Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial

Abstract

Objective: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia.

Design: Randomised, double blind, placebo controlled trial.

Setting: Referral hospital in Cape Town, South Africa.

Participants: 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo.

Intervention: 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery.

Main outcome measure: The primary outcome was prolongation of gestation.

Results: Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm.

Conclusions: This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible.

Trial registration: Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Mercy Health Foundation, Peter Joseph Pappas research grant programme, Preeclampsia Foundation, and South African Medical Research Council self-initiated research grants programme; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Fig 1

Flowchart of screening, randomisation, and follow-up. *Primary outcome was measured from time of taking first tablet until delivery. This woman delivered before taking her first dose so it was not possible to calculate prolongation of gestation

Fig 2

Kaplan-Meier survival curves for prolongation of gestation (days) between treatment arms overall and by gestational age stratum. *Numbers indicate how many participants had not given birth at the different timepoints