Therapeutic Strategies for Preventing Thrombophilia-Associated Pregnancy Complications
Anticoagulants and aspirin are the best studied and most commonly utilized therapeutic agents used to prevent pregnancy complications in thrombophilic women.
Anticoagulant Therapy During Pregnancy & the Postpartum Period
The use of anticoagulant therapy during pregnancy requires consideration of potential risks to the fetus, as well as to the mother.
Fetal Complications of Anticoagulant Therapy
Potential fetal complications of maternal anticoagulant therapy include teratogenicity, bleeding and pregnancy loss. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) do not cross the placenta[75–77] and, therefore, are safe for the fetus.[78–81] Vitamin K antagonists, like warfarin, cross the placenta and have the potential to cause teratogenicity (e.g., embryopathy and CNS abnormalities), as well as pregnancy loss and fetal bleeding.[78,82–87] Although an invitro study did not demonstrate transplacental passage of fondaparinux (Arixtra®, GlaxoSmithKline, London, UK), a subsequent investigation documented antifactor Xa activity in the umbilical cord plasma in newborns of five mothers treated with this medication. A small number of reports of the successful use of this agent in pregnant woman have been published;[90–96] however, most of these involve second trimester or later exposure. Pregnant women were excluded from participating in clinical trials evaluating new oral direct thrombin (e.g., dabigatran etexilate [Pradaxa®, Boehringer Ingelheim GmbH, Ingelheim, Germany]), and anti-Xa inhibitor (rivaroxaban [Xarelto®, Bayer Pharma AG, Berlin, Germany] and apixaban [Eliquis®, Bristol-Myers Squibb, NY, USA]) agents and the human reproductive risks of these medications are unknown. The Summaries of Product Characteristics for dabigatran etexilate and rivaroxaban describe animal reproductive toxicity.[97,98] The use of these new oral anticoagulants in pregnancy should be avoided.
Maternal Complications of Anticoagulant Therapy
LMWH is the preferred anticoagulant for the prevention and treatment of VTE in pregnancy.[10,99–101] Bleeding in pregnant women receiving LMWH is uncommon.[81,99,101] Although heparin-induced thrombocytopenia (HIT) can occur with LMWH therapy, reported cases during pregnancy are rare. LMWHs also have a lower risk of osteoporosis than UFH and it appears that bone loss with the use of prophylactic LMWH during pregnancy is not different from normal physiologic losses during pregnancy.[104–106] Adverse skin reactions to LMWH, including bruising, urticarial rashes, well-circumscribed erythematous lesions (due to a delayed type IV hypersensitivity reaction), skin necrosis (often due to vasculitis) and HIT, have a reported incidence during pregnancy that ranges from 1.8 to 29%.[99,107,108] Although most LMWH-induced skin lesions are benign, the diagnosis of HIT should be excluded.
Anticoagulant Management at the Time of Delivery & Postpartum
Careful planning can reduce the risk of maternal hemorrhage and epidural hematoma at the time of delivery in women receiving anticoagulants. Full-dose subcutaneous LMWH administered in twice-daily doses should be discontinued 24 h before induction of labor or cesarean section, while patients taking once-daily therapeutic LMWH should take only 50% of their dose on the morning of the day prior to delivery.[10,109] For prophylactic LMWH, discontinuation 12–24 h prior to delivery should suffice.[10,110]
Patients receiving anticoagulants should be instructed to withhold their injections if they believe they have entered labor spontaneously. If spontaneous labor occurs in fully anticoagulated women, neuroaxial anesthesia should not be employed. Where the level of anticoagulation is uncertain and where laboratory support allows for rapid assessment of heparin levels, testing can be considered to guide anesthetic and surgical management.
Anticoagulants should be recommenced postdelivery as soon as adequate hemostasis is assured. Although definitive recommendations are lacking, LMWH generally can be started 12–24 h post delivery in uncomplicated deliveries (although some experts are comfortable with an earlier start). However, resumption of full-dose LMWH following epidural catheter removal should wait 24 h (longer with bloody or traumatic insertions). If warfarin is to be used postpartum, it can begin at the same time that LMWH is initiated. Once an international normalized ratio of at least 2.0 is achieved, LMWH can be discontinued. Warfarin and LMWH are both considered safe for breastfeeding women.[10,111–113] Breastfeeding women were excluded from trials evaluating the new oral anticoagulants and the manufacturers of dabigatran and rivaroxaban both recommend against using these medications in this patient population.[10,97,98]
Aspirin Therapy During Pregnancy
Aspirin crosses the placenta and animal studies have shown that this drug may increase the risk of congenital anomalies. Aspirin therapy during the second and third trimester has not been shown to increase the risk of pregnancy loss, neonatal hemorrhage or growth restriction. However, aspirin use during the first trimester has been reported to slightly increase the risk of gastroschisis (OR: 2.37; 95% CI: 1.44–3.88). An increased risk of miscarriage with aspirin use was noted in one population-based study; however, the number of aspirin users was small, aspirin doses were unknown and users may have had conditions associated with an increased risk of pregnancy loss.
Recommendations for Prevention of Pregnancy-Related VTE in Women With Thrombophilia
Pregnancy-related VTE and, consequently, maternal mortality from PE can be reduced by providing thromboprophylaxis to those patients at increased risk of thrombosis. However, given the absence of robust trials in this area, optimal prophylaxis of pregnant thrombophilic women remains controversial and management decisions should take patient preferences into account.
Prophylaxis during pregnancy usually involves long-term parenteral LMWH. Although this is safe for the fetus and large trials in nonpregnant women have shown that LMWH is at least as safe and effective as UFH when used for prophylaxis in high-risk patients, it is expensive, inconvenient and painful to administer. Most women can tolerate these injections; however, for a distinct minority they are an unacceptable burden. Some women may also perceive that the use of prophylaxis creates an undesirable 'medicalization' of their pregnancy. Given the distribution of DVT throughout all three trimesters, antepartum prophylaxis should be instituted early in the first trimester if it is to be utilized. The threshold for recommending postpartum prophylaxis is lower than for antepartum prophylaxis due to the shorter length of required treatment (i.e., 6 weeks) and the higher average daily risk of VTE in the postpartum period.
Several dosing regimens of LMWH have been used for prophylaxis of VTE during pregnancy ( Table 2 ). Maternal weight gain and increased renal clearance of LMWH during pregnancy has led to the suggestion that clinicians should periodically monitor the anticoagulant effect of prophylactic dose LMWH using anti-Xa levels.[118,119] However, the appropriate 'target range' for prophylaxis is uncertain and there is no evidence to support the contention that dose adjustment to attain a specific anti-Xa level increases the safety or efficacy of prophylaxis. Moreover, routine monitoring of anti-Xa levels is expensive, inconvenient and it may be unreliable.[120–122]
The rational administration of prophylaxis depends on identifying those at sufficiently high risk of VTE that the potential benefits outweigh the risks and burdens of this intervention. Therefore, based on available data, serious consideration of routine antepartum and postpartum prophylaxis in asymptomatic thrombophilic women appears warranted only in homozygous carriers of the factor V Leiden or prothrombin gene mutations with a positive family history of VTE ( Table 3 ). Those with no family history probably only merit postpartum prophylaxis. Women with the other inherited thrombophilias probably only require postpartum prophylaxis if there is a positive family history of VTE; in the absence of a family history, pregnant women with thrombophilias other than homozygosity for the factor V Leiden or prothrombin gene mutations probably do not require either antepartum or postpartum prophylaxis. Again, given the limitations of the available data, antepartum clinical vigilance may also be acceptable for patients who are accepting of the VTE risks quoted above and for whom the burden of LMWH prophylaxis outweighs potential benefits. Suggested antepartum and postpartum prophylaxis strategies for asymptomatic thrombophilic women are outlined in Table 3 .
Studies of thromboprophylaxis in pregnant women with prior VTE are limited and consist largely of relatively small observational studies or underpowered randomized trials.[10,123] Since different doses of anticoagulant prophylaxis with LMWH have not been compared directly in terms of efficacy and safety in women with a history of VTE, the optimal dose of LMWH is unknown in this group of patients ( Table 2 ). As available data regarding the impact of thrombophilia on the risk of recurrent VTE during pregnancy is inconsistent, the updated recommendations from the American College of Chest Physicians for the management of pregnant women with prior VTE do not consider the presence or absence of thrombophilia. Available data suggest that pregnant women with a single prior episode of VTE associated with a transient risk factor not related to pregnancy or use of estrogen are at low risk of recurrent antepartum VTE and can be managed with clinical vigilance antepartum rather than antepartum prophylaxis. Antepartum prophylactic or intermediate dose LMWH is favored for other women with prior VTE not receiving long-term anticoagulants, although antepartum clinical vigilance is also acceptable for those for whom the drawbacks and inconvenience of LMWH prophylaxis outweighs potential benefits. Although supportive data from clinical trials are lacking, postpartum prophylaxis for 6 weeks with prophylactic or intermediate-dose LMWH or vitamin K antagonists targeted at international normalized ratio of 2.0–3.0 with an initial course of LMWH is generally recommended for all pregnant women with prior VTE not receiving long-term anticoagulants. Table 3 outlines suggested prophylaxis strategies in this patient population.
Recommendations for the Prevention of Adverse Pregnancy Outcomes in Women With Thrombophilia
There have been a number of studies evaluating the efficacy of steroids, aspirin, UFH or LMWH, and intravenous immunoglobulin in women with APLAs and recurrent pregnancy loss. Of the interventions examined in a systematic review that summarized the data from 13 randomized or quasi-randomized trials of pregnant women with APLAs and a history of at least two unexplained pregnancy losses, only UFH combined with aspirin (two trials; n = 150) reduced the incidence of pregnancy loss (RR: 0.46; 95% CI: 0.29–0.71 when compared with aspirin alone).[125,126] A subsequent third study reported consistent findings (n = 72). Higher dose UFH was not more effective than low-dose UFH.[124,128] On its own, aspirin did not significantly reduce the risk of pregnancy loss compared with usual care or placebo[130,131] (RR: 1.05; 95% CI: 0.66–1.68). LMWH combined with aspirin also failed to significantly affect the likelihood of an unsuccessful pregnancy compared with aspirin alone.[124,132] However, a subsequent meta-analysis that combined data from randomized trials testing the efficacy of a combination of heparin (either UFH or LMWH) and aspirin versus aspirin alone in patients with APLAs and recurrent pregnancy loss that included an additional LMWH study published since the first systematic review, reported a significantly higher frequency of live births in the aspirin and heparin group (74.3%) than in those randomized to aspirin alone (55.8%; RR: 1.3; 95% CI: 1.0–1.7). However, when studies that used LMWH and UFH were analyzed separately, only a trend toward higher birth rate in patients receiving aspirin and LMWH was noted (RR: 1.1; 95% CI: 0.9–1.3). No studies comparing LMWH and UFH were included in either of the previous meta-analyses. The results of two small pilot studies suggest that the combination of LMWH and aspirin may at least be equivalent to UFH and aspirin in preventing recurrent pregnancy loss (RR for pregnancy loss in women receiving LMWH vs UFH: 0.44; 95% CI: 0.17–1.00 and 0.8; 95% CI: 0.26–2.48). Therefore, for women who fulfill the laboratory criteria for APLA syndrome and meet the clinical APLA syndrome criteria based on a history of three or more pregnancy losses, antepartum administration of prophylactic- or intermediate-dose UFH or prophylactic LMWH combined with low-dose aspirin, 75–100 mg/day is recommended ( Table 4 ). Despite the limitations of available data, most centers now use LMWH in this setting because it is more convenient and safer than UFH.
The above treatment is often extrapolated to women with antiphospholipid antibodies and a single late pregnancy loss, intrauterine growth restriction and preeclampsia. However, it is important to note that supportive data is lacking and the use of the above regimens in these patients may result in overtreatment, as an intervention that prevents fetal loss may not prevent other complications.
In a small randomized trial that enrolled women with one previous pregnancy loss after 10 weeks and either the factor V mutation, the prothrombin gene mutation or protein S deficiency, prophylactic dose LMWH (enoxaparin) resulted in a higher live birth rate than did low-dose aspirin (86 vs 29%, respectively). However, interpretation of this trial is complicated by important methodologic limitations and a higher than expected failure rate in the aspirin arm.[138–141] For example, a subsequent cohort study found the live birth rate of subsequent pregnancies after a single pregnancy loss at or later than 12 weeks gestation in carriers of factor V Leiden or the prothrombin mutation was, without intervention, 68% (95% CI: 46–85%). No significant benefit to antithrombotic therapy was found in the subgroup of women with inherited thrombophilia in a prespecified subgroup analysis of the ALIFE trial ( Table 5 ) in which 364 women with two or more unexplained miscarriages at 20 weeks or less were randomly assigned to receive placebo, low-dose aspirin alone (80 mg daily) or low-dose aspirin combined with open-label prophylactic LMWH (nadroparin 2850 units subcutaneously per day). In support of these findings, another prespecified subgroup analysis of a randomized multicenter trial comparing low-dose aspirin, prophylactic LMWH (enoxaparin) and placebo and prophylactic LMWH (enoxaparin) and aspirin in women with recurrent miscarriages also found no statistically significant difference in live birth rate between the three treatment arms in women with thrombophilia (most of whom had had hereditary hypercoagulable states). Thus, taken together, available data do not provide convincing evidence that LMWH (with or without aspirin) improves pregnancy outcome in women with inherited thrombophilia and a history of pregnancy loss.
There are no published placebo-controlled randomized studies assessing the efficacy of anticoagulants in preventing preeclampsia, placental abruption or intrauterine growth restriction in women with antiphospholipid antibodies or hereditary thrombophilias. However, in one multicenter randomized trial, the combination of prophylactic LMWH (dalteparin) and low-dose aspirin started before the 12th week of gestation reduced the risk of recurrent early-onset preeclampsia in women with inherited thrombophilia and a prior history of early-onset hypertensive disorders of pregnancy or small-for-gestational-age infants compared with low-dose aspirin alone (0 vs 8.7%; 95% CI for risk difference: 1.9–15.5%). However, the overall frequency of hypertensive disorders of pregnancy irrespective of gestational age was not different between the treatment arms. Further data from the recently completed TIPPS study in which pregnant women with thrombophilia and increased risk for placental-mediated pregnancy complications or VTE were randomized to LMWH or no LMWH should provide further clarity regarding the role of antithrombotic therapy in these patient populations. Until then, the potential to increase bleeding and the lack of evidence for a causal association between these pregnancy outcomes and thrombophilia mandates caution in the use of anticoagulants in these settings ( Table 4 ).
Expert Rev Hematol. 2013;6(3):287-300. © 2013 Expert Reviews Ltd.