Can Hyperemesis Gravidarum Be Prevented with Metformin?
August 1, 2025
By Ahizechukwu C. Eke, MD, PhD, MPH
Synopsis: Although differences were not statistically significant, women with pre-conceptional metformin exposure appeared to have lower rates of hyperemesis gravidarum and comparable nausea and vomiting symptom severity, suggesting a potential protective effect that warrants further investigation in larger, adequately powered studies.
Source: Sillis L, Heinonen EW, Ceulemans M, et al. Metformin for the prevention of hyperemesis gravidarum: An observational cohort study. BJOG. 2025; May 29. doi: 10.1111/1471-0528.18238. [Online ahead of print].
Hyperemesis gravidarum is a debilitating complication of early pregnancy characterized by intractable nausea and vomiting, resulting in significant maternal morbidity, including dehydration, electrolyte imbalance, and malnutrition, requiring inpatient management.1,2 Despite its clinical burden and its association with adverse outcomes, such as low birth weight, small-for-gestational-age infants, and neurodevelopmental delays, effective prophylactic strategies remain elusive.2
Metformin, a biguanide widely used in the treatment of type 2 diabetes mellitus and polycystic ovary syndrome (PCOS), has demonstrated pleiotropic effects on hormonal regulation, gastrointestinal motility, and inflammation, pathophysiologic mechanisms implicated in hyperemesis gravidarum.3 Metformin likely acts through multiple mechanisms relevant to hyperemesis gravidarum, including improved insulin sensitivity and reduced trophoblast activity (leading to reduced human chorionic gonadotropin [hCG] production).4 More recently, metformin has been shown to modulate hyperemesis gravidarum risk by increasing circulating levels of growth differentiation factor 15 (GDF15), which may induce central desensitization to this hormone and mitigate its emetogenic effects.5
Although metformin generally is considered safe for use during early pregnancy, including the first trimester, evidence supporting its effectiveness in the management or prevention of hyperemesis gravidarum remains limited.6 Given the early gestational onset and potential severity of hyperemesis gravidarum, there is growing interest in evaluating whether metformin, when initiated pre-conceptionally or in early pregnancy, could serve as a safe, low-cost pharmacologic intervention to prevent hyperemesis gravidarum and mitigate its downstream complications.
To address this gap, Sillis et al conducted a systematic evaluation of metformin's prophylactic efficacy, tolerability, and maternal-fetal safety in women at risk of hyperemesis gravidarum.
This study was a secondary observational cohort analysis of the MotherToBaby Pregnancy Studies in the United States and Canada, conducted to assess whether pre-conceptional metformin exposure reduced the risk of hyperemesis gravidarum and nausea and vomiting in pregnancy.7 The study included live-born singleton pregnancies enrolled between 2012 and 2023, and evaluated outcomes in women who had used metformin between the last menstrual period and conception compared with those with no metformin exposure before or during pregnancy. Women with multiple gestation and those who used metformin during pregnancy but not prior to conception were excluded. All data were collected via prospective maternal telephone interviews and corroborated with medical records.
The primary outcome was the occurrence of hyperemesis gravidarum, as defined by maternal self-report or medical record documentation. Secondary outcomes included self-reported nausea and vomiting in pregnancy (based on general questions and the Pregnancy-Unique Quantification of Emesis and Nausea [PUQE] score), duration of nausea and vomiting symptoms, and hospitalizations for hyperemesis gravidarum. Nausea and vomiting of pregnancy was defined as either a PUQE score of ≥ 3 or a positive response to at least one general nausea and vomiting of pregnancy question during the first trimester.
Participants who completed both the PUQE and general symptom questions were classified as having nausea and vomiting of pregnancy if they met the criteria on either measure. The study controlled for confounding using propensity score-adjusted modified Poisson regression, incorporating covariates, including maternal age, socioeconomic status, race, ethnicity, gravidity, pre-pregnancy body mass index (BMI), and substance use during pregnancy. Risk ratios (RRs) and adjusted RRs (aRRs) were reported with 95% confidence intervals (CIs).
Out of 4,547 women enrolled initially, 56 were excluded because of metformin use only during pregnancy, resulting in a final cohort of 4,491 women (80 women exposed to pre-conceptional metformin and 4,411 women unexposed). The most common indications for metformin were PCOS (56.3%), infertility (21.3%), and diabetes (15%). The mean metformin dose was 1,252 mg daily (standard deviation [SD], 662). Metformin-exposed participants were significantly more likely to be obese (BMI ≥ 30 kg/m2; 46.3% vs. 19.2%, P < 0.001), although no significant differences were observed in age, race, or gravidity. The rate of hyperemesis gravidarum was 1.25% (1/80) in the metformin group compared to 2.20% (97/4,411) in the unexposed group (aRR, 0.50; 95% CI, 0.07, 3.39).
Hospitalization for hyperemesis gravidarum occurred in none of the exposed women vs. 8.25% of unexposed women with hyperemesis gravidarum. Nausea and vomiting in pregnancy was reported in 88.9% (32/36) of exposed women and 82.6% (1,664/2,014) of unexposed women (aRR, 1.06; 95% CI, 0.94, 1.19). Duration of nausea and vomiting did not differ significantly between groups: mean nausea duration was 14.8 (SD, 11.8) weeks in exposed women vs. 12.5 (SD, 9.3) weeks in unexposed women (P = 0.515). Mean vomiting duration was 10.4 (SD, 10.8) weeks in exposed women vs. 11.2 (SD, 10.1) weeks in unexposed women (P = 0.590). Mean PUQE scores also were similar (5.83 vs. 5.16; P = 0.229).
Commentary
This observational cohort study evaluating pre-conceptional metformin exposure for the prevention of hyperemesis gravidarum found no statistically significant differences in rates of hyperemesis or nausea and vomiting in pregnancy; however, the direction of effect suggested a potential protective association with metformin. Both groups demonstrated similar symptom duration and severity, with no meaningful differences in measures such as PUQE scores or hospitalization rates. Importantly, the study revealed that women receiving metformin prior to conception were more likely to have higher BMIs and underlying conditions such as PCOS or diabetes, underscoring the need to account for confounding by indication. Although the study was underpowered as a result of the small number of exposed participants and rare outcome events, its findings highlight the feasibility and clinical relevance of testing metformin as a prophylactic agent in future trials, particularly among high-risk populations planning pregnancy.
The pharmacologic treatment of hyperemesis gravidarum remains challenging, with few medications approved specifically for use in pregnancy. First-line therapies include pyridoxine (vitamin B6) and doxylamine, which are considered safe and effective for mild-to-moderate nausea and vomiting of pregnancy.8 In more severe cases, antiemetics such as promethazine, metoclopramide, and ondansetron commonly are used. However, although concerns exist regarding ondansetron’s potential association with small increases in risk of cardiac and oral clefts, large population studies generally have shown reassuring safety profiles.9 Corticosteroids may be considered for refractory hyperemesis gravidarum but generally are avoided in the first trimester because of a possible increased risk of cleft lip/palate.8 Importantly, none of these therapies directly target the pathophysiology of hyperemesis gravidarum, highlighting the need for mechanism-based treatments.
Recent genetic and molecular evidence strongly implicates the GDF15-GFRAL signaling axis as a key driver of hyperemesis gravidarum. A 2024 Nature study by Fejzo et al identified fetal-derived GDF15 levels and maternal sensitivity to this hormone as predictive of hyperemesis gravidarum risk, with higher pre-pregnancy maternal GDF15 levels being protective through desensitization mechanisms.5 Metformin has been shown to increase circulating GDF15 (by desensitizing women who are susceptible to hyperemesis), offering a plausible biologic rationale for its potential preventive effect on hyperemesis gravidarum when started pre-conception.10 In light of the current findings, metformin’s potential role as a prophylactic agent is particularly compelling given its widespread use and generally favorable safety profile in early pregnancy.11
Prolonged vomiting in hyperemesis gravidarum can lead to significant nutritional deficiencies, with thiamine (vitamin B1) deficiency being among the most clinically urgent. Wernicke’s encephalopathy, a life-threatening neurologic condition characterized by ophthalmoplegia, ataxia, and confusion, can develop in patients with prolonged vomiting and inadequate thiamine intake.8 It is essential for clinicians to recognize this risk and initiate early thiamine supplementation in patients with moderate to severe hyperemesis gravidarum, especially before initiating intravenous glucose. The American College of Obstetricians and Gynecologists (ACOG) recommends thiamine supplementation (50 mg daily intravenously or orally) for women with prolonged vomiting, ideally starting as soon as hyperemesis gravidarum is suspected and continuing through recovery.8 This preventive approach is critical to reduce the risk of irreversible neurologic damage.
The severity, recurrence risk, and psychosocial burden of hyperemesis gravidarum underscore the importance of advancing both preventive and therapeutic strategies. Currently, ACOG recommends a stepwise approach to management, beginning with dietary modifications and progressing through pharmacologic therapy as needed.8 Hospitalization for rehydration and nutritional support is appropriate for severe cases. Although metformin is not yet recommended for hyperemesis gravidarum prevention, accumulating mechanistic and clinical data warrant further investigation through prospective clinical trials.
Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.
References
1. Clark SM, Zhang X, Goncharov DA. Inpatient management of hyperemesis gravidarum. Obstet Gynecol. 2024;143(6):745-758.
2. London V, Grube S, Sherer DM, Abulafia O. Hyperemesis gravidarum: A review of recent literature. Pharmacology. 2017;100(3-4):161-171.
3. Prattichizzo F, Giuliani A, Mens E, et al. Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Res Rev. 2018;48:87-98.
4. Nashif SK, Mahr RM, Jena S, et al. Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner. Front Cell Dev Biol. 2023;11:1167097.
5. Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625(7996):760-767.
6. Cassina M, Donà M, Di Gianantonio E, et al. First-trimester exposure to metformin and risk of birth defects: A systematic review and meta-analysis. Hum Reprod Update. 2014;20(5):656-669.
7. Sillis L, Heinonen EW, Ceulemans M, et al. Metformin for the prevention of hyperemesis gravidarum: An observational cohort study. BJOG. 2025; May 29. doi: 10.1111/1471-0528.18238. [Online ahead of print].
8. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 189: Nausea and vomiting of pregnancy. Obstet Gynecol. 2018;131(1):e15-e30.
9. Huybrechts KF, Hernández-Díaz S, Straub L, et al. Association of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring. JAMA. 2018;320(23):2429-2437.
10. Lockhart SM, Saudek V, O Rahilly S. GDF15: A hormone conveying somatic distress to the brain. Endocrine Rev. 2020;41(4):bnaa007.
11. Abolhassani N, Winterfeld U, Kaplan YC, et al. Major malformations risk following early pregnancy exposure to metformin: A systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2023;11(1):e002919.