Metformin prolongs gestation in preterm pre-eclampsia

Use of extended-release metformin can lengthen gestation in women with preterm pre-eclampsia, providing proof of concept that treatment of preterm pre-eclampsia is possible, suggests a study. However, further research is warranted.

A randomized, double-blind, placebo-controlled trial was conducted in a referral hospital in Cape Town, South Africa. A total of 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks’ gestation undergoing expectant management were randomly assigned to either 3-g oral extended-release metformin (n=90) or placebo (n=90) daily, in divided doses, until delivery.

One participant gave birth prior to taking any trial drug. The median time from randomization to delivery was 17.7 days (interquartile range [IQR], 5.4–29.4; n=89) in the metformin group and 10.1 days (IQR, 3.7–24.1; n=90) in the placebo group (median difference [MD], 7.6 days; geometric mean ratio [GMR], 1.39, 95 percent confidence interval [CI], 0.99–1.95; p=0.057). [BMJ 2021;374:n2103]

The median prolongation of gestation among those who continued to take the trial drug at any dose was 17.5 days (IQR, 5.4–28.7; n=76) in the metformin arm relative to 7.9 days (IQR, 3.0–22.2; n=74) in the placebo arm (MD, 9.6 days; GMR, 1.67, 95 percent CI, 1.16–2.42). In women who took the full dosage, the median gestation extension was 16.3 days (IQR, 4.8–28.8; n=40) in the metformin arm versus 4.8 days (IQR, 2.5–15.4; n=61) in the placebo arm (MD, 11.5 days; GMR, 1.85, 95 percent CI, 1.14–2.88).

No difference was noted in the composite maternal, foetal, and neonatal outcomes, as well as circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin.

Notably, birth weight increased nonsignificantly and length of stay decreased in the neonatal nursery in the metformin cohort. No serious drug-related adverse events were reported, but diarrhoea was more common among women who received metformin.

“Although metformin prolonged gestation, it did not reduce circulating levels of antiangiogenic factors—notably, soluble fms-like tyrosine kinase-1, which might be an important driver of disease pathogenesis,” the researchers said. “This finding suggests that metformin prolongs gestation and potentially ameliorates the underlying disease through mechanisms that do not involve a reduction in the secretion of antiangiogenic factors.” [Am J Obstet Gynecol 2020;0:S0002-9378(20)31071-1]

Such occurrence is possible as preclinical studies show that metformin might hold pleiotropic actions that counter both the placental and the maternal vascular pathology of pre-eclampsia. [Am J Obstet Gynecol 2016;214:356.e1-15; Fundam Clin Pharmacol 2019;33:649-658; Biomed Res Int 2019;2019:6547019]

“Although metformin is widely used to treat gestational diabetes, an advantage of repurposing the drug is that it is likely to be safe, especially if administered for a limited duration,” the researchers said. “A further advantage is that metformin is inexpensive and therefore could be widely adopted in low to middle income countries where the problem of preterm pre-eclampsia is most pronounced.”

Although concerns have been noted, a recent epidemiological study found that metformin taken during the antenatal stage did not negatively affect growth and developmental outcomes in childhood. [Am J Obstet Gynecol 2018;219:367.e1-7; J Clin Endocrinol Metab 2018;103:1612-1621; JAMA Pediatr 2019;173:160-168]

“Further trials of metformin should be considered, such as a larger trial of women with preterm pre-eclampsia powered to confirm whether the drug can statistically significantly prolong gestation and to evaluate the benefits to neonates,” the researchers said.

“Lastly, it might be worth evaluating whether metformin can prevent pre-eclampsia,” they added. [J Matern Fetal Neonatal Med 2021;34:2741-2753; Ultrasound Obstet Gynecol 2018;52:706-714; Diabet Med 2018;35:160-172]