Diabetes Drug Metformin: No Impact on Birth Weight in Obese Pregnancy

Marcia Frellick

July 14, 2015

The diabetes drug metformin, used to normalize high blood glucose levels, should not be used to improve pregnancy outcomes in obese women who do not have diabetes, authors conclude in a new study.

Carolyn Chiswick, MBChB, of Tommy's Centre for Maternal and Fetal Health in the Medical Research Council (MRC) Centre for Reproductive Health in Edinburgh, Scotland, and colleagues tested the drug in EMPOWAR, a randomized, controlled trial in 15 National Health Service hospitals in the United Kingdom, to see whether it could reduce excess birth weight. Results were published online July 9 in Lancet Diabetes & Endocrinology.

Accumulating data have shown that obesity in pregnancy is associated with higher birth weight in the offspring and that this is a marker for increased risk of childhood obesity and dying prematurely later in life, the authors explain.

Obese pregnant women are significantly more insulin resistant and hyperglycemic than are pregnant women of a normal weight, and there is evidence that these are the mechanisms by which maternal obesity causes excessive neonatal birth weight.

The researchers set out to examine whether metformin could help prevent the long-term effects of maternal obesity on the offspring. Metformin is widely used in gestational diabetes and is known to be safe to use during pregnancy.

In an accompanying commentary, Jerrie Refuerzo, MD, from the department of obstetrics, gynecology, and reproductive medicine at the University of Texas Health Science Center, Houston, praises the authors' work and notes its importance.

"This well-designed study is one of the first clinical trials to investigate preventive treatment in pregnant women in hopes of providing protection for the unborn child from long-term adverse effects later in life," Dr Refuerzo writes.

The concept that a drug given during fetal development could break the cycle of obese women predisposing their children to obesity, so-called "fetal programing," is exciting, she explains.

"The bold idea that what we do to the fetus during the short and finite period of pregnancy could change and even improve lifelong outcomes of offspring validates the whole concept of prenatal care. If this concept is true, this tiny window of opportunity should not be wasted."

No Effect on Birth Weight, but Time Will Tell on Other Outcomes

In EMPOWAR, the researchers randomly assigned 449 obese pregnant women with body mass index of 30 kg/m2 or greater who were at least 16 years old either to placebo (n=223) or metformin 500–2500 mg/day (n = 226) from 12 to 16 weeks' gestation until delivery. Of those, 434 (97%) were included in the final intention-to-treat analysis.

They found no significant difference in the primary outcome, birth weight: the mean birth weight was 3463 g in the placebo group and 3462 g in the metformin group (P = .7597).

The number of women reporting miscarriage, pregnancy termination, stillbirth, or neonatal death combined was also not significantly different between the groups, seven for metformin vs two for placebo (odds ratio, 3.6; P = .11).

"To our knowledge, EMPOWAR is the first trial of a pharmacological intervention to reduce the risk of ill health in later life, using birth weight as a surrogate marker, in the offspring of obese pregnant women. We conclude that metformin does not have a role in reducing the birth weight of offspring of obese pregnant women," the researchers say.

But they note that further follow-up of the babies will help determine whether and how metformin affects outcomes longer term.

In her editorial, Dr Refuerzo says there could be several reasons the drug did not make a significant difference to birth weight. First, it was given late in the first trimester, whereas giving it closer to conception might make more of a difference, she notes.

Common practice in women with polycystic ovary syndrome — in whom metformin is used, including during pregnancy — is to give it before or near conception.

Adherence also might have been an issue, she says. About two-thirds of patients complied in taking the drug. But only 38% of the metformin patients were adherent to the highest dose of 2500 mg per day, while 62% complied with the 2000-mg/day regimen.

The effects of weight change come at the higher doses of metformin, Dr Refuerzo says, so it's possible not enough patients took the medicine at high enough doses to affect the outcomes.

A third reason is that the greater effect might come later in childhood and not at birth, she says.

Study Adds to Literature on Safety of Metformin During Pregnancy

Study coauthor Jane Norman, MD, professor of maternal and fetal health and director of the Tommy's Centre for Maternal and Fetal Health, said that the third reason may be the most important.

"We are currently planning a follow-up study to investigate this," she told Medscape Medical News.

She also said she agrees with Dr Refuerzo on most of the other points in the commentary.

As to the earlier administration of metformin, that "would limit the generalizability of the intervention, because the majority of women do not consult a healthcare professional for prepregnancy advice, and thus the opportunity to provide the intervention preconception is likely to be limited," she explained.

She added that while it is possible a higher dose could be more effective, it is likely the side effects would preclude administration. Diarrhea and vomiting were significantly higher in the metformin group.

"Women were encouraged to take the maximum tolerable [dose of] metformin, with a 2000-mg dose being taken 62% of the time in compliant women. So the actual doses taken were reasonably high," she says.

Even though metformin was not able to decrease birth weight, she says their research adds to the literature on the safety of metformin in pregnancy.

And "this is important given the widespread use of this drug to treat gestational diabetes," she observes.

The study was funded by the Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership. Dr Norman reports she has no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr Refuerzo has no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online July 9, 2015. Article, Editorial

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