Sharma Neelu, MacGibbon Kimber W, Brecht-Doscher Aimee, Cortessis Victoria K, Fejzo Marlena S
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Hyperemesis Education and Research Foundation, Clackamas, OR.
Am J Obstet Gynecol. 2025 Jun 28. doi: 10.1016/j.ajog.2025.06.055.
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.
妊娠剧吐和严重的妊娠恶心呕吐与不良的母婴及儿童结局相关。据报道，复发风险高达89%。确定一种有效、安全且经济实惠的方法来预防妊娠剧吐对于降低复发风险以及改善母婴和儿童健康至关重要。我们最近证明，妊娠剧吐的遗传易感性是由孕前致吐激素生长分化因子15水平较低介导的，这导致孕期该激素迅速升高时出现超敏反应。由于二甲双胍可提高生长分化因子15的循环水平，我们推测孕前使用二甲双胍会使患者对该激素脱敏，并降低妊娠剧吐和严重妊娠恶心呕吐的风险。
本研究的目的是确定每日使用二甲双胍是否与降低妊娠剧吐和严重妊娠恶心呕吐的风险相关。
通过结构化问卷，2023年1月至2024年9月期间访问妊娠剧吐教育与研究基金会社交媒体网站的访客报告了每次怀孕前一个月每天使用32种常见物质的情况以及妊娠恶心呕吐的程度。使用逻辑回归估计每种物质的使用与随后妊娠中的妊娠剧吐和严重妊娠恶心呕吐之间的粗略和多变量关联。最终的多变量模型包括吸烟情况和产妇年龄；使用的其他药物的数量和类型以及种族和民族影响较小，未被纳入。
共有5414名参与者报告了他们怀孕前一个月的日常用药和物质使用情况以及孕期恶心呕吐的程度。首次怀孕前使用二甲双胍与妊娠剧吐风险降低>70%相关（调整后的相对风险为0.29；95%置信区间为0.12 - 0.71；P = 0.007）。吸烟也与风险显著降低相关（调整后的相对风险为0.51；95%置信区间为0.30 - 0.86；P = 0.011）。相反，选择性5-羟色胺再摄取抑制剂与妊娠剧吐风险增加相关（调整后的相对风险为2.41；95%置信区间为1.33 - 4.38；P = 0.004）。即使在对本研究中确定的86%的复发风险进行调整后，二甲双胍的使用在第二次怀孕时也与妊娠剧吐和严重妊娠恶心呕吐风险降低82%相关（调整后的优势比为0.18；0.06 - 0.59；P = 0.005）。相反，第二次怀孕前使用大麻或选择性5-羟色胺再摄取抑制剂均与风险增加相关（调整后的优势比分别为3.48；1.80 - 6.75；P < 0.001；以及调整后的优势比为1.84；1.12 - 3.04；P = 0.016）。
孕前使用二甲双胍治疗可能会降低严重恶心呕吐的风险，而孕前使用大麻和选择性5-羟色胺再摄取抑制剂可能会增加风险。在受孕前后常规使用的二甲双胍可能是一种安全且经济实惠的治疗方法，可为有妊娠剧吐病史的患者提供，以降低复发几率。有必要进行临床试验来研究孕前使用二甲双胍以降低妊娠剧吐风险，从而减轻相关的不良母婴及后代结局。
