation of TKI treatment [11–15]. In this report, we present an advanced LMS case that suddenly worsened after cessation of pazopanib therapy. 2. Case Presentation A 47-year-old woman (nullipara) with no past history was diagnosed with uterine LMS of FIGO stage IVB, with multiple lung, liver, and bone metastases. We retrospectively reviewed the medical records of the patient so as to assess the outcomes and adverse events of therapy. We used the Response Evaluation Criteria in Solid Tumors (ver 1.1) to assess tumor responses and the Common Terminology Criteria for Adverse Events (ver 4.0) to assess adverse events. The growth modulation index (GMI), the ratio of time to progression (TTP) with present therapy and TTP with previous therapy, is calculated as follows: GMI = TTPpresent therapy/TTPprevious therapy [16]. We calculated the GMI, ratio of TTP after discontinuing pazopanib to TTP while receiving chemotherapy (docetaxel with gemcitabine, adriamycin, and pazopanib).

tio of time to progression (TTP) with present therapy and TTP with previous therapy, is calculated as follows: GMI = TTPpresent therapy/TTPprevious therapy [16]. We calculated the GMI, ratio of TTP after discontinuing pazopanib to TTP while receiving chemotherapy (docetaxel with gemcitabine, adriamycin, and pazopanib). The patient had symptoms of genital bleeding, and a uterine tumor was identified. Findings from a tumor biopsy were suggestive of uterine LMS. The patient was treated with neoadjuvant chemotherapy (docetaxel with gemcitabine) for two courses. However, the primary tumor, peritoneal dissemination, and the lung metastases progressed. The attending physician indicated surgery in order to reduce tumor volume and to confirm diagnosis by pathology. Subsequently, she was treated with surgical resection (total abdominal hysterectomy with bilateral salpingoophorectomy and partial omentectomy). Pathological examination confirmed the uterine LMS diagnosis and the presence of metastatic tumors in both ovaries and the omentum. After resection, the patient underwent chemotherapy (adriamycin) for three courses; although lung metastases became stable, peritoneal dissemination progressed. As we judged the patient's disease to have progressed as a whole, we decided to cease the adriamycin treatment. Subsequently, we treated the patient with pazopanib therapy (800 mg) orally once daily for three months. Prior to commencing pazopanib therapy, her echocardiography findings were normal. The patient did not experience pazopanib therapy-related adverse events at severe grades but did develop grade II hypertension that responded to antihypertensive medication. A CT scan taken three months after starting pazopanib treatment showed that the tumor sizes of the liver and lung metastases and of the peritoneal dissemination were stable (Figure 2). However, pazopanib therapy was discontinued due to the new occurrence of a metastasis to the skin. At this time, we began considering a different type of chemotherapy.

er starting pazopanib treatment showed that the tumor sizes of the liver and lung metastases and of the peritoneal dissemination were stable (Figure 2). However, pazopanib therapy was discontinued due to the new occurrence of a metastasis to the skin. At this time, we began considering a different type of chemotherapy. After ceasing pazopanib therapy, cough symptoms sharply increased for two weeks. Her echocardiography findings were again normal. Additionally, the sum of the patient's tumor diameters increased as follows: for lung metastases, by −10% (during the 3-month-pazopanib treatment) versus by 55% (during the two weeks after ceasing treatment); for liver metastases, by 0% versus by 33%; and for peritoneal dissemination, by 12% versus by 51% (Figure 1). Particularly, the lung metastases sharply increased (Figure 2). The GMI was 0.18 (ratio of TTP after discontinuing pazopanib to TTP while receiving chemotherapy). The patient also experienced sudden worsening of symptoms, such as severe dyspnea which was difficult to control. She had an emergency hospitalization for the severe dyspnea. Large enlargement of the right ventricle and dysfunction of the left ventricle were confirmed by echocardiography. A CT scan did not show any evidence of pulmonary infarction or pulmonary bleeding. Therefore, the patient was diagnosed with acute pulmonary heart. The dyspnea was treated with morphine and oxygen administration; however, the patient's symptoms did not improve. The patient died after four days under sedation. She had died one month after cessation of the pazopanib therapy.

tion or pulmonary bleeding. Therefore, the patient was diagnosed with acute pulmonary heart. The dyspnea was treated with morphine and oxygen administration; however, the patient's symptoms did not improve. The patient died after four days under sedation. She had died one month after cessation of the pazopanib therapy. 3. Discussion A global, double-blind, randomized, phase III trial of pazopanib for metastatic soft-tissue sarcoma compared pazopanib once daily versus placebo as second-line or later treatment for patients with advanced soft-tissue sarcoma [10]. In this trial, progression-free survival was significantly improved in the pazopanib arm (median, 4.6 versus 1.6 months; hazard ratio, 0.31; P < .001). On the basis of the results of the trial, pazopanib is currently recommended as one of the treatments for patients with advanced soft-tissue sarcoma after failure of standard chemotherapy. We experienced pazopanib therapy for an advanced or recurrent uterine LMS patient whose condition suddenly worsened after cessation of pazopanib therapy. The sum of the tumor diameters after cessation sharply increased for two weeks. Furthermore, this patient's sudden tumor size increase after ceasing pazopanib therapy appeared related to uncontrolled severe dyspnea.

or recurrent uterine LMS patient whose condition suddenly worsened after cessation of pazopanib therapy. The sum of the tumor diameters after cessation sharply increased for two weeks. Furthermore, this patient's sudden tumor size increase after ceasing pazopanib therapy appeared related to uncontrolled severe dyspnea. Some reports have claimed that the cessation of TKI therapy has been followed by the rapid progression of what is termed “flare-up” or “tumor flare” [11–15]. The mechanism for this phenomenon has not been clarified. One hypothesis is the rapid growth of TKI-sensitive clones following the discontinuation of the drug [12, 13]. Another possible explanation is that the residual inhibitory effects of the antiangiogenics disappear after cessation of therapy [14]. One such study found that some (23%) patients with EGFR-mutant lung cancer and acquired resistance to TKIs experienced disease flare after discontinuation of TKI and that the median time to flare was 8 days (range 3–21 days) [12]. Another study of tumor flare occurrence and its prognostic role after discontinuing anti-VEGF receptor TKIs investigated patients with metastatic renal cell carcinoma, similarly concluding that TKI discontinuation accelerates tumor growth rate and negatively affects prognosis [15]. Chaft et al. have reported that shorter time to progression on initial TKI treatment and the presence of pleural or central nervous system metastases are associated with tumor flares in patients with lung cancer [12].

ncluding that TKI discontinuation accelerates tumor growth rate and negatively affects prognosis [15]. Chaft et al. have reported that shorter time to progression on initial TKI treatment and the presence of pleural or central nervous system metastases are associated with tumor flares in patients with lung cancer [12]. The growth modulation index (GMI) is the ratio of time to progression (TTP) with present therapy and TTP with previous therapy. It has been suggested that GMI > 1.33 indicates a drug or drug combination is active [16]. In our patient, the GMI was 0.18 (ratio of TTP after discontinuing pazopanib to TTP while receiving pazopanib). This GMI suggests that her disease progressed suddenly after discontinuing pazopanib therapy. A phase II study has shown that trabectedin is a useful therapeutic agent [17] and this new agent was recently approved for treatment of advanced soft-tissue sarcoma; however, we could not use it to treat our patient because it had not yet been approved. Some studies have suggested that continuing some therapies beyond identification of progressive disease can be clinically beneficial; this is termed “beyond PD” [18, 19]. The concept of beyond PD may be relevant to avoidance of “flare-up” or “tumor flare” associated with TKI therapy.

A phase II study has shown that trabectedin is a useful therapeutic agent [17] and this new agent was recently approved for treatment of advanced soft-tissue sarcoma; however, we could not use it to treat our patient because it had not yet been approved. Some studies have suggested that continuing some therapies beyond identification of progressive disease can be clinically beneficial; this is termed “beyond PD” [18, 19]. The concept of beyond PD may be relevant to avoidance of “flare-up” or “tumor flare” associated with TKI therapy. If the patient above had continued pazopanib therapy, such symptoms might have instead been mild. Therefore, when considering this case for sudden tumor growth after ending pazopanib treatment and for absence of adverse events of severe grade, it appears that treatment could have been further continued in light of comparative risks of disease progression. The prognosis of recurrent uterine leiomyosarcomas is poor; thus, disease control is important. 4. Conclusion In conclusion, on the basis of our experience conducting pazopanib therapy for patients with advanced LMS, we conclude that the decision to discontinue pazopanib therapy requires careful consideration. Acknowledgments The authors thank Charles de Kerckhove for editing as per his training through the American Medical Writers Association. Conflicts of Interest The authors declare no potential conflicts of interest relevant to this article. Figure 1 The graph shows the change of tumor size with course of treatment. The sum of the patient's tumor diameters increased after cessation of pazopanib therapy.

Acknowledgments The authors thank Charles de Kerckhove for editing as per his training through the American Medical Writers Association. Conflicts of Interest The authors declare no potential conflicts of interest relevant to this article. Figure 1 The graph shows the change of tumor size with course of treatment. The sum of the patient's tumor diameters increased after cessation of pazopanib therapy. Figure 2 Transverse section of lung in computed tomography. (a) Start of pazopanib therapy. (b) End of pazopanib therapy. (c) After two weeks' cessation of pazopanib therapy.

1. Introduction Accessory axillary breast is a congenital anomaly that is commonly bilateral and does not include areola and nipple in most cases. The diagnosis of accessory breast tissue may be delayed until the first pregnancy, when hormonal fluctuations change the breast composition [1, 2]. In the pregnancy period, symptomatic axillary breast tissue becomes painfully enlarged and a galactocele may rarely develop [2]. Galactoceles can be caused by any etiology that blocks a breast duct during lactation, but, in most cases, it is the result of a benign condition. Galactoceles are similar to ordinary cysts, but, instead of clear fluid, they contain milk. They can mimic fibroadenoma, carcinoma, and other breast masses [3]. The mammographic and sonographic appearances of a galactocele depend upon the amount of fat in the fluid, the viscosity of the fluid, and also the amount of proteinaceous material. Aspiration of milk will generally confirm the diagnosis. Here, we report a case of galactocele in the accessory axillary breast tissue masquerading a suspicious solid mass. The presence of galactocele was confirmed after fine needle aspiration (FNA) of the axillary mass. 2. Case Presentation A 32-year-old woman who was breastfeeding her first baby for 6 months, presented to our Breast Clinic with the complaint of a palpable left axillary lump. She had noticed a lump in her left axillary region before the pregnancy, which became enlarged during the pregnancy and breastfeeding periods.

Galactoceles are similar to ordinary cysts, but, instead of clear fluid, they contain milk. They can mimic fibroadenoma, carcinoma, and other breast masses [3]. The mammographic and sonographic appearances of a galactocele depend upon the amount of fat in the fluid, the viscosity of the fluid, and also the amount of proteinaceous material. Aspiration of milk will generally confirm the diagnosis. Here, we report a case of galactocele in the accessory axillary breast tissue masquerading a suspicious solid mass. The presence of galactocele was confirmed after fine needle aspiration (FNA) of the axillary mass. 2. Case Presentation A 32-year-old woman who was breastfeeding her first baby for 6 months, presented to our Breast Clinic with the complaint of a palpable left axillary lump. She had noticed a lump in her left axillary region before the pregnancy, which became enlarged during the pregnancy and breastfeeding periods. Physical examination revealed a 4 cm mass in the subcutaneous tissue of the left axilla. The mass was nontender and unattached to skin. There were no evidences of inflammation such as skin color discoloration in the left axilla or fever. Ultrasound examination of the axillary region revealed a hypoechoic, well-defined mass with irregular shape and margins and nonparallel orientation measuring 2.5∗3.5∗4 cm which was suspicious for a malignant lesion (Figure 1).

re no evidences of inflammation such as skin color discoloration in the left axilla or fever. Ultrasound examination of the axillary region revealed a hypoechoic, well-defined mass with irregular shape and margins and nonparallel orientation measuring 2.5∗3.5∗4 cm which was suspicious for a malignant lesion (Figure 1). Color Doppler ultrasound was performed and did not show vascular flow in the axillary mass. Ultrasound examination of the left breast did not reveal any significant abnormality and lymphadenopathy was not seen in the axilla. There was no significant abnormality at the right breast and axilla except for the proliferative changes of glandular tissue which is a normal finding during lactation and was seen in both breasts. Considering that the patient was in breastfeeding period, our first diagnosis was a galactocele in the accessory breast, but because the sonographic appearance of the axillary mass was not consistent with the ultrasound criteria of a true simple cyst or a typical benign lesion, both the clinician and the patient were concerned and insisted on performing an interventional procedure to rule out possible malignant nature of the lesion. Ultrasound-guided aspiration using a 20-gauge needle was performed for confirming an axillary galactocele. Milky fluid was aspirated and the mass disappeared completely (Figure 2). The aspirated materials were sent for laboratory evaluation. Cytopathologic examination was negative for malignant cells. Based on these findings, the diagnosis of a galactocele of the axillary accessory breast was made.

Considering that the patient was in breastfeeding period, our first diagnosis was a galactocele in the accessory breast, but because the sonographic appearance of the axillary mass was not consistent with the ultrasound criteria of a true simple cyst or a typical benign lesion, both the clinician and the patient were concerned and insisted on performing an interventional procedure to rule out possible malignant nature of the lesion. Ultrasound-guided aspiration using a 20-gauge needle was performed for confirming an axillary galactocele. Milky fluid was aspirated and the mass disappeared completely (Figure 2). The aspirated materials were sent for laboratory evaluation. Cytopathologic examination was negative for malignant cells. Based on these findings, the diagnosis of a galactocele of the axillary accessory breast was made. Additional diagnostic investigations were not indicated in our patient and she was reassured to have a follow-up sonographic examination after 3 months. She returned 4 months later and ultrasound examination was performed. There was no evidence of any left axillary mass and accessory breast tissue with proliferative changes was noted (Figure 3).

tigations were not indicated in our patient and she was reassured to have a follow-up sonographic examination after 3 months. She returned 4 months later and ultrasound examination was performed. There was no evidence of any left axillary mass and accessory breast tissue with proliferative changes was noted (Figure 3). 3. Discussion Galactoceles are benign lesions of the breast that represent encysted collections of milk products. They are mostly detected during lactation or in the third trimester of pregnancy. However, in rare cases, the condition may occur after breastfeeding has stopped, as milk is retained and becomes stagnant within the lactiferous ducts [1, 3, 4]. The presence of galactocele in adult males and young infants has been rarely reported [2, 4]. The presence of galactocele in the axillary accessory breast is a rare occurrence [4, 5]. Although it is most commonly located in the axilla, ectopic or accessory breast tissue may be seen anywhere along the thoracoabdominal milk line. This line extends from the axillary region down to the groin [6]. Axillary accessory breast usually presents as bilateral swellings in the axilla. Various lesions have been reported in the accessory breast in the literature including simple cyst, inflammatory lesions and mastitis, atypical hyperplasia, fibroadenoma, and rarely carcinoma [1].

the axillary region down to the groin [6]. Axillary accessory breast usually presents as bilateral swellings in the axilla. Various lesions have been reported in the accessory breast in the literature including simple cyst, inflammatory lesions and mastitis, atypical hyperplasia, fibroadenoma, and rarely carcinoma [1]. Galactoceles are the most common benign breast lesions in lactating women [2, 3]. Galactoceles can mimic fibroadenoma or breast carcinoma, but they are always benign and do not increase the risk of breast cancer in any way. Galactoceles may have several causes. Three main factors are required to make a galactocele including secretory breast epithelium, present or previous prolactin stimulation and ductal obstruction. Breast surgery, oral contraceptives, and transplacental prolactin passage are reported as other possible causes in creating a galactocele [3]. Clinically, the mass is usually firm and nontender and presents as a tumoral lesion on physical examination. The patient usually notes the lesion during lactation or some period after lactation [2, 3].

Galactoceles are the most common benign breast lesions in lactating women [2, 3]. Galactoceles can mimic fibroadenoma or breast carcinoma, but they are always benign and do not increase the risk of breast cancer in any way. Galactoceles may have several causes. Three main factors are required to make a galactocele including secretory breast epithelium, present or previous prolactin stimulation and ductal obstruction. Breast surgery, oral contraceptives, and transplacental prolactin passage are reported as other possible causes in creating a galactocele [3]. Clinically, the mass is usually firm and nontender and presents as a tumoral lesion on physical examination. The patient usually notes the lesion during lactation or some period after lactation [2, 3]. The imaging appearance of galactocele depends on the amount of fat and proteinaceous material present in the cystic lesion and also the viscosity of the fluid. Pseudolipoma is the name given to the galactocele when the fat content is very high and appears as a completely radiolucent mass [7, 8]. The typical mammographic features of galactocele are a mass with fat-fluid level caused by fat and water. Fat-fluid levels are usually seen on the mediolateral mammographic view with the patient in upright position and a horizontal X-ray beam [2].

ontent is very high and appears as a completely radiolucent mass [7, 8]. The typical mammographic features of galactocele are a mass with fat-fluid level caused by fat and water. Fat-fluid levels are usually seen on the mediolateral mammographic view with the patient in upright position and a horizontal X-ray beam [2]. The interpretation of mammography is usually difficult in young woman particularly during breastfeeding period as mammography is usually very dense in these women. Ultrasound is the imaging method of choice to evaluate breast masses during pregnancy and lactation and mammography should be performed only in special circumstances [7, 8]. The ultrasound appearance of galactocele also depends on the amount of fat and water contents. Galactoceles with various amount of old milk, water, and proteinaceous materials may present as a heterogeneous mass with a pseudo-solid appearance, containing hypoechoic and hyperechoic materials or a complicated cyst-like lesion mimicking breast cancer, but well-defined and distinct margins would suggest a benign lesion [3, 7].

s including benign fibroadenoma and invasive carcinoma should be considered [3, 10]. In general, an ultrasound-guided fine needle aspiration (FNA) and/or core needle biopsy should be performed if a lesion does not have the typical imaging appearance of galactocele or a benign breast lesion in a lactating woman [2, 11]. Milk aspiration can be performed and cyst resolution following aspiration can be a pathognomonic sign of a galactocele. Galactoceles are not serious or dangerous but may be uncomfortable. The typical treatment for a galactocele is to leave them alone. Galactoceles usually resolve spontaneously after the hormonal change associated with pregnancy and lactation is ceased. But, in patients with true discomfort, attempts may be made to drain the galactocele through FNA. Some clinicians have proposed that the diagnostic aspiration of the fluid from the cystic mass may prove to be diagnostic and therapeutic at the same time [2]. In conclusion, the presence of galactocele as a mass in accessory axillary breast tissue is a rare occurrence but that should be kept in mind in pregnant or lactating women presenting with axillary mass. Galactoceles located in the axillary accessory breast may rarely appear as a solid suspicious mass mimicking a malignant lesion. In most cases, FNA usually confirms the correct diagnosis and can be used as a diagnostic and also a therapeutic test in these patients. Acknowledgments The authors thank Mashhad University of Medical Sciences for their valuable support. Conflicts of Interest The authors declare no conflicts of interest.

In conclusion, the presence of galactocele as a mass in accessory axillary breast tissue is a rare occurrence but that should be kept in mind in pregnant or lactating women presenting with axillary mass. Galactoceles located in the axillary accessory breast may rarely appear as a solid suspicious mass mimicking a malignant lesion. In most cases, FNA usually confirms the correct diagnosis and can be used as a diagnostic and also a therapeutic test in these patients. Acknowledgments The authors thank Mashhad University of Medical Sciences for their valuable support. Conflicts of Interest The authors declare no conflicts of interest. Figure 1 Ultrasound examination of the axillary mass reveals a hypoechoic mass with irregular margins. Figure 2 A milky fluid was aspirated with fine needle aspiration of the axillary mass. Figure 3 Proliferative changes in the accessory breast tissue in the axillary region. There is no evidence of mass lesion.

It is difficult to predict the pregnancy outcome and complications associated with endometriosis as major studies conducted in the past were based on either personal history of endometriosis given by patients or retrospective case notes review. Hence, not only does extracting the data regarding the staging, severity, and spread of the disease become challenging for researchers, but it is also very difficult to fully appreciate the impact of each specific stage of disease on the pregnancy outcome. High index of suspicion is required with previous history of endometriosis if women present with irregular uterine contractions and symptoms like severe abdominal pain not relieved by tocolysis with gradually unexplained drop in haemoglobin in the absence of overt haemodynamic instability. 4. Conclusion Antenatal recommendations for specific stage or severity of endometriosis cannot be made; however, it is essential to increase awareness among medical professionals suspecting SHiP in pregnant women presenting with severe constant abdominal pain in the absence of preterm labour. As now even more women with severe endometriosis are achieving successful pregnancy with assisted reproductive technologies, the obstetrician should expect increased frequency of occurrence of such cases in the future. Consent Informed consent was obtained. Disclosure This article does not contain any patient identifiers nor was the patient care affected or influenced in any way. Conflicts of Interest The authors report no conflicts of interest regarding the publication of this paper.

1. Introduction Status asthmaticus is a severe asthma exacerbation that is refractory to bronchodilator and corticosteroid treatment. Standard treatment often employed includes nebulized bronchodilators, magnesium, corticosteroids, and mechanical ventilation. Additional considerations, although rarely used, include sedatives, neuromuscular blockade, or inhaled anesthetics [1]. Case reports of sevoflurane use in emergency departments and the pediatric population exist for the treatment of status asthmaticus prior to extracorporeal membrane oxygenation (ECMO) [2]. However, data regarding the use during pregnancy is limited. Matters are further complicated by the potential of hepatotoxicity with use of halogenated inhaled anesthetics. With informed patient consent, we present a case of refractory status asthmaticus during pregnancy with resultant hepatotoxicity.

1. Introduction Vulvar cancer represents 3–5% of all gynecological malignancies and 1% of all cancers in females [1]. The disease is most commonly observed in postmenopausal women aged 65–70 years [2], presenting primarily with localized pruritus, vulvar mass, bleeding, or pain [3]. Squamous cell carcinoma is the predominant histological type, accounting for 90% [4], followed by melanoma, basal cell or Bartholin's gland carcinoma, sarcoma, and Paget's disease [5]. The dissemination pattern of vulvar neoplasms is mostly lymphogenic and the inguinal and femoral nodes are the primary sites of regional spread [6]. Direct extension to adjacent tissues may also occur, while hematogenous spread to distant organs presents late in the course of vulvar cancer and is rare in the absence of lymph node metastases [3]. Metastasis to the breast from vulvar carcinoma is extremely rare. To our knowledge, only two cases of unilateral breast metastasis have been reported [7, 8]. We report the first case of bilateral metastatic breast carcinoma of vulvar origin.

The dissemination pattern of vulvar neoplasms is mostly lymphogenic and the inguinal and femoral nodes are the primary sites of regional spread [6]. Direct extension to adjacent tissues may also occur, while hematogenous spread to distant organs presents late in the course of vulvar cancer and is rare in the absence of lymph node metastases [3]. Metastasis to the breast from vulvar carcinoma is extremely rare. To our knowledge, only two cases of unilateral breast metastasis have been reported [7, 8]. We report the first case of bilateral metastatic breast carcinoma of vulvar origin. 2. Case An 80-year-old female patient presented in June 2015 with a 4.5 cm vulvar mass, involving the clitoris, the right labium majus, and the right lateral vaginal wall. Bilateral inguinal lymph nodes were palpable. The rest of the physical examination, including breast, was unremarkable. Her previous-year's mammogram was negative. Punch biopsy of the vulvar lesion was performed and the histological examination revealed a high grade, invasive vulvar squamous cell carcinoma. The preoperative evaluation included full blood count, biochemical profile, chest X-ray, and abdominal CT scan. There were no additional imaging findings and blood tests were within the normal range.

ar lesion was performed and the histological examination revealed a high grade, invasive vulvar squamous cell carcinoma. The preoperative evaluation included full blood count, biochemical profile, chest X-ray, and abdominal CT scan. There were no additional imaging findings and blood tests were within the normal range. The patient underwent a radical vulvectomy and bilateral inguinal lymphadenectomy (triple incision technique). The histological report revealed an ulcerated tumor, measuring 4.5 × 4 × 3 cm, which showed features of poorly differentiated invasive squamous cell carcinoma. The surgical margins were free of disease (0,6 cm). Lymph node histopathology revealed tumor infiltration of a single ipsilateral lymph node, while all the lymph nodes dissected from the left groin showed no signs of malignancy. Vulvar lesion was, thus, classified stage IIIA (FIGO staging system) [2]. Patient's postoperative course was uncomplicated and she was discharged after twelve days of hospitalization. Postoperatively, the multidisciplinary team (MDT) suggested adjuvant radiation therapy and the patient received a total dose of 45 Gy to the groin and pelvis.

s, classified stage IIIA (FIGO staging system) [2]. Patient's postoperative course was uncomplicated and she was discharged after twelve days of hospitalization. Postoperatively, the multidisciplinary team (MDT) suggested adjuvant radiation therapy and the patient received a total dose of 45 Gy to the groin and pelvis. Follow-up was performed on an outpatient basis every three months. On her second visit, there were no signs of local recurrence. However, a palpable right breast mass at 9 o'clock position was noted. Mammography confirmed its presence and also revealed a second smaller mass in the contralateral breast. Fine-needle aspiration (FNAC) of both lumps was performed and cytological smears were stained with May-Grunwald-Giemsa and Papanicolaou. Microscopy revealed keratinized and nonkeratinized malignant squamous cells, with refractile cytoplasm, and individual cells lacking cohesion. The metastatic workup, including bone scan and abdominal, pelvic, and chest CT scan, was negative. Considering patient's medical history and the characteristic microscopic pattern of the lesions, diagnosis of metastatic squamous cell breast carcinoma, arising from the primary vulvar cancer, was established. Unfortunately, a few days later, she passed away at home from acute myocardial infarction.

scan, was negative. Considering patient's medical history and the characteristic microscopic pattern of the lesions, diagnosis of metastatic squamous cell breast carcinoma, arising from the primary vulvar cancer, was established. Unfortunately, a few days later, she passed away at home from acute myocardial infarction. 3. Discussion Vulvar cancer metastasizes through local spread, the lymphatic system, and the bloodstream [6]. The dissemination pattern is mostly lymphogenic. Lymphatic dye studies, by Parry-Jones [9], showed that dermal lymphatic network of the vulva courses to the superficial ipsilateral groin lymph nodes and then perforates the cribriform fascia to drain in the deep inguinal (femoral) nodes. Lymphatic drainage takes place from the lateral sites to the ipsilateral groin nodes, while drainage from the midline can be bilateral. At the level of the clitoris some lymph channels may drain directly to the pelvic lymph nodes. Sentinel lymph node (SLN) mapping investigates groin lymph node metastasis and permits less extensive node dissections and recognition of anatomic variations of the lymphatic channels [10, 11]. Distant metastases may occur either as a result of lymphatic embolization, in a stepwise fashion, to the pelvic and para-aortic lymph nodes or as a result of hematogenous spread, mainly to bones, liver, or lung [2]. They are uncommon in the initial presentation and encountered more frequently in the recurrent vulvar cancer, in 8% of patients [12].

either as a result of lymphatic embolization, in a stepwise fashion, to the pelvic and para-aortic lymph nodes or as a result of hematogenous spread, mainly to bones, liver, or lung [2]. They are uncommon in the initial presentation and encountered more frequently in the recurrent vulvar cancer, in 8% of patients [12]. The overall recurrence rate, according to Maggino et al., is 37.2% [12], while Gonzalez Bosquet et al. reported a rate of 26.7% [13]. The distribution of recurrences by site, in the former study, was 53.4% perineal, 18.7% inguinal, 5.7% pelvic, 7.9% distant, and 14.2% multiple. Tumor dimension, lymph node involvement, and stromal and lymph vascular space invasion were demonstrated as prognostic factors, predicting the risk of recurrence [12]. Breast carcinoma is the most common malignant tumor in females. However, metastatic tumors to the breast are rare and account for 0.5–1.5% of all breast cancers in clinical series and 6.6% in autopsy series [14, 15]. The commonest cause is spread from a contralateral breast carcinoma. Excluding hematologic malignancies, the most common primary sites are cutaneous melanoma, bronchogenic carcinoma, gastric carcinoma, and genitourinary tumors [16]. Among gynecologic cancers, the most frequent metastatic to the breast is ovarian cancer [17] but sporadic reports pertaining to other primary gynecologic malignancies, including cancers of the endometrium, cervix, fallopian tube, and choriocarcinoma, have been reported [15, 16, 18].

noma, and genitourinary tumors [16]. Among gynecologic cancers, the most frequent metastatic to the breast is ovarian cancer [17] but sporadic reports pertaining to other primary gynecologic malignancies, including cancers of the endometrium, cervix, fallopian tube, and choriocarcinoma, have been reported [15, 16, 18]. The breast is an exceptional site of metastasis from vulvar carcinoma. Only two cases have been described in the literature. In the first case, a 49-year-old woman, surgically treated for a stage II vulvar squamous cell carcinoma, presented 4 months after the operation with a 4 × 3 cm lump in the left breast [7]. The histological and immunohistochemical characteristics of the excisional biopsy specimen, the presence of human papilloma virus genome, demonstrated by in situ hybridization, in both vulvar and breast specimens and the absence of BRST2 confirmed the diagnosis. Surgical margins of the excisional biopsy were free and no further treatment was given. The patient remained free of disease for at least 73 months. In the second case, a 42-year-old patient, suffering from a stage IVA vulvar squamous cell carcinoma, underwent radical vulvectomy and bilateral inguinal lymphadenectomy followed by external pelvic irradiation, as inguinal lymph nodes and the inferior surgical border were infiltrated by the tumor [8]. A recurrence in the left breast was confirmed by biopsy 3 months later. A modified radical mastectomy was performed and the patient received 3 cycles of adjuvant chemotherapy (cyclophosphamide, adriblastine, and cisplatin). She died at 11 months, in the context of cerebral metastasis.

were infiltrated by the tumor [8]. A recurrence in the left breast was confirmed by biopsy 3 months later. A modified radical mastectomy was performed and the patient received 3 cycles of adjuvant chemotherapy (cyclophosphamide, adriblastine, and cisplatin). She died at 11 months, in the context of cerebral metastasis. The recognition of a breast lesion as primary or metastatic is crucial since it affects management and prognosis. A palpable, mobile, painless, well-circumscribed lump, localized at the upper outer quadrant, is the most common clinical presentation. Mammography usually depicts multiple or bilateral lesions, round and smooth, without speculation [15]. In contrast to primary breast carcinoma, the clinical and the radiological size of metastatic lesions coincide because of a minimal desmoplastic reaction around them [18]. Diagnosis is generally achieved histologically by fine-needle aspiration cytology or open biopsy [19]. FNA can differentiate between metastatic deposit and primary breast cancer, resulting in the avoidance of mastectomy and the implementation of the appropriate adjuvant therapy [20, 21].

stic reaction around them [18]. Diagnosis is generally achieved histologically by fine-needle aspiration cytology or open biopsy [19]. FNA can differentiate between metastatic deposit and primary breast cancer, resulting in the avoidance of mastectomy and the implementation of the appropriate adjuvant therapy [20, 21]. In the current case, a typical aspect of squamous cell carcinoma associated with keratinization was observed in the breast lesions by FNA. Squamous cells are normally not found inside the breast. Thus, primary squamous cell carcinoma of the breast is a very rare tumor accounting for less than 0.1% of all invasive breast carcinomas and may arise from squamous metaplasia into an adenocarcinoma [22] or in cysts, abscesses, chronic inflammation, and fibroadenomas [23]. Its diagnosis requires the following: the absence of elements other than malignant epidermoid cells, the independence of the lesion from adjacent dermal structures, and the exclusion of other squamous carcinomas in the patient [8, 11, 24]. Consequently, our patient's medical history, in addition to the bilateral breast mass presentation, amplified the diagnosis of metastatic breast cancer. The prognosis of breast metastasis is poor as widespread tumor dissemination is implied. Most patients die within the year following the diagnosis. Treatment is palliative, based on chemotherapy and sometimes comfort surgery [18].

In the current case, a typical aspect of squamous cell carcinoma associated with keratinization was observed in the breast lesions by FNA. Squamous cells are normally not found inside the breast. Thus, primary squamous cell carcinoma of the breast is a very rare tumor accounting for less than 0.1% of all invasive breast carcinomas and may arise from squamous metaplasia into an adenocarcinoma [22] or in cysts, abscesses, chronic inflammation, and fibroadenomas [23]. Its diagnosis requires the following: the absence of elements other than malignant epidermoid cells, the independence of the lesion from adjacent dermal structures, and the exclusion of other squamous carcinomas in the patient [8, 11, 24]. Consequently, our patient's medical history, in addition to the bilateral breast mass presentation, amplified the diagnosis of metastatic breast cancer. The prognosis of breast metastasis is poor as widespread tumor dissemination is implied. Most patients die within the year following the diagnosis. Treatment is palliative, based on chemotherapy and sometimes comfort surgery [18]. 4. Conclusion This publication is an additional case of vulvar cancer metastasis to a rare location, the breast. Diagnosis was based on converging clinical, histological, and radiological facts. Differential diagnosis between primary and metastatic lesions is demanded for the appropriate and cost-effective patient management. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper.

1. Introduction Peritoneal keratin granuloma is a rare lesion included among reactive tumor-like lesions of the peritoneum. It can be secondary to endometrioid adenocarcinoma with squamous differentiation of the endometrium and ovary and atypical polypoid adenomyoma of the endometrium and in association with ruptured dermoid cysts. The prognostic significance of these lesions is unknown and it seems to have no interference with prognosis, when no viable tumor cells are detected. Here we describe a case of an endometrioid adenocarcinoma of the endometrium, in a woman with polycystic ovaries in which diffuse peritoneal keratin granulomas were found with no viable tumor implants which intraoperatively were misinterpreted as diffuse carcinomatosis.

ognosis, when no viable tumor cells are detected. Here we describe a case of an endometrioid adenocarcinoma of the endometrium, in a woman with polycystic ovaries in which diffuse peritoneal keratin granulomas were found with no viable tumor implants which intraoperatively were misinterpreted as diffuse carcinomatosis. 2. Case Presentation A 40-year-old woman with a body mass index (BMI) of 37 and a past medical history of polycystic ovary syndrome, presented to her gynaecologist complaining of irregular vaginal bleeding. Her menarche was at the age of 16 and her menstrual cycle was infrequent and irregular. Endometrial biopsies (D&C) have been examined at the age of 33 and 38 years. At the age of 38, she was diagnosed with atypical adenomatous hyperplasia of the endometrium and she was put on progestagen therapy. A few months later, she experienced a new episode of irregular vaginal bleeding and after an additional D&C she was diagnosed with endometrioid adenocarcinoma of the endometrium. As a routine pre-op check, tumor markers were requested. Her serum CA125 and serum CA19.9 were elevated to 69.00 U/ml (normal < 35.00 U/ml) and 91.60 U/ml (normal < 35.00 U/ml), respectively. The magnetic resonance imaging (MRI) of the lower abdomen revealed invasion of more than 50% of the myometrium and of the uppermost uterine cervical stroma. Blurring of the sigmoid fat and prominent inguinal, para-aortic and mesenteric lymph nodes were also described with a maximum lymph node diameter of 1.5 cm. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, omentectomy, and appendicectomy were performed. Intraoperative peritoneal washings were also carried out. Multiple peritoneal nodules, <0.5 cm in diameter, suspicious of disseminated carcinomatosis, were found during surgery in the pouch of Douglas, over loops of small bowel, and in the mesentery of the small bowel. Multiple biopsies were taken. Due to increased BMI, para-aortic lymphadenectomy was not performed. No frozen section was requested because it was appreciated that a positive result would not affect the overall surgical management.

the pouch of Douglas, over loops of small bowel, and in the mesentery of the small bowel. Multiple biopsies were taken. Due to increased BMI, para-aortic lymphadenectomy was not performed. No frozen section was requested because it was appreciated that a positive result would not affect the overall surgical management. Grossly, the uterine corpus, including both cornua, was filled with a polypoid papillary mass, measuring 11, 5 × 5, 5 cm, extending into the uterine cervix (Figure 1). Both ovaries were enlarged with multiple peripherally located follicular cysts and dense peripheral stroma, consistent with the clinical history of polycystic ovaries.

erine corpus, including both cornua, was filled with a polypoid papillary mass, measuring 11, 5 × 5, 5 cm, extending into the uterine cervix (Figure 1). Both ovaries were enlarged with multiple peripherally located follicular cysts and dense peripheral stroma, consistent with the clinical history of polycystic ovaries. Histologically, the tumor of the uterine corpus was a superficially invasive, moderately differentiated, tubulopapillary adenocarcinoma of the endometrium, of endometrioid type with multiple foci of squamous differentiation (Figures 2(a)–2(c)). Immunohistochemically, there was positive expression of hormone receptors and p53 (Figure 3). The tumor was extending superficially to the uterine cervix (Figure 4). All 18 pelvic lymph nodes were unremarkable. In addition, on the serosal surface of bilateral ovaries, fallopian tubes, and the appendix, multiple microscopic granulomas were found, composed of amorphous irregularly laminated eosinophilic deposits of keratin, associated with ghost squamous cells and surrounded by foreign body giant cells (Figures 5(a)–5(c)). There were also reactive mesothelial cells close to keratin granulomas. In retrospect, similar degenerate squamous cells were found in extensive, mainly superficial areas of the uterine tumor (Figure 6) as well as filling and distending the lumen of the fallopian tubes, bilaterally (Figures 7(a)–7(c)).

ures 5(a)–5(c)). There were also reactive mesothelial cells close to keratin granulomas. In retrospect, similar degenerate squamous cells were found in extensive, mainly superficial areas of the uterine tumor (Figure 6) as well as filling and distending the lumen of the fallopian tubes, bilaterally (Figures 7(a)–7(c)). Intraoperative peritoneal washings showed scattered mesothelial cells, occasional clusters of atypical cells of mesothelial origin, rare anucleate squames, and an occasional keratin granuloma. Overall, the endometrial carcinoma was of UICC/FIGO stage II. 3. Discussion Peritoneal keratin granuloma is a rare lesion included under granulomatous lesions of the peritoneum [1]. Such peritoneal reaction can be infectious or noninfectious in aetiology [1]. The noninfectious type can be secondary to neoplasms of the female genital tract, like endometrioid adenocarcinoma with squamous differentiation of the endometrium and ovary and atypical polypoid adenomyoma of the endometrium or seen in association with ruptured dermoid cysts. They are also found in ruptured ovarian teratoma and nonneoplastic conditions, such as spilled amniotic fluid, or in intraperitoneal renal dialysis-associated peritoneal squamous metaplasia [1].

endometrium and ovary and atypical polypoid adenomyoma of the endometrium or seen in association with ruptured dermoid cysts. They are also found in ruptured ovarian teratoma and nonneoplastic conditions, such as spilled amniotic fluid, or in intraperitoneal renal dialysis-associated peritoneal squamous metaplasia [1]. Peritoneal keratin granulomas refer to the finding of nests of keratinized anucleate squamous cells surrounded by a foreign body type giant cell reaction, either on the peritoneal surface or within subperitoneal connective tissue. These so-called keratin granulomas do not contain any glandular epithelium. The typical histological appearances in previously reported cases were similar to ours.

anucleate squamous cells surrounded by a foreign body type giant cell reaction, either on the peritoneal surface or within subperitoneal connective tissue. These so-called keratin granulomas do not contain any glandular epithelium. The typical histological appearances in previously reported cases were similar to ours. Spontaneous reflux of exfoliated necrotic squamous metaplastic cells or keratin from the squamous element of the endometrial tumor to the peritoneum or its retropulsion through the tubal lumina due to endometrial sampling has been postulated as the pathogenetic mechanism of the 27 cases [2–7] of PKG associated with an endometrial adenocarcinoma with squamous differentiation [2–5]. The above induce a foreign body granulomatous reaction [3] and include frequent association with cervical stenosis, corneal location of the primary tumor, presence of keratin clumps within the lumen of the tube, and superficial location of squamous necrotic cells in the endometrial carcinoma [4]. In our case, all the above-mentioned requirements were met. The uterine cavity was filled with a tumor which was causing distention of the corneal part of the fallopian tubes and there was extensive squamous differentiation of the endometrioid adenocarcinoma, in about 1/20 of the tumor, which was more pronounced in superficial areas, where extensive degeneration and necrosis of the endometrial carcinoma were present (Figure 8). The tubes were massively distended and filled with numerous anucleate squames, which obviously spread to the peritoneum, leading to a florid granulomatous peritoneal reaction to keratin.

more pronounced in superficial areas, where extensive degeneration and necrosis of the endometrial carcinoma were present (Figure 8). The tubes were massively distended and filled with numerous anucleate squames, which obviously spread to the peritoneum, leading to a florid granulomatous peritoneal reaction to keratin. The commonly reported process of keratinization in endometrial carcinomas could be influenced by irradiation, surgical trauma, partial removal of the tumoral mass, hormonal factors, infection, or transfusion, but the aetiology is usually unknown [4]. Sometimes the tumor cells may undergo keratinization after entering into the peritoneal cavity [4]. These may be visible to the surgeon and mimic peritoneal carcinomatosis macroscopically, as it was the case with our surgeons. As long as no glandular component is identified histologically, keratin granulomas should not be considered tumor spread and should not result in upstaging. In such cases, the areas should be thoroughly sampled by the gynaecologist and carefully examined microscopically by the pathologist to exclude the presence of viable tumor cells. Furthermore, reactive mesothelial hyperplasia near the keratin granulomas may occur. Peritoneal washings no longer contribute to endometrial cancer staging; nevertheless, they continue to be performed by the clinicians, even though a positive report may carry a risk of overdiagnosis, as it may be difficult to distinguish between reactive mesothelial and tumor cells. There is only one report on the cytohistological correlation of PKGs [8]. In our case, atypical cells in the peritoneal washings were immunoreactive for calretinin (Figure 8), indicative of mesothelial origin. There were also scattered anucleate orangeophilic squames (Figure 9), which could not have been of cutaneous origin, as the cytological sampling technique was not transcutaneous (paracentesis) and an occasional keratin granuloma, positive for ker5/6 (Figure 10). Cytological evidence of keratin in peritoneal washings does not infer a diagnosis of metastatic carcinoma, but careful scrutiny has to be done, to exclude the presence of malignant cells.

gical sampling technique was not transcutaneous (paracentesis) and an occasional keratin granuloma, positive for ker5/6 (Figure 10). Cytological evidence of keratin in peritoneal washings does not infer a diagnosis of metastatic carcinoma, but careful scrutiny has to be done, to exclude the presence of malignant cells. After revision of the literature, only 33 similar cases had been reported till 2012. Tripathy et al. (2010) [7] and Montes et al. (1961) [9] were the first to describe a case of well-differentiated adenocarcinoma of the uterine corpus in which so-called “pigmented nodules” composed of foreign body keratin granulomas were identified on and below the serosal surface of the uterus and the proximal end of the fallopian tube. These authors suggested that squamous metaplasia and keratinization of endometriotic epithelium might lead to the formation of granulomas.

so-called “pigmented nodules” composed of foreign body keratin granulomas were identified on and below the serosal surface of the uterus and the proximal end of the fallopian tube. These authors suggested that squamous metaplasia and keratinization of endometriotic epithelium might lead to the formation of granulomas. Chen (1978) [2] described five cases of uterine “adenoacanthoma” with peritoneal foreign body granulomatous reaction to keratin. These authors postulated that the pathway of entrance of keratin into the peritoneal cavity to be spontaneous reflux from the endometrial tumor, including a frequent association with cervical stenosis, a corneal location of the primary tumor leading to transtubal spreading. William et al. (1984) [10] and Wotherspoon et al. (1989) [5] reported two additional cases, associated with an “adenosquamous carcinoma” and an “adenoacanthoma” of the uterus, respectively. Kim and Scully (1990) [4] reported 22 cases of peritoneal keratin granulomas with carcinomas of endometrium and ovary and atypical polypoid adenomyoma of the endometrium, constituting the largest review of cases published in the literature. It was the first time that such peritoneal lesions were described to be related to endometrioid adenocarcinoma of the ovary (five cases). Wu et al. (2006) [11] described the other case of peritoneal keratin granuloma in association with ovarian adenocarcinoma. It was suggested by Kim and Scully (1990) [4] that tearing of the capsule of the tumor or malignant cell penetrating the ovarian surface was the way of cells in entering the peritoneal cavity. The last two published cases, by Van der Horst and Evans (2008) [6], refer to carcinomas of the endometrium also. A case with twelve-year follow-up of an endometrioid adenocarcinoma of the endometrium with disseminated peritoneal keratin granulomas and viable tumor implants was also reported in 2012 [12]. Interpreted as disseminated disease leading to a palliative approach with only brachytherapy and hormonal therapy, the outstanding survival could suggest no adverse effect on the prognosis of such peritoneal lesions even with viable tumor implants.

in granulomas and viable tumor implants was also reported in 2012 [12]. Interpreted as disseminated disease leading to a palliative approach with only brachytherapy and hormonal therapy, the outstanding survival could suggest no adverse effect on the prognosis of such peritoneal lesions even with viable tumor implants. The prognostic significance of keratin peritoneal granulomas with or without viable tumor implants is difficult to assess because of the small number of cases in the literature. Lack of or short follow-up in some cases and postoperative radiotherapy, chemotherapy, or both, which might have influenced the natural course of any postoperative residual peritoneal lesions, makes it more difficult to interpret the real prognostic significance of these lesions. Some authors suggest that they have no prognostic significance when no viable cells are found in the granulomas. The combination of contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance is mentioned to be helpful for the preoperative differential diagnosis [13].

The prognostic significance of keratin peritoneal granulomas with or without viable tumor implants is difficult to assess because of the small number of cases in the literature. Lack of or short follow-up in some cases and postoperative radiotherapy, chemotherapy, or both, which might have influenced the natural course of any postoperative residual peritoneal lesions, makes it more difficult to interpret the real prognostic significance of these lesions. Some authors suggest that they have no prognostic significance when no viable cells are found in the granulomas. The combination of contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance is mentioned to be helpful for the preoperative differential diagnosis [13]. In the current study, we document a very rare case involving a patient with polycystic ovaries syndrome, who presented with a huge endometrial tumor which filled the uterus and protruded through the cervical os. The tumor was an endometrioid adenocarcinoma of the endometrium which was accompanied by multiple peritoneal keratin granulomas attributed to the squamous element of the tumor, transpassing the lumen of the fallopian tubes and eliciting a giant cell reaction. Our findings are in concordance with Chen et al.'s [3] and Wotherspoon et al.'s [5] proposed pathogenetic mechanism of spontaneous reflux of keratinized squamous cells through the lumen of the fallopian tubes into the peritoneal cavity in tumors associated with cervical stenosis or a corneal location. For the first time, we confirm microscopically the proposed pathogenetic mechanism of PKG formation. The fallopian tubes in our case were distended and filled with anucleate squames originated from the squamous metaplastic element of the endometrial adenocarcinoma.

sociated with cervical stenosis or a corneal location. For the first time, we confirm microscopically the proposed pathogenetic mechanism of PKG formation. The fallopian tubes in our case were distended and filled with anucleate squames originated from the squamous metaplastic element of the endometrial adenocarcinoma. Because peritoneal granulomatosis can resemble disseminated carcinomatosis macroscopically, the knowledge of this rare entity is essential to avoid upstaging of the patient. Our patient underwent brachytherapy and whole irradiation and is well after fifteen months of follow-up. Furthermore, the findings of scattered anucleate squames and keratin granuloma in the peritoneal washings constitute the second cytohistologic reference of PKGs [8]. Acknowledgments The authors would like to express their gratitude to Nikolaos Trapezontas for his invaluable assistance with the submission process of the manuscript. Consent Written consent has been provided from the patient. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Macroscopic appearance of a cross-sectioned uterus filled with a polypoid papillary mass, extending into the uterine cervix. Figure 2 Microscopic appearance of endometrioid carcinoma with foci of squamous differentiation. Figure 3 Immunostain: positive expression of p53 in endometrial carcinoma. Figure 4 H&E stain: superficial invasion of the uterine cervix by the endometrial carcinoma.

Figure 1 Macroscopic appearance of a cross-sectioned uterus filled with a polypoid papillary mass, extending into the uterine cervix. Figure 2 Microscopic appearance of endometrioid carcinoma with foci of squamous differentiation. Figure 3 Immunostain: positive expression of p53 in endometrial carcinoma. Figure 4 H&E stain: superficial invasion of the uterine cervix by the endometrial carcinoma. Figure 5 H&E stain: microscopic appearances of multiple keratin granulomas, composed of ghost squamous cells surrounded by foreign body giant cells, found on the serosal surface of bilateral ovaries, fallopian tubes, the appendix, and omentum. Figure 6 H&E stain: degenerate squamous cells found in superficial areas of the uterine tumor. Figure 7 H&E stain: similar to Figure 6, degenerate squamous cells are filling and distending the lumen of the fallopian tubes (in various magnifications). Figure 8 Immunostain for calretinin: atypical cell cluster in peritoneal washings of mesothelial origin. Figure 9 Pap stain: scattered anucleate squame in peritoneal washings. Figure 10 Immunostain for Ker5/6: keratin granuloma with positive expression in peritoneal washings.

1. Introduction Uterine myomas are the most common benign growths affecting female reproductive system, occurring in 20–40% of women [1], whereas the incidence rate in pregnancy is estimated from 0.1 to 3.9%. The lower incidence in pregnancy is due to the association with infertility and low pregnancy rates and implantation rates after in vitro fertilization treatment [2]. Uterine myomas, usually, are asymptomatic during pregnancy. However, occasionally, pedunculated fibroids torsion or other superimposed complications may cause acute abdominal pain. Urinary and gastroenteric symptoms may occur due to the rapid increase in size in reason of hyperestrogenic environment and, consequently, compression and displacement of surrounding organs. Additionally, fibroids predispose to pregnancy complications, including early miscarriage, antepartum bleeding, preterm labor, premature rupture of membranes, fetal malpresentations, labor dystocia, and postpartum hemorrhage.

restrogenic environment and, consequently, compression and displacement of surrounding organs. Additionally, fibroids predispose to pregnancy complications, including early miscarriage, antepartum bleeding, preterm labor, premature rupture of membranes, fetal malpresentations, labor dystocia, and postpartum hemorrhage. Conservative management with anti-inflammatory therapy is considered a gold standard, and surgery is generally avoided during pregnancy because of the risks of hysterectomy secondary to severe hemorrhage, pregnancy injury, and pregnancy loss [3]. The main conditions that induce inevitably the surgical procedure are the torsion of pedunculated fibroids or rare cases of necrosis, resultant inflammatory peritoneal reaction, and, finally, if symptoms persist after 72 hours of pharmacological therapy [4–7]. Therefore, the diagnosis needs a particular attention for the appropriate management choice. Surgical removal fibroids in pregnancy can be performed by laparotomy or laparoscopy technique taking into account the volume and location of nodules [1, 8]. Laparoscopy can be considered in selected cases such as small, subserous, pedunculated myomas. There are many controversies in performing myomectomy during cesarean section because of the risk of hemorrhage [3]. Nevertheless, the majority of indication arises before labor and delivery due to acute symptoms leading to a discussion regarding the need for intervention during pregnancy.

Laparoscopy can be considered in selected cases such as small, subserous, pedunculated myomas. There are many controversies in performing myomectomy during cesarean section because of the risk of hemorrhage [3]. Nevertheless, the majority of indication arises before labor and delivery due to acute symptoms leading to a discussion regarding the need for intervention during pregnancy. Therefore, we present a case of successful multiple laparotomic myomectomy at 17 + 2 weeks of gestational age and a systematic review of the literature in order to clarify the approach to this pathologic condition and its effect on pregnancy outcome. 2. Case Report Uterine myomas are usually asymptomatic during pregnancy. However, pedunculated fibroids torsion may occasionally cause acute abdominal pain [1]. Most cases of laparotomic myomectomy described in literature have been performed during a cesarean section due to the risk of managing them surgically at low gestational age [2–4]. We present a case of a successful multiple laparotomic myomectomy during the second trimester of pregnancy.

2. Case Report Uterine myomas are usually asymptomatic during pregnancy. However, pedunculated fibroids torsion may occasionally cause acute abdominal pain [1]. Most cases of laparotomic myomectomy described in literature have been performed during a cesarean section due to the risk of managing them surgically at low gestational age [2–4]. We present a case of a successful multiple laparotomic myomectomy during the second trimester of pregnancy. A 36-year-old, morbidly obese primigravida presented at our emergency room at 17 + 0 weeks of gestational age complaining of abdominal pain. At clinical examination, the uterus appeared to be of higher volume compared to the gestational age, the abdomen was painful but treatable, and the obstetrical examination was normal. The patient was then referred to US Unit of our Department for further evaluation. The sonographic assessment revealed the presence of three subserous uterine myomas located on anterior wall (maximum diameter: 13.2 cm), the right wall (maximum diameter: 12.6 cm), and the left wall (maximum diameter: 11.7 cm) of the uterus, respectively. All myomas were vacuolated inside as for suspected necrosis. The scan also showed other multiple myomas less than 3 cm in size. Vital signs were monitored (blood pressure 140/90 mmHg, maternal heart rate 124 bmp, SO2 94%, apyretic). Amniotic fluid was normal and fetal well-being was preserved. Thus, the patient was admitted to the High-Risk-Pregnancy Unit. When collecting the medical history, the first trimester ultrasound scan, performed at 11 weeks' gestation, revealed the presence of the same lesions with a size of 10.8 cm, 10.2 cm, and 6.14 cm, respectively.

was normal and fetal well-being was preserved. Thus, the patient was admitted to the High-Risk-Pregnancy Unit. When collecting the medical history, the first trimester ultrasound scan, performed at 11 weeks' gestation, revealed the presence of the same lesions with a size of 10.8 cm, 10.2 cm, and 6.14 cm, respectively. Laboratory studies demonstrated rising inflammatory markers (C-reactive protein: 354 mg/L; WBC: 16.92 × 103 μL). Due to the persistence of the symptoms, despite of two days of analgesic, antispastic, and antibiotic therapy, after multidisciplinary discussion, and a thorough counseling to inform the parents of the surgical and postoperative risks connected with uterine surgery during the gestation, the patient underwent surgery. Laparotomy approach by longitudinal skin incision, considering the volume and the position of the myomas, was performed under general anesthesia. Three huge bulky subserous pedunculated myomas were evidenced, the largest located at the uterine fundus, with a maximum diameter of 15 cm and a torsion of its pedicle (Figure 1). Furthermore, intra-abdominal adhesions were found within peritoneal cavity. Blunt dissection was undertaken to free the omentum and look for the appendix, which was normal. The three large myomas evidenced by ultrasound were removed and sent for pathologic examination. A pelvic drainage was left and removed 24 hours postoperatively. Pathology showed widespread phenomena of necrosis, especially in the myoma with torsion of its pedicle.

e omentum and look for the appendix, which was normal. The three large myomas evidenced by ultrasound were removed and sent for pathologic examination. A pelvic drainage was left and removed 24 hours postoperatively. Pathology showed widespread phenomena of necrosis, especially in the myoma with torsion of its pedicle. During the following nine days, the patient received antibiotics, low molecular heparin, and progesterone, and fetal heartbeat was checked daily. Considering the improvement in clinical condition, the patient was discharged with an indication to treatment with progesterone and low molecular heparin. Three weeks later, at 21 weeks' gestation, the patient was admitted again due to abdominal pain. Obstetrical evaluation revealed cervical effacement and the transvaginal ultrasound scan showed a reduction of cervical length (18 mm), funneling, and sludge. An ultrasound scan was performed showing good fetal variables. Consequently, the therapy with progesterone was increased. The patient had a positive vaginal culture for Staphylococcus haemolyticus, urine culture was negative, and C-reactive protein resulted to be positive. Therefore, antibiotic therapy with macrolides was given, according to antibiogram result. A cervical cerclage was proposed to the patient, but she refused to undergo the procedure.

had a positive vaginal culture for Staphylococcus haemolyticus, urine culture was negative, and C-reactive protein resulted to be positive. Therefore, antibiotic therapy with macrolides was given, according to antibiogram result. A cervical cerclage was proposed to the patient, but she refused to undergo the procedure. Hospitalization lasted for seven days; then the woman was discharged due to an improvement of her clinical condition. The patient underwent obstetric evaluation every two weeks until she presented in labor and delivered vaginally at 38 + 1 weeks' gestation a healthy female newborn of 2940 g, appropriate for gestational age according to national growth curves [9]. Apgar score was 9/10 at 1′ and 5′ respectively. 3. Data Source and Literature Search To identify potentially eligible studies, we searched PubMed, Scopus, and Cochrane Library (all from inception to 16 March 2017). No language restrictions were initially applied. We used a combination of key words and text words represented by “myomectomy,” “myoma,” and “pregnancy.”

3. Data Source and Literature Search To identify potentially eligible studies, we searched PubMed, Scopus, and Cochrane Library (all from inception to 16 March 2017). No language restrictions were initially applied. We used a combination of key words and text words represented by “myomectomy,” “myoma,” and “pregnancy.” Two reviewers (Annachiara Basso and Mariana Rita Catalano) independently screened the titles and abstracts of records retrieved through database searches. Both reviewers recommended studies for the full-text review. The screen of full-text articles recommended by at least one reviewer was done independently by the same two reviewers and assessed for inclusion in the systematic review. Disagreements between reviewers were resolved by consensus. For all full-text manuscripts, reference lists were analyzed in order to find additional eligible studies. 4. Results The electronic database search provided a total of 1855 results. After duplicate exclusion, there were 1611 citations left. Of these, 1508 were not relevant to the review based on title and abstract screening. 103 studies were considered for full-text assessment, of which 40 were excluded for the following reasons: we could not translate 31 articles, while nine papers could not be retrieved even after international librarian search. Overall, 63 [3–6, 10–67] articles were incorporated for further assessment. The study selection process is shown in Figure 2. The main characteristics of the selected studies are included in Table 1.

4. Results The electronic database search provided a total of 1855 results. After duplicate exclusion, there were 1611 citations left. Of these, 1508 were not relevant to the review based on title and abstract screening. 103 studies were considered for full-text assessment, of which 40 were excluded for the following reasons: we could not translate 31 articles, while nine papers could not be retrieved even after international librarian search. Overall, 63 [3–6, 10–67] articles were incorporated for further assessment. The study selection process is shown in Figure 2. The main characteristics of the selected studies are included in Table 1. 5. Discussion Our review included 197 women undergoing myomectomy during pregnancy. The procedure was successful in 184 women, while in the remaining 13 cases a miscarriage or fetal demise happened after the myomectomy. In 14 cases, a laparoscopic approach was chosen; in one case there was a vaginal surgery, while all the other cases for which the surgical information was available underwent laparotomy. These data confirm that the most used surgical intervention for myomas during pregnancy is the laparotomy route. Maternal outcomes were favorable after myomectomy, with only two episodes of hemoperitoneum [33, 67], one uterine abscess [39], and only one woman requiring perioperative blood transfusion [61].

In 14 cases, a laparoscopic approach was chosen; in one case there was a vaginal surgery, while all the other cases for which the surgical information was available underwent laparotomy. These data confirm that the most used surgical intervention for myomas during pregnancy is the laparotomy route. Maternal outcomes were favorable after myomectomy, with only two episodes of hemoperitoneum [33, 67], one uterine abscess [39], and only one woman requiring perioperative blood transfusion [61]. Moreover, the analysis of all reports was limited by two factors: (1) the heterogeneity of diagnostic information as well as descriptive data connected to operation and pathology examination which did not allow clear categorization of the pathology preoperatively and postoperatively and (2) the large amount of missing or unreported data. 6. Conclusion Myomectomy is a feasible procedure if performed during pregnancy. Candidates need to be chosen carefully among those with symptomatic myomas, since abdominal surgery during pregnancy can be associated with an increased risk for the development of the great obstetrical syndromes, especially preterm labor and delivery. Disclosure This paper has been presented in part at the 19th National Congress of the Italian Society of Perinatal Medicine (Società Italiana di Medicina Perinatale, SIMP), Naples (Italy), 19–21 January 2017. Conflicts of Interest The authors declare that there are no conflicts of interest. Figure 1 Myoma of the uterine fundus with evidence of torsion of its pedicle. Figure 2 Study selection process. Table 1 Characteristics of the relevant studies.

Disclosure This paper has been presented in part at the 19th National Congress of the Italian Society of Perinatal Medicine (Società Italiana di Medicina Perinatale, SIMP), Naples (Italy), 19–21 January 2017. Conflicts of Interest The authors declare that there are no conflicts of interest. Figure 1 Myoma of the uterine fundus with evidence of torsion of its pedicle. Figure 2 Study selection process. Table 1 Characteristics of the relevant studies. Reference Number of patients Gestational age at diagnosis (weeks) Gestational age at myomectomy (weeks) Type of surgery Fibroid maximum volume (cm) Mode of delivery Gestational age at delivery Neonatal outcome (Apgar, birthweight, pH) De Carolis et al., 2001 18 nd 13 LPT 8 CS 39 8/8, 3150 g nd 23 LPT 40 CS 38 8/8, 2670 g nd 19 LPT 14 VD 36 8/9, 3080 g nd 17 LPT 21 CS 38 8/9, 3060 g nd 19 LPT 15 Fetal demise at 19 weeks nd 20 LPT 6 VD 41 9/9, 2970 g nd 19 LPT 12 CS 39 7/9, 3180 g nd 8 LPT 9 CS 40 9/9, 3300 g nd 12 LPT 8 CS 38 9/10, 2780 g nd 17 LPT 24 CS 38 9/9, 3900 g nd 15 LPT 10 CS 40 8/10, 3170 g nd 17 LPT 13 CS 39 9/10, 3100 g nd 6 LPT 15 nd nd nd nd 20 LPT 8 CS 39 9/10, 2860 g nd 10 LPT 16 CS 40 9/10, 3500 g nd 16 LPT 10 CS 39 9/10, 3930 g nd 13 LPT 14 CS 39 9/9, 3180 g nd 7 LPT 15 CS 38 9/10 - 2550 g Domenici et al., 2014 1 16 16 LPT 20 CS 38 8/9 - 3250 g Michalas et al., 1995 1 14 15 LPT 20 CS 39 2800 g Danzer et al., 2001 1 12 12 LPT 10 CS 37 9/10, 3235 g; 9/10, 2810 g Lozza et al., 2011 1 12 16 LPT 18 CS 36 9/9, 2280 g Joó et al., 2001 1 8 25 LPT 12 CS 40 3600 g

Reference Number of patients Gestational age at diagnosis (weeks) Gestational age at myomectomy (weeks) Type of surgery Fibroid maximum volume (cm) Mode of delivery Gestational age at delivery Neonatal outcome (Apgar, birthweight, pH) De Carolis et al., 2001 18 nd 13 LPT 8 CS 39 8/8, 3150 g nd 23 LPT 40 CS 38 8/8, 2670 g nd 19 LPT 14 VD 36 8/9, 3080 g nd 17 LPT 21 CS 38 8/9, 3060 g nd 19 LPT 15 Fetal demise at 19 weeks nd 20 LPT 6 VD 41 9/9, 2970 g nd 19 LPT 12 CS 39 7/9, 3180 g nd 8 LPT 9 CS 40 9/9, 3300 g nd 12 LPT 8 CS 38 9/10, 2780 g nd 17 LPT 24 CS 38 9/9, 3900 g nd 15 LPT 10 CS 40 8/10, 3170 g nd 17 LPT 13 CS 39 9/10, 3100 g nd 6 LPT 15 nd nd nd nd 20 LPT 8 CS 39 9/10, 2860 g nd 10 LPT 16 CS 40 9/10, 3500 g nd 16 LPT 10 CS 39 9/10, 3930 g nd 13 LPT 14 CS 39 9/9, 3180 g nd 7 LPT 15 CS 38 9/10 - 2550 g Domenici et al., 2014 1 16 16 LPT 20 CS 38 8/9 - 3250 g Michalas et al., 1995 1 14 15 LPT 20 CS 39 2800 g Danzer et al., 2001 1 12 12 LPT 10 CS 37 9/10, 3235 g; 9/10, 2810 g Lozza et al., 2011 1 12 16 LPT 18 CS 36 9/9, 2280 g Joó et al., 2001 1 8 25 LPT 12 CS 40 3600 g Çelik et al., 2002 5 nd 22 LPT 13 CS 38.6 +/− 1.1 10, 3200 g nd 18 LPT 10 CS 38.6 +/− 1.1 9, 3400 g nd 20 LPT 12 CS 38.6 +/− 1.1 10, 3600 g nd 16 LPT 15 CS 38.6 +/− 1.1 8, 3100 g nd 13 LPT 20 CS 38.6 +/− 1.1 9, 2800 g Hasbargen et al., 2002 1 18 18 LPT 15 CS 36 8/9, 2495 g Umezurike and Feyi-Waboso, 2005 1 19 19 LPT 32 VD 38 8/10, 3500 g Usifo et al., 2007 1 13 13 LPT 17 CS 38 3990 g Suwandinata et al., 2009 1 nd 18 LPT nd CS 37 8/9, 2950 g Bhatla et al., 2009 1 8 19 LPT 28 VD 38 2740 g

Çelik et al., 2002 5 nd 22 LPT 13 CS 38.6 +/− 1.1 10, 3200 g nd 18 LPT 10 CS 38.6 +/− 1.1 9, 3400 g nd 20 LPT 12 CS 38.6 +/− 1.1 10, 3600 g nd 16 LPT 15 CS 38.6 +/− 1.1 8, 3100 g nd 13 LPT 20 CS 38.6 +/− 1.1 9, 2800 g Hasbargen et al., 2002 1 18 18 LPT 15 CS 36 8/9, 2495 g Umezurike and Feyi-Waboso, 2005 1 19 19 LPT 32 VD 38 8/10, 3500 g Usifo et al., 2007 1 13 13 LPT 17 CS 38 3990 g Suwandinata et al., 2009 1 nd 18 LPT nd CS 37 8/9, 2950 g Bhatla et al., 2009 1 8 19 LPT 28 VD 38 2740 g Leite et al., 2009 1 1st trimester 17 LPT 10 CS 39 9/10, 3315 g Isabu et al., 2010 1 14 14 LPT nd CS 37 2700 g Leach et al., 2011 1 11 11 LPT 14 CS 40 9/9, 4356 g Doerga-Bachasingh et al., 2012 1 9 10 LPT 15 CS 37 nd Jhalta et al., 2016 1 13 13 LPT 16 VD 39 8/10, 3000 g Kosmidis et al., 2015 1 10 10 LPS 8 nd nd nd Saccardi et al., 2015 1 9 15 LPS 24 CS 41 4460 g, 7.2 Obara et al., 2014 1 6 13 VAG 6 VD 40 2775 g Currie et al., 2013 1 11 11 LPS 8 nd nd nd Kobayashi et al., 2013 1 21 21 LPT 8 CS 37 2730 g MacCiò et al., 2012 3 8 19 LPS 11 CS 39 3150 g 20 20 LPS 10 VD 40 3310 g 20 20 LPS nd CS 39 3050 g Shafiee et al., 2012 1 15 21 LPS 15 CS 38 nd Ardovino et al., 2011 1 14 14 LPS 6 VD 40 3216 g Müller Vranjes et al. 1 14 18 LPT 35 CS 33 10/10, 1750 g, 7.28 Son et al., 2011 1 18 18 LPS 9 VD 39 3740 g Kasum 2010 1 15 15 LPT 9 VD 38 nd Fanfani et al., 2010 1 25 25 LPS 9 VD 40 2950 g Adeyemi et al., 2007 1 19 19 LPT 30 VD 39 7/10, 3500 g Okonkwo and Udigwe, 2007 1 19 24 LPT nd CS nd nd Dracea and Codreanu, 2006 1 12 13 LPT 24 VD nd nd Melgrati et al., 2005 1 24 24 LPS 7 VD 39 9/9 Sentilhes et al., 2003 1 17 17 LPS 5 CS 37 3530 g

Son et al., 2011 1 18 18 LPS 9 VD 39 3740 g Kasum 2010 1 15 15 LPT 9 VD 38 nd Fanfani et al., 2010 1 25 25 LPS 9 VD 40 2950 g Adeyemi et al., 2007 1 19 19 LPT 30 VD 39 7/10, 3500 g Okonkwo and Udigwe, 2007 1 19 24 LPT nd CS nd nd Dracea and Codreanu, 2006 1 12 13 LPT 24 VD nd nd Melgrati et al., 2005 1 24 24 LPS 7 VD 39 9/9 Sentilhes et al., 2003 1 17 17 LPS 5 CS 37 3530 g Lolis et al., 2003 13 nd 16 LPT nd CS 37 3340 g nd 15 LPT nd CS 39 3600 g nd 19 LPT nd CS 37 2970 g nd 16 LPT nd CS 36 3000 g nd 15 LPT nd Fetal demise at 15 weeks nd 15 LPT nd CS 37 2740 g nd 16 LPT nd CS 38 3180 g nd 16 LPT nd CS 39 3515 g nd 16 LPT nd CS 39 3190 g nd 19 LPT nd CS 38 2920 g nd 17 LPT nd CS 38 3520 g nd 16 LPT nd CS 38 3000 g nd 15 LPT nd CS 29 1606 g Donnez et al., 2002 1 Before pregnancy 25 LPT 22 CS 35 2280 g Williamson, 1908 1 22 22 LPT 32 VD 23 Neonatal death Stewart, 1906 1 20 20 LPT 24 VD 40 nd Wittich et al., 2000 1 12 15 LPT 20 CS 37 9/9, 3275 g Majid et al., 1997 1 17 18 LPT 24 Fetal demise 19 weeks Algara et al., 2015 1 18 18 LPS 7 VD 24 nd Lockyer, 1914 1 21 21 LPT nd VD 40 2300 g von Hoffmann, 1911 3 16 16 LPT nd VD 40 3630 g 22 25 LPT nd Fetal demise at 25 weeks 14 15 LPT nd VD 40 nd Andrews, 1910 1 Before pregnancy 9 LPT nd VD 40 nd Swayne, 1908 2 20 20 LPT nd nd nd nd 16 16 LPT nd VD 24 nd Doran, 1906 1 20 21 LPT 10 VD 40 nd Evans, 1899 1 20 20 LPT 7 nd nd nd Exacoustòs and Rosati, 1993 13 nd <26 nd nd N.G 40 (8), preterm > 32 (5) nd

von Hoffmann, 1911 3 16 16 LPT nd VD 40 3630 g 22 25 LPT nd Fetal demise at 25 weeks 14 15 LPT nd VD 40 nd Andrews, 1910 1 Before pregnancy 9 LPT nd VD 40 nd Swayne, 1908 2 20 20 LPT nd nd nd nd 16 16 LPT nd VD 24 nd Doran, 1906 1 20 21 LPT 10 VD 40 nd Evans, 1899 1 20 20 LPT 7 nd nd nd Exacoustòs and Rosati, 1993 13 nd <26 nd nd N.G 40 (8), preterm > 32 (5) nd Burton et al., 1989 8 nd 13 LPT 18 VD 40 nd nd 15 LPT 14 Fetal demise 15 weeks nd nd LPT 5 VD 40 nd nd nd LPT 5 VD 40 nd nd nd LPT 5 VD 40 nd nd nd LPT 5 VD 40 nd nd nd LPT 5 VD 40 nd nd nd LPT 5 nd nd nd Rella et al., 1980 1 10 12 LPT nd VD 27 Neonatal death Pelosi et al., 1995 1 13 15 LPS 6 CS 39 nd Pelissier-Komorek et al., 2012 1 10 13 LPT 22 VD 35 2280 g Mollica et al., 1996 18 8–17 10–19 LPT >10 CS (17), VD (1) nd >7 (18), >2500 g (17), <2500 g (1) Febo et al., 1997 3 nd 12–19 LPT N.G. CS (2), abortion (1) 37-38 nd Bonito et al., 2007 5 nd 9–15 LPT 3.5–14.5 CS (2), VD (3) 38.2 9 +/− 0.83, 3200–4072 g Vázquez Camacho et al., 2009 1 7 16 LPT 6.2 VD 40 9/9 Makar et al., 1989 1 12 17 LPT 13,500 g CS 38 9/9, 3950 g Horno Liria, 1962 1 16 16 LPT nd VD 40 3600 g Alanis et al., 2008 1 7 12 LPT 30 VD 38 2330 g

Febo et al., 1997 3 nd 12–19 LPT N.G. CS (2), abortion (1) 37-38 nd Bonito et al., 2007 5 nd 9–15 LPT 3.5–14.5 CS (2), VD (3) 38.2 9 +/− 0.83, 3200–4072 g Vázquez Camacho et al., 2009 1 7 16 LPT 6.2 VD 40 9/9 Makar et al., 1989 1 12 17 LPT 13,500 g CS 38 9/9, 3950 g Horno Liria, 1962 1 16 16 LPT nd VD 40 3600 g Alanis et al., 2008 1 7 12 LPT 30 VD 38 2330 g Ardizzone, 1955 27 8 8 LPT nd nd nd nd 8 8 LPT nd nd nd nd 8 8 LPT nd Miscarriage at 9 weeks 24 24 LPT nd Fetal demise at 25 weeks 8 8 LPT nd Miscarriage at 8 weeks 16 16 LPT nd nd nd nd 8 8 LPT nd nd nd nd 8 8 LPT nd nd nd nd 12 12 LPT nd Fetal demise at 14 weeks 20 20 LPT nd nd nd nd 16 16 LPT nd nd nd nd 20 20 LPT nd nd nd nd 20 20 LPT nd nd nd nd 12 12 LPT nd nd nd nd 12 12 LPT nd Fetal demise at 13 weeks 8 8 LPT nd nd nd nd 8 8 LPT nd nd nd nd 12 12 LPT nd Fetal demise at 13 weeks 12 12 LPT nd nd nd nd 16 16 LPT nd Fetal demise at 17 weeks 8 8 LPT nd nd nd nd 12 12 LPT nd nd nd nd 12 12 LPT nd nd nd nd 12 12 LPT nd nd nd nd 8 8 LPT nd nd nd nd 12 12 LPT nd Fetal demise at 12 weeks 12 12 LPT nd nd nd nd Cozzi, 1967 16 nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd nd 16 LPT nd VD 38 nd nd 8 LPT nd VD 40 nd nd 12 LPT nd VD 38 nd nd 8 LPT nd VD 40 nd nd 16 LPT nd VD 40 nd nd 20 LPT nd VD 36 nd nd 8 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 16 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd Rochet et al., 1964 14 nd nd LPT 10 nd nd nd

Cozzi, 1967 16 nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd nd 16 LPT nd VD 38 nd nd 8 LPT nd VD 40 nd nd 12 LPT nd VD 38 nd nd 8 LPT nd VD 40 nd nd 16 LPT nd VD 40 nd nd 20 LPT nd VD 36 nd nd 8 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 12 LPT nd VD 40 nd nd 16 LPT nd VD 40 nd nd 8 LPT nd VD 40 nd Rochet et al., 1964 14 nd nd LPT 10 nd nd nd Sciannameo et al., 1996 1 20 20 LPT 4 nd nd nd nd, not determined; CS, cesarean section; VD, vaginal delivery; LPT, laparotomy; LPS, laparoscopy; VAG, vaginal surgery.

1. Introduction Spontaneous haemoperitoneum in pregnancy (SHiP) due to endometriosis is very rare. Preoperative diagnosis can be challenging as SHiP may not always present with signs of haemorrhagic shock. We present such a case which was managed successfully in pregnancy with optimum foetal and maternal outcome. 2. Case Report We present the case of a 41-year-old primigravida, who presented at 32 weeks with sudden onset of severe lower abdominal pain without any uterine activity. This was a dichorionic-diamniotic (DCDA) twin pregnancy, following IVF (in vitro fertilisation) for subfertility secondary to severe endometriosis. This was her fourth admission with abdominal pain in pregnancy. On each previous admission, no definite cause was found and a laxative was given to treat constipation. On admission, pain score was eight, with ten being the maximum of the scale. The vital signs were stable. Abdominal palpation revealed generalised tenderness with no guarding or palpable contraction. There was no evidence of bleeding and the cervical os was closed on speculum examination. The cardiotocograph (CTG) showed unprovoked atypical deceleration with reduced baseline variability which classified CTG as pathological in nonlabouring women. Hence, a plan was made to deliver the babies with emergency caesarean section. Haemoglobin was 105 gm/L, and it was 111 gm/L two weeks prior to this surgery.

n. The cardiotocograph (CTG) showed unprovoked atypical deceleration with reduced baseline variability which classified CTG as pathological in nonlabouring women. Hence, a plan was made to deliver the babies with emergency caesarean section. Haemoglobin was 105 gm/L, and it was 111 gm/L two weeks prior to this surgery. Intraoperatively, there was massive haemoperitoneum although the uterus was intact. After delivery of twins and closure of the lower segment, the uterus was exteriorised and the abdominal cavity was explored to find the source of this unexpected bleeding. On elevating the uterus from the pelvis, fresh arterial bleeding was observed from an approximately 4 cm spherical necrotic tissue close to the left uterosacral ligament. This necrotic tissue was sloughed off leaving a cavity, haemostasis was secured by stitching the bleeding point by using a 2/0 PDS suture, and the bleeding was stopped. There was no breach of integrity or communication between the posterior uterine wall and endometrial cavity. As the left ureter was against the left wall of this cavity, the urologist was requested to stent the left ureter prophylactically before further exploration was done. Upper abdominal exploration by general surgeons also revealed an intact liver and spleen and no other cause of bleeding was identified. There was evidence of old haematoma in the Pouch of Douglas (POD) which may suggest gradual smaller bleeds from the necrotic mass correlating with abdominal pain on previous admissions. Total blood loss was 5000 mL intraoperatively. The patient was adequately resuscitated by the anaesthetic team and received six units of packed red blood cells and two units of fresh frozen plasma.

D) which may suggest gradual smaller bleeds from the necrotic mass correlating with abdominal pain on previous admissions. Total blood loss was 5000 mL intraoperatively. The patient was adequately resuscitated by the anaesthetic team and received six units of packed red blood cells and two units of fresh frozen plasma. Postoperatively, the patient was transferred to the ITU and made uneventful recovery. She developed postpartum cardiomyopathy two weeks following delivery. Regular follow-up was arranged by the Cardiology Team ten months postnatally; cardiac investigations including echocardiography and cardiac MRI revealed normal cardiac function and structure. Histology of the necrotic tissue confirmed endometriosis. 3. Discussion Spontaneous haemoperitoneum in pregnancy (SHiP) due to endometriosis is a rare condition and was an unexpected finding in our case given the stable observation with no drop in haemoglobin.

Postoperatively, the patient was transferred to the ITU and made uneventful recovery. She developed postpartum cardiomyopathy two weeks following delivery. Regular follow-up was arranged by the Cardiology Team ten months postnatally; cardiac investigations including echocardiography and cardiac MRI revealed normal cardiac function and structure. Histology of the necrotic tissue confirmed endometriosis. 3. Discussion Spontaneous haemoperitoneum in pregnancy (SHiP) due to endometriosis is a rare condition and was an unexpected finding in our case given the stable observation with no drop in haemoglobin. The patient was investigated in her previous hospital for infertility and diagnosed to have stage III endometriosis (ASRM classification). She had laparoscopic partial cystectomy done for bilateral ovarian endometriomas and endometriotic spots were found on the sigmoid colon as well. A year later, a second operative laparoscopic diathermy treatment to pelvic endometriotic spots was performed along with dye test revealing bilateral patent tubes. The endometriosis involved the ureters also and an attempt was made to lift the pelvic side wall overlying the ureters; however, the peritoneum was quite thick making endometriotic spot complete excision difficult. In the end, there was a small amount of endometriosis left untreated close to the left ureter. We assume this site may correlate with the same necrotic area found at caesarean section at the back side of the uterus close to the left ureter.

ritoneum was quite thick making endometriotic spot complete excision difficult. In the end, there was a small amount of endometriosis left untreated close to the left ureter. We assume this site may correlate with the same necrotic area found at caesarean section at the back side of the uterus close to the left ureter. In the literature, the pathophysiology of haemoperitoneum from endometriosis is explained as stimulation of preexisting endometriotic implants by endogenous progesterone inducing decidualisation process [1] and invasion of the adjacent vessels or bleeding from decidualised endometriosis implants [2] resulting in spontaneous bleeding. SHiP can happen in any trimester but most commonly during the third trimester [3]. This condition has been described outside labour in 61%, 18% during labour [4], and 21% in the early postpartum period [5]. SHiP is unpredictable and usually presents with vague abdominal pain in women with a history of endometriosis not relieved by mild analgesia or tocolytics [6]. Endometriosis in pregnancy is associated with perforation of the appendix and sigmoid colon [7, 8], rupture of the uterus [9], and spontaneous bleeding from uteroovarian vessels secondary to endometriosis and urohaemoperitoneum [10]. In the literature, we find conflicting evidence regarding the impact of endometriosis on the pregnancy outcomes.

Endometriosis in pregnancy is associated with perforation of the appendix and sigmoid colon [7, 8], rupture of the uterus [9], and spontaneous bleeding from uteroovarian vessels secondary to endometriosis and urohaemoperitoneum [10]. In the literature, we find conflicting evidence regarding the impact of endometriosis on the pregnancy outcomes. A big cohort study from Canada [11] looked into the adverse outcomes in 31,068 women who had a pregnancy between 1997 and 2008. They concluded that 784 women had endometriosis, and out of those (n = 784) 183 had increased incidence of fetal loss, including spontaneous abortion and stillbirth. A longitudinal observational study from Japan [12] identified 330 women (out of 9,186 participants) with a history of endometriosis, showing significantly increased incidence of preterm PROM (premature rupture of membranes) and placenta previa regardless of receiving ART (assisted reproductive technology). However, the authors highlighted that the study was based on patient self-reported questionnaires information on whether they had been diagnosed with endometriosis during the past year, ever had endometriosis, or ever received infertility treatment.

previa regardless of receiving ART (assisted reproductive technology). However, the authors highlighted that the study was based on patient self-reported questionnaires information on whether they had been diagnosed with endometriosis during the past year, ever had endometriosis, or ever received infertility treatment. In a nationwide Swedish study [13] including 1,442,675 singleton births, researchers assessed the association between adverse pregnancy outcome, ART (assisted reproductive technology), and a previous diagnosis of endometriosis. They found out that endometriosis appears to be a risk factor for preterm birth, caesarean section, antepartum haemorrhage, placental complications, and preeclampsia irrespective of ART used. On the contrary to the abovementioned studies [11–13], a systemic review [2] concluded that complications of endometriosis during pregnancy are rare and there is no evidence that the disease has a major detrimental effect on pregnancy outcomes. Similarly, in the context of endometriosis and IVF pregnancies, a recent retrospective case matched study [14] of 239 women concluded that the rate of preterm birth, live birth, incidence of hypertensive disorders, gestational diabetes, small and large for gestational age newborns, and neonatal problems did not differ in IVF treated versus control group; however, placenta previa was more common in women with endometriosis than controls.

men concluded that the rate of preterm birth, live birth, incidence of hypertensive disorders, gestational diabetes, small and large for gestational age newborns, and neonatal problems did not differ in IVF treated versus control group; however, placenta previa was more common in women with endometriosis than controls. It is difficult to predict the pregnancy outcome and complications associated with endometriosis as major studies conducted in the past were based on either personal history of endometriosis given by patients or retrospective case notes review. Hence, not only does extracting the data regarding the staging, severity, and spread of the disease become challenging for researchers, but it is also very difficult to fully appreciate the impact of each specific stage of disease on the pregnancy outcome. High index of suspicion is required with previous history of endometriosis if women present with irregular uterine contractions and symptoms like severe abdominal pain not relieved by tocolysis with gradually unexplained drop in haemoglobin in the absence of overt haemodynamic instability.

ation (ECMO) [2]. However, data regarding the use during pregnancy is limited. Matters are further complicated by the potential of hepatotoxicity with use of halogenated inhaled anesthetics. With informed patient consent, we present a case of refractory status asthmaticus during pregnancy with resultant hepatotoxicity. 2. Case A 31-year-old, gravida 2 para 1001, patient was transferred to our medical ICU at 23 2/7 weeks of gestation with status asthmaticus complicated by acute hypercarbic respiratory failure. She was intubated and paralyzed with a pH < 7.0 and pCO2 > 130. The picture was further complicated by marked bronchoconstriction with elevated PEEP and increased airway resistance nonresponsive to nebulized beta agonists, glucocorticoid, magnesium, and epinephrine treatments. She was initially stabilized on continuous nebulizers, magnesium, propofol, ketamine, and inhaled helium-oxygen (heliox) mixture. Due to persistent difficulty with oxygenation and limited ventilation over a 24-hour period, ECMO was considered: during this time, the patient's oxygen saturation was 85–94% with arterial pH 6.8–7.2. However, due to the potential complications associated with ECMO use during pregnancy, a decision was made to add an inhaled anesthetic for its bronchodilator effects. The patient was transitioned to an anesthesia ventilator system that could provide heliox with inhaled anesthetic. Sevoflurane was initiated, allowing us to lower our peak pressures and maintain oxygen saturations >95%. During this time, the patient was noted to have elevated blood pressure (137–166/70–82 mmHg) requiring intravenous treatment. A 24-hour urine protein was found to be elevated at 739 mg. On review of the patient's previous records, it was determined that the patient was likely a chronic hypertensive with history of antihypertensive medication use and no further workup was undertaken.

essure (137–166/70–82 mmHg) requiring intravenous treatment. A 24-hour urine protein was found to be elevated at 739 mg. On review of the patient's previous records, it was determined that the patient was likely a chronic hypertensive with history of antihypertensive medication use and no further workup was undertaken. Over the next 24 hours, the patient was noted to have improved oxygenation and the sevoflurane was discontinued. She was transitioned back to a traditional ventilator. She remained hypercapnic but maintained a normal pH while on heliox, steroids, propofol, and ketamine. The following day, the patient was noted to have an acute rise in her liver enzymes with an AST of 91 U/L and ALT of 32 U/L; platelets at that time were 243 K/UL. The liver enzymes were noted to progressively rise over the next 10 days while the platelet count remained normal (196–316 K/UL).

ds, propofol, and ketamine. The following day, the patient was noted to have an acute rise in her liver enzymes with an AST of 91 U/L and ALT of 32 U/L; platelets at that time were 243 K/UL. The liver enzymes were noted to progressively rise over the next 10 days while the platelet count remained normal (196–316 K/UL). The patient's respiratory status continued to slowly improve during this time as she was weaned off of the paralytic, corticosteroids, and ketamine. We were able to decrease her peak pressures and elevated PEEP. She was ultimately extubated on hospital day 10. Due to altered mental status, she was reintubated. CT head was negative. Her laboratory evaluation at that time showed AST 161 U/L, ALT 329 U/L, Cr 0.28 mg/dL, Hgb 9.4 g/dL, Plt 261 K/UL, LDH 1029 U/L, and 24-hour urine protein 1245 mg. Diagnosis of atypical hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP syndrome) was considered a possibility. However, due to her periviable gestational age, hematology and hepatology were consulted to rule out other potential etiologies. An extensive autoimmune and infectious workup was done that included antinuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, ADAMTS-13, acute and chronic hepatitis panels, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and human herpes virus 6, all of which were unremarkable. Of note, the maternal Rhesus status was negative. Given that maternal blood transfusion did not occur, Rh incompatibility was unlikely to explain the maternal findings. Abdominal ultrasound was performed and noted to be within normal limits. The patient was reextubated 2 days later.

s 6, all of which were unremarkable. Of note, the maternal Rhesus status was negative. Given that maternal blood transfusion did not occur, Rh incompatibility was unlikely to explain the maternal findings. Abdominal ultrasound was performed and noted to be within normal limits. The patient was reextubated 2 days later. On hospital day 15, the patient's AST peaked at 1146 U/L and ALT peaked at 3168 U/L. Alkaline phosphatase and total bilirubin remained within normal limits. A liver biopsy showed acute hepatitis with prominent apoptotic hepatocytes, cholestasis, and increased sinusoidal inflammatory cells (Figure 1). Immunostains for herpes simplex virus I and II and in situ hybridization for Epstein-Barr virus were negative. There was no significant steatosis or fibrosis, frank necrosis, or fibrin deposition. Given the absence of features of an underlying chronic liver disease and a negative viral and autoimmune hepatitis workup, the findings were consistent with acute drug induced liver injury, most likely due to sevoflurane exposure. Her respiratory status continued to improve and she was discharged from the hospital. No additional episodes of hypertension were noted. Liver enzymes returned to normal over a two-month period (AST 16 U/L and ALT 7 U/L) and repeat 24-hour urine protein was 188 mg two months after the episode. With prolonged periods of maternal hypoxia during the initial 24 hours of hospitalization, there was concern for fetal hypoxic encephalopathy. However, a fetal MRI performed four weeks after the inciting maternal event failed to demonstrate evidence of hypoxic insult. The patient was induced at term due to new-onset oligohydramnios. A healthy term neonate was delivered via spontaneous vaginal delivery without short-term complications despite prolonged maternal hypoxia, acidemia, and permissive hypercarbia.

the inciting maternal event failed to demonstrate evidence of hypoxic insult. The patient was induced at term due to new-onset oligohydramnios. A healthy term neonate was delivered via spontaneous vaginal delivery without short-term complications despite prolonged maternal hypoxia, acidemia, and permissive hypercarbia. 3. Discussion Severe, acute asthma generally leads to significant air trapping, hyperinflation, decreased venous return, and potentially detrimental hemodynamic consequences. The mainstay of treatment revolves around the administration of inhaled bronchodilators and systemic glucocorticoids. The decision to intubate a patient with a severe asthma exacerbation is based upon clinical judgment in conjunction with arterial blood gas measurement. As a general rule, if the patient demonstrates progressive fatigue, continued work of breathing, or alterations in consciousness, intubation is indicated [3]. These patients often will also require deep sedation and paralysis to prevent further complications. In life-threatening exacerbations, such as the patient presented here, nontraditional therapies may be utilized. This can include a helium-oxygen mixture to decrease airflow resistance, magnesium sulfate for bronchodilatory effects, ketamine for potential bronchodilatory effects, or inhalational anesthetics [3]. The mechanism of action for inhaled anesthetics is unclear, but it is thought that these agents have direct bronchodilatory effects on the airways and an increase in cholinergic tone. Halothane, isoflurane, and sevoflurane have been shown to be effective in case reports [2]. Hypotension is usually the limiting factor with use of these agents and bronchoconstriction can be seen after discontinuation of the medications. Additionally, when maternal ventilation is suboptimal, a concern for fetal hypoxemia exists. In our case, particularly due to gestational age, our focus was improving maternal ventilation as opposed to delivery of a periviable neonate. While cordocentesis is an option to assess fetal oxygen saturation, we felt the clinical benefit would be minimal in this situation. Additionally, in the presence of maternal academia, the fetal oxygen disassociation curve would experience a left-ward shift allowing for increased amounts of oxygen delivery to the neonate despite fetal acidosis.

option to assess fetal oxygen saturation, we felt the clinical benefit would be minimal in this situation. Additionally, in the presence of maternal academia, the fetal oxygen disassociation curve would experience a left-ward shift allowing for increased amounts of oxygen delivery to the neonate despite fetal acidosis. HELLP syndrome, a disorder marked by hemolysis, elevated liver enzymes, and low platelets, has a typical onset in the third trimester. It can be difficult to differentiate HELLP syndrome from other disease processes due to multiorgan involvement. The differential diagnoses include acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, systemic lupus erythematosus, and antiphospholipid syndrome [4]. At this gestational age, maternal mortality is reported at ~1% with perinatal mortality rate of 7–22% [5]. Rare case reports of HELLP syndrome occurring at periviable gestational age have been reported in the literature [6–9], all associated with triploidy, molar pregnancy, or antiphospholipid syndrome. It is important to ensure that the diagnosis of HELLP syndrome is accurate during the periviable period as it has significant implications on pregnancy outcome. Continuing the pregnancy may result in significant maternal morbidity/mortality with severe end organ damage but treatment requires delivery of a fetus who will require a prolonged NICU admission and will face high rates of morbidity and mortality. As such, when a patient presents with hepatic dysfunction at an early gestational age, a thorough assessment of hepatotoxicity should include consideration of disorders beyond the spectrum of hypertensive disorders of pregnancy. Furthermore, evaluation via liver biopsy may assist with making an accurate diagnosis and guiding appropriate treatment.

nts with hepatic dysfunction at an early gestational age, a thorough assessment of hepatotoxicity should include consideration of disorders beyond the spectrum of hypertensive disorders of pregnancy. Furthermore, evaluation via liver biopsy may assist with making an accurate diagnosis and guiding appropriate treatment. In our case, a thorough evaluation by hepatology and hematology was performed, including a negative viral and autoimmune workup. Eventually a liver biopsy was performed, and the histologic features were consistent with drug induced livery injury. The typical findings of HELLP syndrome including frank necrosis, periportal hemorrhage, and fibrin deposition were not observed [5]. Sevoflurane, the halogenated inhaled anesthetic used to treat the patient's status asthmaticus, was the presumed inciting agent. Review of the literature has rare reports of sevoflurane-associated hepatotoxicity, primarily in Japanese literature [10]. The patient's overall state of persistent acidosis likely made her more susceptible to hepatotoxicity. Older halogenated anesthetics cause hepatotoxicity via production of trifluoroacetic acid (TFA) that subsequently produce trifluoroacetylated components and cause an immunogenic response in the patient, resulting in hepatitis. Compared to these older halogenated anesthetics, sevoflurane has low hepatotoxic potential as it is metabolized into hexafluoroisopropanol (HFIP) rather than TFA. HFIP has less protein binding capacity, does not accumulate, and is rapidly converted into a stable nontoxic compound that is excreted in the urine. Ultimately, its low hepatotoxic potential makes it the preferred inhaled anesthetic for patients with hepatic disease or at risk for postoperative hepatic injury; however, the risk of hepatotoxicity from TFA still exists [11].

late, and is rapidly converted into a stable nontoxic compound that is excreted in the urine. Ultimately, its low hepatotoxic potential makes it the preferred inhaled anesthetic for patients with hepatic disease or at risk for postoperative hepatic injury; however, the risk of hepatotoxicity from TFA still exists [11]. The use of sevoflurane for the treatment of persistent status asthmaticus is an option during pregnancy. Should failure of traditional therapy occur, the addition of sevoflurane has the potential to improve the patient's clinical course. Practitioners should remain aware of the potential of hepatotoxicity, particularly in the presence of acidosis. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Liver biopsy. (a) Hematoxylin and eosin ×20: liver biopsy specimen showing lobular disarray with numerous apoptotic hepatocytes (arrows) and increased sinusoidal inflammatory cells. No steatosis or frank necrosis is present. (b) Hematoxylin and eosin ×40: liver biopsy specimen showing lobular disarray, prominent apoptotic hepatocytes, and biliary stasis, compatible with recent drug induced liver injury.

1. Background The clinical syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) is primarily coagulopathic in origin, occurring in the later stages of pregnancy after the 37th week [1]. Manifestations of HELLP can begin as epigastric pain, anemia, and platelet consumption by macroangiopathic means. The liver receives the overwhelming brunt of the coagulopathy leading to an increase in liver enzyme turnover and subsequent production [1]. HELLP syndrome is relatively uncommon, but this traumatic obstetric condition occurs at a rate of 0.1% [1]. It evolves most commonly from hypertension and can progress into severe preeclampsia or eclampsia [1–3]. HELLP syndrome can lead to cortical blindness, liver rupture, cerebral edema, hemorrhagic stroke, and subarachnoid hemorrhage [4–12]. Hemorrhagic stroke and subarachnoid brain bleeds are the most feared sequelae and the main cause of mortality from HELLP syndrome [1, 13]. Prognosis is poor in HELLP if stroke occurs in the brainstem, thalamus, and basal ganglia regions, leading to downstream ramifications with short- or long-term neurologic deficits [1, 14]. Maternal neurological deficits are lower in younger women with other risk factors evenly affecting all age groups [15, 16]. Additionally there is limited difference between strokes in pregnant and nonpregnant women [15, 16]. Prompt brain computed tomography (CT) or magnetic resonance imaging (MRI) and a multidisciplinary management approach by obstetricians and neurosurgeons are required for a favorable outcome or prognosis [1, 3, 17, 18]. HELLP, in general, provides a grim prognosis for maternal survivability while not increasing the odds of fetal mortality, which is already compromised by preeclampsia or eclamptic episodes [19].

nary management approach by obstetricians and neurosurgeons are required for a favorable outcome or prognosis [1, 3, 17, 18]. HELLP, in general, provides a grim prognosis for maternal survivability while not increasing the odds of fetal mortality, which is already compromised by preeclampsia or eclamptic episodes [19]. 2. Presentation of the Case A 37-year-old, Gravida 6, Para 1-0-4-1, Hispanic female with advanced maternal age (AMA), history of one previous low transverse cesarean delivery 12 years ago, multiple uterine leiomyomas, chronic hypertension on Methyldopa (Aldomet) 500 mg orally, twice daily, heterozygosity for Methylenetetrahydrofolate Reductase (MTHFR) deficiency with having a 677 cytosine > thymine mutation found in 35% of Caucasian population, recurrent pregnancy loss (RPL) on Aspirin 81 mg daily and progesterone (Endometrin) 100 mg suppositories, Rh negative (s/p RhoGAM), presented at 26 weeks and 6 days of gestational age due to epigastric pain, midline upper abdominal pain, and pressure radiating to her back for one day. Obstetric history was relevant for three previous spontaneous abortions, the last occurring three years priorly, history of fetal demise at 29 weeks due to fetal gastroschisis in which patient was inducted and delivered vaginally. Physical exam showed tenderness to palpation of the epigastric region and right upper quadrant. Fetal monitoring was reassuring. Laboratory studies revealed hemolysis, elevated liver enzymes (ALT 200 IU/L, AST 209 IU/L), and low platelets 104 K/mm3, accompanied by severe intrauterine growth restriction (IUGR) confirmed by ultrasound and compared to previous ultrasound (3 weeks priorly). Current ultrasound correlated to a 22 weeks and 2 days of gestation, with a fetal weight of 564 grams. It is notable that the predicted mean weight is 1040 grams for an average normal fetus at 26 6/7 weeks' gestational age making our measured value less than 1st percentile [20].

o previous ultrasound (3 weeks priorly). Current ultrasound correlated to a 22 weeks and 2 days of gestation, with a fetal weight of 564 grams. It is notable that the predicted mean weight is 1040 grams for an average normal fetus at 26 6/7 weeks' gestational age making our measured value less than 1st percentile [20]. The patient was placed on magnesium sulfate intravenous drip for seizure prophylaxis and fetal neuroprotection and received two doses of betamethasone for fetal lung maturity. Initial pregnancy induced hypertension (PIH) lab values showed elevated liver function tests (LFTs) with ALT of 200 IU/L and AST 209 IU/L as well as low platelets, 104 K/mm3. These values improved, after starting magnesium sulfate and betamethasone, to ALT of 131 IU/L, AST of 66 IU/L, and platelets 143 K/mm3 immediately prior to classical cesarean delivery. Due to concomitant diagnosis of HELLP and IUGR, planned scheduled delivery after completion of second dose of steroid was made for this patient [21]. The aim was to deliver the fetus under controlled condition with maximum availability of help, including presence of multidisciplinary team of neonatal intensive care unit (NICU), respiratory therapy, and obstetrics team.

nned scheduled delivery after completion of second dose of steroid was made for this patient [21]. The aim was to deliver the fetus under controlled condition with maximum availability of help, including presence of multidisciplinary team of neonatal intensive care unit (NICU), respiratory therapy, and obstetrics team. No more than 36 hours from initial presentation, the patient received morphine 0.3 mg intrathecal anesthesia and subsequently underwent repeat classical cesarean delivery at 27 weeks and 1 day for HELLP and IUGR. Her condition was further complicated by intraoperative disseminated intravascular coagulation (DIC) treated with intraoperative blood transfusion products including 2 units of packed red blood cells (PRBCs), 2 units of fresh frozen plasma (FFP), and platelets leading to a noticeable decrease in intraoperative bleeding. The patient delivered a male neonate with weight of 596 grams and APGARs of 7 and 9 in 1 minutes and 5 minutes, respectively, and was transferred to the neonatal intensive care unit (NICU) in stable condition. On postoperative day 1 (POD 1), her DIC appeared to be resolving and lab values showed improvement: ALT 63 IU/L, AST 39 IU/L, and Plt 142 K/mm3. She had an unremarkable postoperative recovery and was discharged on postoperative day 2 on Methyldopa (Aldomet) 500 mg BID and a follow-up appointment in the clinic in 2 days for staple removal and blood pressure check.

red to be resolving and lab values showed improvement: ALT 63 IU/L, AST 39 IU/L, and Plt 142 K/mm3. She had an unremarkable postoperative recovery and was discharged on postoperative day 2 on Methyldopa (Aldomet) 500 mg BID and a follow-up appointment in the clinic in 2 days for staple removal and blood pressure check. On postoperative day 4, the patient returned to clinic with severe headache for 1 day, photophobia, blood soaked bandages, and an initial blood pressure of 169/78 mmHg. She denied any upper abdominal pain. The patient was immediately admitted to the inpatient service and started on magnesium sulfate drip and Methyldopa (Aldomet) 500 mg BID improving the blood pressure to 140s/80s mmHg. PIH lab values were sent (ALT 51 IU/L, AST 45 IU/L, and Plt 184 K/mm3) and CT scan of the head without contrast ordered to rule out any intracranial bleeding or hemorrhage. CT scan of brain without contrast (please see Figure 1) showed mild density in the left horizontal fissure, as well as Sylvian fissure, consistent with a mild subarachnoid hemorrhage. An intensive care unit (ICU) consult was placed and patient immediately transferred to ICU and started on labetalol IV drip followed by nicardipine IV drip with neurosurgery consult. Further imaging by CT-angiogram, magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) were inconclusive. The patient had a cerebral angiogram in the catheterization lab, which confirmed subarachnoid hemorrhage (SAH) due to a bleeding intracranial aneurysm.

ine IV drip with neurosurgery consult. Further imaging by CT-angiogram, magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) were inconclusive. The patient had a cerebral angiogram in the catheterization lab, which confirmed subarachnoid hemorrhage (SAH) due to a bleeding intracranial aneurysm. The patient was transferred to a tertiary level of care facility and underwent attempted placement of endovascular aneurysm coiling (coil embolization) by interventional radiology (IR) followed by successful left pterional/temporal craniotomy and surgical clipping of the left middle cerebral artery (MCA) aneurysm (placement of intracranial aneurysmal clip) by neurosurgery (please see Figure 2). Following craniotomy the patient complained of intermittent headache but did not have any neurological deficits or sequelae. Follow-up blood pressure maintained a value of 130s/80s mmHg while on Aldomet. The infant was also doing well and was in stable condition in the NICU.

The patient was transferred to a tertiary level of care facility and underwent attempted placement of endovascular aneurysm coiling (coil embolization) by interventional radiology (IR) followed by successful left pterional/temporal craniotomy and surgical clipping of the left middle cerebral artery (MCA) aneurysm (placement of intracranial aneurysmal clip) by neurosurgery (please see Figure 2). Following craniotomy the patient complained of intermittent headache but did not have any neurological deficits or sequelae. Follow-up blood pressure maintained a value of 130s/80s mmHg while on Aldomet. The infant was also doing well and was in stable condition in the NICU. 3. Discussions Hypertension is the number one underlying cause and focus for treatment options in HELLP syndrome because it predisposes individuals to preeclampsia and subsequent HELLP syndrome [2, 3, 22–25]. Complications of HELLP syndrome range from cortical blindness, liver rupture, cerebral edema, subarachnoid hemorrhage, and most commonly hemorrhagic stroke [2, 4, 6–8, 10–12]. Most patients with hemorrhagic stroke present with headache as their main concern [9, 26–28]. A very rare complication is DIC and/or postpartum subarachnoid hemorrhage can transpire in a patient with HELLP syndrome undergoing spinal anesthesia. Though experimental, a bolus of remifentanil has shown promising effects but is limited due to the risk of neonatal depression [5, 29, 30]. The diagnosis is clinically based, with the added combination of CT visualization of increased density within regions of the brain, leading to a correlated diagnosis showing vascular brain bleeds in conjunction with neurological deficits [9, 17]. Findings can be further confirmed by MRI/MRA or IR [1]. Rapid assessment with imaging in conjunction with magnesium sulfate infusion and urgent neurosurgical decisions at a tertiary care hospital have shown positive outcomes as was seen with our patient [3, 18, 25, 31, 32].

njunction with neurological deficits [9, 17]. Findings can be further confirmed by MRI/MRA or IR [1]. Rapid assessment with imaging in conjunction with magnesium sulfate infusion and urgent neurosurgical decisions at a tertiary care hospital have shown positive outcomes as was seen with our patient [3, 18, 25, 31, 32]. 4. Conclusion HELLP syndrome is an uncommon and traumatic event which can complicate a pregnancy, leading to neurological deficits if not treated in a responsive and rapid manner. The central aggravating factor seems to be hypertension inducing a preeclamptic or eclamptic episode and complications thereof. The syndrome itself is manifested by anemia, increased liver enzymes, and decreasing platelet counts with a majority of neurological defects occurring due to hemorrhagic stroke or subarachnoid hemorrhage. Generally, HELLP syndrome provides a grim prognosis for maternal survivability, which can be improved by aggressive hypertension monitoring. Fortunately, as in this case, the incidence of maternal neurological deficits decreases in younger patients and does not increase fetal mortality which may already be compromised by preeclampsia or eclampsia. It is important for obstetricians and nursing teams to emphasize and reemphasize the signs and symptoms of preeclampsia during prenatal visits and hospital admissions and upon discharge to all postpartum patients especially in higher risk population group with diagnosis of chronic hypertension, gestational hypertension, HELLP, preeclampsia, and eclampsia.

nursing teams to emphasize and reemphasize the signs and symptoms of preeclampsia during prenatal visits and hospital admissions and upon discharge to all postpartum patients especially in higher risk population group with diagnosis of chronic hypertension, gestational hypertension, HELLP, preeclampsia, and eclampsia. Educating patients on importance of close monitoring and measuring blood pressure at home, at least twice daily by the patient, and providing home blood pressure log sheet, prescription with appropriate dose of antihypertensive medications and blood pressure machine (Sphygmomanometer), and follow-up by visiting nurse services (VNS) to visit and evaluate the patient and monitor blood pressure at least twice weekly at home, as well as patient's early return visit to clinic for blood pressure check in 2-3 days following hospital discharge, all can aid in early diagnosis and address the issue of hypertension and other morbidities and mortalities associated with it. Obstetricians should also be very cautious; although many cases of headache and elevated blood pressure in preeclamptic patients can be treated by managing patient's hypertension with antihypertensives (and addition of magnesium sulfate if indicated), supportive therapy and medications for headache, and serial neurological exam, it is important to keep in mind that intracranial hemorrhage still can be one of the etiologies for headaches in these patients which requires additional prompt brain imaging and neurosurgery evaluation.

n of magnesium sulfate if indicated), supportive therapy and medications for headache, and serial neurological exam, it is important to keep in mind that intracranial hemorrhage still can be one of the etiologies for headaches in these patients which requires additional prompt brain imaging and neurosurgery evaluation. Rapid assessment, diagnostic exams, brain imaging, and neurosurgery consultation are vital necessities for the obstetrician involved in order to provide the best long-term prognosis for mother and fetus. Acknowledgments The authors would like to thank Ms. Judith Wilkinson, Medical Librarian at Lincoln Medical and Mental Health Center Science Library, for providing the reference articles. Conflicts of Interest The authors did not report any potential conflicts of interest. Figure 1 CT scan of brain without contrast axial view, on October 19, 2016, 15:51 PDT. There is mild density in the left horizontal fissure, as well as Sylvian fissure, consistent with a mild subarachnoid hemorrhage (red circles). No large acute infarction or other parenchymal lesions are identified. Figure 2 CT scan of brain without contrast axial view on November 11, 2016, after left temporal craniotomy and clipping of left MCA aneurysm: showing the clip in the area of the proximal left middle cerebral artery (red circles).

1. Introduction Ectopic pregnancy is diagnosed in 1.3–2.0% of all reported pregnancies and is an important cause of maternal morbidity and occasionally mortality [1]. Symptoms and signs of ectopic pregnancy vary but include abdominal or pelvic pain, missed period, vaginal bleeding, and gastrointestinal or urinary symptoms as well as pressure or pain on defecation. Transvaginal sonography (TVS) is the method of choice for the diagnosis of ectopic pregnancy [2]. An ectopic pregnancy can frequently be visualized by TVS as an inhomogeneous pelvic mass and free fluid within the pouch of Douglas. In fact, the increased frequency of positive scans has led to a reduction in the number of unnecessary laparoscopies [3]. Ectopic pregnancies with low serum human chorionic gonadotrophin (hCG) levels are known to be especially challenging to diagnose. Chronic ectopic pregnancy is such a subgroup and is characterized by symptoms and signs of mild to moderate intensity and low serum levels of β-HCG [4, 5]. Chronic ectopic pregnancy resulting in perforation of the rectum and rectal bleeding despite moderate symptoms and decreasing low levels of β-HCG, as described in the present report, represents a novel clinical complication of this type of pregnancy. 2. Case Presentation A previously healthy 31-year-old woman, gravida 3, para 3, was admitted to the hospital with a history of lower abdominal pain lasting more than two weeks. On the day she was admitted, her pain had suddenly increased in intensity and she had noted the presence of fresh blood on her toilet paper.

Ectopic pregnancies with low serum human chorionic gonadotrophin (hCG) levels are known to be especially challenging to diagnose. Chronic ectopic pregnancy is such a subgroup and is characterized by symptoms and signs of mild to moderate intensity and low serum levels of β-HCG [4, 5]. Chronic ectopic pregnancy resulting in perforation of the rectum and rectal bleeding despite moderate symptoms and decreasing low levels of β-HCG, as described in the present report, represents a novel clinical complication of this type of pregnancy. 2. Case Presentation A previously healthy 31-year-old woman, gravida 3, para 3, was admitted to the hospital with a history of lower abdominal pain lasting more than two weeks. On the day she was admitted, her pain had suddenly increased in intensity and she had noted the presence of fresh blood on her toilet paper. The woman had been examined by a gynecologist three days earlier after experiencing mild to moderate abdominal pain. She had had a copper intrauterine device (IUD) for three years and usually had regular periods. However, for the last few weeks, she had only experienced some spotting. A physical examination by the gynecologist revealed some vaginal discharge, but no vaginal bleeding. The uterus and the adnexa were tender when bimanual palpation was performed. Ultrasound showed an endometrial lining of approximately 5 mm. The IUD was located in the uterine cavity. Both ovaries were normal, but some fluid was seen in the right fallopian tube. No fluid was visualized in the pouch of Douglas. The gynecologist tried to remove the IUD, but this procedure was unsuccessful since the IUD strings could not be seen. The patient's temperature was 36.7°C. However, routine biochemistry showed that serum CRP was 100 g/L and β-HCG was 412 mIU/mL. The gynecologist concluded that the woman had a pelvic infection and prescribed doxycycline and metronidazole tablets. As the serum β-HCG was suggestive of an early stage of pregnancy, an ectopic pregnancy could not be excluded. A follow-up consultation was therefore scheduled for three days later. The patient was also encouraged to contact a hospital immediately if her condition worsened.

scribed doxycycline and metronidazole tablets. As the serum β-HCG was suggestive of an early stage of pregnancy, an ectopic pregnancy could not be excluded. A follow-up consultation was therefore scheduled for three days later. The patient was also encouraged to contact a hospital immediately if her condition worsened. Two days later, the patient saw fresh blood on her toilet paper. Her pain was also more intense. Following the recommendation of the gynecologist, she contacted the hospital. When she arrived at the hospital, her condition was in general good. She reported pain of mild to moderate intensity. No blood was seen in the vagina, but gynecological examination revealed a fixed tender mass behind her uterus. The size of the mass was difficult to assess due to patient tenderness. However, TVS confirmed a 6 × 5 cm mass containing hypoechoic and anechoic areas. Very little fluid was visualized in the pouch of Douglas. Rectal examination revealed fresh blood. Due to rectal bleeding, a rectoscopy was performed, which identified a 1.5 cm wide perforation in the anterior wall of the rectum surrounded by tumor-like tissue with active bleeding about 15 cm from the anal verge. Several biopsies were obtained for histopathological examination since malignancy could not be excluded. Laboratory tests showed that serum CRP had increased to 179 g/L, while β-HCG had decreased to 366 mIU/mL. The patient's hemoglobin count was 11.5 g/100 mL.

issue with active bleeding about 15 cm from the anal verge. Several biopsies were obtained for histopathological examination since malignancy could not be excluded. Laboratory tests showed that serum CRP had increased to 179 g/L, while β-HCG had decreased to 366 mIU/mL. The patient's hemoglobin count was 11.5 g/100 mL. A laparoscopy was performed immediately after the rectoscopy. Several pelvic inflammatory bowel adhesions had to be removed before the right fallopian tube was identified in the pouch of Douglas. The ampullary part of the fallopian tube was dilated to approximately 5 cm. Both the tube and the right ovary were substantially damaged due to inflammatory reaction and a salpingo-oophorectomy was performed. The rectal perforation was identified and sutured. The patient's postoperative recovery was uneventful and serum β-HCG was undetectable five days after laparoscopy. Cervical and vaginal swabs for bacterial culture taken at the initial gynecological examination were negative. Histopathological examination of biopsies from both the rectum and the tube confirmed chronic ectopic pregnancy (Figure 1). Chronic and acute inflammatory reactions were diagnosed in tissue biopsies from the fallopian tube and the removed ovary as well as in rectal biopsies. There were no signs of malignancy.

negative. Histopathological examination of biopsies from both the rectum and the tube confirmed chronic ectopic pregnancy (Figure 1). Chronic and acute inflammatory reactions were diagnosed in tissue biopsies from the fallopian tube and the removed ovary as well as in rectal biopsies. There were no signs of malignancy. 3. Discussion Rectal bleeding is an extremely rare complication of ectopic pregnancy. A review of the literature found only eight cases, all representing acute and dramatic events involving massive intestinal bleeding caused by interstitial tubal pregnancies or true abdominal pregnancies [6]. The terminal ileum, sigmoid colon, and caecum were the parts of the gastrointestinal tract most commonly involved. The rectum was the source of bleeding in only one case.

resenting acute and dramatic events involving massive intestinal bleeding caused by interstitial tubal pregnancies or true abdominal pregnancies [6]. The terminal ileum, sigmoid colon, and caecum were the parts of the gastrointestinal tract most commonly involved. The rectum was the source of bleeding in only one case. In the present report, the symptoms were of mild to moderate intensity and had been ongoing for more than 2 weeks. Rectal bleeding was also modest. As confirmed by the histopathological examination, the patient suffered from a chronic ectopic pregnancy. This type of pregnancy accounts for approximately 6% of all ectopic pregnancies and typically presents with repeated episodes of lower abdominal pain and vaginal bleeding of varying severity [7]. Although the pathogenesis of chronic ectopic pregnancy is not fully known, it has been hypothesized that growth of trophoblastic tissue causes gradual destruction of the tubal wall, resulting in a slow, episodic leakage of blood [4]. The presence of blood, trophoblastic tissue, and disrupted tubal tissue in the peritoneal cavity is thought to provoke an inflammatory reaction resulting in the development of an organized hematocele and adhesions.

tissue causes gradual destruction of the tubal wall, resulting in a slow, episodic leakage of blood [4]. The presence of blood, trophoblastic tissue, and disrupted tubal tissue in the peritoneal cavity is thought to provoke an inflammatory reaction resulting in the development of an organized hematocele and adhesions. Chronic ectopic pregnancy is often difficult to differentiate from pelvic inflammatory disease, endometriosis, and uterine fibroids when TVS is performed [7]. The mass that occurs in this type of pregnancy is typically produced by adhesions between the inflamed tube and surrounding structures, blood, and necrotic debris after degeneration of the conceptus, yielding a heterogenous echo pattern [8]. In the present case, fluid was seen in the right fallopian tube at the initial examination. The ultrasound finding combined with a serum CRP of 100 g/L indicated that the patient suffered from pelvic inflammatory disease. Antibiotics were therefore prescribed. However, cervical and vaginal swabs taken at the initial gynecological examination were negative. Thus, the high CRP levels probably reflect that the pelvic inflammation had reached a stage where the gastrointestinal tract had become involved. The prescription of antibiotics at the initial consultation was clearly due to a misdiagnosis and can only be described as mismanagement.

cological examination were negative. Thus, the high CRP levels probably reflect that the pelvic inflammation had reached a stage where the gastrointestinal tract had become involved. The prescription of antibiotics at the initial consultation was clearly due to a misdiagnosis and can only be described as mismanagement. An intrauterine pregnancy can be visualized using TVS with serum β-HCG levels as low as 1000 IU/L [9]. In cases of chronic ectopic pregnancy, serum β-HCG levels are usually much lower due to a very small amount of live villi [10]. It is of immense clinical importance that follow-up consultations are performed until the final pregnancy outcome is known. Serial serum β-HCG measurements are clearly helpful in cases where an ectopic pregnancy cannot be excluded. However, in some cases of chronic ectopic pregnancy, serum β-HCG levels are undetectable and pregnancy tests are therefore negative [10, 11]. The present case is unique because it shows that chronic ectopic pregnancy can cause perforation of the rectum, despite symptoms of moderate intensity and decreasing low levels of serum β-HCG. Acknowledgments The authors would like to thank Johan Mölne and Oscar Tator, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden, for performing the histopathological examinations. Conflicts of Interest The authors declare that they have no conflicts of interest regarding the publication of this paper.

Acknowledgments The authors would like to thank Johan Mölne and Oscar Tator, Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden, for performing the histopathological examinations. Conflicts of Interest The authors declare that they have no conflicts of interest regarding the publication of this paper. Figure 1 Biopsies from the rectal wall with glandular epithelium (a) with positive staining for CK7 (b) and estrogen receptor (c) indicating an origin from the gynecological tract. Biopsies from the removed fallopian tube with chorion villi ((d), arrow) with positive staining for HCG ((e), arrow).

1. Introduction Necrotising fasciitis (NF) is a severe infection involving the skin, subcutaneous tissue, and superficial fascia, which often has a fulminant course and a potentially lethal outcome [1–5]. It is a rare infection with an estimated incidence of 0.4 per 100,000 in the general population and a mortality rate of up to 34% [5, 6]. Majority of cases result from trivial trauma; however, surgery is an independent risk factor [4, 5, 7]. The microbiology of wound infections resulting in necrotising fasciitis (types I–III) is primarily polymicrobial, cutting across a wide range of highly virulent pathogens as detailed in a recent review by Hakkarainen et al. [5]. However, Methicillin-resistant Staphylococcus aureus (MRSA) has been implicated in up to a third of cases [8]. Necrotising fasciitis had been earlier described by Hippocrates in the 5th century BC [9], but its association with caesarean section was first reported by Gretz et al. in 1962 [10]. Since then, Goepfert et al. [11] in an 8-year retrospective analysis of 5048 caesarean deliveries reported 9 cases, giving an incidence rate of 1.8 per 1000 caesarean deliveries while Schorge and colleagues [12] recorded five cases over a 15-year period.

aesarean section was first reported by Gretz et al. in 1962 [10]. Since then, Goepfert et al. [11] in an 8-year retrospective analysis of 5048 caesarean deliveries reported 9 cases, giving an incidence rate of 1.8 per 1000 caesarean deliveries while Schorge and colleagues [12] recorded five cases over a 15-year period. Though a multidisciplinary team is best suited to handle such cases [3, 5], there is still an invaluable need to rely on general practitioners to perform a number of procedures in our setting where specialists are rare [13]. We herein report to the best of our knowledge the first case of widespread postcaesarean necrotising fasciitis successfully managed in a resource-limited primary health care centre in rural Cameroon with acceptable cosmetic results. 2. Case Presentation We report a 19-year-old lady with a previous vaginal delivery who underwent a lower segment caesarean section (CS) for acute foetal distress at 39-week gestation. She delivered a healthy male baby and the surgery lasted 43 minutes. There were no intraoperative complications. She has no known medical condition and had an uncomplicated antenatal course.

a previous vaginal delivery who underwent a lower segment caesarean section (CS) for acute foetal distress at 39-week gestation. She delivered a healthy male baby and the surgery lasted 43 minutes. There were no intraoperative complications. She has no known medical condition and had an uncomplicated antenatal course. On day 4 after CS, she complained of lower abdominal pains. On examination, she was afebrile (temperature 37.1°C); other vital signs were within normal ranges and the incision site was clean with no evidence of surgical site infection. She was managed with analgesics (tramadol) and ampicillin was continued as part of her routine postoperative care. By day 5 postop, she developed an acute abdomen. The incision site had become very tender and soft tissue crepitation was noted on either side of the incision. Due to limited resources, only a white cell count, HIV status, random blood glucose, and a haemoglobin level could be done whose values were 39.800 cells/mm3, HIV negative, 116 mg/dL, and 8.3 g/dL, respectively. A decision to do an exploratory laparotomy was taken. Upon reopening the lower segment incision (Pfannenstiel), a pungent and offensive greenish seropurulent discharge oozed from the site. Further exploration revealed abundant foul smelling ascites and an extensive spread of greyish necrotic tissues involving the skin, subcutaneous tissue, recti muscles, fascia, and anterior serosa of myometrium. The hysterotomy site was nondraining and hyperaemic. An intraoperative diagnosis of necrotising fasciitis was made and all necrotic tissues were excised; the peritoneal cavity was thoroughly washed out and mopped using an adapted abdominal mop due to unavailability of a suction machine. This “abdominal mop” consisted of a commercially available baby napkin (diaper) made of cloth which was sterilised in an autoclave before it was used (Figure 1). Two locally adapted drains (drip lines attached to a urine bag) were also inserted. The resulting anterior abdominal wound was left open to heal by secondary intention and she was transfused a pint of whole blood in the immediate postoperative period. No samples were sent for analyses due to financial constraints. Empiric broad spectrum intravenous antibiotics (metronidazole, ceftriaxone, and gentamycin) were added and appropriate fluid support was also provided. Daily wound care was done during which necrotic tissues in the anterior abdominal wall were debrided to a bleeding edge.

sent for analyses due to financial constraints. Empiric broad spectrum intravenous antibiotics (metronidazole, ceftriaxone, and gentamycin) were added and appropriate fluid support was also provided. Daily wound care was done during which necrotic tissues in the anterior abdominal wall were debrided to a bleeding edge. However, due to a deteriorating clinical state (septic shock: managed by continuation of empiric antibiotics and IV crystalloids: normal saline and Hartmann's solutions), abundant drainage, and continual progression of necrosis, the wound was extensively debrided approximately 2 cm beyond the bleeding edges to ensure adequate resection on day 6 after laparotomy. The large defect (Figure 2) with neither recti muscles nor fascia was covered with the improvised abdominal mop after each daily wound dressing (Figure 3). During this time, her baby was doing quite well and for fear of transmitting the infection to the infant, the child was often times separated from the mother and was bottle-fed with expressed breast milk.

recti muscles nor fascia was covered with the improvised abdominal mop after each daily wound dressing (Figure 3). During this time, her baby was doing quite well and for fear of transmitting the infection to the infant, the child was often times separated from the mother and was bottle-fed with expressed breast milk. Once adequate margins on her anterior abdominal wall were obtained, evolution was remarkable as routine daily wound care did not show further necrosis, and there were decreased drainage and a marked improvement in her overall clinical status. In addition to her regular daily meals, nutritional support with Glycine max (in undocumented quantities) was provided (oral consumption). Two weeks after extensive debridement, a granulating and healthy looking wound was seen and regular breastfeeding had resumed. By the 15th week, the abdominal defect had closed and intraabdominal organs were nonvisible (Figure 4). She was discharged to be followed up on an outpatient basis; however, due to financial constraints regarding her bills, she remained in the health facility. Without any reconstructive surgery, complete closure of wound was achieved by week 25 after extensive debridement with appreciable cosmetics (Figure 5).

Figure 4). She was discharged to be followed up on an outpatient basis; however, due to financial constraints regarding her bills, she remained in the health facility. Without any reconstructive surgery, complete closure of wound was achieved by week 25 after extensive debridement with appreciable cosmetics (Figure 5). 3. Discussion Necrotising fasciitis (NF), also referred to as the “flesh-eating disease,” is a life-threatening infection which is usually polymicrobial in nature and requires timely surgical intervention and aggressive antibiotic therapy. It is a rapidly spreading infection and can involve all the layers of the soft tissue compartments as well as deeper tissues in the pelvis [3, 14–16]. Risk factors include diabetes, hypertension, anaemia, malnutrition, surgery, obesity, immunosuppression, peripheral vascular disease, alcoholism, smoking, and renal disease [3–5, 7, 14–17]. The condition is quite rare in obstetric literature with only about half a dozen cases reported in the last decade and it is often associated with high morbidity and mortality even with optimal treatment in specialised units, especially with infections extending to the pelvis [3, 4, 15–17] as in the current case report.

he condition is quite rare in obstetric literature with only about half a dozen cases reported in the last decade and it is often associated with high morbidity and mortality even with optimal treatment in specialised units, especially with infections extending to the pelvis [3, 4, 15–17] as in the current case report. Clinically, most patients present with a dusky looking wound margin, bullae, crepitus, and signs of inflammation including swelling, induration (which may be difficult to recognize in dark skin patients), and severe pain disproportionate to local findings at the affected site [3–5, 7, 15–17]. Typically, the infection spreads along fascia planes due to its less robust blood supply and the overlying tissue can appear unaffected as noted in this case report. It is this feature that renders NF particularly difficult to diagnose without surgical intervention [5, 7, 16]. Thus, a high index of suspicion is warranted for early recognition as it characteristically spreads rapidly and can lead to systemic toxicity with a resultant multiorgan dysfunction and consequent death [3–5, 7, 15–17]. Worth reiterating is the fact that though paraclinical examinations including imaging modalities may be helpful [7]; the definitive diagnosis of NF is established surgically via direct visualization of fascia planes and muscle tissue [5, 16].

with a resultant multiorgan dysfunction and consequent death [3–5, 7, 15–17]. Worth reiterating is the fact that though paraclinical examinations including imaging modalities may be helpful [7]; the definitive diagnosis of NF is established surgically via direct visualization of fascia planes and muscle tissue [5, 16]. Whilst treatment with antibiotics plays an irreplaceable role in the management of NF, surgical intervention is the mainstay of management and should be done promptly as there is no room for “wait and watch policy” [3–5, 7, 16, 17]. Antibiotic therapy without debridement is associated with a mortality rate approaching 100% [5, 18]. As observed in this case report and similar published literature [3–5, 7, 15, 16], debridement may be serial and leaving the abdomen open is consistent with damage control laparotomy techniques which also has an added advantage of preventing abdominal compartment syndrome. Specialised materials like the Bogotá bag have been used to protect the abdominal viscera especially the bowels in such cases [16]; however, an improvised cloth (sterilised baby napkin) was effective in our resource-constraint setting. Once the infection has been cleared, a number of reconstructive surgical procedures can be done to ensure complete wound closure and enhance cosmetic appearance [3, 15].

cera especially the bowels in such cases [16]; however, an improvised cloth (sterilised baby napkin) was effective in our resource-constraint setting. Once the infection has been cleared, a number of reconstructive surgical procedures can be done to ensure complete wound closure and enhance cosmetic appearance [3, 15]. This case underscores the importance of a high index of suspicion and prompt surgical intervention, even in the absence of hallmark features in managing necrotising fasciitis. Whilst not undermining the paramount importance of a highly specialised multidisciplinary team in managing such rare life-threatening conditions in sophisticated units, we have reported a successful management by primary health care physicians (general practitioners) with locally adapted materials in a resource-limited setting where referrals to tertiary centres seems a death sentence due to the associated unbearable financial burden. Though it is recommended that antibiotic treatment be adjusted according to microbiological findings, the role of empiric broad spectrum antibiotics in controlling the spread of the infection in such settings cannot be overemphasized. Nutrition with cost-effective and readily available food supplements like soya bean (Glycine max: 38–45% protein content) is an effective adjunct to enhance healing. Our case management may not be standard, but it is subject to refinement and sets the platform for improvising in the management of various pathologies in the many health care-deprived resource-disadvantaged communities in Sub-Saharan Africa with little or no access to specialised care.

tive adjunct to enhance healing. Our case management may not be standard, but it is subject to refinement and sets the platform for improvising in the management of various pathologies in the many health care-deprived resource-disadvantaged communities in Sub-Saharan Africa with little or no access to specialised care. Acknowledgments The authors wish to sincerely thank the nurses who took part in the care of this patient especially Mr. Abungwo Emmanuel, Geraldine Mokem, Fofack Alvine, and Fondzenyuy Yvette. Consent Written informed consent was obtained from the mother of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review. Conflicts of Interest The authors declare that they have no conflicts of interest. Figure 1 (a) Shows locally available baby napkin (diaper) in its original package; (b) shows some napkins placed in an autoclave; and (c) Depicts napkins undergoing the sterilisation process. Figure 2 Large abdominal defect exposing bowel and uterus as seen on day 10 after extensive debridement. Figure 3 Sterilised baby napkin (diaper) used in covering abdominal defect after each dressing. Figure 4 (a) and (b) Depicting wound healing process at weeks 15 and 22, respectively. Figure 5 Completely healed anterior abdominal wall with appreciable cosmetics.

1. Introduction Intramural hematoma of the esophagus (IHE) is a rare condition in which bleeding starts within the submucosal layer causing the hematoma formation and the dissection of the esophageal wall [1, 2]. IHE is considered part of a spectrum of esophageal injuries that include local mucosal tears (Mallory-Weiss syndrome), full-thickness rupture (Boerhaave's syndrome), and dissecting intramural hematoma [3]. Although these syndromes are usually associated with severe vomiting, dissecting IHE is not always associated with an increase in intraesophageal pressure. Other underlying causes of submucosal bleeding can be any one of the following: coagulopathy and abnormal hemostasis, trauma, and portal hypertension. IHE has severe implications but an excellent prognosis when managed conservatively [4, 5]. We report the case of a dissecting intramural hematoma of the esophagus acutely complicating a preeclamptic woman shortly after Cesarean section.

IHE is considered part of a spectrum of esophageal injuries that include local mucosal tears (Mallory-Weiss syndrome), full-thickness rupture (Boerhaave's syndrome), and dissecting intramural hematoma [3]. Although these syndromes are usually associated with severe vomiting, dissecting IHE is not always associated with an increase in intraesophageal pressure. Other underlying causes of submucosal bleeding can be any one of the following: coagulopathy and abnormal hemostasis, trauma, and portal hypertension. IHE has severe implications but an excellent prognosis when managed conservatively [4, 5]. We report the case of a dissecting intramural hematoma of the esophagus acutely complicating a preeclamptic woman shortly after Cesarean section. 2. Case Presentation A 37-year-old G2P1 woman of Indian origin was admitted in the Obstetrical Department of the University Hospital of Verona with a 32-week dichorionic twin gestation. She complained of moderate dyspnea (SpO2 98%) and sudden ankle swelling; her blood pressure was high and had significant proteinuria (>30 mg/mmol on spot protein-creatinine). Obstetric history included a term vaginal delivery and a laparoscopic salpingectomy for ectopic pregnancy. She had conceived the index pregnancy after an in vitro fertilization and embryo transfer (IVF-ET) in India. In her country of origin, she had gone through regular antenatal visits, receiving vaginal progesterone, anticoagulant therapy with LMWH for multiple venous thromboembolism risk factors, and levothyroxine due to a pregestational autoimmune hypothyroidism. Prophylactic cerclage had also been placed in India at 14 weeks where she was started on a daily low-dose aspirin regimen.

enatal visits, receiving vaginal progesterone, anticoagulant therapy with LMWH for multiple venous thromboembolism risk factors, and levothyroxine due to a pregestational autoimmune hypothyroidism. Prophylactic cerclage had also been placed in India at 14 weeks where she was started on a daily low-dose aspirin regimen. At admission, treatment was started with oral labetalol 100 mg every 8 hours and a 2-day betamethasone course for fetal lung maturation. Aspirin was discontinued, while LMWH was kept, due to multiple risk factors: age (37 years), twin pregnancy, IVF/ART, and preeclampsia. Twenty-four-hour proteinuria was 2,1 g/d and preeclampsia was confirmed. Platelet count showed a reduction from 125 × 109/L at admission to 98 × 109/L. Ultrasound evaluation showed a normal growth, normal amniotic fluid, and Doppler indices of uterine blood flow for both fetuses. At 33 weeks of gestation, the patient was delivered with a C-section under general anesthesia due to an uncontrolled rise of the blood pressure failing to respond to treatment (160/100 mmHg) and a further platelet count reduction (91,000/dL). Bleeding amounted to 600 mL. After C-section, no evidence of coagulopathy was observed with stable platelet count. Hemoglobin levels (11.5 g/dL) as well as other coagulation indexes remained in the normal range. The newborns weighted 2090 g and 1830 g and were transferred to the Neonatology Intensive Care unit to be treated for prematurity.

00 mL. After C-section, no evidence of coagulopathy was observed with stable platelet count. Hemoglobin levels (11.5 g/dL) as well as other coagulation indexes remained in the normal range. The newborns weighted 2090 g and 1830 g and were transferred to the Neonatology Intensive Care unit to be treated for prematurity. After Cesarean, a sudden increase of blood pressure (175/110 mmHg) was observed and intravenous labetalol was started along with magnesium sulphate for eclampsia prevention. LMWH was continued to prevent postpartum and postoperative DVT. Treatment effectively lowered the blood pressure and obtained a stable condition, with the patient only complaining of moderate heartburn and occasional vomiting. Accordingly, H2 receptor antagonists therapy was started. On the first postoperative day, the patient suddenly complained of a right side retrosternal pain extending to the shoulder blade, nausea, vomiting, and dysphagia. Occurrence of HELLP syndrome was ruled out since platelet count and liver enzymes were normal and no signs of hemolysis were recorded. ECG and chest X-ray were both negative. The following day hematemesis was observed which warranted the indication of a gastroscopy. In the initial phase of the endoscopic evaluation, an eccentric mass was seen, completely obliterating the lumen of the esophagus, which prompted the end of the procedure (Figure 1). A chest CT scan showed bilateral pleural effusion and confirmed an intramural hematoma of the posterior esophageal wall, extending 15 cm caudally (Figure 2); no active bleeding was seen.

After Cesarean, a sudden increase of blood pressure (175/110 mmHg) was observed and intravenous labetalol was started along with magnesium sulphate for eclampsia prevention. LMWH was continued to prevent postpartum and postoperative DVT. Treatment effectively lowered the blood pressure and obtained a stable condition, with the patient only complaining of moderate heartburn and occasional vomiting. Accordingly, H2 receptor antagonists therapy was started. On the first postoperative day, the patient suddenly complained of a right side retrosternal pain extending to the shoulder blade, nausea, vomiting, and dysphagia. Occurrence of HELLP syndrome was ruled out since platelet count and liver enzymes were normal and no signs of hemolysis were recorded. ECG and chest X-ray were both negative. The following day hematemesis was observed which warranted the indication of a gastroscopy. In the initial phase of the endoscopic evaluation, an eccentric mass was seen, completely obliterating the lumen of the esophagus, which prompted the end of the procedure (Figure 1). A chest CT scan showed bilateral pleural effusion and confirmed an intramural hematoma of the posterior esophageal wall, extending 15 cm caudally (Figure 2); no active bleeding was seen. The patient was transferred to ICU where she remained hemodynamically stable, with no sign of perforation and no mediastinal involvement. A conservative management was chosen: supportive care and parenteral nutrition, administration of proton pump inhibitors to decrease gastric acid production, and broad-spectrum antibiotic therapy.

s transferred to ICU where she remained hemodynamically stable, with no sign of perforation and no mediastinal involvement. A conservative management was chosen: supportive care and parenteral nutrition, administration of proton pump inhibitors to decrease gastric acid production, and broad-spectrum antibiotic therapy. The chest CT control two days later showed no modification of the hematoma with no active bleeding and improvement of the pleural effusion. Nine days after the initial diagnosis and eleven days after C-section, a new episode of hematemesis required a repeat CT scan. This time a reduction of the hematoma was seen with concomitant blood collection in the stomach. Gastroscopy was indicated, blood content aspirated, and the active bleeding controlled with local therapy. The patient was transfused with 2 units of packed red cells. After this episode, the patient was discharged from ICU and transferred to a surgical ward where conservative treatment was continued until restarting of food intake; the subsequent course was uncomplicated. A control chest CT, 17 days after C-section, showed an open lumen, a reduction of the thickness of the esophageal wall, and an almost complete resolution of the parietal hematoma (Figure 3). The patient was discharged asymptomatic 20 days after the initial diagnosis under antihypertensive and antacid therapy. A detailed chart including medications, laboratories results, images, and procedures throughout hospitalization is presented in Table 1.

A control chest CT, 17 days after C-section, showed an open lumen, a reduction of the thickness of the esophageal wall, and an almost complete resolution of the parietal hematoma (Figure 3). The patient was discharged asymptomatic 20 days after the initial diagnosis under antihypertensive and antacid therapy. A detailed chart including medications, laboratories results, images, and procedures throughout hospitalization is presented in Table 1. 3. Discussion Pathogenesis of intramural esophageal bleeding leading to hematoma formation and submucosal dissection is often unclear. Several causes have been proposed: emetogenic, traumatic, related to aortic disease, and coagulopathic; in few instances, the cause remains undetermined. Severe bleeding results in proximal or distal intramural dissection, as the hematoma develops concentrically or eccentrically, as in the present case [5]. About one-fifth of patients appear to have a spontaneous origin, although this may be associated with an underlying predisposition: abnormal pressure changes within the esophagus or a coagulation disorder [6].

l intramural dissection, as the hematoma develops concentrically or eccentrically, as in the present case [5]. About one-fifth of patients appear to have a spontaneous origin, although this may be associated with an underlying predisposition: abnormal pressure changes within the esophagus or a coagulation disorder [6]. Although the direct cause was not clear, we do not consider emesis a relevant contributing factor in the present case. The patient complained of little vomiting, not strong enough, in our opinion, to raise the intrathoracic pressure and to produce intramural trauma and hemorrhage. Instead, we believe the following were precipitating factors: coagulopathy secondary to LMWH treatment and platelet reduction in association with high blood pressure during the episode of severe preeclampsia. Even though no case of IHE in association with gestational hypertension has ever been described, it is a well-known fact that preeclampsia carries an increased risk of bleeding and of several hemorrhagic complications such as liver, renal, and intracranial hematoma [7–10]. We also tend to exclude the iatrogenic trauma from intubation during general anesthesia since no abnormal manoeuver was reported by the anesthesiologist.

Although the direct cause was not clear, we do not consider emesis a relevant contributing factor in the present case. The patient complained of little vomiting, not strong enough, in our opinion, to raise the intrathoracic pressure and to produce intramural trauma and hemorrhage. Instead, we believe the following were precipitating factors: coagulopathy secondary to LMWH treatment and platelet reduction in association with high blood pressure during the episode of severe preeclampsia. Even though no case of IHE in association with gestational hypertension has ever been described, it is a well-known fact that preeclampsia carries an increased risk of bleeding and of several hemorrhagic complications such as liver, renal, and intracranial hematoma [7–10]. We also tend to exclude the iatrogenic trauma from intubation during general anesthesia since no abnormal manoeuver was reported by the anesthesiologist. Clinical presentation of this case with chest pain and dysphagia matches the observations of other authors: gradually increasing chest pain (66–84%) localized in the retrosternal or epigastric region and odynophagia/dysphagia (26–59%), exacerbated by swallowing [5]. Differently from the Mallory-Weiss syndrome where the debut symptom is usually hematemesis, this complaint is an infrequent initial manifestation of IHE. According to other studies, the clinical triad of retrosternal pain, difficulty in swallowing, and hematemesis is present in just one-third of cases [11]. Hematemesis occurs when the intramural hematoma expands and the mucosa ruptures. Blood loss is usually moderate, and only 10% of the patients will require a transfusion [12].

to other studies, the clinical triad of retrosternal pain, difficulty in swallowing, and hematemesis is present in just one-third of cases [11]. Hematemesis occurs when the intramural hematoma expands and the mucosa ruptures. Blood loss is usually moderate, and only 10% of the patients will require a transfusion [12]. In any preeclamptic woman presenting with chest pain, other complications which need to be ruled out are HELLP syndrome, congestive cardiac failure, liver hematoma, or liver rupture. The association of chest pain with dysphagia and hematemesis helps the clinician in reaching the correct diagnosis of this rare situation which has a 2 : 1 female preponderance and a mortality rate of 7–9% after either surgical or medical treatment [13]. Endoscopy is considered the first-line diagnostic tool and it revealed the esophageal lesion in our case. However, this technique has some disadvantages when compared with chest CT scan since it is an invasive procedure which may not reveal the abnormality in the absence of a mucosal tear and may further damage the esophageal wall. Chest CT has the advantage of being noninvasive and finds indication to confirm the diagnosis and to exclude active bleeding; besides the esophageal wall, it explores the aorta and other mediastinal structures, thus excluding other thoracic processes [5].

ce of a mucosal tear and may further damage the esophageal wall. Chest CT has the advantage of being noninvasive and finds indication to confirm the diagnosis and to exclude active bleeding; besides the esophageal wall, it explores the aorta and other mediastinal structures, thus excluding other thoracic processes [5]. After the diagnostic confirmation, the hematoma was treated conservatively and resolved in less than 3 weeks, a length of time necessary to obtain the spontaneous drainage, the complete healing of the mucosal tear, and the recovery of a normal esophageal peristalsis [5, 14]. Although most bleeding in IHE can be managed medically, surgical drainage and repair of the laceration or therapeutic angiography may become an urgent indication in those cases of massive hemorrhage and hemodynamically unstable patients [15]. In conclusion, although a rare event, IHE may unexpectedly complicate the pregnant state. Diagnosis is not always simple, since chest pain is a presenting symptom found in other conditions, particularly in a preeclamptic woman. Medical treatment is associated with full recovery in most cases and surgical or endoscopic interventions are rarely required. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Endoscopic view of a bluish mass obliterating the lumen of the proximal esophagus. Figure 2 Second post-C-section day chest CT sagittal view of the esophageal hematoma (black arrow) infiltrating the posterior wall.

Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Endoscopic view of a bluish mass obliterating the lumen of the proximal esophagus. Figure 2 Second post-C-section day chest CT sagittal view of the esophageal hematoma (black arrow) infiltrating the posterior wall. Figure 3 Chest CT transverse view of (a) hematoma (white arrow) displacing the esophageal lumen on 2nd day after C-section. (b) Normal esophageal anatomy and lumen patency after full recovery, 17 days after C-section. Table 1 Time chart of the entire hospitalization period. Admission     C-section Pain symptoms IHE diagnosis   Bleeding episode   Discharge Treatment Aspirin Stop HLMW • • • • • • Mg       • • Betamethasone   • • Laboratory Hb (gr/dL) 11.7 12.1 12.2 11.2 9.5 8.7 7.8 6.5 8.4 11.2 INR   0.84 0.83 0.84 0.79 0.87 0.94 1 1.06 1.01 PLT (103/dL) 125 114 122 91 103 131 127 264 307 353 AST/ALT (UI/L) —/39 46/35 —/36 —/39 —/24 —/18   —/16   38/43 BP 140/95 130/90 140/90 160/100 175/110 120/80 <140/90 <140/90 <140/90 <140/90 24 h U proteins   2.1 gr               0.89 gr Imaging/procedures Chest CT           • • • • Endoscopy           •   • Blood transfusion               • Day 1 2 3 8 9 10 12 19 25 30

1. Introduction Mature cystic teratoma, which is the most common benign ovarian tumor type, is known to occasionally undergo malignant transformation. Malignant transformation of mature cystic teratoma is extremely difficult either to predict or to detect early. Moreover, the mechanism of malignant transformation has not as yet been elucidated. We experienced a case with a mature cystic teratoma that had undergone malignant transformation over a period of 10 years. We herein present this case with a literature review.

s extremely difficult either to predict or to detect early. Moreover, the mechanism of malignant transformation has not as yet been elucidated. We experienced a case with a mature cystic teratoma that had undergone malignant transformation over a period of 10 years. We herein present this case with a literature review. 2. Case Our patient was a 67-year-old woman, gravida 4, para 1. Her past medical history included epilepsy diagnosed at 56 years of age, unspecified cardiopulmonary arrest at age 57 years, peritonitis due to acute perforated gastric ulcer, venous thrombosis of the lower limb, and pulmonary arterial embolism. She was also allergic to numerous drugs and diagnostic agents (e.g., contrast media, nonsteroidal anti-inflammatory drugs, and sodium valproate). She visited the department of surgery at our hospital with chief complaints of appetite loss, nausea, and vomiting that had persisted for the prior two weeks. Because abdominal plain computed tomography (CT) revealed ileus and an abdominal incisional hernia, she was immediately admitted with a diagnosis of ileus caused by the incisional hernia. Moreover, a tumor measuring 21 cm in longest diameter was detected in the pelvis (Figure 1(a)). She was thus referred to our department for detailed examination and treatment. At the initial examination, the abdomen was soft without tenderness, rebound tenderness, or muscular defense. An easily movable mass extending from the right lower abdomen to the level of the umbilicus was palpated. The patient had undergone omental implantation for acute perforated gastric ulcer 10 years earlier. Preoperative abdominal plain CT had revealed a right ovarian tumor measuring 6 cm in diameter (Figure 1(b)), which contained a part of calcification and fatty components; however, there had been no findings suggestive of malignancy, such as a solid component or a mural nodule. The right ovarian tumor was radiologically diagnosed with a mature cystic teratoma. After surgery for the acute perforated gastric ulcer, she had not been referred to the department of gynecology. No further examination of the right ovarian tumor was performed. She had not been followed up for the ovarian tumor. When the findings of abdominal plain CT performed during the current admission were compared to those of the abdominal CT obtained 10 years earlier, the ovarian tumor was noted to have grown markedly in size and to be partially solid.

ight ovarian tumor was performed. She had not been followed up for the ovarian tumor. When the findings of abdominal plain CT performed during the current admission were compared to those of the abdominal CT obtained 10 years earlier, the ovarian tumor was noted to have grown markedly in size and to be partially solid. The CT performed during the current admission also revealed fatty components in the ovarian cyst. On the basis of these findings, malignant transformation of the mature cystic teratoma was suspected. Furthermore, pelvic plain magnetic resonance imaging (MRI) also showed a cyst measuring 21 cm in longest diameter that was partially solid on the right side of the uterine body (Figure 2(a)). The solid components detected on T2-weighted images (Figure 2(b)) showed high signal intensity on diffusion-weighted images (Figure 2(c)) and low signal intensity on apparent diffusion coefficient maps, which suggested a malignant lesion. In addition, blood tests revealed tumor marker elevations: CEA, 7.1 ng/mL (<4.9 ng/mL); CA125, 58.3 U/mL (<35 U/mL); CA19-9, 405.8 U/mL (<37 U/mL); and SCC antigen, 6.2 ng/mL (<1.5 ng/mL). Based on the clinical course, imaging findings, and elevated tumor markers, malignant transformation of the previously recognized mature cystic teratoma was strongly suspected. Sixteen days after the initial examination, semiurgent surgery was performed. While neither lymphadenopathy nor distant metastasis was detected by imaging studies, the operation consisted of abdominal bilateral adnexectomy and repair of the abdominal incisional hernia in consideration of the patient's general condition. The intraoperative findings included slight accumulation of ascites with a pink tinge due to blood and swelling of the right ovary, which was larger than a newborn's head, whereas there were no signs of capsule rupture, torsion abnormality, and so on. We detected no macroscopic abnormalities in the uterus or the left adnexa. Neither disseminated lesions nor lymphadenopathy was observed in the peritoneal cavity. The tumor in the right ovary was unilocular and weighed 2960 g, containing both fatty components and hair. Moreover, protruding lesions were observed on a portion of the tumor wall (Figure 3). Cytology of ascites was negative. Histologically, cystic wall was lined by squamous epithelium and contained horny materials inside the cyst. Mature bone tissue and hair were also observed. Focally, granulation tissue was formed.

air. Moreover, protruding lesions were observed on a portion of the tumor wall (Figure 3). Cytology of ascites was negative. Histologically, cystic wall was lined by squamous epithelium and contained horny materials inside the cyst. Mature bone tissue and hair were also observed. Focally, granulation tissue was formed. Squamous cell carcinoma was found in the solid part protruding inside the cyst wall. There was a transition between squamous epithelium and squamous cell carcinoma (Figure 4). The postoperative clinical diagnosis was ovarian cancer FIGO stage IA, pT1aNxM0 due to malignant transformation of a mature cystic teratoma which had first been noted 10 years earlier. Given the history of allergy to multiple drugs, cardiopulmonary arrest, venous thrombosis of the lower limb, and pulmonary arterial embolism, postoperative chemotherapy was not planned. As of two years since surgery, no recurrence has been observed.

a mature cystic teratoma which had first been noted 10 years earlier. Given the history of allergy to multiple drugs, cardiopulmonary arrest, venous thrombosis of the lower limb, and pulmonary arterial embolism, postoperative chemotherapy was not planned. As of two years since surgery, no recurrence has been observed. 3. Discussion Mature cystic teratoma, which is a commonly observed benign ovarian tumor in young women, is a germ cell tumor containing fat, hair, teeth, cartilage, and so forth. It is the most common type of benign ovarian tumor [1] accounting for approximately 20% of all ovarian tumors according to Hurwitz et al. [2]. A quarter of ovarian tumors are reportedly of the germ cell type, most of which are mature cystic teratomas [3]. Mature cystic teratoma is known to occasionally become malignant, and the majority of such transformations result in SCC. Malignant transformation was reported in 1.8% of 8000 patients with a mature cystic teratoma by Peterson [4] and 1% to 2% of such patients by Hurwitz et al. [2], while Kim et al. reported that malignant transformation was observed in 4 of 560 patients (0.6%) who underwent surgery for a mature cystic teratoma at their facility [5]. According to histological types, SCC accounts for the majority of cases, 80% to 90% according to Hurwitz et al. [2] and approximately 80% as reported by Hackethal et al. [3]. Adenocarcinoma [2, 6] and malignant melanoma [6] have also been reported. Kikkawa et al. reported that 42 cases with a mature cystic teratoma undergoing malignant transformation included 37 cases developing SCC, while the remaining cases had an adenocarcinoma or malignant melanoma [6]. According to a review of 277 cases with malignant transformation of a mature cystic teratoma into SCC described in 64 articles with sufficient data that were selected from among 126 articles published between 1978 and 2007, the mean age was 55 years, and the tumor diameter was 10 cm or longer in many cases [3, 7]. Moreover, Hackethal et al. reported that the diameter exceeded 100 mm in several cases with mature cystic teratoma undergoing malignant transformation [3]. Chen et al. reported that the cut-off value was 137 ± 57 mm [8], while Kikkawa et al. reported that it was 99 mm [9]. Regarding age, the reported mean ages were 48 [2] and 55 ± 14.4 years [8], whereas malignant transformation is reportedly common in patients 50 years of age or older [3].

g malignant transformation [3]. Chen et al. reported that the cut-off value was 137 ± 57 mm [8], while Kikkawa et al. reported that it was 99 mm [9]. Regarding age, the reported mean ages were 48 [2] and 55 ± 14.4 years [8], whereas malignant transformation is reportedly common in patients 50 years of age or older [3]. As for diagnostic criteria, the reported cut-off values for age were 40 [5, 10] and 45 years [9].

g malignant transformation [3]. Chen et al. reported that the cut-off value was 137 ± 57 mm [8], while Kikkawa et al. reported that it was 99 mm [9]. Regarding age, the reported mean ages were 48 [2] and 55 ± 14.4 years [8], whereas malignant transformation is reportedly common in patients 50 years of age or older [3]. As for diagnostic criteria, the reported cut-off values for age were 40 [5, 10] and 45 years [9]. Malignant transformation of a mature cystic teratoma is mainly detected by diagnostic imaging. It is considered to be important to focus on the presence or absence of solid components on pelvic MRI images [11]. In SCC cases, the SCC antigen is regarded as being a useful tumor marker [7]. Kikkawa et al. performed screening by measuring SCC antigen (<2.0 ng/mL), CA 125 (<35 U/mL), CA 19-9 (<37 U/mL), and CEA (<5.0 ng/mL) levels in cases with malignantly transformed mature cystic teratomas, reporting that diagnostic efficiencies were 63%, 50%, 28%, and 45%, respectively [9]. In our 67-year-old patient with SCC measuring 21 cm in diameter, these tumor markers (CEA, 7.1 ng/mL; CA 125, 58.3 U/mL; CA 19-9, 405.8 U/mL; and SCC antigen, 6.2 ng/mL) were elevated, and MRI revealed solid components suggestive of malignancy. Thus, in terms of age, histological type, tumor diameter, tumor marker elevations, and MRI findings, our case represents a typical example of the generally known features of patients with malignant transformation of a mature cystic teratoma. Although mature cystic teratoma is a frequently observed benign ovarian tumor, it may become malignant as seen in our case. Thus, these teratomas require continuous follow-up, and patients also need to be informed about the possibility of malignant transformation at the time of explanation.

of a mature cystic teratoma. Although mature cystic teratoma is a frequently observed benign ovarian tumor, it may become malignant as seen in our case. Thus, these teratomas require continuous follow-up, and patients also need to be informed about the possibility of malignant transformation at the time of explanation. Although the mechanism of malignant transformation of a mature cystic teratoma remains unknown, involvement of the human papilloma virus has been suggested [12, 13]. Moreover, no reports have mentioned how long it takes for a mature cystic teratoma to become malignant. In fact, it is difficult to estimate when malignant transformation occurred in our case. However, because the cancer was diagnosed as stage IA despite an interval of 10 years, we assume that malignant transformation had progressed very slowly. The peak age at diagnosis of mature cystic teratoma and the mean age of patients experiencing malignant transformation of a teratoma differ by at least 10 years, though there is one report describing an 85-year-old patient with a mature cystic teratoma that did not undergo malignant transformation [14]. Thus, malignant transformation appears to take a very long time. However, because it is difficult to predict or achieve early detection of malignant transformation, caution must be exercised when patients with mature cystic teratomas are followed up long-term.

eratoma that did not undergo malignant transformation [14]. Thus, malignant transformation appears to take a very long time. However, because it is difficult to predict or achieve early detection of malignant transformation, caution must be exercised when patients with mature cystic teratomas are followed up long-term. We experienced a case with a mature cystic teratoma which underwent malignant transformation during an interval of 10 years since its initial detection. Although mature cystic teratoma is a benign tumor, surgery or regular follow-up needs to be planned after due consideration of the risk of malignant transformation. Conflicts of Interest The authors declare no conflicts of interest. Figure 1 (a) Abdominal plain computed tomography (current). A huge mass measuring 21 cm in longest diameter can be seen in the right cranial portion of the uterine body. The mass is partially solid, suggesting malignancy. (b) Abdominal plain computed tomography (image obtained 10 years prior to the current admission). A mature cystic teratoma measuring 6 cm in diameter is observed on the right side. There are no findings suggestive of malignancy, such as a mural nodule or a solid component.

ass is partially solid, suggesting malignancy. (b) Abdominal plain computed tomography (image obtained 10 years prior to the current admission). A mature cystic teratoma measuring 6 cm in diameter is observed on the right side. There are no findings suggestive of malignancy, such as a mural nodule or a solid component. Figure 2 Pelvic plain magnetic resonance imaging. (a) T2-weighted image in the sagittal plane. A cyst measuring 21 × 19 × 12 cm is observed. It is partially solid. (b) T2-weighted image in the horizontal plane. (c) Diffusion-weighted image in the horizontal plane. The solid components observed on the T2-weighted image show high signal intensity on the diffusion-weighted image (⬅). The cyst is suspected to be a malignant lesion. Figure 3 Resected specimen. Protruding lesions are observed on a portion of the wall of the right ovarian tumor. Figure 4 Histologically, squamous cell carcinoma was observed inside the cyst (left side of the picture). Granulation tissue containing hair was also found (right side of the picture) (H&E staining, ×100).

1. Introduction Marfan syndrome (MFS) is an autosomal dominant hereditary disorder of connective tissue; its incidence is estimated to be around 1 : 5.000, with no differences in gender or ethnic background. In 90% of cases, it is associated with mutations in the FBN1 gene that encodes fibrillin [1]. The clinical manifestations of the gene may involve multiple organs with various severity, particularly affecting the cardiovascular, skeletal, and ocular systems. The clinical and instrumental diagnosis is based on observation of the Ghent criteria, proposed in 1996 by De Paepe et al. [2], ranging from the familiarity to multiorgan involvement and they were recently revised by Loeys et al. in 2010 [3]. Some manifestations are evident since childhood (such as ectopia lentis), while others were at a later date, such as the lumbosacral dural ectasia; the main cause of morbidity and mortality is related to aortic dilation and acute aortic dissection. Cardiovascular manifestations, such as aortic dilatation and dissection, are responsible for 90% of deaths attributed to MFS [4, 5]. The disease is not associated with a reduction in fertility; in fact it is common to find a pregnant woman with the syndrome. In such a case, it would be appropriate to have an accurate clinical evaluation before pregnancy, particularly an echocardiography, to assess the size of the aortic root: a diameter greater than 40 mm puts the patient at risk of its rupture.

in fertility; in fact it is common to find a pregnant woman with the syndrome. In such a case, it would be appropriate to have an accurate clinical evaluation before pregnancy, particularly an echocardiography, to assess the size of the aortic root: a diameter greater than 40 mm puts the patient at risk of its rupture. As reported in literature, the obstetric management of women with MFS seems now well coded, with favorable outcome if the aortic root diameter is less than 40 mm. The increase in aortic size during pregnancy is not unique in women with MFS but is known to occur during normal healthy pregnancies and with increased severity in women with preeclampsia [6]. Some recent guidelines advise women with MFS to avoid pregnancy or, alternatively, undergo surgical ascending aortic replacement prior to conception, if the aorta measures > 4 cm [7]. Literature suggests a 1% risk of aortic dissection or significant cardiac event in women with an aortic root diameter of <40 mm [8]. The risk is increased when the aortic root diameter is >40 mm, if there is a rapid increase in aortic dimensions or in the context of a family history of dissection [9]. However, the presence of ectasia of the dural sac has been considered the major cause of failure of locoregional anesthesia during cesarean section. The purpose of this study is to present the case of a MFS pregnant woman at term with an extensive dural ectasia who had a successful cesarean section with epidural anesthesia during her second pregnancy.

of the dural sac has been considered the major cause of failure of locoregional anesthesia during cesarean section. The purpose of this study is to present the case of a MFS pregnant woman at term with an extensive dural ectasia who had a successful cesarean section with epidural anesthesia during her second pregnancy. 2. Case Report F. S. is a 35-year-old, 180 cm tall, 85 Kg patient, suffering from MSF with a lumbosacral dural ectasia, who was subjected to a cesarean section at 37 weeks and 3 days of gestation. She reports that the mother was very high and died suddenly before the age of 50; her maternal grandfather was particularly high too, and her brother was myopic and had severe scoliosis. Medical history was positive for ectopia lentis (diagnosed when she was 6 years old), dorsal scoliosis (treated with corset from 10 to 14 years of age), and mild ectasia of the aortic arch. Previously she underwent right saphenectomy and right breast fibroadenoma enucleation. Physical examination showed skeletal abnormalities such as high arched palate, opening of the arms greater than height, pectus carinatum internalized to the right, flat feet, bilateral valgus, and arachnodactyly. Striae were evident on the skin of her chest, shoulders, back, and abdomen. On cardiovascular examination, a metallic click and systolic murmur were auscultated with a stethoscope. Heart sounded valid and rhythmic, with good hemodynamic compensation, and ECG had a normal sinus rhythm and normal track with a medium pulse of 65 beats per minute. The patient was normotensive (BP 120/70 mmHg). Echocardiogram showed a mild dilatation of the aortic root (42 mm), normal ventricular function, and a mild mitral valve prolapse without regurgitation.

hemodynamic compensation, and ECG had a normal sinus rhythm and normal track with a medium pulse of 65 beats per minute. The patient was normotensive (BP 120/70 mmHg). Echocardiogram showed a mild dilatation of the aortic root (42 mm), normal ventricular function, and a mild mitral valve prolapse without regurgitation. The obstetric history showed an uneventful previous C-section delivery in 2004. She had a spinal block anesthesia after spinal anesthesia, which was converted into a general one. In the postoperative period, she had a hemorrhage due to uterine atony treated with oxytocin and prostaglandins and recovery in intensive care. After five days, the patient was discharged in good medical condition and she was followed up every 6 months and had a prophylactic therapy with beta-blockers. In 2007, because of a lumbar pain, she performed a lumbosacral MRI that showed ectasia of the distal dural sac with cystic dilatation of some nerve roots. This finding is one of the major diagnostic criteria of MFS. In 2009, she started a second pregnancy and she was under the care of the outpatient obstetric clinic of the Santo Bambino Hospital in Catania (Sicily). During her first trimester of pregnancy, the patient was asymptomatic with good cardiovascular compensation and she did not take any medication. She has been monthly subjected to obstetric visits; she also had three ultrasound scans (one for each trimester of pregnancy), two cardiological examinations (at the beginning and near term), and two maternal echocardiographies (at 22 weeks and near term) in order to monitor the aortic root. The fetal growth was regular. At 37 weeks + 3 days, because of the occurrence of uterine contractions, the patient was admitted to the hospital for cesarean section. Considering the previous bad experience during spinal anesthesia (lack of efficacy with use of general anesthesia), being aware of the presence of the ectasia of the dural sac during the preoperative evaluation of the patient, epidural anesthesia was proposed to perform her second cesarean section. This type of anesthesia allows a better circulation and distribution of the anesthetic, overcoming the problems related to spinal anesthesia in the presence of dural ectasia. The drugs administered epidurally require dosages from 5 to 10 times higher and volumes greater than those calculated for the subarachnoid space.

This type of anesthesia allows a better circulation and distribution of the anesthetic, overcoming the problems related to spinal anesthesia in the presence of dural ectasia. The drugs administered epidurally require dosages from 5 to 10 times higher and volumes greater than those calculated for the subarachnoid space. The advantages of an epidural block include a lower incidence and severity of maternal hypotension, thanks to the reduced rate of sympathetic block, a lower risk of headache due to accidental dural puncture, and the possibility of an accurate control of level and duration of anesthesia. The patient was informed about the type of regional anesthesia chosen and monitored. She was continuously under noninvasive monitoring (ECG, arterial blood pressure, and oxygen saturation) and she was premedicated with ranitidine 50 mg and metoclopramide 10 mg in saline solution. She was placed in a sitting position and then the locoregional block in epidural anesthesia was performed by a midline approach with the placement of an epidural catheter, through a 17-gauge Tuohy needle, positioned between L2 and L3. She was given lidocaine 400 mg (20 ml of 2%) with 1 mEq of sodium bicarbonate and 50 mcg of fentanyl. The anesthetic block was manifested within three minutes without side effects. After 15 minutes, the cesarean section started, because the sensory block was sufficiently high (T4) for cesarean section. The systolic blood pressure remained stable (110–125/70 mmHg) for the entire duration of surgery and the postoperative period. There was no evidence of intraoperative and postoperative complications and the patient did not report any pain symptoms. Short-term prophylaxis for infection was administered (3 g ampicillin/sulbactam) after the delivery of the baby as well as 20 IU of oxytocin. After 30 minutes from the anesthetic block, 1 mg of morphine + 75 mcg of clonidine and 12 mg of naropine were injected in the epidural space through the catheter. After an hour from the beginning of the anesthetic block, an ongoing anesthesia with 0,1% naropine, 250 mg at 10 ml/h, was placed in the infusion pump for epidural. At the end of the surgery, for further analgesia, a 75 mg of diclofenac i.m and 0.2 mg of methylergometrine i.m. were administered. The patient was kept under observation for 2 hours and then transferred to the ward. The male newborn was 3.250 g, and he was extracted after 30 minutes since the moment epidural catheter was placed and 1 minute after the skin incision.

, a 75 mg of diclofenac i.m and 0.2 mg of methylergometrine i.m. were administered. The patient was kept under observation for 2 hours and then transferred to the ward. The male newborn was 3.250 g, and he was extracted after 30 minutes since the moment epidural catheter was placed and 1 minute after the skin incision. The Apgar score in the first minute was 9, and it was 10 after five minutes. The epidural catheter was removed 12 hours after cesarean section. The postoperative course was regular, with her discharge on the fourth day after C-section. A 12-day heparin prophylaxis was performed for venous thromboembolism prevention. After a follow-up of five years, we can assert that the patient is in good health and the aortic root diameter is always 42 mm. 3. Discussion MFS is an autosomal dominant disorder of the connective tissue related to mutation of the gene for fibrillin, a glycoprotein that is the major component of extracellular microfibrils, whose gene maps to chromosome 15. MFS involves different organs and systems with varying severity: for this reason, its diagnosis is mainly clinical and instrumental and, then, molecular. It is based on the observation of the Ghent criteria and revised criteria [10].

s the major component of extracellular microfibrils, whose gene maps to chromosome 15. MFS involves different organs and systems with varying severity: for this reason, its diagnosis is mainly clinical and instrumental and, then, molecular. It is based on the observation of the Ghent criteria and revised criteria [10]. In literature, there are many experiences on the management of pregnant women with MS [9–13]. Pregnancy can be considered at low risk in the absence of significant aortic dilatation and mitral insufficiency. In women with low cardiac involvement, the risk of aortic dissection, endocarditis, and congestive heart failure in pregnancy is estimated to be only 1%. The risk is higher during the third trimester of pregnancy due to the increase of the hemodynamic stress. During pregnancy and postpartum period, echocardiography should be frequently performed, depending on the extent of the initial dilatation of the aortic root, in order to monitor the cardiovascular system and the possible progressive aortic dilatation. Beta-blockers reduce the risk of aortic dilatation and cardiac complications, but they seem to increase the tone and uterine contractility, and they might reduce the flow in the umbilical artery causing low birth weight infants. They were not used in our pregnant woman.

In literature, there are many experiences on the management of pregnant women with MS [9–13]. Pregnancy can be considered at low risk in the absence of significant aortic dilatation and mitral insufficiency. In women with low cardiac involvement, the risk of aortic dissection, endocarditis, and congestive heart failure in pregnancy is estimated to be only 1%. The risk is higher during the third trimester of pregnancy due to the increase of the hemodynamic stress. During pregnancy and postpartum period, echocardiography should be frequently performed, depending on the extent of the initial dilatation of the aortic root, in order to monitor the cardiovascular system and the possible progressive aortic dilatation. Beta-blockers reduce the risk of aortic dilatation and cardiac complications, but they seem to increase the tone and uterine contractility, and they might reduce the flow in the umbilical artery causing low birth weight infants. They were not used in our pregnant woman. The dural ectasia is one of the major criteria for diagnosis of MFS and it is present in over 2/3 of adults affected [14–16] and the prevalence of severe (degrees 2 and 3) involvement of dura mater was higher in patients harboring premature termination codon mutations compared to those carrying missense mutations [17]. It is hypothesized that, in Marfan's syndrome, the dura mater is weaker and, as a result, cerebrospinal fluid pulsation eventually leads to dural ectasia with gradual bone erosion. The dural ectasia is characterized by a swelling of the dural sac and of the spinal canal and, sometimes, of the nerve sheaths. Although it can occur along the entire channel, the most frequent site is the lumbosacral spine. The most common clinical symptoms, which can be intensified by the supine position, are low back pain, headache, asthenia, decreased sensitivity below and around the affected section, and, occasionally, rectal pain and/or discomfort in the genital area [16, 18]. The extension of the dural expansion is variable; sometimes the lesion is confined to focal dilation of the dural coating of the nerve roots, near their exit from the spinal column: they are called “radicular cysts.” The chronic dilatation of the dural sac can also exert an erosive effect against adjacent bone structures of the spine. The indirect signs of bone damage can be observed with radiographic test (Rx) and by examination of Computed Tomography (CT). However, the gold standard for the evaluation of dural ectasia is RM, for the quality of anatomical detail and for its multiplanarity. The prevalence of dural ectasia in patients with MS is variable from 63% to 92%, probably in relation to the imaging modality used in the various studies [19–21]. In a study published in 1999, out of 83 MFS patients examined by MRI, the dural ectasia was detected in 92% of cases and in none of the patients in the control group. However, high prevalence of dural ectasia (41%) exits even in patients with MFS without back pain [16]. No correlation was found with the presence of aortic dilatation; therefore, dural ectasia has no predictive value on cardiovascular prognosis in these patients.

cases and in none of the patients in the control group. However, high prevalence of dural ectasia (41%) exits even in patients with MFS without back pain [16]. No correlation was found with the presence of aortic dilatation; therefore, dural ectasia has no predictive value on cardiovascular prognosis in these patients. Regarding the clinical expression, dural ectasia is often clinically silent or can be occasionally associated with low back pain or lumbosciatica. However, a clear correlation between low back pain and dural ectasia has not been demonstrated. For the best management of labor and delivery of MFS patients, it is clear that the primary goal is the reduction of cardiovascular stress, and cesarean section is often performed for the prevention of cardiovascular complications. Patients with an aortic root < 4 cm in diameter at the time of delivery have a similar outcome for vaginal and cesarean section delivery, but cesarean section is preferred in patients with an aortic root > 4 cm because the risk for cardiac decompensation is extremely high [22]. However, aortic dissection has been reported even in the absence of preexisting aortic root dilatation [22].

very have a similar outcome for vaginal and cesarean section delivery, but cesarean section is preferred in patients with an aortic root > 4 cm because the risk for cardiac decompensation is extremely high [22]. However, aortic dissection has been reported even in the absence of preexisting aortic root dilatation [22]. Fluctuation in hemodynamic parameters secondary to pain and anxiety of labor may have negative effects on the cardiovascular system; high blood pressure tends to develop aortic aneurysms due to weakened vascular media in patients with MFS, and myocardial ischemia and heart failure can also be caused by an increased myocardial oxygen demand resulting in high blood pressure; thus, the main goal is to prevent high blood pressure [23]. For all these reasons, cesarean section is frequently planned. The type of anesthesia has been discussed too. General anesthesia causes blood pressure variations during intubation; therefore peripheral anesthesia seems preferable because of slow onset and gradual progression of epidural block. Since the spontaneous birth determines increase in blood pressure during contractions, the use of epidural analgesia reduces pain, blood pressure, and heart rate. Cesarean section was performed in our patient because she already had a cesarean section.

le because of slow onset and gradual progression of epidural block. Since the spontaneous birth determines increase in blood pressure during contractions, the use of epidural analgesia reduces pain, blood pressure, and heart rate. Cesarean section was performed in our patient because she already had a cesarean section. In some studies, regional anesthesia has been practiced successfully in MFS patients, both during labor analgesia and during cesarean section. Combined spinal-epidural anesthesia is preferred over general anesthesia for cesarean section in patents with MFS because combined spinal-epidural anesthesia provides excellent hemodynamic stability, and adequate postoperative pain control may be obtained via epidural analgesia. However, many cases of spinal anesthesia failure have been reported in Marfan patients, possibly due to dural ectasia [24, 25]. Few cases of incorrect or inadequate spread of intrathecal local anesthetic in patients with this syndrome have been described. Lacassie et al. [26] performed continuous spinal anesthesia in two patients with an incrementally increased dose of bupivacaine, but they stopped further administration of bupivacaine after 21 ml for the fear of potential neurological damage. They also reported an irregular distribution of spinal anesthesia due to unpredictable and inadequate spread of intrathecal local anesthetics in patients with MFS. One of the most important factors influencing the height of the block in patients receiving spinal anesthesia is the volume of CSF in the lumbosacral space, which contributes to the variability in the spread of spinal block. Kim et al. [27] reported a successful perioperative management of a patient with MFS and dural ectasia for cesarean section using epidural anesthesia. The surgically adequate level of anesthesia was achieved 30 min after the epidural injection of 27 ml of 2% lidocaine with epinephrine (1 : 200) and fentanyl (100 mcg).

Kim et al. [27] reported a successful perioperative management of a patient with MFS and dural ectasia for cesarean section using epidural anesthesia. The surgically adequate level of anesthesia was achieved 30 min after the epidural injection of 27 ml of 2% lidocaine with epinephrine (1 : 200) and fentanyl (100 mcg). In summary, the evaluation of pregnant women with MFS requires multidisciplinary management with a close cooperation between gynecologist, cardiologist, anesthesiologist, and neonatologist. Pregnancy should be programmed after complete evaluation of the patient and the definition of specific risks. Relevant is the echocardiographic assessment of aortic root dilation. During pregnancy, the obstetric management is not significantly different, but it is burdened with a higher frequency of premature rupture of membranes, the side effects of the drugs used, where indicated, for the prevention of aortic rupture, and the risk of aortic dissection. The anesthetic management during delivery is debated. Regional anesthesia has been successfully used during cesarean section, but there is a significant probability of erratic and inadequate intrathecal spread of local anesthetics, most likely as a result of dural ectasia. In these patients, epidural anesthesia may be a particularly useful technique during cesarean delivery because it allows adequate spread and action of local anesthetic and controlled onset of anesthesia, analgesia, and sympathetic block with low risk of complications. We report the perioperative management of a patient with MFS and lumbosacral dural ectasia who underwent successful cesarean delivery using epidural technique anesthesia. In her previous pregnancy, the failed spinal anesthesia during cesarean section was converted to general anesthesia due to the unknown presence of dural ectasia at that time.

ve management of a patient with MFS and lumbosacral dural ectasia who underwent successful cesarean delivery using epidural technique anesthesia. In her previous pregnancy, the failed spinal anesthesia during cesarean section was converted to general anesthesia due to the unknown presence of dural ectasia at that time. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper.

1. Background Overall, congenital Müllerian anomalies occur in ~1.5% of females (0.1–3%) [1], with bicornuate uterus constituting 25% of Müllerian class 4 uterine anomalies [2]. Grimbizis et al. reported a prevalence of 4.3% for the general population, about 3.5% in infertile women, and about 13% in women with recurrent pregnancy losses [3]. The pathophysiology of this type of anomaly involves incomplete fusion of both uterine horns during embryogenesis; the bicornuate uterus is formed when the Müllerian ducts incompletely fuse at the level of the uterine fundus. In this anomaly, the lower uterus and cervix are completely fused, resulting in 2 separate but communicating endometrial cavities, a single-chamber cervix and vagina. A muscular intrauterine septum is also present, and this defect corresponds externally to an indentation or groove at the fundus. Subclassification into complete or partial categories depends on septum length. Complete uterine septa that extend either to the internal or external os are known as bicornuate unicollis uterus and bicornuate bicollis uterus, respectively (Figure 1) [4]. 2. Case Report We present a rare case of Müllerian dysgenesis of P.C., a 24-year-old primigravida who presented to the maternity emergency department with severe generalised abdominal pains at 35 weeks. She was pale on clinical examination and haemodynamically unstable.

The pathophysiology of this type of anomaly involves incomplete fusion of both uterine horns during embryogenesis; the bicornuate uterus is formed when the Müllerian ducts incompletely fuse at the level of the uterine fundus. In this anomaly, the lower uterus and cervix are completely fused, resulting in 2 separate but communicating endometrial cavities, a single-chamber cervix and vagina. A muscular intrauterine septum is also present, and this defect corresponds externally to an indentation or groove at the fundus. Subclassification into complete or partial categories depends on septum length. Complete uterine septa that extend either to the internal or external os are known as bicornuate unicollis uterus and bicornuate bicollis uterus, respectively (Figure 1) [4]. 2. Case Report We present a rare case of Müllerian dysgenesis of P.C., a 24-year-old primigravida who presented to the maternity emergency department with severe generalised abdominal pains at 35 weeks. She was pale on clinical examination and haemodynamically unstable. Abdominal palpation revealed a 35 cm fundal height, longitudinal lie, and baby in cephalic presentation; her abdomen was too tender for deeper palpation; fetal heart tones could not be heard on hand held Doppler and cardiotocographic auscultation. No bleeding was noted vaginally with a closed cervical os.

2. Case Report We present a rare case of Müllerian dysgenesis of P.C., a 24-year-old primigravida who presented to the maternity emergency department with severe generalised abdominal pains at 35 weeks. She was pale on clinical examination and haemodynamically unstable. Abdominal palpation revealed a 35 cm fundal height, longitudinal lie, and baby in cephalic presentation; her abdomen was too tender for deeper palpation; fetal heart tones could not be heard on hand held Doppler and cardiotocographic auscultation. No bleeding was noted vaginally with a closed cervical os. She had a subumbilical midline scar which on further inquiry was due to what was a negative laparotomy for preoperative diagnosis of ectopic pregnancy at 8-week gestation during the current pregnancy. No abnormalities were noted during surgery at that point. She was resuscitated with two litres of normal saline and six units of blood grouped and cross matched. Emergency caesarean section was done with a tentative preoperative diagnosis of concealed abruptio placentae. Abdominal entry through a subumbilical midline incision was employed; two litres of haemoperitoneum and tortuous vessels over the gravid uterus were encountered; on further exploration bicornuate uterus was noted intraoperatively (Figure 2). The traditional Kerr uterine incision was made and baby delivered (fresh stillbirth). Placental tissue was adherent to entire myometrium all the way to serosa, with areas of active haemorrhage at point of attachment. Attempted removal left a large defect that was actively bleeding (Figure 3).

ound due to the patient's high body mass index. Expertise in such cases is often required to obtain an accurate diagnosis [10]. Although sonographic evaluation revealed a high suspicion of placental invasion in our first case, MRI was nondiagnostic and final diagnosis of bladder invasion was confirmed intraoperatively. Hematuria is a rare occurrence comprising 25% of all placenta percreta cases [11]. Although not a sensitive finding, placenta percreta with bladder invasion should be suspected in any pregnant woman presenting with gross hematuria and a history of previous cesarean sections [12]. Placental bladder infiltration is a potentially life-threatening situation and therefore mandates a multidisciplinary surgical management, adequate number of blood products, neonatal intensive care, and the option of uterine artery embolization if needed. Hysterectomy without any attempts to remove the placenta is the recommended option [13]. Separation of the bladder from the placenta may cause severe blood loss. Even in cases with major intraoperative bleeding, bladder integrity preservation should be one of the primary surgical goals. Cesarean section and hysterotomy can be carried out through the bladder incision whenever this is unavoidable. Preoperative placement of ureteric stents is essential to minimize ureteral injury.

Abdominal entry through a subumbilical midline incision was employed; two litres of haemoperitoneum and tortuous vessels over the gravid uterus were encountered; on further exploration bicornuate uterus was noted intraoperatively (Figure 2). The traditional Kerr uterine incision was made and baby delivered (fresh stillbirth). Placental tissue was adherent to entire myometrium all the way to serosa, with areas of active haemorrhage at point of attachment. Attempted removal left a large defect that was actively bleeding (Figure 3). Upon further evaluation a decision to perform unilateral caesarean hemihysterectomy was made due to active on going haemorrhage at the point of placental attachment. Bilateral ovarian preservation was carried out successfully; the uterine vessels on the ipsilateral side were skeletonized and ligated achieving haemostasis. The ureters were identified from the level of the pelvic brim and followed along their entire length to the bladder to rule out any possible urinary tract abnormalities that occasionally coexist with Müllerian anomalies. Lavage was done and abdomen closed in layers. She received 4 units of whole blood and recovered without complications. 3. Discussion This rare occurrence is presented with most of the possible acute emergencies in obstetrics right from early pregnancy to delivery. Bicornuate uterus may not be the commonest differential diagnosis one would be looking for in a gynaecologic clinic especially when there has not been any antecedent infertility, miscarriage, menstrual irregularity, or abnormal uterine bleeding history as in our case.

obstetrics right from early pregnancy to delivery. Bicornuate uterus may not be the commonest differential diagnosis one would be looking for in a gynaecologic clinic especially when there has not been any antecedent infertility, miscarriage, menstrual irregularity, or abnormal uterine bleeding history as in our case. Bicornuate uterus may present with menstrual abnormalities or miscarriages or may be asymptomatic only to be diagnosed retrospectively. This may be during management for miscarriages, caesarean delivery, or hysteroscopy or following hysterosalpingography for fertility workup [5]. It may rarely be misdiagnosed for ectopic pregnancy as the pregnant horn may sonographically resemble an ectopic with the attendant nonpregnant uterus. Judicious approach at laparotomy and laparoscopy is required during surgical intervention for suspected ectopic pregnancies. Possible risks during surgical intervention may include inadvertent hemihysterectomy for a pregnancy that would otherwise have grown to viability [6]. This patient had a negative laparotomy for ectopic pregnancy and was fortunate the pregnancy was not interfered with as both tubes were grossly normal with no intraperitoneal haemorrhage noted. She was reviewed at 20 weeks with a scan showing a live intrauterine pregnancy and hence followed up as per the normal routine pregnancy schedule.

egative laparotomy for ectopic pregnancy and was fortunate the pregnancy was not interfered with as both tubes were grossly normal with no intraperitoneal haemorrhage noted. She was reviewed at 20 weeks with a scan showing a live intrauterine pregnancy and hence followed up as per the normal routine pregnancy schedule. She was admitted in late third trimester with severe abdominal pains and was haemodynamically unstable necessitating emergency caesarean section where a placenta percreta was encountered. There is no strong evidence for placental assessment screening due to paucity of cases to conduct large studies; however there are cases of placental accreta and hemihysterectomy encountered intraoperatively in bicornuate uterus [7]. A colour flow Doppler ultrasound or MRI of placenta would be helpful in establishing whether abnormal placentation exists for better planning of delivery and consenting processes whereby hemihysterectomy is discussed prior to delivery. 4. Conclusions A gravid horn of a bicornuate uterus may rarely be misdiagnosed for an ectopic pregnancy in early pregnancy; however endometrial lining continuity is of paramount to assess and rule out other forms of Müllerian dysgenesis sonographically. Postpartum haemorrhage due to placenta percreta is ultimately managed by caesarean hysterectomy. Consent The patient gave written informed consent for the material to be published. Conflicts of Interest The authors declare no conflicts of interest.

4. Conclusions A gravid horn of a bicornuate uterus may rarely be misdiagnosed for an ectopic pregnancy in early pregnancy; however endometrial lining continuity is of paramount to assess and rule out other forms of Müllerian dysgenesis sonographically. Postpartum haemorrhage due to placenta percreta is ultimately managed by caesarean hysterectomy. Consent The patient gave written informed consent for the material to be published. Conflicts of Interest The authors declare no conflicts of interest. Authors' Contributions Mandeep Sura clerked patient, assisted in surgery, and reviewed the manuscript. Sammy Ngichabe performed surgery, initial write-up, literature review, manuscript review, and final submission. Figure 1 Figure 2 Figure 3

1. Introduction Placenta percreta represents a rare pregnancy complication where the placenta invades the uterine myometrium and occasionally adjacent organs, such as the bladder. The prevalence of all types of abnormally invasive placenta (accreta, increta, and percreta) has been increased due to the rise in the cesarean section rate. It is estimated that invasive placenta cases have risen to 10 times over the last 50 years. Approximately 1/500 to 1/2500 deliveries are complicated by invasive placenta [1]. Placenta percreta is associated with significant morbidity. When placenta percreta is invading the bladder, mortality rates may be as high as 9.5% and 24% for mother and baby, respectively [2]. Herein we report two cases of placenta percreta with bladder invasion, one of which was diagnosed prenatally during the second trimester of pregnancy. In the second case, the diagnosis was made antenatally during the 35th weeks of pregnancy immediately prior to the emergency cesarean section.

nd baby, respectively [2]. Herein we report two cases of placenta percreta with bladder invasion, one of which was diagnosed prenatally during the second trimester of pregnancy. In the second case, the diagnosis was made antenatally during the 35th weeks of pregnancy immediately prior to the emergency cesarean section. 2. Case Presentation 2.1. Case  1 A 39-year-old woman (gravida 3, para 2) was referred to our department during the 24th week of pregnancy due to gross hematuria. Τhe pregnancy was uncomplicated till then; however the diagnosis of complete placenta previa was made during the anatomic scan three weeks prior to her admission. She had two previous cesarean sections and no other medical history. An abdominal sonographic evaluation revealed a viable fetus with appropriate biometrical parameters and normal amniotic fluid, while transvaginal scan suggested the presence of complete placenta previa with bladder wall invasion (Figure 1). She was admitted to our department for expectant management. A course of steroids was administered to promote fetal lung maturation. On hospital day #1, bladder irrigation was performed by the urologists and a Foley catheter was placed in order to control hematuria. The patient had intermittent macroscopic hematuria and cystoscopy was performed on day #4 in order to confirm the diagnosis; however the examination was inconclusive. On hospital day #10, evaluation of the placenta with magnetic resonance imaging (MRI) was also nondiagnostic. The patient was asymptomatic by day #20 and she was discharged from the hospital. Two days later, however, the woman became symptomatic and was then readmitted with hematuria and vaginal bleeding. She had a hematocrit of Ht 22.1% and hemoglobin Hb 6.8 mg/dL and was transfused with two units of blood. The patient went into labor and she was immediately transferred to the operating room. A multidisciplinary team by obstetricians, midwifes, urologists, neonatologists, and anesthetists was on site. A viable male baby, weighing 1000 gr, was delivered by cesarean section and concomitant abdominal hysterectomy. The baby was transferred to the NICU where he was intubated. Dissection of the placenta from the anterior uterine wall created a large defect on the dome of the bladder. The bladder was repaired with two layers of continuous Vicryl 0 suture. A Foley catheter and an intraperitoneal drain were placed. The patient required transfusion of 20 units of various blood products intraoperatively.

on of the placenta from the anterior uterine wall created a large defect on the dome of the bladder. The bladder was repaired with two layers of continuous Vicryl 0 suture. A Foley catheter and an intraperitoneal drain were placed. The patient required transfusion of 20 units of various blood products intraoperatively. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day. She made a good recovery; however urologic evaluation one month postoperatively revealed a vesicovaginal fistula, which was surgically treated at a later date. The baby was discharged three months after delivery.

on of the placenta from the anterior uterine wall created a large defect on the dome of the bladder. The bladder was repaired with two layers of continuous Vicryl 0 suture. A Foley catheter and an intraperitoneal drain were placed. The patient required transfusion of 20 units of various blood products intraoperatively. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day. She made a good recovery; however urologic evaluation one month postoperatively revealed a vesicovaginal fistula, which was surgically treated at a later date. The baby was discharged three months after delivery. 2.2. Case  2 A 26-year-old woman (gravida 4, para 3) presented in our emergency department with vaginal bleeding during the 35th week of pregnancy. She had three previous cesarean sections and no antenatal screening during the present pregnancy. She was transferred to the labor ward where appropriate for gestational age embryo and anterior placenta previa detected during abdominal ultrasound scan. An emergency cesarean section was scheduled and just prior to the operation a Foley catheter was inserted to the bladder which drained blood. The cesarean section was carried out with a vertical incision high in the anterior uterine wall. A male baby weighing 2250 gr was delivered with Apgar scores of 8 and 9 and was transferred to the NICU for further evaluation. Interrupted Vicryl 1 sutures were used for closure of the uterine wall. Intraoperative bleeding was moderate and no transfusion was necessary at that point. A urologist evaluated and repaired the bladder defect which was away from both ureteral orifices. The patient made an unremarkable recovery and both she and the baby were discharged on the 5th postoperative day. The Foley catheter was removed on the 10th postoperative day.

nd no transfusion was necessary at that point. A urologist evaluated and repaired the bladder defect which was away from both ureteral orifices. The patient made an unremarkable recovery and both she and the baby were discharged on the 5th postoperative day. The Foley catheter was removed on the 10th postoperative day. 3. Discussion The exact incidence of placenta percreta remains unclear, since the invasiveness of the placenta is not always established, making it difficult to distinguish between placenta percreta, increta, and accreta. Earlier reports describe the incidence of placenta percreta as within 1 : 1000 to 1 : 70,000 births [3]. Placenta percreta represents the most severe form of placental invasiveness which requires aggressive evaluation and management to decrease morbidity. Multiparity, prior uterine surgery, most commonly cesarean section, and advanced maternal age have been all identified as risk factors for developing this complication of pregnancy [4]. There is a linear increase in the incidence of invasive placenta with the number of previous cesarean deliveries. Diagnosis should always be suspected in any pregnancy with previous uterine scar and detection of a low-lying placenta or placenta previa. It is estimated that when the detection of placenta previa is made in a woman with three previous cesarean sections, there is a 40% chance of the occurrence of placenta accrete [5]. Both cases in our report had previous cesarean sections and, in the first case, the diagnosis of placenta previa was established during the 21st week's anatomic scan.

e detection of placenta previa is made in a woman with three previous cesarean sections, there is a 40% chance of the occurrence of placenta accrete [5]. Both cases in our report had previous cesarean sections and, in the first case, the diagnosis of placenta previa was established during the 21st week's anatomic scan. Prenatal diagnosis of placenta percreta can help reduce maternal/fetal morbidity and mortality by allowing us to choose the best time and place of delivery. Specific sonographic criteria have been recommended for a timely diagnosis of morbidly adherent placenta. Detailed medical history and high index of suspicion is essential in these cases. The sonographic features include an inability to visualize the normal retroplacental clear zone, irregularity of the serosa-bladder interface, intraplacental lacunar spaces, and hypervascularity between the placenta and the bladder when using the color Doppler, resembling a large aneurysm [6–9]. Transvaginal scan was indicative of placental invasion in our first case, since there was a distinct disruption of the bladder wall (Figure 1(b)). We employ the use of magnetic resonance imaging (MRI) to confirm diagnosis. Magnetic resonance imaging (MRI) has similar performance status to the ultrasound; however it can be helpful in cases where placenta is difficult to visualize on ultrasound due to the patient's high body mass index. Expertise in such cases is often required to obtain an accurate diagnosis [10]. Although sonographic evaluation revealed a high suspicion of placental invasion in our first case, MRI was nondiagnostic and final diagnosis of bladder invasion was confirmed intraoperatively.

Even in cases with major intraoperative bleeding, bladder integrity preservation should be one of the primary surgical goals. Cesarean section and hysterotomy can be carried out through the bladder incision whenever this is unavoidable. Preoperative placement of ureteric stents is essential to minimize ureteral injury. Another more recent optional management involves the placenta to be left in situ during cesarean delivery and postoperative methotrexate injection [14, 15]. Concomitant vascular embolization minimizes intraoperative blood loss and may facilitate postoperative placental involution. In such cases, regular postpartum monitoring is required, since complete regression of the placental remnants may take several months to ensue. None of our cases were treated conservatively. Although diagnosis in the first of our cases was made several weeks prior to the operation, emergency cesarean section and hysterectomy were performed based on the sudden deterioration of the patient's condition. In the second case, cesarean section was performed with a high vertical incision and no attempts to separate the bladder were made. Blood loss was controllable and hence hysterectomy was avoided [16]. Bladder was repaired with two layers of sutures in both cases. Potential long-term consequences of bladder damage include fistulas, urinary incontinence, and sexual dysfunction.

high vertical incision and no attempts to separate the bladder were made. Blood loss was controllable and hence hysterectomy was avoided [16]. Bladder was repaired with two layers of sutures in both cases. Potential long-term consequences of bladder damage include fistulas, urinary incontinence, and sexual dysfunction. Patients with suspected placenta percreta with bladder invasion should be counseled about the potential risks of all management options. The surgical plan should be documented and alternative treatments should be available. The woman should become aware that efforts to preserve her uterus might increase morbidity and that planned hysterectomy is a safer option than peripartum hysterectomy. Conflicts of Interest No potential conflicts of interest were reported by the authors. Figure 1 (a) Complete placenta previa. (b) Disruption of the bladder-placental interface indicated by red arrows. (c) Color Doppler revealed hypervascularity between the placenta and the bladder.

1. Introduction Preeclampsia is a diagnosis marked by new onset hypertension and proteinuria with usual onset after 20 weeks' gestational age. Previable preeclampsia is a rare entity with most reported cases associated with trophoblastic disease, triploidy, and antiphospholipid antibody syndrome [1–5]. Only a few published case reports exist describing onset of “pure” preeclampsia, with no identifiable predisposing factors other than advanced maternal age, at less than 20 weeks [6, 7]. We report a case of previable preeclampsia occurring prior to 20 weeks' gestation in a patient with a novel diagnosis of C4 glomerulopathy.

few published case reports exist describing onset of “pure” preeclampsia, with no identifiable predisposing factors other than advanced maternal age, at less than 20 weeks [6, 7]. We report a case of previable preeclampsia occurring prior to 20 weeks' gestation in a patient with a novel diagnosis of C4 glomerulopathy. 2. Case Report A 27-year-old, gravida 3 para 0020, was transferred to our institution at 18 weeks' gestational age with new onset severe hypertension (blood pressure > 180/100 mmHg) and >10 g of protein on spot urine. Upon arrival to the labor and delivery unit, she was started on intravenous magnesium sulfate for eclampsia prophylaxis. Intermittent intravenous antihypertensive treatment was required for severe hypertension (blood pressure > 160/105 mmHg) but she was overall controlled with oral labetalol and nifedipine. Her 24-hour urine protein was 8822 mg. Her serum labs were unremarkable with a hemoglobin of 10.6 gm/dL, platelet count of 183 K/UL, creatinine of 0.6 mg/dL, AST/ALT of 24/15 U/L, and uric acid of 4.4 mg/dL. Nephrology was consulted and an extensive work-up was done. A low complement C4 of <8.0 was found. The patient, otherwise, had a negative renal ultrasound, antiphospholipid antibody studies, antinuclear antibody, C-ANCA/P-ANCA, myeloperoxidase antibody, serine protease 3 antibody, glomerular basement membrane antibody, viral hepatitis panel, thyroid stimulating hormone (TSH), and urine drug screening. Due to concern for preexisting renal pathology, the decision was made to proceed with a renal biopsy.

ies, antinuclear antibody, C-ANCA/P-ANCA, myeloperoxidase antibody, serine protease 3 antibody, glomerular basement membrane antibody, viral hepatitis panel, thyroid stimulating hormone (TSH), and urine drug screening. Due to concern for preexisting renal pathology, the decision was made to proceed with a renal biopsy. Initial light microscopy findings were consistent with a thrombotic microangiopathic lesion, compatible with preeclampsia. On review with the pathologist, the main finding was glomerular endotheliosis and glomerular capillary double contours (Figure 1). There was no artery or arteriole involvement and there was no thrombi or red blood cell fragmentation. Immunofluorescence microscopy showed weak (1+) segmental glomerular staining for IgM and C1q and no staining for IgG, IgA, C3, or κ or λ light chains. The biopsy findings, the new onset severe hypertension, and new onset nephrotic range proteinuria in the absence of any other definable etiology led us to the eventual diagnosis of preeclampsia.

copy showed weak (1+) segmental glomerular staining for IgM and C1q and no staining for IgG, IgA, C3, or κ or λ light chains. The biopsy findings, the new onset severe hypertension, and new onset nephrotic range proteinuria in the absence of any other definable etiology led us to the eventual diagnosis of preeclampsia. After a few days, the patient began to develop worsening hypertension despite being on increasing doses of oral labetalol and nifedipine, requiring additional intravenous antihypertensives for breakthrough severe range blood pressures. She also developed persistent neurologic symptoms consistent with posterior reversible encephalopathic syndrome. Her serum labs, including creatinine, remained stable. Due to the severe nature of her preeclampsia at a previable gestational age, pregnancy termination was recommended. Within 6 hours of the patient's delivery, she no longer required intravenous antihypertensive therapy. Her neurologic symptoms resolved within 72 hours of delivery. She had a follow-up visit with nephrology 17 days after delivery and her urinalysis demonstrated no protein. Her serum labs at that time included hemoglobin of 12.0 gm/dL, platelet count of 307 K/UL, creatinine of 0.74 mg/dL, and AST/ALT of 25/17 U/L. Following her delivery, electron microscopic examination of the biopsy revealed numerous subendothelial and mesangial electron dense deposits within the glomerulus. Subsequent immunostain for C4d demonstrated intense staining of the glomerular capillaries. These findings were felt to be consistent with C4 glomerulopathy.

Following her delivery, electron microscopic examination of the biopsy revealed numerous subendothelial and mesangial electron dense deposits within the glomerulus. Subsequent immunostain for C4d demonstrated intense staining of the glomerular capillaries. These findings were felt to be consistent with C4 glomerulopathy. 3. Comment Preeclampsia is generally thought of as a disease that develops after 20 weeks' gestation; however, case reports have been published describing onset prior to the 20 weeks. There have been 4 cases described in the setting of pregnancy complicated by trophoblastic disease or triploidy, as well as one case complicated by antiphospholipid antibody syndrome [1–5]. Two additional cases, in women of advanced maternal age, have been described—being coined “pure” preeclampsia due to the lack of any identifiable etiology or predisposing factor. In both cases, the women had a history of preeclampsia in a prior pregnancy and one of the women had known chronic hypertension [6, 7]. These unique cases present many challenges as we must consider all diagnostic possibilities—such as lupus nephritis, hemolytic-uremic syndrome, antiphospholipid antibody syndrome, or thrombotic thrombocytopenic purpura [8]. In these difficult scenarios, renal biopsy can be a safe and useful tool in identifying the correct diagnosis and guiding appropriate management.

must consider all diagnostic possibilities—such as lupus nephritis, hemolytic-uremic syndrome, antiphospholipid antibody syndrome, or thrombotic thrombocytopenic purpura [8]. In these difficult scenarios, renal biopsy can be a safe and useful tool in identifying the correct diagnosis and guiding appropriate management. On renal biopsy, the most common pathologic findings in preeclampsia include endotheliosis, podocyte vacuolation, mesangial cell proliferation, and renal tubule protein casts; in addition, immunofluorescence microscopy is commonly positive for multiple complement components (C3, C1q, and C4d) and immunoglobulins (usually IgM) [9]. The findings of C4-dominant staining and numerous electron dense deposits in this case were unusual. A recently published article described 3 patients with similar findings and proposed a novel diagnosis for this entity, C4 glomerulopathy [10]. The presence of glomerular C4d, a split product of C4, is indicative of C4 activation, which can occur as a result of activation of either the classical complement pathway or the lectin pathway. Immune complex glomerulonephritides (e.g., lupus) often activate the classical pathway activation by the binding of C1q to the antibody-containing immune complexes, which can result in glomerular deposition of immunoglobulins, C3, C1q, and C4d. In the lectin pathway, lectin proteins bind to sugars (mannose) located on the microbial membranes or carbohydrate structures, which in turn activate C4 and bypass C1q activation [10]. In C4 glomerulopathy, the presence of bright C4d and negative or minimal staining for immunoglobulins, C1q, and C3 is suggestive of a lectin pathway abnormality [11]. The question is as follows: How does the lectin pathway get activated?

carbohydrate structures, which in turn activate C4 and bypass C1q activation [10]. In C4 glomerulopathy, the presence of bright C4d and negative or minimal staining for immunoglobulins, C1q, and C3 is suggestive of a lectin pathway abnormality [11]. The question is as follows: How does the lectin pathway get activated? The currently proposed theories have included genetic factors, acquired autoantibodies, or even a paraprotein that interferes with the lectin pathway that may play a role in the development of C4 glomerulopathy [9, 12]. Lectin pathway activation has been demonstrated in some immune complex glomerular diseases, including poststreptococcal glomerulonephritis and IgA nephropathy, though those diseases have a very different microscopic appearance. In line with these proposed mechanisms, an extensive work-up was done in this patient to determine whether there were any underlying processes present that would have led to abnormal activation of the lectin pathway or other channels in the complement pathway. As part of this work-up she had negative screening for immune and infectious etiologies, in addition to a normal serum protein electrophoresis, a negative paraprotein analysis, and normal light chain analysis. We also assessed different components of her complement system including C3 and Factor H and Factor B levels, which were all normal. Her serum C4 level, which was low during the time of her initial disease presentation, normalized three weeks after her delivery. If it is not a preexisting entity, then one may speculate that there is a component of pregnancy and/or a mechanism of preeclampsia that activates the lectin complement pathway.

all normal. Her serum C4 level, which was low during the time of her initial disease presentation, normalized three weeks after her delivery. If it is not a preexisting entity, then one may speculate that there is a component of pregnancy and/or a mechanism of preeclampsia that activates the lectin complement pathway. To our knowledge, there are only four other known cases of a pregnancy being complicated by C4 glomerulopathy, and unfortunately the current status of the patients and the outcomes of any subsequent pregnancies are unknown [9, 10, 13]. With little known information on the physiology and mechanism of lectin complement pathway activation, it is difficult to counsel the patient on risk of recurrence of such an adverse pregnancy outcome in a subsequent pregnancy. Using the best available data, we quoted a recurrence risk of 50–60% but also emphasized that there was approximately a 30% chance that the disease onset could be prior to 28 weeks' gestational age [14–16]. Conflicts of Interest The authors declare that there are no conflicts of interest regarding the publication of this paper. Figure 1 Some key renal biopsy findings. (a) PAS-stained section showed (arrows) duplication of glomerular basement membranes and endotheliosis (PAS stain; bar = 50 μm). (b) Immunohistochemical stain demonstrated C4d deposition within glomerular capillaries (highlighted by arrowheads). (c) Electron microscopy demonstrated conspicuous subendothelial electron dense deposit (arrow).

1. Case Report The case is a 29-year-old woman with a history of grade IV endometriosis and infertility. In 2011, she had surgery twice where endometrioses were diagnosed in the pelvic organs, the bowel, and the diaphragm. In 2015, she was referred to the Fertility Clinic after 1 year of infertility. Anti-Mullerian hormone (AMH) was 15 pmol/L. Initially, three intrauterine inseminations were done followed by IVF treatment with a standard antagonist protocol, where she received follitropin alpha (Gonal-f®) 150 IU daily for eight days. Choriongonadotropin (hCG; Ovitrelle) 6500 IU was given to induce ovulation. Nine oocytes were collected from eleven follicles. Two blastocysts were transferred and luteal support was given using vaginal progesterone. She did not become pregnant and did not develop OHSS. The second IVF treatment involved an antagonist protocol with Menotropin (hMG; Menopur®) 187.5 IU daily for 7 days. To induce ovulation she now received hCG (Pregnyl®) 10.000 IU. Five follicles were aspirated, and four oocytes were retrieved. On day 2, one embryo was transferred and she did not become pregnant. In the luteal phase, vaginal progesterone was supplemented with hCG 1500 IU every third day. Three doses were given. Thirteen days after the second oocyte retrieval, the patient was hospitalized primarily due to pain in the right side of the chest and dyspnoea. Initial examination by a cardiologist revealed tachypnea, dyspnoea, and tachycardia. Saturation was 100%, respiratory rate was 18/min, there was no rise in temperature, pulse was 82 beats/min, and blood pressure was 120/83 mmHg. There was no abdominal distension or ascites and no signs of thrombosis of the lower or upper extremities. Electrocardiogram (ECG) and blood tests were normal except for slightly elevated leukocytes 12.6 × 109/l. On suspicion of pulmonary embolism, a computed tomography (CT) was made, showing a pleural effusion on the right side. There were no signs of pulmonary embolism (Figure 1).

mbosis of the lower or upper extremities. Electrocardiogram (ECG) and blood tests were normal except for slightly elevated leukocytes 12.6 × 109/l. On suspicion of pulmonary embolism, a computed tomography (CT) was made, showing a pleural effusion on the right side. There were no signs of pulmonary embolism (Figure 1). The patient was then transferred to the gynecological department and admitted due to suspicion of OHSS. A pelvic ultrasound showed enlarged ovaries on both sides measuring 5,7 cm × 3,9 cm (right ovary) and 7,8 cm × 6,3 cm (left ovary) and a minimal amount of ascites. Thoracentesis was performed in local anesthesia by ultrasound guidance. A 7F pigtail catheter was introduced. Total 1.000 ml of clear yellow pleural fluid was drained during thoracentesis. Analysis of the sample showed negative cytological test for endometriotic cells and culture showed no signs of infection (bacteria and fungi). The patient received low molecular weight heparin Innohep® (Tinzaparin) 4500 IU subcutaneous prophylactically for 10 days. After 3 days, the symptoms and fluid production ceased, and repeated chest X-ray showed no pleural effusion (Figure 2). The patient recovered completely and was discharged. 2. Discussion To our knowledge, this is the first case of OHSS with pleural effusion as the only clinical manifestation in a young woman undergoing IVF due to severe endometriosis. According to evidence-based Danish Clinical Guidelines, our case was classified as having a mild degree of OHSS since the largest ovarian measurement was less than eight cm [1, 2].

he first case of OHSS with pleural effusion as the only clinical manifestation in a young woman undergoing IVF due to severe endometriosis. According to evidence-based Danish Clinical Guidelines, our case was classified as having a mild degree of OHSS since the largest ovarian measurement was less than eight cm [1, 2]. OHSS is a relatively common iatrogenic complication to controlled ovarian stimulation occurring in 0.5–5% of women undergoing IVF [3, 4]. The syndrome normally presents with ovarian enlargement and an acute fluid shift into extravascular spaces primarily causing accumulation of ascites in the abdomen. The pathogenesis is partly related to increased vascular permeability [5]. Risk factors are women with polycystic ovarian syndrome (PCOS), a high ovarian reserve, that is, elevated levels of anti-Mullerian hormone (AMH) and a high antral follicle count (AFC), previous OHSS, young age, high doses of rFSH, high number of oocytes collected, and high oestradiol levels at the end of stimulation [6]. Additionally luteal support using repetitive doses of hCG is known to increase the risk of OHSS, as reviewed by Fatemi et al. [7], and substantiated in the Cochrane Systematic Review including 94 randomised controlled trials comparing different luteal phase support regimens. The conclusion was that the use of repeated hCG injections as luteal support does increase the risk of OHSS [8].

o increase the risk of OHSS, as reviewed by Fatemi et al. [7], and substantiated in the Cochrane Systematic Review including 94 randomised controlled trials comparing different luteal phase support regimens. The conclusion was that the use of repeated hCG injections as luteal support does increase the risk of OHSS [8]. Our case had none of the OHSS risk factors, except that she was exposed to repeated hCG injections. Further, in her first ART cycle, she had no OHSS or pulmonary complaints despite the fact that more oocytes were retrieved. She did however not receive repeated hCG injections in her first ART cycle. HCG has multiple actions, including effects on the endometrium and endometrial angiogenesis during early implantation [9] Further, hCG stimulates corpus luteum to produce progesterone but also to some degree estrogen which is known to activate and maintain endometriosis. As such the endometriotic implants at the diaphragm may have been stimulated repeatedly by exogenous hCG and thus caused the effusion. Apposing this explanation is that her abdominal endometriosis did not cause effusions and thus ascites. Severe OHSS is estimated to occur in 1% of women undergoing IVF [10, 11]. Symptoms include massive ascites, decreased effective blood volume, oliguria, thromboembolic complications, pleural and pericardial effusions, and sometimes even death. The occurrence of pleural effusion, that is, hydrothorax in patients with OHSS, is below 10% [10].

ted to occur in 1% of women undergoing IVF [10, 11]. Symptoms include massive ascites, decreased effective blood volume, oliguria, thromboembolic complications, pleural and pericardial effusions, and sometimes even death. The occurrence of pleural effusion, that is, hydrothorax in patients with OHSS, is below 10% [10]. Endometrial implants, such as at the diaphragm, pleura, and pericardium, are uncommon. The cause of such implantation sites is unknown, but the theories include metaplastic transformation, lymphatic, hematogenous, and transdiaphragmatic migration [12, 13]. Thoracic endometriosis syndrome (TES) is a rare and complex disease, but nonetheless it is well described [13]. Symptoms include haemothorax, pneumothorax, and haemoptysis. TES in relation to IVF has been described in two case reports. In the first case, the patient presented with early OHSS three days after oocyte retrieval. A chest computed tomography showed bilateral pleural effusion and a subsequent thoracentesis revealed hemorrhagic pleural fluid. This case had 30 oocytes retrieved and developed OHSS with hemorrhagic pleural effusion as described above [14]. The second case developed pneumothorax after in vitro fertilization and embryo transfer. She had 13 oocytes collected [15].

pleural effusion and a subsequent thoracentesis revealed hemorrhagic pleural fluid. This case had 30 oocytes retrieved and developed OHSS with hemorrhagic pleural effusion as described above [14]. The second case developed pneumothorax after in vitro fertilization and embryo transfer. She had 13 oocytes collected [15]. Pleural effusion without intra-abdominal ascites is an extremely rare presentation of OHSS [16]. The first case of isolated pleural effusion associated with OHSS was described in 1975 [17]. Since then only few case reports have been published and none of these cases had endometriosis [17–20]. As described previously, pleural effusion mainly occurs in the severe forms of OHSS and in general together with other signs of OHSS. Predominantly, pleural effusion develops on the right side [21], the explanation being that lymphatic drainage may differ between the two sides and that the diaphragmatic recess is greater on the right side. It is also a possibility that pleural effusion is derived from a liquid shift from abdominal ascites [21, 22]. To our knowledge, there are no data explaining why pleural fluid does not drain into the abdominal cavity. To conclude, we hypothesize that this patient, who had only 4 oocytes aspirated, developed isolated hydrothorax as a result of repeated hCG injections in the luteal phase. The theory behind this is that the exogenous hCG stimulated the endometriotic lesions at the diaphragm and as a consequence induced the pleural effusion. As the patient did not achieve pregnancy, her symptoms ceased when exogenous hCG was withdrawn.

ydrothorax as a result of repeated hCG injections in the luteal phase. The theory behind this is that the exogenous hCG stimulated the endometriotic lesions at the diaphragm and as a consequence induced the pleural effusion. As the patient did not achieve pregnancy, her symptoms ceased when exogenous hCG was withdrawn. 3. Summary We present a rare manifestation of OHSS, more specifically isolated pleural effusion. Furthermore, it developed in an endometriosis patient with a rather low response to controlled ovarian stimulation The patient was however given repetitive doses of hCG, which is known to increase the risk of OHSS. The pleural effusion may be caused by hCG induced stimulation of the endometriotic lesions on the diaphragm Consent The patient has given written consent for publication of the current case report and accompanying pictures. Conflicts of Interest The authors report no conflicts of interest. Authors' Contributions All authors were involved in the patient's care. Negjyp Sopa drafted the manuscript. All authors participated in the design. Elisabeth Clare Larsen and Anders Nyboe Andersen edited and coordinated the manuscript. All authors read and approved the final manuscript. Figure 1 Figure 2

1. Introduction Infections of primate erythroparvovirus 1 (also known as parvovirus B19) are responsible for erythema infectiosum, polyarthropathy syndromes, and transient aplastic crisis in patients with underlying hemolytic disorder in both adults and children [1, 2]. Among adults, more than 50% have contracted the virus with a lifelong maintenance of immunity. Maternal infection with parvovirus B19 during pregnancy can cause severe anemia which might lead to nonimmune fetal hydrops and fetal death [3–5]. Nonimmune hydrops fetalis, a rare condition with an unknown etiology in 20–50% of cases, occurs mostly between 11 and 23 weeks of gestation after maternal B19 infection [6, 7]. Recent studies report that hydrops development, after infection is confirmed, is about 1–1,6% while fatality rate is almost 50% and 18% with and without intrauterine transfusion, respectively [8–12]. Despite the high fatality rate, there are only a few data for the Greek population considering B19 infection during pregnancy and there are no cases reported about fetal hydrops caused by B19 virus. We present a case report of a 35-year-old pregnant woman of Greek origin, being at the 21st week of gestation, with the presence of viral DNA, transient aplastic crisis, and hydrops fetalis due to parvovirus B19 infection that without further therapy led to a safe pregnancy result.

ut fetal hydrops caused by B19 virus. We present a case report of a 35-year-old pregnant woman of Greek origin, being at the 21st week of gestation, with the presence of viral DNA, transient aplastic crisis, and hydrops fetalis due to parvovirus B19 infection that without further therapy led to a safe pregnancy result. 2. Case Presentation A 35-year-old, Greek, pregnant woman was examined in our Obstetrics Clinic on the basis of a regular gestation surveillance at the 21st week of gestation. The woman had no medical history of thalassemia and she was pregnant for the second time. Her first delivery was performed with cesarean section. Her obstetric ultrasound revealed 21-week gestational age, normal placenta location (grade 0), and fetal heart beat from 140 to 150 bpm. The patient did not mention any unusual symptoms. No vaginal bleeding was noted. After approximately 3 weeks, her first child presented signs of erythema infectiosum on the head, torso, and upper extremities. The pediatrician estimated parvovirus B19 infection and recommended serum laboratory data of the woman in order to diagnose possible transmission by her first child. Being 24 weeks' pregnant, she was again presented to our Obstetrics Clinic. Apart from a mild fatigue, pulse rate of 92 beats/min, and respiratory rate of 18 breaths/min, no major clinical manifestations were reported. Her laboratory data showed values of haematocrit estimated at 31,6%, hemoglobin 10.8 g/dl, and red blood cell count 3.74 M/μl.

she was again presented to our Obstetrics Clinic. Apart from a mild fatigue, pulse rate of 92 beats/min, and respiratory rate of 18 breaths/min, no major clinical manifestations were reported. Her laboratory data showed values of haematocrit estimated at 31,6%, hemoglobin 10.8 g/dl, and red blood cell count 3.74 M/μl. Appropriate volumes of whole blood were drawn from the patient. The serum fractions were allowed to clot at room temperature prior to centrifugation. The serum samples had been stored at −20°C until tested for B19 IgM antibody, IgG antibody, and B19 DNA. A commercial kit ELISA (RecomWell; Mikrogen GmbH, Neuried, Germany) based on parvovirus B19 recombined capsid proteins was used for the detection of anti-B19 IgM and IgG antibodies in serum. Parvovirus serology (anti-IgM/IgG) was determined using ELISA. Consecutive IgM-IgG tests confirmed the diagnosis. The first detection, 4 weeks before the cesarean section, revealed IgG: 40 U/mL and IgM: 8.4 U/mL (<0,9 negative) and the second detection after 3 weeks revealed IgG: 35 U/mL and IgM: 2,8 U/mL. The patient's blood was tested once more 2 weeks afterwards and the results were IgG: 35 U/mL and IgM: 2,8 U/mL that indicated a recent infection. The woman was under close surveillance with serum tests and ultrasound-Doppler imaging. The condition of the fetus was normal and stable. A couple of weeks later, ultrasound revealed the presence of ascites within the peritoneal cavity as an indication of hydrops fetalis (Figure 1).

L that indicated a recent infection. The woman was under close surveillance with serum tests and ultrasound-Doppler imaging. The condition of the fetus was normal and stable. A couple of weeks later, ultrasound revealed the presence of ascites within the peritoneal cavity as an indication of hydrops fetalis (Figure 1). For the viral detection, a parvovirus genotype 1–3-specific TaqMan real-time PCR assay was also included, for the assessment of B19 DNA level. Commercially available kit was used for the isolation and the extraction of DNA (Qiagen GmbH, Hilden, Germany) following the manufacturer's instructions. For quantification the international standard 99/800 was used (NIBSC, Potters Bar, UK). In all previous samples for set time points the B19V-DNA was detected (1.0 × 103 to 1.7 × 1012 geq/mL). Bone marrow biopsy was not performed and direct and indirect antiglobulin tests were not examined because haemolytic anemia was not included in the differential diagnosis. The condition of the gestation was well-controlled, without any unusual signs and symptoms, when three months later oligohydramnios was presented, due to rupture of the fetal membranes, and a cesarean section was performed resulting in a normal looking healthy baby boy (Apgar score 8 at 1′ and 9 at 5′, body weight 3108 gr). Cord blood of the newborn was tested for parvovirus B19 to prove vertical transmission. After delivery, her reticulocytopenia was absent.

ed, due to rupture of the fetal membranes, and a cesarean section was performed resulting in a normal looking healthy baby boy (Apgar score 8 at 1′ and 9 at 5′, body weight 3108 gr). Cord blood of the newborn was tested for parvovirus B19 to prove vertical transmission. After delivery, her reticulocytopenia was absent. 3. Discussion Parvovirus B19 is a single-stranded DNA virus of the family Parvoviridae and genus Erythrovirus and the first human virus of this family to be discovered in human blood samples [2]. Correlation of parvovirus and aplastic crisis has been confirmed [13–15]. Moreover, B19 infection has been recognized as an etiologic factor of erythema infectiosum in haematologically normal persons, while cases of nonimmune hydrops fetalis were reported by Anderson and Hurwitz in 1988, when a pregnant woman was diagnosed with B19 infection [16, 17]. The incubation period usually ranges from 4 to 14 days, the rash usually occurs 2-3 weeks after initial infection, and patients are most contagious few days before the rash [18]. Failure of differentiation from proerythroblast into later stage erythroid precursors leads to transient aplastic crisis in patients with shortened lifespan of erythrocytes because of an underlying haemolytic problem, such as spherocytosis, sickle cell anemia, autoimmune haemolytic anemia, thalassemia, and G6PD deficiency [2]. B19 infection may present pancytopenia; however, its role as an etiology of true aplastic anemia is ambiguous [18].

patients with shortened lifespan of erythrocytes because of an underlying haemolytic problem, such as spherocytosis, sickle cell anemia, autoimmune haemolytic anemia, thalassemia, and G6PD deficiency [2]. B19 infection may present pancytopenia; however, its role as an etiology of true aplastic anemia is ambiguous [18]. In order to evaluate the risks of perinatal outcome (before confirmation of maternal infection) for pregnant women of Greek origin, MEDLINE was used to detect reports of acute Parvovirus B19 infections during pregnancy which were addressed to Greek hospitals. Exindari et al. reported in 2011 the epidemiological and clinical characteristics for B19 infections in northern Greece while Daniilidis et al. presented in 2014 a case-study control of 206 pregnant women infected by B19 virus during the 2005–2009 period. However, in contrast to international literature, there are no reports considering the main manifestation caused by B19 virus infection during pregnancy in the Greek population [19, 20]. Nonimmune hydrops fetalis is rare (1 in 3,000) with unknown etiology in many cases (20%–50%) and may occur when a nonimmune woman is infected by B19 parvovirus, usually in the first 20 weeks of pregnancy and can result in fetal death in 2–6% of cases [6, 7, 18]. Many women of childbearing age are susceptible to infection and the seroconversion rate is estimated at 1.5% per year [10]. From the infected fetuses, in the first half of pregnancy, 85% develop hydrops within 10 weeks, but severe anemia after 21 weeks is not observed [5].

lt in fetal death in 2–6% of cases [6, 7, 18]. Many women of childbearing age are susceptible to infection and the seroconversion rate is estimated at 1.5% per year [10]. From the infected fetuses, in the first half of pregnancy, 85% develop hydrops within 10 weeks, but severe anemia after 21 weeks is not observed [5]. A case of maternal severe transient aplastic crisis, on the background of shortened lifespan of erythrocytes, was recently reported due to B19 infection during pregnancy [21]. In addition, Rajput et al. reported a case of severe aplastic anemia in a previously healthy adult female because of acute parvovirus B19 infection [22]. Our patient presented transient aplastic crisis without known history of haemoglobinopathy, a case rarely reported. Furthermore, we observed indication of hydrops fetalis in the second half of gestation. Erythrocyte transfusion, corticosteroids, IVIG, or intrauterine transfusion were not administered, even though spontaneous resolution of hydrops fetalis is only 34% [23]. Weekly fetal ultrasound examination and adequate surveillance led to a safe delivery of a healthy baby without any complications. Imaging studies and blood tests of a 1-month follow-up were normal. Since the infected children living at home represent the major infectious source, a vaccine could probably be the most suitable precautionary measure [8]. Acknowledgments The authors are grateful to the patient for allowing them to describe her case history. Conflicts of Interest The authors report no conflicts of interest.

Our patient presented transient aplastic crisis without known history of haemoglobinopathy, a case rarely reported. Furthermore, we observed indication of hydrops fetalis in the second half of gestation. Erythrocyte transfusion, corticosteroids, IVIG, or intrauterine transfusion were not administered, even though spontaneous resolution of hydrops fetalis is only 34% [23]. Weekly fetal ultrasound examination and adequate surveillance led to a safe delivery of a healthy baby without any complications. Imaging studies and blood tests of a 1-month follow-up were normal. Since the infected children living at home represent the major infectious source, a vaccine could probably be the most suitable precautionary measure [8]. Acknowledgments The authors are grateful to the patient for allowing them to describe her case history. Conflicts of Interest The authors report no conflicts of interest. Figure 1 Ascites in the peritoneal cavity with the two umbilical arteries encircling the urinary bladder.

1. Introduction Stress urinary incontinence (SUI) is defined as the involuntary loss of urine with provocative maneuvers, such as cough, laugh, and sneeze [1]. Synthetic mid-urethral mesh slings are the most common primary surgical treatment for SUI and have been designated as the standard of care by the American Urogynecologic Society [2]. In recent years, synthetic mesh has come under increased scrutiny by the Federal Drug Administration (FDA) due to concerns over patient safety [3]. A major complication of mid-urethral slings is erosion where tissue overlying the mesh becomes thin and weak leading to exposure within an adjacent organ [4]. Vaginal erosion rates for mesh repairs range from 7% to 20% and may present several years after the index procedure [5]. Burch procedures are being performed with greater frequency in recent years, in part due to the FDA notification about synthetic mesh use [6]. The complication of erosion is not unique to sling operations. This can also occur with Burch procedures. We present 2 cases of suture erosion into the urethra and bladder, both discovered years after a Burch colposuspension.

A major complication of mid-urethral slings is erosion where tissue overlying the mesh becomes thin and weak leading to exposure within an adjacent organ [4]. Vaginal erosion rates for mesh repairs range from 7% to 20% and may present several years after the index procedure [5]. Burch procedures are being performed with greater frequency in recent years, in part due to the FDA notification about synthetic mesh use [6]. The complication of erosion is not unique to sling operations. This can also occur with Burch procedures. We present 2 cases of suture erosion into the urethra and bladder, both discovered years after a Burch colposuspension. 2. Case Presentation 2.1. Case 1 A 67-year-old white female with urinary hesitancy, frequency, and urgency incontinence was referred to our clinic for urogynecology consultation after failing standard therapy with approximately 6 months of anticholinergic medications and behavioral modifications. Past surgical history was significant for a Burch colposuspension about 10 years prior to examination. Past medical history was significant for chronic obstructive pulmonary disease having been a prior smoker. She quit approximately 5 years prior to evaluation. Physical examination revealed a Grade 3 rectocele and Grade 3 enterocele. Cough stress test in lithotomy was negative. Urethral hypermobility was less than 30 degrees. Urodynamics confirmed elevated bladder pressures and increased bladder sensation which was consistent with obstructed voiding.

ears prior to evaluation. Physical examination revealed a Grade 3 rectocele and Grade 3 enterocele. Cough stress test in lithotomy was negative. Urethral hypermobility was less than 30 degrees. Urodynamics confirmed elevated bladder pressures and increased bladder sensation which was consistent with obstructed voiding. Cystourethroscopy was performed which showed an eroded suture at the level of the proximal urethra near the bladder neck (Figure 1). We utilized a 24 Fr resectoscope with a cold-knife to cut the suture. The suture retracted back into the bladder and was removed with cystoscopy at the end of the case. The prolapse and obstructed voiding was treated with abdominal sacrocolpopexy. Her postoperative course was uneventful and the patient had complete resolution of symptoms by her 6-week postoperative visit. 2.2. Case 2 A 48-year-old white female with recurrent urinary tract infections for the past year was referred to our clinic for urogynecology consultation having failed treatment with nitrofurantoin suppression. Past surgical history was significant for a Burch colposuspension six years earlier. Past medical history was significant for chronic obstructive pulmonary disease and chronic bronchitis. The patient had a 30-pack year smoking habit. Physical examination revealed no significant pelvic prolapse. Cough stress test in lithotomy was negative. Urethral hypermobility was less than 30 degrees. Cystourethroscopy was performed which showed suture erosion at the right and left anterior bladder wall just inferior to the dome (Figures 2(a) and 2(b)).

2.2. Case 2 A 48-year-old white female with recurrent urinary tract infections for the past year was referred to our clinic for urogynecology consultation having failed treatment with nitrofurantoin suppression. Past surgical history was significant for a Burch colposuspension six years earlier. Past medical history was significant for chronic obstructive pulmonary disease and chronic bronchitis. The patient had a 30-pack year smoking habit. Physical examination revealed no significant pelvic prolapse. Cough stress test in lithotomy was negative. Urethral hypermobility was less than 30 degrees. Cystourethroscopy was performed which showed suture erosion at the right and left anterior bladder wall just inferior to the dome (Figures 2(a) and 2(b)). The patient underwent laser cystolitholapaxy to remove the eroded suture material. Her postoperative course was uneventful. The patient presented for a 3-month follow-up without a recurrence of urinary tract infection. 3. Discussion Highly publicized medicolegal trials in the US imply that some of the worst complications surrounding incontinence surgery are unique to mesh. This has led to more surgeons and patients preferring abdominal colposuspension to treat SUI. Our cases illustrate that suture injury/erosion is not unique to synthetic mid-urethral sling operations.

colegal trials in the US imply that some of the worst complications surrounding incontinence surgery are unique to mesh. This has led to more surgeons and patients preferring abdominal colposuspension to treat SUI. Our cases illustrate that suture injury/erosion is not unique to synthetic mid-urethral sling operations. In the first case, the suture erosion was most likely a source of bladder irritation contributing to the patient's urgency and incontinence. This type of complication related to Burch is well described. In as early as 1999, Dwyer et al. reported suture misplacement or erosion as an infrequent but important complication of Burch colposuspension and should be suspected with persistent irritative voiding symptoms [7]. Vaginal enterocele, as seen in this patient, occurs in up to 40 percent of cases after Burch [8]. Overelevation of the bladder neck at the time of Burch can change the vesicovaginal angle resulting in this type of pelvic prolapse. Treating the enterocele with sacrocolpopexy and removing the extruded suture via cystoscope was done to avoid reopening the space of Retzius. Significant scar tissue is likely to be encountered with reopening the space of Retzius, thereby increasing the risk of hemorrhage and bladder injury. Similarly, laser cystolitholapaxy was used to treat the eroded suture material in the second case to avoid the space of Retzius and decrease the risk of significant patient morbidity.

ar tissue is likely to be encountered with reopening the space of Retzius, thereby increasing the risk of hemorrhage and bladder injury. Similarly, laser cystolitholapaxy was used to treat the eroded suture material in the second case to avoid the space of Retzius and decrease the risk of significant patient morbidity. In conclusion, Burch colposuspension is thought to carry a lesser risk of complications of erosion of a foreign body and is thus being favored by many patients and physicians over synthetic slings for the treatment of SUI. However, as we have demonstrated with these two case reports, suture erosion can occur following Burch and may present in a delayed fashion. A high index of suspicion may be required to make the diagnosis given the variable symptom presentation. Cystoscopy is critical to diagnosis. 4. Conclusions Erosion is a complication associated with different types of incontinence surgery and not unique to mesh based sling operations. Burch colposuspension should not be favored solely to avoid erosion, and patients should be counseled accordingly. Cystourethroscopy performed intraoperatively or postoperatively is essential for early diagnosis and treatment of complications related to incontinence surgery. Consent The authors have obtained written consent from the patients to publish their respective cases/figures. Conflicts of Interest The authors have no relevant conflicts of interest to report. Figure 1 Cystoscopic image of an eroded suture at the level of the proximal urethra near the bladder neck.

Cystourethroscopy performed intraoperatively or postoperatively is essential for early diagnosis and treatment of complications related to incontinence surgery. Consent The authors have obtained written consent from the patients to publish their respective cases/figures. Conflicts of Interest The authors have no relevant conflicts of interest to report. Figure 1 Cystoscopic image of an eroded suture at the level of the proximal urethra near the bladder neck. Figure 2 Cystoscopic images showing suture erosion at the right and left anterior bladder wall just inferior to the dome.

In the article titled “Prenatal Diagnosis of Cardiac Diverticulum with Pericardial Effusion in the First Trimester of Pregnancy with Resolution after Early Pericardiocentesis” [1], there were errors in Tables 2 and 3 and in the text citations of some references in the Discussion. The errors in the in-text citations of references in the Discussion should be corrected as follows: The original text: Ultrasonographic findings associated with diverticula include pericardial effusion, cardiomegaly, septal defects and arrhythmia with fetal death before delivery, and hydrops [6,13,14]. The corrected text: Ultrasonographic findings associated with diverticula include pericardial effusion, cardiomegaly, septal defects and arrhythmia with fetal death before delivery, and hydrops [6, 13, 28, 32]. The original text: Thus, the observation of pericardial effusion makes it necessary to examine the cardiac function [1, 6, 15]. The corrected text: Thus, the observation of pericardial effusion makes it necessary to examine the cardiac function [1, 6, 16]. The original text: Five of them showed spontaneous resolution (71%) and 2 resulted in intrauterine death (29%): one of them, which occurred on week 26, was associated with trisomy 18 and the other, which occurred on week 29, was associated with treated twin-to-twin transfusion syndrome and death of one of the twins after treatment [6, 16].

ve of them showed spontaneous resolution (71%) and 2 resulted in intrauterine death (29%): one of them, which occurred on week 26, was associated with trisomy 18 and the other, which occurred on week 29, was associated with treated twin-to-twin transfusion syndrome and death of one of the twins after treatment [6, 16]. The corrected text: Five of them showed spontaneous resolution (71%) and 2 resulted in intrauterine death (29%): one of them, which occurred in week 26, was associated with trisomy 18 and the other, which occurred in week 29, was associated with treated twin-to-twin transfusion syndrome and death of one of the twins after treatment [6, 17]. The original text: The prognosis of this entity is generally good, although the outcome largely depends on the size and location of associated anomalies. Cases of rupture, both pre- and postnatal, arrhythmia, fetal death, heart failure, and coronary insufficiency have been described [9, 16, 18,21, 23]. In these patients, serial control examinations are necessary to detect possible complications. In general, postnatal progression is good and surgery is not necessary in asymptomatic cases [19].

pre- and postnatal, arrhythmia, fetal death, heart failure, and coronary insufficiency have been described [9, 16, 18,21, 23]. In these patients, serial control examinations are necessary to detect possible complications. In general, postnatal progression is good and surgery is not necessary in asymptomatic cases [19]. The corrected text: The prognosis of this entity is generally good, although the outcome largely depends on the size and location of associated anomalies. Cases of rupture, both pre- and postnatal, arrhythmia, fetal death, heart failure, and coronary insufficiency have been described [9, 16, 17,28, 29]. In these patients, serial control examinations are necessary to detect possible complications. In general, postnatal progression is good and surgery is not necessary in asymptomatic cases [18]. Errors in Table 2 should be corrected as follows.  Row 25: Williams et al. (2009) [3] should be Abi-Nader et al. (2009) [2]. Rows 29, 30, and 31: Abi-Nader et al. (2009) [2] should be Williams et al. (2009) [3]. Row 32: Williams et al. (2009) [3] should be Paoletti et al. (2012) [20]. Row 33: Paoletti and Robertson (2012) [20] should be Nam et al. (2010) [21]. Row 34: Nam et al. (2010) [21] should be Olorón et al. (2011) [22]. Errors in Table 3 should be corrected as follows.  Rows 4 and 11: Cavallé-Garrido et al.: the reference in the bibliography is [6]. Row 7: McAuliffe et al. [27] should be Del Río et al. [18]. Row 8: Pradhan et al. [28] should be Davidson et al. [15]. Row 9: McAuliffe et al. [27] should be Koshiishi et al. [17]. Row 10: Perlitz et al. [30] should be Menahem [31].

Errors in Table 3 should be corrected as follows.  Rows 4 and 11: Cavallé-Garrido et al.: the reference in the bibliography is [6]. Row 7: McAuliffe et al. [27] should be Del Río et al. [18]. Row 8: Pradhan et al. [28] should be Davidson et al. [15]. Row 9: McAuliffe et al. [27] should be Koshiishi et al. [17]. Row 10: Perlitz et al. [30] should be Menahem [31]. Row 12: Carles et al. [24] should be Johnson et al. [16]. Row 13: Cesko et al. [25] should be Bernasconi et al. [26]. Rows 14 and 15: Brachlow et al. [23] should be McAuliffe et al. [27]. Row 19: Williams et al. [3] should be Abi-Nader et al. [2]. Row 21: Abi-Nader et al. [2] should be Williams et al. [3]. The corrected tables are shown in Tables 2 and 3. Table 2 Description of the cases of cardiac diverticulum reported in the literature. Author GA di Size Sex Location Karyotype Associated anomalies Intervention Prenatal progression Neonatal Follow-up 1 Kitchiner et al. (1990) [13] 33 — Female Apex VI — Cardiomegaly No Stable Vaginal delivery 40 w; cardiomegaly, tachypnea, heart murmur, muscular IVC, mild mitral regurgitation Asymptomatic at 3.5 months of life 2 Hornberger et al. (1994) [9] 31 — — Lateral wall below tricuspid valve (RV) — — No — — — 3 Carles et al. (1995) [24] 13 — Male Apex LV — Pericardial effusion TOP 14 w — — — 4 Cesko et al. (1998) [25] 17 — Male Apex RV 46XY Pericardial effusion TOP 22 w Stable — — 5 Cavallé-Garrido et al. (1997) [6] 20 Large Female Lateral wall below mitral valve (LV) Trisomy 18 Ventricular septal defect, hydrops No Fetal death 26 w — —

3 Carles et al. (1995) [24] 13 — Male Apex LV — Pericardial effusion TOP 14 w — — — 4 Cesko et al. (1998) [25] 17 — Male Apex RV 46XY Pericardial effusion TOP 22 w Stable — — 5 Cavallé-Garrido et al. (1997) [6] 20 Large Female Lateral wall below mitral valve (LV) Trisomy 18 Ventricular septal defect, hydrops No Fetal death 26 w — — 6 Cavallé-Garrido et al. (1997) [6] 19 Small Female Apex RV — No No Stable; spontaneous resolution at 34 w Asymptomatic Asymptomatic at 22 months of life 7 Cavallé-Garrido et al. (1997) [6] 19 Small — Apex RV — Pericardial effusion PC 20 w Stable Asymptomatic Asymptomatic at 12 months of life 8 Cavallé-Garrido et al. (1997) [6] 36 Small Male Lateral wall below tricuspid valve (RV) — Pericardial effusion — — — Asymptomatic at 18 months of life 9 Johnson et al. (1996) [16] 19 3 mm Female Apex RV 46XX Pericardial effusion PC 20 w No relapse after PC, no growth Eutocic delivery 41 w; weight 3700 grams Asymptomatic Asymptomatic at 16 months of life 10 Brachlow et al. (2002) [23] 32 — — Apex LV — Cardiomegaly No Stable — Asymptomatic at 6 months of life 11 Bernasconi et al. (2004) [26] 22 10 × 5 mm Male LV lateral wall below mitral valve∗ 46XY Pericardial effusion PC 22 w — Fetal death 26 w, probably due to diverticulum rupture — 12 McAuliffe et al. (2005) [27] 13 4 × 6 mm Male Apex RV 46XY First trimester NT 4.2 mm Pericardial effusion PC 16 w Resolution of the effusion; CD stable Eutocic delivery 38 w; weight of 3070 grams Asymptomatic Asymptomatic at 10 months of life

11 Bernasconi et al. (2004) [26] 22 10 × 5 mm Male LV lateral wall below mitral valve∗ 46XY Pericardial effusion PC 22 w — Fetal death 26 w, probably due to diverticulum rupture — 12 McAuliffe et al. (2005) [27] 13 4 × 6 mm Male Apex RV 46XY First trimester NT 4.2 mm Pericardial effusion PC 16 w Resolution of the effusion; CD stable Eutocic delivery 38 w; weight of 3070 grams Asymptomatic Asymptomatic at 10 months of life 13 McAuliffe et al. (2005) [27] 13 4 × 3 mm Male Apex RV 46XY First trimester NT 2 mm Pericardial effusion PC 14 w Resolution of the effusion; CD stable Eutocic delivery 38 w; weight 3150 grams Asymptomatic Asymptomatic at 8 months of life 14 Prefumo et al. (2005) [1] 14 5 × 5 Male Apex RV 46XY First trimester NT 3.7 mm Pericardial effusion, ascites, skin edema PC 16 w Resolution of the effusion and hydrops; CD stable; mild cardiomegaly Vaginal full-term eutocic delivery; asymptomatic Asymptomatic at 22 months of life 15 Prefumo et al. (2005) [1] 12 1 mm — Apex RV — First trimester NT 1.2 mm Pericardial effusion No Spontaneous resolution of PE with 21 w; CD stable Full-term eutocic delivery, asymptomatic Asymptomatic at 17 months of life 16 Gardiner et al. (2009) [19] 14 2-3 mm — Apex RV Normal Pericardial effusion PC 14 w Resolution of the effusion and hydrops CD collapsed Asymptomatic at birth — 17 Gardiner et al. (2009) [19] 14 2-3 mm — Apex RV Normal Pericardial effusion TOP — — —

15 Prefumo et al. (2005) [1] 12 1 mm — Apex RV — First trimester NT 1.2 mm Pericardial effusion No Spontaneous resolution of PE with 21 w; CD stable Full-term eutocic delivery, asymptomatic Asymptomatic at 17 months of life 16 Gardiner et al. (2009) [19] 14 2-3 mm — Apex RV Normal Pericardial effusion PC 14 w Resolution of the effusion and hydrops CD collapsed Asymptomatic at birth — 17 Gardiner et al. (2009) [19] 14 2-3 mm — Apex RV Normal Pericardial effusion TOP — — — 18 Del Río et al. (2005) [18] 13 5 × 5 Female Apex RV 46XX Pericardial effusion, septal defect AV∗∗ No Spontaneous resolution at 28 w Eutocic delivery 40 w; weight 3400 grams, asymptomatic at birth Correction of septal defect at 3 months of life, resection of diverticulum; Asymptomatic at 8 months of life 19 Wax et al. (2007) [14] 20 6 × 9 mm Male Junction base RV-infundibulum — No No Stable Full-term eutocic delivery; Weight 3689 grams, asymptomatic; small permeable FO Asymptomatic at 18 months of life 20 Koshiishi et al. (2007) [17] 24 7 × 10 mm — Lateral wall below tricuspid valve (RV) — Mild pericardial effusion; MC pregnancy with laser intervention for TTTS at week 20 where donor fetus died No Stable Prenatal fetal death at 29 w — 21 Pradhan et al. (2007) [28] 28 — — Apex LV — Fetal arrhythmia Hydrops fetalis Medical treatment (digoxin) — Vaginal delivery 40 w Asymptomatic at 12 months of life 22 Barberato et al. (2009) [29] 16 5 × 5,7 mm — Apex LV — Mild pericardial effusion PC 20 w Discrete enlargement of PE with normal heart function Prenatal fetal death 37 w —

21 Pradhan et al. (2007) [28] 28 — — Apex LV — Fetal arrhythmia Hydrops fetalis Medical treatment (digoxin) — Vaginal delivery 40 w Asymptomatic at 12 months of life 22 Barberato et al. (2009) [29] 16 5 × 5,7 mm — Apex LV — Mild pericardial effusion PC 20 w Discrete enlargement of PE with normal heart function Prenatal fetal death 37 w — 23 Barberato et al. (2009) [29] 30 12 × 13 mm — Mitral subvalvular — LV dilatation and reduced systolic function No Stable — Asymptomatic at 6 months of life 24 Davidson et al. (2009) [15] 20 — — Apex RV — Pericardial effusion No Spontaneous resolution — Surgical treatment 25 Abi-Nader et al. (2009) [2] 21 5 × 5,5 mm Male RV — Pericardial effusion PC 24 w Mild tricuspid regurgitation at 31 CD stable Full-term delivery Asymptomatic at a year of life 26 Perlitz et al. (2009) [30] 22 7 × 4 mm Male RV lateral wall — No No Stable, CD growth up to 9 × 9 mm Eutocic delivery week 40; weight 4010 grams Asymptomatic at birth Asymptomatic at a year of life 27 Menahem (2010) [31] 19 — — Apex LV — Pericardial effusion — No controls performed Full-term live birth Asymptomatic at 10 months of life 28 Carrard et al. (2010) [32] 13 2,6 × 2,9 mm Male RV lateral wall 46XY First trimester NT 2.2 mm Pericardial effusion PC 17 w Resolution after PC; CD collapsed at 26 w Eutocic delivery 40 w, 2780 grams Asymptomatic at 11 months of life

27 Menahem (2010) [31] 19 — — Apex LV — Pericardial effusion — No controls performed Full-term live birth Asymptomatic at 10 months of life 28 Carrard et al. (2010) [32] 13 2,6 × 2,9 mm Male RV lateral wall 46XY First trimester NT 2.2 mm Pericardial effusion PC 17 w Resolution after PC; CD collapsed at 26 w Eutocic delivery 40 w, 2780 grams Asymptomatic at 11 months of life 29 Williams et al. (2009) [3] 22 3-4 mm Male RV 46XY Pericardial effusion PC 18 w Reaccumulation after treatment and resolution at 32-33 w PROM 34 w; intubation due to prematurity; caesarean section; weight 2460 gr; 2 muscle IVCs Asymptomatic at 14 months of life 30 Williams et al. (2009) [3] 21 11 × 15 mm Male RV lateral wall below tricuspid valve — Isolated — — Eutocic delivery; weight 2780 gr; asymptomatic at birth Asymptomatic at 16 months of life 31 Williams et al. (2009) [3] 25 26 × 16 mm (37 s) Male RV — Arrhythmia and reduced systolic function Induced delivery — Caesarean section 38 + 5 w; weight 3270 grams; mild reduction of systolic function and premature ventricular contractions at birth Asymptomatic at 3 years of life, on prophylactic treatment with acetyl salicylic acid 32 Paoletti and Robertson (2012) [20] 17 — — Apex LV Normal Mesocardia, per-membranous IVC No Stable Full-term live birth Asymptomatic at 2 years of life 33 Nam et al. (2012) [21] 21 1,6 × 0,4 mm — Apex LV Normal Defect on thoracoabdominal midline TOP — — —

31 Williams et al. (2009) [3] 25 26 × 16 mm (37 s) Male RV — Arrhythmia and reduced systolic function Induced delivery — Caesarean section 38 + 5 w; weight 3270 grams; mild reduction of systolic function and premature ventricular contractions at birth Asymptomatic at 3 years of life, on prophylactic treatment with acetyl salicylic acid 32 Paoletti and Robertson (2012) [20] 17 — — Apex LV Normal Mesocardia, per-membranous IVC No Stable Full-term live birth Asymptomatic at 2 years of life 33 Nam et al. (2012) [21] 21 1,6 × 0,4 mm — Apex LV Normal Defect on thoracoabdominal midline TOP — — — 34 Olorón et al. (2011) [22] 31 12 mm (postnatal) — RV lateral wall below tricuspid valve — — No Ventricular septal defect Full-term live birth; asymptomatic at birth; symptoms at 45 days of life: closure of septal defect at 3 months of life Asymptomatic at 10 months of life 35 Our case 14 2 mm Male Apex RV 46XY Pericardial effusion PC 17 w PE resolution after treatment; CD Stable; moderate cardiomegaly; normal heart function Full-term live birth; spontaneous eutocic delivery 40 + 1 w; weight 3150 grams Asymptomatic at 4 years of life GA di: gestational age at diagnosis; RV: right ventriculum; LV: left ventriculum; w: weeks of pregnancy; TOP: termination of pregnancy; PC: pericardiocentesis; CD: cardiac diverticulum; IVC: interventricular communication; PE: pericardial effusion; PROM: premature rupture of membranes; NT: nuchal translucency. ∗Diagnosis was made during the pathological examination after death. ∗∗Diagnosis of the ventricular septal defect was made after birth.

35 Our case 14 2 mm Male Apex RV 46XY Pericardial effusion PC 17 w PE resolution after treatment; CD Stable; moderate cardiomegaly; normal heart function Full-term live birth; spontaneous eutocic delivery 40 + 1 w; weight 3150 grams Asymptomatic at 4 years of life GA di: gestational age at diagnosis; RV: right ventriculum; LV: left ventriculum; w: weeks of pregnancy; TOP: termination of pregnancy; PC: pericardiocentesis; CD: cardiac diverticulum; IVC: interventricular communication; PE: pericardial effusion; PROM: premature rupture of membranes; NT: nuchal translucency. ∗Diagnosis was made during the pathological examination after death. ∗∗Diagnosis of the ventricular septal defect was made after birth. Table 3 Management and outcomes of the cases with cardiac diverticulum and pericardial effusion. Reference GA PE GA di Loc. Size (mm) Intervention PE findings Prenatal progression Postnatal progression 1 Carles et al. [24] 13 — Apex LV — TOP 14 w — — — 2 Cesko et al. [25] 17 AP Apex RV 3 mm TOP 22 w — — — 3 Gardiner et al. [27] 14 14 Apex RV 2-3 mm TOP — — — 4 Cavallé-Garrido et al. [6] 19 — RV 3 mm No — Spontaneous resolution at 34 w Asymptomatic at 22 months 5 Cavallé-Garrido et al. [6] 20 — LV lateral wall below mitral valve large No — Prenatal fetal death at 26 w, trisomy 18 — 6 Prefumo et al. [1] 12 12 Apex LV 1 mm No — Spontaneous resolution, effusion disappeared at 14 weeks; CD was not visible on ultrasound examination from week 21 Asymptomatic at birth; effusion or diverticulum not visible Asymptomatic at 17-month follow-up

5 Cavallé-Garrido et al. [6] 20 — LV lateral wall below mitral valve large No — Prenatal fetal death at 26 w, trisomy 18 — 6 Prefumo et al. [1] 12 12 Apex LV 1 mm No — Spontaneous resolution, effusion disappeared at 14 weeks; CD was not visible on ultrasound examination from week 21 Asymptomatic at birth; effusion or diverticulum not visible Asymptomatic at 17-month follow-up 7 Del Río et al. [18] 13 13 Apex RV 5 × 5 mm No — Spontaneous resolution; CD did not grow Perimembranous IVC IVC and IAC (postnatal) Asymptomatic up to 3 months of age; surgical treatment Asymptomatic at 8 months of age 8 Davidson et al. [15] 20 20 Apex RV — No — Spontaneous resolution; CD did not grow Surgical treatment at birth 9 Koshiishi et al. [17] 21 24 RV lateral wall 7 × 10 mm No — Fetal death on week 29 — 10 Menahem [31] 19 19 Apex LV — No   No control performed Full-term live birth; asymptomatic at 10 months of age; heart murmur; no treatment 11 Cavallé-Garrido et al. [6] 19 — Apex RV — PC 20 w — No PE relapse, CD did not grow Full-term live birth; asymptomatic at 12 months of age 12 Johnson et al. [16] 19 19 Apex RV 3 mm PC 20 w 7 cm3 yellow fluid, 20 gr/L proteins (transudate), acellular No PE relapse, CD did not grow Full-term live birth; asymptomatic at 16 months of age; no treatment 13 Bernasconi et al. [26] 22 AP Pared lateral LV 10 × 5 mm PC 25 w 25 mL old blood fluid Intrauterine fetal death at 26 weeks (CD rupture) —

12 Johnson et al. [16] 19 19 Apex RV 3 mm PC 20 w 7 cm3 yellow fluid, 20 gr/L proteins (transudate), acellular No PE relapse, CD did not grow Full-term live birth; asymptomatic at 16 months of age; no treatment 13 Bernasconi et al. [26] 22 AP Pared lateral LV 10 × 5 mm PC 25 w 25 mL old blood fluid Intrauterine fetal death at 26 weeks (CD rupture) — 14 McAuliffe et al. [27] 13 13 Apex RV 4 × 6 mm PC 16 w 3 mL serohematic fluid, 18 gr/L proteins (transudate), lymphocytes and mesothelial cells No PE relapse or enlarging; CD was not visible on week 37 Full-term live birth; asymptomatic at 10 months of age; no treatment 15 McAuliffe et al. [27] 13 13 Apex RV 4 × 3 mm PC 14 w 0.8 mL serohematic fluid, 15 gr/L proteins (transudate) No PE relapse; CD did not grow Full-term live birth; asymptomatic at 8 months of age; no treatment 16 Prefumo et al. [1] 14 14 Apex RV 5 × 5 mm PC 16 w 5 mL clear fluid No PE relapse; CD did not grow; mild cardiomegaly Full-term live birth; asymptomatic at 22 months of age; no treatment 17 Gardiner et al. [19] 14 14 Apex RV 2-3 mm PC 14 w 2 mL yellow fluid No PE relapse; CD did not grow Full-term live birth; asymptomatic; no treatment 18 Carrard et al. [32] 13 15 Apex RV 2.6 × 2.9 PC 17 w 4 mL clear fluid, 21 g/L proteins (transudate) No PE relapse; diverticulum was not visible from week 26 on Full-term live birth; asymptomatic at 11 months of age; no treatment

17 Gardiner et al. [19] 14 14 Apex RV 2-3 mm PC 14 w 2 mL yellow fluid No PE relapse; CD did not grow Full-term live birth; asymptomatic; no treatment 18 Carrard et al. [32] 13 15 Apex RV 2.6 × 2.9 PC 17 w 4 mL clear fluid, 21 g/L proteins (transudate) No PE relapse; diverticulum was not visible from week 26 on Full-term live birth; asymptomatic at 11 months of age; no treatment 19 Abi-Nader et al. [2] 21 21 Apex RV 5 × 4.5 PC 24 w Yellow fluid 10 mL, 15.4 g/L proteins (transudate), lymphocytes Complete resolution one week after PC; CD did not grow Full-term live birth; asymptomatic at one year of age; no treatment 20 Barberato et al. [29] 16 16 — — PC 20 w Blood-stained fluid Moderate growth of PE size as compared with postpuncture effusion; expectant approach; intrauterine fetal death on week 37 — 21 Williams et al. [3] 12 22 Apex RV — PC 18 w — Relapse one week later and subsequent spontaneous resolution on week 32-33 — 22 Our case 12 14 Apex RV 2 mm PC 17 w Clear yellow fluid, acellular, transudate No PE relapse; CD did not grow Full-term live birth; asymptomatic at birth; treatment with ASA; asymptomatic at 4 years of age GA PE: gestational age at pericardial effusion; GA di: gestational age and diverticulum diagnosis; RV: right ventriculum, LV: left ventriculum; w: weeks of pregnancy; PC: pericardiocentesis; CD: cardiac diverticulum; IVC: interventricular communication; PE: pericardial effusion.

1. Introduction Diabetes insipidus (DI) during pregnancy is an uncommon medical problem estimated to occur in two to six of 100,000 pregnancies [1]. One possible explanation is release of vasopressinase, a cysteine aminopeptidase, from the placenta leading to a fourfold increase in the rate of breakdown of arginine vasopressin (AVP) [2]. AVP regulates water reabsorption in the kidney and a decreased level leads to water loss. Other cases have been caused by uncommon hypothalamic-pituitary disorders leading to deficient secretion of AVP [3–5]. Timely diagnosis can be challenging because symptoms of polyuria, defined as a urine output exceeding 3 liters per day, and polydipsia may be attributed to the state of pregnancy. We present a case of transient DI in a woman during her third trimester of twin pregnancy and a second case of postpartum DI secondary to Sheehan syndrome to illustrate two different causes of DI associated with pregnancy and to highlight the difficulty in making a diagnosis of DI in the peri- and postpartum states. 2. Case  1 A 28-year-old para 1 woman was admitted in the 33rd week of gestation for hypertension and elevated liver enzymes. Concern for acute fatty liver of pregnancy or early preeclampsia prompted Cesarean section, which yielded two viable female infants. Her prenatal course was uncomplicated until week 25, when she developed polyuria and polydipsia leading to intake of 12 liters of water daily. The quantity and significance of the polyuria were initially not recognized and attributed to the gestational state.

d Cesarean section, which yielded two viable female infants. Her prenatal course was uncomplicated until week 25, when she developed polyuria and polydipsia leading to intake of 12 liters of water daily. The quantity and significance of the polyuria were initially not recognized and attributed to the gestational state. On examination, her temperature was 37.1°C, blood pressure was 128/76 mmHg, and pulse was 90 beats per minute with normal skin turgor and no peripheral edema. Admission laboratory data included elevated liver enzymes and normal serum sodium that increased to 154 mmol/L after C-section (Table 1). Postpartum she had polyuria up to 1000 mL/h, 24-hour fluid intake was 9.5 liters, and urine output was 10.6 liters. She exhibited severe thirst, ongoing dilute polyuria, and elevated serum osmolality during her water deprivation test unresponsive to 8-arginine vasopressin (Pitressin) but responsive to 1-deamino-8-D-arginine-vasopressin (DDAVP), which provided the patient with substantial relief (Table 2). Liver function tests improved at five days postpartum, but DI persisted, requiring DDAVP 10 μg intranasally twice a day. Brain MRI (Figures 1(a) and 1(b)) showed loss of the normal hyperintense posterior pituitary signal consistent with AVP depletion. By eighteen days postpartum, her polyuria and polydipsia resolved, and DDAVP was discontinued. Urine osmolality was 687 mOsm/kg. Four months postpartum, repeat MRI (Figures 1(c) and 1(d)) showed return of the hyperintense posterior pituitary signal, consistent with AVP repletion.

y signal consistent with AVP depletion. By eighteen days postpartum, her polyuria and polydipsia resolved, and DDAVP was discontinued. Urine osmolality was 687 mOsm/kg. Four months postpartum, repeat MRI (Figures 1(c) and 1(d)) showed return of the hyperintense posterior pituitary signal, consistent with AVP repletion. 3. Case  2 A 35-year-old nulliparous woman in her 29th week of an uncomplicated gestation presented for severe, generalized abdominal pain. Ultrasound was concerning for pelvic free fluid. She subsequently decompensated and was rushed to the emergency room for resuscitation. She required fluid boluses, pressors, intubation, and emergent C-section. Hemorrhage ensued, and she underwent an exploratory laparotomy where her ruptured splenic artery aneurysm was ligated and spleen was removed, resulting in hemostasis. She required 18 units of transfused packed red blood cells. The baby did not survive.

quired fluid boluses, pressors, intubation, and emergent C-section. Hemorrhage ensued, and she underwent an exploratory laparotomy where her ruptured splenic artery aneurysm was ligated and spleen was removed, resulting in hemostasis. She required 18 units of transfused packed red blood cells. The baby did not survive. Her past medical history was notable for polycystic kidney disease diagnosed in adulthood and a family history of polycystic kidney disease in her mother and brother. Postoperatively, her exam was notable for a soft abdomen and closed midline incision. Ten days afterwards while still in-house, she noted onset of polyuria and polydipsia initially attributed to fluid shifts from her resuscitation, postpartum, and postoperative state. However, those symptoms worsened upon discharge. She reported strong desire for cold fluids and polyuria that interrupted sleep. Four weeks later, she was admitted for wound infection and noted to have up to 450 mL/hr of urine output with osmolality 101 mOsm/kg and elevated serum osmolality 297 mOsm/kg. She responded well to DDAVP 10 μg  intranasally with concentration of her urine and relief of symptoms. She was subsequently maintained on nightly intranasal DDAVP. She denied headache or vision problems. Results of her pituitary hormone panel included TSH 4.05 U/mL, free T4 0.9 ng/dL, PRL 25 ng/mL, FSH 1.1 [<15.0 mIU/mL], LH 0.5 [<15.0 mIU/mL], estradiol 121 [100–400 pg/mL], and cortisol 7.9 μg/dL. She had no symptoms suggesting hypothyroidism or adrenal insufficiency. Brain MRI (Figures 2(a) and 2(b)) showed lack of normal hyperintense posterior pituitary signal and small pituitary size for age and postpartum state. Repeat morning cortisol was 17.3 μg/dL. She had eventual resumption of menses. Two years later, she had a spontaneous pregnancy and uneventful delivery of a full-term healthy baby boy. Her DI has persisted and remains controlled on DDAVP.

posterior pituitary signal and small pituitary size for age and postpartum state. Repeat morning cortisol was 17.3 μg/dL. She had eventual resumption of menses. Two years later, she had a spontaneous pregnancy and uneventful delivery of a full-term healthy baby boy. Her DI has persisted and remains controlled on DDAVP. 4. Discussion Diabetes insipidus is characterized by polyuria and polydipsia. Since these symptoms are nonspecific and may be attributed to the gestational state, DI during pregnancy is often overlooked and diagnosis is delayed. Indeed, in normotensive healthy human pregnant subjects, the osmotic threshold for AVP release and thirst perception is decreased compared to nonpregnant subjects [6]. The change in osmotic threshold may be mediated by human chorionic gonadotropin (hCG), as administration of hCG to women during the menstrual luteal phase has been shown to induce similar threshold changes for ADH release and thirst [7, 8]. As a result of these set point changes, plasma osmolality in normal pregnancy decreases to about 270 mosmol/kg and plasma sodium concentration decreases 4 to 5 meq/L below nonpregnancy levels [9]. In addition to a physiologic decrease in threshold for thirst perception, urinary frequency, defined as voiding more than 7 times per day, and nocturia, defined as voiding more than or equal to 2 times per night, are common and can affect 80–95% of pregnant women [10–12]. Yet in DI, the polyuria is generally of rapid onset and defined by abnormally high volumes of dilute urine exceeding three liters per day and the thirst can be intense.

7 times per day, and nocturia, defined as voiding more than or equal to 2 times per night, are common and can affect 80–95% of pregnant women [10–12]. Yet in DI, the polyuria is generally of rapid onset and defined by abnormally high volumes of dilute urine exceeding three liters per day and the thirst can be intense. In general, the evaluation of patients with suspected DI begins with a detailed history including rate of onset of polyuria, appearance of urine, and measurement of fluid intake and urine output. Typical findings include increased serum osmolality though, notably, the osmolality may be comparable to that of a nonpregnant woman in light of the decreased physiologic set point that occurs in pregnancy, elevated serum sodium concentration, and decreased urine osmolality when fluid is restricted. An increase in urine osmolality of at least 50% in response to DDAVP is consistent with central versus nephrogenic DI. The water restriction test must be performed in a monitored setting because potentially severe volume depletion and hypernatremia can occur in patients with significant polyuria. During pregnancy, the test is generally not recommended or must be undertaken with significant caution and low threshold to terminate since dehydration can lead to uteroplacental insufficiency.

nitored setting because potentially severe volume depletion and hypernatremia can occur in patients with significant polyuria. During pregnancy, the test is generally not recommended or must be undertaken with significant caution and low threshold to terminate since dehydration can lead to uteroplacental insufficiency. DI associated with pregnancy can result from decreased AVP production associated with pathological processes involving the hypothalamus and pituitary such as lymphocytic hypophysitis and infundibulitis or postpartum hemorrhage or from increased AVP destruction secondary to increased vasopressinase activity by means of enhanced placental production or decreased clearance in the setting of liver dysfunction. Patients with prepregnancy mild subclinical central DI that may have been present due to prior hypothalamic/pituitary disease experience worsening of symptoms which are unmasked by the increased vasopressinase activity during gestation. Furthermore, the marked increase in glomerular filtration rate during pregnancy may worsen preexisting subclinical nephrogenic DI.

tral DI that may have been present due to prior hypothalamic/pituitary disease experience worsening of symptoms which are unmasked by the increased vasopressinase activity during gestation. Furthermore, the marked increase in glomerular filtration rate during pregnancy may worsen preexisting subclinical nephrogenic DI. Transient DI of pregnancy attributed to increased vasopressinase activity typically presents in the third trimester. Loss of the hyperintense posterior pituitary signal indicating a decrease in AVP reserves has been reported [13]. Our first case also documents return of the hyperintense posterior pituitary signal following resolution of gestational DI. There appears to be an association with hepatic abnormalities perhaps because liver dysfunction results in decreased hepatic degradation of vasopressinase [14]. Prior gestational history may also be notable for occurrence of polyuria and polydipsia [13]. In our first patient, twin pregnancy with an extra placenta likely contributed to increased vasopressinase production while hepatic abnormalities hindered its clearance, leading to DI. Her diagnosis was delayed until the postpartum setting when her urine output was quantified. The water deprivation test might not have been needed since the patient was already hypernatremic and a vasopressin challenge could have been done. But notably, during the deprivation test, our patient had better response to DDAVP than AVP, consistent with involvement of vasopressinase in the pathogenesis of her DI, as vasopressinase cleaves the N-terminus of AVP and oxytocin and DDAVP lacks an amino group, thereby protecting it from degradation.

d have been done. But notably, during the deprivation test, our patient had better response to DDAVP than AVP, consistent with involvement of vasopressinase in the pathogenesis of her DI, as vasopressinase cleaves the N-terminus of AVP and oxytocin and DDAVP lacks an amino group, thereby protecting it from degradation. Our second case is the first report of isolated DI secondary to Sheehan syndrome from rupture of a splenic artery aneurysm. Sheehan syndrome is a well-known complication of postpartum hemorrhage that typically manifests with anterior pituitary hormone deficiencies including lactation failure and amenorrhea. Rare cases of DI in the setting of Sheehan syndrome have been reported, nearly all of which involved anterior pituitary hypofunction; we found only one case with isolated DI [3]. Only one reported case of Sheehan syndrome was secondary to ruptured splenic artery aneurysm [15]. Our patient's history of polycystic kidney disease may have predisposed her to aneurysm development [16]. Despite a known history of large volume blood loss placing her at risk of Sheehan syndrome, her diagnosis of DI was delayed until her readmission for a wound infection when the amount of polyuria was recorded.