medwireNews: Adding insulin to metformin in early pregnancy does not increase the risk for stillbirth or congenital malformities compared with switching to insulin monotherapy in women with type 2 diabetes, research suggests.
“Because pregnant women are typically excluded from preapproval randomized trials, no direct evidence of the safety of diabetes medications during pregnancy exists before a drug is approved,” Yu-Han Chiu (Harvard TH Chan School of Public Health, Boston, Massachusetts, USA) and co-authors remark in the Annals of Internal Medicine.
They add that post-approval trials typically include women who are at least 10 weeks into their pregnancy, which is too late to assess the teratogenic effect of the drugs.
In the absence of randomized trial evidence, guidelines recommend that pregnant women with type 2 diabetes discontinue metformin treatment and switch to insulin based on teratogenicity concerns, but Chiu and colleagues say their data suggest that these recommendations “may require reconsideration.”
The researchers carried out an emulated target trial, which uses carefully selected observational data to mimic a randomized controlled trial, among 12,489 pregnant women receiving metformin for type 2 diabetes before their last menstrual period (LMP) who were registered in a US Medicaid healthcare administration database between 2000 and 2018.
Of these, 1557 added insulin to their existing metformin therapy within 90 days of their LMP and 850 switched to insulin monotherapy.
Chiu and team estimated that the risk for nonlive birth was slightly higher among the women receiving insulin plus metformin than among those using insulin monotherapy, at 34.3% versus 32.7%, which corresponded to a risk ratio of 1.02.
The estimated risk for live birth with congenital malformations was 5.7% among women given insulin plus metformin and 8.0% among those given insulin monotherapy, resulting in a risk ratio of 0.72. However, the researchers note that the confidence intervals for this estimate were wide and suggested that “anything between a 49% decrease and a 9% increase in risk for congenital malformations [with insulin plus metformin] was highly compatible with our data.”
Of note, cardiac malformations were the most common congenital malformations in both treatment groups.
The researchers note that their findings may be subject to some residual confounding by glycemic control and BMI as this information could either be mismeasured or was unavailable.
Nonetheless, they conclude: “By explicitly emulating a target trial, we avoided design-induced biases when estimating the risk for nonlive birth.”
A second study, published in the same issue of the Annals of Internal Medicine, looked at the impact of paternal metformin use on congenital malformations.
In line with the findings among women, Ran Rotem, also from the Harvard TH Chan School of Public Health, and co-investigators found that the newborns of fathers who used metformin in the 90 days before conception were not at increased risk for major congenital malformations relative to those whose fathers had not used metformin.
In an accompanying editorial, Sarah Martins da Silva, from the University of Dundee in the UK, says that the results of both studies “suggest that metformin is a safe and effective treatment option for [type 2 diabetes] for men and women trying to conceive as well as managing hyperglycemia in pregnant women in the first trimester.”
She agrees with Chiu et al, commenting that “it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
Ann Intern Med 2024; doi:10.7326/M23-2038
Ann Intern Med 2024; doi:10.7326/M23-1405
Ann Intern Med 2024; doi:10.7326/M24-0883
