| This proposal aims to assess the effectiveness of aspirin and aspirin combined with low-molecular-weight heparin (LMWH) as compared to usual care, i.e. no treatment, in women with unexplained RM. The research question is whether aspirin or aspirin combined with LMWH in women with unexplained RM results in an increased number of live births in subsequent pregnancies as compared to no treatment. Whether specific subgroups, in particular women with hereditary thrombophilia, benefit more than other women with RM, is a secondary part of the research question. Recurrent miscarriage (RM) affects up to 3% of fertile couples, but evidence-based interventions aimed to improve the prognosis of subsequent pregnancies are not available for the vast majority of women with RM. Aspirin and/or anticoagulant treatment are increasingly being prescribed to women with unexplained RM since uncontrolled series have suggested a beneficial effect. However, there is no firm evidence that these interventions are effective, while the risks, side-effects and treatment burden from daily injections are well known.Thus, a randomized, controlled, multi-center study entitled ALIFE study (Anticoagulants for LIving FEtuses) comparing 3 different strategies including placebo in women with a history of unexplained RM is proposed. Women with a history of at least 2 miscarriages or intra-uterine fetal deaths, either unexplained or associated with hereditary thrombophilia, who have the desire to conceive or are less than 6 weeks pregnant are eligible. Main exclusion criteria are chromosomal abnormalities in the woman or male partner, antiphospholipid antibody syndrome (APLS), and previous venous thromboembolism.Patients will be randomized to one of 3 study arms. These are placebo (for aspirin), low-dose aspirin, or low-dose aspirin combined with low-dose low-molecular-weight heparin (LMWH). The administration of aspirin will be double-blinded and placebo-controlled.The primary outcome measure is live birth rate. Main secondary outcome measures are various types of bleeding, adverse pregnancy outcome, thromboembolic complications, and side effects.To detect that treatment with low-dose aspirin plus LMWH leads to a 15% higher rate of live births than that achieved with placebo, or low-dose aspirin alone, 103 evaluable patients per arm (i.e. a total of 309 patients) are necessary (power of 80% at a significance level of 0.05). The study duration will be 2 years. The study protocol has been written and approved by 5 METCs and its feasibility has been established. Recruitment of patients is planned in the first year of the study; the second year will be used to await pregnancy outcome in included patients, analysis of data, and drafting of the manuscript. |
