Should Pregnant Women With Type 2 Use Metformin?
Kim Boggess, MD
Professor of Obstetrics and Gynecology at the University of North Carolina
Type 2 Diabetes
American Diabetes Association Research Funding
Clinical Translational Research Grant
Pregnancy poses serious risks for both mothers with type 2 diabetes and their babies. Up to one-third of women with type 2 who get pregnant have adverse outcomes, from stillbirth and miscarriage to macrosomia, a condition in which babies are unusually big when they’re born. The risk for poor outcomes only increases when diabetes is not well managed.
With younger people increasingly diagnosed with type 2 diabetes, the disease is becoming a common problem in OB-GYN offices around the country. Maternal fetal medicine specialist Kim Boggess, MD, estimates that more than 100,000 women with type 2 in the United States are pregnant each year. “With the obesity epidemic, we’re seeing more women with pregestational diabetes or [preexisting type 2] diabetes that is diagnosed very early in pregnancy,” says Boggess, a professor of obstetrics and gynecology at the University of North Carolina. “Type 2 diabetes is the most common form of pregestational diabetes we encounter.”
Treating pregnant women with type 2 can be tricky. That’s because pregnancy radically alters the way a woman’s body works. Even in pregnancies uncomplicated by diabetes, insulin resistance goes up, meaning the body has to produce more insulin to successfully signal the body to absorb glucose from the blood. People with type 2 already struggle with insulin resistance, pushing their pancreas harder and harder to produce insulin until it begins to fail. Pregnancy adds to that burden.
Doctors usually treat high blood glucose during pregnancy with insulin injections. Because the hormone doesn’t cross the placenta to affect the developing fetus, it’s the go-to treatment for diabetes during pregnancy. But because women with type 2 already struggle to produce enough insulin to meet their prepregnancy needs, even insulin injections sometimes can’t close the gap during pregnancy. “The ‘insulin, insulin, and more insulin’ regimen is not achieving what we need in terms of neonatal outcomes,” Boggess says. “We have patients who are taking 100 units of insulin a day, and we still can’t get [their diabetes] under control.”
Instead of adding more and more insulin, Boggess wants to address the insulin resistance itself using metformin, one of the most common drugs used to treat type 2 diabetes. Metformin shows promise as a standard treatment for pregnant women with type 2.
Based on studies done in women with gestational diabetes, researchers think metformin is safe to use in pregnancy. But there isn’t a lot of specific data on how it works in women with type 2. And there are few studies that show metformin’s long-term effects on babies whose mothers used the drug during earlier stages of their pregnancies. “There’s a lot we don’t know about metformin exposure,” Boggess says. Studies in mice suggest babies whose mothers used metformin may be smaller at birth and face higher risks of obesity later in life, for example.
To conclusively show whether metformin is both safe and effective for women with type 2 during pregnancy, Boggess and coinvestigator Diane Berry, PhD, are conducting a study to see if women on metformin have fewer pregnancy complications than women using insulin alone.
The study is ambitious: Boggess hopes to enroll almost 1,000 pregnant women with type 2 diabetes. Beginning in their second trimester, when the nausea and vomiting of morning sickness pass, half will be given a placebo and insulin, and half will receive metformin and insulin. At the end of the study, researchers will see if there were differences in pregnancy outcomes between the two groups. They’ll also track how much insulin the women used in order to see if metformin reduced the need for insulin injections.
With funding from the American Diabetes Association, Boggess is going further, taking blood samples from women in the study 24 and 38 weeks into their pregnancies. The idea is to search for biological indicators that set the women apart from pregnant women without diabetes. She’s looking, in particular, for unusual levels of hormones, including leptin and adiponectin, which she thinks may serve as indicators for how the body reacts to metformin.
By comparing participants’ blood before and after 10 weeks of metformin use, Boggess says, she and her team will be able to see the effects of metformin in detail. If the drug does prove safe and effective in reducing neonatal complications, the detailed blood results could help them understand why: The results could later be used in animal models, where hormone levels could be tweaked to observe their effects. “We want to see if the addition of metformin will improve biomarkers,” she says.
Boggess expects metformin to work well for the women in the study. If she’s right, it could change how doctors treat diabetes in pregnancy, encouraging clinicians to prescribe metformin earlier and more often, for example. “If we prove the hypothesis that metformin improves adverse neonatal effects,” Boggess says, “it would lend credence to the idea that we should be prescribing it to all pregnant women with type 2 diabetes.” In other words: The drug’s benefits would outweigh possible downsides, such as an increased obesity risk for the baby later in life.
It’s possible, of course, that metformin won’t reduce adverse outcomes. That too would be important knowledge. “Using it without evidence of benefit when there’s potential for harm is not a good idea,” says Boggess. “Whether we show a benefit or not, we can make a statement about [whether it makes sense to use when treating] these women.”
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