Metformin for the Prevention of Hyperemesis Gravidarum: Cautious Enthusiasm*Cathy Nelson-Piercy - catherine.nelson-piercy@nhs.netMelanie Nana, Catherine Williamson, Rebecca PainterHyperemesis gravidarum (HG), the most severe form of nausea and vomiting in pregnancy (NVP), affects around 3% of pregnant women, and can result in both maternal and fetal morbidity and mortality (Nana M et al. Lancet. 2025 in press). It is the commonest reason for hospital admission in the first trimester of pregnancy. With appropriate antiemetics and intravenous fluids symptoms can be ameliorated in most women (Nelson-Piercy et al. 2024;131(7):e1-e30). However, the short- and long-term consequences on maternal mental health and offspring physical and neurocognitive development (Nijsten K et al. Am J Obstet Gynecol. 2022;227(3):414-429) as well as the significant financial burden on health services make prevention of HG desirable.GDF15, a hormone present in non-pregnant people, in particular after tissue damage and starvation, is secreted by trophoblast, rising rapidly in early pregnancy. It causes taste aversion, nausea, and vomiting. Genome-wide association studies of women with HG and/or NVP identified mutations and genetic variation in GDF15 and its receptor, GFRAL, associated with severe HG. Experimental studies have shown that chronic low serum GDF15 increases the effects of subsequent high GDF15 in pregnancy, and that ‘pre-conditioning’ with GDF15 can ameliorate the symptoms caused by high GDF15 exposure. It was therefore hypothesised that preconception ‘pre-conditioning’ with GDF15 raising agents could protect against HG.Metformin, a cheap and widely accessible medication safely used in pregnancy for gestational and pre-gestational diabetes mellitus (DM), and polycystic ovarian syndrome, has been shown to increase levels of GDF15, and could render women less sensitive to fetally derived GDF15. Metformin may therefore be a safe and attractive candidate for HG-prevention.Sillis et al. (Sillis et al. BJOG 2025) compared rates of HG and NVP in 80 women exposed to metformin pre-pregnancy with 4411 unexposed women. Their finding of a reduction of rates of HG (n=1/80; 1.25% vs. n=97/4,411; 2.20%) in the metformin group, albeit non-significant, is exciting, as it could have immediate clinical applicability in contrast to the lengthy development and safety testing of specific GDF15 blockers for use in pregnancy.Overweight, pre-gestational medical conditions, and assisted reproductive techniques (ART) are all HG-risk factors. The authors acknowledge adjusting for important confounders, including indication for metformin and ART would have further strengthened the study, but was not within the methodological scope. Additionally, the study was unable to establish a dose-effect relation, defining optimal pre-pregnancy metformin dose or duration and timing in relation to conception. Further, symptom severity was minimally recorded, making it impossible to comment on whether HG-severity improved alongside reduction in prevalence.   We agree with the authors that large multicentre studies including diverse populations are needed. Most importantly, prospective randomized controlled trials will ensure control for potential confounders. Studies suggest only a small proportion of women carry GDF15 mutations; while providing promise for some women it isn’t the story for all. This may have contributed to the lack of statistical significance in Sillis et al’s study. While the results offer hope, metformin to prevent HG must not be allowed to enter routine clinical practice before appropriate clinical studies have been performed to confirm its efficacy and to inform optimal dose and duration of treatment.The authors declare no conflict of interest.