Hyperemesis gravidarum, marked by severe nausea and vomiting during pregnancy, can lead to dehydration, weight loss, and repeated hospitalizations. Emerging evidence links HG to high levels of placentally derived growth differentiation factor-15 (GDF-15), which rises rapidly in early pregnancy. Paradoxically, lower GDF-15 levels before conception appear to increase susceptibility to HG, suggesting that preconception “conditioning” of this pathway could reduce risk.
Metformin, a commonly prescribed and pregnancy-safe drug, is known to increase circulating GDF-15 levels. To explore whether this effect translates into lower HG risk, Loïs M. van der Minnen from the Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, and colleagues conducted a large population-based cohort study using Danish national health registries.
The study included nearly 1.45 million singleton pregnancies with a gestational age of at least 10 weeks between 1998 and 2018. Metformin exposure was identified through prescription redemption records up to two years before conception, allowing the researchers to assess both duration of use and timing relative to pregnancy. Overall, 1.9% of pregnancies were complicated by HG, with a recurrence rate of 26%.
The study led to the following notable findings:
• Overall, preconception metformin use did not reduce the prevalence or recurrence of hyperemesis gravidarum (HG) compared with non-users.
• Duration and timing of metformin use influenced HG risk.
• Women who used metformin for at least six months before conception had a lower prevalence of HG (1.1%) compared with those using it for less than two months, corresponding to a 51% reduction in adjusted odds.
• Continuing metformin into the first month of pregnancy was associated with 39% lower odds of developing HG compared with discontinuation more than six months before conception.
• Short-term preconception metformin use was not linked to a meaningful reduction in HG risk.
• These findings remained significant after adjusting for metformin indication and other potential confounding factors.
According to the authors, the findings support the hypothesis that sustained preconception exposure to metformin may raise GDF-15 levels enough to reduce vulnerability to HG. They noted that longer treatment duration and continuation up to or into early pregnancy appear to be critical for any protective effect.
While the observational design limits causal inference, the study provides a strong rationale for future randomized trials. If confirmed, preconception metformin could represent the first preventive strategy for hyperemesis gravidarum in women at high risk, potentially easing the clinical and emotional burden of this debilitating condition.
Reference:
Van der Minnen, L. M., Vendelbo, J. H., Pedersen, L. H., & Painter, R. C. (2025). Preconception metformin and hyperemesis gravidarum in Denmark– clinical implications of GDF-15’s etiological role. American Journal of Obstetrics and Gynecology. https://doi.org/10.1016/j.ajog.2025.12.060
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