Metformin has limited benefit in obese pregnant women without diabetes

Last Updated: 2016-02-03

By Gene Emery

NEW YORK (Reuters Health) - Giving metformin to obese pregnant women who don't have diabetes may limit maternal weight gain, but it does not improve neonatal birth weight, a new study of 450 women has found.

Treatment with the diabetes drug seemed to lower the odds of preeclampsia, but it failed to improve the odds of gestational diabetes, adverse neonatal outcomes or giving birth to a large-for-gestational-age child.

Metformin therapy also increased the risk of side effects compared to placebo treatment.

"Our assumption was, this increase in weight is pathological and if we gave a drug that reduced insulin resistance and hypoglycemia, the baby size would normalize, but it didn't," senior author Dr. Hassan Shehata of Epsom and St. Helier University Hospitals in London told Reuters Health by phone.

However, "the secondary outcomes were interesting because the material weight gain was significantly lower and, to our surprise, the preeclampsia was significantly lower as well," he said.

The British trial, known as MOP, appears in the February 4 New England Journal of Medicine. It focused on women with a body-mass index higher than 35 at a time when obesity levels have been rising rapidly in both developed and developing countries.

In the group randomized to receive metformin, the dose went from 1 g per day in the first week, and then increased by 0.5 g each week until it reached 3.0 g daily. All of the volunteers received personalized advice on healthy eating and were encouraged to exercise for half hour daily.

"We know obese pregnant women have a higher incidence of having babies on the bigger side," said Dr. Shehata. "The large-for-gestational-age rate is normally about 10%. In obese pregnant women it's about 20%."

With the metformin therapy, 16.8% of the babies were large for gestational age; with placebo the rate was 15.4% (p=0.79)

The median maternal weight gain was 4.6 kg for the 202 women on metformin versus 6.3 kg for the 198 on placebo (p<0.001). The preeclampsia rates were 3.0% and 11.3% respectively (p=0.001).

Rates for maternal gestational diabetes, postpartum hemorrhage, gestational diabetes mellitus and Cesarean delivery were not significantly different between the two groups.

Dr. Jill Crandall, an endocrinologist and professor of clinical medicine at the Albert Einstein College of Medicine in New York City, who was not connected with the research, said, "Metformin is increasingly being used to treat diabetes during pregnancy (including gestational diabetes). But its use for women with normal glucose metabolism is not as common and this study does not provide a very strong justification for treating these women."

"The one exception," she told Reuters Health in an email, "might be in the prevention of preeclampsia, which was significantly reduced in the women in this study."

"Although fetal weight was the defined primary outcome for this study, it's interesting to note that there was a trend toward improvement in several other fetal outcomes (respiratory distress, hyperbilirubinemia, for example)," Dr. Crandall said. Those improvements may not have been statistically significant because of the small size of the study, she added.

Metformin produced significantly more diarrhea, headache and nausea and vomiting. Overall, 51% of the drug recipient had at least one side effect versus 31% of placebo recipients. However, metformin recipients were no more likely than people getting placebo to stop taking their tablets or have their dose reduced.

"Our side effects were not as bad as reported in other trials," Dr. Shehata said. "We have found that by starting with a low dose and making the patient aware of the possible side effects, then increasing the dose gradually, you get better compliance and less issues about side effects."

The lack of maternal weight gain could have some health advantages for women, he said, because women tend to put on more weight with each additional pregnancy. "So by the third child, she has put on more weight and it's that much more difficult to lose it." Metformin may help there.

Because "nothing is known about the possible long-term effects of intrauterine metformin exposure," Dr. Crandall said, "it's possible that improved health outcomes (for example, body fat distribution) might be shown later in postnatal life. I hope the investigators continue to follow these mothers and children."

Dr. Shehata and his colleagues are also trying to develop a study of 2,000 to study the reduction in preeclampsia.

"That's a very interesting finding for us," said Dr. Shehata. "It's a problem people have been trying to solve for decades."

The study had no commercial funding.

SOURCE: http://bit.ly/1OVA29Z

N Engl J Med 2016.