Introduction

Inherited bleeding disorders are lifelong conditions that are associated with a broad spectrum of bleeding manifestations. Women with inherited bleeding disorders may face several haemostatic challenges during pregnancy and childbirth. Pregnancy in these women requires specialised and individualised management provided by a multidisciplinary team of obstetricians, haematologists and anaesthetists. Advance planning, in addition to a good understanding and awareness of the potential maternal and neonatal complications, are essential in ensuring an optimal outcome. In this review, we addresses different types of inherited bleeding disorders and the physiological changes in coagulation during pregnancy in affected women. We also address the specific aspects of the obstetric management of women with inherited bleeding disorders, including prenatal diagnosis and antenatal, intrapartum and postnatal care. Von Willebrand disease and carriership of haemophilia account for most inherited bleeding disorders in women, and are discussed in details in this review. Similar principles, however, apply to the obstetric management of the rarer inherited bleeding disorders. Key points in the management of these rarer disorders are summarised in the final section.

von Willebrand disease

von Willebrand disease (VWD) is the most common inherited bleeding disorder, with an estimated prevalence of about 1% from population screening studies. von Willebrand disease is the result of a quantitative or qualitative defect in von Willebrand factor (VWF), a large multimeric protein that mediates platelet adhesion and serves as a carrier protein for factor VIII (FVIII). Three main types of VWD exist. Type I VWD is characterised by a partial deficiency of VWF. It accounts for 70–80% of cases and is usually mild. Type 2 VWD is caused by a functional defect of the VWF protein. It consists of four subtypes based on their different pathophysiologic mechanisms ( Table 1 ). Type 1 and most type 2 VWD are transmitted as an autosomal dominant trait. Type 3 VWD is characterised by a virtual absence of VWF, and is therefore typically severe. The inheritance is autosomal recessive.

von Willebrand disease

von Willebrand disease (VWD) is the most common inherited bleeding disorder, with an estimated prevalence of about 1% from population screening studies. von Willebrand disease is the result of a quantitative or qualitative defect in von Willebrand factor (VWF), a large multimeric protein that mediates platelet adhesion and serves as a carrier protein for factor VIII (FVIII). Three main types of VWD exist. Type I VWD is characterised by a partial deficiency of VWF. It accounts for 70–80% of cases and is usually mild. Type 2 VWD is caused by a functional defect of the VWF protein. It consists of four subtypes based on their different pathophysiologic mechanisms ( Table 1 ). Type 1 and most type 2 VWD are transmitted as an autosomal dominant trait. Type 3 VWD is characterised by a virtual absence of VWF, and is therefore typically severe. The inheritance is autosomal recessive.

Haemophilia A and B

Haemophilias A and B are caused by a deficient or defective coagulation factor VIII (FVIII) or IX (FIX), respectively. They are less common than VWD but are the most frequent severe inherited bleeding disorders. They can cause significant morbidity and mortality through a spectrum of bleeding manifestations, including easy bruising, deep-muscle and joint bleeding, spontaneous, post-surgery or traumatic bleeding, and intracranial bleeding. Both are X-linked recessive disorders, hence men inherit the condition and women are affected as carriers. Carriers of haemophilia are expected to have a clotting factor level around 50% of normal, as they have only one affected chromosome. A wide range of values (5–219 IU/dL), however, has been reported as a result of lyonisation (random inactivation of one of each pair of X chromosomes). Some haemophilia carriers may have low factor levels, and are therefore at risk of severe bleeding complications.

Rare bleeding disorders

The rare bleeding disorders include the inherited deficiencies of coagulation factors, such as fibrinogen, factor (F) II, FV, FV and FVIII, FVII, FX, FXI, FXIII, and multiple deficiencies of vitamin-K-dependent factors. Their clinical manifestations range from mild to severe. They are usually transmitted in an autosomal recessive manner. They represent about 3–5% of all the inherited bleeding disorders. The estimated prevalence (of the homozygous or double heterozygous forms) varies between 1 in 500,000 and 1 in 2 million in the general population. The prevalence of these rare bleeding disorders, however, is much higher in countries where consanguineous marriages are relatively common. Another exception is FXI deficiency, which is particularly common in Ashkenazi Jews in whom the heterozygote frequency is 8%. Because of the rarity of these disorders, limited data are available on the clinical manifestations, diagnosis and management of affected individuals, especially during pregnancy. It is, therefore, particularly important that these women are managed in close collaboration with specialised centres and haematologists to ensure optimal pregnancy outcome.

Haemostatic changes in pregnancy

Various haemostatic changes occur during normal pregnancy and are presented in Table 2 . They are generally in the direction of hypercoagulability and are considered to be in preparation for the haemostatic challenge of delivery. In women with inherited bleeding disorders, similar haemostatic responses to pregnancy are seen. This can result in normalisation of the haemostatic defect in some of these women. The response, however, is variable in different inherited bleeding disorders, and large inter–individual variations also exist among women with the same disorder. Furthermore, women with factor deficiencies may not achieve the same factor levels during pregnancy as those of women without factor deficiencies.

Factor VIII levels increase progressively in carriers of haemophilia A during pregnancy, reaching its peak in the third trimester. Consequently, most carriers of haemophilia A have normal (over 50 IU/dL) FVIII levels at term. In contrast, FIX level does not increase significantly during pregnancy. Most carriers of haemophilia B with a low baseline (non-pregnant) level will continue to have the haemostatic defect at term.

A progressive increase in levels of FVIII coagulant activity (FVIII C), VWF antigen and VWF activity (VWF: AC) is seen during pregnancy in most women with type 1 VWD, with the greatest improvement seen in the third trimester. Most of these women achieve factor levels greater than 50 IU/dL at term. Lack of improvement in the haemostatic defect, however, has been reported in women with severe type 1 VWD. Similarly, women with type 3 VWD show no increase in their FVIII and VWF levels. In type 2 VWD, FVIII and VWF antigen levels usually increase during pregnancy, but most studies show minimal or no increase in VWF: AC levels and a persistently abnormal pattern of multimers, reflecting the increased production of abnormal VWF. This pattern, however, varies between individuals and different subtypes of type 2 VWD. In women with subtype 2 N VWD, FVIII levels often remain low despite increased FVIII and VWF production during pregnancy owing to impaired binding by the abnormal VWF. The diagnosis of type 2 N VWD during pregnancy could be mistaken for carriership of haemophilia A or it may be masked by an increase in FVIII level to the normal range in milder cases. In subtype 2B, thrombocytopaenia may develop or worsen during pregnancy because of increased production of the abnormal intermediate VWF multimers, which bind to platelets and induce spontaneous platelet aggregation. For this reason, additional monitoring of platelet count is recommended in these women. Type 2B VWD should be included in the differential diagnosis of thrombocytopaenia during pregnancy, especially in women with a personal or family bleeding history, as it could be misdiagnosed as idiopathic thrombocytopaenic purpura, resulting in unnecessary and ineffective therapy.

Limited data are available on the haemostatic response to pregnancy in women with rare bleeding disorders. In general, their haemostatic abnormalities persist throughout pregnancy, especially in women with homozygote or severe deficiency.

Preconceptual counselling

Identification of affected or carrier status should ideally be carried out before pregnancy for women from families with inherited bleeding disorders in order to allow appropriate preconceptual counselling and early pregnancy management. This is particularly important for carriers of haemophilia or families with severe inherited bleeding disorders. Preconceptual counselling has two main purposes. The first is to provide the women and their partner with adequate information on the genetic implications of their disorders, their reproductive choices and the management of their pregnancies, including options of prenatal diagnosis. This would assist them in reaching a decision that is appropriate to their situation. The second is to allow planning for pregnancy and to perform a trial of desmopressin if appropriate. Other aspects of preconceptual care include immunisation against hepatitis A and B for those likely to require blood transfusion, and general advice such as folic acid supplementation.

Prenatal diagnosis

Prenatal diagnosis forms an integral part of the care provided for women and families affected by inherited bleeding disorders. It is primarily considered in carriers of haemophilia because of the severity of the disorder in their male offspring and the knowledge of genetic defects in many of the affected families. In each pregnancy, carriers of haemophilia have a 50% chance of having a male fetus that is affected and a 50% chance of having a female fetus that is also a carrier. Options available for prenatal diagnosis of haemophilia are presented in Table 3 . In other inherited bleeding disorders, the option of prenatal diagnosis is offered when the fetus is at risk of being affected with severe forms of the disorder and generally when the causative mutation has been identified.

Invasive prenatal diagnostic methods, such as chorionic villus sampling and amniocentesis, allow definitive diagnosis but are associated with a risk of procedure-related fetal loss. Chorionic villus sampling is the method most widely used today for the prenatal diagnosis of haemophilia or other severe forms of inherited bleeding disorders. It is carried out at 11–14 weeks gestation under ultrasound guidance. It has the advantage of earlier diagnosis compared with amniocentesis, which is carried out at 15–20 weeks gestation. Both are associated with an approximate 1% risk of miscarriage. Cordocentesis, ultrasound-guided fetal blood sampling, is carried out at around 18–20 weeks gestation to obtain fetal blood for clotting factor assay. The procedure-related fetal loss rate has been reported as 1–2%. It is not commonly carried out today, but may be an option for cases in which the causative mutation cannot be identified. Although prenatal diagnosis is now widely available, the uptake rate of prenatal diagnosis and termination of pregnancies affected with haemophilia remains low. Many carriers of haemophilia do not consider haemophilia to be a sufficiently severe disorder to justify termination of pregnancy. In addition, a substantial improvement has taken place in the management of haemophilia and the quality of life of affected individuals.

When invasive prenatal diagnosis has not been opted for by the parents, non-invasive determination of fetal gender is useful in the management of pregnancies at risk of haemophilia. The identification of male fetuses enables the management plan for labour and delivery to be refined to avoid the use of instrumental deliveries and invasive monitoring techniques (e.g. fetal blood sampling) in pregnancies at risk. Fetal gender determination can be done easily and accurately by ultrasound from the second trimester. When conducted in the first trimester, it has the added advantage of allowing the avoidance of invasive prenatal testing (chorionic villus sampling) in female fetuses. Fetal sex can be determined at 11–14 weeks gestation by ultrasound assessment of the fetal genital tubercle. Accuracy of this method increases with advancing gestation from 70% at 11 weeks to 99% at 12 weeks and 100% at 13 weeks. Another non-invasive method of determining fetal gender is the analysis of free fetal DNA in maternal plasma. Using real-time quantitative polymerase chain reaction, several groups have shown a 100% sensitivity and specificity in the detection of male fetuses. This test is currently available in certain laboratories in the UK for indications such as haemophilia. The combined use of both non-invasive methods can increase the confidence of women and clinicians in the accuracy of these tests, and provides carriers of haemophilia a reliable option of avoiding invasive testing in female fetuses. Recently, non-invasive specific prenatal diagnosis of haemophilia through analysis of free fetal DNA in maternal blood was achieved using digital polymerase chain reaction based on a relative mutation dosage approach.

Pre-implantation genetic diagnosis is another relatively new technique that uses in-vitro fertilization to create embryos that can be tested to identify unaffected embryos and selectively transferred to the uterus. This can eliminate the difficult decision of whether to terminate an affected pregnancy. Reports have been published of its success in carriers of haemophilia. It is likely to become a realistic option for some individual cases in the near future. Further evidence on its efficacy and safety, however, is still required. The cost and stress of in-vitro fertilization also need to be considered.

Antenatal management

Potential haemostatic challenges during pregnancy include miscarriage, antepartum haemorrhage and invasive procedures, such as prenatal diagnostic tests, termination of pregnancy and insertion of cervical cerclage. These events can be complicated by excessive, prolonged bleeding, or both, especially in the first half of the pregnancy when clotting factor levels may not have risen significantly. It is, therefore, important to assess the relevant clotting factor level and arrange prophylactic cover, if necessary, before invasive procedures and in cases of miscarriage to minimise the bleeding risk. Ideally, clotting factor levels should be checked at booking, and at 28 and 34 weeks of gestation, especially in women with low pre-pregnancy levels. Having factor levels checked at planned intervals allows their availability in acute situations when factor levels often cannot be accessed easily. Monitoring in the third trimester is of particular importance for the appropriate management of labour and delivery, which will be addressed in the next section. A management plan for labour and delivery should be devised during pregnancy and be made available when the woman presents in labour or for a planned delivery.

A summary of prophylaxis and treatment options during pregnancy available for each inherited bleeding disorders is shown in Table 4 . They are specialised treatments, hence should be provided under the supervision of the haemophilia centre and haematologists. When prophylaxis or treatment is required, recombinant products, if available, should be regarded as the products of choice to avoid the potential risk of viral transmission. In general, haemostatic cover is required for women with subnormal factor levels undergoing invasive procedures during pregnancy, or if they experience significant bleeding or haematoma.