Early Prophylactic Enoxaparin for the Prevention of Preeclampsia and Intrauterine Growth Restriction: A Randomized Trial

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are among the many causes of maternal and perinatal morbidity and mortality. Prior studies have shown that introduction of low-dose aspirin before 16 weeks of gestation can lead to a reduction in the prevalence of preterm PE and IUGR. However, aspirin is at present recommended only for women who are at high risk of developing PE and IUGR, and this fails to include a significant proportion of pregnant women. Low-molecular-weight heparin (LMWH) may have the potential to improve placental development and inhibit pathways leading to PE and IUGR based on its antithrombotic effects. Currently, LMWH is offered as a complementary treatment to low-dose aspirin in some high-risk women. The goal of this study was to investigate its efficacy through a randomized controlled trial. This study was multicenter, randomized, open-label, parallel-controlled trial conducted in Spain. Women were eligible to participate if they were between 6.0 and 15.6 weeks' gestation and had any of the following in a prior pregnancy: severe PE leading to delivery before 34 weeks gestation, newborn weight less than the third percentile or less than the 10th percentile with documented abnormal Doppler in the umbilical artery (pulsatility index [PI] >95th percentile) during pregnancy before 34 weeks of gestation and/or placental abruption or unexplained intrauterine death after 20 weeks of gestation, and uterine artery mean PI Doppler >95th percentile at 12 to 13.6 weeks in the current pregnancy. Preeclampsia was defined according to the International Society for the Study of Hypertension in Pregnancy. Pregnant women were randomly assigned to receive no treatment or LMWH until 36 weeks' gestation. Women who had a history of early-onset PE were also advised to take low-dose aspirin. Women were seen in the clinic every 4 weeks until 34 weeks' gestation and then every 2 weeks until delivery. At each visit, blood pressure, urine dipstick, and adverse events were recorded. Each patient also had an ultrasound to assess fetal well-being at each visit. This study began in March 2012 and ended November 2015. In all, 283 women were consented, and 146 were randomly assigned to the LMWH group, whereas 137 were randomly assigned to the no-treatment group. Of these women, 74 were enrolled based on an adverse obstetric history (n = 43), previous intrauterine fetal death (n = 22), and placental abruption (n = 9). The remaining 204 patients were enrolled based on uterine artery mean PI Doppler of greater than the 95th percentile between 12 and 13.6 weeks and/or first-trimester PE. Overall, there was no significant difference in the percentage of women with placental insufficiency complications during their pregnancy who were assigned to the treatment versus no treatment groups (34.7% in the LMWH group and 32% in the control group; P = 0.64; odds ratio, 1.13; 95% confidence interval, 0.68-1.85). There were also no significant differences in secondary outcomes between the 2 groups. The results from this study found that there is no difference in the risk of PE or adverse maternal/fetal events when taking LMWH compared with no treatment. Based on these results, providers should not recommend LMWH alone as a method to prevent PE or IUGR. Further research is needed to assess the efficacy of LMWH given together with low-dose aspirin in preventing placental complications.