Sometime in the first weeks of a pregnancy, a small cluster of cells embedded in the uterine wall begins producing a hormone called GDF15. The signal rises steeply through the first trimester, leveling off only as the placenta consolidates its role as the fetus’s life-support system. In most pregnancies, this hormonal tide causes nausea and passes. In roughly 2 percent, it tips into something far more serious: hyperemesis gravidarum, a condition so severe that eating becomes nearly impossible, and dehydration and malnutrition can threaten both mother and child.
Key Takeaways
- GDF15 triggers severe nausea in some pregnant women, causing hyperemesis gravidarum, which can threaten both mother and child.
- Recent research identifies ten genes linked to hyperemesis gravidarum, revealing a complex interplay of biological factors.
- The study suggests that matching treatments to genetic profiles may enhance effectiveness, as existing medications provide limited relief.
- TCF7L2, a gene associated with hyperemesis gravidarum, also influences GLP-1, potentially connecting weight-loss drugs to pregnancy sickness treatment.
- The evolving understanding of hyperemesis gravidarum shifts its perception from psychological to biological origins, highlighting the condition’s heritable aspect.
Why GDF15 triggers such catastrophic vomiting in some women and not others has been one of the more intriguing puzzles in reproductive medicine. The answer, it turns out, comes down to a kind of biological priming. Women who carry a variant that keeps their GDF15 levels unusually low before pregnancy are more sensitive to the hormone’s sudden surge when pregnancy begins. Their bodies, in a sense, haven’t been calibrated for what’s coming. Earlier work by Marlena Fejzo at the Keck School of Medicine of USC established this link. What her latest research reveals, published this week in Nature Genetics, is that GDF15 is only part of a considerably larger picture.
The new study analyzed genetic data from nearly 11,000 women with hyperemesis gravidarum and more than 460,000 controls drawn from nine international biobanks, covering European, Asian, African and Latino ancestries. Ten genes now have robust statistical links to the condition. Four were already known. Six are newly identified. “Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” Fejzo said. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”
The new genes do not cluster neatly around a single biological pathway. They implicate appetite regulation, brain plasticity, hormone signaling, and insulin metabolism, suggesting that hyperemesis gravidarum is not a disease with one mechanism but something more like a convergence zone, where multiple physiological systems all arrive at the same miserable outcome through different routes.
One of the new finds is likely to attract attention beyond reproductive medicine. TCF7L2 is best known as one of the strongest genetic risk factors for type 2 diabetes. It may also influence GLP-1, a gut hormone that controls blood sugar and suppresses appetite and nausea. This is the same hormonal family targeted by semaglutide and the broader class of weight-loss drugs currently reshaping treatment for diabetes and obesity. In the brain’s area postrema, a region involved in detecting circulating signals and triggering vomiting, the GLP-1 receptor sits in the same cluster of neurons as GFRAL, the receptor for GDF15 itself. That two of the strongest HG genes now have receptors sharing the same brainstem neighborhood is, at minimum, worth investigating further. “This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said of TCF7L2.
Three of the newly identified genes are enriched in the brain rather than the placenta. SLITRK1, SYN3 and IGSF11 all play roles in how synapses form and how the brain learns. Specifically, SYN3 regulates dopamine release, while SLITRK1 knockout mice show disruptions in serotonin signaling. Both dopamine and serotonin are the targets of common antiemetic drugs used to treat hyperemesis, which may explain why these medications vary widely in effectiveness from one patient to another. The researchers suggest these neuronal genes could underlie something called conditioned taste aversion, a well-documented mechanism by which the brain, once it associates a particular stimulus with nausea, builds a lasting and sometimes extreme aversion to it. If your brain is wired to form those connections more readily, pregnancy sickness could spiral into something self-reinforcing and very hard to treat.
There is also a parallel with cancer medicine that the researchers flag, though carefully. Six of the ten HG genes are also associated with cachexia, the wasting syndrome in which cancer patients lose weight, appetite and muscle mass. The overlap in underlying biology raises the possibility that insights from HG research might travel in both directions. Animal studies have already shown that manipulating GDF15, GFRAL and TCF7L2 can reduce cachexia symptoms in mice.
“Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said. The study’s statistical architecture also allowed the researchers to disentangle maternal from fetal genetic contributions, which is not straightforward. For GDF15, the maternal and fetal genomes push in opposite directions: the mother’s low-exposure variant increases her sensitivity to the hormone, while the fetal variant influences how much GDF15 the placenta actually produces. Both can contribute to the same severe outcome through different mechanisms. For other loci, including genes involved in placental development, the effects appear to be carried almost entirely by the maternal genome.
The practical upshot of all this genomic mapping is beginning to take shape. Existing treatments remain inadequate: Zofran, currently the most effective drug available, provides only partial relief for around half of patients. But the genetic findings suggest that matching patients to treatments based on their genetic profiles might improve those odds, since the serotonin and dopamine pathways show clear patient-to-patient variation. More immediately, Fejzo’s team has received approval to launch a clinical trial of metformin, a diabetes drug that raises GDF15 levels. The hypothesis is that priming women with slightly higher GDF15 before pregnancy could reduce the sensitivity that makes the hormone’s early-pregnancy surge so destabilizing. Whether it works is still an open question, but it is the kind of mechanistically grounded question the condition has long lacked.
For most of its history, hyperemesis gravidarum was treated as a psychological problem, a byproduct of anxiety or ambivalence about pregnancy. Women were sent home or dismissed as exaggerating. The fact that the condition has a heritability of roughly 12 percent, that its risk loci show signs of evolutionary constraint, and that it is now mapped to ten discrete genomic regions makes that history increasingly difficult to sustain. The genes do not care what doctors once believed. They point, in several different directions at once, toward biology.
Source: https://www.nature.com/articles/s41588-026-02564-4
Hyperemesis gravidarum is a severe form of pregnancy sickness affecting approximately 2 percent of pregnant women. Unlike ordinary morning sickness, it causes nausea and vomiting so persistent and intense that eating becomes extremely difficult, often requiring hospitalization and sometimes leading to serious malnutrition in both mother and baby.
The strongest known cause is sensitivity to GDF15, a hormone produced by the fetal placenta during early pregnancy. Women whose bodies have been exposed to lower levels of GDF15 before pregnancy are more sensitive to its sudden rise and more likely to develop severe symptoms. A new study published in Nature Genetics has now identified nine additional genes linked to the condition, pointing to roles for brain plasticity, appetite signaling and insulin metabolism alongside the hormonal mechanism.
Several medications are available, including vitamin B6, antihistamines, and ondansetron (Zofran). Even the most effective current drugs provide only partial relief in about half of patients. Researchers are now testing metformin, a diabetes drug that raises GDF15 levels, as a potential preventive treatment for women who have had hyperemesis in previous pregnancies.
Partly, yes. The condition has an estimated heritability of around 12 percent, meaning genetic factors account for a meaningful share of individual risk. Women who have had hyperemesis in one pregnancy are at elevated risk in subsequent pregnancies, and family history is a recognized risk factor. The new Nature Genetics study has now doubled the number of confirmed genetic associations, identifying ten genes linked to the condition across multiple ancestry groups.
It is too early to say. The new research found that TCF7L2, a newly identified HG risk gene, may influence GLP-1, the same gut hormone targeted by drugs like semaglutide (Ozempic). Additionally, the receptors for GDF15 and GLP-1 appear to share the same cluster of neurons in the brain’s area postrema. Whether drugs targeting this pathway might help with hyperemesis is not yet known, and pregnant women cannot safely take most GLP-1 receptor agonists in their current forms. The biological overlap is notable enough to warrant further investigation.
