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Mode of delivery and neonatal bleeds in hemophilia
Richards et al.,8 with an overall head bleed rate of 3.5% and some data on prematurity (29 premature children; 6.0% in the series), had the same issue. It is, however, pos- sible that extreme prematurity is under-represented in the registry due to mortality before diagnosis.
The frequency of major bleeds and ICH for all neonates was similar to previous studies.9,17,18 When splitting the group into instrumental VD and non-instrumental VD, and CS prior to and during labor, only instrumental VD was identified as a risk factor. A recent study from the UK on ICH in bleeding disorders had similar findings and identified instrumental delivery as a clear risk factor with a RR of 10.6.19 This is also known from the normal popu- lation, but in lower frequencies: Towner et al. reported ICH frequencies of 1 of 860 for VE and 1 of 664 for forceps and VE, which means that the risk for ICH in hemophilic neonates born by instrumental delivery is roughly 80-fold higher in our series.12 In a recent published meta-analysis from Davies and Kadir, CS was proposed as a safer option for children born with hemophilia, but the comparison was made with historical cohorts.7 In our prospective cohort, there was no difference in incidence of major bleeds and ICH in neonates born by vaginal delivery (both instrumental and non-instrumental) compared to CS (prior to and during labor): 5.2% versus 6.4% in major bleeds, and 2.3% versus 1.7% for ICH. A planned CS with the intention to perform CS prior to labor did not prevent neonates from experiencing ICH or major bleeds in com- parison to planned VD. This information is important when counseling a pregnant carrier. It has also been shown in other studies that CS does not prevent neonatal bleeds.4,8,9 Studies from the normal population with 583,340 births included show that vaginal delivery with- out instruments and CS prior to labor were the safest option but ICH still occurred (1 of 2,750 CS prior to labor, and 1 of 1,900 delivered spontaneously).12
A known family history of hemophilia (KFH) had some influence on the mode of delivery: 36% (167 of 466) were delivered by CS in the KFH group compared to 28% (123 of 445) in the no known family history group (NFH) (P=0.00038). The group of neonates in the NFH group present the ‘true risk’ of neonatal bleeds in a child with hemophilia, since no precautionary measures had been taken with respect to hemophilia on the obstetric proce- dures. However, there was no significant difference in the rate of major bleeds and ICH between KFH and NFH. Regarding vaginal delivery, 4.5% of the children in the NFH group compared to 4.7% in the KFH had a major bleed and 2.7% had ICH in the NFH-group compared to 1.7% in the KFH-group. This may be explained by our findings, that the mode of delivery (CS vs. vaginal deliv- ery) did not impact the rate of major bleeds and ICH. Similar findings were shown in a recent study of Kulkarni et al. in which 547 neonates with all severities of hemo- philia were included.20 The reason to choose a planned CS was hemophilia in 45%; but in 55%, other maternal and fetal reasons played a role illustrating that the planning of a delivery is a complicated and multifactorial task.
Prenatal diagnosis was performed in 14% (62 of 466) of known carriers, and in these cases it was definitely known that they were carrying a child with hemophilia. In this subgroup, 51.6% were delivered by CS, demonstrating a statistically significant impact on the decision to choose a CS delivery. We do not have data on how many carriers terminated pregnancy after PND with an affected fetus, so
Table 6. Planned vaginal delivery versus planned Cesarean section – major bleeds and intracranial hemorrhage (ICH).
Planned VD
VD without instruments VD instrumental
CS during labor
VD not known with
or without instruments
Planned CS
CS prior to labor CS during labor
Planning not known P-value; RR (CI)
n ICH n (%)
703 17 (2.4) 541 10 68 7
70 0
24 0
134 2 (1.5) 125 2
9 0
89 1 0.753; 1.62
(0.38,6.93)
Major bleeds n (%)
34 (4.8) 18 13
3
0
5 (3.7) 5
0
5 0.822; 1.30
(0.52,3.25)
VD: vaginal delivery; CS: Cesarean section; RR: relative risk.
the numbers on PND might be underestimated. However, recent figures from Sweden indicate that carriers today often choose PND in order to prepare for having a hemo- philia child and not for termination of the pregnancy; but this may not be the case in all participating centers.21
One child died from ICH, representing 1 of 786 boys with severe hemophilia (0.13%), and 1 of 20 of all ICH (5%). These numbers are low compared to historical data, but they are in line with a recent CDC report that included all ICH with a mortality rate of around 2.5%.22 These numbers may be underestimated due to undiagnosed or unreported cases.
It would have been of interest to analyze the risks and outcomes for the carrier mothers who gave birth to a child with hemophilia according to delivery mode, but our reg- istry is limited to pediatric data.
In summary, vaginal delivery and Cesarean section carry similar risks of ICH and major bleeds in neonates with severe and moderate hemophilia, and pregnant carriers of hemophilia should be informed about different options for mode of delivery and their potential risks.
Acknowledgments
The authors thank study coordinator Ella van Hardeveld and statistician Susann Ullén for their help with this study. We would like to acknowledge unrestricted funding from Bayer AG, Baxter/Baxalta/ Shire, CSL Behring, Pfizer, Novonordisk, Sobi and Grifols to the PedNet group that were partly used for this study.
Appendix
PedNet Haemophilia Research Foundation contributors to this study.
Europe
C Altisent Roca, Unitat Hemofilia, Hospital Vall d’Hebron, Barcelona, Spain; MT Alvarez Romàn, Unidad de Coagulopatías, Hospital Universitario La Paz, Madrid, Spain
M Bührlen, Gesundheit Nord, Klinikum Bremen Mitte, Prof.- Hess-Kinderklinik, Bremen, Germany; HM van den Berg, PedNet Haemophilia Research Foundation, Baarn, The Netherlands; E Chalmers, Department of Haematology, Royal Hospital for Children, Glasgow, UK; H Chambost, Pediatric Haematology Oncology Department, Children Hospital La
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