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Abstract

Low-molecular-weight heparin is the anticoagulant of choice in pregnancy. Enoxaparin has been increasingly used over the past 20 years in pregnant women at risk of thrombosis and pregnancy complications. The main indications are prophylaxis of venous thromboembolism and prevention of pregnancy loss in thrombophilic women. Other indications include treatment of venous thromboembolism, prophylaxis of arterial thrombosis in pregnant women with mechanical heart valves and prevention of late gestational complication such as pre-eclampsia and intrauterine growth restriction. Enoxaparin does not cross the placenta and is safe for the fetus. Maternal side effects are uncommon and include mild localized allergic reactions in 2% and increased bleeding in 2%, which is dose dependent. Heparin-induced thrombocytopenia is very rare and bone resorption is not clinically relevant. The mechanisms of action of enoxaparin in pregnancy are multiple and include anti-factor Xa (anti-Xa) activity in maternal circulation, tissue factor pathway inhibitor release from endothelial cells and trophoblasts at the placental level as well as anti-inflammatory effects.

Keywords

enoxaparin heparin pregnancy thrombophilia thrombosis

Pregnancy is an acquired hypercoagulable state with a four- to tenfold increased thrombotic risk during gestation and the postpartum period. One in 1000 women will develop venous thromboembolism (VTE) in association with pregnancy [1] and the risk of recurrent event during gestation is 2–13%, 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 becomes an important issue [3].

Finally, the recent association of thrombophilia with pregnancy complications, including miscarriages, pre-eclampsia, placental abruption, intrauterine growth restriction and fetal death, have lead to consideration of antithrombotic prophylaxis in a substantial percentage of pregnant women [4]. Recurrent pregnancy loss affects 1–3% of women of reproductive age while pre-eclampsia and in utero growth retardation (IUGR) each occur in 3–5% of gestations. In Israel, 15,000 out of 150,000 yearly gestations are complicated by vascular complications and a thrombophilic risk factor is found in approximately 50%. Extrapolation to the USA, where thrombophilia is somewhat less common, would imply that anticoagulant therapy may be considered in approximately 1–2% of gestations. Thus, anticoagulant therapy in pregnancy is a major healthcare issue.

Platelet antagonists such as aspirin are used in pregnancy for the prevention of arterial thrombosis and in women with antiphospholipid antibodies (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 with 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 for women with mechanical heart valve, where their use can be considered in the second and third trimester.

Unfractionated heparin (UFH), which does not cross the placenta, was 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 (HIT) and the low but real risk of increased severe osteoporosis that can manifest as vertebral fractures [7 –9]. These risks, 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

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 LMWH should be monitored during gestation.

LMWHs are chemically derived polysaccharides with a mean molecular weight of approximately 5000 Da [12]. Like UFH, they do not cross the placenta [13,14]. Their activity is mostly anti-factor Xa (anti-Xa) and less anti-thrombin (anti-IIa). The anti-Xa:anti-IIa ratio varies between different LMWH preparations ( Table 1 ) [12]. Enoxaparin, like other LMWHs, does not cross the placenta, thus ensuring a good safety profile in pregnancy. The placental barrier is crucial since direct application of LMWHs has toxic effects on rat embryo development [15,16]. There are important pharmacokinetic differences between enoxaparin and other LMWHs and UFH, and therefore these molecules cannot be regarded as interchangeable [17]. Enoxaparin has a higher and more consistent bioavailability after subcutaneous administration than UFH, a longer plasma half-life and is less strongly bound to plasma proteins.

Table 1.

Low-molecular-weight heparin preparations: characteristics, efficacy and safety profile.

LMWH	Molecular weight	Anti-Xa:anti-IIa ratio	Skin reactions* (%)
Enoxaparin	4500	4.3	1
Dalteparin	6000	2.5	3
Tinzaparin	6500	2.0	NA
Nadroparin	4300	3.2	4
Certoparin	3800	2.0	0

Anti-IIa: Thrombin factor-IIa; Anti-Xa: Anti-factor Xa; LMWH: Low-molecular-weight heparin; NA: Not available.

Modified with permission from [20].

While the rate of HIT is practically negligible, and clinically significant osteoporosis is rare, LMWH preparations differ in prevalence of skin reactions ( Table 1 ). 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 [18 –20]. Theoretically, long-term administration of LMWH may be associated with bone resorption. However, in vitro studies demonstrate a species-specific effect of heparin on osteoclast formation [21]. The pharmacokinetics of enoxaparin sodium are significantly different during pregnancy than in the same women when not pregnant.

During early and late pregnancy, maximum concentration and the last measurable anti-Xa activity level were lower than in the nonpregnant state [22]. Mean retention time of anti-Xa activity varies from 5.2 h (dalteparin) to approximately 7 h (enoxaparin, nadroparin). Bioavailability of prophylactic doses of LMWHs range from 86% (dalteparin) to 98% (enoxaparin, nadroparin) [23].

Safety of LMWH

A recent collaborative study demonstrated the safety of using LMWH during 486 gestations [18]. 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.

Reported experience in pregnancy is largely with enoxaparin followed in decreasing order by dalteparin, nadroparin and tinzaparin.

A retrospective French study on use of enoxaparin during 624 pregnancies revealed a good safety profile [19].

In addition to its anticoagulant activity, enoxaparin mechanisms of action in pregnancy may involve anti-inflammatory effects and modulation of angiogenic pathways [24]. A major indication of LMWH is prophylaxis of VTE in pregnancy in high-risk women. A number of studies demonstrated a good efficacy and safety profile for enoxaparin in this indication [19,25].

More recently, a meta-analysis by Greer and Nelson-Piercy evaluated approximately 2800 pregnancies treated with LMWH and reported a very low risk of maternal and neonatal bleeding, no HIT and only one vertebral fracture [20]. While HIT is indeed rare, these cases can be managed by danaparoid sodium or fondaparinux [27].

In view of the differences in their efficacy and safety profiles, LMWH are clearly not interchangeable [28]. As the pharmacokinetics of some, but not all, LMWHs is predictable [29], once-daily use can be anticipated for the majority of indications ( Table 2 ). However, with certain indications such as treatment of thrombosis in index pregnancy or in high-risk patients, such as women with combined thrombophilia or with APLA syndrome, twice-daily injections 12 h apart recommended ( Table 2 ). Special precautions should be taken in women with renal insufficiency and in those with extremely low or high body weight (<40 kg and >120 kg) [30]. The need for monitoring of LMWH in pregnancy is still debatable [31]. 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 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 and 0.6–1.0 U/ml are anticipated for prophylactic and therapeutic regimens, respectively. A recent UK study reported on the therapy of VTE in pregnancy, with enoxaparin achieving median peak anti-Xa levels of 0.8 IU/ml (range 0.44–1.0 IU/ml) [32].

Table 2.

Enoxaparin in pregnancy: indications and regimens.

	Prophylactic regimens	Therapeutic regimens
Indication	Standard risk, previous VTE or pregnancy complications	Mechanical heart valves
		Established VTE
		High-risk, previous VTE or pregnancy complications
Enoxaparin	0.5 mg/kg/24 h	1 mg/kg/12 h

VTE: Venous thromboembolism.

In case of invasive procedures such as chorionic villous sampling or amniotic fluid puncture, LMWH should be avoided at least 12 h before the procedure and can be reintroduced 6 h after the procedure. Guidelines for LMWH use at labor suggest termination at least 12 or 24 h before epidural anesthesia according to LMWH regimen (prophylactic or therapeutic dose) ( Table 1 ). Discontinuing enoxaparin 12 h prior to delivery was sufficient in 284 women receiving the drug compared with 16,132 controls, with postpartum hemorrhage occurring in 2.1 and 1.9%, respectively [33].

LMWHs are reintroduced 6 h after delivery for a period of 6 weeks. In women with indications for long-term anticoagulation, LMWH 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 prophylaxis of thrombosis in pregnant women with mechanical heart valves has evolved during the past few years. Early experience with inadequate dosing and monitoring result in thromboembolic complications including valve thrombosis. This led to a warning against enoxaparin use in this setting. However, more recently gathered information suggests that if enoxaparin is used at therapeutic doses of 1 mg/kg subcutaneously every 12 h and anti-Xa levels are carefully monitored, with a goal of 1.0 IU/ml, the rate of thrombotic complications is low [34]. In fact, according to the recent American College of Chest Physicians (ACCP) guidelines, LMWH at therapeutic doses is an option for these high-risk pregnancies [35].

Prevention of pregnancy loss

LMWH has recently been evaluated mainly by nonrandomized, placebo-controlled trials in women with thrombophilia and pregnancy complications. Our 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/day, 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 a success rate of only 20% in these 50 women in prior gestations without antithrombotic therapy [36].

Carp and colleagues reported a cohort study undertaken to assess the effect of enoxaparin on subsequent live birth rate in women with three or more consecutive pregnancy losses and hereditary thrombophilia [37]. 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.

LIVE-ENOX is a multicenter study recently conducted in Israel comparing two doses of enoxaparin, 40 mg/day and 40 mg/every 12 h, given throughout pregnancy, starting at 5–10 weeks of gestation and for 6 weeks at the pospartum period, to 180 women with thrombophilia and recurrent pregnancy loss [38]. The results demonstrated equal efficacy in terms of live birth rate: 84 versus 78%, respectively. Moreover, enoxaparin seemed to be useful in prevention of late pregnancy complications such as IUGR, pre-eclampsia and placental abruption [39]. The rate of adverse events was low and no significant safety concerns were raised. Enoxaparin prophylaxis was monitored by anti-Xa levels, with significant increases in anti-Xa total and free tissue factor pathway inhibitor (TFPI) levels associated with successful gestational outcome [40].

Gris and colleagues demonstrated the superiority of enoxaparin compared with low-dose aspirin in prevention of pregnancy loss in women with thrombophilia and a previous pregnancy loss after 10 weeks of gestation [41]. Live birth rate with enoxaparin was 86% compared with 29% with aspirin. A recent randomized study evaluated enoxaparin 40 mg/day versus low-dose aspirin in women with recurrent pregnancy loss without thrombophilia [42]. The result demonstrated 94 versus 81% live birth rate in the enoxaparin and low-dose aspirin group, respectively.

In addition to their anticoagulant activity in the maternal circulation, LMWHs may exert local favorable systemic hemostatic effects at the placental level by potentially restoring TFPI on trophoblasts [43,44]. Disruption of the endothelial cell protein C receptor (EPCR) gene in mice causes placenta thrombosis and early embryonic mortality [45]. Treatment with enoxaparin in pregnancy delayed embryonic mortality, potentially due to improve hemostasis at the fetal–maternal interface.

While significant progress has been made in the treatment of women with gestational vascular complications, ideally large, placebo-controlled trials should be advocated [46]. However, there are logistical and ethical difficulties that limit enrollment in such studies [47,48]. In view of the hesitance of the industry to perform of large trials in pregnancy, such studies will probably need support from healthcare institutions.

More recently it has been suggested that some types of infertility, including repeated in vitro fertilization (IVF) failure, may be associated with abnormal hemostasis either in the maternal circulation (thrombophilia) [49] or locally at the uterus vessels level. Following early small-scale studies [50], randomized studies utilizing LMWH are advocated in this setting.

Conclusion

The data presented suggest that enoxaparin is safe in pregnancy for mother and fetus. Enoxaparin is effective in prophylaxis of gestational VTE and prevention of pregnancy loss in women with trombophilia. Prospective randomized trials are indicated to explore the role of enoxaparin in prevention of late pregnancy complications and in prevention of thrombosis in women with mechanical heart valves.

Future perspective

The following developments are likely to occur in the field within 5 years. First, the role of enoxaparin and other LMWHs in prevention of pregnancy loss in women with or without thrombophilia will be either confirmed or disputed. This is due to the fact that a number of studies addressing these indications are currently underway. Second, enoxaparin will be evaluated in the setting of prevention of late pregnancy complications including pre-eclampsia, IUGR and placental abruption.

Executive summary

Low-molecular-weight heparin is the drug of choice in pregnancy.

Enoxaparin does not cross the placenta and is safe for mother and fetus.

Enoxaparin exerts its effects in maternal circulation and locally at the placental level.

Enoxaparin has a proven efficacy in prevention of gestationalvenous thromboembolism.

Enoxaparin may prevent pregnancy loss in women with thrombophilia.

Enoxaparin has been used in uncontrolled trials to prevent late pregnancy complications (pre-eclampsia, in utero growth retardation, placental abruption) in women with thrombophilia.

Dose of enoxaparin in pregnancy is according to the thrombotic risk with higher doses in women at high risk.

In women with mechanical heart valves enoxaparin can be used in therapeutic doses (1 mg/kg every 12 h) with frequent monitoring of peak anti-factor Xa (Xa) levels (approximately 1.0 IU/ml).

Third, the role of LMWH in infertility, implantation failure and especially in women with repeated IVF failures will be explored. Finally, the mechanisms of action of enoxaparin will be further explored, thereby enabling more accurate therapy in terms of timing of initiation dose needed and length of treatment.

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Enoxaparin Use in Pregnancy: State of the Art

Abstract

Keywords

Low-molecular-weight heparin

Safety of LMWH

Prevention of pregnancy loss

Conclusion

Future perspective

References