Metformin may Prevent Recurrence of Hyperemesis Gravidarum among those with prior history: Study

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 risk of reoccurrence and improving maternal, fetal, and child health. We recently demonstrated that genetic predisposition to hyperemesis gravidarum is mediated by low pre-pregnancy levels of the emetogenic hormone Growth and Differentiation Factor 15, resulting in hypersensitivity to its rapid rise during pregnancy. Because metformin increases circulating levels of the Growth and Differentiation Factor 15, we hypothesized that use of metformin before pregnancy will desensitize patients to the hormone and lower the risk of severe nausea and vomiting in pregnancy and hyperemesis gravidarum.

The objective of the study is to determine whether daily use of metformin is associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum. By 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 level of nausea and vomiting of pregnancy. Crude and multivariate associations between use of each substance and severe nausea and vomiting of pregnancy/hyperemesis gravidarum in the subsequent pregnancy were estimated by logistic regression. Final multivariate models included tobacco use and maternal age; number and type of additional drugs used, and race/ethnicity had little influence and were not retained. Results: A total of 5414 participants reported on daily medication/substance use in the month prior to pregnancy and level of nausea and vomiting during pregnancy. Using metformin before the first pregnancy was associated with >70% reduction of risk of hyperemesis gravidarum [aRR=0.29 (95%CI=0.12-0.71, P=0.007,]. Tobacco use was also associated with a significant reduction of risk [aRR=0.51 (95%CI=0.30-0.86), P=0.011]. Conversely, selective serotonin reuptake inhibitors were associated with an increased risk of hyperemesis gravidarum [aRR=2.41 (95%CI=1.33-4.38), P=0.004]. Use of metformin was also associated with an 82% reduction in risk of severe nausea and vomiting of pregnancy/hyperemesis gravidarum [aOR=0.18 (0.06-0.59), P=0.005] in the 2nd pregnancy, even after adjustment for the 86% recurrence risk identified in this study. Conversely, use of cannabis or selective serotonin reuptake inhibitors prior to the second pregnancy were each associated with increased risk [aOR=3.48 (1.80-6.75), P<0.001]; aOR=1.84 (1.12-3.04), P=0.016]. Pre-pregnancy metformin treatment may decrease risk of severe nausea and vomiting, while pre-pregnancy cannabis use and/or selective serotonin reuptake inhibitors may increase risk. Metformin, which is routinely used pre and post conception, may be a safe and affordable treatment to offer patients with a prior history of hyperemesis gravidarum to decrease the chance of recurrence. Clinical trials are warranted to investigate metformin use prior to pregnancy to lower hyperemesis gravidarum risk, thereby mitigating the associated adverse maternal and offspring outcomes.