Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT

J Thromb Haemost. 2012 Jan;10(1):64-72. doi: 10.1111/j.1538-7836.2011.04553.x.

Abstract

Background: Early-onset hypertensive disorders (HD) of pregnancy and small-for-gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk.

Objectives: Adding low-molecular-weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early-onset HD (pre-eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies.

Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were< 12 weeks gestation.

Inclusion criteria: previous delivery< 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected.

Intervention: either daily LMWH (dalteparin, 5000 IU weight-adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone.

Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age.

Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention-to-treat.

Results: Low-molecular-weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects.

Trial registration: http://www.isrctn.org) (isrctn87325378).

Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspirin / administration & dosage*
  • Drug Therapy, Combination
  • Female
  • Gestational Age
  • Heparin, Low-Molecular-Weight / administration & dosage*
  • Humans
  • Pre-Eclampsia / drug therapy
  • Pre-Eclampsia / prevention & control*
  • Pregnancy
  • Secondary Prevention
  • Thrombophilia / complications
  • Thrombophilia / drug therapy*
  • Treatment Outcome

Substances

  • Heparin, Low-Molecular-Weight
  • Aspirin

Supplementary concepts

  • Thrombophilia, hereditary

Associated data

  • ISRCTN/ISRCTN87325378