Obstetrics researcher Marlena Fejzo knows a thing or two about nausea and vomiting in pregnancy.
As she endured sickening nausea in her second pregnancy, unable to keep any food down and feeling too weak to stand, doctors told Fejzo her illness was all in her head.
In a way, it was… just not how they so callously meant.
Fejzo leads a team of researchers that now, after decades of research, has singled out one hormone which acts on the brain to cause vomiting as the likely cause of morning sickness – and added a stack of new evidence to back up their claims.
Researchers have had their sights set on a particular hormone called GDF15 ever since it was first detected at high levels in the blood serum of pregnant women in 2000.
Since then, twin studies and genomic sequencing studies of people with severe nausea and vomiting in pregnancy have pointed to a genetic component of their illness involving two genes, including the one that encodes GDF15. The lines of evidence were aligning.
Nausea and vomiting are very common in the first trimester of pregnancy, but in around 2 percent of cases or 1 in 50 pregnancies, a most severe form develops known as hyperemesis gravidarum (HG).
Fejzo's own experience of hyperemesis lit a fire in her to keep searching for the underlying cause. In early 2022, she and her colleagues uncovered a few new rare and common genetic variants in the GDF15 gene which they linked to the risk of HG. But the interplay between these genetic quirks, and the GDF15 hormone remained unclear.
Now, Fejzo, from the University of Southern California Keck School of Medicine, and colleagues have shared their latest batch of evidence to support the idea that GDF15 triggers hyperemesis.
Like many other proteins, GDF15 levels surge during pregnancy, and it seems some women are more sensitive to the hormone than others.
"Our findings place GDF15 at the mechanistic heart of [nausea and vomiting in pregnancy] and HG and clearly point the way to strategies for its treatment and prevention," the researchers write in their preprint, which has not yet been peer-reviewed.
News that scientists might have landed on the cause of hyperemesis should bring some relief to those who are pregnant, even if no new treatments have been developed from the discovery just yet.
For starters, Fejzo and colleagues found that GDF15 levels were measurably higher in a group of about 60 women with hyperemesis than in another similarly sized group of unaffected pregnant women, adding strength to previous findings.
"We can now conclude with confidence that higher circulating levels of GDF15 in maternal blood are associated with an increased risk of HG," Fejzo and colleagues write.
Next, they compared pregnant women and unborn babies carrying different genetic variants for GDF15, and found that "the vast majority" of GDF15 in healthy pregnancies comes from the fetus and placenta. Though the researchers note that mothers might contribute more GDF15 to the mix when their pregnant bodies are under the severe stress of hyperemesis.
Returning to the previously identified genetic variants linked to HG, Fejzo and her team found women with these variants had markedly lower levels of the GDF15 hormone circulating in their blood when they weren't pregnant.
That somewhat surprising finding made a bit more sense when the researchers analyzed data from a separate study of over 18,000 Scottish women. It showed that women who had higher levels of GDF15 before pregnancy actually had a lower risk of developing hyperemesis.
Likewise, women with beta-thalassemia, a blood condition that happens to raise GDF15 levels outside of pregnancy, rarely experienced nausea and vomiting when pregnant, a small survey of 20 women found.
It's as if having higher levels of GDF15 before pregnancy offers some protection against hyperemesis, desensitizing women to the hormone so it has less of a vomit-inducing effect, Fejzo and colleagues suggest.
Altogether, they say the new evidence suggests that "the severity of nausea and vomiting of pregnancy is the result of the interaction of fetal-derived GDF15 and the mother's sensitivity to this peptide, which is substantially determined by her prior exposure to the hormone."
More research is needed to flesh out this hypothesis, but the hope is that boosting GDF15 levels before pregnancy could help prevent HG, whilst lowering them during pregnancy might ward off nausea.
However, researchers are especially cautious of the potential harms of candidate therapies given during pregnancy, so safety will be a top priority.
"Since the tragedy of thalidomide, concerns about safety have understandably been very prominent in discussions of novel treatments for HG," the team concludes.
The research has been posted to the preprint server bioRxiv, ahead of peer review.