A Case Study: Preconception Metformin Use in Recurrent Hyperemesis Gravidarum

Written By Ambria Repass

Background

Hyperemesis gravidarum (HG) is a severe pregnancy complication characterized by persistent nausea and vomiting, dehydration, weight loss, and substantial maternal morbidity. Recent advances have identified growth differentiation factor 15 (GDF15) as a primary mediator of HG pathophysiology (Fejzo et al., 2018; Fejzo et al., 2019).

GDF15 is a placentally derived hormone that rises sharply in early pregnancy, activating nausea, vomiting, and aversive pathways in the brain (Mullican et al., 2017). Evidence suggests that HG is not solely related to elevated GDF15 levels, but rather to heightened sensitivity or maladaptation to rapid GDF15 increases in susceptible individuals (Fejzo et al., 2019).

Metformin is known to increase circulating GDF15 independent of insulin signaling (Coll et al., 2020). This has led to a novel hypothesis: preconception exposure to elevated GDF15 may induce central adaptation or desensitization, thereby reducing the severity of nausea when pregnancy-associated GDF15 surges occur.

Patient History

The patient is a 33-year-old female with a history of three prior pregnancies, each complicated by severe hyperemesis gravidarum beginning between 6 and 7 weeks gestation.

Across all three pregnancies, clinical features included:

  • Severe and persistent nausea and vomiting

  • Inability to maintain oral intake

  • Difficulty gaining and maintaining weight

  • Recurrent dehydration requiring intravenous fluids

  • Significant impairment of daily functioning

Symptoms were refractory to standard antiemetic therapies. The patient had no other relevant medical history, including diabetes mellitus or other metabolic disease.

Intervention

Based on emerging research implicating GDF15 hypersensitivity in HG (Fejzo et al., 2018; Fejzo et al., 2019), the patient initiated metformin therapy prior to conception under medical supervision at Cultivate Functional Medicine. 

The patient started on Metformin 500mg daily and titrated slowly up to 2000mg daily based on nausea tolerability. It took approximately five weeks to reach and maintain 2000mg daily. She was initially started on an immediate release formulation, but switched to extended release after the first month.

The patient received a positive pregnancy test after approximately two weeks at a dose of 2000mg daily, and maintained this dose until nausea began at six weeks. At this time, she began a taper with discontinuation due to nausea around eight weeks gestation.

Outcome

During the fourth pregnancy, the patient experienced onset of nausea at six weeks gestation, which is consistent with her prior pregnancies. However, the severity of nausea was significantly reduced with only intermittent vomiting occurring during the first trimester. The patient was able to maintain oral intake without the need for intravenous hydration and did not experience weight loss. 

Based on first trimester experience, the symptoms did not meet diagnostic criteria for hyperemesis gravidarum and represented a substantial improvement compared to all prior pregnancies.

No adverse maternal or fetal outcomes related to metformin exposure have been observed, although the fetus is not yet to term.

Discussion

This case supports emerging evidence positioning GDF15 as a central driver of hyperemesis gravidarum, particularly in individuals who exhibit heightened sensitivity to rapid hormonal changes (Fejzo et al., 2019). The patient’s improved clinical course is consistent with the hypothesis that preconception GDF15 exposure may attenuate the central nervous system response to pregnancy-related GDF15 surges.

Metformin has been shown to raise circulating GDF15 through mechanisms involving mitochondrial stress signaling and integrated stress response pathways, independent of insulin regulation (Coll et al., 2020). This provides a biologically plausible mechanism by which preconception metformin use could reduce HG severity in susceptible individuals.

While metformin is not approved for HG prevention, its safety profile in pregnancy is well documented in other clinical contexts (Rowan et al., 2008; Zhu et al., 2019), supporting its consideration for further study in this population.

Limitations

This case study is limited by small sample size, its observational nature, and loosely structured titration plan. Causality cannot be established.

Prospective studies are needed to directly test the GDF15 sensitization hypothesis in patients with recurrent HG.

Conclusion

In a patient with recurrent hyperemesis gravidarum across three pregnancies, preconception metformin use was associated with a marked reduction in symptom severity during a subsequent pregnancy. This case adds clinical support to emerging evidence implicating GDF15-mediated mechanisms in HG and suggests that pre-pregnancy hormonal conditioning may represent a promising preventive strategy for high-risk individuals.



References 

Coll, A. P., Chen, M., Taskar, P., Rimmington, D., Patel, S., Tadross, J. A., … O’Rahilly, S. (2020). GDF15 mediates the effects of metformin on body weight and energy balance. Nature Medicine, 26(11), 1727–1735. https://doi.org/10.1038/s41591-020-1056-x

Fejzo, M. S., Trovik, J., Grooten, I. J., Sridharan, K., Roseboom, T. J., Vikanes, Å., … Mullin, P. M. (2019). GDF15 linked to maternal risk of hyperemesis gravidarum. Nature Medicine, 25(6), 934–938. https://doi.org/10.1038/s41591-019-0451-1

Fejzo, M. S., Myhre, R., Colodro-Conde, L., MacGibbon, K. W., Sinsheimer, J. S., Reddy, J., … Vikanes, Å. (2018). Genetic analysis of hyperemesis gravidarum reveals association with GDF15 and IGFBP7. Nature Communications, 9, 1–9. https://doi.org/10.1038/s41467-018-03258-0

Mullican, S. E., Lin-Schmidt, X., Chin, C. N., Chavez, J. A., Furman, J. L., Armstrong, A. A., … Rangwala, S. M. (2017). GFRAL is the receptor for GDF15 and mediates the anorectic effects of GDF15. Nature Medicine, 23(10), 1215–1219. https://doi.org/10.1038/nm.4392

Rowan, J. A., Hague, W. M., Gao, W., Battin, M. R., & Moore, M. P. (2008). Metformin versus insulin for the treatment of gestational diabetes. The New England Journal of Medicine, 358(19), 2003–2015. https://doi.org/10.1056/NEJMoa0707193

Zhu, B., Zhang, L., Fan, Y., & Zhou, J. (2019). Metformin versus insulin in gestational diabetes mellitus: A meta-analysis of randomized controlled trials.Journal of Diabetes Research, 2019, 1–10. https://doi.org/10.1155/2019/4067093

Ambria Repass
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