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27 Metformin to treat Preterm Pre-eclampsia (PI-2): A randomised, double blind, placebo-controlled trial

      Objective

      Preterm preeclampsia has high rates of maternal and perinatal morbidity and mortality. No drugs have clearly shown a prolongation in gestation. Preclinical studies have identified metformin as a potential treatment.

      Study Design

      We performed a double-blind, randomised placebo-controlled trial at Tygerberg Hospital, South Africa. We randomly assigned women with preterm preeclampsia between 26+0 to 31+6 weeks gestation and undergoing expectant management to 3 grams of oral metformin XR (extended released) in divided doses, or placebo. The primary outcome was prolongation of pregnancy. Secondary outcomes included maternal and neonatal composite, and individual outcomes. Before the trial we performed metformin pharmacokinetic studies on 15 women with preterm preeclampsia.

      Results

      Between Feb 2018 and Mar 2020 we randomly allocated 180 participants to receive metformin (n=90) or placebo (n=90). Pharmacokinetic studies demonstrated oral metformin XR resulted in good circulating drug concentrations. The primary outcome analysis included 87 allocated to metformin and 84 assigned to placebo. The median time from randomization to delivery was 16.2 days (interquartile range (IQR), 5.2-28.8 days) in the metformin group and 9.5 days (IQR 3.4-22.7) days in the placebo group (difference of 6.7 days (95% Confidence Interval (CI) -0.17 to 13.64; P=0.056; Fig 1). In a pre-specified per protocol analysis that included only those who were compliant, the median prolongation was 16.2 (IQR 5.3-27.5; n=75) versus 7.4 (IQR 2.9-21.2; n=72) days, respectively (difference of 8.4 days, 95%CI 1.0-15.8; P=0.026). There were trends towards increased birthweight (1538g vs 1402g, difference of 136g, 95% CI-12 to 285;P=0.07) and a decreased length of stay (12 vs 18.0, difference of 6 days (95% CI-0.4 to 12.4;P=0.07) in the neonatal nursery among those in the metformin group (Table 1). There were no differences in composite maternal or neonatal outcomes or circulating concentrations of sFlt-1 or placental growth factor.

      Conclusion

      In women with preterm preeclampsia, metformin prolongs gestation and may improve neonatal outcomes.
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