Prepregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum.

Abstract

Severe nausea and vomiting of pregnancy and hyperemesis gravidarum are associated with adverse maternal, fetal, and child outcomes. The recurrence risk is reported to be as high as 89%. Identifying an effective, safe, and affordable method to prevent hyperemesis gravidarum is critical to reducing the risk for reoccurrence and improving maternal, fetal, and child health. We recently demonstrated that a genetic predisposition to hyperemesis gravidarum is mediated by low prepregnancy levels of the emetogenic hormone, growth and differentiation factor 15, which leads to hypersensitivity to its rapid rise during pregnancy. Because metformin increases circulating levels of growth and differentiation factor 15, we hypothesized that the use of metformin before pregnancy will desensitize patients to the hormone and lower the risk for severe nausea and vomiting in pregnancy and hyperemesis gravidarum. The objective of the study was to determine whether daily use of metformin is associated with a lower risk for severe nausea and vomiting of pregnancy and hyperemesis gravidarum. Through means of a structured questionnaire, visitors to the Hyperemesis Gravidarum Education and Research Foundation social media sites from January 2023 to September 2024 reported daily use of 32 common substances in the month before each pregnancy and the level of nausea and vomiting of pregnancy. Crude and multivariate associations between the use of each substance and severe nausea and vomiting of pregnancy and hyperemesis gravidarum in the subsequent pregnancy were estimated using a logistic regression. The final multivariate models included tobacco use and maternal age; the number and type of additional drugs used and race and ethnicity had little influence and were not retained. A total of 5414 participants reported their daily medication and substance use in the month before pregnancy and the level of nausea and vomiting during pregnancy. Using metformin before the first pregnancy was associated with a >70% reduction in the risk for hyperemesis gravidarum (adjusted relative risk, 0.29; 95% confidence interval, 0.12-0.71; P=.007). Tobacco use was also associated with a significant reduction in the risk (adjusted relative risk, 0.51; 95% confidence interval, 0.30-0.86; P=.011). Conversely, selective serotonin reuptake inhibitors were associated with an increased risk for hyperemesis gravidarum (adjusted relative risk, 2.41; 95% confidence interval, 1.33-4.38; P=.004). The use of metformin was also associated with an 82% reduction in the risk for severe nausea and vomiting of pregnancy and hyperemesis gravidarum (adjusted odds ratio, 0.18; 0.06-0.59; P=.005) in the second pregnancy, even after adjustment for the 86% reoccurrence risk identified in this study. Conversely, the use of cannabis or selective serotonin reuptake inhibitors before the second pregnancy were each associated with increased risk (adjusted odds ratio, 3.48; 1.80-6.75; P<.001; and adjusted odds ratio, 1.84; 1.12-3.04; P=.016, respectively). Prepregnancy metformin treatment may decrease the risk for severe nausea and vomiting, whereas prepregnancy cannabis use and selective serotonin reuptake inhibitors may increase the risk. Metformin, which is routinely used before and after conception, may be a safe and affordable treatment to offer patients with a history of hyperemesis gravidarum to decrease the chance of reoccurrence. Clinical trials are warranted to investigate metformin use before pregnancy to lower the risk for hyperemesis gravidarum, thereby mitigating the associated adverse maternal and offspring outcomes.