Description of the condition
Congenital bleeding disorders are relatively uncommon, however, they may be challenging during acute episodes. During pregnancy these disorders may present a haemostatic challenge resulting in excessive bleeding and as a cause of obstetric haemorrhage, bleeding disorders are often underestimated. Inherited bleeding disorders, mainly von Willebrand disease (VWD), haemophilia A and B factor XI and factor VII deficiency account for almost 90% of all women with inherited bleeding disorders (Chi 2007). Deficiencies in factors such as fibrinogen, prothrombin, factor V, FX, FXIII are comparatively rare.
Von Willebrand disease results from either a quantitative or qualitative defect in von Willebrand factor (VWF). A physiological increase in VWF (with levels in blood plasma up to normality) is often seen during pregnancy in women with a severe form of VWD (excluding type 3), but intrapatient variability is wide (Conti 1986). A rapid fall of VWF occurs following delivery in women with VWD, and they are more prone to both early haemorrhage (blood loss of more than 500 ml within 24 hours of delivery of the baby) and late haemorrhage (any significant loss between 24 hours and 6 weeks after the birth) in the puerperium. The occurrence of early and late postpartum haemorrhage (PPH) among VWD is 16% to 29% and 20% to 29%, respectively (Greer 1991; Kadir 1998).
Congenital haemophilias are X-linked recessive bleeding disorders that result from deficiencies of coagulation factors VIII and IX. Most female carriers of haemophilia have levels of factor VIII (or IX) within the normal range, but a significant proportion have a modest reduction in the baseline level. The baseline level is seldom lower than 20% of the normal level and should therefore be enough to protect against significant bleeding problems in day-to-day life (Giangrande 2003). Female carriers of haemophilia A who are pregnant, usually have normal levels of factor VIII by the third trimester, because even in those with low levels at the beginning, factor VIII increases as gestation advances. However, those with levels of factor VIII (or IX) less than 50% (< 0.50 IU/mL) are at increased risk of bleeding when facing haemostatic challenges (Lusher 1978). In normal pregnancy, levels of factor VIII nearly double over the normal baseline value, whereas factor IX levels do not rise significantly (Stirling 1984). Female carriers of haemophilia A are at increased risk of haemorrhagic complications, both early and late PPH, after invasive procedures, miscarriage and delivery because of the rapid fall in the increased pregnancy-induced maternal clotting factor levels (FVIII) after delivery. The incidence of early and late PPH is increased among haemophilia A carriers (22% and 11%, respectively) (Kadir 1997) compared with the general population (5% and 0.7%, respectively) (Lee 1981).
Factor XI deficiency (haemophilia C) is a very rare inherited bleeding disorder in the general population but is very common in the Ashkenazi Jewish population (Bolton-Maggs 1988). It can be homozygous or heterozygous. The level of factor XI does not rise during pregnancy and there is poor correlation between level of factor XI and bleeding tendency (Bolton-Maggs 1988). Bleeding tendency is likely to be associated with a level less than 15% and varies in the same individual following different haemostatic challenges. Therefore, the unpredictable nature of this disease makes its management during pregnancy and childbirth difficult.
Inherited factor VII deficiency is a very rare autosomal recessive disorder. Only homozygous and compound heterozygous individuals develop haemorrhagic manifestations, heterozygous individuals are usually asymptomatic. Clinical prototypes vary from mild to severe and do not correlate with factor VII levels.
Congenital platelet dysfunction disorders, being autosomal recessive disorders, are rare. Defects are in the platelet GPIb complex (Bernard-Soulier Syndrome) or GPIIb-IIIa complex (Glanzmann thrombasthenia) or in abnormal secretion and thromboxane synthesis. Bleeding tendencies are severe in Bernard-Soulier Syndrome and Glanzmann thrombasthenia, which need platelet transfusion. Bleeding in platelet dysfunction disorders, due to abnormal secretion and thromboxane synthesis, is mild, but can be life-threatening following surgery or trauma.
Vaginal delivery is considered safe, although, if possible, procedures that could increase the risk of haemorrhage (episiotomies, fetal scalp electrodes, instrumental deliveries) should be avoided. It is also better to avoid prolonged second stage labour. Caesarean section is generally to be pursued for obstetric indications only (Lee 2006), but no strong evidence comparing vaginal and Caesarean delivery exists.
Description of the intervention
Desmopressin acetate (DDAVP) is a synthetic analogue (1-deamino-8-D-arginine vasopressin) of the antidiuretic hormone L-arginine-vasopressin with haemostatic properties. It induces VWF release from endothelial cells and is safe for the fetus, since it does not cross the placenta in detectable amounts (Mannucci 2005) and does not pass into breast milk in any significant amount. There have been no adverse effects on reproduction observed in animal studies (Sanofi-Aventis 2007).
In those with inherited bleeding disorders, DDAVP infusion results in a two- to six-fold increase from baseline in factor VIII and VWF plasma levels, although individuals have differing responses (Lethagen 1987). The therapeutic peak level is achieved in 30 to 90 minutes. When repeated DDAVP doses were given every 12 to 24 hours, there is generally a gradual diminishing of the initial factor VIII activity increase noted with the first dose. However, the initial response is reproducible in any particular patient if two or three days elapse between administrations. The usual therapeutic dose is 0.3 to 0.4 µg/kg given intravenously over a period of 30 minutes; it may be administered subcutaneously or intranasally. As absorption is erratic, DDAVP is administered intravenously when administered prophylactically in surgical procedures (Nicholos 2008). Since its first clinical use in 1977, DDAVP has become the treatment of choice for patients with haemophilia A with factor VIII between 5% and 50%. It increases the density of platelet surface glycoprotein receptors and increases plasma level of factor VIII (Levi 2003; Mannucci 1975; Wun 1995). An average two- to six-fold factor VIII increase is observed in most patients and a return to baseline occurs usually within eight hours. It is also of potential value in VWD type 1 because it can increase VWF in the blood. It also increases platelet adhesiveness and shortens bleeding time. As a result of its antidiuretic effects, there is a risk of fluid overload and hyponatraemia (Mannucci 1997), which can lead to seizures in susceptible individuals, particularly young children and pregnant women (Mannucci 2005). Hence during therapy, fluid intake should be limited and plasma sodium levels frequently monitored. Treatment with DDAVP is not indicated for haemophilia B and is of no value in type 3 VWD; a variable response would be expected in VWD types 2A and 2B, which overall account for approximately 20% of the VWD cases. It is also not indicated for treating people with a deficiency in factor XI or factor VII.
How the intervention might work
In patients with some level of deficient factors (VWD type 1, some VWD type 2, mild and moderate haemophilia A) and in patients with platelet function defects, DDAVP increases the plasma concentration of factor VIII and VWF through endogenous release of the patient's own stores. By increasing the concentration of the deficient factor to values in the normal range, DDAVP administration normalizes the haemorrhagic risk or stops the bleeding in responsive patients.
Why it is important to do this review
This review is important given that bleeding complications in women with congenital bleeding disorders are an important cause of obstetrical morbidity and mortality. It is necessary to establish whether the use of DDAVP is safe, effective and affordable for VWD and haemophilia A patients for preventing and treating bleeding episodes related to pregnancy. In contrast to fresh frozen plasma and derivatives, DDAVP has no risks of blood-borne viral infections. There is currently no available systematic appraisal of the evidence of the use of DDAVP to prevent and treat bleeding complications in pregnancy-related bleeding.