Details of the study
The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.
The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.
The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.
Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).
Study strengths and limitations
The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.8
This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.
Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.
The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●
WHAT THIS EVIDENCE MEANS FOR PRACTICE
This elegant, and vital, randomized controlled trial provides double take-home messages: There is no value in testing for inherited thrombophilias in RPL, as they occur in a similar prevalence in the general population, and there is no significant difference in live birth rate from LMWH treatment in women with RPL and inherited thrombophilias compared with surveillance. Consequently, the increased cost of medication and testing can be averted.
MARK P. TROLICE, MD, MBA