Symptomatic haemophilia A: management during pregnancy and the postpartum period

Abstract

As an X linked disorder, the presence of severe symptomatic haemophilia A is an extremely rare disorder in women. Therefore there are no high-level evidence-based guidelines when it comes to pregnancy. Although there have been advances in the fields of prenatal counselling and maternal-fetal care, the management of these gestations continues to embody a challenge for any medical team. We report the successful management of a pregnant woman with symptomatic haemophilia A, from pregnancy to the postpartum period. Our aim is to enhance knowledge on this topic, and further improve outcomes for these mothers and their offspring.

Background

Haemophilia A is an X linked hereditary disorder caused by deficiency of clotting factor VIII.¹ Although it has a classic sex-linked mode of transmission, it is estimated that 1 per 100 000 female carriers are symptomatic.² Several genetic mechanisms for the expression of the disease phenotype in women have been already suggested.¹

These women are at risk of severe bleeding complications throughout their life course.³ Concerns increase when it comes to pregnancy and delivery, due to manifestations like fatal maternal postpartum haemorrhage, or intracranial haemorrhage in an affected newborn.⁴ There is usually a correlation between the severity of the bleeding manifestations and the level of the factor VIII. The condition is considered severe when there is less than 1% of normal factor VIII activity, moderate within 1%–5% activity and mild when it is greater than 5%.³

Although there have been advances in the fields of prenatal counselling and maternal-fetal care, management of these gestations continues to embody a challenge. There are no high-level evidence-based guidelines for management of pregnancy in women with symptomatic haemophilia A, since there are only a few case reports published on this subject.⁵ In this paper we report a successful multidisciplinary approach, from pregnancy to postpartum, of a woman with symptomatic haemophilia A.

Case presentation

The patient was a 29-year-old primigravida with haemophilia A (factor VIII activity of 1.1%) who presented at the first trimester. She was diagnosed in early childhood due to spontaneous haemorrhagic events. A mutation in the F8 gene was identified (homozygote inversion at intron 22), however the exact mechanism behind its inheritance remained unclear. There was no family history, and although her asymptomatic mother was a carrier of the mutation, her father was not. She had been extensively studied during this period, and no other haemostatic abnormality was found.

The woman had been receiving lifelong care through a comprehensive haemophilia treatment centre at our institution. Good control of her disease had been achieved at adulthood with prophylactic recombinant FVIII concentrate, at a dose of 1500 IU weekly.

From genetic counselling, the couple knew that the odds of transmission to a male fetus would be 100%, if there were two copies of the mutated gene. The conception ended up being spontaneous, following a failed attempt to perform preimplantation genetic diagnosis. The male gender of the fetus was ascertained at the first trimester by a non-invasive fetal DNA test. A maternal array comparative genomic hybridization was suggested to pursue investigation about the possible implications of this rare genetic arrangement over the fetus, however the pregnant patient declined to pursue further studies.

A written antepartum and peripartum treatment plan, with the consensus of all specialists involved, was readily available on her medical record. During pregnancy, targeted factor activity (50%–200%) was achieved by administration of 2000 UI of intravenous recombinant factor VIII concentrate three times a week (with an average factor activity of 97%). Pregnancy was uncomplicated by haemorrhagic events, but she ended up being admitted at 35 weeks and 5 days due to pre-eclampsia.

Treatment

The recombinant factor regimen was maintained in the inpatient setting, but with an extra 1000 UI dose being administered before any intramuscular procedure. A caesarean section (CS) was performed at 36 weeks and 4 days due to a non-reassuring fetal status. Since there had been more than 24 hours since the previous factor administration, an additional dose of 2000 UI of intravenous recombinant factor VIII concentrate was administered just before going into the operating room, so there would be no contraindication to the procedures required, including the epidural anaesthesia. The surgery was uneventful. The cord blood sample confirmed the newborn’s haemophilia A.

After delivery, 2000 UI of the factor VIII concentrate was administrated twice a day during the first 48 hours, and once a day afterwards. Her lowest haemoglobin level was 8.8 g/dL, and there was no need for transfusion support.

Outcome and follow-up

The patient and her newborn were discharged 3 days after the delivery, with instructions for tight follow-up in the subsequent weeks. However she was readmitted a few hours later due to abdominal pain. From her initial blood work there were no other findings, besides a haemoglobin level of 9.4 g/dL. CT scan revealed an abdominal wall haematoma, without signs of active bleeding (figure 1). An extra dose of recombinant FVIII was readily administered. A few hours later her factor VIII activity was above the haemostatic target (124%), and the haematoma had been successfully managed conservatively.

Figure 1.

CT scan performed 4 days after delivery. An oval image at the abdominal wall suggestive of a local haematoma can be seen. (A) Sagittal plane (B) Axial plane.

Discussion

Symptomatic haemophilia A with severe features in women is extremely rare, but it has been associated with great morbidity and mortality.² Not unexpectedly, there is limited evidence on obstetric management and outcomes of pregnancies in these women.^1–3 From prevention of bleeding events during gestation and postpartum, to mode of delivery, and analgesia, there are several safety concerns for both mother and offspring.¹

A written treatment plan that adheres to published evidence, and that which results from a consensus of all involved specialists, should be readily available.⁶ The early determination of the fetus’ sex allowed prompt elaboration of a patient-centred multidisciplinary care plan for this woman. This plan, including the recombinant FVIII factor doses needed, depending on the procedure required, was available on the patient’s medical record. We believe it was a determining factor for the overall outcome.

The bleeding risk in a haemophilic mother with subnormal levels of FVIII should be assessed by measurement of her plasma factor levels, and proactively managed throughout pregnancy.⁷ In this case, FVIII activity on the normal range during pregnancy was successfully achieved with 2000 UI of intravenous recombinant concentrate three times a week, from the first to the third trimesters.

Approximately 4% of the men with haemophilia will have intracranial haemorrhage in the neonatal period, a condition associated with neurological deficits and mortality.^{8 9} Even extracranial haemorrhage may confer serious morbidity.⁹ It is acknowledged that fetuses at risk should be delivered by the least traumatic method, but the optimal mode of delivery for a fetus at risk remains a subject of debate.⁶ Ljung et al published one of the largest series to date on the optimal mode of delivery for haemophilia carriers. It is a retrospective review of the mode of delivery, and perinatal bleeding complications among 117 children with moderate to severe haemophilia A or B born in Sweden between 1970 and 1990. They found 23 events of neonatal bleeding associated with delivery. The incidence of neonatal cranial haemorrhage was 3% (3/87) with vaginal delivery, 64% (11/17) with vacuum extraction and 15% (3/13) with CS. The authors concluded that the risk of serious bleeding when performing a normal vaginal delivery is small for the offspring expected to be affected by haemophilia; however, they emphasise that it should be performed by the least traumatic method, with avoidance of prolonged labour and instrumentation, and with early access to CS, if the vaginal delivery does not proceed in a normal way.¹⁰ In a subsequent review, James et al pointed out that among the three cases of cranial haemorrhage in the CS setting, two women had previously been in labour, and that the single case of intracranial haemorrhage that occurred after elective CS could be attributed partly to severe prematurity.¹¹ Since it is not possible to predict which woman undergoing a vaginal delivery will ultimately require operative delivery, it is plausible that mortality and morbidity from intracranial haemorrhage can be reduced by elective CS delivery prior to onset of labour.¹¹ However, a general policy of delivery by CS in all cases where the fetus is known to be at risk of haemophilia cannot be expected to eliminate either intracranial haemorrhage, or other bleeding manifestations among haemophilic neonates.¹¹ In addition, in a subsequent observational study on bleeding complications during pregnancy and delivery in haemophilia carriers, CS was the only variable independently associated with an increased risk of maternal bleeding, in the primary and secondary postpartum periods.¹²

Therefore, regarding delivery, there is no ‘one size fits all’ approach. The optimal mode of delivery should be thoroughly evaluated on a case-by-case basis.¹² In the management plan elaborated in this case, if the delivery had to be scheduled, it was decided that a CS, instead of induction of labour, would be chosen, mainly because the pregnant woman being nulliparous, there would be a high probability of an unfavourable cervix at the start of induction, and overall higher odds of ending up needing an instrumental delivery, or emergent CS. In the setting of spontaneous labour the haematology team would be informed to determine the dose of the recombinant FVIII factor needed.

The readmission because of an abdominal wall haematoma highlights the need for tight monitoring during the postpartum period. Prophylaxis measures at delivery may prevent postpartum haemorrhage in the immediate period after delivery in these women, but they are still at risk of secondary postpartum haemorrhage for several weeks after delivery.⁴ This was apparent from the study by Nau et al, where these women had a higher risk of haemorrhage in the postpartum period compared with the general population, and with more than a third (37%) of all the 35 bleeding events occurring during the secondary postpartum period.¹² In conclusion, this case throws light on how to manage pregnancy and the postpartum period in women with symptomatic haemophilia A carrying a male fetus, which represents an uncommon event. We believe that the most important factor for successful management of these pregnancies is multidisciplinary planning, coordination of care and timely communication between the medical team, usually involving obstetrics, genetics, haematology, neonatology and anaesthesiology. Future larger prospective studies are required in order to compare current prevention and management strategies, so high-level evidence-based guidelines can be published.

Patient’s perspective.

It was hard to deal with this situation at the beginning of the pregnancy: all the uncertainty on the baby’s health and the risks I was under as well. Having a team supporting us at every moment of the pregnancy and the postpartum period was very important. This disease has been part of my life, and now is part of our family.

Learning points.

• The management of pregnancy of women with symptomatic haemophilia A is a challenge. Currently there are no high-level evidence-based guidelines available.

• These women and their newborns require complex, optimal and multidisciplinary care in a specialised centre, from preconception, to pregnancy and the postpartum period.

• A patient-centred plan must be defined early during the course of the pregnancy, and be readily available in the patients’ medical record.

• Postpartum haemorrhage, especially that occurring during the secondary postpartum period, should be carefully prevented and accounted for.

Ethics statements

Patient consent for publication

Obtained.