Metformin may prolong gestation in women with preterm pre-eclampsia, according to a South African and Australian study.
The study, published in The BMJ, was based on suggestions from previous research that metformin’s actions might mitigate placental and maternal vessel disease.
It randomised 180 women to either 3g extended release metformin or placebo daily on a diagnosis of preterm pre-eclampsia between 26 and 31 weeks gestation.
The median time from randomisation to delivery in the metformin arm was 17.7 days compared to 10.1 days in the placebo arm (P=0.057).
There were no significant differences between the groups in composite maternal outcomes including maternal death, eclampsia, pulmonary oedema, severe renal impairment, cerebral vascular event and placental abruption.
Similarly, there was no statistically significant difference between the groups in fetal or neonatal outcomes including intrauterine death, fetal growth restriction at birth, grade III or IV intraventricular haemorrhage, necrotising enterocolitis and bronchopulmonary dysplasia.
Circulating levels of soluble fms-like tyrosine kinase-1, placental growth factor, or soluble endoglin concentrations, or the soluble fms-like tyrosine kinase-1 to placental growth factor ratio did not differ between the groups.
Among the exploratory outcomes, the study found more women in the metformin arm reached 34 weeks’ gestation (40% v 28%; 12.7%, −1.1% to 26.4%) and fewer women in the metformin arm delivered because of fetal indications (33% v 44%; −11.9%, −26.0% to 2.3%); although the differences were not statistically significant.
Similarly, infant birth weights were non-significantly increased (1620 g v 1510 g; difference 110 g, 95% confidence interval −80 to 300) and median length of admission in the neonatal nursery was non-significantly shorter (11 days v 16 days, a difference of 5 days, geometric mean ratio 0.86, 95% confidence interval 0.62 to 1.20).
There were no serious adverse events reported however women receiving metformin reported more diarrhoea and nausea than the other women.
“This trial found that metformin extended release was associated with a clinically meaningful prolongation of gestation, although the difference was not statistically significant,” the study authors said.
“However, given there is biological plausibility; the prespecified per protocol analyses (showing a 9.6 day prolongation in those continuing to take any dose of metformin and a 11.5 day difference in those who took the full dose), which were significant; and favourable neonatal outcomes (neonates in the metformin arm were 110 g heavier, spent a third less time in the tertiary care neonatal nursery at Tygerberg Hospital, and 12 days less in any neonatal nursery), we are cautiously optimistic that metformin treatment has a beneficial effect on prolongation of gestation.”
The investigators, led by Associate Professor Catherine Cluver from Stellenbosch University and the University of Melbourne, said the study provides proof of concept that treatment of preterm pre-eclampsia was possible however further trials were needed.
They said the advantages of metformin were that it was inexpensive and likely to be safe, especially when administered for a limited duration.