Does LMWH improve live birth rate in women with inherited thrombophilia and miscarriage history?

The use of low-molecular-weight heparin (LMWH) during pregnancy did not increase the likelihood of live birth compared with standard surveillance in women with inherited thrombophilia who have experienced multiple miscarriages, according to a multinational study presented at ASH 2022.

Participants in the phase III, open-label ALIFE2 study were 326 women aged 18–42 years (mean age 33 years, 83 percent Caucasian) with ≥2 miscarriages (median 3) and inherited thrombophilia (factor V Leiden, prothrombin 20210A mutation, antithrombin, protein C, or protein S deficiency) who were actively trying to conceive or <7 weeks into pregnancy. Approximately one-third of the participants was aged ≥36 years and 70 percent had experienced ≥3 miscarriages prior to enrolment. Women with an indication for anticoagulants during pregnancy were excluded.

Upon receiving a positive urine pregnancy test, the women were randomized 1:1 to receive self-administered subcutaneous LMWH (enoxaparin 40 mg, dalteparin 5,000 IU, tinzaparin 4,500 IU, or nadroparin 2,850 IU) QD plus standard pregnancy surveillance (usual care comprising regular prenatal visits, tests, and ultrasound examinations) or usual care only, initiated within 7 weeks of pregnancy and continued until end of pregnancy*. The participants were followed up until 6 weeks after delivery.

Live birth rate did not differ between participants assigned to LMWH or usual care (71.6 percent vs 70.9 percent; adjusted odds ratio [adjOR], 1.08, 95 percent confidence interval [CI], 0.65–1.78; p=0.770). [ASH 2022, abstract LBA-5]

Adverse events (AEs)** occurred at a greater rate in participants in the LMWH vs usual care arm (43.9 percent vs 26.5 percent; OR, 2.17, 95 percent CI, 1.32–3.55; p=0.0016).

The difference in AE rate was primarily due to easy bruising, minor bleeding, and injection-site skin reactions. Rates of major bleeding and other more severe AEs did not significantly differ between groups.

There was also no difference between groups pertaining to incidence of pre-eclampsia or delivery of small for gestational age infants, said principal investigator Dr Saskia Middeldorp from the Radboud University Medical Center, Nijmegen, the Netherlands.

Any benefit to routine testing for thrombophilia? 

According to Middeldorp, previous observational studies have suggested a link between inherited thrombophilia and recurrent miscarriage. As inherited thrombophilia has been tied to an increased risk of blood clots, miscarriage is thought to occur due to the development of clots in the placenta.

“It has become common medical practice to test women experiencing recurrent miscarriage for inherited thrombophilia and to treat those found to have the condition with injectable blood thinners, despite absence of evidence that this improves their chances of having a successful pregnancy,” she pointed out.

“[This study showed that] in pregnant women with inherited thrombophilia and recurrent miscarriage, LMWH does not increase live birth rate,” she remarked. “Testing for thrombophilia is costly and should only be done if it will have therapeutic consequences.”

She noted limitations including the open-label study design, small cohort, and cross-over of 18 women from the usual care to the LMWH group, though excluding these women did not change the outcomes.

Despite the findings, the study has a positive outlook, said Middeldorp. “It’s important to keep in mind that approximately one in three to four of all pregnancies ends in a miscarriage. Our study showed that, with standard pregnancy care – and without expensive testing and burdensome medication use – slightly more than 70 percent of women had a live birth, [which is what we typically see in the general population],” she highlighted.