Metformin may extend gestation in preterm preeclampsia

Metformin can prolong gestation by almost a week in women with preterm preeclampsia, according to the PI-2 study presented at the 2021 SMFM Meeting.

“[Currently,] there is no definitive treatment [for preeclampsia] other than delivery,” experts said. “[Hence,] a therapeutic that could quench the disease process would be useful to treat preterm preeclampsia, as it could allow these pregnancies to safely continue to a gestation where foetal outcomes are significantly improved.”

In the phase II, double blind PI-2 trial, 180 women with preterm preeclampsia were randomized 1:1 to receive oral metformin XR (extended release) 3 g or placebo daily. Participants were between 26–31 weeks of gestation and all were taking antihypertensive medications. [SMFM 2021, abstract 27]

Gestation time was longer by 6.7 days in the metformin group compared with the placebo group in the intention-to-treat population (median time to delivery from randomization, 16.2 vs 9.5 days; p=0.056). According to the researchers, a delay in delivery by 5 days is considered to be clinically relevant.

The difference between groups became significant in the per-protocol analysis, which included only women who were compliant to their treatment (median time to delivery, 16.2 vs 7.4 days; p=0.026) — with gestation time extended by 8.4 days.

The difference was even more pronounced when restricting the analysis to only those who took the full dose until delivery (n=100; median, 16.2 vs 4.8 days; p=0.008).

Infants in the metformin group tended to be heavier by 136 g on average than those in the placebo group (mean weight, 1,538 vs 1,402 g; p=0.07), although the difference was not statistically significant.

It is possible that with longer gestation period, infants tended to gain more in birthweight, explained the researchers.

Also, neonatal stay at nursery facilities trended shorter by 6 days for infants in the metformin group vs the placebo group (mean, 12 vs 18.0 days; p=0.07), which again did not reach statistical significance.

“There were no differences in composite maternal or neonatal outcomes or circulating concentrations of sFlt-1 or placental growth factor,” reported presenting author Dr Cathy Cluver from Stellenbosch University in Cape Town, South Africa.

“In women with preterm preeclampsia, metformin prolongs gestation and may improve neonatal outcomes,” she noted.

Nonetheless, as the study subjects were relatively small in number and restricted to women in Cape Town, Cluver cautioned against generalizing the results to other populations. She also acknowledged that the dosing of metformin exceeds the typical dosage used, which constitutes a study limitation.

Cluver suggested that larger studies be conducted in the future to validate these findings and path the way for more research into therapeutics for preterm preeclampsia.