Pregnancy and delivery outcomes in women with Hemophilia A and B: A multicenter cohort study from the Italian association of haemophilia centers

Abstract

Abstract Introduction: Hemophilia A and B are traditionally recognized as X-linked recessive disorders that primarily affect males. However, women can also be affected, either as carriers of the genetic mutation (HC-A, HC-B) or, less commonly, as symptomatic individuals with low Factor VIII or IX levels (<40%) due to skewed X-chromosome inactivation or biallelic mutations (HW-A, HW-B). While many carriers are asymptomatic, some experience significant bleeding, especially after trauma, surgery, pregnancy, or childbirth. In carriers and affected women, the typical coagulation changes of pregnancy may be inadequate, increasing the risk of antepartum and postpartum hemorrhage. The extent of this risk and the best management strategies remain uncertain. It is unclear how well factor levels predict bleeding complications or how other clinical or lab parameters influence risk. This study assessed obstetric and hemostatic outcomes in women with hemophilia A or B, either as carriers or symptomatic individuals carriers or symptomatic, followed by Italian reference centers, with a focus on correlations between factor levels, bleeding events, delivery mode, and the use of hemostatic therapies. Methods This multicenter, retrospective cohort study was conducted under the coordination of the Italian Association of Hemophilia Centers (AICE). All participating centers obtained ethical approval from their respective Institutional Review Boards. Women were eligible for inclusion if they had a confirmed diagnosis according to ISTH criteria HC-A, HC-B, HW-A, or HW-B and a history of pregnancy over a ten year period between December 2011 and December 2021. Data were collected retrospectively from medical records between January 2022 and December 2024. For each participant, the following variables were extracted and analyzed: age at hemophilia diagnosis, bleeding history as assessed by the ISTH Bleeding Assessment Tool (ISTH-BAT) score, laboratory measurements of coagulation factor VIII or IX activity (FVIII:c or FIX:c), complete blood counts, history of invasive prenatal diagnostic procedures (e.g., amniocentesis), detailed obstetric history including number and outcomes of pregnancies, mode of delivery (vaginal vs cesarean section), occurrence of bleeding events during pregnancy, delivery and the postpartum period, and the need for hemostatic treatments or transfusions. Results A total of 94 women from seven haemophilia reference centers met the inclusion criteria and were enrolled: 48 were HC-A, 27 were HW-A, 11 were HC-B, and 4 were HW-B. The median age at hemophilia diagnosis was 27 years, with a wide range from 2 to 45 years, reflecting the variable clinical presentation and timing of diagnosis in this population. The median ISTH-BAT score was 1.74 with a range between 0–11. Overall 174 pregnancies were reported: 95 ended with vaginal deliveries, 59 with cesarean sections, and 10 first-trimester miscarriages. A prenatal diagnosis to determine fetal sex or assess for hemophilia was required in 99 pregnancies (56.8%). Bleeding complications during pregnancy occurred in 12 cases (6.7%), while delivery amd postpartum hemorrhages (PPH) were documented in 20 cases (12.9%). Notably, hemostatic treatment—either prophylactic or therapeutic—at the time of delivery was administered to 31 women (20%), based on physician assessment of the bleeding risk. Postpartum treatment was needed in 5 women (3.2%). Blood transfusions were required in three cases due to PPH; one woman also received fresh frozen plasma. No statistically significant correlation was observed between bleeding events and coagulation factor levels (p=1.2), nor between bleeding and the administration of hemostatic treatments (p=0.297). However, among HC e HW, an inverse trend between ISTH-BAT scores and coagulation factor levels (p=0.08) was noted, suggesting that bleeding phenotype may be influenced by additional variables beyond the measured factor VIII or Factor IX activity. Conclusions This multicenter analysis highlights the complexity of bleeding risk in women with hemophilia. FVIII:c and FIX:c levels alone do not reliably predict bleeding in carriers, pointing to a multifactorial etiology involving bleeding history, obstetric issues, and genetic factors. The notable rate of postpartum hemorrhage stresses the need for early multidisciplinary planning. Despite available genetic counseling, prenatal screening uptake remains just over 50%, revealing a gap in preventive care.