Title: Anticoagulants to improve live birth in women with recurrent miscarriage and inherited thrombophilia: the ALIFE2 trial
Funder: Department of Health and Social Care

Abstract: BACKGROUND Inherited thrombophilia (factor V leiden, prothrombin G20210A and deficiencies of protein C, protein S and antithrombin III) are associated with an increased risk of recurrent miscarriage. Based on this association, it has been hypothesized that anticoagulant therapy reduces the number of miscarriages and stillbirths in women with thrombophilia. In women with acquired thrombophilia, as in the antiphospholipid syndrome, treatment with anticoagulants was shown to increase the chance of live birth.(1;2) Anticoagulant treatment has already been advocated and adopted by many clinicians, despite the absence of randomized controlled trials showing a benefit of this expensive and potentially harmful intervention. Some women with recurrent miscarriage and inherited thrombophilia receive treatment for 9 months, whereas others are withheld potentially effective treatment. Hence, a clinical trial with adequate randomization and power that addresses the efficacy of anticoagulant therapy in women with recurrent miscarriage and inherited thrombophilia is urgently needed. Investigators of the Scottish-initiated SPIN study showed that the combination of aspirin and low-molecular-weight heparin does not improve live birth rates in women with a history of unexplained recurrent miscarriage.(3) Similar results for the combination of low-molecular-weight heparin as well as for aspirin alone were obtained by the applicants in the ALIFE trial.(4) Interestingly, the subgroup of women with thrombophilia had a better chance of live birth after anticoagulant intervention, but this subgroup lacked statistical power for a more definite conclusion. Despite a lack of evidence, the adoption to prescribe LMWH to women with recurrent miscarriage and inherited thrombophilia is already advocated by many physicians. Eight months of injections with LMWH is expensive, and the mostly mild but very common side effects such as pain, itching and haematomas put a serious strain on women. If LMWH proves to be effective, these women are more than willing to undergo these side effects, but without evidence for efficacy, this is unacceptable. STUDY DESIGN We propose a randomised intervention study (ALIFE2 study) to evaluate the efficacy of LMWH in women with recurrent miscarriage and inherited thrombophilia on live birth. Pregnant women with a history of two or more miscarriages with confirmed inherited thrombophilia (factor V Leiden or prothrombin G20210A mutation, or deficiency of protein C, protein S or antithrombin) will be randomised to either LMWH plus standard pregnancy surveillance or standard pregnancy surveillance alone. The primary outcome of the study is live birth; secondary outcomes include other adverse pregnancy outcomes such as preterm birth and preeclampsia, as well as safety outcomes such as clinically relevant bleeding, minor bleeding and thrombocytopenia. POTENTIAL BENEFIT TO PATIENTS AND NHS Patients, as well as the NHS will benefit from the study, irrespective of the study outcome. In case LMWH does improve the live birth rate, women with recurrent miscarriage and inherited thrombophilia can be offered an effective treatment. If, on the other hand, LMWH is not proven to be effective, then women could be spared a burdensome and expensive treatment. Furthermore, in the absence of effective treatment, testing for inherited thrombophilia in these women could be reduced and thus this would represent significant financial saving for the NHS and other health services.

Lay abstract: Women who experience recurrent miscarriage are desperate for a treatment to increase their chance of live birth in a next pregnancy. For women with acquired blood clotting disorders, treatment with anticoagulant drugs is effective. Unfortunately, for women with inherited blood clotting disorders, no evidence of such treatment exists. This means that no treatment can be prescribed with the knowledge that the benefits outweigh any side effects. It is therefore the objective of the ALIFE2 study to evaluate whether an anticoagulant drug (low-molecular-weight heparin) increases the chance of a successful pregnancy in women with recurrent miscarriage and inherited blood clotting disorders. Women who participate in the ALIFE2 study will be randomised to receive either treatment with LMWH or to receive standard pregnancy surveillance and supportive care during their next pregnancy. Treatment with LMWH is considered safe in pregnancy for both the mother and the child as it does not cross the placenta, but women who use LMWH may have side effects such as easy bruising, or itching at the injection site. Data on the outcome of the pregnancy (live birth or no live birth) as well as pregnancy complications and adverse treatment effects will all be recorded, to study whether LMWH is effective and whether its efficacy outweighs potential side effects.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;BLOOD