Heparin for Women With Recurrent Miscarriage and Inherited Thrombophilia (ALIFE2): An International Open-Label, Randomized Controlled Trial

Abstract

ABSTRACT Thrombophilia has been implicated in the cause of recurrent miscarriage, which affects approximately 3% of couples trying to conceive. International professional guidelines recommend heparin anticoagulation for antiphospholipid syndrome, an acquired thrombophilia responsible for approximately 15% of recurrent miscarriage, but not for other inherited thrombophilias due to an absence of evidence. Many clinicians prescribe heparin to women with recurrent miscarriage and inherited thrombophilia despite the professional recommendations. This international, open-label, randomized controlled trial aimed to compare the effect of low-molecular weight heparin (LMWH) and standard pregnancy surveillance on livebirth rates in women with recurrent miscarriage and inherited thrombophilia. Women aged 18–42 years with recurrent miscarriages who were attempting to conceive or less than 7 weeks pregnant and had an inherited thrombophilia were recruited across 40 hospitals in 5 countries. Women were randomly assigned to LMWH or no LMWH in a 1:1 ratio. Women randomized to LMWH self-administered it once a day subcutaneously, beginning as soon as possible after a positive pregnancy test and before 7 weeks of gestation and continuing throughout pregnancy. The primary study outcome was livebirth after 24 weeks of gestation. Livebirth was compared across randomized treatment groups using an χ 2 test with continuity correction, then a sensitivity analysis with logistic regression to adjust for stratification factors. A total of 326 women were randomized between August 2012 and January 2021. Of these, 164 were randomized to LMWH plus standard care and 162 to standard care alone. In the standard care group, 30 patients ultimately received LMWH for thromboprophylaxis per professional treatment guidelines. The mean age of participants was 33 years, and the median number of miscarriages before randomization was 3 (interquartile range, 2–4), with two thirds of patients having a history of 3 or more miscarriages. The most common thrombophilia diagnoses were heterozygosity for factor V Leiden, prothrombin G20210A mutation, and protein S deficiency. The livebirth rate was 72% (116/162) in the LMWH group, and 71% (112/158) in the standard care group, and no statistical significant was detected between the groups even after adjustment (odds ratio, 1.08; 95% confidence interval, 0.65–1.78; P = 0.77). No differences in adverse pregnancy outcomes or complications were observed between the groups. Easy bruising was reported by 45% (73) women in the LMWH group and 10% (16) in the standard care group. This randomized controlled trial demonstrates that although LMWH is safe in women with recurrent pregnancy loss and inherited thrombophilia, it does not result in an increased live birth rate compared with standard pregnancy surveillance.