Beyond Morning Sickness: How the Brain May Explain Hyperemesis Gravidarum

Morning sickness is often portrayed as a routine part of pregnancy: feeling a little nauseous, being sick, and getting on with the day. But for some women, it is anything but routine.

Nausea and vomiting affect around 70% of pregnancies, but hyperemesis gravidarum (HG) is much more severe. It can make it difficult to eat or drink normally, cause significant weight loss and dehydration, and in some cases require hospital treatment. DAnd despite its name, morning sickness is not confined to the morning. Symptoms can occur throughout the day and night, although vomiting tends to peak in the morning.

HG has also become more widely discussed in recent years, including through Catherine, Princess of Wales, speaking about her own experiences. But while increased awareness is important, I was more interested in why pregnancy makes some women so sick. For a long time, the biology behind pregnancy sickness remained something of a mystery. Then, in 2023, research published in Nature provided important insight, identifying a hormone called growth differentiation factor 15 (GDF15) as a key player.

Meet GDF15

GDF15 belongs to the transforming growth factor-β (TGF-β) superfamily and is produced by tissues in response to cellular stress. During pregnancy, the placenta produces particularly large amounts, making it one of the most abundant peptides released by human trophoblasts.

What makes GDF15 particularly interesting, from a neuroscience perspective, is where it acts. Its receptor is found predominantly in the hindbrain, where GDF15 signalling can trigger aversive responses including reduced food intake and, in humans,  nausea and vomiting.

In other words, pregnancy sickness may not simply originate in the stomach. A hormone produced by the developing placenta enters the mother's circulation and communicates directly with the brain. This raises an important question: is having more GDF15 enough to explain why some women develop HG?

It may be about sensitivity, not just levels

Researchers found that circulating GDF15 levels were higher in pregnant women experiencing vomiting, and in those with HG, than in women reporting little or no nausea and vomiting. Genetic and mass spectrometry analyses also suggested that the feto-placental unit is the predominant source of GDF15 in maternal blood during pregnancy.

The relationship between GDF15 and HG becomes more interesting when researchers consider exposure before pregnancy. Although women experiencing HG tend to have higher circulating GDF15 during pregnancy, several genetic variants associated with increased HG risk are linked to lower GDF15 levels outside pregnancy. Meanwhile, women with β-thalassaemia, a condition associated with chronically elevated GDF15, reported substantially less nausea and vomiting during pregnancy than matched controls. Although GDF15 levels were not measured during pregnancy in this group, the findings are consistent with the hypothesis that long-term exposure to the hormone may reduce sensitivity to its effects.

So, how could higher GDF15 during pregnancy be associated with more severe symptoms, while higher levels before pregnancy appear protective? The researchers proposed desensitisation. The maternal brain may become accustomed to GDF15 following prolonged exposure, meaning that a sudden increase during pregnancy could produce a much stronger response in someone whose levels were previously low.

Can previous exposure change the brain's response?

To investigate this idea, the researchers turned to mice. There is an important limitation here: mice cannot directly demonstrate nausea or vomiting. Instead, the researchers measured one established effect of GDF15 signalling: suppression of food intake.

Adult mice were given either a long-acting form of GDF15 or a control injection. This increased circulating GDF15 to around 47 times the normal levels and temporarily reduced food intake. Three days later, both groups received an acute injection of recombinant human GDF15. Control mice showed the expected reduction in food intake and body weight. However, mice previously exposed to GDF15 showed a much smaller response.

This suggests that previous exposure to GDF15 can reduce the brain's response to a subsequent increase, supporting the idea that the pathway can become desensitised.

The researchers tested this idea another way using mice genetically lacking GDF15. When given a relatively low dose of GDF15, these mice reduced their food intake, whereas their wild-type littermates did not. This suggests that the response to GDF15 depends partly on how much exposure the brain has experienced previously.

This could help explain the human findings: HG may not simply be a consequence of producing more GDF15. Instead, symptoms could reflect an interaction between how much GDF15 the pregnancy produces and how sensitive the maternal brain is to it.

What about nausea?

This is where the evidence needs to be interpreted carefully. A reduction in food intake in a mouse is not the same as nausea or vomiting in a human. The mouse experiments therefore demonstrate changes in GDF15 signalling and appetite, rather than directly modelling HG.

There is, however, evidence from other animal models linking GDF15 more directly to vomiting. In non-humban primates, blocking GDF15 reduced vomiting caused by cisplatin, a chemotherapy drug that rapidly increases circulating GDF15. 

What does this mean for HG?

Taken together, the findings suggest that HG may depend on both how much GDF15 the pregnancy produces and how sensitive the maternal brain is to it. The placenta increases GDF15 in the mother's circulation, while previous exposure to the hormone may influence how strongly the brain responds. This could help explain why pregnancy sickness varies so dramatically between women.

If GDF15 signalling contributes to HG, targeting this pathway could potentially provide a treatment that addresses an underlying biological mechanism, rather than simply managing symptoms. Possible approaches include blocking GDF15 signalling during pregnancy or, theoretically, increasing GDF15 exposure before pregnancy to induce desensitisation.

However, these approaches remain experimental. Much more work is needed to understand their timing, dosing and safety, particularly because any treatment during pregnancy must consider both mother and developing foetus. For now, there is no GDF15-targeted treatment for HG.

GDF15 also raises an evolutionary question. Why might pregnancy make us feel sick in the first place?

The hormone is thought to act as a signal of physiological stress, communicating with the brain and promoting behaviours that help an organism avoid potential threats. During early pregnancy, the placenta produces particularly large amounts of GDF15.

One theory is that pregnancy sickness may have developed as a protective response, encouraging avoidance of potentially harmful foods, toxins and infections at a time when the developing foetus may be particularly vulnerable.

A biological response that evolved to protect us is not necessarily harmless when it becomes excessive or persists beyond its useful purpose. We see a similar principle in pain: acute pain serves an important protective function, warning us of actual or potential tissue damage, but persistent pain can become chronic and debilitating. In most pregnancies, nausea and vomiting are temporary and eventually subside. In HG, however, this response can become severe enough to have a major impact on daily life and require medical treatment.

There is still plenty we do not know. GDF15 is unlikely to explain every aspect of HG, and important questions remain about how this pathway produces nausea and vomiting, and how previous exposure to GDF15 may influence the body's response.

References:

• Fejzo, M. S., Trovik, J., Grooten, I. J., et al. (2019). Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nature Reviews Disease Primers, 5, 62. https://doi.org/10.1038/s41572-019-0110-3

• Gadsby, R., Ivanova, D., Trevelyan, E., Hutton, J. L. & Johnson, S. (2020). Nausea and vomiting in pregnancy is not just ‘morning sickness’: data from a prospective cohort study in the UK. British Journal of General Practice, 70(697), e534–e539. https://doi.org/10.3399/bjgp20X710885

• BBC News. (2020). Catherine, Duchess of Cambridge, speaks about her experience of hyperemesis gravidarum.BBC News. https://www.bbc.co.uk/news/uk-51511596

• Fejzo, M., Rocha, N., Cimino, I., et al. (2024). GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature, 625, 760–767. https://doi.org/10.1038/s41586-023-06921-9

• Breen, D. M., Kim, H., Bennett, D., et al. (2020). GDF-15 neutralization alleviates platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and nonhuman primates. Cell Metabolism, 32(6), 938–950.e6. https://doi.org/10.1016/j.cmet.2020.10.023

• Profet, M. (1992). Pregnancy sickness as adaptation: A deterrent to maternal ingestion of teratogens. In J. H. Barkow, L. Cosmides & J. Tooby (Eds.), The Adapted Mind: Evolutionary Psychology and the Generation of Culture (pp. 327–365). Oxford University Press. https://doi.org/10.1093/oso/9780195060232.003.0009

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