The Obstetrician & Gynaecologist 2007;9:1:27-33
doi: 10.1576/toag.9.1.027.27293
Copyright © 2007 by the Royal College of Obstetricians and Gynaecologists.
Management of women with inherited bleeding disorders in pregnancy
Claudia Chi, MBBS, Clinical Research Fellow1 and
Rezan A Kadir, MD FRCS MRCOG, Consultant Obstetrician and Gynaecologist2
1. Department of Obstetrics and Gynaecology, Royal Free Hospital, London NW3 2QG, UK
2. Department of Obstetrics and Gynaecology, Royal Free Hospital, Pond Street, London NW3 2QG, UK Email: rezan.abdul-kadir{at}royalfree.nhs.uk (corresponding author)
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Abstract
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Key content: - Pregnancy in women with inherited bleeding disorders requires specialised and individualised care using a multidisciplinary approach with obstetricians, midwives, haematologists and anaesthetists.
- Childbirth presents an intrinsic haemostatic challenge in these women and obstetricians may be the first to encounter haemorrhagic complications.
- An understanding and awareness of these disorders and close collaboration between obstetricians and haematologists are essential in ensuring a successful outcome.
Learning objectives:
- To understand the basic principles in the obstetric management of women with inherited bleeding disorders.
- To know the options available for prenatal diagnosis.
- To be aware of the increased risk of haemorrhagic complications in these women and their offspring.
Ethical issues:
- Advances in prenatal diagnosis and treatment of inherited bleeding disorders create complex dilemmas for families affected by these disorders.
Please cite this article as: Chi C, Kadir RA. Management of women with inherited bleeding disorders in pregnancy. The Obstetrician & Gynaecologist 2007;9:27–33.
Keywords carriers of haemophilia / factor XI deficiency / preconceptual counselling / prenatal diagnosis / von Willebrand disease
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Introduction
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Inherited bleeding disorders are not common but they are lifelong. Their prevalence and effects on women are far greater than previously realised. Many clinicians are not familiar with these disorders but may encounter such women under difficult or acute conditions. Childbirth presents a haemostatic challenge to women who can otherwise remain asymptomatic. Bleeding disorders may be the underlying cause of obstetric haemorrhage, and are often overlooked by clinicians.
This review addresses specific aspects of the obstetric management of women with inherited bleeding disorders, including prenatal diagnosis and antenatal, intrapartum and postnatal care. A multidisciplinary approach to their management with close collaboration between haematologists and obstetricians, at all stages, is necessary for the delivery of the best possible care. Inherited bleeding disorders discussed in this review include von Willebrand disease, carriership of haemophilia A and B, and factor XI deficiency, which account for almost 90% of all women with inherited bleeding disorders. Similar principles apply to the obstetric management of other rare inherited bleeding disorders listed in Table 1. However, because of their rarity and the need for more specialised care, they are not covered specifically in this review.
Von Willebrand disease
Von Willebrand disease is the most common inherited bleeding disorder, with a prevalence of approximately 1%.1,2 It results from either a quantitative or qualitative defect in von Willebrand factor (VWF), a large multimeric protein which mediates platelet adhesion and serves as a carrier protein for factor VIII. There are three main types of von Willebrand disease. Type 1 is characterised by a partial deficiency of VWF antigen. It accounts for 70–80% of cases and is usually mild. Type 2 is caused by a functional defect of the VWF protein. It consists of four subtypes based on their different pathophysiologic mechanisms (Table 2). Both types 1 and 2 are transmitted as an autosomal dominant trait. Type 3 is characterised by a virtual absence of von Willebrand factor and is, therefore, typically severe. It is an autosomal recessive disorder and affected individuals are either homozygotes or compound heterozygotes.
Haemophilia A and B
Haemophilias A and B result from deficiencies of coagulation factors VIII (FVIII) and IX (FIX), respectively. They are less common than von Willebrand disease but are the most common severe inherited bleeding disorders. They can cause significant morbidity and mortality through a spectrum of bleeding manifestations of various severities, for example, easy bruising, deep muscle and joint haemorrhage, spontaneous or post-surgery/post-traumatic bleeding and intracranial bleeding. Both are X-linked recessive disorders: men inherit the condition and women are affected as carriers. Haemophilia A affects 1 in 5 000 live male births and haemophilia B 1 in 30 000 live male births. Carriers of haemophilia usually have a clotting factor level around 50% of normal as they have only one affected chromosome. However, a wide range of values (22–116 iu/dl) have been reported as a result of lyonisation (random inactivation of one of each pair of X chromosomes).3,4 Some haemophilia carriers have very low factor levels and are, therefore, at risk of severe bleeding complications.5
Factor XI deficiency
Factor XI (FXI) deficiency is a rare inherited bleeding disorder. However, it is particularly common in Ashkenazi Jews, in whom the heterozygote frequency is 8%.6 FXI levels (normal range = 70–150 iu/dl) are severely reduced (<15 iu/dl) in homozygotes and partially deficient (15–70 iu/dl) in heterozygotes.7 Unlike haemophilias A and B, there is a poor correlation between bleeding tendency and FXI levels in patients with FXI deficiency.7,8 The bleeding tendency can also vary in the same individual following different haemostatic challenges. This unpredictable nature of FXI deficiency makes management for pregnancy and delivery particularly difficult.
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Preconceptual counselling
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Identification of affected or carrier status should ideally be carried out before pregnancy for women in families with inherited bleeding disorders, to allow appropriate preconceptual counselling and early pregnancy management. This is most important for women who are carriers of haemophilia or couples with FXI deficiency or type 3 von Willebrand disease. The preconceptual period is important if a trial of desmopressin is being considered.
Carrier detection for haemophilia is based on four different methods:
- Pedigree analysis, using the knowledge of X-linked recessive inheritance, to assess a woman's risk from her position in the family tree. Daughters of a man with haemophilia are obligate carriers.
- Phenotypic assessment based on assays of plasma FVIII, FIX and, in some cases, VWF.
- Direct gene mutation detection.
- Indirect gene analysis involving the use of linked polymorphic markers to track heredity of a haemophilia gene within a pedigree when the mutation is not known.
Direct gene analysis allows definitive diagnosis of carrier or non-carrier status while the other methods only ascertain risk of carriership of haemophilia. As 20% of all people with haemophilia A and 50% of those with severe haemophilia have intron 22 inversion mutation, this is the starting point of direct mutation detection for severe cases. Mutation screening is performed in the remaining 80%. At our centre more than 95% of causative mutations are currently identified through direct gene analysis. When this not possible, linkage analysis is then undertaken.
Preconceptual counselling has two roles. The first is to provide women and their partners 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 will assist them to reach a decision that is appropriate to their situation. Psychological support should be available during all aspects of counselling with an understanding of the ethnic and cultural influences on each individual. 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, for example, regarding folic acid supplementation.
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Prenatal diagnosis
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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 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 von Willebrand disease the option of prenatal diagnosis is offered when the fetus is at risk of being affected by severe forms of the disorder, principally type 3. Similarly, in FXI deficiency, prenatal diagnosis is offered when there is a risk of severe FXI deficiency in the child. Because of the large number of different genetic mutations implicated in FXI deficiency, prenatal diagnosis is often difficult except in Ashkenazi Jews, in whom there are two predominant mutations.6
Invasive methods
Invasive prenatal diagnostic methods, such as chorionic villus sampling (CVS) and amniocentesis, allow definitive diagnosis but are associated with a risk of procedure related fetal loss. CVS is the method most widely used today for the prenatal diagnosis of haemophilia and other severe forms of inherited bleeding disorders. It is performed at 11–14 weeks of gestation under ultrasound guidance. It has the advantage of earlier diagnosis compared with amniocentesis, which is performed at 15–20 weeks of gestation. Both are associated with a 1% risk of miscarriage. Cordocentesis (ultrasound guided fetal blood sampling) is performed at around 18–20 weeks of gestation to obtain fetal blood for clotting factor assay. The procedure related fetal loss rate was reported as 1.4%.9 It is rarely performed today but can be an option for cases in which the causative mutation cannot be identified. While prenatal diagnosis is now widely available, the uptake rate of termination of pregnancies affected by haemophilia remains low. Many carriers do not consider haemophilia to be a sufficiently severe disorder to justify termination of pregnancy.10 There also has been a substantial improvement in the management of haemophilia and the quality of life of affected individuals.
Non-invasive determination of fetal sex
When parents do not opt for invasive prenatal diagnosis, non-invasive determination of fetal sex is very useful in the management of pregnancies at risk of haemophilia. The identification of male fetuses, which have a 50% chance of being affected, enables the management plan for labour and delivery to be refined to avoid the use of instrumental deliveries and invasive monitoring techniques (for example, fetal blood sampling) in pregnancies at risk. Fetal sex determination can be done easily and accurately by ultrasound from the second trimester. When performed in the first trimester, it has the added advantage of avoiding invasive prenatal testing (CVS) in female pregnancies.11 Fetal sex can be determined at 11–14 weeks of gestation by ultrasound assessment of the fetal genital tubercle.11,12,13 The accuracy of this method increases with advancing gestation: from 70.3% at 11 weeks to 98.7% at 12 weeks and 100% at 13 weeks.12
Another non-invasive method of determining fetal sex is the analysis of free fetal DNA in maternal circulation. Using real-time quantitative PCR, several groups have demonstrated a 100% sensitivity and specificity in the detection of male fetuses.11,14,15 The combined use of both methods increases the confidence of women and clinicians in the accuracy of these tests and provides carriers of haemophilia with a reliable option for avoiding invasive testing in female pregnancies.11 However, at present both tests are still being performed in research settings and are not yet widely available in the UK.
Preimplantation genetic diagnosis
Preimplantation genetic diagnosis is a relatively new technique that uses in vitro fertilisation (IVF) to create embryos. They can then be tested to identify unaffected embryos and be selectively transferred to the uterus. This can eliminate the difficult decision of whether or not to terminate an affected pregnancy. There have been reports of its success recently in carriers of haemophilia.16 It is likely to become a realistic option for some individual cases in the near future. However, further evidence on its efficacy and safety is still required. The cost and stress of IVF also need to be considered.
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Antenatal management
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Pregnancy is accompanied by various haemostatic changes. These include a rise in levels of factor VIII coagulant activity and von Willebrand factor antigen and activity (VWF:Ag and VWF:Ac) in normal women, as well as in carriers of haemophilia A and women with type 1 von Willebrand disease.17,18,19 In contrast, factor IX and XI levels do not rise significantly during pregnancy.17,18
It is vital to check clotting factor levels and arrange prophylactic cover, if necessary, before any invasive procedures (for example, prenatal testing or termination of pregnancy) and in cases of spontaneous miscarriage. These events can be complicated by excessive or prolonged bleeding as they commonly occur in the first trimester when the clotting factor levels may not have risen significantly. Treatment is not usually required in carriers of haemophilia A and women with type 1 von Willebrand disease during late pregnancy or at delivery, as clotting factor levels often rise to within normal ranges. However, there is still great variability in an individual's haemostatic response to pregnancy and a significant proportion can still have low clotting factor levels at term, particularly those with severe deficiencies.
In type 2 von Willebrand disease, FVIII coagulant activity and VWF:Ag levels normally increase during pregnancy, but most studies show minimal or no rise in VWF activity with a persistently abnormal pattern of multimers, reflecting an increased production of abnormal VWF.19,20,21 Despite the increase in factor VIII and VWF production during pregnancy, FVIII coagulant activity levels are often low in women with subtype 2N von Willebrand disease because of impaired binding by the abnormal VWF.21 In subtype 2B von Willebrand disease, thrombocytopenia can develop or worsen during pregnancy because of the increased production of abnormal intermediate VWF multimers which bind to platelets and induce spontaneous platelet aggregation.22 For this reason additional monitoring of platelet count is recommended in women with type 2 von Willebrand disease. Women with type 3 von Willebrand disease show no increase in their FVIII coagulant activity, VWF:Ag and VWF:Ac levels during pregnancy.18
Often it is not possible to check clotting factor levels in acute situations. Therefore, routine monitoring of the relevant clotting factor levels should be carried out at booking, 28 and 34 weeks of gestation and before any invasive procedures. Testing at 28 weeks of gestation can be useful for women who might deliver early, allowing better management, should labour ensue. Prophylactic treatment, such as recombinant clotting factor, clotting factor concentrates, tranexamic acid or desmopressin, depending on the bleeding disorder (see Table 4), should be arranged when factor levels are less than 50 iu/dl for FVIII, FIX, VWF:Ag and VWF:Ac or less than 70 iu/dl for FXI to cover invasive procedures, labour, delivery and the first few postpartum days. It is also important to consider each individual's bleeding tendency, particularly in women with FXI deficiency.
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Table 4
Treatment options for carriers of haemophilia and women with von Willebrand disease or factorXI deficiency during labour, delivery and in the postpartum period
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Labour and delivery
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Labour and delivery are critical times for women with inherited bleeding disorders and their affected child as they can be exposed to various haemostatic challenges. Delivery at a tertiary obstetric unit with an on-site haemophilia centre is not required for all of them. However, close liaison with the haemophilia centre or haematologist throughout pregnancy is essential and arrangement for delivery should be made in advance. It is recommended that women with a severe deficiency, or carrying an affected/potentially affected fetus, plan the delivery at a unit where the necessary expertise in the management of bleeding disorders, resources for laboratory testing and clotting factor treatments are readily available.
Women with inherited bleeding disorders are at increased risk of bleeding complications during and after delivery, especially if their factor levels are subnormal. There is some evidence that even carriers of haemophilia with normal factor levels have increased haemorrhagic risk compared with non-carriers.23 At the beginning of labour, maternal blood samples should be taken for group and save, full blood count and coagulation screening. Factor levels are generally not measurable in the acute setting. Planning for delivery should be done on the basis of the third trimester levels.
For women with low factor levels, intravenous access should be established and prophylactic treatment given to cover labour and delivery. The aim of prophylactic treatment is to raise factor levels to above 50 iu/dl for FVIII, FIX, VWF:Ag and VWF:Ac or to 70 iu/dl for FXI for vaginal delivery or caesarean section. Treatment options available are shown in Tables 1 and 4. As they are specialised therapies, they should be provided under the supervision of a haematologist. When treatment is required, recombinant products, if available, should be regarded as the products of choice to avoid the potential risk of viral transmission.24 Desmopressin, a synthetic analogue of the antidiuretic hormone vasopressin, increases the plasma concentration of FVIII and VWF through endogenous release.25,27 It is effective in selective cases and has the advantage of avoiding the risks of bloodborne viral infection. A test dose, often given as part of the preconceptual assessment, is recommended, as the response is variable between individuals. It can be given parenterally (intravenously or subcutaneously) or as a nasal spray. As a result of its antidiuretic effects, there is a risk of fluid overload and hyponatraemia.28 Therefore, fluid intake should be restricted to 1.5 litres in 24 hours with its use and repeated administration avoided.
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Regional anaesthesia/analgesia
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The use of regional anaesthesia/analgesia in women with bleeding disorders is controversial because of the potential risk of epidural or spinal haemorrhage and haematoma, which can lead to permanent neurological damage. However, provided the coagulation screen is normal and levels of the relevant factor activity during the third trimester is above 50 iu/dl, regional anaesthesia is not contraindicated.17,29 In women with levels of factor activity below 50 iu/dl or severe forms of inherited bleeding disorders (such as type 2 and 3 von Willebrand disease and homozygote FXI deficiency), the use of regional anaesthesia is generally not recommended and should only be considered after careful evaluation of the potential risks and benefits, along with appropriate counselling and adequate haemostatic cover. The woman, anaesthetist, haematologist and obstetrician should jointly make a decision on its use in advance. An experienced anaesthetist should perform the regional block. The extent of motor block should be assessed frequently until the anaesthetic has worn off and the catheter has been removed. If the degree of motor block is more than that expected or if it appears to be prolonged, investigations should be carried out to check for development of an epidural haematoma. If factor levels cannot be checked before removal, prophylaxis must be continued until after catheter removal as the pregnancy induced rise in factor levels can quickly reverse after delivery and bleeding in the spinal canal can then arise. Intramuscular analgesia should be avoided in women with bleeding disorders.
Invasive intrapartum monitoring techniques (for example, use of a fetal scalp electrode, fetal blood sampling) and instrumental deliveries (ventouse, midcavity or rotational forceps) should be avoided in pregnancies where the fetus is at risk of a bleeding disorder, as serious head bleeding can result from these procedures. Caesarean section does not appear to eliminate the risk of serious neonatal bleeding complications.30 Therefore, normal vaginal delivery is not contraindicated in these pregnancies. However, prolonged labour should be avoided and delivery achieved by the least traumatic method. Early recourse to caesarean section should be considered to minimise the risk of neonatal bleeding complications. Low forceps delivery is considered less traumatic than caesarean section when the head is deeply engaged in the pelvis and an easy outlet delivery is anticipated. Delivery in these cases needs to be performed by an experienced obstetrician.
A cord blood sample should be collected from neonates at risk of moderate or severe inherited bleeding disorders to assess coagulation status and clotting factor levels. This enables identification and early management of newborns at risk of haemorrhagic complications. If delivery has been traumatic or if there are clinical signs suggestive of head bleeding, a cranial ultrasound should be performed. It is also advisable to consider prophylactic cover in these cases. Intramuscular injections should be avoided in neonates at risk until the coagulation status is known. Vitamin K should be given orally and routine immunisations given intradermally or subcutaneously. Any surgical procedures (for example, circumcision) should be delayed until the coagulation status of the neonate is known. When assessing the neonatal clotting factor levels, it should be appreciated that these correlate with gestational age and reach adult levels at 6 months of age. It is, therefore, not reliable to diagnose mild forms of inherited bleeding disorders at birth and cord blood samples should not be taken to diagnose these mild disorders.
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Postpartum management
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Women with inherited bleeding disorders are at increased risk of haemorrhagic complications after termination of pregnancy, miscarriage and delivery. They are at risk of both primary and secondary postpartum haemorrhage (PPH) because of the rapid fall in the pregnancy induced rise in maternal clotting factor levels (FVIII and VWF) after delivery. The incidence of primary and secondary PPH is increased among haemophilia carriers17 (22% and 11%, respectively) and women with FXI deficiency18 (16% and 20%, respectively) compared with the general population (5% and 0.7%, respectively).31,32 Similarly, for women with von Willebrand disease, primary PPH has been shown to complicate 16–29% of pregnancies, while secondary PPH complicates 20–29%.18,19,21
Bleeding complications such as PPH usually occur in women with von Willebrand disease and carriers of haemophilia when maternal clotting factor is low (<50 iu/dl). The risk of bleeding can, therefore, be minimised by prophylactic treatment with desmopressin or clotting factor concentrate when appropriate. In women with FXI deficiency, factor levels may not reflect the risk of haemorrhage. Those with severely low levels or a positive bleeding history will require prophylactic treatment, especially if delivery is operative. The aim of prophylactic treatment is to raise factor levels to above 50 iu/dl for FVIII, FIX, VWF:Ag and VWF:Ac or to 70 iu/dl for FXI during labour and delivery and to maintain this for at least 3 days after vaginal delivery and at least 5 days after caesarean section (see Table 4). Care should be taken in minimising maternal genital and perineal trauma to reduce the risk of postpartum haemorrhage. It is also important not to overlook the obstetric causes of PPH.
Women with inherited bleeding disorders can experience prolonged and/or intermittent secondary postpartum haemorrhage.18,20 Tranexamic acid, intranasal desmopressin (in acute episodes) or the combined oral contraceptive pill (in non-breastfeeding women) can be used to control this type of postpartum bleeding (Table 4). With the average time of presentation of PPH in women with von Willebrand disease being 15.7 ± 5.2 days,33 there is potentially the need for prophylaxis and/or close observation for up to several weeks postpartum.
Pregnancy is a well recognised risk factor for venous thromboembolism (VTE). Women with bleeding disorders have an inherently low risk for VTE. However, bleeding disorders do not fully protect against it.34 Thromboprophylaxis post-delivery should be considered in the presence of additional risk factors, especially the use of clotting factor concentrates. Replacement therapy corrects the coagulation defect and, therefore, is likely to return the risk of VTE in these women closer to that of the general population. Factor XI concentrates, in particular, have a prothrombotic potential, hence its concomitant use with tranexamic acid should be avoided. There is a fine balance between the risk of thrombosis and haemorrhage in women with inherited bleeding disorders. Each individual requires careful risk assessment for VTE and general measures such as avoidance of dehydration and prolonged immobility should be adopted to minimise the risk.
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Conclusion
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Optimal obstetric management of women with inherited bleeding disorders requires a good understanding of these disorders and an awareness of the potential maternal and neonatal complications. A multidisciplinary team of obstetricians, haematologists, and anaesthetists should collaboratively formulate a prospective and individualised management strategy.
It is generally suitable for women with a mild bleeding disorder to have shared antenatal care between their local obstetric unit and a tertiary centre allied to a haemophilia centre with the delivery planned at their local unit. However, it is recommended for women with severe or rare inherited bleeding disorders and those carrying an affected, or potentially affected, fetus to deliver at a tertiary unit with an on-site haemophilia centre. The plan of management should be well documented in the case notes with a copy given to the woman to allow effective communication. Availability of and adherence to management guidelines help to minimise maternal and neonatal complications. These measures collectively improve the care provided for these women and their pregnancy outcomes (see Box ).
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References
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TOP
Abstract
Introduction
