Scientists identify main cause of extreme nausea and vomiting during pregnancy

Extreme nausea and vomiting during pregnancy is linked to 10 genes, one of which is likely the main cause of the condition, the largest genetic study of its kind to date has found.

Most people experience some degree of nausea and vomiting during early pregnancy, but up to 10.8% have symptoms so severe that they are unable to eat or drink and may require hospitalization. This condition, called hyperemesis gravidarum (HG), can last throughout pregnancy, but there is currently no Food and Drug Administration-approved treatment.

Now, a new study published Tuesday (April 14) in the journal Nature Genetics provides evidence that the gene for hormone growth differentiation factor 15 (GDF15) is the main cause of HG, which has been suggested by other studies.

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The study also identified six additional genes associated with the condition, including a gene that may control the production of glucagon-like peptide-1 (GPL-1), a hormone involved in regulating insulin and appetite. This gene is also the largest known genetic risk factor for type 2 diabetes.

These findings may spur the development of new treatment options and targets for HG.

“This will help us explore new treatments and find ways to better predict, diagnose, treat, and prevent HG in the future,” lead study author Marlena Fezzo, an HG expert at the Keck School of Medicine at the University of Southern California, told Live Science. Fejzo consults with pharmaceutical companies conducting clinical trials of GDF15 drugs.

Find the cause of HG

The pregnancy hormone human chorionic gonadotropin (hCG) has long been thought to support HG because it is the first hormone produced by the placenta after conception and its levels spike during early pregnancy. Estrogen has also been suggested as a possible cause, as its levels rise dramatically.

However, a recent study by Fejzo and colleagues has focused on GDF15 as a likely cause of HG. They identified specific mutations in the GDF15 gene that significantly increased the risk of the condition, and found that one rare mutation increased the risk tenfold.

But because the researchers used data primarily from people of European descent to identify this genetic risk factor, Fezo said they wanted to see if their findings generalized to a more diverse population.

So, in the new study, the research team combined data from nine independent studies of HG in the United States and Europe. They compared the whole genomes and autosomes (chromosomes excluding the X and Y sex chromosomes) of approximately 11,000 people diagnosed with HG and more than 420,000 people who had been pregnant but did not have HG. Although most of the data still came from individuals of European descent, the dataset also included approximately 13,000 people of Asian descent, more than 1,200 people of African descent, and 75 people of Latinx descent.

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The research team found 10 genes associated with increased risk of HG, with the GDF15 gene being the top signal across all populations, Fejzo said.

“They’re related, so we can’t necessarily say they’re the cause,” she says. However, given the strength of the signal and generalizability, Fejzo said this study provides indirect evidence of a causal relationship between HG and GDF15.

Ultimately, the results of this large study, combined with previous work by Fejzo’s team and other groups, establish a causal link between GDF15 and this condition, she said.

For the first time, researchers also identified an association with TCF7L2, a major genetic risk factor for type 2 diabetes and new-onset hyperglycemia during pregnancy. Previous research has found that this gene may control GPL-1, the same hormone mimicked by drugs such as Ozempic and Wegovy.

Fejzo said the discovery “appears to be an attractive new target to explore” for the development of new drugs for HG.

Other genes identified in the study are associated with learning and memory, and others are associated with wasting syndrome and appetite. The study found no genetic association with hCG or estrogen, the authors wrote in their paper.

This “incredibly well-conducted” study “confirmed” that the GDF15 pathway is a major cause of HG in a wide and diverse population, said Dr. Andrew Householder, an emergency physician specializing in HG and a consultant to a pharmaceutical company conducting trials of GDF15 drugs.

“This should finally put an end to the debate of HG as a sensitivity to hCG and estrogen,” Householder, who was not involved in the study, told Live Science via email.

Each of the 10 genes identified “deserves detailed study,” he added. The fact that they span many major biological pathways, touching on everything from insulin signaling to learning, “really shows how complex the HG disease process is.”

It’s unclear exactly why learning and memory genes are linked, but one theory is that these genes may be involved in wiring the extreme food aversion responses seen in HG patients, Fezizo said.

Fezo and her team aim to begin clinical trials this summer. This includes administering metformin, a diabetes drug that increases GDF15, to patients with a history of HG. Because enrolled patients plan to have more children in the near future, the trial will test whether metformin causes desensitization of patients to GDF15 before pregnancy. Once pregnant, it is expected to reduce nausea and vomiting.

While treatments are being sought, Fezzo said people can find guidance and support on the website of the Hyperemesis Education and Research (HER) Foundation, which supports research, advocacy and education about HG. Fejzo is a volunteer board member and research director for the HER Foundation.