Studies have shown an association between recurrent miscarriage and inherited thrombophilia. It has been hypothesized that anticoagulant therapy might reduce both number of miscarriages and adverse pregnancy outcomes in these women and this is widely practiced despite lack of solid evidence. In the absence of randomized controlled trials that assess the efficacy of low-molecular-weight heparin (LMWH) therapy in women with recurrent miscarriage and inherited thrombophilia, a randomized clinical trial that addresses this topic was highly needed.


Design: The ALIFE 2 trial was an investigator-initiated, international open-label randomized controlled trial. The Netherlands coordinated recruitment in 15 hospitals in the Netherlands, USA, Belgium, and Slovenia. The UK coordinated 26 sites including sites in England, Scotland, Wales and Northern Ireland. The study protocol was approved by the institutional review boards of all participating centres, and in the UK, NRES, MHRA and HRA. Written informed consent was obtained from all patients prior to randomization. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35).

Study population: Women (18-42 years) who had two or more pregnancy losses and confirmed inherited thrombophilia (factor V Leiden, prothrombin 20210A mutation, antithrombin, protein C or protein S deficiency) who were actively trying to conceive or less than 7 weeks pregnant were eligible for inclusion. Women were excluded if duration of current pregnancy was 7 weeks or more, if they had an indication for anticoagulant treatment during pregnancy, a contraindication for LMWH, a known allergy for LMWH or previous enrolment in this trial.

Randomisation and intervention: Women were randomly assigned (1:1) to use subcutaneous LMWH once daily (enoxaparin 40 mg, dalteparin 5,000 IU, tinzaparin 4,500 IU or nadroparin 3,800 IU) versus standard pregnancy surveillance once they had a positive urine pregnancy test. LMWH was started ≤ 7 weeks of pregnancy and continued until the end of pregnancy.

Outcomes: The primary outcome measure was live birth rate. Secondary outcomes included adverse pregnancy outcomes, such as miscarriage, obstetric complications (premature delivery, pre-eclampsia, HELLP syndrome, intrauterine growth restriction), and congenital malformations. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions to the prescribed study medication.

Statistical analysis: Analysis includedall available datafrom all women who were randomized and did not withdraw consent to be followed up, as per the intention-to-treat principle. Exploratory subgroup analyses investigated the effect of age, number of previous miscarriages, previous live birth and type of inherited thrombophilia.


Between August 2012 and January 2021, 10,626 women with recurrent miscarriage were assessed for eligibility, most of whom were not eligible due to absence of inherited thrombophilia. A total of 428 women were registered, of whom 326 women conceived and were randomized. 164 were assigned to the LMWH group and 162 were assigned to the standard surveillance group. The mean age was 33 years, approximately one third being 36 years or older, and the majority was of caucasian ethnicity (83%). The median number of miscarriages prior to randomization was 3, and 70% had a history of 3 or more miscarriages. The most common thrombophilia types were heterozygosity for factor V Leiden (56%), prothrombin 20210A mutation (25%), and protein S deficiency (14%). Aspirin was used as co medication in 11%. Observed live birth rates were 116/162 (71.6%) in the LMWH group and 112/158 (70.9%) in the standard surveillance group (adjusted OR 1.08 (95% CI 0.65 to 1.78)(absolute difference 0.7% (95% CI -9.2% to 10.6%). Adverse events were reported for 39 women (23.8%) in the LMWH group and 37 (22.8%) women in the standard surveillance group.


Compared with standard surveillance, the use of LMWH did not result in higher live birth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. On the basis of our findings, we do not advise routine use of LMWH in women with recurrent pregnancy loss and confirmed inherited thrombophilia, and we advise against routine testing for inherited thrombophilia in women with recurrent pregnancy loss.

Middeldorp:Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Abbvie: Honoraria; Viatris: Honoraria; Sanofi: Honoraria; Norgine: Honoraria; GSK: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astra Zeneca: Honoraria.

We present a RCT where we assess the efficacy of low-molecular-weight heparin (LMWH) to improve live birth in women with inherited thrombophilia and a history of recurrent miscarriage. This is not a labeled indication of LMWH.

Author notes

Asterisk with author names denotes non-ASH members.

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