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Metformin may help prolong gestation in pregnant women with pre-eclampsia

25/09 - In pregnant women with pre-eclampsia, metformin may help prolong gestation and improve fetal and maternal outcomes, a new study suggests.

Researchers conducted a randomized, double-blind clinical trial including 180 women with preterm pre-eclampsia between 26 to 31+6 weeks' gestation, of whom 90 were allocated to take extended-release metformin. They found that the medication prolonged gestation by a median of 7.6 days compared with the placebo group, although that result wasn't statistically significant, according to the report published in The BMJ.

"In our study, we have shown that women who had preterm preeclampsia who then took metformin stayed pregnant for a week longer than those who took a placebo (or dummy) tablet," said the study's first author, Dr. Catherine Cluver, an associate professor and maternal-fetal medicine subspecialist in the department of obstetrics and gynecology at Stellenbosch University in Cape Town, South Africa.

"The babies of the women who took metformin also spent 12 days less in hospital," Dr. Cluver said in an email. "It is the first time that a treatment given to mums with preterm pre-eclampsia to keep them pregnant for a week longer might have worked. It could mean that preterm pre-eclampsia can now be treated and that we can slow disease progression right down."

Although the medication was developed for diabetes, research has suggested it may help women with pre-eclampsia by improving the function of blood vessel linings, Dr. Cluver said.

"When a pregnant woman develops pre-eclampsia, the lining of her blood vessels - the endothelium - is affected and there are specific proteins - biomarkers - that increase in the blood stream," she added. "Our pre-clinical team, led by Professor Stephen Tong at Mercy Hospital for Women in Melbourne, Australia, has shown in laboratory work that metformin improves endothelial function and decreases these biomarkers. We think metformin stabilizes the lining of the blood vessels in women with preterm preeclampsia."

The researchers enrolled women admitted to Tygerberg Hospital in Cape Town, South Africa, a large academic referral center in a region with high rates of pre-eclampsia, according to the report. The trial included only women who were candidates for expectant management and had no clinical indication for immediate delivery, based on the assessments of attending doctors.

Eligible women were those who were able to give informed consent, were not currently using metformin, and had a fetus without structural anomalies. Women with diabetes or gestational diabetes, contraindications to metformin, use of drugs that might interact with metformin, or multiple gestations were excluded.

Women receiving the trial drug took 3 grams of extended-release metformin, in 1g doses three times a day, until delivery.

For the primary outcome, the median time from randomization to delivery in women treated with metformin was 17.7 days and 10.1 days in those who received placebo, a median difference of 7.6 days (geometric mean ratio 1.39).

The researchers also looked at subgroups.

Among women who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 days compared with 7.9 days in the placebo arm, a median difference of 9.6 days. The geometric mean ratio of 1.67 was statistically significant.

Among the 61 women who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 days compared with 4.8 days in the placebo arm, a median difference of 11.5 days. The geometric mean ratio was 1.85, also statistically significant.

One of the study's limitations, the authors note, is that Tygerberg Hospital's policy is for women undergoing expectant management to deliver at 34 weeks, and 40% of women in the metformin group and 28% in the placebo group delivered for this reason. It's possible prolongation of gestation would have been greater had expectant management continued beyond 34 weeks.

In addition, the authors write, "this was a single centre study where the women had a high incidence of HIV, obesity, and chronic hypertension, potentially limiting the generalisability of our results."

The new study is "interesting," said Dr. Hyagriv N. Simhan, a specialist in maternal/fetal medicine at UPMC Magee-Womens Hospital and a professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh School of Medicine, in Pennsylvania, who wasn't involved in the research.

"The notion that insulin resistance may be related to pre-eclampsia does have some scientific basis, so studying metformin in this context is intriguing," Dr. Simhan said in an email.

"Importantly, metformin was discontinued at a relatively high proportion due to side effects, so this may account for the lack of statistical significance in the primary outcome," Dr. Simhan said. "In my view, the study does not justify the clinical use of metformin for prolongation of pregnancy in pregnant people diagnosed with preterm pre-eclampsia. Perhaps, though, there is justification for further research, in larger, better-designed, trials to explore this topic further."

While the subgroups showed statistically significant results, "those would not be appropriate subgroups from which to draw conclusions regarding effectiveness," Dr. Simhan said.

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