Postpartum Hemorrhage in Hemophilia a and B Carriers after Enhanced Prophylactic Clotting Factor Suppletion: The Pregnancy and Inherited Bleeding Disorders Study (PRIDES)

Background: While hemophilia mostly affects males through X-linked inheritance, female hemophilia carriers (HCs) can experience extensive bleeding, such as postpartum hemorrhage (PPH, ≥ 500 mL). To reduce the risk of severe PPH (≥ 1000 mL), pregnant HCs in the Netherlands receive clotting factor suppletion based on their third trimester Factor (F) VIII or FIX levels. Prior research showed a higher prevalence of severe PPH in HCs compared to the general Dutch population (12.5% vs. 7.7%), leading to a revision of the Dutch guideline in 2018. The third trimester cut-off value for clotting factor suppletion was changed from < 50 IU/dL to < 80 IU/dL, and peak target FVIII/FIX levels at delivery were increased from > 100 IU/dL to > 150 IU/dL. The change in the cut-off value and target peak clotting factor levels was initiated to aim for similar physiological VWF activity and FVIII levels as in the general population during childbirth, with the goal to reduce the incidence of (severe) PPH in women with VWD.

Aim: to assess the incidence of (severe) PPH in HCs, after the implementation of the novel Dutch Hemophilia guideline in 2018.

Methods: The study is a multicenter, observational cohort study in all six Dutch hemophilia treatment centers. All ongoing HCs pregnancies > 10 weeks of gestation were eligible. Prophylactic FVIII or FIX suppletion was indicated during delivery for pregnancies with third trimester FVIII/FIX levels < 80 IU/dL. Baseline parameters, FVIII/FIX activity levels, blood count parameters, total vaginal blood loss < 24 hours postpartum, and obstetric risk factors were recorded.

Statistical analysis: we used descriptive statistics for baseline parameters, obstetric risk factors and delivery outcomes, including PPH incidence. Logistic regression was used for multivariate analysis with primiparity, cesarean section and a history of PPH as possible confounders. Subgroup analysis was performed in those with and without indication for prophylactic clotting factor suppletion (third trimester levels < 80 IU/dL and ≥ 80 IU/dL.

Results: between September 2018 and March 2024, 170 deliveries were recorded, 88.3% (n=150/170) in hemophilia A carriers. Overall, 47.6% (n=81/170) were primipara HCs. History of PPH occurred in 14.2% (n=24/170). Cesarean section occurred in 24.1% (n=41/170). The incidence of PPH and severe PPH was 33.5% (n=57/170) and 12.4% (n=21/170), respectively. Median blood loss was 300 mL (IQR 200-540).

20% (n=34/170) of the deliveries had third trimester levels < 80 IU/dL and 73.5% (n=25/34) received prophylactic clotting factor suppletion during delivery. The ≥ 80 IU/dL group received prophylaxis in 2.2% (n=3/136). There were less cesarean sections in the < 80 IU/dL group, however this was not significantly lower (14.7%, n=5/34 vs. 26.5%, n=36/136, p-value 0.18). Overall, 44.1% (n=15/34) in the < 80 IU/dL group and 48.5% (n=66/136) in the ≥ 80 IU/dL group were primipara. The < 80 IU/dL group had a lower incidence of a history of PPH (8.8%, n=3/34 vs. 15.4%, n=21/136), but this was not significant (p-value 0.32).

In the < 80 IU/dL group, the PPH incidence was 29.4% (n=10/34) compared to 34.6% (n=47/136) in the ≥ 80 IU/dL group (p-value 0.57). Multivariate analyses showed no difference in PPH incidence when adjusted for cesarean section, a history of PPH, and primiparity (adjusted OR 1.11, 95% CI 0.48-2.71). The incidence of severe PPH was similar in the < 80 IU/dL group (11.8%, n= 4/34) vs. the ≥ 80 IU/dL group (12.5%, n= 17/136, p-value 0.91, adjusted OR of 1.07, 95% CI 0.36-0.93). Median blood loss was 300 mL (IQR 200-500, < 80 IU/dL group) vs. 365 mL (IQR 200-580, ≥ 80 IU/dL group, p-value 0.27).

Conclusion: Prophylactic clotting factor suppletion in HCs with third trimester FVIII or FIX levels < 80 IU/dL results in similar (severe) PPH incidence as in deliveries of HCs with third trimester levels ≥ 80 IU/dL who do not receive prophylaxis, after adjustment for obstetric risk factors. The overall incidence of PPH in HCs remains high.

Future analysis: Upcoming analysis focusses on comparing the subgroups with third trimester levels < 50 IU/dL and between 50-80 IU/dL who received more intensive clotting factor supplementation with data from a cohort study on PPH in HCs during the six years prior to the guideline revision. In addition, the incidence of PPH and obstetric risks factors in the general Dutch population during the same period as the PRIDES study will be compared.

Kruip:Roche: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Eikenboom:CSL Behring: Research Funding. Punt:CSL Behring: Current Employment. Coppens:Pfizer: Honoraria; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria; F. Hoffman-La Roche: Research Funding; Spark Therapeutics: Honoraria; Novo Nordisk: Research Funding; Sobi: Honoraria, Research Funding; European Association for Haemophilia and Allied Disorders (EAHAD): Other: Non-financial conflicts of interest: Member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD); Bayer: Honoraria, Research Funding. Moenen:Bayer: Research Funding; Octapharma: Research Funding. Peters:Pfizer: Research Funding. Schutgens:Hemab: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Octapharma: Research Funding; Roche: Research Funding; Sobi: Research Funding; Takeda: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding. van Galen:Octapharma: Research Funding.