Non-Insulin Diabetes Medications Safe for Infants in Early Pregnancy

Carolyn E. Cesta, PhD

Credit: ResearchGate

Infants exposed to second-line antidiabetic therapy including GLP-1 agonists in utero do not face an increased risk of major congenital malformations (MCM) at birth, according to new data from an observational cohort analysis.

In new data from an international, population-based assessment of pregnant women with type 2 diabetes, a team of investigators observed that the risk of infant MCMs was not largely increased relative to the significantly increased rate of pregnant women receiving second-line antidiabetic therapy. Though the findings warrant further confirmation and continuous monitoring in the era of increasing diabetes rates and available second-line agents, they also contribute to the understood safety of drug classes including GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors.

Led by Carolyn E. Cesta, PhD, of the Centre for Pharmacoepidemiology at Karolinska Institute in Sweden, investigators sought to assess periconceptual use of recommended second-line, noninsulin therapy for diabetes and each drug class’ associated risk with MCM in infants. Both type 2 diabetes prevalence, and concurrent use of popularizing antidiabetic therapies, have become common in women of reproductive age, the team noted.

“For patients with type 2 diabetes who are planning pregnancy or who are already pregnant, the guideline-recommended treatment has traditionally been insulin, due to the limited data on the safety of noninsulin antidiabetic medication for fetal development,” investigators wrote. “However, the intentional use of metformin during pregnancy has become more common and unintended exposure to second-line noninsulin ADM medications during the first trimester, although still rare, has also increased over time.”

Cesta and colleagues collected data from 6 large population-based health care databases across 4 Nordic countries, the US and Israel to construct a cohort of pharmacologically-treated women with type 2 diabetes at the approximate time of conception. They first described time trends of noninsulin antidiabetic medication use in pregnancy over time, then compared the overall and cardiac-specific MCM risk in infants born to women with periconceptional use of such therapies versus those born to women who used insulin.

Periconceptional exposure was defined as ≥1 prescription fill of sulfonylureas, DPP-4 inhibitors, GLP-1 rector agonists, and SGLT-2 inhibitors, or active comparator insulin from 90 days before pregnancy to end of first trimester. The team estimated relative risks (RRs) via log-binominal regression models.

Investigators first observed a significantly greater rate of periconceptional exposure to second-line noninsulin antidiabetic therapies among women in the US: 295 per 100,000 pregnancies—versus 32 per 100,000 in the Nordic countries and 73 per 100,000 in Israel. Overall, the most common medications included metformin only (50%); insulin (34%); sulfonylureas (9.0%); DPP-4 inhibitors (4.5%); GLP-1 receptor agonists (6.2%); and SGLT-2 inhibitors (2.2%). Periconceptual use of all second-line noninsulin therapy increased over the observed time period.

The standard prevalence of MCMs was 3.7% among all observed infants, versus 5.3% among infants born to women with type 2 diabetes. The prevalence of MCMs among infants born to women trated with insulin was 7.8%. The rate of MCMs infants born to women treated with each second-line antidiabetic drug class, and their adjusted relative risks compared to insulin, were as follows:

• Sulfonylureas, 9.7% (RR, 1.18; 95% CI, 0.94 – 1.48)
• GLP-1 agonists, 8.3% (RR, 0.95; 95% CI, 0.72 – 1.26)
• SGLT-2 inhibitors, 7.0% (RR, 0.98; 95% CI, 0.65 – 1.46)
• DPP-4 inhibitors, 6.1% (RR, 0.83; 95% CI, 0.64 – 1.06)

Cesta and colleagues concluded that, despite infants being at a higher risk of overall and cardiac-based MCMs when born to women with pregestational type 2 diabetes versus the general population, there was no such discernable significant risk in infants born to women treated with these drug classes instead of insulin.

“Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise risk estimates in the future as data accumulate,” the team concluded.

Reference

^{Cesta CE, Rotem R, Bateman BT, et al. Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy. JAMA Intern Med. Published online December 11, 2023. doi:10.1001/jamainternmed.2023.6663}