Scientists identify main cause of extreme nausea and vomiting in pregnancy

An extreme form of nausea and vomiting during pregnancy is linked to 10 genes, one of which is likely the main culprit behind the condition, according to the largest genetic study of its kind to date.

Most people experience some degree of nausea and vomiting during early pregnancy, but up to 10.8% have symptoms so severe that they stop being able to eat and drink and may even require hospitalization. This condition, called hyperemesis gravidarum (HG), can last throughout a person's entire pregnancy, but it currently lacks any Food and Drug Administration-approved treatments.

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

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

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

"It's going to be helpful as far as exploring new avenues for therapies and exploring ways to better predict, diagnose, treat and potentially prevent HG in the future," study first author Marlena Fejzo, an expert in HG at the Keck School of Medicine of the University of Southern California, told Live Science. Fejzo consults for a pharmaceutical company trialing a GDF15 drug.

Finding the cause of HG

The pregnancy hormone human chorionic gonadotropin (hCG) — the first hormone made by the placenta after conception — was long thought to underpin HG because its levels surge in early pregnancy. Estrogen was also suggested as a possible cause, as its levels also rise dramatically.

But recent research by Fejzo and her colleagues has zeroed in on GDF15 as a likely cause of HG. They've pinpointed specific mutations in the GDF15 gene that significantly boost the risk of the condition, with one rare mutation increasing the risk tenfold.

But because the researchers identified this genetic risk factor primarily using data from people of European ancestry, Fejzo said she wanted to see if the finding generalized to more diverse populations.

So, in the new study, the team combined data from nine independent studies of HG from across the U.S. and Europe. They compared the whole genomes and autosomes — the chromosomes excluding the X and Y sex chromosomes — of nearly 11,000 people with diagnosed HG and over 420,000 people with a history of pregnancy but no HG. Most data still came from individuals of European descent, but the datasets also included roughly 13,000 people of Asian ancestry, over 1,200 people of African ancestry, and 75 people of Latino ancestry.

The team found 10 genes associated with a heightened risk of HG, with the gene for GDF15 as the top signal across all populations, Fejzo said.

"These are associations, so we can't necessarily say that they're causative," she said. However, this study provides indirect evidence for a causal link between HG and GDF15, given the strength and generalizability of the signal, Fejzo said.

Ultimately this large study's findings, combined with the previous work by Fejzo's team and other groups, establishes a causal link between GDF15 and the condition, she said.

In a first, the researchers also identified an association with TCF7L2, the leading genetic risk factor for type 2 and gestational diabetes, which is new-onset high blood sugar in pregnancy. Previous research found that this gene may regulate GPL-1, the same hormone mimicked by drugs like Ozempic and Wegovy.

Fejzo said this discovery "seems like a fascinating new target to explore" to develop new drugs for HG.

Other genes pinpointed in the study are linked to learning and memory, while others are tied to wasting syndrome and appetite. No genetic links to hCG or estrogen were identified in the work, the authors wrote in the paper.

This "incredibly well-done" research "cements" the GDF15 pathway as the primary driver of HG across a wide and diverse population, said Dr. Andrew Housholder, an emergency physician who specializes in HG and consults for a pharmaceutical company trialing a GDF15 drug.

"It should finally end the discussion of HG as a sensitivity to hCG and estrogen," Housholder, who was not involved in the research, told Live Science in an email.

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

The exact reason learning and memory genes are linked is unclear, but one theory suggests they may play a part in wiring the extreme food aversion responses seen in people with HG, Fejzo said.

Fejzo and her team aim to launch a clinical trial this summer. It will involve giving metformin, a diabetes medication that increases GDF15, to patients with a history of HG. The patients being enrolled are planning to have more children in the near future, so the trial will test whether metformin desensitizes them to GDF15 ahead of conception. The hope would be to reduce their nausea and vomiting once they are pregnant.

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