Enoxaparin Does Not Prevent Placenta-Mediated Complications in Pregnant Women With Severe Preeclampsia

Pregnant women who have severe preeclampsia (a disease characterized by impaired vascular response to placentation) before 34 weeks of pregnancy are at an increased risk for severe maternal and perinatal complications, including a higher risk of developing eclampsia during subsequent pregnancies and a lower-than-average birthweight.

Though research has suggested that prophylactic doses of low-molecular-weight heparin (LMWH) can decrease the risk of these placenta-mediated complications, results from a multicenter, randomized trial of women with a history of severe preeclampsia showed that treatment with the LMWH enoxaparin (combined with low-dose aspirin) did not reduce the risk of recurrent preeclampsia, perinatal death, or maternal death, compared with low-dose aspirin alone. The study was published in Obstetrics & Gynecology.

In the open-label, controlled HEPEPE (Heparin-Preeclampsia) trial, Bassam Haddad, MD, of the Department of Obstetrics–Gynecology and Reproductive Medicine at the University Paris Est Créteil in France, and investigators enrolled 257 women from 16 secondary- or tertiary-care centers in France between November 14, 2009, and February 21, 2015.

Women with a singleton pregnancy (confirmed by ultrasound) were eligible for inclusion. Patients were excluded if they:

  • had a contraindication to receive heparin or aspirin
  • had antiphospholipid antibody syndrome or acquired thrombophilia (positive for lupus anticoagulants, anticardiolipin, or anti-ß2 glycoprotein antibodies)

Patients were randomized 1:1 before 14 weeks of pregnancy to receive either aspirin 100 mg (n=127) or aspirin with subcutaneous enoxaparin 4,000 IU daily (n=130). Aspirin was stopped at 35 weeks of pregnancy, while enoxaparin was continued until delivery. Thirteen patients were excluded after randomization or lost to follow-up, for a final patient population of:

  • 122 patients in the aspirin-only group (mean age = 31.5±4.4 years)
  • 122 patients in the enoxaparin–aspirin group (mean age = 31.7±4.9 years)

Patients were monitored every four weeks (from 12 to 36 weeks of pregnancy) for the composite morbidity outcome, adverse events, weight, blood pressure, and study drug compliance (via a patient-recorded diary review). The composite morbidity endpoint included: incidence of preeclampsia, small size for gestational age (birthweight less than the 10th percentile), placental abruption, perinatal death, and maternal death. Preeclampsia was defined as blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg in a woman who was normotensive before 20 weeks of pregnancy and had significant proteinuria.

The primary composite outcome did not differ between the two groups: 34.4 percent in the enoxaparin–aspirin group (n=42) and 41 percent in the aspirin-only group (n=50; relative risk [RR] = 0.84; 95% CI 0.61-1.16; p=0.29). See TABLE for outcomes of each element of the composite morbidity endpoint.

Enoxaparin was well tolerated, Dr. Haddad and authors noted. In the enoxaparin–aspirin group, 13 patients (10.7%) experienced any-grade bleeding, compared with seven patients (5.7%) in the aspirin-only group (RR=1.86; 95% CI 0.77-4.50; absolute RR = –24.9%; p=0.16). There were no significant differences in major or minor bleeding.

“Systemic inflammation is hypothesized to contribute to endothelial dysfunction in preeclampsia, and LMWH has emerged as a novel therapeutic option to prevent impaired placentation-related complications because it has been shown to be anti-inflammatory and improve vascular functions,” the authors stated. However, these results “highlight the importance of multicenter studies before [instituting the routine use of drugs such as prophylactic enoxaparin].”

The study is limited by its open-label design and the lack of a placebo cohort.


Haddad B, Winer N, Chitrit Y, et al. Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized controlled trial. Obstet Gynecol. 2016;128:1053-63.

TABLE. Outcomes Related to Composite Morbidity
  Enoxaparin plus Aspirin


Aspirin alone


Relative risk Absolute risk reduction p Value
Preeclampsia* 22





(95% CI 0.49-1.35)


(95% CI −5.9-14.1)

Severe preeclampsia± 16





(95% CI 0.50-1.78)


(95% CI −0.8-0.9)

Small for gestational age† 26





(95% CI 0.50-1.22)


(95% CI −4.8-16.7)

Placental abruption 3





(95% CI 0.21-4.86)


(95% CI −3.9-3.9)

Perinatal death 1





(95% CI 0.03-2.20)


(95% CI −1.1-6)

Maternal death 0 0
*Defined as systolic blood pressure (BP) ≥140 mm Hg or diastolic BP ≥90 mm Hg in a woman who was normotensive before 20 weeks of pregnancy and significant proteinuri

†Excludes one early loss in the aspirin alone group.

±Defined as ≥1 of the following criteria: systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg on two occasions at least 6 hours apart while the patient was on bed rest; proteinuria ≥5 g in a 24-hour urine specimen or ≥3 g on two random urine samples collected at least 4 hours apart