Timing of initiation of low-molecular-weight heparin administration in pregnant women with antiphospholipid syndrome: a randomized clinical trial of efficacy and safety

Abstract

ObjectiveWe aimed to evaluate the effect of different timing of initiation of low-molecular-weight heparin (LMWH) administration on the pregnancy outcomes in women with antiphospholipid syndrome (APS).Materials and methodsA randomized controlled study was conducted on women with obstetrical APS. All participants were randomly divided at documentation of positive pregnancy test into two groups; early initiation group in which LMWH therapy was started once positive pregnancy test was established (in the fifth week of gestation), and later initiation group in which LMWH therapy was started after sonographic confirmation of fetal cardiac pulsation (in the seventh week of gestation). In both groups, LMWH (enoxaparin) was given at a dose of 40 mg/day subcutaneously and the therapy continued until end of pregnancy. The primary outcome measure was ongoing pregnancy rate and the secondary outcome measures were fetal loss, live birth rate, preterm labor before 34 weeks of gestation, intrauterine growth restriction (IUGR), and congenital fetal malformations.ResultsNinety-four women (48 in the early initiation group and 46 in the later initiation group) were subjected to final analysis. The ongoing pregnancy rate was significantly higher in the early initiation group than in the later initiation group (81.2% vs 60.9%; P=0.040). However, both groups were similar in the incidences of fetal loss, preterm labor before 34 weeks of gestation, and IUGR, and live birth rate. No recorded congenital fetal malformations in both groups.ConclusionEarly administration of LMWH for pregnant women with obstetrical APS reduces early pregnancy loss, but does not affect the incidence of late obstetrical complications.

Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome—What is the evidence?

“…42 Also, late pregnancy complications associated with antiphospholipid syndrome, including preeclampsia, intrauterine growth restriction, and intrauterine fetal death, were not statistically significantly different between the two study groups. 42 Similarly, another placebo-controlled trial reported higher ongoing pregnancy rates at 24 weeks' gestation in women treated with LMWH and aspirin preconceptionally, but live birth overall was not affected. 43 Initiation of heparin preconceptionally would be undesirable from a patient's perspective, but whether heparin can be safely discontinued after the first trimester of pregnancy requires further investigation.…”

“…Live birth rates differed between the groups, 70.8% in the early initiation group and 56.5% in the later initiation group, respectively, but this difference was not statistically significant 42 . Also, late pregnancy complications associated with antiphospholipid syndrome, including preeclampsia, intrauterine growth restriction, and intrauterine fetal death, were not statistically significantly different between the two study groups 42 . Similarly, another placebo‐controlled trial reported higher ongoing pregnancy rates at 24 weeks’ gestation in women treated with LMWH and aspirin preconceptionally, but live birth overall was not affected 43 .…”

“…A recent study that compared early initiation of LMWH (gestational age 5 weeks) to later initiation observed ongoing pregnancy rates of 81% at 12 weeks’ gestation and 61%, respectively. Live birth rates differed between the groups, 70.8% in the early initiation group and 56.5% in the later initiation group, respectively, but this difference was not statistically significant 42 . Also, late pregnancy complications associated with antiphospholipid syndrome, including preeclampsia, intrauterine growth restriction, and intrauterine fetal death, were not statistically significantly different between the two study groups 42 .…”

Heparin Use in Pregnant Women Diagnosed With Thrombophilia: Obstetric Outcomes

“…Assumingly, the anticoagulant properties of heparin help mitigating thrombosis in placental microvasculature and present anti-inflammatory action resulting from adhesion protein blockage, from trophoblast differentiation promotion and from reduced binding between antiphospholipid autoantibodies and trophoblastic cells [8,[14][15][16][17][18]. According to a recent study focused on assessing pregnancy progression rate in women with acquired thrombophilia, the early-onset of heparin use has increased ongoing pregnancy rates (81.2% vs. 60.9%, P=0.040), although it did not reduce late complications [19].…”

Heparin beyond anti-coagulation

“…As such, this functional profile appears helpful for certain obstetric patients to improve the clinical outcomes through alleviating the hyper-coagulant state, modulating micro-vascular/placental biology, among other modes [10] . To date while the expanded indications in this perspective are yet to be corroborated by relevant large-scale clinical trials for regulatory approval in terms of the drug labeling update, there has been a professional consensus that heparin agents can be used as an empirical approach to treat or prevent early pregnancy complications such as spontaneous abortion [ 10 , 11 ]. In this regard, prophylactic management with LMWH of standardized dosage until abortion or delivery has been demonstrated to significantly raise the live-birth rates (by 20%~30%) in patients suffering from recurrent miscarriage, and particularly in the cases with antiphospholipid antibody or methylenetetrahydrofolate reductase gene polymorphisms [ 11 , 12 ].…”