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

Thursday, January 28, 2021

4:00 PM – 4:15 PM EST

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.

Primary & Presenting Author(s)

Catherine Anne Cluver, MD, PhD

Stellenbosch University
Cape Town, Western Cape

Coauthor(s)

RH

Richard Hiscock, MBBS

Mercy Perinatal
University of Melbourne, Australia
ED

Eric H. Decloedt, MBBCH, PhD

Stellenbosch University
Western Cape, South Africa
DH

David R. Hall, MBBCH, MD

Stellenbosch University
Western Cape, South Africa
SS

Sonja Schell, RN

Stellenbosch University
Western Cape, South Africa
Ben Mol, MD, PhD

Monash University
Melbourne, Victoria
FB

Fiona Brownfoot, MBBS, PhD

Mercy Perinatal
Melbourne, Australia
TK

Tu'uhevaha Kaitu' u-Lino, PhD

Mercy Perinatal, University of Melbourne
Melbourne, Australia
SW

Susan Walker, MBBS, MD

Mercy Hospital for Women, University of Melbourne
Melbourne, Australia
ST

Stephen Tong, MD, PhD

University of Melbourne
Melbourne, Australia