A new study points to a cause and a potential treatment for severe nausea and vomiting during pregnancy, with findings in both lab animals and in humans.
In a research article published Dec. 13 in Nature, scientists from the University of Southern California Keck School of Medicine and the University of Cambridge described how they verified their previous hypothesis that a hormone is the culprit behind hyperemesis gravidarum, or HG, a severe condition characterized by uncontrollable vomiting in pregnancy that can lead to weight loss, dehydration and hospitalization. Results from mouse studies and genetic research in humans suggest that it may be possible to lower levels of the hormone in those at risk of HG, illuminating a potential therapeutic path.
“What makes the study a major advance is that it goes beyond establishing a correlation between GDF15 and nausea and vomiting in pregnancy, and provides genetic evidence for a potential causal mechanism,” University of Exeter researchers Alice Hughes, Ph.D. and Rachel Freathy, Ph.D., who were not affiliated with the new research, wrote in a perspective article for Nature.
Nausea and vomiting accompany pregnancy in about 70 to 80% of cases, mainly during the first trimester in the form of “morning sickness,” research shows. Another 2% experience HG, which can be potentially dangerous for both the pregnant parent and the fetus. Expecting mothers with HG are at higher risk of fetal loss than those without the condition, with rates as high as 37% by some estimates. Despite this, the HG is currently only treated by supportive care.
Lead researcher and Fiercest Women in Life Sciences 2023 awardee Marlena Fejzo, Ph.D., is all too familiar with HG herself. As she told Fierce in Nov. 2023, her own hospitalization and subsequent pregnancy loss from the condition drove her to study it. “I knew that it was something biological,” Fejzo recalled in her earlier interview. “I could feel like I was being poisoned.”
Research published in Feb. 2022 by Fejzo and colleagues found a link between HG and a mutation in the gene that encodes GDF15, a hormone that helps regulate appetite (and has caught the attention of pharmaceutical companies in the business of weight loss drugs). GDF15 is known to induce vomiting by acting on the brainstem and has been implicated in anorexia in cancer patients who undergo chemotherapy.
In the new study, the researchers used mass spectrometry and genotyping to show that women with the mutation in the gene for GDF15 have unusually low levels of the hormone prior to pregnancy, but higher levels of it when they become pregnant compared to women without the mutation. Most of the GDF15 that was found in the blood of the pregnant women with the low-GDF15 gene variant came from the fetus, the researchers’ analysis showed. These women were also more likely to develop HG.
“The finding that a high risk of HG is related to genetic variants that are associated with low levels of GDF15 in the non-pregnant state is consistent with a causal relationship because genotypes cannot be changed by lifestyle factors that might not normally confound a correlation between exposure to something in the environment and a disease,” Hughes and Freathy wrote in their Nature article. That link was further validated by the intriguing finding that women with the blood condition beta-thalassemia, who are known to have high levels of GDF15, “rarely report nausea and vomiting in pregnancy,” they added.
Fejzo and her team hypothesized that women with the low-GDF15 variant were more likely to develop HG because they were more sensitive to it. They tested out this idea in mice: One group was given a long-acting form of GDF15 and another was left untreated. When both groups were given a single, acute dose of GDF15, the mice that had been pre-treated with the hormone were less likely to experience appetite suppression than the ones that had not been exposed. (Appetite suppression was used as a proxy for nausea in this case, as mice can’t vomit.)
Additionally, the researchers found that interactions between the fetus and the mother also impact the risk of HG in women with naturally low levels of GDF15. A genetic analysis on 17 pregnancies showed that HG was less frequent among mothers and babies that both carried the same gene variant that causes low GDF15.
“Because the risk of HG might be moderated by the genetics of the fetus, future studies that account for maternal, fetal and paternal hapylotypes would be a valuable addition to this work,” Hughes and Freathy wrote.
Fejzo’s team will next look for interventions for HG, starting by seeing if exposure to GDF15 prior to pregnancy can reduce nausea, vomiting and even the risk of HG altogether. They are in the process of obtaining funding for a study that will assess whether the drug metformin, which increases GDF15 levels, is safe to use in patients who have had HG in the past, according to a press release from USC.
They’ll also look to anti-GDF15 drugs that are in clinical trials for cancer-related cachexia. Aveo Pharmaceuticals and Pfizer both have such drugs in phase 1.