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Objective To assess the obstetric outcome in women with von Willebrand's disease or factor XI deficiency.
Setting Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital.
Population Women with von Willebrand's disease (n= 31) and with factor XI deficiency (n= 11) registered at the Royal Free Hospital Haemophilia Centre who had had a pregnancy within the previous 17 years (1980–1996), including 84 in women with von Willebrand's disease and 28 in women with factor XI deficiency.
Methods Women were interviewed and details of the obstetric history were obtained. The records of the Haemophilia Centre and the women's maternity records were also reviewed.
Results Threatened miscarriage occurred in 33% and 14% of pregnancies with von Willebrand's disease and factor XI deficiency, respectively. Excluding recurrent miscarriages, 14/68 (21%) of pregnancies with von Willebrand's disease and one pregnancy with factor XI deficiency miscarried spontaneously. There was an increased incidence of primary and secondary post-abortal bleeding complications. Factor VIJI and von Willebrand factor antigen and activity levels increased significantly in pregnancy in all women apart from those with severe von Willebrand's disease. Factor XI, however, did not show any significant change. No neonatal haemorrhagic complications in association with the birth process were reported, although ventouse and difficult forceps deliveries were avoided. Extensive perineal bruising and haematoma was reported in three women with von Willebrand's disease; two of these were associated with forceps delivery. The incidence of primary postpartum haemorrhage was 185% in von Willebrand's disease and 16% in factor XI deficiency. Blood transfusion was required in six cases of von Willebrand's disease and two cases of factor XI deficiency. Ten of fourteen instances of primary postpartum haemorrhage occurred when maternal factor levels were < 50 IU/dL with no prophylactic treatment for labour. The incidence of secondary postpartum haemorrhage was 20% in von Willebrand's disease and 24% in factor XI deficiency. None of the women who had prophylactic treatment during labour or the puerperium suffered any significant bleeding complications. There were three neonatal bleeding complications.
Conclusion Pregnancy, labour and the puerperium are associated with significant bleeding problems in women with von Willebrand's disease or factor XI deficiency, but these are largely preventable. Specialist obstetric care in close liaison with the haemophilia centre is essential to minimise maternal deficiency. and neonatal complications.
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Von Willebrand's disease is now recognised as the most common inherited bleeding abnormality with a prevalence of 0.8%1 to 1.3%2. It comprises a heterogenous group of autosomally inherited bleeding disorders. The commonest form of the disease, which accounts for approximately 70% of all cases, is type 1. This type is characterised by equally low plasma levels, usually between 5 and 40 IU/dL, of factor VIII and von Willebrand factor antigen and activity as assessed by ristocetin-induced cofactor assay. This is caused by reduced production of normally functioning von Willebrand factor, resulting in a secondary defect of factor VIII3. The pathophysiological basis of type 2 is qualitative abnormalities of von Willebrand factor. Type 2 comprises many different subtypes and is phenotypically very heterogeneous. Subtype 2 is characterised by the absence of large and intermediate size multimers and ristocetin-induced platelet agglutination in platelet rich plasma. In subtype 2B only large multimers are absent and interaction between platelets and von Willebrand factor is increased4. Subtype 2M has decreased platelet dependent function but normal multimers. Subtype 2N has a defect of factor VIII binding. Type 3 is the least common of all forms of von Willebrand's disease and is characterised by very low (or even undetectable) levels of plasma von Willebrand factor and factor VIII with severe bleeding manifestations.
Factor XI deficiency is a rare bleeding disorder with autosomal mode of inheritance. Factor XI levels are severely reduced (< 15 IU/dL) in homozygotes and partially deficient or low normal in heterozygotes5. Factor XI deficiency is particularly common in Ashkenazi Jews where the carrier rate is as high as 9%6. However, the disorder has been described in all racial groups. In the United Kingdom it is responsible for 3% of all women with bleeding disorders on the Haemophilia Centre Directors’ national register, and in some parts of the country a significant proportion of women have no known Jewish ancestry7.
Obstetric management and maternal and neonatal haemorrhagic complications in women with von Willebrand's disease have been addressed in several previous case reports and studies including small numbers of women and pregnancies8–10. The largest series reported by a single centre described 24 pregnancies in 13 women with von Willebrand's disease11. Apart from a description of the risk of bleeding during delivery and the puerperium5, there is no published literature on the obstetric experience in women with factor XI deficiency. The Royal Free Haemophilia Centre is one of largest in the UK. In this paper we report our experience over the previous 17 years of pregnancies complicated by von Willebrand's disease or factor XI deficiency.
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This is a large retrospective review of obstetric experience and outcome in women with von Willebrand's disease or factor XI deficiency, highlighting the high incidence of post-abortal and postpartum bleeding complications, as well as appropriate methods of management to minimise the risk of these complications. During the last 10 years there has been better understanding and advances in the treatment and prophylaxis of bleeding complications of these inherited bleeding disorders and increased awareness among obstetricians. Therefore, this study may not represent present day practice and may over-estimate pregnancy-associated complications because of the retrospective nature of the study (including pregnancies from as early as 1980). Most of the pregnancies from 1990 and onwards were managed in collaboration with the Haemophilia Centre, factor levels were monitored during pregnancy, and prophylaxis was considered when appropriate.
Preconceptional counselling should be given to women with inherited bleeding disorders and the genetic implications of their disorder should be discussed. The risk of a woman with type 1 von Willebrand's disease transmitting the disease to her child is 50%, as this type is autosomal dominant. However, only 33% of children born to these women are clinically affected, probably because of variable penetrance and expression of the abnormal gene12. The same is true for type 2A and most cases of type 2B. However, the situation is more complicated for the other subtypes of type 2 von Willebrand's disease. Extensive family studies are required to assess this risk. Type 3 von Willebrand's disease is an autosomal recessive disorder, and affected individuals are either homozygotes or compound heterozygotes. If a child with type 3 has already been born in the family, the risk of a subsequent child being affected is 25%. As type 3 von Willebrand's disease is a serious condition, the option of prenatal diagnosis should be offered to affected families.
Haemostatic response to pregnancy is variable in different types and subtypes of von Willebrand's disease. In type I von Willebrand's disease there is usually a progressive increase in factor VIII procoagulant activity, von Willebrand factor antigen and activity, and correction of the bleeding time during pregnancy10,13,14. Failure of primary haemostasis to improve significantly in pregnancy, especially severely affected type 1 women, has been reported11,15. In subtypes 2A and 2B, the production of von Willebrand factor may increase throughout the pregnancy, but the abnormal multimetric pattern remains unchanged9. This may explain the lack of clinical improvement in pregnancy and the greater risk of postpartum haemorrhage in these women than those with type 1 von Willebrand's disease11. In addition, women with subtype 2B may develop worsening thrombocytopenia during pregnancy16 due to increased production of the abnormal intermediate von Willebrand factor multimers. These multimers bind to platelets and induce spontaneous platelet aggregation.
Women with type 3 von Willebrand's disease show very little or no increase in their factor VIII and von Willebrand factor plasma levels. In our study while factor levels showed a significant increase in general, they failed to increase in both of our women with type 3 von Willebrand's disease.
Because of the great variability of haemostatic response of von Willebrand's disease to pregnancy between individuals and even in different pregnancies in the same individual (as seen in one of our patients) regular monitoring of coagulation factors is required. Von Willebrand factor activity has been considered17 to be the best predictor for risk of bleeding in pregnant women with von Willebrand's disease and bleeding may still occur in women with normal factor VIII procoagulant activity. Therefore, it is essential to monitor both von Willebrand factor antigen and activity levels, together with factor VIII procoagulant activity during pregnancy. The platelet count should also be monitored in type 2B women16. In women with factor levels < 50 IU/dL during the third trimester, appropriate prophylactic therapy for delivery requires correction of the quantitative and or qualitative von Willebrand factor defect, in addition to elevation of factor VIII levels. This means administration of products which contain von Willebrand factor (e.g. 8Y, Blood Product Laboratory; or Haemate P, Hoechst) and not pure factor VIII preparations.
The change in factor XI during pregnancy in factor XI deficient women has not been studied, and controversial results have been obtained in pregnant women in general, one study showing an increase18 and another a fall in factor XI levels19. In our study there was no significant change in factor XI levels. Prospective studies are required to assess factor XI changes during pregnancy in factor XI deficient women.
Vaginal bleeding during the first trimester has been estimated to occur in 16% of all pregnant women20. In our study 33% of pregnancies in women with von Willebrand's disease reported bleeding in the first trimester, and the overall spontaneous miscarriage rate was 21%. Therefore, although there appears to be a higher incidence of vaginal bleeding in the first trimester in women with von Willebrand's disease, there is no increase in the miscarriage rate. It is possible that these women seek medical care for any vaginal bleeding, even if minor, more readily than other pregnant women. The number of factor XI deficient pregnancies complicated by vaginal bleeding that also miscarried were too few to draw any conclusions. The incidence of antepartum haemorrhage did not seem to be higher than the general population in both von Willebrand's disease and factor XI deficiency. Our study also highlights the high risk of bleeding complications associated with miscarriages. Factor VIII and von Willebrand factor levels do not rise significantly until the second trimester by which stage many miscarriages have already occurred. Therefore, factor levels should be checked before termination of pregnancy and in women presenting with spontaneous miscarriage. Prophylactic treatment should be given when factor levels are < 50 IU/dL.
Labour and delivery are critical periods for women with bleeding disorders and their affected infants. The baby is potentially at risk of serious scalp haemorrhage, including scalp abrasions, cephalhaematoma, subgaleal haematoma and intracranial haemorrhage from the process of birth, invasive monitoring techniques or instrumental deliveries. Therefore, it is recommended that delivery should be achieved by the least traumatic method. Prolonged labour, and especially prolonged second stage of labour, should be avoided and early recourse to caesarean section should be considered. Vacuum extraction and mid cavity forceps and forceps involving the rotation of the head should be avoided. However, low forceps delivery may be considered less traumatic than caesarean section when the head is deeply engaged in the pelvis; delivery can be achieved as an easy outlet procedure, performed by an experienced obstetrician. An elective caesarean section has been recommended for delivery in women with type 2 and type 3 von Willebrand's disease8 to avoid bleeding complications in the newborn infant. Our study group included two vaginal deliveries in a woman with type 2B, a vaginal delivery and a low forceps in two women with type 3 von Willebrand's disease, with no neonatal complications. Three of these babies were later confirmed to have mild von Willebrand's disease.
At the time of delivery an anticoagulated sample of cord blood should be collected and sent to the haemophilia laboratory within two hours of collection for investigation. However, when assessing the neonatal clotting factor levels, it should be appreciated that these correlate with gestational age21 and reach adult levels at age of six months22. Thus, although severe forms of these disorders can be diagnosed at the time of birth, mild forms are not always reliably diagnosed, and the child should be screened later during the first year of life. Vitamin K should be given to the infant orally; immunisation by intradermal route and hepatitis B immunisation should be considered23. Intramuscular injections should be avoided, and the parents should be advised to postpone any circumcision at least until the diagnosis of bleeding disorders in the infant has been confirmed or refuted.
The risk of haematoma following regional anaesthesia in women with bleeding disorders and even in fully anticoagulated patients, has been reported to be low24,25. However, most anaesthetists are reluctant to perform spinal or epidural anaesthesia in these women. In our series regional analgesia/anesthesia for labour or caesarean section was used in eight pregnancies with von Willebrand's disease and in two that were factor XI deficient with no complications. We therefore advocate that these women should not be denied the benefits of regional blocks. Each woman should be assessed individually. Provided that clotting factors are > 50 IU/dL during the third trimester and the coagulation screen is normal when the woman presents in labour, these procedures could be made available.
The high incidence of primary postpartum haemorrhage in von Willebrand's disease, in particular in women with variant von Willebrand's disease, is well documented10,11. In our study the incidence of primary postpartum haemorrhage associated with von Willebrand's disease was 18.5%, and the majority occurred when maternal clotting factor was < 50 IU/dL with no prophylactic treatment for labour. As maternal coagulation factor activity falls rapidly after delivery the risk of secondary postpartum haemorrhage is even higher with a reported incidence of 25%11 to 28%10. We report an incidence of 20%. The incidence of primary and secondary postpartum haemorrhage has not been determined in women with factor XI. However, it has been reported that childbirth in factor XI deficient women is accompanied by relatively few problems5. Our study contrasts with this as the incidence of primary and secondary postpartum haemorrhage was 16% and 24%, respectively. None of the women with von Willebrand's disease or factor XI deficiency who received prophylactic treatment for labour and puerperium had any significant bleeding complication.
The risk of maternal haemorrhage complications can be avoided by minimising maternal trauma at delivery and prophylactic treatment with 1 -deamino-8-arginine vasopressin (DDAVP) or clotting factor concentrates when appropriate. It has been advocated that prophylactic administration of blood products containing von Willebrand factor be given to those with factor VIII procoagulant activity and von Willebrand factor activity levels < 50 IU/dL, and to all women with variant von Willebrand's disease10. Prophylactic infusion should start at the onset of labour, with the aim of raising factor VIII procoagulant activity and von Willebrand factor activity to > 50 IU/dL; this should be maintained for three to four days after vaginal delivery and four to five days after caesarean section23. DDAVP can be used in women with type 1 von Willebrand's disease and some of women with type 2A disease, as they respond favourably to this treatment with no risk of viral transmission. However, women with type 3 von Willebrand's disease do not respond to DDAVP, and it is contraindicated in women with type 2B disease as it can precipitate thrombocytopenia26. None of the women with von Willebrand's disease who received prophylaxis in our study had any significant bleeding complication. Because of the unpredictable nature of bleeding tendency, its poor relation to factor XI level5 and limited experience of pregnancy management in women with factor XI deficiency, labour and delivery should be managed with caution in a centre where appropriate treatment with fresh frozen plasma can be given promptly if there is any bleeding complication. Prophylaxis to cover caesarean section should be considered, especially in homozygous women. Fresh frozen plasma provides adequate haemostatic cover for operative procedures but carries the risk of viral transmission. Because of this risk, factor XI concentrate was introduced and its efficacy at preventing bleeding has been confirmed27,28. Recent data have shown that factor XI concentrate is associated with thrombosis27,28, and this should be considered when used in pregnancy or the postpartum period. In our study factor XI concentrate was used prophylactically for an amniocentesis, two caesarean sections and a normal vaginal delivery in two women without any complications.
Pregnancy, labour and puerperium are associated with particular problems in women with von Willebrand's disease or factor XI deficiency and their infants. Increased awareness and better understanding of these disorders by obstetricians and close collaboration with the local haemophilia centre is essential to achieve optimal outcome and to minimise maternal and neonatal complications. Management guidelines should be available and strictly followed by all the staff involved in the management of women with these complications.
This study was supported by the Katharine Dormandy Trust, charity number: 262434.