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Cervical cancer is preventable; however, it remains one of the leading causes of cancer-related death among women in low- and middle-income countries.1 Although cervical cancer incidence has decreased in high-income countries owing to the implementation of screening programs, cervical cancer rates remain elevated in poor and medically underserved communities.2 A number of tools are available for the early detection and treatment of cervical cancer and its precursors in low-resource settings. Screening tests include Pap and human papillomavirus (HPV) testing as well as visual inspection with acetic acid.3 Depending on the setting, patients who screen positive undergo further testing with colposcopy and biopsy or immediate treatment using cryotherapy or a loop electrosurgical excision procedure (LEEP) to remove precancerous lesions and prevent progression to invasive cancer. These clinic-based procedures provide a cost-effective means of preventing cervical cancer.4,5 Unfortunately, medically underserved areas lack sufficient numbers of trained providers, in part due to limited opportunities for hands-on training.6

to remove precancerous lesions and prevent progression to invasive cancer. These clinic-based procedures provide a cost-effective means of preventing cervical cancer.4,5 Unfortunately, medically underserved areas lack sufficient numbers of trained providers, in part due to limited opportunities for hands-on training.6 There are commercially available mannequins to help teach cervical cancer screening skills, but these simulators are costly for use in low-resource settings (Table 1). Low-cost options include flashcards developed by Jhpiego to teach providers to recognize lesions during visual inspection with acetic acid.7 To practice biopsy, cryotherapy, and LEEP, animal tissue is often used (eg, beef tongue), but these models do not integrate the ability to teach screening, detection, and treatment skills. Table 1. Skills Trained Using Common Cervical Cancer Training Models Compared With LUCIA METHOD We developed and evaluated LUCIA (Low-cost Universal Cervical cancer Instructional Apparatus), a low-cost cervical cancer training model ($47) that can be used to provide hands-on training for all of the necessary skills related to cervical cancer prevention.

Table 1. Skills Trained Using Common Cervical Cancer Training Models Compared With LUCIA METHOD We developed and evaluated LUCIA (Low-cost Universal Cervical cancer Instructional Apparatus), a low-cost cervical cancer training model ($47) that can be used to provide hands-on training for all of the necessary skills related to cervical cancer prevention. LUCIA is a portable simulation model designed to act as a hands-on teaching aid for clinician education. LUCIA allows trainees to practice cervical cancer screening, diagnosis, and early treatment techniques while simulating a gynecologic exam (Fig. 1). LUCIA consists of a wooden pelvic frame, a vaginal canal (made from polyvinyl chloride pipe, waterproof fabric, and foam), cervical model holders, and a variety of cervical models. There are two cervical model holders: a stationary holder and a holder with a rotating arm attached to a small clamp. The cervical model holder with a small clamp is lined with aluminum foil so that a conductive current can pass through when practicing LEEPs. Both allow different cervical models to be interchanged so trainees can practice different skills. Fig. 1. Front (A) and side (B) view of the LUCIA model. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019.

LUCIA is a portable simulation model designed to act as a hands-on teaching aid for clinician education. LUCIA allows trainees to practice cervical cancer screening, diagnosis, and early treatment techniques while simulating a gynecologic exam (Fig. 1). LUCIA consists of a wooden pelvic frame, a vaginal canal (made from polyvinyl chloride pipe, waterproof fabric, and foam), cervical model holders, and a variety of cervical models. There are two cervical model holders: a stationary holder and a holder with a rotating arm attached to a small clamp. The cervical model holder with a small clamp is lined with aluminum foil so that a conductive current can pass through when practicing LEEPs. Both allow different cervical models to be interchanged so trainees can practice different skills. Fig. 1. Front (A) and side (B) view of the LUCIA model. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. LUCIA includes 20 three-dimensional printed cervical models (printed using polylactic acid) painted to depict the visible differences between a normal cervix, benign findings such as Nabothian cysts, cervical precancerous lesions including acetowhite changes, high-grade cervical precancer with abnormal vasculature, and findings consistent with invasive cervical cancer (Fig. 2). These models are used to practice identifying abnormal findings as well as provide hands-on training. LUCIA also comes with six molds used to make cervical models from ballistics gel (see Appendix 2, available online at http://links.lww.com/AOG/B274, for instructions to make gel models). All cervical models are designed to anatomic scale (3-cm diameter, 2–2.5-cm length), and to be interactive to train the user to perform a variety of skills.

ix molds used to make cervical models from ballistics gel (see Appendix 2, available online at http://links.lww.com/AOG/B274, for instructions to make gel models). All cervical models are designed to anatomic scale (3-cm diameter, 2–2.5-cm length), and to be interactive to train the user to perform a variety of skills. Fig. 2. Image of a complete set of reusable three-dimensional printed cervical models. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. The three-dimensional printed cervical models are used to train visual inspection with acetic acid and colposcopy (Figs. 3 and 4). Precancerous cervical models are painted with thermochromic paint that changes color from pink to white when exposed to temperatures above 88°F. This allows “white lesions” to appear after the application of hot water to simulate a positive visual inspection with acetic acid or colposcopy result when acetic acid is applied. The high-grade precancer and cancer models have vasculature painted on them using red paint, which absorbs green light, causing the vessels to appear dark when using the green filter feature of a colposcope.

ater to simulate a positive visual inspection with acetic acid or colposcopy result when acetic acid is applied. The high-grade precancer and cancer models have vasculature painted on them using red paint, which absorbs green light, causing the vessels to appear dark when using the green filter feature of a colposcope. Fig. 3. Image of one of the low-grade precancer cervical models inside the pelvic frame of LUCIA before (A), during (B), and after (C–F) hot water is applied during a simulated visual inspection with acetic acid procedure. The appearance of white lesions after hot water is applied simulates a positive visual inspection with acetic acid result. Five seconds after (C), 1 minute after (D), 2 minutes after (E), and 3 minutes after (F). Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. Fig. 4. Images of LUCIA being used for colposcopy practice. A mobile colopscope (mobileODT) is used to visualize the cervical model inside the pelvic frame with (B) and without (A) a green filter applied. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019.

Fig. 3. Image of one of the low-grade precancer cervical models inside the pelvic frame of LUCIA before (A), during (B), and after (C–F) hot water is applied during a simulated visual inspection with acetic acid procedure. The appearance of white lesions after hot water is applied simulates a positive visual inspection with acetic acid result. Five seconds after (C), 1 minute after (D), 2 minutes after (E), and 3 minutes after (F). Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. Fig. 4. Images of LUCIA being used for colposcopy practice. A mobile colopscope (mobileODT) is used to visualize the cervical model inside the pelvic frame with (B) and without (A) a green filter applied. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. Two normal and precancerous cervical models are printed using NinjaFlex material and are designed with a penetrable endocervical canal. These models are used to train providers to perform Pap and HPV sample collection and endocervical curettage (ECC; Fig. 5). During use, the models are moistened and corn flour is used to cover the outside surface and line the endocervical canal. The flour can then be removed using different cervical brushes and swabs to demonstrate adequate sample collection. Collected flour is visible on the tip of the brush or curette when extracted.

5). During use, the models are moistened and corn flour is used to cover the outside surface and line the endocervical canal. The flour can then be removed using different cervical brushes and swabs to demonstrate adequate sample collection. Collected flour is visible on the tip of the brush or curette when extracted. Fig. 5. Image of cervical model inside the pelvis of LUCIA being used for Pap test, human papillomavirus (HPV), and endocervical swab collection and endocervical curettage training. Insets show instruments after use. Before applying corn flour (A), after applying corn flour (B), during Pap test and HPV collection (C), after Pap test and HPV collection (D), endocervical swab (E), and endocervical curettage (F). Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019.

ttage training. Insets show instruments after use. Before applying corn flour (A), after applying corn flour (B), during Pap test and HPV collection (C), after Pap test and HPV collection (D), endocervical swab (E), and endocervical curettage (F). Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. The gel cervical models are one-time use models used to teach cervical biopsy, cryotherapy, and LEEP. The biopsy gel models are made with four black beads (600 micrometers) lining the edge of the “squamocolumnar junction.” The beads serve as targets to be removed using biopsy forceps, simulating cervical biopsy extraction (Fig. 6). For cryotherapy training, a cryogun can be used to treat the outer surface of the gel cervical model. The model becomes white when frozen and returns to its pink color over time, similar to a human cervix during and after cryotherapy (Fig. 7). For LEEP training, a standard LEEP machine can be used to remove a large sample from the gel cervical model. A “white lesion,” painted on the center of the model using liquid paper, acts as a target that trainees must remove while performing a LEEP (Fig. 8). Fig. 6. Images of biopsy gel cervical model inside the pelvic frame of LUCIA before (A), during (B), and after (C) a cervical biopsy is taken. The pink ring in the center of the model represents the squamocolumnar junction. Inset image shows biopsy containing the removed black bead. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019.

l model inside the pelvic frame of LUCIA before (A), during (B), and after (C) a cervical biopsy is taken. The pink ring in the center of the model represents the squamocolumnar junction. Inset image shows biopsy containing the removed black bead. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. Fig. 7. Images of cervical gel model inside LUCIA before (A), during (B), and after (C–F) cryotherapy training. One minute after (C), 4 minutes after (D), 7 minutes after (E), and 10 minutes after (F). Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. Fig. 8. Images of cervical gel model inside LUCIA before (A), during (B), and after (C) loop electrosurgical excision procedure (LEEP) training. Inset image shows LEEP sample that was removed. Parra. Low-Cost Cervical Cancer Training Apparatus. Obstet Gynecol 2019. The cost of LUCIA is $47 and includes the pelvic frame, vaginal canal, both cervical model holders, the three-dimensional printed cervical models, and six cervical gel molds (Appendix 3, available online at http://links.lww.com/AOG/B274). For skills training, an assembled LUCIA model is placed on the edge of a table and the trainee sits facing the labial opening. The appropriate cervical model is placed in a holder and is visible when looking through the vaginal canal with a speculum.

The cost of LUCIA is $47 and includes the pelvic frame, vaginal canal, both cervical model holders, the three-dimensional printed cervical models, and six cervical gel molds (Appendix 3, available online at http://links.lww.com/AOG/B274). For skills training, an assembled LUCIA model is placed on the edge of a table and the trainee sits facing the labial opening. The appropriate cervical model is placed in a holder and is visible when looking through the vaginal canal with a speculum. Practice of each skill begins with the trainee separating the labia and inserting a speculum. An external light is used to better visualize the cervix, such as a head lamp or book lamp adhered to the pelvic frame. Once the speculum is in place, the trainee can then practice performing Pap and HPV sample collection, visual inspection with acetic acid, colposcopy, cervical biopsy, ECC, cryotherapy, or LEEP on the cervical model. Once complete, the cervical model in the holder can be switched out to practice another skill. Video 1, available online at http://links.lww.com/AOG/B275, shows these skills being performed using LUCIA.

on, visual inspection with acetic acid, colposcopy, cervical biopsy, ECC, cryotherapy, or LEEP on the cervical model. Once complete, the cervical model in the holder can be switched out to practice another skill. Video 1, available online at http://links.lww.com/AOG/B275, shows these skills being performed using LUCIA. Video 1. Low-cost Universal Cervical cancer Instructional Apparatus (LUCIA) demonstration video. A live demonstration of how to use the LUCIA model for cervical cancer prevention training. Video created by Sonia Parra. Used with permission. EXPERIENCE LUCIA was evaluated as a teaching aid in cervical cancer training courses organized by the Project ECHO team from the University of Texas MD Anderson Cancer Center. Project ECHO is a telementoring program linking expert physicians with primary care clinicians in medically underserved areas through regular video conferences.8 MD Anderson complements Project ECHO with locally held courses to increase the capacity of local medical providers for cervical cancer screening, diagnosis, and treatment.

is a telementoring program linking expert physicians with primary care clinicians in medically underserved areas through regular video conferences.8 MD Anderson complements Project ECHO with locally held courses to increase the capacity of local medical providers for cervical cancer screening, diagnosis, and treatment. In 2017 and 2018, six training courses were held using LUCIA in El Salvador (n=1); South Texas along the Mexico border (n=2), Sherman, Texas (n=1); and Mozambique (n=2). Institutional Review Board approval to evaluate the models was obtained from MD Anderson and Rice University (Protocol PA17-0562). Anonymous standardized provider evaluations were administered at three courses (Appendix 4, available online at http://links.lww.com/AOG/B274) and completed by 70 participants (36 in El Salvador; 18 in Sherman, Texas; and 16 in Beira, Mozambique). Results are summarized in Table 2 and qualitative feedback is summarized in Appendix 5, available online at http://links.lww.com/AOG/B274. LUCIA received a median score of 4 out of 5 for usefulness, skill improvement, and skill evaluation, and a median score of 5 out of 5 for likelihood to recommend the model and learning value. Table 2. Summary of Cervical Cancer Training Courses by City

In 2017 and 2018, six training courses were held using LUCIA in El Salvador (n=1); South Texas along the Mexico border (n=2), Sherman, Texas (n=1); and Mozambique (n=2). Institutional Review Board approval to evaluate the models was obtained from MD Anderson and Rice University (Protocol PA17-0562). Anonymous standardized provider evaluations were administered at three courses (Appendix 4, available online at http://links.lww.com/AOG/B274) and completed by 70 participants (36 in El Salvador; 18 in Sherman, Texas; and 16 in Beira, Mozambique). Results are summarized in Table 2 and qualitative feedback is summarized in Appendix 5, available online at http://links.lww.com/AOG/B274. LUCIA received a median score of 4 out of 5 for usefulness, skill improvement, and skill evaluation, and a median score of 5 out of 5 for likelihood to recommend the model and learning value. Table 2. Summary of Cervical Cancer Training Courses by City The evaluation also asked participants to compare LUCIA with Jhpiego flashcards and an animal tissue model (beef tongue, Appendix 6 available online at http://links.lww.com/AOG/B274) for cervical cancer skills training. Over the three courses, 52 of 70 (74%) respondents preferred LUCIA over Jhpiego flashcards for visual inspection with acetic acid training. Cryotherapy was evaluated only during the course held in El Salvador, where 25 of 36 (69%) respondents preferred LUCIA over the animal tissue model for cryotherapy training. However, only 47% and 41% of respondents preferred LUCIA over the animal tissue model for biopsy and LEEP training, respectively. The main criticism was that the gel models felt too soft and did not cut like real cervical tissue. To overcome this, we increased the gel concentration for biopsy models from 30% to 35% gel wt/vol concentration and the LEEP models from 10% to 15% gel wt/vol concentration for our last course in Beira, Mozambique. We also kept the models refrigerated until immediately before use. A majority of participants in Beira preferred LUCIA for all skills evaluated (14/16 for visual inspection with acetic acid training, 9/16 for biopsy training, 9/16 for LEEP training).

5% gel wt/vol concentration for our last course in Beira, Mozambique. We also kept the models refrigerated until immediately before use. A majority of participants in Beira preferred LUCIA for all skills evaluated (14/16 for visual inspection with acetic acid training, 9/16 for biopsy training, 9/16 for LEEP training). DISCUSSION In 2018, the Director-General of the World Health Organization made a global call to action to eliminate cervical cancer, which included improving access to early-stage diagnosis and treatment.9 Improved access includes increasing the number of medical providers trained in the skills of early cervical cancer screening and prevention. LUCIA is a portable, low-cost simulation model that can be used to provide hands-on, comprehensive training for cervical cancer screening, diagnosis, and early treatment techniques in low-resource areas in the United States and globally, where cervical cancer remains a common cancer in women.

screening and prevention. LUCIA is a portable, low-cost simulation model that can be used to provide hands-on, comprehensive training for cervical cancer screening, diagnosis, and early treatment techniques in low-resource areas in the United States and globally, where cervical cancer remains a common cancer in women. In comparison with other models used for hands-on cervical cancer training, LUCIA can train providers on more skills at lower cost. The adaptability to simulate a variety of different skills makes LUCIA an excellent tool to increase local capacity to screen, diagnose, and treat precancerous cervical lesions based on local standards. For example, in rural areas of Latin America and Africa, clinicians and patients have limited access to medical facilities and equipment and therefore often rely on a “screen-and-treat” approach for cervical cancer prevention using visual inspection with acetic acid followed by cryotherapy of visible lesions.10 To better implement “screen-and-treat” methods in rural areas, educators could use LUCIA to teach rural clinicians how to perform visual inspection with acetic acid and cryotherapy. However, in a hospital setting with reliable access to electricity and equipment, local educators may use LUCIA to train clinicians in colposcopy and LEEP.

nt “screen-and-treat” methods in rural areas, educators could use LUCIA to teach rural clinicians how to perform visual inspection with acetic acid and cryotherapy. However, in a hospital setting with reliable access to electricity and equipment, local educators may use LUCIA to train clinicians in colposcopy and LEEP. Supported by the NCI of the NIH under award numbers R01 CA186132-01 and R01 CA186132-Supplement, the Rice Engineering Alumni Student Project Grant Program, the Lemelson Foundation—Developing Country Program, the Cancer Prevention and Research Institute of Texas (CPRIT) PP150012, the Prevent Cancer Foundation, the Raul Tijerina Foundation, and the Joe Family Fund. Financial Disclosure The authors did not report any potential conflicts of interest. Presented as a poster at the annual meeting of the Society of Gynecologic Oncology, March 24–27, 2018, New Orleans, Louisiana. * For a list of co-authors making up the Rice360 Student Team, see Appendix 1 online at http://links.lww.com/AOG/B274. The authors thank the Project ECHO team, especially Ellen Baker, MD, MPH, Melissa Lopez, MS, and Mila Salcedo, MD, PhD, at the University of Texas MD Anderson Cancer Center for including LUCIA as part of their cervical cancer education program, as well as all medical personnel who provided feedback on the model. They would also like to thank Veronica Leautaud, PhD, from the Rice360 Institute for Global Health for assistance in coordinating model development. Sonia Parra would like to acknowledge the support of the Baylor College of Medicine Medical Scientist Training Program.

dical personnel who provided feedback on the model. They would also like to thank Veronica Leautaud, PhD, from the Rice360 Institute for Global Health for assistance in coordinating model development. Sonia Parra would like to acknowledge the support of the Baylor College of Medicine Medical Scientist Training Program. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B276. Figure No available caption

Shoulder dystocia is a term for an obstetric emergency in which the progression of labor is halted after the delivery of the head. The incidence of shoulder dystocia ranges from 0.2–3%.1,2 It is a poorly predictable event associated with risk factors such as fetal macrosomia, maternal diabetes, previous dystocia, postterm pregnancy, male neonatal gender, and precipitous or prolonged second stage of labor, among others.3–5 Shoulder dystocia can potentially result in injuries to the neonate and the mother.6 Traditionally, shoulder dystocia is managed with McRoberts maneuver, with suprapubic pressure applied to disimpact the anterior shoulder.1 In cases in which shoulder dystocia remains unresolved after that sequence, the shoulder shrug technique can be used as an alternative to manage the dystocia and deliver the neonate. This article presents and discusses three cases of unresolved dystocia successfully managed using the shoulder shrug technique. TECHNIQUE The shoulder shrug technique is a modification of previously described maneuvers that attempt to resolve a shoulder dystocia. The technique is shown in Video 1, available online at http://links.lww.com/AOG/B402. The technique requires the obstetrician to follow certain steps (Fig. 1A–F) to resolve the dystocia:Grasp the posterior shoulder at the axilla using the obstetrician's thumb and index finger in a pincer grip so that the tips of the thumb and index finger come together in the axillary fossa. Pull the axilla out toward the head of the neonate to shrug the shoulder and retract the shoulder toward the vaginal opening.

TECHNIQUE The shoulder shrug technique is a modification of previously described maneuvers that attempt to resolve a shoulder dystocia. The technique is shown in Video 1, available online at http://links.lww.com/AOG/B402. The technique requires the obstetrician to follow certain steps (Fig. 1A–F) to resolve the dystocia:Grasp the posterior shoulder at the axilla using the obstetrician's thumb and index finger in a pincer grip so that the tips of the thumb and index finger come together in the axillary fossa. Pull the axilla out toward the head of the neonate to shrug the shoulder and retract the shoulder toward the vaginal opening. Maintain the pincer grip of the shrugged shoulder and, using the opposite hand, hold the head and retracted shoulder together as a unit Rotate this unit toward the neonate's face 180 degrees (this will allow the impacted anterior shoulder to roll toward neonate’s chest as it moves toward the posterior position). If unable to rotate toward the face, the opposite direction may be attempted. As long as the shrugged shoulder remains inferior to the symphysis pubis, it will be deliverable anteriorly. Now proceed with delivery of the remaining shoulder posteriorly. On rotation, the trapped anterior shoulder should be deliverable posteriorly.

Rotate this unit toward the neonate's face 180 degrees (this will allow the impacted anterior shoulder to roll toward neonate’s chest as it moves toward the posterior position). If unable to rotate toward the face, the opposite direction may be attempted. As long as the shrugged shoulder remains inferior to the symphysis pubis, it will be deliverable anteriorly. Now proceed with delivery of the remaining shoulder posteriorly. On rotation, the trapped anterior shoulder should be deliverable posteriorly. Fig. 1. Failure of progression due to shoulder dystocia. Flex the neck toward the anterior shoulder, then slide hand behind the posterior shoulder (A). Clamp the thumb and index finger around the posterior shoulder (B). With the thumb and index finger, form a pincer grip through the axilla, resembling an “OK” sign (C). Retract the posterior shoulder toward the shrug position (elevation of the shoulder). Arrow represents movement of the posterior shoulder to the shrug position (D). Restore the head toward the body's axis to form the head–shoulder unit and rotate this unit 180 degrees in the direction of the chest. Arrow represents counterclockwise rotation of the head and shoulder unit (E). On rotation, the anterior shoulder is now posterior and has advanced from the dystocia; normal delivery now proceeds with minimal forward traction. Arrow represents delivery of the neonate (F). Sancetta. Shrug Maneuver for Shoulder Dystocia. Obstet Gynecol 2019.

nterclockwise rotation of the head and shoulder unit (E). On rotation, the anterior shoulder is now posterior and has advanced from the dystocia; normal delivery now proceeds with minimal forward traction. Arrow represents delivery of the neonate (F). Sancetta. Shrug Maneuver for Shoulder Dystocia. Obstet Gynecol 2019. Video 1. The shoulder shrug maneuver. The video highlights a new technique to facilitate delivery during shoulder dystocia. Video created by Ricardo Leante, MS. Used with permission. EXPERIENCE The following three clinical cases involve situations in which McRoberts maneuver and suprapubic pressure failed to resolve shoulder dystocia. We used the technique described above, which was discovered by chance during a difficult delivery. Consents were obtained for all three patients. This case series does not require review and approval under DHHS 45 CFR 46 by the policies of the Baptist Health South Florida institutional review board.

shoulder dystocia. We used the technique described above, which was discovered by chance during a difficult delivery. Consents were obtained for all three patients. This case series does not require review and approval under DHHS 45 CFR 46 by the policies of the Baptist Health South Florida institutional review board. The first patient is a 46-year old woman, G8P6, with a history of six vaginal deliveries, including that of a macrosomic neonate weighing 9 lbs. 5 oz. At 39 weeks of gestation, her spontaneous labor included a 2-hour first stage and a second stage that lasted less than 30 minutes. She delivered the head while the obstetrician was en route to the hospital. Two neonatologists and assisting obstetrics nurses were unable to deliver the neonate using routine maneuvers. On arrival at the hospital, the obstetrician attempted the McRoberts maneuver, which failed, and then proceeded to deliver the posterior arm with traction at the axilla using the thumb and index finger of the right hand. The posterior shoulder was able to be shrugged outward toward the fetal head. Having concern regarding the possibility of fracture of the humerus during extraction of the posterior arm, the head and the shrugged shoulder were held together as a unit that was then rotated 180 degrees counterclockwise. At that point, the posterior shoulder was positioned anterior and inferior to the symphysis pubis and the previously impacted shoulder was posterior. Delivery then proceeded without complication. Apgar scores at 1 and 5 minutes for the neonate were 9 and 9, and birth weight was 10 lbs. 6 oz. The neonate had no injuries. Maternal injury was limited to first-degree tear.

d anterior and inferior to the symphysis pubis and the previously impacted shoulder was posterior. Delivery then proceeded without complication. Apgar scores at 1 and 5 minutes for the neonate were 9 and 9, and birth weight was 10 lbs. 6 oz. The neonate had no injuries. Maternal injury was limited to first-degree tear. The second patient was a 37-year old woman, G5P2, with a previous successful vaginal birth after cesarean delivery of 9 lb 0 oz neonate. She was at 41 3/7 weeks of gestational age when she was admitted in active labor. Her labor progressed normally, with a 4-hour first stage and an 18-minute second stage. A shoulder dystocia with an anteriorly impacted left shoulder could not be relieved with McRoberts maneuver and suprapubic pressure. The shoulder shrug maneuver of the right shoulder then was performed as described. This enabled the impacted shoulder to be dislodged as it moved posteriorly, and the delivery then was carried out uneventfully. However, it was noted that the rotation was successful only in the clockwise direction. The neonate weight 9 lb 2 oz and was had Apgar scores of 9 and 9 at 1 and 5 minutes. A mild left brachial plexus palsy resolved by the 2-week follow-up visit. This brachial plexus palsy involved the neonate's anterior impacted shoulder.

ver, it was noted that the rotation was successful only in the clockwise direction. The neonate weight 9 lb 2 oz and was had Apgar scores of 9 and 9 at 1 and 5 minutes. A mild left brachial plexus palsy resolved by the 2-week follow-up visit. This brachial plexus palsy involved the neonate's anterior impacted shoulder. The third patient was a 28-year old woman, G3P2, who had a history of shoulder dystocia with her second delivery. She underwent induction of labor at 41 3/7 weeks of gestation. She had cervical ripening with Foley bulb technique, followed by induction with Pitocin. Her first stage was 10 hours, and her second stage was 2 minutes. McRoberts maneuver and suprapubic pressure were attempted but were unsuccessful in relieving a shoulder dystocia. The shoulder shrug maneuver was completed, with delivery without complications. Apgar scores for the neonate were 9 and 9 at 1 and 5 minutes, and birth weight was 9 lb 14 oz. Maternal injury consisted of second-degree tear, which was repaired. The neonate had no injuries.

unsuccessful in relieving a shoulder dystocia. The shoulder shrug maneuver was completed, with delivery without complications. Apgar scores for the neonate were 9 and 9 at 1 and 5 minutes, and birth weight was 9 lb 14 oz. Maternal injury consisted of second-degree tear, which was repaired. The neonate had no injuries. DISCUSSION Historically, maneuvers for management of shoulder dystocia were introduced through articles in the literature and at conferences. Woods7 maneuver was described in 1942, in which a screw-like rotation maneuver was presented to alleviate the need for excessive traction to the head during delivery, in an attempt to reduce the likelihood of brachial plexus palsy and facilitate delivery. This technique uses a rotation inside the anatomic structures of the symphysis pubis, sacral promontory, and coccyx while simultaneously applying downward external pressure on the neonate's buttock. In 1964, Rubin's8 maneuver was introduced and showed a method to reduce the transverse diameter of the shoulder. In the Rubin's maneuver, finger pressure is directed on the posterior aspect of both anterior and posterior shoulders in an effort to adduct the shoulder toward the chest, thereby reducing the overall circumference of the shoulder to allow delivery. Unfortunately, these techniques do not always work and often simply replace the position of the two shoulders, which still remain behind the symphysis pubis, leaving the dystocia unresolved. Additionally, these two maneuvers have been associated with higher rates of injury in large cohort studies.6,9

to allow delivery. Unfortunately, these techniques do not always work and often simply replace the position of the two shoulders, which still remain behind the symphysis pubis, leaving the dystocia unresolved. Additionally, these two maneuvers have been associated with higher rates of injury in large cohort studies.6,9 The McRoberts maneuver was introduced in 1983, involving maternal repositioning, and is currently accepted as the initial maneuver for management of shoulder dystocia.10 The American College of Obstetricians and Gynecologists’ current recommendation is to start with McRoberts maneuver and suprapubic pressure, with a success rate of 24–62%.9,11 If unsuccessful, an empiric management proceeds to delivery of the posterior shoulder as secondary maneuver.12 This is successful in about 84% of cases.6,13 Another useful technique includes the Zavanelli maneuver, which, when performed promptly after failed initial procedures, has a high success rate.14–16

24–62%.9,11 If unsuccessful, an empiric management proceeds to delivery of the posterior shoulder as secondary maneuver.12 This is successful in about 84% of cases.6,13 Another useful technique includes the Zavanelli maneuver, which, when performed promptly after failed initial procedures, has a high success rate.14–16 Current data indicate that the total rate of neonatal injury from shoulder dystocia is around 5.2%; most of these are brachial plexus, humerus, and clavicle injuries, which increase morbidity yet commonly resolve without long-term sequelae.6,17 When faced with a shoulder dystocia that fails to resolve after the McRoberts maneuver with suprapubic pressure sequence, it is important to proceed with an alternative that reduces neonatal and maternal injury. Delivery of the posterior arm is a possible maneuver, yet it requires that the neonate's hand be accessible to sweep across the chest. This can be very difficult in large neonates or with constricted maternal anatomy.18 Also, aggressive attempts during this process can lead to humeral or clavicular fractures. Although this will allow for delivery, it is not an ideal outcome. Conversely, the shoulder shrug technique advances the posterior shoulder to the introitus, reducing the transverse diameter of the shoulders, and the posterior hand is not manipulated. As well, by moving the posterior shoulder and head as a single unit, additional traction forces on the brachial plexus are avoided. Once the head–shoulder unit is rotated 180 degrees, the delivery proceeds rapidly, without the need to completely deliver the posterior arm.

ers, and the posterior hand is not manipulated. As well, by moving the posterior shoulder and head as a single unit, additional traction forces on the brachial plexus are avoided. Once the head–shoulder unit is rotated 180 degrees, the delivery proceeds rapidly, without the need to completely deliver the posterior arm. The requirement of this technique is a posterior shoulder that is capable of being shrugged inferiorly toward the neonate's head. Special attention is paid to minimizing stretch of the brachial plexus. The shrugged shoulder should have no stretch whatsoever because the direction of traction is toward the head. If rotation of the unit is toward the neonate's face, as recommended, the anterior impacted shoulder would move toward the neonate's chest during rotation and, likewise, would not have significant traction on the brachial plexus. In addition, the shoulders would be adducted, hence reducing the transverse diameter to aid delivery.8 In certain circumstances, the posterior shoulder can be trapped by the sacral promontory and not able to be shrugged. In the author's experience, in two cases (not discussed in this article) in which this has occurred, return to McRoberts maneuver resulted in delivery of the anterior shoulder. Perhaps, in these circumstances, the angle of the anterior shoulder is in a more favorable position for delivery.

and not able to be shrugged. In the author's experience, in two cases (not discussed in this article) in which this has occurred, return to McRoberts maneuver resulted in delivery of the anterior shoulder. Perhaps, in these circumstances, the angle of the anterior shoulder is in a more favorable position for delivery. The shoulder shrug maneuver is a technique that can be added to any obstetrician's management of shoulder dystocia. Because the maneuver involves only the obstetrician's hands and no use of additional tools, it can be easily learned during simulation training and used during cases of dystocia.1 Department of Obstetrics and Gynecology, Baptist Hospital of Miami, Miami, Florida; St. George's University, Great River, New York; and Ross University School of Medicine, Miramar, Florida. Financial Disclosure The authors did not report any potential conflicts of interest. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B387.

arch, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors' personal interests, financial or nonfinancial, relating to this research and its publication have been disclosed. METHODS We conducted this single-arm, phase 2 FDA trial at 12 sites in the United States. All investigators had experience placing IUDs. Participating site IRBs approved this study. Here, we report outcomes from the original 1-year study and through the end of study, to 3 years of use. Participants completed the informed consent process before study participation and agreed to continue into the 2-year extension. Study enrollment began in June 2015 and data collection finished in March 2019. The investigators followed Good Clinical Practice guidelines and the Declaration of Helsinki. The study sponsor, Sebela Pharmaceuticals Inc, designed the study and oversaw its conduct.

e Gynecologic Oncology Group protocol 278 (NCT01649089), in which patients with stage IA1–IB1 cervical carcinomas, including adenocarcinomas, will be surgically treated with simple hysterectomy and pelvic lymphadenectomy, may help clarify whether simple hysterectomy is sufficient for all microinvasive cervical cancers. For patients who are ultimately diagnosed with microinvasive adenocarcinoma after hysterectomy, the risk of lymph node metastases ranges from less than 1% to 3%, with observational study data limited by the fact that lymphadenectomy was not performed in all patients.27,28 Therefore, lymph node assessment at the time of surgery for AIS is acceptable but not required and should be guided by the surgeon's risk assessment, which may include factors such as margin status of the preceding excisional specimen or postexcisional endocervical sampling results, pathologist concern for malignancy, HPV results (HPV-16– or -18–positive vs other high-risk HPV type), and patient risk factors (eg, immunosuppression).

In 2016, Brazil had the highest cesarean delivery in the world, with 30–40% of public sector and 80–90% of private sector births by cesarean delivery, even though a 2014 study found 70–80% of Brazilian women delivering in the private sector prefer a vaginal delivery.1 In Brazil, few hospitals use risk stratification, a well-documented strategy to reduce unnecessary cesarean delivery,2 and many women are scheduled for elective cesarean delivery at times driven by convenience. Little attention is given to the resources, ambience, and approaches that can accommodate the longer timeframe of physiologic or augmented labor.3A theoretical-conceptual framework by Torres4 proposed four principle contributors to excess caesarean delivery in the Brazilian private sector: 1) medical convenience, 2) autonomous obstetric practice, 3) a “maternity hotel” model of obstetric care, and 4) medicalization of childbirth.

physiologic or augmented labor.3A theoretical-conceptual framework by Torres4 proposed four principle contributors to excess caesarean delivery in the Brazilian private sector: 1) medical convenience, 2) autonomous obstetric practice, 3) a “maternity hotel” model of obstetric care, and 4) medicalization of childbirth. Although quality improvement (QI) methods have been successfully used in the United States for cesarean delivery reduction,5–7 they have not been widely deployed in middle-income countries where the world's highest cesarean delivery rates are found.8,9 Using a QI collaborative model,10 we tested four drivers of increased vaginal delivery 1) coalition-building of stakeholders with the common purpose of ensuring “appropriate delivery,” 2) empowering pregnant women to choose their preferred mode of delivery, 3) implementation of new care models favoring physiologic birth, and 4) improved information systems for continuous learning by health care providers. We hoped to increase the frequency of vaginal delivery in 28 Brazilian hospitals by 100% over 20-months (May 2015–December 2016) while not increasing perinatal risks.

y, 3) implementation of new care models favoring physiologic birth, and 4) improved information systems for continuous learning by health care providers. We hoped to increase the frequency of vaginal delivery in 28 Brazilian hospitals by 100% over 20-months (May 2015–December 2016) while not increasing perinatal risks. METHODS Our initiative to increase vaginal delivery followed efforts by the Brazilian public prosecutor to sue the private sector for lack of response to the high cesarean delivery rates,11 and two successful small scale prototypes: one that demonstrated the effectiveness of a “baby-friendly” model of obstetric care12 and a QI intervention that resulted in increased vaginal delivery.13 In December 2014, a call was issued to Brazil's approximately 5,500 active maternities (1,848 private and the remainder public) for up to 28 hospitals (based on available project resources) to participate in Project Parto Adequarto (Project Appropriate Birth) Collaborative if they met the following criteria: more than 500 births per year, commitment to include at least 30% of all deliveries in the intervention, cesarean delivery rate greater than 75%, and a Patient Safety Committee established according to Ministry of Health recommendations. In private hospitals, obstetric care was delivered by a mix of staff obstetricians and independent obstetricians paid on a fee-for-service basis. For private hospitals, eligibility also included subscription to insurance schemes that supported this initiative, and allocation of less than 50% of the beds to the public sector. In public hospitals, care was delivered by a mix of midwives and obstetricians employed by the hospitals. In both settings, anesthesiologists provide epidural analgesia if requested by women in labor. To better understand how the intervention needed to be adapted in a variety of hospital contexts, facilities were selected to represent all five geographic regions of Brazil.

wives and obstetricians employed by the hospitals. In both settings, anesthesiologists provide epidural analgesia if requested by women in labor. To better understand how the intervention needed to be adapted in a variety of hospital contexts, facilities were selected to represent all five geographic regions of Brazil. Forty hospitals indicated interest in joining Project Parto Adequarto. Of these 28 hospitals (24 private and four public), selected on the basis of best fit with the eligibility criteria, participated in the full initiative of learning sessions, data sharing, learning network participation, and QI coaching (“Intensive hospitals”). The 12 applicant hospitals that were not selected were invited to participate in learning sessions and data sharing but did not receive QI coaching (“Follower hospitals”). Three hospitals familiar with QI methods participated in learning sessions as expert mentors, but their data were not included in the analysis (“Mentor hospitals”) (Fig. 1). Fig. 1. Selection and participation of hospitals in Project Appropriate Birth. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020.

Forty hospitals indicated interest in joining Project Parto Adequarto. Of these 28 hospitals (24 private and four public), selected on the basis of best fit with the eligibility criteria, participated in the full initiative of learning sessions, data sharing, learning network participation, and QI coaching (“Intensive hospitals”). The 12 applicant hospitals that were not selected were invited to participate in learning sessions and data sharing but did not receive QI coaching (“Follower hospitals”). Three hospitals familiar with QI methods participated in learning sessions as expert mentors, but their data were not included in the analysis (“Mentor hospitals”) (Fig. 1). Fig. 1. Selection and participation of hospitals in Project Appropriate Birth. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020. To account for secular trends in the rate of vaginal delivery, Project Parto Adequarto retrospectively identified a comparison group of eight hospitals in São Paulo that were similar to the five São Paulo intervention hospitals with respect to size, population characteristics, resources, insurance coverage, and health care provider mix, but had not applied to join Project Parto Adequarto (“Comparator hospitals”). We obtained vaginal delivery rates for these eight hospitals from the Ministry of Health. Unlike for intervention hospitals, we were unable to risk-stratify deliveries in the Comparator hospitals. Therefore, we could compare trends only in overall vaginal delivery rates at these hospitals, as opposed to trends in only low risk vaginal deliveries.

rates for these eight hospitals from the Ministry of Health. Unlike for intervention hospitals, we were unable to risk-stratify deliveries in the Comparator hospitals. Therefore, we could compare trends only in overall vaginal delivery rates at these hospitals, as opposed to trends in only low risk vaginal deliveries. Based on close consultation with the hospitals during the set-up phase, Project Parto Adequarto hospitals targeted one of six defined subpopulations for the intervention: 1) all pregnant women in labor admitted through the emergency department (9,907 deliveries), 2) pregnant women in labor classified Robson 1–414 (14,660 deliveries), 3) pregnant women in labor classified Robson 1–5 (937 deliveries), 4) all pregnant women in labor assisted by obstetricians on shift (7,709 deliveries), 5) all primiparous women in labor (8,934 deliveries), and 6) nonselected pregnant women presenting in labor (8,934 deliveries). Project Parto Adequarto organized improvement activities around four specific drivers of increased vaginal delivery:1) A coalition of stakeholders with the common purpose of ensuring appropriate delivery (hospital leadership commitment to create an environment that is visibly supportive of vaginal delivery, building hospital leadership understanding and competence in using QI methods, new payer models to support vaginal delivery). 2) Empowerment of pregnant women to choose their preferred mode of delivery (shared decision making, a policy to respect birthing plans, support for birth companions, provision of prenatal information to women on delivery options).

Project Parto Adequarto organized improvement activities around four specific drivers of increased vaginal delivery:1) A coalition of stakeholders with the common purpose of ensuring appropriate delivery (hospital leadership commitment to create an environment that is visibly supportive of vaginal delivery, building hospital leadership understanding and competence in using QI methods, new payer models to support vaginal delivery). 2) Empowerment of pregnant women to choose their preferred mode of delivery (shared decision making, a policy to respect birthing plans, support for birth companions, provision of prenatal information to women on delivery options). 3) New care models favoring physiologic birth (working in teams that include midwives, rooms that support physiologic birth, midwife-assisted low-risk deliveries, following best practices for low-risk birth, use of Robson classification to identify low-risk birth). Using a simulation laboratory, Sociedade Beneficente Israelita Brasileira Albert Einstein–trained 480 health professionals from all 43 Intensive and Follower hospitals on assisting vaginal birth. Between August 2015 and July 2016, two separate 2-day training sessions were provided each week to groups of about 10 professionals from each hospital. 4) Information systems for continuous learning by health care providers (real time measurement systems for cesarean delivery, walk rounds using organizational learning boards).

3) New care models favoring physiologic birth (working in teams that include midwives, rooms that support physiologic birth, midwife-assisted low-risk deliveries, following best practices for low-risk birth, use of Robson classification to identify low-risk birth). Using a simulation laboratory, Sociedade Beneficente Israelita Brasileira Albert Einstein–trained 480 health professionals from all 43 Intensive and Follower hospitals on assisting vaginal birth. Between August 2015 and July 2016, two separate 2-day training sessions were provided each week to groups of about 10 professionals from each hospital. 4) Information systems for continuous learning by health care providers (real time measurement systems for cesarean delivery, walk rounds using organizational learning boards). These drivers were derived from scientific literature; previous experience with improving the percentage of vaginal deliveries in Brazil12,15; the collective experience and knowledge of an expert group of clinicians, administrators, insurers, pregnant women, and mothers who were assembled at the start of the initiative; and global systematic reviews led by the World Health Organization.16,17

with improving the percentage of vaginal deliveries in Brazil12,15; the collective experience and knowledge of an expert group of clinicians, administrators, insurers, pregnant women, and mothers who were assembled at the start of the initiative; and global systematic reviews led by the World Health Organization.16,17 This initial set of drivers formed the organizing framework for ideas for improvement (see Appendix 1, available online at http://links.lww.com/AOG/B660) generated by the teams; ideas were added, modified, or eliminated as they were tested by hospital QI teams for effectiveness. Implicit within the drivers were a number of socio-adaptive change features, including hospital leadership being encouraged to visibly and actively support the Project Parto Adequarto initiative through active participation in daily huddles and walk rounds. In the context of the Brazilian doctor-led model of care, physicians were encouraged to work more collaboratively with pregnant women, nursing staff, midwives, and doulas during labor. In addition, hospital staff were encouraged to codesign labor and care plans with pregnant women and families, and to design antenatal sessions to empower women to contribute more to decisions made during pregnancy and labor.

rk more collaboratively with pregnant women, nursing staff, midwives, and doulas during labor. In addition, hospital staff were encouraged to codesign labor and care plans with pregnant women and families, and to design antenatal sessions to empower women to contribute more to decisions made during pregnancy and labor. Implementation was designed with national scale up of interventions to promote vaginal delivery in mind, following the phased scale-up approach outlined in the Institute for Healthcare Improvement Scale-Up Framework.18 In this Framework, the Project Parto Adequarto phase of the project was an initial test of scale-up to further develop the changes and tools in new contexts, to validate the findings of the earlier prototype study,13 and build will at multiple levels of the Brazilian health system to undertake the next phases of the national scale up. Project Parto Adequarto started in December 2014 with the selection of the Intensive, Follower, and Mentor groups. From January to April 2015 (set-up period), Intensive and Follower hospitals were asked to retrospectively collect data on vaginal delivery from January to December 2014 (baseline period), and prospectively collect vaginal delivery data from January 2015 onward. They were given information about the intervention and asked to form QI teams. The first learning session took place in May 2015, and Project Parto Adequarto ended in December 2016 (intervention period).

anuary to December 2014 (baseline period), and prospectively collect vaginal delivery data from January 2015 onward. They were given information about the intervention and asked to form QI teams. The first learning session took place in May 2015, and Project Parto Adequarto ended in December 2016 (intervention period). The Breakthrough Series Collaborative approach,10 applied during the intervention period to the 28 Intensive hospitals, included a 3-day learning session in May 2015; 2-day learning sessions in August 2015, October 2015, and March 2016; and a 1-day learning session in November 2016. These sessions gathered teams from participating hospitals to receive basic training on QI methods, design initial tests of change to increase vaginal delivery, and share experiences of successes and challenges in implementing the changes. Teams typically included a representative of executive leadership, an obstetrician, and an obstetric nurse. Some teams included a patient representative. During the action periods between the learning sessions, teams were coached to work with other clinicians engaged in obstetric care at their sites to test and implement changes using plan-do-study-act cycles.13 Teams reported data on their activities and outcomes into a database shared among all teams as site-based, aggregated, de-identified data.

ween the learning sessions, teams were coached to work with other clinicians engaged in obstetric care at their sites to test and implement changes using plan-do-study-act cycles.13 Teams reported data on their activities and outcomes into a database shared among all teams as site-based, aggregated, de-identified data. Project Parto Adequarto was supported by three levels of leadership: 1) the steering committee, comprising members from the Agencia Nacional de Saude Suplementar, the Sociedade Beneficente Israelita Brasileira Albert Einstein, the Ministry of Health, and the Institute for Healthcare Improvement, met quarterly to review project progress and guided the work through iterative changes in project implementation design (eg, emphasis on low-risk women, duration of action periods); 2) the operations team (the Sociedade Beneficente Israelita Brasileira Albert Einstein and the Institute for Healthcare Improvement) coordinated activities, conducted learning sessions, provided virtual coaching and feedback, supported clinical training (simulation sessions), hosted meetings with local, regional, and national stakeholders, conducted site visits, and was responsible for dissemination of project progress; and 3) hospital QI teams were expected to include, at a minimum, a senior manager to remove obstacles and barriers (eg, resources, local policies), clinical experts (obstetricians and nurses or midwives), and patient representatives. Teams were expected to meet regularly to plan and execute plan-do-study-act cycles and share their data on the Collaborative's electronic platform. A few teams included a patient representative.

rriers (eg, resources, local policies), clinical experts (obstetricians and nurses or midwives), and patient representatives. Teams were expected to meet regularly to plan and execute plan-do-study-act cycles and share their data on the Collaborative's electronic platform. A few teams included a patient representative. Project Parto Adequarto used an observational comparative longitudinal study to assess changes in patient outcomes, including mode of delivery over time, before and after the QI initiative in participating hospitals, and in a comparison group of nonparticipating hospitals. Additionally, to update and redesign its implementation strategy, Project Parto Adequarto conducted a survey to seek feedback from participating hospitals on the changes they had found most useful in driving toward appropriate birth.

e in participating hospitals, and in a comparison group of nonparticipating hospitals. Additionally, to update and redesign its implementation strategy, Project Parto Adequarto conducted a survey to seek feedback from participating hospitals on the changes they had found most useful in driving toward appropriate birth. Although the primary outcome for the Project Parto Adequarto participants was the percentage of vaginal deliveries in the target subpopulations, we also assessed the percentage of vaginal deliveries for all deliveries in a comparative subgroup analysis. Secondary outcomes included the Net Promoter Score, an indicator of the likelihood of patients and families to recommend the institution to friends or colleagues19–22 adverse maternal and newborn outcomes, based on the Joint Commission criteria (maternal death, intrapartum or neonatal death with birth weight 2.5 kg or more, uterine rupture, maternal admission to the intensive care unit, birth trauma [neonatal], return to operating room, admission to neonatal intensive care unit (NICU) for neonates with birth weights of 2.5 kg or more for more than 24 hours, Apgar score less than 7 at 5 minutes, blood transfusion, third- or fourth-degree perineal tear)23; and NICU admission rate for neonates with birth weights of 2.5 kg or more.

turn to operating room, admission to neonatal intensive care unit (NICU) for neonates with birth weights of 2.5 kg or more for more than 24 hours, Apgar score less than 7 at 5 minutes, blood transfusion, third- or fourth-degree perineal tear)23; and NICU admission rate for neonates with birth weights of 2.5 kg or more. The 28 Intensive hospitals were asked to produce monthly data reports (measures described above and accumulated learning) for the baseline and intervention periods. These reports were discussed during monthly virtual meetings between the Institute for Healthcare Improvement technical support team and the hospital teams. Through a data-reporting platform (IHI Extranet), teams tracked their and other teams' progress on the indicators described. As is common in many QI projects, not all hospitals provided the monthly reports, despite the Project Parto Adequarto project managers' efforts to collect data from the onset of the initiative. Thirteen Intensive hospitals provided data for each of the baseline and intervention months. Within 4 months of the start of the intervention, 26 of the 28 Intensive hospitals were reporting timely, accurate, and complete monthly data. Two nonreporting hospitals were excluded from the analysis (one hospital closed down and the other never reported data). The Follower hospitals provided very few data on the project indicators but did contribute qualitative data for learning. The quantitative analysis is based on data reported by Intensive hospitals.

. Two nonreporting hospitals were excluded from the analysis (one hospital closed down and the other never reported data). The Follower hospitals provided very few data on the project indicators but did contribute qualitative data for learning. The quantitative analysis is based on data reported by Intensive hospitals. Two types of analyses were used. We used statistical process control24 methods to explore variation in outcomes over time and, in particular, to explore the effect of key events such as learning sessions and the introduction of specific changes. In addition, we used a Poisson regression (incidence rate ratio and a 95% confidence interval) to estimate the change in the rate of vaginal deliveries in the target population in each hospital in the Intensive group, from the year before the start of Project Parto Adequarto (baseline period: January–December 2014) to the year after the set-up period of Project Parto Adequarto (full implementation period: January–December 2016). To estimate the change in rate of vaginal deliveries in the Intensive group relative to the comparison group, we used a difference-in-difference approach. We used Poisson regression to compare change in annual percentage of vaginal deliveries for all hospital deliveries in the Intensive and the comparison groups during equivalent baseline and implementation periods.

ries in the Intensive group relative to the comparison group, we used a difference-in-difference approach. We used Poisson regression to compare change in annual percentage of vaginal deliveries for all hospital deliveries in the Intensive and the comparison groups during equivalent baseline and implementation periods. Twelve months after the start of Project Parto Adequarto, all hospitals in the Intensive, Follower, and Mentor groups were asked to identify the “change ideas” that, in their opinion, had the greatest effect on increasing the percentage of vaginal deliveries. Hospitals were asked to provide anonymous responses to a survey asking 1) what changes had they implemented and 2) in their opinion, what was the strength of those changes in driving optimal mode of delivery (Appendix 2, available online at http://links.lww.com/AOG/B660). The responses were summarized and analyzed by two authors (P.B., A.J.P.) and used to provide an updated Driver Diagram and Change Package.

they implemented and 2) in their opinion, what was the strength of those changes in driving optimal mode of delivery (Appendix 2, available online at http://links.lww.com/AOG/B660). The responses were summarized and analyzed by two authors (P.B., A.J.P.) and used to provide an updated Driver Diagram and Change Package. Institutional review board approval was not sought because this was a QI project within maternal and newborn programs in public and private hospitals, aimed at improving the reliability of existing local, governmental, and World Health Organization protocols. Each hospital received a detailed description of how the data would be used by Project Parto Adequarto and how aggregated individual hospital data would be shared for learning within a private electronic platform. No individual patient data were collected. Data were reported by hospital as de-identified aggregate subpopulation data. Hospital subpopulations that were included in the initiative were identified either by level of risk or by empanelment with type of health care provider (eg, hospital employee or independent contractor). RESULTS Of the 28 hospitals in the Intensive group, two hospitals withdrew from the initiative. One hospital closed, and another never activated QI teams or tested implementation changes. Neither hospital submitted data for Project Parto Adequarto.

Institutional review board approval was not sought because this was a QI project within maternal and newborn programs in public and private hospitals, aimed at improving the reliability of existing local, governmental, and World Health Organization protocols. Each hospital received a detailed description of how the data would be used by Project Parto Adequarto and how aggregated individual hospital data would be shared for learning within a private electronic platform. No individual patient data were collected. Data were reported by hospital as de-identified aggregate subpopulation data. Hospital subpopulations that were included in the initiative were identified either by level of risk or by empanelment with type of health care provider (eg, hospital employee or independent contractor). RESULTS Of the 28 hospitals in the Intensive group, two hospitals withdrew from the initiative. One hospital closed, and another never activated QI teams or tested implementation changes. Neither hospital submitted data for Project Parto Adequarto. All hospitals were in medium- to large-sized cities across Brazil (ranging from 147,000–12 million people). In total, 36% of women (84,151 out of 228,612) who delivered in the 26 reporting Intensive hospitals over the 20-month intervention period (May 2015–December 2016) were targeted for improvement during the initiative (Table 1). Table 1. Types of Hospital Participants in Project Parto Adequarto

All hospitals were in medium- to large-sized cities across Brazil (ranging from 147,000–12 million people). In total, 36% of women (84,151 out of 228,612) who delivered in the 26 reporting Intensive hospitals over the 20-month intervention period (May 2015–December 2016) were targeted for improvement during the initiative (Table 1). Table 1. Types of Hospital Participants in Project Parto Adequarto During the intervention period, efforts to improve the clinical skills and care models in the participating Intensive hospitals were associated with significant change in care practices and in the delivery environment favorable for vaginal delivery (Table 2). Table 2. Elements of Care Before and After Project Parto Adequarto

During the intervention period, efforts to improve the clinical skills and care models in the participating Intensive hospitals were associated with significant change in care practices and in the delivery environment favorable for vaginal delivery (Table 2). Table 2. Elements of Care Before and After Project Parto Adequarto Fig. 2. U-chart of vaginal birth percentages in the target population of 13 hospitals in the Intensive group reporting continuously throughout the baseline, intervention, and follow-up periods. Learning session 1: hospitals introduced to the model for improvement. Hospitals introduced to more than 100 change concepts and ideas (from literature) to increase vaginal births. Hospitals began participation in clinical training for vaginal delivery practices after learning session 1. Learning session 2: hospitals shared their first experiences using the model for improvement. Hospitals introduced to specific concepts and ideas for patient and family engagement. Hospitals practiced “all teach, all learn” for the first time, exchanging experiences in the storyboard walkaround format. Learning session 3: health plans (insurance companies) formally invited to join the collaborative and to support participating hospitals in their transformation. Synthesized learning from testing and narrowed down the change package from more than 100 change concepts to 18 high-effect concepts and corresponding ideas. Learning session 4: hospitals introduced to methods and tools to promote physician engagement in improvement work and behavior change. Learning session 5: celebrated results and motivated hospitals. Selected hospitals shared their success stories on stage. Identified bright spot hospitals to lead subsequent phase. Set the vision for a national campaign in 2020. UCL, upper control limit; LCL, lower control limit. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020.

d motivated hospitals. Selected hospitals shared their success stories on stage. Identified bright spot hospitals to lead subsequent phase. Set the vision for a national campaign in 2020. UCL, upper control limit; LCL, lower control limit. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020. For 13 Intensive hospitals that provided data reports consistently for the entire baseline and intervention periods, statistical process control analysis detected an increase in vaginal deliveries in the target populations from a baseline of 21.7% in 2014 to 35.5% over the intervention period (Fig. 2). Using Poisson regression, adjusting for clustering at the hospital level, vaginal deliveries increased from an average of 21.5% (95% CI 15.8–29.2%) in 2014 to 34.8% (95% CI 28.9–41.9%) in 2016, a relative increase of 1.62 (95% CI 1.27–2.07, P<.001), equivalent to a 62% increase in vaginal deliveries (Table 3). All 26 Intensive hospitals reported monthly data on vaginal delivery from June 2015 onward (4 months after the start of Project Parto Adequarto). Both groups of Intensive hospitals (13 hospitals in the complete reporting group and 13 hospitals in the incomplete reporting group) had similar average rates of vaginal delivery in June 2015 (30% and 30%), the first month when all 26 hospitals were reporting, and similar average rates of vaginal delivery in 2016 (35% and 37%).

ps of Intensive hospitals (13 hospitals in the complete reporting group and 13 hospitals in the incomplete reporting group) had similar average rates of vaginal delivery in June 2015 (30% and 30%), the first month when all 26 hospitals were reporting, and similar average rates of vaginal delivery in 2016 (35% and 37%). Fig. 3. A. U-chart of vaginal birth percentages among total hospital births in five hospitals comprising the Intensive group (São Paulo). B. U-chart of vaginal birth percentages among total hospital births in eight hospitals comprising the Comparison group (São Paulo). UCL, upper control limit; LCL, lower control limit. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020. Table 3. Primary Outcome of Vaginal Births in 2014 and 2016 by Intensive and Comparator Groups

Fig. 3. A. U-chart of vaginal birth percentages among total hospital births in five hospitals comprising the Intensive group (São Paulo). B. U-chart of vaginal birth percentages among total hospital births in eight hospitals comprising the Comparison group (São Paulo). UCL, upper control limit; LCL, lower control limit. Borem. Quality Improvement for Cesarean Delivery in Brazil. Obstet Gynecol 2020. Table 3. Primary Outcome of Vaginal Births in 2014 and 2016 by Intensive and Comparator Groups We compared average vaginal delivery rates for all deliveries in the five Intensive hospitals based in São Paulo with eight similar nonparticipating hospitals also in the São Paulo area for 2014 (baseline), 2015 (set-up), and 2016 (full implementation). From statistical process control analysis, vaginal births for all mothers in the Intensive hospitals increased from 15.6% to 23.0% and from 11.0% to 13.0% in the Comparator hospitals (Table 3 and Fig. 3A and B). After accounting for the small secular increase in Comparator hospitals, Poisson regression detected a relative (difference of differences) increase of about 21% in vaginal births in the Intensive compared with Comparator hospitals (RI 1.21, 1.05–1.41, P=.01, Table 3). The small increase in vaginal delivery rates in the Comparator group occurred around the time of the Project Parto Adequarto announcement (January 2015), with no further increase over the ensuing 2 years (Fig. 3B).

vaginal births in the Intensive compared with Comparator hospitals (RI 1.21, 1.05–1.41, P=.01, Table 3). The small increase in vaginal delivery rates in the Comparator group occurred around the time of the Project Parto Adequarto announcement (January 2015), with no further increase over the ensuing 2 years (Fig. 3B). For assessment of the association of vaginal delivery rates with secondary outcomes, complete data were available in a small number of hospitals in the Intensive group from January 2015 to December 2016. Although vaginal delivery increased significantly in all of the hospitals included in this secondary analysis, NICU admission rates, adverse events, and Net Promoter Score showed no change in reported values (Tables 4–6). Table 4. Neonatal Intensive Care Unit Admissions in 2014 and 2016 for the Intensive Group Table 5. Adverse Events in 2015 and 2016 for the Intensive Group Table 6. Net Promoter Score in 2015 and 2016 for the Intensive Group We received 32 responses from 40 hospitals surveyed for feedback on the percentage of hospitals implementing the different changes and the perceived value (strength) of the change ideas presented in the Driver Diagram/Change Package (Appendix 2, available online at http://links.lww.com/AOG/B660). Based on the results of this survey and the observations of the Project Parto Adequarto team, the theoretical health system drivers of improvement were modified and the effective implementation change ideas were condensed to reflect the change ideas that were considered most closely linked to the improvement in performance.

on the results of this survey and the observations of the Project Parto Adequarto team, the theoretical health system drivers of improvement were modified and the effective implementation change ideas were condensed to reflect the change ideas that were considered most closely linked to the improvement in performance. DISCUSSION Hospital participation in a Brazilian QI learning collaborative was associated with a 62% increase in vaginal delivery over 20 months without change in harm. The increase in vaginal delivery was linked to changes associated with four drivers of vaginal delivery: a broad coalition, a vaginal delivery-centered care model, engaging women in decision-making, and a learning environment for change. Two observations suggests a plausible association25 between the Project Parto Adequarto interventions and the observed changes in vaginal delivery: linkage of process changes with significant increases in vaginal delivery, and minimal change in vaginal delivery in eight nonintervention private hospitals in São Paulo. As with other QI initiatives, some intervention hospitals initially struggled to establish systems for regular data reporting. Only hospitals reporting complete data for all phases of Project Parto Adequarto (including baseline) were included in the quantitative analysis. The failure of Follower hospitals to engage in Project Parto Adequarto and report their results points to the importance of site-based coaching in QI collaboratives.

porting. Only hospitals reporting complete data for all phases of Project Parto Adequarto (including baseline) were included in the quantitative analysis. The failure of Follower hospitals to engage in Project Parto Adequarto and report their results points to the importance of site-based coaching in QI collaboratives. We incorporated evidence-based changes known to be associated with decreased cesarean delivery frequency in our theory of change and provided clinical training, because confidence of health care providers in supporting vaginal delivery is reportedly a barrier to reducing cesarean delivery.17 A Cochrane review identified studies that had a small effect in reducing cesarean delivery rates using strategies to promote guideline enforcement.26 In small-scale studies, use of Robson classification to identify low-risk women was linked to a decrease in cesarean delivery.4,14,27 QI approaches have been associated, with modest results, in decreased cesarean delivery rates in the United States.5,28,29 Using QI collaboratives, Main et al7 recently reported a decrease in cesarean delivery (29–25%) with no difference in safety measures for low-risk women in 56 hospitals in California. Project Parto Adequarto included three of the interventions used in the California Collaborative (no elective cesarean delivery before 39 weeks of gestation, feedback to physicians on their rates of cesarean delivery, and use of multidisciplinary teams).

safety measures for low-risk women in 56 hospitals in California. Project Parto Adequarto included three of the interventions used in the California Collaborative (no elective cesarean delivery before 39 weeks of gestation, feedback to physicians on their rates of cesarean delivery, and use of multidisciplinary teams). The strengths of our approach include the combination of four theoretical drivers of health system change with evidence-based interventions of vaginal delivery (clinical training, Robson classification, and feedback). Because prenatal care was not part of the intervention, we made least progress with the engagement of women in decision making. To make changes more acceptable and feasible for the local physicians and organizations, Project Parto Adequarto hospitals had flexibility to decide which low-risk women to target for vaginal delivery. This resulted in variation in the composition of the target populations. As we move into the next phase of the work, we are promoting a common risk-stratification system—the Robson classification—across all hospitals.

rto Adequarto hospitals had flexibility to decide which low-risk women to target for vaginal delivery. This resulted in variation in the composition of the target populations. As we move into the next phase of the work, we are promoting a common risk-stratification system—the Robson classification—across all hospitals. The possibility of bias in favor of the 13 hospitals with complete reporting is unlikely given our observation that complete- and incomplete-reporting hospital cohorts had similar average percentages of vaginal deliveries from the time that all hospitals reported (June 2015) to the end of the project. Because we were unable to risk-stratify deliveries in the Comparator hospitals, we could only compare trends in vaginal delivery rates for all (ie, not just low-risk) deliveries for hospitals in this analysis, resulting in low baseline and postintervention vaginal delivery rates for both Comparator and intervention hospitals. External factors that could have increased vaginal delivery included legal action and activist groups pressurizing private hospitals to change maternity care practice in favor of vaginal delivery. The small change in vaginal delivery in Comparator hospitals, coinciding with the Project Parto Adequarto launch, suggest external political and social factors that prompted the formation of Project Parto Adequarto may, on their own, have transiently increased secular rates of vaginal delivery for all hospitals.

ivery. The small change in vaginal delivery in Comparator hospitals, coinciding with the Project Parto Adequarto launch, suggest external political and social factors that prompted the formation of Project Parto Adequarto may, on their own, have transiently increased secular rates of vaginal delivery for all hospitals. The promising Project Parto Adequarto strategy has important lessons for efforts to reverse the global rise in cesarean delivery. Use of evidence-based interventions delivered through QI methods and obstetric re-training fostered an environment that allowed obstetricians to change their clinical practice. Although the high baseline cesarean delivery rates in Brazil offered a great opportunity for improvement, the change ideas that emerged from Project Parto Adequarto, adapted to local contexts and supplemented with new ideas using QI methods, are applicable in all countries with excess cesarean delivery rates. Despite rapid progress, the cesarean delivery rate at the end of Project Parto Adequarto remained more than double the average in high-income nations. Change strategies, such as deeper engagement of women in decision making and uniform use of risk criteria are being tested in a much larger group more than 100 hospitals in Brazil, striving toward higher targets (more than 85%) for vaginal delivery in low-risk women, with national scale up of the approach envisioned within the next 2 years. The projected was funded through a grant from Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE).

The promising Project Parto Adequarto strategy has important lessons for efforts to reverse the global rise in cesarean delivery. Use of evidence-based interventions delivered through QI methods and obstetric re-training fostered an environment that allowed obstetricians to change their clinical practice. Although the high baseline cesarean delivery rates in Brazil offered a great opportunity for improvement, the change ideas that emerged from Project Parto Adequarto, adapted to local contexts and supplemented with new ideas using QI methods, are applicable in all countries with excess cesarean delivery rates. Despite rapid progress, the cesarean delivery rate at the end of Project Parto Adequarto remained more than double the average in high-income nations. Change strategies, such as deeper engagement of women in decision making and uniform use of risk criteria are being tested in a much larger group more than 100 hospitals in Brazil, striving toward higher targets (more than 85%) for vaginal delivery in low-risk women, with national scale up of the approach envisioned within the next 2 years. The projected was funded through a grant from Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). Financial Disclosure Paulo Borem disclosed that MSD Brasil (Merck for Mothers) is currently supporting the second phase of this project. The Institute for Healthcare Improvement (IHI) received a grant from Merck for Mothers to run the second phase of this project. MSD Brasil has extended the project for two more years and this second grant was given to SBIBAE. He is a senior director at the IHI. Rita de Cássia Sanchez disclosed that she is an employee of Albert Einstein Jewish Hospital, one of partners working with hospitals present in the Colaborative Parto Adequado. Ademir Jose Petenate disclosed receiving funds from the IHI. Daniel Peres disclosed that he is employed by the IHI. The other authors did not report any potential conflicts of interest.

is an employee of Albert Einstein Jewish Hospital, one of partners working with hospitals present in the Colaborative Parto Adequado. Ademir Jose Petenate disclosed receiving funds from the IHI. Daniel Peres disclosed that he is employed by the IHI. The other authors did not report any potential conflicts of interest. Presented at the Institute for Healthcare Improvement Forum on Quality and Safety, December 9–12, 2018, Orlando, Florida; and at the IHI/BMJ Forum on Quality and Safety, March 27–29, 2019, Glasgow, Scotland. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B661.

Women seeking a highly effective, reversible, and hormone-free contraceptive method have one option, a copper intrauterine device (IUD). Although more than 150 million women have used copper IUDs globally,1 there have not been significant design improvements brought to the U.S. market in more than 35 years. The VeraCept Copper IUD includes several innovations (Fig. 1). The nitinol frame is small (32 mm×30 mm) and flexible, able to conform to anatomic variations of the uterus and smaller than the 32 mm×36 mm T380A. This novel low-dose copper and nitinol IUD comes preloaded in an applicator with a tapered, rounded tip and has precut strings 7.8 cm in length—innovations not available in any currently available copper IUD outside of the United States. The placement applicator has a narrow diameter (3.7 mm) compared with the T380A (4.4 mm). The low-dose copper and nitinol IUD contains 175 mm2 of copper placed in strategic locations, close to the internal os of the cervix and at the cornua bilaterally. This permits a copper load of less than half of that in the currently U.S. Food and Drug Administration (FDA)–approved copper T380A, and this is less copper than in any available copper IUD globally. With less than half the copper load of the only current available FDA-approved copper IUD, the lower copper load in the new IUD may decrease copper-associated problems of cramping and bleeding. Nitinol, a nickel and titanium alloy, is a novel material for an IUD frame. It was chosen for its superelasticity that permits compression in a narrow insertion tube and expansion to fill the space of a vessel or cavity. It is commonly used in interventional radiology for guidewires, stents, and inferior vena cava filters.2

ol, a nickel and titanium alloy, is a novel material for an IUD frame. It was chosen for its superelasticity that permits compression in a narrow insertion tube and expansion to fill the space of a vessel or cavity. It is commonly used in interventional radiology for guidewires, stents, and inferior vena cava filters.2 Fig. 1. VeraCept intrauterine device (A); VeraCept intrauterine device inserter (B). Images courtesy of Sebela Pharmaceuticals. Used with permission. Turok. Low-Dose Copper IUD Phase 2. Obstet Gynecol 2020.

ol, a nickel and titanium alloy, is a novel material for an IUD frame. It was chosen for its superelasticity that permits compression in a narrow insertion tube and expansion to fill the space of a vessel or cavity. It is commonly used in interventional radiology for guidewires, stents, and inferior vena cava filters.2 Fig. 1. VeraCept intrauterine device (A); VeraCept intrauterine device inserter (B). Images courtesy of Sebela Pharmaceuticals. Used with permission. Turok. Low-Dose Copper IUD Phase 2. Obstet Gynecol 2020. Two early clinical studies of this device provide reassuring data. An initial study of 463 parous women supported safety and efficacy. Investigators identified no insertion-related infections or perforations and a single pregnancy for a Pearl Index of 0.3 per 100 woman-years (95% CI 0.1–1.2). Expulsions occurred in 2.1% of participants at 6 months (Reeves MF, Katz BH, Canela J, Hathaway M, Tal M. Initial evaluation of a novel nitinol, low-dose-copper intrauterine contraceptive [abstract]. Contraception 2014;90:315.). The second study used a randomized controlled design to compare the method to the copper T380S IUD (a modification of the Copper T380A in which the copper sleeves on the IUD's arms terminate at the end of the IUD's plastic arms). The novel device was associated with statistically significant lower pain scores at placement.3 In addition, low-dose copper and nitinol IUD users had greater continuation rates, fewer expulsions, and fewer removals for pain and bleeding complaints at 12 months compared with copper T380S users. These results founded the basis for an FDA phase 2 study to assess over 36 months the efficacy, safety, tolerability, and discontinuation rates of this new, low-dose copper IUD.

eater continuation rates, fewer expulsions, and fewer removals for pain and bleeding complaints at 12 months compared with copper T380S users. These results founded the basis for an FDA phase 2 study to assess over 36 months the efficacy, safety, tolerability, and discontinuation rates of this new, low-dose copper IUD. ROLE OF THE FUNDING SOURCE Sebela Pharmaceuticals, Inc, funded this study, and the research team includes Sebela employees who participated in data interpretation, as well as review, approval of, and decision to submit this manuscript. The authors had access to relevant aggregated study data and other information (such as study protocol, analytic plan and report, validated data table, and clinical study report) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors' personal interests, financial or nonfinancial, relating to this research and its publication have been disclosed.

ation and agreed to continue into the 2-year extension. Study enrollment began in June 2015 and data collection finished in March 2019. The investigators followed Good Clinical Practice guidelines and the Declaration of Helsinki. The study sponsor, Sebela Pharmaceuticals Inc, designed the study and oversaw its conduct. Enrollment began in June 2015 and concluded in March 2016. Participants were between 18 and 40 years of age at study initiation, healthy, with regular menstrual cycles of (28±5 days) for the 3 months before enrollment, premenopausal, nonpregnant, sexually active, and at risk for pregnancy in an established relationship of 1 year expecting coital frequency of at least once per month through study participation. In addition, participants agreed to use the study contraceptive as their sole method to prevent pregnancy and accepted the risk of pregnancy. This study excluded people at low risk of pregnancy, including those breastfeeding without having had two consecutive normal menses, having used depo medroxyprogesterone acetate within the previous 10 months, using exogenous hormones, and those less than 6 weeks postpartum. We excluded those with prior IUD complications; heavy or painful menses; suspected or known abnormalities of the cervix, uterus, or ovaries; and those with known intolerance to nickel or copper, including Wilson's disease. Infection-related exclusions included any pelvic infection of the cervix, uterus, or fallopian tubes within the previous 3 months; mucopurulent cervicitis at the time of IUD placement; high risk of sexually transmitted infections (eg, multiple sexual partners); or acquired immunodeficiency syndrome (AIDS). We anticipated enrolling 25 women aged 36–40 for whom we would only assess safety data. All participants had testing for Chlamydia trachomatis and Neisseria gonorrhea within 1 month of or at the time of IUD placement. We assured normal cervical cytology on Pap testing within the 2012 ASCCP guidelines4 or a result of atypical squamous cells of undetermined significance with negative high-risk human papilloma virus testing before IUD placement.

ydia trachomatis and Neisseria gonorrhea within 1 month of or at the time of IUD placement. We assured normal cervical cytology on Pap testing within the 2012 ASCCP guidelines4 or a result of atypical squamous cells of undetermined significance with negative high-risk human papilloma virus testing before IUD placement. The study sponsor trained and certified each of the investigators, limited to two per site, in insertion technique. Placement occurred any cycle day consistent with Centers for Disease Control and Prevention guidelines.5 Placement technique employed tenaculum placement, sounding, and prescribed placement of the study IUD as directed by the study sponsor (Sebela Pharmaceuticals, Inc). All site investigators performing IUD placements received one-on-one training and direct observation by a single expert in use of the IUD inserter. Site clinical investigators used cervical dilation and pain medication at their discretion and confirmed IUD placement by transvaginal ultrasound scan immediately after placement. Site principal investigators made management decisions based on ultrasound findings independently or in conjunction with a central ultrasound reader if needed. If the initial placement attempt failed, a second attempt could be performed within 7 days. Participants reported baseline bleeding information. A research assistant assessed pain at IUD placement using a 5-point Likert scale (no pain, some pain, painful, moderately painful, and very painful). Investigators rated IUD ease of placement as very easy, easy, neither easy or hard, hard, or very hard.

ithin 7 days. Participants reported baseline bleeding information. A research assistant assessed pain at IUD placement using a 5-point Likert scale (no pain, some pain, painful, moderately painful, and very painful). Investigators rated IUD ease of placement as very easy, easy, neither easy or hard, hard, or very hard. Research staff provided participants with paper diaries used during the first 52 weeks of participation to record daily absence or presence of menstrual or other bleeding (none, spotting, normal, or heavy), use of menstrual bleeding products, IUD expulsion, use of additional birth control methods, presence of abnormal pain or cramping, and all days on which intercourse occurred. Research staff did not instruct participants to check IUD string length but they advised them to return for concerning bleeding or cramping suggestive of expulsion.

eeding products, IUD expulsion, use of additional birth control methods, presence of abnormal pain or cramping, and all days on which intercourse occurred. Research staff did not instruct participants to check IUD string length but they advised them to return for concerning bleeding or cramping suggestive of expulsion. In-person follow-up appointments occurred at 6, 13, 26, and 52 weeks in the first year. At each visit, investigators confirmed correct IUD placement by speculum or digital examination and transvaginal ultrasound scan when the IUD strings were not seen or palpated. These visits also included a pregnancy test, a physical examination, diary review and an interview to identify any potential adverse events and concomitant medications. Phone contact occurred monthly to confirm daily diary completion to week 52. When no information on intercourse or backup contraception was available for some cycles for a given participant, mostly after week 52, when diary collection ceased, we assumed the rate of evaluable cycles for that participant would be the same as the cycles with information provided on intercourse and backup contraception. For example, if a participant provided information on 13 cycles in the first year and 10 of the cycles were evaluable, that evaluable rate of 76.9% (10/13) would be used for future cycles. So, if she continued to participate for eight more cycles, we estimated that 6.2 cycles (76.9%) were evaluable. Participant compensation varied by site. The maximum compensation for attending all study visits ranged from $175 to $745.

were evaluable, that evaluable rate of 76.9% (10/13) would be used for future cycles. So, if she continued to participate for eight more cycles, we estimated that 6.2 cycles (76.9%) were evaluable. Participant compensation varied by site. The maximum compensation for attending all study visits ranged from $175 to $745. We informed participants requesting IUD discontinuation of the need to use an alternative method of contraception for 2 weeks after removal and provided a package of progestin-only birth control pills if desired. We followed those requesting IUD removal for desire of pregnancy with monthly phone contact for 6 months. At the 52-week visit, an investigator assessed IUD placement by transvaginal ultrasound examination and offered participants continued use of the IUD until 3 years with end of 28-day cycle contacts and in-person follow-up every 6 months. Participants extending use beyond 1 year did not systematically collect diary data. Discontinuation visits occurred when participants desired discontinuation, or reported an expulsion or pregnancy. We defined expulsion as partial or complete, with the study device moving respectively part way into the vagina or all the way out of the body.

g use beyond 1 year did not systematically collect diary data. Discontinuation visits occurred when participants desired discontinuation, or reported an expulsion or pregnancy. We defined expulsion as partial or complete, with the study device moving respectively part way into the vagina or all the way out of the body. We chose the sample size to provide an estimate on pregnancy and adverse effects consistent with the goals of an FDA phase 2 study. The primary outcome measure was effectiveness, evaluated as the pregnancy rate at 12 months measured by the Pearl Index. We also assessed pregnancy rates by life-table analysis and assessed pregnancy rates by both methods annually up to 3 years. Secondary outcomes included rates of placement success, expulsion, discontinuation rates, reason for discontinuation, adverse events, serious adverse events, and bleeding and spotting patterns. A medical monitor conducted monthly reviews assessing safety concerns and pregnancies. Formation of a clinical events committee was planned if there was more than one pregnancy in the first 12 months of use among all participants. The evaluable for pregnancy population included those 18–35 years of age at enrollment, with at least one report of pregnancy status after enrollment, having at least one cycle with intercourse reported without use of any other contraceptive method, or became pregnant with the IUD in place.

use among all participants. The evaluable for pregnancy population included those 18–35 years of age at enrollment, with at least one report of pregnancy status after enrollment, having at least one cycle with intercourse reported without use of any other contraceptive method, or became pregnant with the IUD in place. Investigators at each study site assessed adverse event severity and their relationship to IUD use. We employed the Medical Dictionary for Regulatory Activities in reporting adverse events in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Statisticians conducted analyses using SAS 9.4.

verity and their relationship to IUD use. We employed the Medical Dictionary for Regulatory Activities in reporting adverse events in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Statisticians conducted analyses using SAS 9.4. RESULTS Table 1 presents the demographic characteristics of the 286 enrollees after screening 417 potential participants. This includes 261 participants aged 18–35 years who comprise the population evaluated for efficacy. We enrolled an additional 25 participants aged 36–40 who contributed only to the safety outcome data. Participants had a mean age of 27.1 (SD±5.28) with 41 participants (14.3%) in the 18–21 range and 25 (8.7%) in the 36–40 range. The majority (60.8%) reported nulliparity. Figure 2 reports participant flow over the 36-month study period. Success with first placement attempt occurred for 267 participants, and 19 required a second attempt. Three enrollees did not have successful placement and one of those did not have a second attempt. Investigators dilated the cervix at placement for 41 (14.5%) participants. No perforations occurred. A minority of participants reported the placement to be moderately painful (42, 14.8/%) or very painful (12, 4.2%). Investigators reported ease of placement at first attempt as “very easy” for 173 participants (61.1%) and “easy” for 86 (30.4%). Thirty-six participants received prophylactic ibuprofen for IUD insertion and 168 reported use of nonsteroidal antiinflammatory drugs for bleeding, cramping, or both. Chlamydia testing before IUD placement was positive for 0 of 284 participants. Only two participants were tested at the time of placement.

or 86 (30.4%). Thirty-six participants received prophylactic ibuprofen for IUD insertion and 168 reported use of nonsteroidal antiinflammatory drugs for bleeding, cramping, or both. Chlamydia testing before IUD placement was positive for 0 of 284 participants. Only two participants were tested at the time of placement. Table 1. Demographics of Participants Enrolled in a Phase 2 Study of a Low-Dose Copper Intrauterine Device Fig. 2. Participant flowchart for low-dose copper and nitinol intrauterine device (IUD). Turok. Low-Dose Copper IUD Phase 2. Obstet Gynecol 2020. Investigators identified one intrauterine pregnancy in year 1 and an ectopic pregnancy in year 3. The primary outcome of 1-year Pearl Index was 0.52 (95% CI 0.01–2.87) and was 0.46 (95% CI 0.06–1.67) over 3 years. Table 2 presents the number of treatment cycles, Pearl Indicies, and life-table pregnancy rates by year and cumulatively. Throughout the study, 36% of cycles were “assumed evaluable,” and all of those occurred in years 2 and 3. Table 2. Pregnancy Rate Through 36 Months With Estimated Number of Cycles (18–35-Year-Old Women)

Investigators identified one intrauterine pregnancy in year 1 and an ectopic pregnancy in year 3. The primary outcome of 1-year Pearl Index was 0.52 (95% CI 0.01–2.87) and was 0.46 (95% CI 0.06–1.67) over 3 years. Table 2 presents the number of treatment cycles, Pearl Indicies, and life-table pregnancy rates by year and cumulatively. Throughout the study, 36% of cycles were “assumed evaluable,” and all of those occurred in years 2 and 3. Table 2. Pregnancy Rate Through 36 Months With Estimated Number of Cycles (18–35-Year-Old Women) Five expulsions occurred over 36 months (1.8%); three occurred in year 1, of which two were in nulliparous women. In the first year, 30 participants (10.4%) discontinued for adverse events related to the study drug (Table 3). In years 2 and 3, the corresponding figures were 14 (7.9%) and four (2.9%). In the first year of use, nine participants reported discontinuations for bleeding, seven for pain or cramping, and seven for a combination of bleeding and pain or cramping. Mean bleeding days per cycle decreased from 7.6 in cycle 1 to 5.2 in cycle 13. In total, early discontinuation in the first year occurred for 23 (8.1%) participants owing to issues related to bleeding or discomfort and 38 (10.6%) participants for all other reasons. Over the 3-year course of the study, discontinuation occurred for 48 (17.0%) participants for adverse events, 34 (12.0%) withdrew consent, 30 (10.6%) were lost to follow-up, and 18 (6.4%) for other reasons (including 10 desiring pregnancy). Figure 3 reports the Kaplan-Meier curve for continuation over the 36-month study.

er the 3-year course of the study, discontinuation occurred for 48 (17.0%) participants for adverse events, 34 (12.0%) withdrew consent, 30 (10.6%) were lost to follow-up, and 18 (6.4%) for other reasons (including 10 desiring pregnancy). Figure 3 reports the Kaplan-Meier curve for continuation over the 36-month study. Table 3. Adverse Events Reported in Low-Dose Copper and Nitinol Intrauterine Device Users Over the First 12 Months of Use (n=283) Fig. 3. Kaplan-Meier curve of low-dose copper and nitinol intrauterine device continuation up to 36 months. At the end of 12 months, participants were offered extension trial, with 41 declining. One month calculated as 30 days. Turok. Low-Dose Copper IUD Phase 2. Obstet Gynecol 2020. The report of adverse events dramatically dropped with time. Over the entire 3 years of follow-up, participant report of dysmenorrhea and pelvic pain occurred for 120 (42.4%) and pelvic pain for 35 (12.4%). However, only eight (2.8%) and five (1.8%) participants reported these symptoms in the second year. Of the 10 serious adverse events, investigators determined seven to be nonrelated to the study drug and the remaining three to be unlikely related to the study drug including one ectopic pregnancy, one hemorrhagic cyst, and one case of pelvic inflammatory disease diagnosed 119 days after IUD placement. The participant with pelvic inflammatory disease had negative results on C trachomatis and N gonorrhea screening 3 months before IUD placement but tested positive for N gonorrhea at the time of diagnosis.

regnancy, one hemorrhagic cyst, and one case of pelvic inflammatory disease diagnosed 119 days after IUD placement. The participant with pelvic inflammatory disease had negative results on C trachomatis and N gonorrhea screening 3 months before IUD placement but tested positive for N gonorrhea at the time of diagnosis. DISCUSSION This phase 2 FDA study of the low-dose copper and nitinol IUD demonstrates the method effectively prevented pregnancy in a group of largely nulliparous users over 3 years. This is the first U.S. study of the product. Our findings demonstrate efficacy and safety data as expected for a highly effective, reversible method and are consistent with point estimates for other recent FDA studies of intrauterine contraceptives.6,7 The low expulsion rate, 1.1% in the first year when expulsions are most common, may be the result of the flexible frame design.

monstrate efficacy and safety data as expected for a highly effective, reversible method and are consistent with point estimates for other recent FDA studies of intrauterine contraceptives.6,7 The low expulsion rate, 1.1% in the first year when expulsions are most common, may be the result of the flexible frame design. The data presented compare favorably with historic data for the Copper T380A, the only currently available, FDA-approved copper IUD in the United States. The low-dose copper and nitinol IUD design with less copper caused fewer discontinuations for bleeding and cramping compared with a T380S.3 In this study, the lack of comparator group precludes a direct comparison. However, comparing 1-year outcomes for the low-dose copper and nitinol IUD between this study and the prior randomized controlled trial, the expulsion rate trended lower in this study (1.1% vs 5.0%) and the discontinuation rate for bleeding and pain trended higher (8.1% vs 3.5%). We did not assess the effect of other novel IUD design features including preloaded IUD and precut strings that simplify IUD placement.

d the prior randomized controlled trial, the expulsion rate trended lower in this study (1.1% vs 5.0%) and the discontinuation rate for bleeding and pain trended higher (8.1% vs 3.5%). We did not assess the effect of other novel IUD design features including preloaded IUD and precut strings that simplify IUD placement. Strengths of the study include scientific rigor with 100% source validation of the data and a low loss-to-follow-up rate. The diverse study population from 12 geographically distinct U.S. sites supports external validity. With nulliparous women comprising the majority of participants, the data support safety and efficacy in this group of users. As a phase 2 trial, the inclusion and exclusion criteria were more rigid and the follow-up more extensive than expected in general use. Study weaknesses include the expected limitations of an FDA phase 2 study, including the sample size, which precludes subanalyses based on characteristics and lack of a comparator. This novel, low-dose copper contraceptive demonstrated high efficacy and safety in this phase 2 FDA trial supporting initiation of a phase 3 study.Authors' Data Sharing Statement Will individual participant data be available (including data dictionaries)? No. What data in particular will be shared? Not available. What other documents will be available? Not available. When will data be available (start and end dates)? Not applicable. By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable. Supported by Sebela Pharmaceuticals, Inc.

What data in particular will be shared? Not available. What other documents will be available? Not available. When will data be available (start and end dates)? Not applicable. By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable. Supported by Sebela Pharmaceuticals, Inc. Financial Disclosure David K. Turok is a consultant for Sebela Pharmaceuticals. Anita L. Nelson receives research support from Agile Pharmaceutical, Bayer Women's HealthCare, Merck, and Sebela Pharmaceuticals, Inc. She serves on speakers' bureaus for American Regency, Bayer Women's HealthCare, and Merck. She serves as a consultant and on advisory boards for Agile Pharmaceutical, AMAG, American Regency, Bayer Women's HealthCare, Merck, Sebela Pharmaceuticals, Inc, and TherapeuticsMD. Courtney A. Schreiber is a consultant for Danco Laboratories, LLC. The Department of Obstetrics and Gynecology, University of Pennsylvania, receives contraceptive research funding from Bayer, Daré, FHI360, Medicines360, and Sebela. The Department of Obstetrics and Gynecology at the University of Utah receives research funding from Bayer, Cooper Surgical, Medicines360, Merck, and Sebela Pharmaceuticals. Kevin Peters, Mary Jo Schreifels, and Bob Katz are employed by Sebela Pharmaceuticals, the study sponsor. Clint Dart completed work on this project as an employee of Health Decisions contracted by Sebela Pharmaceuticals, Inc. Presented as a poster at the Society of Family Planning Annual Meeting, October 19–21, 2019, Los Angeles, California.

Financial Disclosure David K. Turok is a consultant for Sebela Pharmaceuticals. Anita L. Nelson receives research support from Agile Pharmaceutical, Bayer Women's HealthCare, Merck, and Sebela Pharmaceuticals, Inc. She serves on speakers' bureaus for American Regency, Bayer Women's HealthCare, and Merck. She serves as a consultant and on advisory boards for Agile Pharmaceutical, AMAG, American Regency, Bayer Women's HealthCare, Merck, Sebela Pharmaceuticals, Inc, and TherapeuticsMD. Courtney A. Schreiber is a consultant for Danco Laboratories, LLC. The Department of Obstetrics and Gynecology, University of Pennsylvania, receives contraceptive research funding from Bayer, Daré, FHI360, Medicines360, and Sebela. The Department of Obstetrics and Gynecology at the University of Utah receives research funding from Bayer, Cooper Surgical, Medicines360, Merck, and Sebela Pharmaceuticals. Kevin Peters, Mary Jo Schreifels, and Bob Katz are employed by Sebela Pharmaceuticals, the study sponsor. Clint Dart completed work on this project as an employee of Health Decisions contracted by Sebela Pharmaceuticals, Inc. Presented as a poster at the Society of Family Planning Annual Meeting, October 19–21, 2019, Los Angeles, California. For a list of site principal investigators, sites, and institutions, see Appendix 1 online at http://links.lww.com/AOG/B781. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews are available at http://links.lww.com/AOG/B782. Figure No available caption

Racial and ethnic disparities in maternal health outcomes are a national public health crisis.1 Black non-Hispanic and indigenous women face greater risk of maternal morbidity2 and are two to four times more likely to die from pregnancy-related causes compared with white non-Hispanic women1; some groups of Asian and Hispanic women also face higher risks of maternal morbidity and mortality.2,3 In a recent report, the Centers for Disease Control and Prevention (CDC) identified lack of access to quality care as a key contributor to pregnancy-related deaths.4 Health insurance enrollment is a prerequisite for access to quality health care before, during, and after pregnancy.5 Limited evidence on racial–ethnic differences in perinatal insurance status suggests that significant disparities exist. In 2016, 7% of Hispanic women were uninsured at birth compared with only 3.5% of white women.6 There are also racial–ethnic differences in the type of coverage that pregnant women hold at delivery: a higher proportion of births to white women were paid by private insurance (63.3%) compared with black women (27.7%), indigenous women (19.7%) and Hispanic women (28.4%) in 2016.6 Finally, there is also evidence of racial–ethnic differences in perinatal insurance continuity: an analysis of data from 29 states in 2009 found that black non-Hispanic, Hispanic, and indigenous women were more likely to report unstable coverage from preconception to delivery.7

.7%) and Hispanic women (28.4%) in 2016.6 Finally, there is also evidence of racial–ethnic differences in perinatal insurance continuity: an analysis of data from 29 states in 2009 found that black non-Hispanic, Hispanic, and indigenous women were more likely to report unstable coverage from preconception to delivery.7 The objective of this cross-sectional analysis was to investigate the association between maternal race–ethnicity and insurance status before, during, and after pregnancy and the frequency of insurance disruptions across these time points. METHODS We used PRAMS (the Pregnancy Risk Surveillance and Monitoring System) survey data collected in 40 states and New York City from 2015 to 2017. The CDC Division of Reproductive Health administers PRAMS in collaboration with state health departments.8 From birth certificate data, participating states select a sample representative of all women who delivered a liveborn neonate. The survey collects data using a standardized mail and telephone survey of recently postpartum women, including demographic characteristics, insurance status, health care utilization, and health outcomes before, during, and after pregnancy. As in prior studies, we limited our sample to respondents with complete insurance information (93.9% of the total sample).7,9

mail and telephone survey of recently postpartum women, including demographic characteristics, insurance status, health care utilization, and health outcomes before, during, and after pregnancy. As in prior studies, we limited our sample to respondents with complete insurance information (93.9% of the total sample).7,9 We used PRAMS data to classify insurance status at three time points: 1) preconception, measured as insurance held in the month before conception; 2) delivery, measured as the primary payer for the childbirth episode; and 3) postpartum, measured as insurance held at the time of the postpartum survey. Nearly all women (97.1%) completed the survey 3 or more months after childbirth. Preconception and postpartum insurance variables were self-reported. For 88.9% of women, we coded delivery insurance as the primary payer for childbirth recorded by the delivery institution (eg, hospital) on the birth certificate. For the remaining 12.0% of women without payment information from the birth certificate, we used self-reported delivery insurance. For all women in the sample with both birth certificate and self-reported responses for delivery, 88.3% had concordant responses.

livery institution (eg, hospital) on the birth certificate. For the remaining 12.0% of women without payment information from the birth certificate, we used self-reported delivery insurance. For all women in the sample with both birth certificate and self-reported responses for delivery, 88.3% had concordant responses. We followed methods that the CDC previously used to hierarchically characterize insurance coverage at each time point into one of three categories: Medicaid, private, or uninsured.7 The Medicaid category included women who reported enrollment in Medicaid or a state-named Medicaid program. The private category included women who reported private insurance alone or in combination with Medicaid and women who reported TRICARE or other military insurance. The uninsured category included women who reported no insurance. Consistent with the U.S. Census,10 other national surveys,11 and previous analyses of the PRAMS,7 women who reported only Indian Health Service (IHS) were also classified as uninsured. This is because the IHS provides a system of health care delivery, largely primary care, not health insurance.10 The only exception was Alaska, where the IHS response option on the PRAMS included other state-specific programs, and thus was classified as Medicaid.7

Health Service (IHS) were also classified as uninsured. This is because the IHS provides a system of health care delivery, largely primary care, not health insurance.10 The only exception was Alaska, where the IHS response option on the PRAMS included other state-specific programs, and thus was classified as Medicaid.7 We also generated four measures of insurance continuity between each time point: 1) continuous insurance, defined as insured with no change in insurance status; 2) private–Medicaid discontinuity, defined as moving between Medicaid and private coverage; 3) uninsurance discontinuity, defined as moving between any type of insurance and uninsurance; and 4) continuous uninsurance, defined as being without insurance with no change in insurance status.

no change in insurance status; 2) private–Medicaid discontinuity, defined as moving between Medicaid and private coverage; 3) uninsurance discontinuity, defined as moving between any type of insurance and uninsurance; and 4) continuous uninsurance, defined as being without insurance with no change in insurance status. The PRAMS survey data include maternal race–ethnicity information from the birth certificate. These self-reported variables are collected using a maternal worksheet and entered into the birth certificate application by the delivery facility. PRAMS does not include information on maternal place of birth or immigration status; however, recent commentary has suggested that perinatal outcomes for Hispanic women should be reported separately by country of origin to account for the growing disparity in birth outcomes for U.S.-born and non–U.S.-born Hispanic women.12,13 Further, studies of uninsurance among reproductive-aged women have found that nearly 1 in 3 noncitizen women are uninsured, compared with 9% of U.S.-born citizens.14 Thus, we used primary language (English or Spanish) as a proxy for country of origin for Hispanic women. Language is one of the most frequently used, and strongest predictors of, acculturation,15 and has been used as a proxy for nativity or acculturation in other studies of health disparities among Hispanic populations in the United States.16 This resulted in seven distinct race–ethnicity categories: white non-Hispanic; black non-Hispanic; Hispanic Spanish-speaking; Hispanic English-speaking; indigenous (American Indian or Alaskan Native), Asian and Pacific Islander; and a composite of missing, unknown, or mixed race.

nic populations in the United States.16 This resulted in seven distinct race–ethnicity categories: white non-Hispanic; black non-Hispanic; Hispanic Spanish-speaking; Hispanic English-speaking; indigenous (American Indian or Alaskan Native), Asian and Pacific Islander; and a composite of missing, unknown, or mixed race. We calculated the unadjusted, weighted proportion of women with each insurance category for each perinatal time point, as well as the proportion of women within each category of insurance continuity from preconception to postpartum. We also examined unadjusted estimates of uninsurance for each time point by state of residence. We stratified all descriptive statistics by race–ethnicity.

insurance category for each perinatal time point, as well as the proportion of women within each category of insurance continuity from preconception to postpartum. We also examined unadjusted estimates of uninsurance for each time point by state of residence. We stratified all descriptive statistics by race–ethnicity. We used multivariable logistic regression models to estimate the association between uninsurance at each time point and race–ethnicity, adjusting for age, education, marital status, state of residence, and household income as a percentage of the federal poverty level. An interaction between household income and race–ethnicity was also included as racial–ethnic disparities in insurance status may vary by income level given differences in insurance options for women of different incomes. Categorical coverage of pregnancy under Medicaid covers women up to 200% of the federal poverty level in the median state; income-based Medicaid covers parents and caregivers up to 138% of the federal poverty level in the median state; Affordable Care Act Marketplace subsidies cover women from 100 to 400% of the federal poverty level in all states; and employer-sponsored coverage covers working, generally higher income, women. For interpretability, we reported the results of the logistic regression models as predicted probabilities. We also calculated the adjusted average marginal differences in the predicted probability of uninsurance between white non-Hispanic women (the reference category) and other racial–ethnic categories.

ncome, women. For interpretability, we reported the results of the logistic regression models as predicted probabilities. We also calculated the adjusted average marginal differences in the predicted probability of uninsurance between white non-Hispanic women (the reference category) and other racial–ethnic categories. We set a 95% CI a priori and conducted all analyses using Stata 15.1. Design features and survey weights provided by the CDC were applied with Stata's survey commands to account for the complex survey design. We calculated predicted probabilities using the Stata margins command with covariates held at observed sample values. The University of Michigan Institutional Review Board deemed this study of de-identified survey data exempt from review. RESULTS The sample included 107,921 women with complete insurance information. Table 1 presents the demographic characteristics of the sample. TABLE 1. Sample Characteristics by Race–Ethnicity

We set a 95% CI a priori and conducted all analyses using Stata 15.1. Design features and survey weights provided by the CDC were applied with Stata's survey commands to account for the complex survey design. We calculated predicted probabilities using the Stata margins command with covariates held at observed sample values. The University of Michigan Institutional Review Board deemed this study of de-identified survey data exempt from review. RESULTS The sample included 107,921 women with complete insurance information. Table 1 presents the demographic characteristics of the sample. TABLE 1. Sample Characteristics by Race–Ethnicity The unadjusted rate of uninsurance at preconception was 9.4% (95% CI 9.0–9.8) among white non-Hispanic women (Fig. 1; Appendix 1 [Appendix 1 is available online at http://links.lww.com/AOG/B772]). We found higher rates of preconception uninsurance among black non-Hispanic (12.8%, 95% CI 12.0–13.7), Hispanic English-speaking (22.3%, 95% CI 20.6–24.1), Hispanic Spanish-speaking (55.1%, 95% CI 53.0–57.1), and indigenous women (23.7%, 95% CI 21.3–26.2). At delivery, all race–ethnicities except Hispanic Spanish-speaking women (13.6%, 95% CI 12.1–15.1) had rates of uninsurance less than 5%. Patterns of uninsurance in the postpartum period were similar to preconception. Notably, half of Hispanic Spanish-speaking women were uninsured postpartum (53.4%, 95% CI 51.4–55.5).

At delivery, all race–ethnicities except Hispanic Spanish-speaking women (13.6%, 95% CI 12.1–15.1) had rates of uninsurance less than 5%. Patterns of uninsurance in the postpartum period were similar to preconception. Notably, half of Hispanic Spanish-speaking women were uninsured postpartum (53.4%, 95% CI 51.4–55.5). Fig. 1. Insurance status by time period and race–ethnicity. Data are weighted proportions; other, mixed, or unknown race–ethnicity not shown. Daw. Racial–Ethnic Disparities in Perinatal Insurance Coverage. Obstet Gynecol 2020. White non-Hispanic (75.3%, 95% CI 74.7–75.8) and Asian and Pacific Islander (75.5%, 95% CI 73.7–77.2) women had higher rates of continuous insurance compared with all other racial–ethnic categories (Fig. 2; Appendix 2 [Appendix 2 is available online at http://links.lww.com/AOG/B772]). Only 55.4% of black non-Hispanic women had continuous insurance (95% CI 54.2–56.6); 24.9% experienced a private–Medicaid discontinuity (95% CI 23.8–25.9), and 19.2% experienced an insurance–uninsurance discontinuity (95% CI 18.2–20.2). Approximately 50% of indigenous women had continuous insurance (95% CI 46.8–53.0); 17.3% had a private–Medicaid discontinuity (95% CI 15.0–19.8); and 31.5% has an uninsurance discontinuity (95% CI 28.9–34.2). Hispanic Spanish-speaking women had the lowest rate of continuous insurance (20.5%, 95% CI 18.9–22.2), a result of high rates of insurance–uninsurance discontinuity (59.0%, 95% CI 57.0–61.1) and continuous uninsurance (8.5%, 95% CI 7.3–9.9).

CI 15.0–19.8); and 31.5% has an uninsurance discontinuity (95% CI 28.9–34.2). Hispanic Spanish-speaking women had the lowest rate of continuous insurance (20.5%, 95% CI 18.9–22.2), a result of high rates of insurance–uninsurance discontinuity (59.0%, 95% CI 57.0–61.1) and continuous uninsurance (8.5%, 95% CI 7.3–9.9). Fig. 2. Insurance continuity from preconception to postpartum by race–ethnicity. Data are weighted proportions; other, mixed, or unknown race–ethnicity not shown. Daw. Racial–Ethnic Disparities in Perinatal Insurance Coverage. Obstet Gynecol 2020. Among black non-Hispanic women, the percentage with any period of uninsurance ranged from 6.7% (95% CI 2.7–15.9) in New Mexico to 47.0% in South Dakota (95% CI 36.6–57.7) (Appendix 3, available online at http://links.lww.com/AOG/B772). In 18 states, at least two thirds of Hispanic Spanish-Speaking women experienced uninsurance in the perinatal period. State variation was also wide among white non-Hispanic women, ranging from 2.6% (95% CI 1.8–3.9) in Massachusetts to 29.8% (95% CI 26.7–33.2) in Texas. We did not calculate state-specific estimates for indigenous or Asian-Pacific Islander women owing to small sample sizes.

perienced uninsurance in the perinatal period. State variation was also wide among white non-Hispanic women, ranging from 2.6% (95% CI 1.8–3.9) in Massachusetts to 29.8% (95% CI 26.7–33.2) in Texas. We did not calculate state-specific estimates for indigenous or Asian-Pacific Islander women owing to small sample sizes. In adjusted analyses, we found the widest racial disparities in uninsurance in the preconception and postpartum period for women in the lowest income brackets (less than 138% of the federal poverty level and 139–199% of the federal poverty level ) (Fig. 3; Appendix 4 [Appendix 4 is available online at http://links.lww.com/AOG/B772]). For women at less than 138% of the federal poverty level, the predicted probability of uninsurance was 31.7 percentage points (95% CI 28.5–34.9) and 31.4 percentage points (95% CI 28.1–34.7) higher among Hispanic Spanish-speaking women compared with white non-Hispanic women in the preconception and postpartum periods, respectively. Hispanic English-speaking women with incomes less than 138% of the federal poverty level also had a higher predicted probability of preconception uninsurance (7.9 percentage points higher; 95% CI 5.2–10.6) and postpartum uninsurance (9.0 percentage points higher; 95% CI 6.4–11.5) compared with white non-Hispanic women. For each time point, black non-Hispanic women had significantly lower or similar (no statistical difference) probabilities of uninsurance compared with white non-Hispanic women, despite having significantly higher unadjusted rates of preconception and postpartum uninsurance.

1.5) compared with white non-Hispanic women. For each time point, black non-Hispanic women had significantly lower or similar (no statistical difference) probabilities of uninsurance compared with white non-Hispanic women, despite having significantly higher unadjusted rates of preconception and postpartum uninsurance. Fig. 3. Adjusted predicted probability of uninsurance by time period, race–ethnicity, and household income. Preconception (A), delivery (B), and postpartum (C). Data are predicted probabilities calculated based on a logistic regression model adjusted for age, education, marital status, state of residence, household income, and an interaction term between household income and race–ethnicity; all covariates held at sample observed values. Bars represent 95% CIs. Asian or Pacific Islander and other, mixed, or unknown race–ethnicity are not shown. Daw. Racial–Ethnic Disparities in Perinatal Insurance Coverage. Obstet Gynecol 2020. In general, the magnitude of racial–ethnic differences decreased with increasing household income. For the highest income bracket (400% of the federal poverty level or higher), we found higher uninsurance rates for indigenous women at each time point. We did not find statistically significant racial–ethnic differences in uninsurance for black non-Hispanic or Hispanic women in the highest income bracket.

hold income. For the highest income bracket (400% of the federal poverty level or higher), we found higher uninsurance rates for indigenous women at each time point. We did not find statistically significant racial–ethnic differences in uninsurance for black non-Hispanic or Hispanic women in the highest income bracket. DISCUSSION Using multistate data from 2015 to 2017, we found wide racial–ethnic disparities in insurance status and continuity of insurance coverage across the preconception, pregnancy, and postpartum periods. In the general adult and pediatric populations, uninsurance and changes between types of insurance are associated with disruptions in physician care, increased emergency department use, worsened self-reported quality of care and poor health status.17–19 Racial–ethnic disparities in insurance stability, thus, may contribute to disparities in the receipt and continuity of care across the perinatal period.

of insurance are associated with disruptions in physician care, increased emergency department use, worsened self-reported quality of care and poor health status.17–19 Racial–ethnic disparities in insurance stability, thus, may contribute to disparities in the receipt and continuity of care across the perinatal period. Nearly half of all black non-Hispanic women had discontinuous insurance from preconception to postpartum and one in four experienced a private–Medicaid discontinuity. However, within income groups, we found that the adjusted predicted probability of preconception and postpartum uninsurance was lower or nonsignificant for black non-Hispanic compared with white non-Hispanic women. This suggests that the population-level black-white disparity in perinatal uninsurance is largely explained by lower average household incomes among black non-Hispanic women (50.4% had household incomes less than 138% of the federal poverty level in our sample) and, in turn, higher rates of Medicaid coverage during pregnancy, which is a less stable source of coverage (65.8% compared with 29.9% for white non-Hispanic women in our sample).

age household incomes among black non-Hispanic women (50.4% had household incomes less than 138% of the federal poverty level in our sample) and, in turn, higher rates of Medicaid coverage during pregnancy, which is a less stable source of coverage (65.8% compared with 29.9% for white non-Hispanic women in our sample). Spanish-speaking Hispanic women had the highest rates of discontinuous insurance, and nearly one in 10 were continuously uninsured from preconception to postpartum. This is consistent with prior research that identified non-English language as a predictor of postpartum uninsurance.20 This finding is likely to partly reflect the limited insurance options available to immigrant women. Legal immigrants, with the exception of refugees and asylees, are subject to a 5-year waiting period for Medicaid eligibility. Although marketplace subsidies are available to immigrant women with incomes between 100% and 400% of the federal poverty level, more than half of Hispanic Spanish-speaking women in our sample had incomes less than 138% of the federal poverty level. This group is likely also partially comprised of undocumented women, who account for nearly 7% of births in the United States21 and are four times more likely than U.S. citizens to be uninsured,22 a result of more limited access to employer-sponsored coverage and restrictions on eligibility for public programs such as Medicaid.

p is likely also partially comprised of undocumented women, who account for nearly 7% of births in the United States21 and are four times more likely than U.S. citizens to be uninsured,22 a result of more limited access to employer-sponsored coverage and restrictions on eligibility for public programs such as Medicaid. Finally, we found that half of indigenous women experienced discontinuous insurance from preconception to postpartum (50.1%). This heterogeneous group—which comprise women from tribal nations with varied cultures in diverse communities—is often not analyzed in studies of pregnancy-related outcomes; however, the limited studies of indigenous women have found higher rates of no or inadequate prenatal care23,24 and higher infant23 and maternal mortality1 rates compared with nonindigenous women.1,23,24 In this analysis, indigenous women had the highest rate of Medicaid coverage at delivery compared with any other racial–ethnic group. Thus, ensuring Medicaid stability before and after pregnancy may be critical for coverage continuity and access to care in this population.

ates compared with nonindigenous women.1,23,24 In this analysis, indigenous women had the highest rate of Medicaid coverage at delivery compared with any other racial–ethnic group. Thus, ensuring Medicaid stability before and after pregnancy may be critical for coverage continuity and access to care in this population. This study has several limitations. First, the PRAMS survey does not contain the detail necessary to examine transitions in continuity across private insurance plans (private–private discontinuity) or Medicaid programs (Medicaid–Medicaid discontinuity). Thus, estimates of insurance disruptions are likely conservative. Second, we are not able to examine within-plan changes that could affect the continuity of care, for example, if a woman's provider is removed from her insurer’s network over the course of pregnancy. Third, the results may not generalize to the 10 states not included in the survey, namely, Arizona, California, Florida, Idaho, Indiana, Minnesota, Mississippi, Nevada, North Carolina, and South Carolina. However, the included states represent a broad range of geographies and racial–ethnic compositions. The median income thresholds for Medicaid eligibility in 2019 are also similar in included and excluded states (138% of the federal poverty level and 102% of the federal poverty level for low-income parents, respectively, and 206% and 199% for pregnant women, respectively).25 Fourth, respondents self-report insurance status at the preconception and postpartum time points, which may be subject to recall and reporting bias. However, we would expect any reporting bias to be constant within individuals over the perinatal period, which would not affect measures of insurance changes. Finally, race–ethnicity information on the birth certificate could be subject to error or misreporting. Previous validation studies comparing race–ethnicity information from birth certificates to other sources have found high reliability for white, black, and Hispanic mothers, but lower specificity for indigenous populations.26–28 This could result in an underreporting of indigenous mothers in our sample.

r misreporting. Previous validation studies comparing race–ethnicity information from birth certificates to other sources have found high reliability for white, black, and Hispanic mothers, but lower specificity for indigenous populations.26–28 This could result in an underreporting of indigenous mothers in our sample. The American College of Obstetricians and Gynecologists29 and the American Medical Association30 have recently called for interventions to mitigate perinatal insurance disruptions. One proposal, under consideration at the federal level31 and in several states,32 is the extension of pregnancy Medicaid coverage from 60 days to one year postpartum.32–35 Our findings suggest that this policy change has the potential to reduce racial–ethnic disparities in insurance disruptions experienced by Hispanic, black non-Hispanic, and indigenous women who are disproportionally enrolled in pregnancy Medicaid and experience higher rates of uninsurance in the postpartum period. However, proposals to extend postpartum Medicaid do not address the disparities in uninsurance that we observed in the preconception period, which were similar in magnitude to those after birth. Reducing disparities in preconception coverage is also an important target for policy change, particularly as the prevalence of chronic conditions is rising among women giving birth in the United States.36 Many risk factors for adverse maternal and infant outcomes are best addressed before pregnancy, including chronic conditions, health behaviors, and exposures.37

is also an important target for policy change, particularly as the prevalence of chronic conditions is rising among women giving birth in the United States.36 Many risk factors for adverse maternal and infant outcomes are best addressed before pregnancy, including chronic conditions, health behaviors, and exposures.37 In this analysis of data from 40 states, we found wide racial–ethnic disparities in perinatal insurance coverage and in continuity of coverage. Policies to improve continuity of coverage, especially for low-income Medicaid beneficiaries, are needed to reduce racial–ethnic disparities in perinatal uninsurance. Supported by a grant awarded to Drs. Admon (PI), Dalton (Co-I), and Winkelman (Co-I) from the Health Resources and Services Administration (HRSA) of the Department of Health and Human Services (HHS) as part of an award totaling $100,000. The contents of the manuscript are those of the authors and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS, or the federal government. Jamie Daw's work on this project was supported by a Calderone Junior Faculty Prize. The funders had no role in the study design, writing of the report, or the decision to submit the article for publication.

do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS, or the federal government. Jamie Daw's work on this project was supported by a Calderone Junior Faculty Prize. The funders had no role in the study design, writing of the report, or the decision to submit the article for publication. Financial Disclosure Vanessa Dalton received grant funding from the Agency for Healthcare Research (ARHQ) and Quality, National Institutes for Health (NIH), American Association of Obstetricians and Gynecologists Foundation, the Laura and John Arnold Foundation, National Institute for Reproductive Health and Blue Cross Blue Shield Foundation. She is also a paid contributing editor for the Medical Letter and an author for UpToDate. She has also serviced as a paid expert witness for Bayer, a consultant for Bind and has participated on study sections for the NIH and ARHQ. The other authors did not report any potential conflicts of interest. The authors thank all PRAMS study participants and members of the PRAMS Working Group. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B773.

Postpartum hemorrhage is one of the major complications in obstetrics and one of the leading causes of maternal mortality worldwide, especially in developing countries, where it accounts for 25% of maternal deaths.1,2 The use of intravenous tranexamic acid is recommended for the treatment of postpartum hemorrhage if oxytocin and other uterotonics fail to stop bleeding or if it is thought that the bleeding may be partly due to trauma.3 Intravenous administration of tranexamic has been shown to be safe and effective in trauma and surgery, with no apparent increase in vascular occlusive events.4 One of the main barriers to rapid treatment with tranexamic acid is the need for intravenous injection.5 The effective plasma concentration of tranexamic acid that has been shown to cause significant inhibition of systemic fibrinolysis in adults is 5–10 micrograms/mL, with near maximal inhibition between 10 and 15 micrograms/mL.6 At a minimum concentration of 5 micrograms/mL, tranexamic acid has been shown to increase the clot lysis time from 6 to 16 minutes.7 Our study was designed to investigate the pharmacokinetics of oral tranexamic acid, a key step toward considering its use, especially in low-resourced countries, in an oral form for treatment or prophylaxis of postpartum hemorrhage.

The effective plasma concentration of tranexamic acid that has been shown to cause significant inhibition of systemic fibrinolysis in adults is 5–10 micrograms/mL, with near maximal inhibition between 10 and 15 micrograms/mL.6 At a minimum concentration of 5 micrograms/mL, tranexamic acid has been shown to increase the clot lysis time from 6 to 16 minutes.7 Our study was designed to investigate the pharmacokinetics of oral tranexamic acid, a key step toward considering its use, especially in low-resourced countries, in an oral form for treatment or prophylaxis of postpartum hemorrhage. METHODS The study was conducted at the University Obstetric Unit, Teaching Hospital—Jaffna, after obtaining ethical approval from Ethics Review Committee of the Faculty of Medicine, University of Jaffna. All procedures performed were in accordance with good clinical practice. The study cohort comprised 12 healthy postpartum women aged 24–33 years who delivered singleton neonates vaginally.8 Recruited participants were screened for contraindications to tranexamic acid: past and current history of intravascular clotting, hemorrhagic events, and procoagulant disorders. None of the pregnancies had been complicated by pregnancy-related medical disorders, and patients with any preexisting comorbidities were not studied. In addition to history and examination, electrocardiogram, liver function and renal function tests, full blood count, and coagulation profile were performed during the screening process. Written informed consent was obtained from all participants.

METHODS The study was conducted at the University Obstetric Unit, Teaching Hospital—Jaffna, after obtaining ethical approval from Ethics Review Committee of the Faculty of Medicine, University of Jaffna. All procedures performed were in accordance with good clinical practice. The study cohort comprised 12 healthy postpartum women aged 24–33 years who delivered singleton neonates vaginally.8 Recruited participants were screened for contraindications to tranexamic acid: past and current history of intravascular clotting, hemorrhagic events, and procoagulant disorders. None of the pregnancies had been complicated by pregnancy-related medical disorders, and patients with any preexisting comorbidities were not studied. In addition to history and examination, electrocardiogram, liver function and renal function tests, full blood count, and coagulation profile were performed during the screening process. Written informed consent was obtained from all participants. All participants underwent routine active management of the third stage, with intravenous oxytocin 10 international units after delivery of the neonate, delayed cord clamping, and controlled cord traction to deliver the placenta. Blood loss was estimated by weighing swabs and blood collected in a waterproof drape on the labor ward.

nts underwent routine active management of the third stage, with intravenous oxytocin 10 international units after delivery of the neonate, delayed cord clamping, and controlled cord traction to deliver the placenta. Blood loss was estimated by weighing swabs and blood collected in a waterproof drape on the labor ward. An arterial line was established to obtain blood; 1 hour after delivery, all study participants were administered the same preparation of 2 g of immediate-release tranexamic acid orally with 50 mL of water, which corresponds in strength to 1 g of intravenous tranexamic acid used to treat postpartum haemorrhage.5,9 The tranexamic acid preparation was supplied by the Teaching Hospital—Jaffna, and all participants were monitored for 24 hours for adverse effects. Blood samples (1.8 mL) were collected in tubes containing 0.2 mL of 3% sodium citrate at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after administration of tranexamic acid and were immediately transported to the Biochemistry Laboratory, Faculty of Medicine, University of Jaffna, where the tranexamic acid assay was carried out. Within 1 hour of collection, samples were centrifuged at 2,000g for 15 minutes at room temperature, and supernatants were stored at −70°C until analysis.

amic acid and were immediately transported to the Biochemistry Laboratory, Faculty of Medicine, University of Jaffna, where the tranexamic acid assay was carried out. Within 1 hour of collection, samples were centrifuged at 2,000g for 15 minutes at room temperature, and supernatants were stored at −70°C until analysis. During the analysis, samples were pretreated with leucine dehydrogenase, and plasma tranexamic acid concentration was determined by Shimadzu 10Avp high-performance liquid chromatography using ortho-phthalaldehyde derivatization as previously described.10–13 Samples were analyzed on an Ultra C18 5 micrometer 4.6×150-mm column, and the tranexamic acid derivative was detected fluorometrically (Fluorometer Shimadzu RF-10Axl). Samples for quality control were prepared with a known quantity of standard tranexamic acid added to analyte-free human plasma. Peak area for the high-performance liquid chromatography assay was well correlated for plasma concentration from 0 micrograms/mL to 15 micrograms/mL. The accuracy of the assay method was between 97% and 99%. Descriptive statistics were calculated from plasma concentration compared with time data for single-dose pharmacokinetic parameters: maximum observed plasma concentration and time to maximum plasma concentration and their SDs using SPSS Statistics 23.

ograms/mL. The accuracy of the assay method was between 97% and 99%. Descriptive statistics were calculated from plasma concentration compared with time data for single-dose pharmacokinetic parameters: maximum observed plasma concentration and time to maximum plasma concentration and their SDs using SPSS Statistics 23. The linear trapezoidal method was used to calculate the area under the curve for drug concentration. Geometric means were calculated to estimate the time pharmacologically effective drug concentrations were reached and the duration for which the pharmacologically effective concentrations lasted. Elimination half-life for tranexamic acid was calculated as a parameter describing the linear terminal slope of the log concentrations. RESULTS A total of 12 postpartum women participated in this study. The mean age of the participants was 29 years, with a range of 24–33 (Table 1). None of the participants developed any adverse effects during the observational period. Among the 12 participants, the mean maximum observed plasma concentration was 10.06 micrograms/mL (range 8.56–12.22 micrograms/mL). The maximum observed plasma concentration was greater than 10 micrograms/mL in eight participants. The mean time to maximum plasma concentration was 2.92 hours (range 2.5–3.5 hours) (Fig. 1 and Box 1). Table 1. Demographics of the Participants

RESULTS A total of 12 postpartum women participated in this study. The mean age of the participants was 29 years, with a range of 24–33 (Table 1). None of the participants developed any adverse effects during the observational period. Among the 12 participants, the mean maximum observed plasma concentration was 10.06 micrograms/mL (range 8.56–12.22 micrograms/mL). The maximum observed plasma concentration was greater than 10 micrograms/mL in eight participants. The mean time to maximum plasma concentration was 2.92 hours (range 2.5–3.5 hours) (Fig. 1 and Box 1). Table 1. Demographics of the Participants Fig. 1. Mean plasma concentration of tranexamic acid in micrograms/mL vs time curve after a single dose of 2 g of oral tranexamic acid in postpartum women. Error bars represent the range. Muhunthan. Oral Tranexamic Acid in Postpartum Women. Obstet Gynecol 2020. Box 1. Pharmacokinetic Values Cmax: 10.06 micrograms/mL Range: 8.56–12.22 micrograms/mL Tmax: 2.92 h Range: 2.5–3.5 h AUC0–12: 49.16 micrograms.h/mL Range: 43.75–52.69 micrograms.h/mL % deviation from the mean: 92.5–111% T1/2: 1.65 h Mean time course of concentration 5 micrograms/mL or greater (h) Initial: 0.87 Final: 6.73 Duration: 5.86 Cmax, maximum observed plasma concentration; Tmax, time to maximum plasma concentration; AUC0–12, area under the curve for drug concentration; T1/2, half-life.

Range: 43.75–52.69 micrograms.h/mL % deviation from the mean: 92.5–111% T1/2: 1.65 h Mean time course of concentration 5 micrograms/mL or greater (h) Initial: 0.87 Final: 6.73 Duration: 5.86 Cmax, maximum observed plasma concentration; Tmax, time to maximum plasma concentration; AUC0–12, area under the curve for drug concentration; T1/2, half-life. Because the effective plasma concentration of tranexamic acid that has been shown to cause significant inhibition of systemic fibrinolysis in adults is 5–10 micrograms/mL, we have presented the time course of plasma concentrations of tranexamic acid of 5 micrograms/mL and greater.6,7 After administration, the mean time taken to reach the plasma concentration of 5 micrograms/mL was 0.87 hours and lasted until 6.73 hours after the administration of the drug. The duration for which plasma tranexamic acid concentration remained greater than 5 micrograms/mL was 5.86 hours. Half-life was 1.65 hours. Area under the curve for drug concentration was 49.16 micrograms.h/mL, with a range of 43.75–54.69 micrograms.h/mL between individual patients, with percentage deviations of 92.5–111%.

duration for which plasma tranexamic acid concentration remained greater than 5 micrograms/mL was 5.86 hours. Half-life was 1.65 hours. Area under the curve for drug concentration was 49.16 micrograms.h/mL, with a range of 43.75–54.69 micrograms.h/mL between individual patients, with percentage deviations of 92.5–111%. DISCUSSION We found that pharmacologically effective concentrations could be achieved within 1 hour of administration of 2 g oral tranexamic acid in postpartum women. Being able to achieve pharmacologically effective concentrations of 5 micrograms/mL and greater in postpartum women with the above oral dose within 1 hour was encouraging, because the World Health Organization guideline recommends the use of tranexamic acid within a 3-hour of window from birth.4 Though not comparable with intravenous administration of tranexamic acid, where effective plasma concentration is reached immediately, orally administered tranexamic acid shows potential to be effective in the management of postpartum hemorrhage. This effective concentration is supported by a recent meta-analysis that concluded that the plasma tranexamic acid concentrations in adults from 10 micrograms/mL to 15 micrograms/mL provide near maximal inhibition of fibrinolysis, and concentrations from 5 micrograms/mL to 10 micrograms/mL provide significant inhibition of systemic fibrinolysis in adults.6,7 Further, this effective concentration lasted for almost 6 hours.

amic acid concentrations in adults from 10 micrograms/mL to 15 micrograms/mL provide near maximal inhibition of fibrinolysis, and concentrations from 5 micrograms/mL to 10 micrograms/mL provide significant inhibition of systemic fibrinolysis in adults.6,7 Further, this effective concentration lasted for almost 6 hours. The maximum observed plasma concentration of 10.06±0.79 micrograms/mL is lower than the previously reported plasma concentrations of 13–14.8 micrograms/mL after a single oral-dose regimen in nonpregnant patients.9,14 This may be a result of the higher volume of distribution in postpartum women. The elimination half-life of 1.65 hours is shorter than previously reported values of 2–3 hours for nonpregnant patients.15 Because 95% of tranexamic acid is excreted by the kidneys, an increase of glomerular filtration rate by 50% during pregnancy may explain this observation.9,16 The main limitations of our study were its small sample size and relatively low body mass index of the study participants. Given the promising pharmacokinetic properties, we recommend additional studies with larger sample sizes to investigate the potential of oral tranexamic acid for the treatment or prophylaxis of postpartum hemorrhage. Supported by a university research grant (Ref: URG/2014/07) from the University of Jaffna, Sri Lanka. Financial Disclosure The authors did not report any potential conflicts of interest.

Given the promising pharmacokinetic properties, we recommend additional studies with larger sample sizes to investigate the potential of oral tranexamic acid for the treatment or prophylaxis of postpartum hemorrhage. Supported by a university research grant (Ref: URG/2014/07) from the University of Jaffna, Sri Lanka. Financial Disclosure The authors did not report any potential conflicts of interest. The authors thank the obstetric registrars Mahendran Thanuya and Rajendraseelan Thuvarathipan, from Teaching Hospital—Jaffna, for assisting us in blood sample collection and monitoring participants for adverse effects; laboratory technicians Kirubahary Sritharan, Mahalingam Sutharsan, Kulasingam Thayananthan, and Thayalini Sukirthan for performing all the laboratory blood assays; and Nagaraja Varathan from the Department of Mathematics and Statistics for their help in the statistical and mathematical calculations. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B775.

The incidence of cervical adenocarcinoma in situ (AIS) is rising, and though an increase in the number of diagnoses of in situ squamous cell carcinoma has been associated with a concomitant decrease in the incidence of invasive squamous cell carcinoma owing to earlier diagnosis and treatment, a similar decrease in subsequent invasive adenocarcinoma has not occurred.1 This suggests delayed diagnosis of AIS, a shorter interval of disease progression from clinically evident AIS to invasive adenocarcinoma, or both. Although other cervical cancer screening management guidelines provide specific algorithms for initial screening and management,2–5 they do not provide detailed recommendations for management and surveillance of AIS, especially when conservative management is desired. The purpose of these guidelines is to provide clinicians with information and recommendations for diagnosis and management of cervical AIS. BACKGROUND Epidemiology The incidence of cervical AIS has increased over the past few decades, especially among individuals aged 30–40 years.1,6 The mean age at diagnosis is 35–37 years,6,7 and the current incidence rate is approximately 6.6 per 100,000 persons, increasing to 11.2 per 100,000 persons at the peak age of 30–39 years.6 The average interval between a diagnosis of clinically detectable AIS and early invasive cancer is at least 5 years.8 Additionally, approximately 55% of patients with AIS have a coexisting squamous lesion.7

is approximately 6.6 per 100,000 persons, increasing to 11.2 per 100,000 persons at the peak age of 30–39 years.6 The average interval between a diagnosis of clinically detectable AIS and early invasive cancer is at least 5 years.8 Additionally, approximately 55% of patients with AIS have a coexisting squamous lesion.7 Etiology and Risk Factors Human papillomavirus (HPV) infection, particularly infection with HPV-16, -18, or both, is the primary risk factor for AIS and associated cervical cancer. Although HPV-18 is associated with only 8% of all high-grade dysplasia (cervical intraepithelial neoplasia [CIN] 2 or worse and AIS) diagnoses (compared with 46–58% for HPV-16), it is associated with 38–50% of AIS diagnoses and 50% of all invasive cancer diagnoses (squamous cell carcinoma plus adenocarcinoma).6,9–11 Therefore, factors that inhibit suppression of HPV are additional risk factors for AIS, such as immunosuppression (eg, rheumatologic disease on two or more immunosuppressants, human immunodeficiency virus [HIV], solid organ transplant) and smoking. Some studies also suggest oral contraceptive pill use as a risk factor for AIS.12 Conversely, vaccination against HPV is anticipated to be protective, with early evidence of this demonstrated by a decrease in incidence rate of AIS in the first 8 years of the HPV Vaccine Impact Monitoring Project among women aged 21–24 years, despite stable incidence rates in women aged 25–29 years and increases in women aged 30–39 years.6

against HPV is anticipated to be protective, with early evidence of this demonstrated by a decrease in incidence rate of AIS in the first 8 years of the HPV Vaccine Impact Monitoring Project among women aged 21–24 years, despite stable incidence rates in women aged 25–29 years and increases in women aged 30–39 years.6 GUIDELINE QUESTIONS This clinical practice guideline addresses the following clinical questions: 1) What clinical evaluation and diagnostic tests should be performed for individuals with suspected cervical AIS? 2) How should diagnostic or therapeutic excisional procedures be performed? 3) What are the recommendations for patients undergoing definitive surgical management with positive compared with negative excisional biopsy margins? 4) Which patient and disease criteria should be used to identify individuals who are eligible for fertility-sparing therapy? 5) What is the recommended surveillance after treatment of AIS? 6) How should AIS be managed during pregnancy? (Fig. 1). Fig. 1. Summary of adenocarcinoma in situ management recommendations. *Cold knife conization or loop electrosurgical excision procedure acceptable provided an adequate specimen can be obtained: 1) intact, nonfragmented (top-hat serial endocervical excisions unacceptable); 2) length of specimen must be at least 10 mm. HPV, human papillomavirus. Teoh. Adenocarcinoma-in-Situ Recommendations. Obstet Gynecol 2020.

or loop electrosurgical excision procedure acceptable provided an adequate specimen can be obtained: 1) intact, nonfragmented (top-hat serial endocervical excisions unacceptable); 2) length of specimen must be at least 10 mm. HPV, human papillomavirus. Teoh. Adenocarcinoma-in-Situ Recommendations. Obstet Gynecol 2020. METHODS Guideline Development Process The authors reviewed the available evidence, contributed to the development of the guidelines, provided critical review of the guidelines, and finalized the guideline recommendations. The guidelines were also reviewed and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Education Committee, SGO Publications Committee, and the SGO board members before submission for publication. The recommendations were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current cervical cancer screening and dysplasia management guidelines, observational studies, and meta-analyses; phase III randomized clinical trials for management of AIS do not currently exist. A list of the MeSH terms searched are included in Appendix 1, available online at http://links.lww.com/AOG/B790.

idence from current cervical cancer screening and dysplasia management guidelines, observational studies, and meta-analyses; phase III randomized clinical trials for management of AIS do not currently exist. A list of the MeSH terms searched are included in Appendix 1, available online at http://links.lww.com/AOG/B790. The terminology used in these guidelines was adopted from the American Society for Colposcopy and Cervical Pathology (ASCCP) management guidelines3 using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses. Similar to the ASCCP guidelines, the terms “recommended,” “preferred,” “acceptable,” “unacceptable,” and “not recommended” are used to describe interventions. Table 1. Rating the Recommendations CLINICAL CONSIDERATIONS AND RECOMMENDATIONS Clinical Question 1 What clinical evaluation and diagnostic tests should be performed for patients with suspected cervical AIS?

The terminology used in these guidelines was adopted from the American Society for Colposcopy and Cervical Pathology (ASCCP) management guidelines3 using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses. Similar to the ASCCP guidelines, the terms “recommended,” “preferred,” “acceptable,” “unacceptable,” and “not recommended” are used to describe interventions. Table 1. Rating the Recommendations CLINICAL CONSIDERATIONS AND RECOMMENDATIONS Clinical Question 1 What clinical evaluation and diagnostic tests should be performed for patients with suspected cervical AIS? Recommendation 1.1 Evaluation of abnormal cytology or a positive HPV test result or both is recommended per the ASCCP Risk-Based Management Consensus Guidelines (BII), and colposcopic examination should be performed using the ASCCP colposcopy standards (Table 2).13 Atypical glandular cells (AGC) and HPV-16 and -18 are associated with AIS and should be evaluated with colposcopy, endocervical sampling, and endometrial biopsy, as recommended by the ASCCP Risk-Based Management Consensus Guidelines (http://www.asccp.org/consensus-guidelines). Given the association of HPV-18 with AIS, endocervical sampling in the setting of a positive HPV-18 test result regardless of colposcopy findings is acceptable (CIII). Table 2. ASCCP Risk-Based Colposcopy Standards and Atypical Glandular Cells Evaluation

Recommendation 1.1 Evaluation of abnormal cytology or a positive HPV test result or both is recommended per the ASCCP Risk-Based Management Consensus Guidelines (BII), and colposcopic examination should be performed using the ASCCP colposcopy standards (Table 2).13 Atypical glandular cells (AGC) and HPV-16 and -18 are associated with AIS and should be evaluated with colposcopy, endocervical sampling, and endometrial biopsy, as recommended by the ASCCP Risk-Based Management Consensus Guidelines (http://www.asccp.org/consensus-guidelines). Given the association of HPV-18 with AIS, endocervical sampling in the setting of a positive HPV-18 test result regardless of colposcopy findings is acceptable (CIII). Table 2. ASCCP Risk-Based Colposcopy Standards and Atypical Glandular Cells Evaluation Recommendation 1.2 A diagnostic excisional procedure is recommended for all patients with AIS diagnosed on cervical biopsy, as well as all patients whose cervical biopsy and endocervical curettage results are negative in the setting of cytology results showing AIS or AGC-favor neoplasia. For persistent AGC-not otherwise specified, refer to ASCCP Risk-Based Management Consensus Guidelines. A diagnostic excisional procedure is recommended to rule-out an invasive adenocarcinoma, even when definitive hysterectomy is planned (AII).

ative in the setting of cytology results showing AIS or AGC-favor neoplasia. For persistent AGC-not otherwise specified, refer to ASCCP Risk-Based Management Consensus Guidelines. A diagnostic excisional procedure is recommended to rule-out an invasive adenocarcinoma, even when definitive hysterectomy is planned (AII). Literature Review Nearly all AIS lesions are asymptomatic and thus are diagnosed during cervical cancer screening examinations. A cytologic diagnosis of AGC results in a diagnosis of AIS in 3–4% of cases and invasive cervical adenocarcinoma in 2%.14 However, any degree of cytologic atypia can be indicative of AIS, and one study showed AIS diagnosis is most often preceded by a low-grade cytologic abnormality (atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion).6 Moreover, because these lesions originate from inside the endocervix, the abnormal cells are often missed on cytology.3 The ASCCP Risk-Based Management Consensus Guidelines provide individualized recommendations for evaluation of abnormal cytologic or positive HPV test results or both (http://www.asccp.org/consensus-guidelines). Although not specified by the ASCCP management guidelines, given the high rate of HPV-18–positive AIS, endocervical sampling for any patient who tests positive for HPV-18 is acceptable. An endocervical sample can be obtained using an endocervical curette, which may provide cervical stroma to aid in grading of dysplasia, or an endocervical brush, which is less prone to insufficient sampling and may have higher sensitivity.3,15,16

cal sampling for any patient who tests positive for HPV-18 is acceptable. An endocervical sample can be obtained using an endocervical curette, which may provide cervical stroma to aid in grading of dysplasia, or an endocervical brush, which is less prone to insufficient sampling and may have higher sensitivity.3,15,16 Adenocarcinoma in situ frequently coexists with squamous dysplasia. When concomitant AIS and CIN are diagnosed, management should proceed per the recommendations for AIS. When AIS is diagnosed on cervical biopsy, approximately 15% will be associated with an invasive adenocarcinoma.17 Therefore, the next step in evaluation is a diagnostic excisional procedure to confirm the diagnosis, assess the extent of disease, evaluate for coexisting squamous lesions, and exclude invasive adenocarcinoma before definitive management. A diagnostic excisional procedure is also recommended when cervical biopsies and endocervical curettage are negative in the setting of cytology results of AIS, AGC-favor neoplasia, or persistent AGC-not otherwise specified. A diagnostic excisional procedure before definitive management with hysterectomy is recommended to evaluate for invasive adenocarcinoma, which may require radical hysterectomy; if negative margins are not achieved on the first excision specimen, a second excisional procedure is recommended before hysterectomy to exclude an invasive cancer unless this cannot be performed safely. Clinical Question 2 How should diagnostic or therapeutic excisional procedures be performed?

Adenocarcinoma in situ frequently coexists with squamous dysplasia. When concomitant AIS and CIN are diagnosed, management should proceed per the recommendations for AIS. When AIS is diagnosed on cervical biopsy, approximately 15% will be associated with an invasive adenocarcinoma.17 Therefore, the next step in evaluation is a diagnostic excisional procedure to confirm the diagnosis, assess the extent of disease, evaluate for coexisting squamous lesions, and exclude invasive adenocarcinoma before definitive management. A diagnostic excisional procedure is also recommended when cervical biopsies and endocervical curettage are negative in the setting of cytology results of AIS, AGC-favor neoplasia, or persistent AGC-not otherwise specified. A diagnostic excisional procedure before definitive management with hysterectomy is recommended to evaluate for invasive adenocarcinoma, which may require radical hysterectomy; if negative margins are not achieved on the first excision specimen, a second excisional procedure is recommended before hysterectomy to exclude an invasive cancer unless this cannot be performed safely. Clinical Question 2 How should diagnostic or therapeutic excisional procedures be performed? Recommendation 2.1 Excisional procedures optimally result in removal of an intact specimen to facilitate accurate interpretation of margin status. Thus, excision by cold knife conization is preferred unless the surgeon is able to consistently remove an intact (“top hat” endocervical excision is unacceptable) specimen of adequate length and width (AII).

edures optimally result in removal of an intact specimen to facilitate accurate interpretation of margin status. Thus, excision by cold knife conization is preferred unless the surgeon is able to consistently remove an intact (“top hat” endocervical excision is unacceptable) specimen of adequate length and width (AII). Recommendation 2.2 Length of the excisional specimen of at least 10 mm is preferred and can be increased to 18–20 mm in patients who have completed childbearing (BII). Endocervical sampling above the excisional bed to evaluate for residual disease is preferred (CIII).

edures optimally result in removal of an intact specimen to facilitate accurate interpretation of margin status. Thus, excision by cold knife conization is preferred unless the surgeon is able to consistently remove an intact (“top hat” endocervical excision is unacceptable) specimen of adequate length and width (AII). Recommendation 2.2 Length of the excisional specimen of at least 10 mm is preferred and can be increased to 18–20 mm in patients who have completed childbearing (BII). Endocervical sampling above the excisional bed to evaluate for residual disease is preferred (CIII). Literature Review Traditionally, cold knife conization has been recommended over loop electrosurgical excision procedures (LEEP) owing to concern that cautery artifact could obscure the diagnosis. However, a meta-analysis of retrospective studies showed no difference in residual disease (LEEP 9.1% vs cold knife conization 11%) or recurrence risk (LEEP 7.0% vs cold knife conization 5.6%) by excisional method despite a higher risk of positive margins with LEEP (44%) compared with cold knife conization (29%; relative risk 1.55, 95% CI 1.34–1.80).18 Thus, the ASCCP management guidelines allow diagnostic excision using any modality, but it is imperative that, “care must be taken to keep the specimen intact and margins interpretable, avoiding fragmentation of the specimen, including ‘top-hat’ serial endocervical excisions.”3 Therefore, except in the hands of a highly skilled LEEP surgeon who is able to obtain an adequate specimen without fragmentation (ie, one intact specimen removed with one pass of the loop; “top hat” excision is unacceptable), excision by cold knife conization is preferred because there is a higher likelihood of the specimen being removed in one piece with adequate depth and width. Length of the conization specimen should be at least 10 mm and can increase to 18–20 mm for patients who have completed childbearing.19,20 For surgeons who are not able to consistently obtain intact excisional specimens with adequate length, referral for the initial excisional procedure to a gynecologic oncologist or other surgeon who specializes in the management of cervical dysplasia is preferred. Data on utility of sampling above the excisional bed are conflicting, but endocervical sampling with endocervical curettage or endocervical brushing above the excisional bed to evaluate for residual disease is preferred owing to the frequent location of AIS within the endocervical canal, which makes determining the extent of the lesion more difficult, and the potential for multifocal disease.7,21,22

ical sampling with endocervical curettage or endocervical brushing above the excisional bed to evaluate for residual disease is preferred owing to the frequent location of AIS within the endocervical canal, which makes determining the extent of the lesion more difficult, and the potential for multifocal disease.7,21,22 Clinical Question 3 What are the recommendations for patients undergoing definitive surgical management with positive compared with negative excisional biopsy margins? Recommendation 3.1 Simple hysterectomy is preferred for patients with confirmed diagnosis of AIS with negative margins on the conization specimen (BIII). Recommendation 3.2 Either modified radical hysterectomy or simple hysterectomy is acceptable for patients with confirmed diagnosis of AIS with positive margins on the conization specimen (CIII). Recommendation 3.3 Surgical assessment of lymph nodes is acceptable at the time of hysterectomy (CIII).

Recommendation 3.1 Simple hysterectomy is preferred for patients with confirmed diagnosis of AIS with negative margins on the conization specimen (BIII). Recommendation 3.2 Either modified radical hysterectomy or simple hysterectomy is acceptable for patients with confirmed diagnosis of AIS with positive margins on the conization specimen (CIII). Recommendation 3.3 Surgical assessment of lymph nodes is acceptable at the time of hysterectomy (CIII). Literature Review Margin status is a predictor for residual and recurrent disease and progression; thus, it is essential that the margin status can be assessed and that margins are negative. Recurrence risk of AIS is only 2.6% with negative margins but increases to 19% when margins are positive.7 Adenocarcinoma in situ is also associated with “skip lesions”—foci of adenocarcinoma cells that are not contiguous. Therefore, even with negative margins, the risk of residual AIS on a second excisional specimen is 20% (compared with 53% if margins are positive), and 2% of patients will be diagnosed with an invasive cancer (compared with 6% if margins are positive). Therefore, simple hysterectomy is recommended for all patients with a confirmed diagnosis of AIS with negative margins on conization. For patients with a persistent positive margin despite repeat excisional procedures, a modified radical hysterectomy or radical trachelectomy for those who desire future pregnancy is acceptable owing to an increased risk of diagnosing an occult invasive carcinoma.23,24 Although, historically, radical hysterectomy has been the treatment of choice for microinvasive adenocarcinoma of the cervix owing to concerns about skip lesions and difficulty determining depth of invasion, retrospective observational studies have not shown that radical surgery for microinvasive adenocarcinoma is associated with a survival benefit compared with simple hysterectomy25–28; therefore, simple hysterectomy even for patients in whom a negative margin cannot be achieved with excisional procedures is acceptable. The ongoing prospective Gynecologic Oncology Group protocol 278 (NCT01649089), in which patients with stage IA1–IB1 cervical carcinomas, including adenocarcinomas, will be surgically treated with simple hysterectomy and pelvic lymphadenectomy, may help clarify whether simple hysterectomy is sufficient for all microinvasive cervical cancers.

by the surgeon's risk assessment, which may include factors such as margin status of the preceding excisional specimen or postexcisional endocervical sampling results, pathologist concern for malignancy, HPV results (HPV-16– or -18–positive vs other high-risk HPV type), and patient risk factors (eg, immunosuppression). The risk of ovarian metastases in patients with invasive adenocarcinoma is 2–5%29–34 (compared with a less than 1% risk in the setting of squamous cell carcinoma). Risk of ovarian metastases increases with increasing clinical stage of disease and deeper stromal invasion and thus is rare in the setting of microinvasive disease.29–32 Furthermore, retrospective observational studies have not shown a difference in recurrence rates or survival when ovaries are left in situ. Therefore, decisions regarding ovarian management at the time of hysterectomy should be individualized based on patient age, hormonal status, and other risk factors. Opportunistic salpingectomy at the time of hysterectomy should be discussed with patients for potential ovarian or fallopian tube cancer risk reduction per the American College of Obstetricians and Gynecologists’ Committee Opinion35 but is not required for management of AIS or adenocarcinoma of the cervix. Clinical Question 4 Which patient and disease criteria should be used to identify patients who are eligible for fertility-sparing surgery?

The risk of ovarian metastases in patients with invasive adenocarcinoma is 2–5%29–34 (compared with a less than 1% risk in the setting of squamous cell carcinoma). Risk of ovarian metastases increases with increasing clinical stage of disease and deeper stromal invasion and thus is rare in the setting of microinvasive disease.29–32 Furthermore, retrospective observational studies have not shown a difference in recurrence rates or survival when ovaries are left in situ. Therefore, decisions regarding ovarian management at the time of hysterectomy should be individualized based on patient age, hormonal status, and other risk factors. Opportunistic salpingectomy at the time of hysterectomy should be discussed with patients for potential ovarian or fallopian tube cancer risk reduction per the American College of Obstetricians and Gynecologists’ Committee Opinion35 but is not required for management of AIS or adenocarcinoma of the cervix. Clinical Question 4 Which patient and disease criteria should be used to identify patients who are eligible for fertility-sparing surgery? Recommendation 4.1 For patients of reproductive age who desire future pregnancy, for whom negative margin status on conization has been achieved, and who are willing and able to adhere to surveillance recommendations, fertility-sparing management with a conization procedure is acceptable (AII). Recommendation 4.2 For patients in whom negative margins cannot be achieved after multiple excisional procedures, fertility-sparing management is not recommended (DIII).

Recommendation 4.1 For patients of reproductive age who desire future pregnancy, for whom negative margin status on conization has been achieved, and who are willing and able to adhere to surveillance recommendations, fertility-sparing management with a conization procedure is acceptable (AII). Recommendation 4.2 For patients in whom negative margins cannot be achieved after multiple excisional procedures, fertility-sparing management is not recommended (DIII). Recommendation 4.3 For patients who initially underwent fertility-sparing management of AIS and have subsequently completed childbearing, either hysterectomy or continued surveillance is acceptable for those who have had consistently negative HPV test results during surveillance (CIII). For patients who have had positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred (CIII).

uently completed childbearing, either hysterectomy or continued surveillance is acceptable for those who have had consistently negative HPV test results during surveillance (CIII). For patients who have had positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred (CIII). Literature Review Unfortunately, AIS is often diagnosed in patients of reproductive age who desire future pregnancy. For these individuals, conservative management with an excisional procedure achieving negative margins is acceptable. Data on long-term outcomes after conservative management of AIS are limited, with small study populations ranging from 28 to 136 patients and average follow-up period of 3–5 years. The recurrence risk for AIS among patients undergoing an excisional procedure is approximately 3%36–41 but has been reported to be as high as 12%.42 One study showed positive HPV test results during surveillance to be the only significant predictor for recurrence (odds ratio [OR] 2.72, 95% CI 1.08–6.87) and positive HPV test results (OR 3.74, 95% CI 1.85–7.62) and positive margins (OR 5.0, 95% CI 1.09–20.0) to be the only predictors for progressive disease.42 Therefore, for patients with consistently negative HPV test results during surveillance, either hysterectomy or continued observation without hysterectomy after completion of childbearing is acceptable. However, for patients who have positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred.

nts with consistently negative HPV test results during surveillance, either hysterectomy or continued observation without hysterectomy after completion of childbearing is acceptable. However, for patients who have positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred. For patients in whom negative margins cannot be achieved after multiple excisional procedures, hysterectomy is recommended, and fertility-sparing management should be pursued only in select cases and after a frank discussion about the significantly increased risk of persistent or recurrent AIS and cancer. Data are lacking on outcomes after radical trachelectomy for treatment of persistent AIS, but it could be considered as an alternative for patients who strongly desire future fertility. Clinical Question 5 What is the recommended surveillance after treatment of AIS? Recommendation 5.1 For patients who undergo definitive management with hysterectomy, surveillance per the ASCCP Risk-Based Management Consensus guidelines (http://www.asccp.org/consensus-guidelines) is recommended for at least 25 years after diagnosis, even if that extends the testing period beyond the age of 65 years (CIII). Recommendation 5.2 i) For patients who undergo fertility-sparing management, surveillance with Pap plus HPV co-testing and endocervical sampling is recommended every 6 months for the first 3 years, then annually for at least 2 years or until hysterectomy is performed (BII).

Recommendation 5.1 For patients who undergo definitive management with hysterectomy, surveillance per the ASCCP Risk-Based Management Consensus guidelines (http://www.asccp.org/consensus-guidelines) is recommended for at least 25 years after diagnosis, even if that extends the testing period beyond the age of 65 years (CIII). Recommendation 5.2 i) For patients who undergo fertility-sparing management, surveillance with Pap plus HPV co-testing and endocervical sampling is recommended every 6 months for the first 3 years, then annually for at least 2 years or until hysterectomy is performed (BII). ii) For patients who have consistently negative co-testing results in the first 5 years of surveillance, extending surveillance to every 3 years indefinitely is acceptable (CIII).

Recommendation 5.2 i) For patients who undergo fertility-sparing management, surveillance with Pap plus HPV co-testing and endocervical sampling is recommended every 6 months for the first 3 years, then annually for at least 2 years or until hysterectomy is performed (BII). ii) For patients who have consistently negative co-testing results in the first 5 years of surveillance, extending surveillance to every 3 years indefinitely is acceptable (CIII). Literature Review Owing to an increased risk of developing vaginal dysplasia after a history of cervical dysplasia, it is recommended that definitive surgical management should be followed by at least 25 years of surveillance per the ASCCP Risk-Based Management Consensus Guidelines, with vaginal colposcopy performed to evaluate high-grade cytology results, persistent low-grade cytology results, or persistent positive HPV test results (two or more); although the HPV test is not currently U.S. Food and Drug Administration–approved for vaginal screening or surveillance, the high negative predictive value of the test can identify those individuals who are at low risk for developing vaginal cancer.43 Management of abnormal vaginal cytology and positive HPV test results in this setting is beyond the scope of these management guidelines and is well-defined in the review article by Khan et al.43

gh negative predictive value of the test can identify those individuals who are at low risk for developing vaginal cancer.43 Management of abnormal vaginal cytology and positive HPV test results in this setting is beyond the scope of these management guidelines and is well-defined in the review article by Khan et al.43 After fertility-sparing management, “long-term follow-up with a combination of co-testing and colposcopy with endocervical sampling” is recommended per the ASCCP guidelines.3 However, the ASCCP guidelines do not specify the frequency of follow-up. A prospective study of 119 conservatively treated patients with AIS showed a persistent, recurrent, or progressive disease rate of 13%, with 4% of recurrences occurring as late as 3 years after the initial excisional procedure.42 Notably, there were no recurrences among patients whose posttreatment surveillance HPV test results were negative, and multivariate analysis showed that HPV status was the strongest predictor for recurrent disease. Sensitivity of HPV testing for persistent, recurrent, or progressive disease is 90%, compared with 60% for cytology.44 Preliminary data suggest the median time to HPV clearance is longer for patients with AIS compared with those with CIN, and thus prolonged surveillance is recommended.44 Given the increased risk of recurrent or progressive disease in the first 36 months after excisional procedure, we recommend co-testing (Pap plus HPV tests) with endocervical sampling (endocervical curettage or endocervical brushing) every 6 months for 3 years, then annual co-testing with or without endocervical sampling for at least 2 years or until hysterectomy at the completion of childbearing.45 For patients with a history of AIS who have at least two consecutive negative co-test results after treatment, the 5-year risk of CIN 2 or worse is 1.5%.45 Although this risk is still substantial compared with the 5-year risk of CIN 2 or worse after negative screening test results without a history of high-grade dysplasia, lengthening the surveillance interval to every 3 years is acceptable for individuals who have consistently negative co-testing results in the first 5 years of surveillance.

still substantial compared with the 5-year risk of CIN 2 or worse after negative screening test results without a history of high-grade dysplasia, lengthening the surveillance interval to every 3 years is acceptable for individuals who have consistently negative co-testing results in the first 5 years of surveillance. Clinical Question 6 How should AIS be managed during pregnancy? Recommendation 6.1 In the absence of a clinical or histologic suspicion of invasive cancer, excisional procedures are not recommended during pregnancy. Colposcopy omitting endocervical sampling is recommended each trimester, with an excisional procedure performed postpartum. Delaying excision to approximately 6–8 weeks postpartum is preferred, but an excisional procedure as early as 4 weeks postpartum is acceptable (BII). Recommendation 6.2 If an excisional procedure is performed during pregnancy owing to suspicion for an invasive cancer, placement of a prophylactic cerclage is acceptable (CIII).

Recommendation 6.1 In the absence of a clinical or histologic suspicion of invasive cancer, excisional procedures are not recommended during pregnancy. Colposcopy omitting endocervical sampling is recommended each trimester, with an excisional procedure performed postpartum. Delaying excision to approximately 6–8 weeks postpartum is preferred, but an excisional procedure as early as 4 weeks postpartum is acceptable (BII). Recommendation 6.2 If an excisional procedure is performed during pregnancy owing to suspicion for an invasive cancer, placement of a prophylactic cerclage is acceptable (CIII). Literature Review Excisional procedures during pregnancy are associated with an increased risk of hemorrhage, spontaneous abortion, and preterm delivery. Additionally, there is a higher rate of residual disease after excisional procedures performed during pregnancy compared with those performed in a nongravid state.46 Therefore, although conization is generally recommended for evaluation of AIS diagnosed on biopsy, it is not recommended during pregnancy unless there is suspicion for an invasive cancer, which would affect the timing of delivery, owing to risk of hemorrhage, infection, premature rupture of membranes, and preterm delivery. If conization is necessary during pregnancy, ideal timing of the procedure is during the second trimester. Excisional procedures should not be performed within 4 weeks of expected delivery owing to increased risk of hemorrhage or extension of the wound. If an excisional procedure is performed during pregnancy, immediate postprocedure placement of a prophylactic cerclage should be considered to decrease risk of hemorrhage and preterm delivery.47,48 If conization is delayed until after delivery, colposcopy each trimester with conization after delivery is recommended owing to a high rate of persistent high-grade dysplasia.49,50 Delaying an excisional procedure until 6–8 weeks postpartum is preferred, but, owing to concern for loss to follow-up resulting from expiration of health insurance postpartum or other factors, performing an excisional procedure as early as 4 weeks postpartum is acceptable.

rate of persistent high-grade dysplasia.49,50 Delaying an excisional procedure until 6–8 weeks postpartum is preferred, but, owing to concern for loss to follow-up resulting from expiration of health insurance postpartum or other factors, performing an excisional procedure as early as 4 weeks postpartum is acceptable. SUMMARY OF RECOMMENDATIONS Incorporating age-appropriate HPV testing into cervical cancer screening is recommended, because HPV testing increases the sensitivity of screening for adenocarcinoma lesions, which often originate inside the endocervical canal and may not be detected on cytology. An excisional procedure to rule out an invasive adenocarcinoma before definitive surgical therapy with hysterectomy is recommended. Obtaining an intact specimen (“top hat” excision is unacceptable) with a length of at least 10 mm is preferred, with a goal of achieving negative margins. For surgeons who are unable to consistently obtain intact excisional specimens with adequate length, referral to a gynecologic oncologist or other cervical dysplasia specialist for excisional biopsy is preferred. Endocervical sampling above the excisional site is preferred to evaluate for residual disease. Hysterectomy is preferred for all patients who have completed childbearing. If negative margins on the excisional specimen(s) cannot be achieved, either a modified radical hysterectomy or simple hysterectomy is acceptable, recognizing the increased (6%) risk of an occult invasive adenocarcinoma. Surgical assessment of lymph nodes is acceptable at the time of hysterectomy.

mpleted childbearing. If negative margins on the excisional specimen(s) cannot be achieved, either a modified radical hysterectomy or simple hysterectomy is acceptable, recognizing the increased (6%) risk of an occult invasive adenocarcinoma. Surgical assessment of lymph nodes is acceptable at the time of hysterectomy. For patients who desire future pregnancy, conservative management with close follow-up provided negative margins can be achieved is acceptable. Co-testing with endocervical sampling every 6 months for 3 years followed by annual co-testing with or without endocervical sampling for at least 2 years or until hysterectomy at the completion of childbearing is recommended. Lengthening the surveillance interval to every 3 years is acceptable for patients who have consistently negative co-testing results in the first 5 years of surveillance. Financial Disclosure Deanna Teoh disclosed that money was paid to her institution by Acelity for an investigator-initiated industry-sponsored clinical trial and Tesaro for serving as site PI for a clinical trial. Ritu Salani received funds from Astra Zeneca, Clovis, Genmab, Tesaro, Ethicon, and IOVANCE. She also receives funds from Genentech for serving on the data and safety monitoring committee. Warner Huh disclosed that he received funds from Inovio for serving on the data safety monitoring board. He also received funds from Antiva and Zilico. The other authors did not report any potential conflicts of interest.

E. She also receives funds from Genentech for serving on the data and safety monitoring committee. Warner Huh disclosed that he received funds from Inovio for serving on the data safety monitoring board. He also received funds from Antiva and Zilico. The other authors did not report any potential conflicts of interest. Presented at the Society of Gynecologic Oncology's Annual Meeting on Women's Cancer, March 24–27, 2018, New Orleans, Louisiana, and the American College of Obstetricians and Gynecologists' Annual Clinical and Scientific Meeting, May 3–6, 2019, Nashville, Tennessee. This evidence-based review and recommendations have been endorsed by ASCCP. Each author has confirmed compliance with the journal's requirements for authorship. Peer reviews and author correspondence are available at http://links.lww.com/AOG/B791.