What causes morning sickness?

“Hey y’all, just found out I’m five weeks pregnant. Definitely a welcome pregnancy, it’s my first, but I have emetophobia [fear of vomiting] and have had constant anxiety about the impending morning sickness literally since I saw that first positive test.” 

In response to this Reddit post from April 2023, a chorus of well wishers shared their experiences and compared their own symptoms to their mothers’ and sisters’. The range of responses attested to the unpredictability of “morning sickness”—the nausea, vomiting, and food aversion that define early pregnancy for many women but inexplicably leave others untouched. Here’s the frustrating reality: despite its high prevalence among expecting women, historically, no one has known what causes morning sickness. And because no one has known what causes it, treatments for morning sickness have been rather thin on the ground. 

But all that could be changing, thanks to a 2023 study by Cambridge University [1]. Researchers found that the hormone “growth differentiation factor 15” (GDF15) plays a major role in morning sickness. Even more helpful, researchers discovered that women can become immune to GDF15’s effects through exposure to the hormone before pregnancy. Major news outlets such as The New York Times celebrated the discovery as a helpful breakthrough for women everywhere, and expressed hope it could lead to the development of better morning sickness treatments.

Nausea and vomiting in pregnancy (NVP), aka morning sickness, vs. hyperemesis gravidarum

At least half of pregnant women experience symptoms of nausea and vomiting in pregnancy (NVP), known colloquially as “morning sickness.” As countless women can verify, “morning sickness” is a bit of a misnomer since the symptoms can occur at any time of day. In most cases, morning sickness symptoms disappear around the end of the first trimester. For between 0.3% and 18% of women, however, the symptoms are both severe and last throughout the entire pregnancy [2]. This condition is known as hyperemesis gravidarum (HG). Until very recently, the underlying causes of morning sickness and HG were considered a mystery by the medical community. 

The connection between GDF15, morning sickness, and hyperemesis gravidarum 

The major breakthrough from the 2023 Cambridge study involves a hormone called GDF15, and it’s normally present in low levels in men and non-pregnant women. On the average day, GDF15 helps the body adapt to cellular stress caused by low oxygen levels, cigarette smoking, endurance exercise and more [1][6]. Increased GDF15 levels actually lower inflammation. 

GDF15 is also well known as an important factor in appetite suppression and weight loss. Metformin, commonly prescribed to treat diabetes (as well as polycystic ovary syndrome), increases GDF15 levels [7]. Researchers first discovered GDF15 back in 2000 and observed that it was naturally high in pregnant women [3].

Later research found that women with hyperemesis gravidarum had much higher levels of GDF15 than women who didn’t experience HG, and other research determined that high levels of GDF15 come mostly from the baby (in its trophoblastic stage of development) rather than from the mother [4][5]. Prior to the 2023 Cambridge study though, research couldn’t definitively answer whether higher GDF15 levels lead to HG or are caused by it.  

Cambridge research: High GDF15 levels cause morning sickness and HG 

After studying over 18,000 participants, the 2023 Cambridge research team similarly found that GDF15 is higher in women who have nausea and vomiting of pregnancy or hyperemesis gravidarum, compared to pregnant women who have neither. They also confirmed that high GDF15 levels actually cause NVP and HG. 

Most surprisingly, the researchers found that higher levels of circulating GDF15 prior to pregnancy were associated with reduced risk of HG and morning sickness. This suggests that women can become desensitized to the effects of GDF15, and not suffer from morning sickness or HG, if they’ve had previous exposure before getting pregnant. This makes sense, since the surge of GDF15 happens in all pregnant women, but not all pregnant women experience morning sickness and very few, by the numbers, suffer hyperemesis gravidarum. 

The Cambridge researchers concluded that fetal-produced GDF15 only triggers a response in women who weren’t sufficiently desensitized to GDF15 ‘s effects before pregnancy. Since 75% of women who experience HG in one pregnancy will experience it in later pregnancies, it might mean that GDF15 desensitization is crucial before the first pregnancy a woman has. 

Mice research mimics the surge of GDF15 that happens during pregnancy

To mimic the natural elevation in GDF15 during pregnancy, the Cambridge study included a mice testing component to see whether previous GDF15 exposure could lead to less nausea and vomiting at higher doses. Researchers found that exposure to small amounts of GDF15 prevented symptoms of food aversion and weight loss due to vomiting when the mice were given a larger dose of the hormone. The smaller initial dose effectively made the rats immune to the effects of the larger dose later on.  

Women with GDF15 exposure before pregnancy are less likely to suffer morning sickness

The Cambridge study also studied whether non-pregnant women with abnormally high levels of GDF15 were protected from NVP and HG once they became pregnant. The researchers conducted a subanalysis on a group of women with β-thalassaemia, a rare blood disorder that causes higher-than-average amounts of GDF15 in the body [1]. When these women became pregnant, only about 5% experienced NVP. This is far less than the 60% of women in the control group (who didn’t have the blood disorder) who experienced morning sickness.

How does this new knowledge about the cause of morning sickness help us better treat it?

The Cambridge researchers opined, “The fact that high GDF15 levels in the non-pregnant state appear to protect against the development of NVP and HG suggests that strategies which safely increase circulating GDF15 levels before pregnancy may be useful in the prevention of these conditions.” And for those wondering about the safety of GDF15 as a possible treatment for morning sickness, the researchers had the following to say: “The safety of recombinant GDF15, at least in the short term and outside of pregnancy, has been demonstrated in Phase 1 clinical trials and this could be administered at low doses before pregnancy with the intention of inducing GDF15/GFRAL desensitization.” 

What about Metformin?

Remember how I mentioned diabetes and PCOS drug Metformin’s effect on GDF15 above? The researchers suggested, “Alternatively, metformin robustly increases GDF15 in humans and could be tested as a prophylactic agent for HG,” but acknowledged that Metformin given to women with gestational diabetes might slow down fetal growth. 

The bottom line on the cause of morning sickness

Now that we know what causes morning sickness, more research is needed to learn how we can safely prevent it. Given how much HG can impact both the mom and the preborn baby’s health, researchers should prioritize exploration of whether desensitization in between pregnancies (whether with Metformin or GDF15 or something else) could prevent repeat HG. Researchers also need to determine what medications can safely be given to non-pregnant women to desensitize them before conceiving, as well as whether anything can safely be given during pregnancy to treat HG. 

References:

[1] Fejzo, M., Rocha, N. et al. “GDF15 linked to maternal risk of nausea and vomiting during pregnancy.” Nature (2023). https://doi.org/10.1038/s41586-023-06921-9.

[2] Fejzo, M., Trovik, J., et al. “Nausea and vomiting of pregnancy and hyperemesis gravidarum.” Nat Rev Dis Primers. 2019 Sep 12;5(1):62. doi: 10.1038/s41572-019-0110-3. PMID: 31515515. 

[3] A. G. Moore, D. A. Brown, W. D. Fairlie, A. R. Bauskin, P. K. Brown, M. L. C. Munier, P. K. Russell, L. A. Salamonsen, E. M. Wallace, S. N. Breit, The Transforming Growth Factor-β Superfamily Cytokine Macrophage Inhibitory Cytokine-1 Is Present in High Concentrations in the Serum of Pregnant Women, The Journal of Clinical Endocrinology & Metabolism, Volume 85, Issue 12, 1 December 2000, Pages 4781–4788, https://doi.org/10.1210/jcem.85.12.7007

[4] Fejzo MS, Sazonova OV, Sathirapongsasuti JF, Hallgrímsdóttir IB, Vacic V, MacGibbon KW, Schoenberg FP, Mancuso N, Slamon DJ, Mullin PM; 23andMe Research Team. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat Commun. 2018 Mar 21;9(1):1178. doi: 10.1038/s41467-018-03258-0. PMID: 29563502; PMCID: PMC5862842.

[5] Turco, M. Y. et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564, 263–267 (2018).

[6] Wang, D., Day, E.A., Townsend, L.K. et al. “GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease.” Nat Rev Endocrinol 17, 592–607 (2021). https://doi.org/10.1038/s41574-021-00529-7.[7] Gerstein, Hertzel C et al. “Growth Differentiation Factor 15 as a Novel Biomarker for Metformin.” Diabetes care vol. 40,2 (2017): 280-283. doi:10.2337/dc16-1682.

Additional Reading:

Is your pregnancy diet up to date with science?

Caffeine, alcohol, and tobacco products during pregnancy: What we know (and what we don’t)