GDF15 and nausea

Metformin and Hyperemesis Gravidarum: A Potential Breakthrough in Treatment

Hyperemesis gravidarum (HG) is much more than morning sickness. It’s a severe condition characterized by intense nausea, vomiting, weight loss, and dehydration. HG can significantly affect both maternal and fetal health. It impacts up to 10% of pregnancies, often leading to hospitalizations and long-term complications. If untreated, it can even be fatal for both the mother and baby. Recent studies suggest that metformin, a medication commonly used to treat type 2 diabetes, might offer a new treatment option. Researchers are investigating how metformin could influence a hormone linked to pregnancy-related nausea—Growth Differentiation Factor 15 (GDF15).

What Is GDF15, and Why Does It Matter in Pregnancy?

Recent groundbreaking research, including studies led by Dr. Marlena Fejzo, has identified GDF15 and its receptor, GFRAL, as key players in the development of HG. Genetic studies show that women with variations in the GDF15 pathway are more likely to develop HG. This finding provides a clear biological explanation for the symptoms of HG. GDF15 is a hormone produced by the placenta during pregnancy. It helps regulate appetite and nausea. Higher levels of GDF15 in early pregnancy are closely linked to nausea and vomiting.

Interestingly, some women with chronic conditions like thalassemia, who naturally have elevated levels of GDF15 before pregnancy, often experience less nausea. This suggests that their bodies may be desensitized to the hormone’s effects. This discovery has shaped new strategies for treatment.

How Might Metformin Help Prevent Hyperemesis Gravidarum?

Metformin is widely prescribed for diabetes and polycystic ovary syndrome (PCOS). Notably, it also raises GDF15 levels gradually over time. This has led researchers to wonder if metformin could help prepare the body to tolerate GDF15, potentially reducing HG symptoms.

This idea is supported by the observation that women with high pre-pregnancy GDF15 levels often don’t experience severe nausea. By gradually increasing GDF15 levels with metformin before pregnancy, it might help lessen the sudden hormonal spike that contributes to HG.

While the concept is still being explored, it marks a significant step toward targeted, biology-based prevention for HG, particularly for women who have experienced it in previous pregnancies.

Metformin, GDF15, and Anti-Aging: A Fascinating Link

Metformin is also being studied for its potential anti-aging effects. These benefits are thought to result from its impact on GDF15. The hormone may help reduce inflammation, improve metabolism, and support healthy cellular function.

These findings strengthen the idea that gradually elevating GDF15, as metformin does, can encourage beneficial changes in the body. In pregnancy, this could mean less sensitivity to the hormone’s nausea-inducing effects.

What This Means for Hyperemesis Gravidarum Patients and Providers

For patients, especially those with a history of HG, this research offers new hope. It also provides an opportunity to have informed discussions with healthcare providers about prevention strategies before conceiving again.

For providers, especially OB-GYNs and maternal-fetal medicine specialists, these findings open a potential new avenue for preconception care, particularly for women with PCOS who are already using metformin.

Although further clinical trials are needed, this research emphasizes the importance of integrating genetic, hormonal, and pharmacologic insights into HG care.

Is Metformin Safe to Use in Pregnancy?

Metformin crosses the placenta, with umbilical cord levels reaching up to 100% of maternal concentrations. However, studies have not shown an increased risk of birth defects or miscarriage.

In Australia, metformin is classified as a Category C drug. This means any effects on the fetus are expected to be temporary and reversible. In the U.S., the FDA no longer uses traditional pregnancy categories. However, current guidelines stress managing maternal health conditions, such as diabetes, to reduce complications.

Metformin has been safely used in pregnancy for decades, particularly for women with PCOS and gestational diabetes. Still, more research is needed to assess its role in HG prevention specifically.

What’s Known About Metformin’s Dosing and Timing?

Studies in women with PCOS have used metformin doses ranging from 1,700 mg to 3,000 mg per day, starting before pregnancy and continuing into the first trimester or beyond. These regimens have been associated with lower risks of gestational diabetes and other complications.

While these findings are promising, they cannot yet be directly applied to HG. The optimal dose, timing, and duration of metformin use for HG prevention remain unclear and will depend on ongoing research and personalized care planning.

Why Metformin Research Matters

For years, HG was misunderstood, with limited treatment options and little research funding. Thanks to advances in molecular genetics and the work of researchers like Dr. Marlena Fejzo, HG is now recognized as a biologically driven condition, not as a psychological or exaggerated issue.

Understanding the hormonal mechanisms behind HG opens the door to more compassionate, evidence-based care—and possibly, for the first time, effective prevention.

Key Takeaways for Patients and Providers

• • GDF15 is a key hormone linked to nausea and vomiting in pregnancy, especially in HG.

  • Metformin gradually increases GDF15, which may desensitize the body and reduce HG symptoms.

  • Starting metformin before pregnancy could be a promising strategy, especially for women at high risk of HG.

  • Metformin has a strong safety record, but clinical trials are still needed to evaluate its role in HG prevention.

  • Shared decision-making is essential—patients and providers should weigh benefits, risks, and individual health histories when considering metformin use during pregnancy.

References

• ​ American Diabetes Association. (2023). Standards of medical care in diabetes—2023. Diabetes Care, 46(Suppl 1), S1–S300.​
• ​ Coll, A. P. et al. (2022). GDF15 mediates the effects of metformin on body weight and energy balance. Nature Metabolism, 4(9), 1178–1191.​
• ​ Drugs.com. (2024). Metformin pregnancy and breastfeeding warnings. Retrieved from drugs.com​
• ​ Fejzo, M. S. et al. (2018). Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications, 9, 1178.​
• ​ Morin-Papunen, L. C. et al. (2019). Metformin therapy improves menstrual frequency and decreases circulating androgens in women with PCOS. JCEM, 104(2), 1234–1245.​
• ​ Novelle, M. G. et al. (2016). Metformin: A hopeful promise in aging research. Cold Spring Harbor Perspectives in Medicine, 6(3), a025932.​
• ​ Patel, S. H. et al. (2021). GDF15 and its role in hyperemesis gravidarum: A systematic review. Obstetrics & Gynecology International, 2021, 1–10.​
• ​ Sarker, S. et al. (2023). The role of GDF15 in pregnancy-induced nausea: New insights. American Journal of Obstetrics and Gynecology, 228(5), 501–510.