Preventing pregnancy loss

In this issue of Blood, 2 articles by The Nîmes Obstetricians and Hematologists–Antiphospholipid Syndrome (NOH-APS) Study Group give us new information about the effects of low-molecular-weight heparin (LMWH) on pregnancy complications in women with prior pregnancy loss and either purely obstetric antiphospholipid syndrome (APS) or inherited thrombophilia. The results better define women at risk, suggest a role for LMWH, and confirm the need for further investigation.^1,2 

APS has been linked to pregnancy complications including fetal loss at all stages of gestation, preeclampsia, eclampsia, placental insufficiency, and premature birth. The inherited thrombophilias, factor V Leiden (FVL) mutation and prothrombin gene (PTG) mutation G20210A, have variable associations with nonthrombotic pregnancy complications; they are believed to play a minimal role in spontaneous abortion or placenta-mediated complications and only a modest role in second- or third-trimester fetal loss.

The NOH-APS study is a large prospective observational study of 6318 women with a history of pregnancy loss. Women with unexplained pregnancy loss, no past history of thrombosis, and meeting criteria for either the diagnosis of obstetric APS (n = 517) or the inherited thrombophilias FVL or PTG (n = 279) were followed during subsequent pregnancies. Rates of recurrent pregnancy loss and other morbidities were compared in separate analyses for patients with obstetric APS or with thrombophilia, with a common control group of women (n = 796) with prior pregnancy loss lacking these diagnoses. Patients identified as having pure obstetric APS received aspirin alone (ASA), 100 mg, when not pregnant; prophylactic-dose enoxaparin (LMWH) was started at the time of a positive pregnancy test and ASA was continued. Women in the thrombophilia group were treated with prophylactic LMWH if they had had 1 prior fetal loss after 10 weeks gestation (late loss); they were not treated with LMWH if they had a history of 3 losses prior to 10 weeks (early loss). In the analyses, patients with obstetric APS, thrombophilia, or the control group were subdivided based on whether prior pregnancy loss manifested as 3 recurrent spontaneous losses before 10 weeks gestation or 1 late fetal loss; the women were followed for subsequent pregnancy outcomes.

For women with inherited thrombophilia, LMWH decreased both fetal death and placenta-mediated complications after first late pregnancy loss compared with controls with the same pregnancy history. The NOH-APS thrombophilia study hints that LMWH heparin may benefit women with recurrent early loss, as these untreated women had higher rates of late pregnancy loss and complications than control women, although numbers were small and not statistically significant. For women with pure obstetric APS, LMWH decreased early and late fetal loss in women with a history of late fetal loss compared with controls but did not decrease placenta-mediated complications to control levels. Although women with obstetric APS and recurrent early loss treated with LMWH had similar early loss rates as control women, they had increased late pregnancy loss. All obstetric APS women had higher rates of placenta-mediated complications than control women.

Studies assessing the role of LMWH in decreasing pregnancy loss and complications have yielded inconsistent results, in part due to study design, small sample size, and heterogeneous definitions of both patient populations and outcomes. Many studies have grouped women with a range of previous obstetrical complications, thrombotic history, and types of thrombophilia.^3,4 

Heparin therapy was initially predicated on the concept that thrombosis in the utero-placental circulation was responsible for pregnancy loss. Early studies suggested a beneficial role for LMWH in decreasing miscarriage in APS^5,6  leading to the more widespread use of LMWH in women with pregnancy loss without APS in an understandable effort to prevent recurrence. Two recent studies, however, have failed to confirm that LWMH or LMWH/ASA decreased miscarriages in women without APS but with a history of 2 prior losses prior to 20 weeks⁷  or 24 weeks⁸  gestation. Evaluation of LMWH in preventing placenta-mediated complications is also limited. A pilot study of women without APS or thrombophilia suggests that LMWH can decrease both placenta-mediated complications and late pregnancy loss, but the numbers of both patients and events are extremely small.⁹ 

The strengths of the NOH-APS studies lie in the patient sample size and the careful classification of both patients and outcomes, providing much needed information on the natural history of women with previous pregnancy loss and subsequently identified obstetric APS, FVL, or PTG. Excluding women with prior thrombosis and distinguishing between pregnancy loss at <10 weeks gestation vs later than 10 weeks gestation, in accordance with criteria for diagnosing APS, may yield more consistent results as etiology for pregnancy loss may be similar in these more closely related groups.

The results confirm the current generally accepted practice of administering LMWH in women with FVL or PTG and prior late pregnancy loss. They raise questions about the recommendations not to use LMWH in women with FVL or PTG with prior pregnancy early loss or complications,¹⁰  especially in light of animal models that suggest heparin may ameliorate nonthrombotic pregnancy complications associated with FVL.¹¹ 

For women with pure obstetric APS, management is less clear. As Bouvier et al suggest, other positive effects of heparin on interrupting complement activation, facilitation of trophoblast invasion, and placentation raise concerns that the current prophylactic-dose LMWH may be insufficient. For now, current practices should continue based on underlying diagnosis of either obstetric APS, or FVL and PTG, and thorough discussion of the risks and benefits of treatment with LMWH for women with a history of pregnancy loss. Based on available information, recommended treatment approaches are listed in the table.

The NOH-APS Study Group has set the stage for future studies by rigorously identifying patient populations at risk, both by defining the underlying disease process and stratifying by time of pregnancy loss. Similar approaches should be used in further randomized controlled trails to improve outcomes in these patients.