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ment for intensive replacement therapy has been identi- fied as a risk factor for inhibitor development in patients with hemophilia A.3
Several studies have been published with quite a uni- form consensus that around 3-4% of boys with hemophil- ia born in countries with a good standard of obstetric care have had ICH diagnosed during the neonatal period.2,4-6 It has also been shown that instrumental delivery using for- ceps or vacuum extraction (VE) is a major risk factor for intra- and extracranial bleeds in neonates with hemophil- ia.5,7,8 However, figures for bleeds associated with uncom- plicated VD and CS and, consequently, recommendations on mode of delivery vary between publications and guide- lines.7,9-11 It is undisputed that the risk of a neonatal bleed in a child with hemophilia is considerably higher than that expected in a non-hemophilia population, although few figures are available. The largest series, among the few studies published on mode of delivery in the normal pop- ulation, suggests an incidence of ICH of 1 per 1,900 in spontaneous VD, 1 per 2,750 in CS with no labor, 1 per 907 delivered by CS during labor, 1 per 860 deliveries with VE, and 1 per 664 delivered with the use of forceps.12 Using these numbers as a reference, the risk for ICH in hemophilia boys is 60 times higher compared to healthy neonates born by VD.
Knowledge of carrier status in a pregnant woman, or the knowledge of confirmed hemophilia in the fetus follow- ing prenatal diagnosis (PND), may impact on obstetric care, especially when planning the mode of delivery. In recent cohorts, around 50% of all cases of hemophilia are sporadic, i.e. newly diagnosed boys without family histo- ry of hemophilia or without any knowledge of carrier sta- tus in the mother at birth.13 Many published studies on the delivery of a hemophilia child have not been able to dis- tinguish between sporadic cases and cases with a known family history of hemophilia. Some studies include neonates with mild hemophilia and, furthermore, it is not always possible to distinguish between CS performed as a result of the baby having hemophilia or for other reasons, and this complicates comparisons between studies.
The PedNet Registry is a prospective, multicenter data- base that includes all children born since 1st January 2000 diagnosed with hemophilia A (HA) or B (HB) of all sever- ities and treated in the 31 participating hemophilia centers in Europe, Canada and Israel.14 Baseline data regarding the neonatal period are collected on mode of delivery, neona- tal events, family history of hemophilia, and gestational age. This longitudinal prospectively collected cohort study makes it possible to address questions of interest on obstetric and neonatal issues.
The aim of this paper was to study the frequency of ICH and other major bleeds in neonates with hemophilia and the association with mode of delivery to improve counseling of pregnant carriers in the future. Furthermore, the results will be stratified according to the presence or absence of a prior knowledge of hemophilia in the family.
Methods
Study group
Data were retrieved from the ‘PedNet Registry’ which is owned and administered by the ‘PedNet Haemophilia Research Foundation’, consisting of 31 international hemophilia treatment centers and registered at clinicaltrials.gov identifier: 02979119. The
purpose of the registry is to promote and facilitate research and healthcare development in children with hemophilia. The PedNet Registry includes all consecutive patients diagnosed and treated in each center born after 1st January 2000. The aim of the PedNet reg- istry is to establish large well-documented birth cohorts of patients with hemophilia enabling studies on side effects and out- come of treatment. Patient data are collected from birth onwards prospectively and consist of all data concerning treatment, side effects and outcome of treatment. Information is collected on mode of delivery and during the first 75 exposure days of treat- ment with factor concentrate; all major bleeds including ICH are registered with detailed information. Approval for data collection was obtained from the institutional review boards of each of the 31 centers taking part in the study, and written informed consent was obtained from the parents or guardians of all participants in accordance with the Declaration of Helsinki. The data quality in the PedNet Registry is monitored regularly and independent audits are carried out in all participating centers.14
Study population
All children included in the Registry by 1st January 2015 with severe (factor VIII/IX activity, < 0.01 IU/mL) or moderate (factor VIII/IX activity, 0.01-0.05 IU/mL) HA and HB and with at least one follow up covering the neonatal period after the initial baseline report were enrolled. This resulted in 926 children born between 1st January 2000 and 1st January 2015 with data on mode of deliv- ery and the neonatal period, defined as 28 days after birth. Prematurity was defined as up to 36 weeks of gestational age.
Data collection
We uniformly collected data on the mode of delivery (including vaginal, vaginal instrumental, CS), and major bleeds including ICH in the neonatal period. Data were also recorded on whether an affected newborn belonged to a family with a known history of hemophilia or was a sporadic case.
Statistical analysis
haematologica | 2019; 104(10)
Mode of delivery and neonatal bleeds in hemophilia
The primary outcome was ICH and major bleeds, the latter defined as a bleed requiring treatment with factor concentrate and not resolving within 24 hours during the neonatal period. The determinants of outcome were mode of delivery and family histo- ry of hemophilia, either known or unknown. Statistical compar-
2
isons between different groups were made using χ test or
Fisher´s exact test at a significance level of 0.05. In the comparison of four subgroups on mode of delivery, an overall test was per- formed to compare the frequencies between all groups simultane- ously. If an overall test was significant, it was followed by pair- wise comparisons between the groups. The results of the pairwise comparisons were corrected for multiple testing by Bonferroni correction. Statistical power was shown by the width and magni- tude of the 95% Confidence Interval (95%CI) according to the CONSORT guidelines. All analyses were performed using IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp., NY, USA, or R: A language and environment for statistical Computing, version 3.4.2. Vienna, Austria, R Foundation for Statistical Computing.
Results
Cohort demography
A total of 926 patients were included, 140 with moder- ate and 786 with severe hemophilia comprising those with HA [n = 803 (86.7%)], and HB [n=123 (13.3%)]. MOD in the 926 patients was vaginal in 633 (68.4%) and
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