Abstract
‘While there is a broad international agreement that low-molecular-weight heparin is the anticoagulant of choice in pregnancy, there is still no consensus among experts with regard to the appropriate dose for the varying indications, the duration of treatment and whether it should be monitored during gestation.’
Pregnancy is an acquired hypercoagulable state with a four- to tenfold increased thrombotic risk during gestation and the postpartum period. One out of 1000 women will develop venous thromboembolism (VTE) in association with pregnancy [1] and the risk of a recurrent event during gestation is between 2 and 13% dependent on the nature of the first event [2].
Arterial thrombosis in pregnancy is less common than VTE but with increasing maternal age, prevention and treatment of arterial disease has become an important issue [3].
In addition, the recent association of thrombophilia with pregnancy complications including; miscarriage, pre-eclampsia, placental abruption, intrauterine growth restriction and fetal death, have led to consideration of antithrombotic prophylaxis in a substantial percentage of pregnant women [4].
Platelet antagonists such as aspirin are used in pregnancy in the prevention of arterial thrombosis and in women with antiphospholipid antibody (APLA) syndrome as an adjunct to anticoagulants [5].
Vitamin K antagonists cross the placenta and are associated with fetal malformations in the first trimester and an increased risk of bleeding in the fetus throughout gestation [6]. Therefore, in general, their use is strictly prohibited after 6 weeks of gestation, except in women with mechanical heart valves in whom their use can be considered in the second and third trimester.
Unfractionated heparin (UFH), which does not cross the placenta, has been widely used in pregnancy for prevention and treatment of gestational thromboembolism. However, some safety concerns have been raised regarding the risk of heparin-induced thrombocytopenia and the low but real risk of increased severe osteoporosis that can manifest by vertebral fractures [7,8]. These, together with variable pharmacokinetics [9] and the need for 2–3 daily injections, have resulted in a less favored place for UFH in pregnancy.
Low-molecular-weight heparin (LMWH) is now the most commonly used anticoagulant for prophylaxis and treatment of VTE in pregnancy and the puerperium. While there is a broad international agreement that LMWH is the anticoagulant of choice in pregnancy [10,11], there is still no consensus among experts with regard to the appropriate dose for the varying indications, the duration of treatment and whether it should be monitored during gestation.
LMWHs are chemically derived polysaccharides with a mean molecular weight of approximately 5000 Da [12]. Similar to UFH, they do not cross the placenta [13,14]. Their activity is mostly anti-factor Xa and less anti-thrombin (factor IIa). The anti-Xa/anti-IIa ratio varies between different LMWH preparations [12] (Table 1). While the rate of heparin-induced thrombocytopenia is practically negligible and clinically significant osteoporosis is rare, LMWH preparations differ in prevalence of skin reactions (Table 1). The lack of large-scale clinical trials is in sharp contrast to the increasing use of these agents in pregnant women. Thus, the evidence for safety and efficacy is largely from meta-analysis of small-scale studies and reported series of patients [15–17].
Low-molecular-weight heparin preparations – characteristics, efficacy and safety profile.
Adapted from Greer IA & Nelson-Piercy C [17]
A recent collaborative study demonstrated the safety of LMWH during 486 gestations [15]. A successful outcome was reported in 83 (89%) of 93 gestations in women with a history of recurrent pregnancy loss and in all 28 gestations in women who experienced pre-eclampsia during a previous pregnancy. A retrospective French study on the use of enoxaparin during 624 pregnancies revealed a good safety profile [16].
More recently, a meta-analysis by Greer and Nelson-Piercy has evaluated around 2800 pregnancies treated with LMWH and reported a very low risk of maternal and neonatal bleeding, no heparin-induced thrombocytopenia and only one vertebral fracture [17].
In view of the differences in their efficacy and safety profiles, LMWHs are clearly not interchangeable [18]. As the pharmacokinetics of some, but not all, LMWHs are predictable [19], once-daily use can be anticipated for the majority of indications (Table 2). However, with certain indications, such as the treatment of thrombosis in index pregnancy or in high-risk patients, for example, in women with combined thrombophilia or with APLA syndrome, twice-daily injections 12 h apart are recommended (Table 2). Special precautions should be taken in women with renal insufficiency and in those with an extremely low or high body weight (less than 40 kg or over 120 kg) [20]. The need for monitoring of LMWH in pregnancy is still debatable [21]. However, in view of the anticipated increase in weight and changes in circulatory distribution, especially in the third trimester, monitoring of anti-Xa levels 3 h post LMWH injection is warranted, particularly in the treatment of established thrombosis and in women at a higher thrombotic risk such as those with combined thrombophilia, APLA syndrome or antithrombin deficiency [4]. Anti-Xa levels of 0.2–0.4 U/ml and 0.6–1.0 U/ml are anticipated for prophylactic and therapeutic regimens, respectively.
Low-molecular-weight heparin preparations – indications and regimens.
VTE: Venous thromboembolism.
In the case of an invasive procedure such as chorionic villous sampling or amniotic fluid puncture, LMWH should be avoided for at least 12 h before the procedure and can be reintroduced 6 h after the procedure. Guidelines for LMWH use during labor suggest termination at least 12 or 24 h before epidural anesthesia according to LMWH regimen (prophylactic or therapeutic dose) (Table 2).
LMWHs are reintroduced 6 h after delivery for a period of 6 weeks. In women with indications for long-term anticoagulation, LMWHs are bridged to vitamin K antagonists in the postpartum period. UFH, LMWH and vitamin K antagonists are safe for use in the lactating mother.
The role of LMWH in pregnant women with a mechanical heart valve is not established [22]. It should be noted that thrombosis and fetal complications are substantial in women with mechanical heart valves with all currently available anticoagulant regimens [23].
An early use of LMWH at a low, ineffective dose resulted in a warning of usage which has recently been eased following evaluation of clinical data of LMWH use at a therapeutic dose regimen [22].
LMWH has recently been advocated in women with thrombophilia and pregnancy complications. The author's group has treated 61 pregnancies in 50 women with thrombophilia who presented with recurrent fetal loss with the LMWH enoxaparin throughout gestation and 4–6 weeks into the postpartum period. Enoxaparin dosage was 40 mg daily, except for patients with combined thrombophilia or in the case of abnormal Doppler velocimetry suggesting decreased placental perfusion, where the dosage was increased to 40 mg twice daily. Of the 61 pregnancies, 46 (75%) resulted in live birth compared with only 20% in these 50 women in prior gestations without antithrombotic therapy [24].
Carp and colleagues reported a cohort study undertaken to assess the effect of enoxaparin on the subsequent live birth rate in women with three or more consecutive pregnancy losses and hereditary thrombophilia [25]. The live birth rate was higher in women treated with enoxaparin, 26 (70.2%) of 37 compared with 21 (43.8%) of 48 in untreated patients. The beneficial effect was mainly in primary aborters and in those with five or more miscarriages.
‘While significant progress has been made in the treatment of women with gestational vascular complication, large placebo-controlled trials should ideally be advocated’
LIVE-ENOX is a multicenter study recently conducted in Israel comparing two doses of enoxaparin, 40 mg daily and 40 mg every 12 h administered throughout pregnancy, starting at 5–10 weeks of gestation and continuing for 6 weeks during the postpartum period, in 180 women with thrombophilia and recurrent pregnancy loss [26]. The results demonstrated equal efficacy in term of live birth rate (84 vs 78%, respectively). Moreover, enoxaparin seemed to be useful in prevention of late pregnancy complications such as intrauterine growth restriction, pre-eclampsia and placental abruption [27]. The rate of adverse events was low and no significant safety concerns were raised.
Gris and colleagues demonstrated the superiority of enoxaparin over low-dose aspirin in the prevention of pregnancy loss in women with thrombophilia and a previous pregnancy loss after 10 weeks of gestation [28]. The live birth rate with enoxaparin was 86% compared with 29% with aspirin.
In addition to their anticoagulant activity in the maternal circulation, LMWH may exert local favorable systemic hemostatic effects at the placental level by potentially restoring tissue factor pathway inhibitor on throphoblasts [29,30].
While significant progress has been made in the treatment of women with gestational vascular complication, large placebo-controlled trials should ideally be advocated [31]. However, there are logistic and ethical difficulties that limit enrollment in such studies [32]. In view of the hesitance of the pharmaceutical industry to perform large trials in pregnancy, such studies will likely need support from healthcare institutions.