Thrombophilia in Pregnancy

Heparin and Heparinoid Compounds

Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the heparinoid danaparoid, do not cross the placenta, and therefore they are safe for the fetus. Although UFH can be used during pregnancy for both the prevention and treatment of VTE, LMWH is generally preferred for these indications because of its better bioavailability, longer plasma half-life, more predictable dose response, and improved safety profile with respect to heparin-associated osteoporosis and HIT. The incidence of bleeding in pregnant women receiving LMWH appears low. A systematic review of 64 studies that included 2777 pregnancies in which LMWH was used in either prophylactic or therapeutic dosages reported frequencies of significant bleeding of 0.43% (95% confidence interval [CI], 0.22% to 0.75%) for antepartum hemorrhage, 0.94% (95% CI, 0.61% to 1.37%) for postpartum hemorrhage, and 0.61% (95% CI, 0.36% to 0.98%) for wound hematoma, for an overall frequency of 1.98% (95% CI, 1.50% to 2.57%) ( Table 33.1 ). Adverse skin reactions, including bruising, urticarial rashes, well-circumscribed erythematous lesions (caused by a delayed type IV hypersensitivity reaction), skin necrosis (often due to vasculitis), and HIT, can occur with either UFH or LMWH. Most LMWH-induced skin lesions are benign; however, HIT should be excluded, even though documented HIT in pregnancy in women treated solely with LMWH is very rare. Bone loss in women receiving prophylactic LMWH appears similar to that seen in a healthy pregnancy. LMWHs are primarily eliminated by renal excretion and can accumulate in the presence of significant renal dysfunction; in nonpregnant patients it has been suggested that therapeutic doses of LMWH not be used in those with a creatinine clearance of less than 30 mL/min.

Although no placental passage of the pentasaccharide fondaparinux was demonstrated in an ex vivo study, a subsequent investigation reported anti–factor Xa activity (at approximately one-tenth the concentration seen in maternal plasma) in the umbilical cord plasma of five newborns of mothers treated with this agent. A small number of reports of the successful use of this agent in pregnant woman have been published ; however, most involve exposure during the second trimester or later. Thus, potential deleterious effects on the fetus cannot be excluded, and fondaparinux use during pregnancy should be restricted to women for whom there is no safer alternative, such as those with HIT (see Chapter 26 ).

Vitamin K Antagonists

Vitamin K antagonists (VKAs), such as warfarin, cross the placenta and have the potential to cause fetal wastage, teratogenicity, and bleeding. The latter likely occurs because the fetal liver is immature and fetal levels of vitamin-K-dependent coagulation factors are low. In a systematic review of the literature published between 1966 and 1997, the use of VKAs throughout pregnancy was found to be associated with congenital anomalies in 35 of 549 live births (6.4%; 95% CI, 4.6% to 8.9%). A systematic review covering the years 2000 to 2009 reported a slightly lower risk estimate (21 in 559, or 3.7%; 95% CI, 1.9% to 4.8%). In both reviews, the most common fetal anomaly was coumarin or warfarin embryopathy, with midfacial hypoplasia and/or stippled epiphyses as the most common manifestations, although limb hypoplasia has been reported in up to one-third of cases. Embryopathy typically occurs after in utero exposure to VKAs during the first trimester of pregnancy, and substitution with heparin at or before 6 weeks' gestation appears to eliminate the risk of embryopathy. VKAs have also been associated with central nervous system abnormalities after exposure during any trimester, but these complications are uncommon. One cohort study reported an increased risk of minor neurodevelopmental problems (odds ratio [OR], 1.7; 95% CI, 1.0 to 3.0) in children who were exposed to coumarins in the second and third trimester of pregnancy compared with age-matched nonexposed children (14% vs. 8%, respectively). However, these problems are likely of minor importance, because there were no differences between exposed and nonexposed children in mean intelligence quotient or performance on tests of reading, spelling, and arithmetic.

Women receiving VKA therapy should be counseled about the risks of these agents before pregnancy occurs. Two strategies can reduce the risk of warfarin embryopathy. The first involves the performance of frequent pregnancy tests and the substitution of adjusted-dose LMWH or UFH for VKAs when pregnancy is achieved. Alternately, VKAs can be replaced with LMWH or UFH before conception is attempted. Either approach has limitations. The first assumes that VKAs are safe during the first 4 to 6 weeks of gestation. Although the second approach minimizes the risks of early miscarriage associated with VKA therapy, it lengthens the duration of exposure to heparin and therefore is more costly and associated with a greater burden of treatment given the requirement for daily subcutaneous injections. The first option may be preferable in patients who can be relied on to follow the required testing regimen ; however, patient preferences should be taken into account. Women who place little value on avoiding the risks, inconvenience, and costs of LMWH therapy of uncertain duration while awaiting pregnancy and place a high value on minimizing the risks of early miscarriage associated with VKA therapy will probably choose to receive LMWH while attempting pregnancy.

Parenteral Direct Thrombin Inhibitors

Placental transfer of recombinant hirudin in rabbits and rats has been documented. Although a few case reports have described successful outcomes with recombinant hirudin use in pregnancy, there are insufficient data to evaluate its safety. Three case reports have been published describing the use of argatroban late in pregnancy. There are no published reports on the use of bivalirudin during pregnancy.

Oral Direct Thrombin and Factor Xa Inhibitors (Direct Oral Anticoagulants [DOACs])

Pregnant women were excluded from participation in clinical trials evaluating oral direct thrombin (e.g., dabigatran) and factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban). The summaries of product characteristics for dabigatran and rivaroxaban describe animal reproductive toxicity and both agents have been shown to cross the human placenta. Between October 2008 and December 2014, the German Embryotox Pharmacovigilance Centre identified 63 pregnancies with rivaroxaban exposure, of which 37 were prospectively followed. Among this latter group, there were 23 live births, 8 elective terminations, and 6 spontaneous abortions. All women discontinued rivaroxaban after recognition of pregnancy; usually in the first trimester, but in one woman treatment continued until gestational week 26. This woman delivered a healthy infant. There was one major malformation (conotruncal cardiac defect) among this cohort; however, the mother suffered from severe systemic lupus erythematosus, had a previous pregnancy affected by tetralogy of Fallot (without rivaroxaban exposure), and was taking several co-medications, at least one of which is known to be fetotoxic. These results provide some reassurance to women inadvertently exposed to rivaroxaban early in pregnancy; the limited number of affected patients does not allow us to rule out a fetopathic effect and therefore cannot be used to support the use of rivaroxaban during pregnancy.

Although treatment of pregnant rats, rabbits, and mice with apixaban after implantation until the end of gestation resulted in fetal exposure to apixaban, there was no associated increased risk for fetal malformations or toxicity. There are no human data for apixaban in pregnancy; however, this drug has also been shown to cross from the maternal to fetal circulation using a dually perfused human placenta model. Studies conducted in pregnant rats and rabbits showed no teratogenic effects when edoxaban was administered orally at doses 49 times the human dose of 60 mg/day normalized to body surface area. Toxicities seen at maternally toxic doses included absent or small fetal gallbladder, increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses. In the edoxaban VTE treatment trial, there were 10 pregnancies with edoxaban exposure during the first 6 weeks of gestation (4 full-term births, 2 pre-term births, 1 first-trimester spontaneous abortion, and 3 elective pregnancy terminations).

The human reproductive risks of DOAC medications remain unknown, and their use in pregnancy currently should be avoided. Women of childbearing potential receiving long-term therapy with DOACs should be counseled about potential fetal risks with these medications. Those who are attempting to conceive should be converted to warfarin or LMWH or failing that, switched to LMWH as soon as pregnancy is confirmed.

Aspirin

Aspirin crosses the placenta, and animal studies have shown that this drug may increase the risk of congenital anomalies. A meta-analysis of 31 randomized studies comparing antiplatelet agents with either placebo or no antiplatelet agents in 32,217 pregnant women at risk of developing preeclampsia reported that aspirin therapy was not associated with an increase in the risk of pregnancy loss, neonatal hemorrhage, or growth restriction ( Table 33.2 ). However, in a meta-analysis of 8 studies that evaluated the risk of congenital anomalies with aspirin exposure specifically during the first trimester, aspirin use was found to be associated with a twofold increase in the risk of gastroschisis (OR, 2.37; 95% CI, 1.44 to 3.88) (see Table 33.2 ). The validity of this estimate is questionable due to a significant risk of bias in the contributing studies. An increased risk of miscarriage with aspirin use was noted in one population-based study ; however, only a few women used aspirin, the aspirin dosages were unknown, and the users may have had conditions associated with an increased risk of pregnancy loss.

Thrombolytic Therapy

Although investigations with iodine 131-labeled streptokinase (SK) or tPA showed minimal transplacental passage, concerns remain about the use of thrombolytic therapy during pregnancy due to potential maternal and placental effects. There have been a few reports of successful thrombolysis in pregnancy. Given the limitations of available data regarding the safety of this intervention in pregnancy, thrombolytic therapy should be reserved for life-threatening maternal thromboembolism.