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

Summary. 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 <12weeks 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 <12weeks gestation. Inclusion criteria: previous delivery <34weeks 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, 5000IU weight-adjusted dosage) with aspirin 80mg or aspirin 80mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) <34weeks 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 <34weeks 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:) (isrctn87325378). Conclusions:Adding LMWH to aspirin at <12weeks gestation reduces recurrent HD onset <34weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA