Written by The HG Collective · Reviewed by HG Clinicians Expert Panel · Last reviewed: July 2026
What causes HG?
For a long time, nobody really knew why some people developed hyperemesis gravidarum (HG) while others did not. Research has now provided a much clearer biological explanation, although the full picture is still developing.
The strongest evidence currently points to a hormone called GDF15 playing a central role in HG. Research also indicates that GDF15 influences the severity of nausea and vomiting across pregnancy more widely. Other genes and biological pathways may affect who develops HG and how severe it becomes.
The central role of GDF15
GDF15 is a hormone that acts on a part of the brain involved in nausea, vomiting and appetite. During pregnancy, the amount circulating in the mother's blood rises sharply, with the great majority coming from the fetus and placenta.
Research suggests that the severity of nausea and vomiting in pregnancy is influenced by the interaction between two things: how much GDF15 is produced during pregnancy and how sensitive the mother is to it.
Some genetic variants associated with HG are linked to lower GDF15 levels before pregnancy. Lower previous exposure may leave some people more sensitive to the sharp rise that occurs once they become pregnant. This does not mean that everyone who develops HG has low GDF15 before pregnancy, or that one mechanism explains every case.
The findings provide the clearest biological explanation for HG discovered so far. They offer compelling evidence that HG has a physical basis—it is not caused by psychological weakness, anxiety or a lack of resilience.
The first genome-wide association study of HG, published in 2018, identified two genome-wide significant genetic associations implicating GDF15 and IGFBP7. The authors were careful to describe these as genetic risk factors rather than proof that either gene alone caused HG.
In 2022, a whole-exome sequencing study of 926 people with HG requiring intravenous fluids and 660 controls found that a common coding variant in GDF15 was the only association to reach exome-wide significance. It also identified a rare GDF15 variant in ten cases and no controls. The study strengthened the evidence for GDF15 but acknowledged that other genes may also be involved.
A 2024 Nature study provided the most detailed account of the mechanism. It found that:
- GDF15 levels were higher in women experiencing vomiting in pregnancy and in those with HG;
- the great majority of GDF15 circulating in maternal blood during pregnancy came from the feto-placental unit;
- rare and common genetic variants associated with HG were linked to lower GDF15 levels outside pregnancy; and
- higher exposure to GDF15 before pregnancy appeared to reduce sensitivity to its effects.
The researchers concluded that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to HG risk. They described the findings as supporting a putative causal role for fetal GDF15, rather than claiming that GDF15 is the sole cause of every case.
The evidence expanded again in 2026. A multi-ancestry genome-wide association study involving 10,974 HG cases and 461,461 controls identified ten genetic associations. These included previously identified associations involving GDF15, GFRAL, IGFBP7 and PGR, alongside six additional loci. The findings reinforce the central importance of the GDF15 pathway while showing that HG biology is likely to involve several genes and pathways.
RCOG described the GDF15 findings as a major advance in understanding pregnancy sickness and said that maternal sensitivity to GDF15 produced by the fetus might underlie the risk of severe nausea and vomiting.
References
- Fejzo MS, Sazonova OV, Sathirapongsasuti JF, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications. 2018;9:1178. https://doi.org/10.1038/s41467-018-03258-0
- Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. 2022. https://doi.org/10.1111/1471-0528.17129
- Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625:760–767. https://doi.org/10.1038/s41586-023-06921-9
- Fejzo M, Wang X, Tan Q, et al. Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting. Nature Genetics. 2026;58:810–820. https://doi.org/10.1038/s41588-026-02564-4
- Royal College of Obstetricians and Gynaecologists. The RCOG welcomes important new study uncovering the cause of pregnancy sickness. 14 December 2023. https://www.rcog.org.uk/news/the-rcog-welcomes-important-new-study-uncovering-the-cause-of-pregnancy-sickness/
What could this mean for treatment?
Understanding the GDF15 pathway creates the possibility of treatments that target the biological mechanism behind HG, rather than only managing its symptoms.
This is an important direction for research, but it is not yet an available treatment. No GDF15-based medicine has currently been approved to prevent or treat HG. Existing treatment should not be delayed or stopped while this research continues.
In the 2024 Nature study, mice exposed to a long-acting form of GDF15 before receiving a larger dose showed a reduced response, suggesting that previous exposure can desensitise the GDF15 system. The researchers proposed that increasing exposure before pregnancy might eventually offer one route to prevention. They also identified blocking GDF15 signalling as a possible treatment approach once symptoms have begun.
These experiments did not test a treatment for HG in pregnant people. They established biological plausibility and possible routes for future drug development, not evidence that either approach is currently safe or effective in pregnancy.
A separate 2024 study identified people with naturally occurring loss-of-function variants in GDF15, including a small number with complete loss of functioning GDF15. No consistent major health problems were identified among the people studied. The authors suggested that this supports further investigation of medicines that block GDF15, but the study did not establish the safety of such treatment during pregnancy or its effectiveness for HG.
References
- Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625:760–767. https://doi.org/10.1038/s41586-023-06921-9
- Gurtan AM, Khalid S, Koch C, et al. Identification and characterization of human GDF15 knockouts. Nature Metabolism. 2024;6:1913–1921. https://doi.org/10.1038/s42255-024-01135-3
How the evidence developed
Dr Marlena Fejzo has played a leading role in changing scientific understanding of HG. Her work with colleagues led to the first genome-wide association study implicating GDF15 and IGFBP7, the subsequent whole-exome sequencing study and the international research that established how fetal GDF15 and maternal sensitivity may interact.
These discoveries are the product of sustained work involving participants with lived experience and international teams across genetics, obstetrics, endocrinology, placental biology and metabolic research. Research is continuing as new genetic associations and biological pathways are identified.
The development of the evidence can be traced across four major studies:
- The 2018 genome-wide association study first identified associations implicating GDF15 and IGFBP7.
- The 2022 whole-exome study identified coding variants in GDF15 associated with HG.
- The 2024 Nature study investigated how fetal production of GDF15 and maternal sensitivity to it interact.
- The 2026 multi-ancestry study confirmed previously identified associations and identified additional genetic loci, broadening the picture beyond a single pathway.
Dr Fejzo was the lead or first-listed author on each of these studies. The author lists also demonstrate the large and increasingly international collaborations involved in developing this evidence.
References
- Fejzo MS, Sazonova OV, Sathirapongsasuti JF, et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications. 2018;9:1178. https://doi.org/10.1038/s41467-018-03258-0
- Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. 2022. https://doi.org/10.1111/1471-0528.17129
- Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625:760–767. https://doi.org/10.1038/s41586-023-06921-9
- Fejzo M, Wang X, Tan Q, et al. Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting. Nature Genetics. 2026;58:810–820. https://doi.org/10.1038/s41588-026-02564-4
What about older theories?
You may still see HG described as being caused by rising levels of hCG, another hormone produced during pregnancy. hCG was investigated for many years because the timing of its rise overlaps with nausea and vomiting in pregnancy, and conditions associated with higher hCG can also be associated with more severe symptoms.
These observations did not establish that hCG directly causes HG. Genetic studies have not found comparable evidence implicating the hCG pathway, while the evidence for GDF15 now includes genetic associations, hormone measurements and experimental work explaining how the mechanism could operate.
This does not prove that hCG has no direct or indirect influence in any pregnancy. It means that hCG is no longer the best-supported central explanation for HG.
The 2022 whole-exome sequencing study found no exome-wide significant association involving genes that encode hCG. Its authors concluded that the results did not support hCG as the principal cause of HG. A genetic study cannot by itself exclude every possible direct or indirect role for hCG, but the contrast with the much stronger and repeatedly replicated GDF15 associations is important.
The 2024 Nature study then provided evidence connecting GDF15 levels, fetal origin, maternal genetic risk and previous exposure to the hormone within one biological model. RCOG described this as a major advance in understanding the cause of pregnancy sickness.
RCOG's Green-top Guideline No. 69 reflects the developing biological evidence while providing clinical recommendations for the diagnosis and management of nausea and vomiting in pregnancy and HG.
References
- Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. 2022. https://doi.org/10.1111/1471-0528.17129
- Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625:760–767. https://doi.org/10.1038/s41586-023-06921-9
- Royal College of Obstetricians and Gynaecologists. The RCOG welcomes important new study uncovering the cause of pregnancy sickness. 14 December 2023. https://www.rcog.org.uk/news/the-rcog-welcomes-important-new-study-uncovering-the-cause-of-pregnancy-sickness/
- Nelson-Piercy C, Dean C, Shehmar M, et al. The management of nausea and vomiting in pregnancy and hyperemesis gravidarum: Green-top Guideline No. 69. BJOG. 2024. https://doi.org/10.1111/1471-0528.17739
What researchers still do not know
The evidence for GDF15 represents a major shift in understanding HG, but important questions remain. Researchers do not yet know precisely why symptoms vary so widely, how all the identified genetic pathways interact or which mechanism-based treatments will be safe and effective during pregnancy.
What has changed is that HG can now be investigated as a biologically grounded disease with identifiable molecular and genetic pathways. That provides a much stronger foundation for better tests, treatments and prevention in the future.
The 2026 multi-ancestry study identified ten genetic associations and highlighted potential roles for appetite, insulin signalling, placental function and brain plasticity. Its findings demonstrate both the importance of the GDF15 pathway and the need to investigate additional mechanisms.
The 2024 Nature study proposed possible approaches to treatment and prevention, but further human research is required before these can be translated into clinical care.
References
- Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625:760–767. https://doi.org/10.1038/s41586-023-06921-9
- Fejzo M, Wang X, Tan Q, et al. Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting. Nature Genetics. 2026;58:810–820. https://doi.org/10.1038/s41588-026-02564-4