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Introduction Vitamin K prophylaxis in infancy aims to reduce the risk of vitamin K deficiency bleeding (VKDB), the consequences of which are potentially lethal [14]. Most countries have implemented vitamin K prophylactic regimens, but the route of administration, the dose, the dosing frequency, and the vitamin K formulation differ widely among regimens. The molecular form of vitamin K currently used in the Netherlands and nearly all countries for intramuscular (IM) and oral vitamin K prophylaxis is phylloquinone (vitamin K1). The efficacy of a single dose of 1 mg IM vitamin K1 is firmly established and is associated with a low risk of VKDB of < 0.2/100,000 newborns [12]. However, its efficacy at a population level is currently threatened by an increasing number of parents opting out [9, 10, 15, 16, 28]. On the other hand, a single dose of oral vitamin K1 prophylaxis—while as effective in preventing classical VKDB—is associated with a much higher risk of late VKDB (roughly 4–7/100,000) [27], which is predominantly manifested by intracranial hemorrhage [20]. The vast majority of prophylactic failures occur in breastfed infants with malabsorption of vitamin K, mostly due to cholestasis [17]. Unfortunately, malabsorption often only becomes apparent after bleeding has occurred. A prophylactic regimen should therefore allow protection for all infants, including those with unrecognized cholestatic liver disease.

ailures occur in breastfed infants with malabsorption of vitamin K, mostly due to cholestasis [17]. Unfortunately, malabsorption often only becomes apparent after bleeding has occurred. A prophylactic regimen should therefore allow protection for all infants, including those with unrecognized cholestatic liver disease. By using targeted surveillance of infants with biliary atresia, it was previously shown that a weekly oral dose of 1 mg vitamin K offered a protection similar to IM administration in infants with cholestasis [23]. In contrast, a daily dose of 25 μg (0.175 mg weekly) was associated with a much higher risk in breastfed infants with biliary atresia and a much higher incidence of late VKDB of ~ 2.1 per 100,000 [23, 25]. To address this, the Dutch prophylactic dose was increased sixfold, from 25 daily to 150 μg daily (1.050 mg weekly) for all breastfed infants in February 2011 [4]. A recent study in patients with biliary atresia questioned the efficacy of this new regimen and suggested that the risk had remained unchanged [29]. The aim of this study is to determine the consequences of a sixfold increase in the oral prophylactic vitamin K dose (150 μg) on the overall incidence of late VKDB and late intracranial VKDB in the Netherlands in comparison with the former oral prophylactic dose of 25 μg. Materials and methods General surveillance From 1 October 2014 to 31 December 2016, the Netherlands Pediatric Surveillance Unit (NSCK) of the Dutch Association for Pediatrics performed a nationwide active surveillance focused on the identification of infants with late VKDB.

A recent study in patients with biliary atresia questioned the efficacy of this new regimen and suggested that the risk had remained unchanged [29]. The aim of this study is to determine the consequences of a sixfold increase in the oral prophylactic vitamin K dose (150 μg) on the overall incidence of late VKDB and late intracranial VKDB in the Netherlands in comparison with the former oral prophylactic dose of 25 μg. Materials and methods General surveillance From 1 October 2014 to 31 December 2016, the Netherlands Pediatric Surveillance Unit (NSCK) of the Dutch Association for Pediatrics performed a nationwide active surveillance focused on the identification of infants with late VKDB. Patient selection Pediatricians were asked to report all infants in whom bleeding may have resulted from VKDB. Reported cases were confirmed as described previously [6]. Briefly, validation was performed using a questionnaire asking for information about the infant, feeding type, clinical presentation, dose and route of vitamin K prophylaxis, associated diseases, laboratory data, and outcome. Confirmed VKDB was diagnosed when prothrombin time (PT) was ≥ 4 times the control value and at least one of the following was present:Platelet count normal or raised in combination with normal fibrinogen values Prothrombin assay returned to normal after vitamin K administration Concentration of PIVKAs (proteins induced in vitamin K absence) exceeding the normal controls [6]

Patient selection Pediatricians were asked to report all infants in whom bleeding may have resulted from VKDB. Reported cases were confirmed as described previously [6]. Briefly, validation was performed using a questionnaire asking for information about the infant, feeding type, clinical presentation, dose and route of vitamin K prophylaxis, associated diseases, laboratory data, and outcome. Confirmed VKDB was diagnosed when prothrombin time (PT) was ≥ 4 times the control value and at least one of the following was present:Platelet count normal or raised in combination with normal fibrinogen values Prothrombin assay returned to normal after vitamin K administration Concentration of PIVKAs (proteins induced in vitamin K absence) exceeding the normal controls [6] Incidence of late (intracranial) VKDB The incidence of late VKDB and late intracranial VKDB in the general pediatric population under the 150 μg regimen was calculated using these data (2014–2016) and was compared with the incidence under the 25 μg regimen by the NSCK in 2005 [6, 25]. Targeted surveillance Infants with late intracranial VKDB were identified by using the Dutch Pediatric Intensive Care Evaluation (PICE) registry between 1 January 2008 and 31 December 2015. The diagnoses of all infants admitted to the eight Dutch pediatric intensive care units (PICUs) are registered in this national registry from 2003 onward.

fants with late intracranial VKDB were identified by using the Dutch Pediatric Intensive Care Evaluation (PICE) registry between 1 January 2008 and 31 December 2015. The diagnoses of all infants admitted to the eight Dutch pediatric intensive care units (PICUs) are registered in this national registry from 2003 onward. Patient selection All infants between the age of 8 days and 6 months who were admitted to a Dutch PICU with intracranial bleeding were identified in the PICE registry using the same procedure as previously described [25]. Briefly, the search strategy included search items that allowed detection through the diagnosis intracranial bleeding, through the symptoms of intracranial bleeding and through the underlying disorder. Search items were “brain dead,” “cerebral infarct or stroke,” “intracranial hemorrhage,” “convulsions,” “meningitis,” “gastro-intestinal bleeding,” “hepatitis,” “other liver diseases,” “biliary atresia,” “neonatal jaundice,” “other gastro-intestinal diseases,” and “coagulation defects” [25]. In case a center had not yet completed its PICE registration during the study period, an analogous in-house search was performed. Medical records of all selected patients were reviewed to identify infants with intracranial bleeding. Discharge letters and laboratory results were used to confirm vitamin K deficiency (VKD) as the cause of bleeding. Also, relevant clinical characteristics were obtained. Late intracranial VKDB was defined as intracranial bleeding confirmed by magnetic resonance imaging or computer tomography, in combination with a PT of ≥ 4 times the control value which normalized after vitamin K administration and/or a raised concentration of PIVKAs. A raised concentration of PIVKAs was defined as exceeding the normal controls [20]. Cases of “highly probable” intracranial bleeding, in combination with the above, were also considered to be late intracranial VKDB. Cases who were diagnosed with VKD before bleeding occurred were considered to be treatment failures.

As. A raised concentration of PIVKAs was defined as exceeding the normal controls [20]. Cases of “highly probable” intracranial bleeding, in combination with the above, were also considered to be late intracranial VKDB. Cases who were diagnosed with VKD before bleeding occurred were considered to be treatment failures. Clinical characteristics Infants with late intracranial VKDB were categorized into two groups according to the type of prophylaxis (25 μg vs. 150 μg). Vitamin K prophylaxis was considered to be given as recommended by the Dutch guideline at that time (1 mg at birth and 25 μg or 150 μg daily until the age of 3 months) unless otherwise specified. As the regimen was changed in February 2011, all patients with late intracranial VKDB who were born after February 2011 were considered to be 150-μg regimen cases. Age at diagnosis was defined as the age of the infant when first seen by a doctor with VKD-related symptoms.

he age of 3 months) unless otherwise specified. As the regimen was changed in February 2011, all patients with late intracranial VKDB who were born after February 2011 were considered to be 150-μg regimen cases. Age at diagnosis was defined as the age of the infant when first seen by a doctor with VKD-related symptoms. Infants were classified as “exclusively breastfed” if they had received exclusively breastmilk from birth onward. Adequate vitamin K administration was defined as administration ≥ 5 times a week. Cholestasis was defined as a concentration of total serum bilirubin ≥ 50 μmol/l with a direct fraction of ≥ 20% [23]. Since the risk of VKDB is not correlated with the degree of conjugated hyperbilirubinemia [24], we also retrieved and described the total and conjugated bilirubin levels. To compare the severity of VKDB under the different regimens, the following parameters were determined: the Pediatric Index of Mortality 2 (PIM2) score, which can be used for comparison of risk-adjusted mortality among infants admitted to a PICU [18]; mechanical ventilation; length of stay at a PICU; neurosurgical intervention; occurrence of neurological sequelae; and mortality. Incidence of late intracranial VKDB The incidence of late intracranial VKDB between 2008 and 2015 was calculated using the number of live births for each year [1, 2].

Infants were classified as “exclusively breastfed” if they had received exclusively breastmilk from birth onward. Adequate vitamin K administration was defined as administration ≥ 5 times a week. Cholestasis was defined as a concentration of total serum bilirubin ≥ 50 μmol/l with a direct fraction of ≥ 20% [23]. Since the risk of VKDB is not correlated with the degree of conjugated hyperbilirubinemia [24], we also retrieved and described the total and conjugated bilirubin levels. To compare the severity of VKDB under the different regimens, the following parameters were determined: the Pediatric Index of Mortality 2 (PIM2) score, which can be used for comparison of risk-adjusted mortality among infants admitted to a PICU [18]; mechanical ventilation; length of stay at a PICU; neurosurgical intervention; occurrence of neurological sequelae; and mortality. Incidence of late intracranial VKDB The incidence of late intracranial VKDB between 2008 and 2015 was calculated using the number of live births for each year [1, 2]. Efficacy of the revised regimen To evaluate the efficacy of the revised regimen, the time between events (median time between consecutive cases) under both regimens was compared, which is inversely related to the incidence. Additionally, we performed a sensitivity analysis by calculating the adjusted incidence of late intracranial VKDB, excluding infants who had received inadequate prophylaxis and infants that had not been exclusively breastfed. Approval for the study was obtained from the Medical Ethical Committee of the University Medical Center Utrecht.

erformed a sensitivity analysis by calculating the adjusted incidence of late intracranial VKDB, excluding infants who had received inadequate prophylaxis and infants that had not been exclusively breastfed. Approval for the study was obtained from the Medical Ethical Committee of the University Medical Center Utrecht. Statistical analysis Clinical and biochemical data were analyzed using a t test in case of a normal distribution and a Mann-Whitney U test for parameters with a non-normal distribution. A Pearson chi-squared test or Fisher’s exact test was used to determine statistical significance between groups in case of dichotomous parameters. A p value < 0.05 was considered statistically significant. SPSS (version 22.0; IBM Corp, Armonk, NY) was used for all analyses. The 95% confidence intervals for the incidences were calculated with R (version 3.3.65126.0_3-0) (supplementary information).

cal significance between groups in case of dichotomous parameters. A p value < 0.05 was considered statistically significant. SPSS (version 22.0; IBM Corp, Armonk, NY) was used for all analyses. The 95% confidence intervals for the incidences were calculated with R (version 3.3.65126.0_3-0) (supplementary information). Results General surveillance Between 1 October 2014 and 31 December 2016, 10 cases with suspected late VKDB were reported to the NSCK. Of these, 1 infant was excluded from analysis because the prolonged coagulation time did not cause a bleeding. Of the remaining 9 cases, late intracranial VKDB was confirmed in 5 infants and suspected in 1 infant in whom PT was measured after parenteral administration of vitamin K. In the remaining 3 infants, bleeding occurred but at a different site (Table 1). One of these infants did not receive vitamin K administration and was therefore excluded from analysis. Under the 150-μg regimen, the incidence of confirmed late VKDB was 1.8 per 100,000 (95% CI, 0.8–3.9), more than 70% of which were intracranial bleedings, accumulating to an incidence of confirmed late intracranial VKDB of 1.3 per 100,000 (95% CI, 0.5–3.2). These incidences were lower than those obtained by the NSCK in 2005 under the 25-μg regimen: 3.2 per 100,000 (95% CI, 1.2–6.9) and 1.6 per 100,000 (95% CI, 0.4–5.1), respectively [6]. However, there are overlapping confidence intervals.Table 1 All registered cases of late VKDB in the Netherlands by general surveillance between October 2014 and December 2016

obtained by the NSCK in 2005 under the 25-μg regimen: 3.2 per 100,000 (95% CI, 1.2–6.9) and 1.6 per 100,000 (95% CI, 0.4–5.1), respectively [6]. However, there are overlapping confidence intervals.Table 1 All registered cases of late VKDB in the Netherlands by general surveillance between October 2014 and December 2016 Sex; age (days) Vitamin K prophylaxis Clinical presentation Late intracranial VKDB Type of feeding APTT(s)/ PT(s)/ INR Underlying disorder Outcome M; 22 1 mg postpartum, 150 μg/day per os Intracranial bleeding Yes BF > 200/ > 180/ NM AATD Died M; 52 Since 10 days postpartum 150 μg/day per os Intracranial bleeding Yes BF > 200/ > 180/ NM Unknown Epilepsy F; 72 1 mg postpartum, 150 μg/day per os Intracranial, nasal, and gastro-intestinal bleeding, hematomas Yes BF > 150/ > 18/ NM PFIC type 2 Died F; 37 1 mg postpartum, 150 μg/day per os Intracranial bleeding Yes BF 58/ 39.9/ 3.92* Biliary atresia Died M; 38 1 mg postpartum, 150 μg/day per os Intracranial and gastro-intestinal bleeding Yes BF 120/ 120/ NM Unknown No sequelae F; 21 1 mg postpartum, 150 μg/day per os Intracranial bleeding Yes BF > 180/ > 90/ NM Suspected PFIC Full recovery F; 45 1 mg postpartum, 150 μg/day per os Hematomas chest and hand No BF > 200/ > 10/ NM Biliary atresia Full recovery M; 19 1 mg postpartum, 150 μg/day per os Umbilical bleeding No BF > 180/ > 180/ NM AATD Unknown M; 17 No administration Gastro-intestinal bleeding No BF 152/ 147/ NM

Unknown No sequelae F; 21 1 mg postpartum, 150 μg/day per os Intracranial bleeding Yes BF > 180/ > 90/ NM Suspected PFIC Full recovery F; 45 1 mg postpartum, 150 μg/day per os Hematomas chest and hand No BF > 200/ > 10/ NM Biliary atresia Full recovery M; 19 1 mg postpartum, 150 μg/day per os Umbilical bleeding No BF > 180/ > 180/ NM AATD Unknown M; 17 No administration Gastro-intestinal bleeding No BF 152/ 147/ NM None Unknown M male, F female, BF breastfeeding, APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, NM not measured, AATD alpha-1 antitrypsin deficiency, PFIC progressive familial intrahepatic cholestasis *Measured after vitamin K administration

AATD Unknown M; 17 No administration Gastro-intestinal bleeding No BF 152/ 147/ NM None Unknown M male, F female, BF breastfeeding, APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, NM not measured, AATD alpha-1 antitrypsin deficiency, PFIC progressive familial intrahepatic cholestasis *Measured after vitamin K administration Targeted surveillance Between 1 January 2008 and 31 December 2015, a total of 45,063 patients were admitted to the eight Dutch PICUs. Of these, 175 infants were diagnosed with intracranial bleeding. Proven or highly suspected non-accidental brain injury (NABI) represented the main cause (73 patients, 42%), followed by accidental head trauma (45 patients, 26%). Late intracranial VKDB was confirmed in 28 infants (16%). Patients with late intracranial VKDB presented significantly earlier than patients with intracranial bleeding due to NABI (50 days vs. 85 days, respectively, p < 0.001). In addition, there was a significant difference between the intracranial localization of hematomas in infants with VKDB and in infants with bleeding due to NABI: the latter group presented primarily with subdural hematomas whereas VKDB predominantly manifested as a combination of subdural and intracerebral bleeding (p = 0.020).

on, there was a significant difference between the intracranial localization of hematomas in infants with VKDB and in infants with bleeding due to NABI: the latter group presented primarily with subdural hematomas whereas VKDB predominantly manifested as a combination of subdural and intracerebral bleeding (p = 0.020). Late intracranial VKDB Under the 25-μg regimen (January 2008–February 2011; 38 months), late intracranial VKDB was confirmed in 18 infants and suspected in 2 additional infants in whom diagnosis could not be confirmed as PT was measured after vitamin K supplementation had been introduced. Under the 150-μg regimen (March 2011–December 2015; 58 months), late intracranial VKDB was confirmed in 10 infants (Table 2). Clinical and biochemical characteristics of infants with confirmed late intracranial VKDB are listed in Table 3. Under the 25-μg regimen, all infants were exclusively breastfed. In all 16 infants in which bilirubin values were available, both the total and direct fractions were raised, suggesting suboptimal bile flow. Of these, 14 infants met the previously described criteria of cholestasis. An underlying disorder predisposing to cholestasis was identified in 12 (67%) infants: biliary atresia (6), α-1 antitrypsin deficiency (2), progressive familial intrahepatic cholestasis (PFIC) (2), Alagille syndrome (1), and extra hepatic biliary obstruction (1). Four of these infants had received inadequate vitamin K administration.Table 2 Causes of intracranial bleeding in infants between the age of 8 days and 6 months admitted to a Dutch PICU between 2008 and 2015 under two different vitamin K oral prophylactic regimens

yndrome (1), and extra hepatic biliary obstruction (1). Four of these infants had received inadequate vitamin K administration.Table 2 Causes of intracranial bleeding in infants between the age of 8 days and 6 months admitted to a Dutch PICU between 2008 and 2015 under two different vitamin K oral prophylactic regimens 25 μg: January 2008–February 2011 150 μg: March 2011–December 2015 Cause Number (%) Number (%) p value Non-accidental brain injury 39 (44) 34 (39) 0.482 Vitamin K deficiency 20 (23) 10 (12) 0.041 Confirmed 18 (21) 10 (12) 0.092 Accidental head trauma 19 (22) 26 (30) 0.244 Other coagulation disorders 1 (1) 3 (3) 0.621 Iatrogenous 2 (2) 2 (2) 1.000 Unknown 1 (1) 4 (5) 0.368 Vascular malformation 1 (1) 3 (3) 0.621 Due to meningitis 1 (1) 3 (3) 0.621 Due to disseminated intravascular coagulation 2 (2) 0 (0) 0.246 Secondarily to sinus thrombosis 1 (1) 1 (1) 1.000 Birth trauma 1 (1) 0 (0) 0.497 Genetic collagen disorder 0 (0) 1 (1) 1.000 Total 88 87 Table 3 Comparison of characteristics of infants with confirmed late intracranial VKDB admitted to a PICU in the Netherlands under the 25-μg and 150-μg oral prophylactic regimens

.246 Secondarily to sinus thrombosis 1 (1) 1 (1) 1.000 Birth trauma 1 (1) 0 (0) 0.497 Genetic collagen disorder 0 (0) 1 (1) 1.000 Total 88 87 Table 3 Comparison of characteristics of infants with confirmed late intracranial VKDB admitted to a PICU in the Netherlands under the 25-μg and 150-μg oral prophylactic regimens 25 μg: January 2008–February 2011 150 μg: March 2011–December 2015 p value Feature Male/female, N (%) 9 (50)/9 (50) 8 (80)/2 (20) 0.226 Birth weight, mean (range), g 3496 (2830–4245) 3352 (2510–4000) 0.509 Age at diagnosis, mean (range), days 45 (28–97) 54 (21–101) 0.337 Weight at diagnosis, mean (range), g 4428 (3170–5500) 4681 (3400–5600) 0.358 Biochemical parameters Bilirubin total, median (range), μmol/l 81 (26–242) 77 (45–246) 0.792 Bilirubin direct, median (range), μmol/l 44 (8–131) 59 (23–206) 0.482 ASAT, median (range), U/l 68 (20–399) 96 (40–526) 0.350 ALAT, median (range), U/l 45 (15–232) 53 (21–224) 0.415 Etiology Exclusively breastfed, N (%) 18 (100) 8 (80) 0.150 Cholestasis, N (%) 14 (78) 8 (80) 0.625 Underlying disorder, N (%) 12 (67) 7 (70) 1.000 Inadequate administration, N (%) 4 (22) 2 (20) 1.000 Short-term outcome MRPIM2, median (P25-P75) 0.17 (0.03–0.29) 0.06 (0.04–0.23) 0.532 Neurosurgical intervention, N (%) 7 (39) 3 (30) 0.703 Mechanical ventilation, N (%) 14 (78) 7 (70) 0.674 Duration of mechanical ventilation, median (range), days 4 (1–13) 4 (2–12) 0.771 Length of stay at a PICU, median (range), days 4 (1–15) 5 (2–15) 0.551 Long-term outcome Died, N (%) 5 (28) 4 (40) 0.677 Neurological sequelae, N (%) 3 (17) 2 (20) 0.635 VKDB vitamin K deficiency bleeding, PICU pediatric intensive care unit, N number, ASAT asparagine aminotransferase, ALAT alanine aminotransferase, MRPIM2 pediatric index of mortality: mortality rate

(1–15) 5 (2–15) 0.551 Long-term outcome Died, N (%) 5 (28) 4 (40) 0.677 Neurological sequelae, N (%) 3 (17) 2 (20) 0.635 VKDB vitamin K deficiency bleeding, PICU pediatric intensive care unit, N number, ASAT asparagine aminotransferase, ALAT alanine aminotransferase, MRPIM2 pediatric index of mortality: mortality rate Under the 150-μg regimen, 8 (80%) out of 10 infants had been exclusively breastfed, and from 1 infant, the feeding type was unknown and 1 infant received formula feeding (unknown type). In all 10 infants, bilirubin was measured; all had raised bilirubin values. Of these, 8 infants met the previously described criteria of cholestasis. An underlying disorder predisposing to cholestasis was specified in 7 infants: biliary atresia (4), α-1 antitrypsin deficiency, PFIC, and Zellweger syndrome (1 each). Two infants had received inadequate vitamin K administration.

bilirubin values. Of these, 8 infants met the previously described criteria of cholestasis. An underlying disorder predisposing to cholestasis was specified in 7 infants: biliary atresia (4), α-1 antitrypsin deficiency, PFIC, and Zellweger syndrome (1 each). Two infants had received inadequate vitamin K administration. Incidence of late intracranial VKDB The annual incidence of late intracranial VKDB under the former regimen of 25 μg vitamin K ranged from 1.6 per 100,000 live births (95% CI, 0.4–5.2) to 4.9 per 100,000 live births (95% CI, 2.4–9.6), with an average incidence of 3.1 per 100,000 live births (95% CI, 1.9–5.0). When infants with suspected VKDB were included in the analysis, the average incidence was 3.4 per 100,000 live births (95% CI, 2.2–5.4). After implementation of the 150-μg regimen, the annual incidence of late intracranial VKDB ranged from 0.6 per 100,000 live births (95% CI, 0.0–3.7) to 1.8 per 100,000 live births (95% CI, 0.5–5.6), with an average incidence of late intracranial VKDB of 1.2 per 100,000 live births (95% CI, 0.6–2.3) (Table 4).Table 4 Incidence of intracranial bleeding and late intracranial VKDB in the Netherlands between 2008 and 2015 under the 25 μg and 150 μg oral prophylactic regimen

.8 per 100,000 live births (95% CI, 0.5–5.6), with an average incidence of late intracranial VKDB of 1.2 per 100,000 live births (95% CI, 0.6–2.3) (Table 4).Table 4 Incidence of intracranial bleeding and late intracranial VKDB in the Netherlands between 2008 and 2015 under the 25 μg and 150 μg oral prophylactic regimen Vitamin K prophylaxis 25 μg 150 μg Year 2008 2009 2010 Jan–Feb 2011 Total March-Dec 2011 2012 2013 2014 2015 Total Live births (N) 184,634 184,915 184,397 29,231 583,117 150,829 175,959 171,341 175,181 170,510 843,820 Patients admitted to a PICU (N) 4831 5205 5518 965 16,519 4775 6014 5897 5881 5977 28,544 Intracranial bleeding (N) 22 31 29 3 85 9* 21 12 22 26 90 Incidence of intracranial bleeding per 100,000 (95% CI) 11.9 (7.7–18.4) 16.8 (11.6–24.1) 15.7 (10.7–22.9) 10.3 (2.7–32.7) 14.6 (11.7–18.1) 6.0 (2.9–11.8) 11.9 (7.6–18.6) 7.0 (3.8–12.6) 12.6 (8.1–19.4) 15.2 (10.2–22.7) 10.7 (8.6–13.2) Late intracranial VKDB (N) 4 3 9 2 18 2 1 3 2 2 10 Incidence of late intracranial VKDB per 100,000 (95% CI) 2.2 (0.7–6.0) 1.6 (0.4–5.2) 4.9 (2.4–9.6) 6.8 (1.2–27.6) 3.1 (1.9–5.0) 1.3 (0.2–5.3) 0.6 (0.0–3.7) 1.8 (0.5–5.6) 1.1 (0.2–4.6) 1.2 (0.2–4.7) 1.2 (0.6–2.3) PICU pediatric intensive care unit, VKDB vitamin K deficiency bleeding *3 infants with intracranial bleeding due to other causes than VKD were born before the new prophylaxis was introduced and were therefore included in the 25-μg prophylaxis group in Table 2

Vitamin K prophylaxis 25 μg 150 μg Year 2008 2009 2010 Jan–Feb 2011 Total March-Dec 2011 2012 2013 2014 2015 Total Live births (N) 184,634 184,915 184,397 29,231 583,117 150,829 175,959 171,341 175,181 170,510 843,820 Patients admitted to a PICU (N) 4831 5205 5518 965 16,519 4775 6014 5897 5881 5977 28,544 Intracranial bleeding (N) 22 31 29 3 85 9* 21 12 22 26 90 Incidence of intracranial bleeding per 100,000 (95% CI) 11.9 (7.7–18.4) 16.8 (11.6–24.1) 15.7 (10.7–22.9) 10.3 (2.7–32.7) 14.6 (11.7–18.1) 6.0 (2.9–11.8) 11.9 (7.6–18.6) 7.0 (3.8–12.6) 12.6 (8.1–19.4) 15.2 (10.2–22.7) 10.7 (8.6–13.2) Late intracranial VKDB (N) 4 3 9 2 18 2 1 3 2 2 10 Incidence of late intracranial VKDB per 100,000 (95% CI) 2.2 (0.7–6.0) 1.6 (0.4–5.2) 4.9 (2.4–9.6) 6.8 (1.2–27.6) 3.1 (1.9–5.0) 1.3 (0.2–5.3) 0.6 (0.0–3.7) 1.8 (0.5–5.6) 1.1 (0.2–4.6) 1.2 (0.2–4.7) 1.2 (0.6–2.3) PICU pediatric intensive care unit, VKDB vitamin K deficiency bleeding *3 infants with intracranial bleeding due to other causes than VKD were born before the new prophylaxis was introduced and were therefore included in the 25-μg prophylaxis group in Table 2 Time between events As a consequence, the median time between consecutive cases increased significantly after the introduction of this regimen, from 24 under the 25-μg regimen to 154 days under the 150-μg regimen (p < 0.001). (Fig. 1a, b).Fig. 1 a Time in days between consecutive cases of late intracranial VKDB under the 25-μg and 150-μg regimens. b Cumulative cases of intracranial VKDB under the 25-μg and 150-μg regimens

fter the introduction of this regimen, from 24 under the 25-μg regimen to 154 days under the 150-μg regimen (p < 0.001). (Fig. 1a, b).Fig. 1 a Time in days between consecutive cases of late intracranial VKDB under the 25-μg and 150-μg regimens. b Cumulative cases of intracranial VKDB under the 25-μg and 150-μg regimens Sensitivity analysis When excluding infants who had received inadequate prophylaxis (4 and 2 infants for the 25-μg and 150-μg regimens, respectively) and infants who developed intracranial VKDB due to treatment failure (1 infant for the 150-μg regimen), the adjusted incidence of late intracranial VKDB under the 25-μg regimen was calculated as 2.4 per 100,000 live births (95% CI, 1.4–4.1). The adjusted incidence under the 150-μg regimen was calculated as 0.8 per 100,000 live births (95% CI, 0.4–1.8).

nial VKDB due to treatment failure (1 infant for the 150-μg regimen), the adjusted incidence of late intracranial VKDB under the 25-μg regimen was calculated as 2.4 per 100,000 live births (95% CI, 1.4–4.1). The adjusted incidence under the 150-μg regimen was calculated as 0.8 per 100,000 live births (95% CI, 0.4–1.8). Discussion In this study, we exploited two independent nationwide surveillance strategies to determine the effect of a sixfold dose increase of oral vitamin K prophylaxis on the incidence of intracranial hemorrhages due to VKD and showed that the incidence of late intracranial VKDB was modestly reduced after introduction of the revised regimen. However, the protection obtained by this sixfold dose increase is limited in comparison with the excellent protection offered by a single dose of IM vitamin K after birth [12] and is unexpectedly lower than a regimen previously used in Denmark with the same cumulative weekly dose of vitamin K [23]. This discrepancy strongly suggests that factors other than the dose must play an important role. Compliance issues with the daily regimen might contribute to poor protection; however, this was the case in only 2 infants for the revised regimen, and previous investigations indicate compliance is generally adequate [21]. Improved fractional absorption of one larger dosage compared with multiple smaller dosages has been suggested, although evidence is currently lacking [29]. Alternatively, the formulation in which vitamin K is administered could be an explanation. Dutch oral vitamin K is dissolved in arachnid oil, the hydrophobic nature of which is likely to impede absorption in infants with suboptimal bile flow. In several countries with oral vitamin K regimens, vitamin K is administered through Konakion® mixed micelles (MM) which more closely resembles the situation in the gut. However, even this formulation does not fully prevent VKDB in infants with cholestasis due to impaired intestinal absorption [26], likely due to micellar decomposition in the stomach as a consequence of low pH [22]. A recent study describes a new formulation of vitamin K prophylaxis which circumvents gastric micellar decomposition and therefore might be a promising oral form of prophylaxis for infants with suboptimal bile flow [19].

sorption [26], likely due to micellar decomposition in the stomach as a consequence of low pH [22]. A recent study describes a new formulation of vitamin K prophylaxis which circumvents gastric micellar decomposition and therefore might be a promising oral form of prophylaxis for infants with suboptimal bile flow [19]. The present study underlines the usefulness of pediatric intensive care registries in assessing the efficacy of national regimens of vitamin K prophylaxis. First, this study confirms that this targeted approach is associated with higher retrieval rates as compared with general surveillance studies [25]. Higher retrieval decreases the risk that differences in calculated incidences are due to variations in retrieval rate rather than changes in the true incidence. It is important to take the higher retrieval rate, thus higher incidences, into account when comparing incidences obtained from general surveillance with those obtained using targeted surveillance. Second, the detailed information regarding timing of events allowed us to calculate the time between events. The latter made it possible to attach statistical significance to the lower incidence of late intracranial VKDB after the change of regimen. We expect this measure to be helpful to assess the efficacy of upcoming prophylactic regimens. Virtually, all patients who develop VKDB despite prophylaxis have evidence of impaired bile flow, highlighting the importance of this risk factor. Of note, in some patients, bile flow is not completely obstructed, and therefore they do not fulfill commonly used criteria for cholestasis [23]. The inability of the 150-μg regimen to protect infants with cholestasis against VKDB has led to a recent advice by the Dutch Health Council to switch from the oral daily 150-μg regimen to a single dose of IM vitamin K prophylaxis at birth [5].

d therefore they do not fulfill commonly used criteria for cholestasis [23]. The inability of the 150-μg regimen to protect infants with cholestasis against VKDB has led to a recent advice by the Dutch Health Council to switch from the oral daily 150-μg regimen to a single dose of IM vitamin K prophylaxis at birth [5]. There is limited recent data of incidences of late VKDB in other countries with oral prophylactic regimens; in addition, prophylactic regimens may vary within countries. The lowest oral dosing regimen of 3 × 1 mg has been accompanied by the highest incidences of late VKDB (1.3 and 1.5 per 100,000 in Germany and Australia, respectively, for the years 1993 and 1994). An oral dosing regimen of 2 × 2 mg vitamin K in Switzerland resulted in an incidence of 1.2 per 100,000 for 1995–2002. For a dosing regimen of 3 × 2 mg, incidences varied from 0.4 to 0.8 per 100,000 in 1995–2001 (Germany), 0.43 per 100,000 (UK), and 0.87 per 100,000 since 2003 (Switzerland). The lowest incidence of late VKDB under oral vitamin K prophylaxis has been described in Denmark: 0.0 per 100,000 in 1992–2000 (2 mg vitamin K at birth, followed by 1 mg weekly for 3 months). However, Denmark switched to IM vitamin K administration in 2000 due to a lack of a licensed product. For countries with IM prophylaxis, lower incidences of 0.37 per 100,000 (Canada), 0.16 per 100,000 (New Zealand), and 0.1 per 100,000 (UK, 1 mg IM vitamin K at birth, 3 × 1 mg orally) have been described [11, 12]. Based on this superior efficacy, the NICE guidelines of 2015 recommend IM vitamin K prophylaxis for all newborns to prevent VKDB [13].

laxis, lower incidences of 0.37 per 100,000 (Canada), 0.16 per 100,000 (New Zealand), and 0.1 per 100,000 (UK, 1 mg IM vitamin K at birth, 3 × 1 mg orally) have been described [11, 12]. Based on this superior efficacy, the NICE guidelines of 2015 recommend IM vitamin K prophylaxis for all newborns to prevent VKDB [13]. Despite its efficacy, IM administration of vitamin K increasingly encounters resistance from parents [9]. Reasons for concern include exposure of the baby to toxic ingredients, excessive dose and side effects, the fear of an, although not substantiated [7], association with cancer, and the painful injections. Inadequate information during the antenatal period about the importance of vitamin K prophylaxis can also be a reason for refusal: parents consider vitamin K unphysiological and therefore gratuitous in uncomplicated birth [16, 28]. Risk factors for parental refusal of IM vitamin K administration were previously described [9, 15]. Vitamin K refusal was more likely to be associated with planned home delivery and midwife-assisted deliveries than hospital delivery and delivery by a physician. In the Netherlands, a substantial part of newborns is delivered at home (18.4% vs. 80.7% in a hospital vs. 0.9% elsewhere) [3] and could consequently be at risk of parental IM vitamin K refusal. Proper counseling, especially during the antenatal period, is therefore of great importance. If parents persist and refuse to have their child injected, the Dutch Health Council presently recommends an oral alternative, namely, 3 doses of 2 mg vitamin K (at birth, after 4–6 days and 4–6 weeks) for breastfed infants [5], based on a Swiss study [8]. The NICE guidelines also recommend oral vitamin K as a second-line option in case of parental decline, although dose and dosage frequency are not specified [13].

ommends an oral alternative, namely, 3 doses of 2 mg vitamin K (at birth, after 4–6 days and 4–6 weeks) for breastfed infants [5], based on a Swiss study [8]. The NICE guidelines also recommend oral vitamin K as a second-line option in case of parental decline, although dose and dosage frequency are not specified [13]. There are some limitations to this study. It is possible that some cases with intracranial VKDB were not admitted to the PICU in case of few symptoms, or died elsewhere and therefore remained unreported. Furthermore, earlier detection of cholestatic liver disease, including biliary atresia, may theoretically decrease the incidence of late VKDB, as these infants are treated with higher vitamin K dosages once diagnosed. However, since there has been no change in the number of registered patients with biliary atresia or the age at diagnosis after introduction of the revised regimen [29], this is not likely to have influenced the results. Finally, targeted surveillance within relevant subpopulations requires the existence of national registries. This in turn demands a substantial and ongoing effort, the importance of which cannot easily be overstated. In conclusion, a sixfold increase in the oral prophylactic vitamin K dose—from 25 to 150 μg daily—resulted in a significant but relatively modest reduction in the incidence of late intracranial VKDB. However, this protection compares poorly to the efficacy of IM vitamin K prophylaxis, indicating that factors other than the dose should be addressed to further improve oral vitamin K prophylactic regimens.

50 μg daily—resulted in a significant but relatively modest reduction in the incidence of late intracranial VKDB. However, this protection compares poorly to the efficacy of IM vitamin K prophylaxis, indicating that factors other than the dose should be addressed to further improve oral vitamin K prophylactic regimens. Electronic supplementary material ESM 1 (DOCX 17 kb) Abbreviations IMIntramuscular NABINon-accidental brain injury NSCKNetherlands Pediatric Surveillance Unit PFICProgressive familial intrahepatic cholestasis PICEPediatric Intensive Care Evaluation PICUPediatric intensive care unit PIM2Pediatric Index of Mortality 2 PIVKAsProteins induced in vitamin K absence PTProthrombin time VKDVitamin K deficiency VKDBVitamin K deficiency bleeding Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The authors thank D.Y. van Haaften-Visser, MD, PhD, for her help in providing data from the previous PICE study. Finally, the authors thank all staff members of the PICUs in the Netherlands, without whose effort data registration and thereby this work would not have been possible. Authors’ contributions Yvette N. Löwensteyn carried out the initial analyses and drafted the initial manuscript. Nicolaas J.G. Jansen designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript. Peter M. van Hasselt conceptualized and designed the study, supervised data collection, and reviewed and revised the manuscript. Members of the Dutch PICE/SKIC working group accommodated data collection and reviewed the manuscript.

Nicolaas J.G. Jansen designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript. Peter M. van Hasselt conceptualized and designed the study, supervised data collection, and reviewed and revised the manuscript. Members of the Dutch PICE/SKIC working group accommodated data collection and reviewed the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. Compliance with ethical statements Approval for the study was obtained from the Medical Ethical Committee of the University Medical Center Utrecht. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.