Extreme Morning Sickness Genes Identified

Morning sickness is not an uncommon condition associated with pregnancy for most women. However, in a small percentage of women (up to 2%), an extreme form of morning sickness called hyperemesis gravidarum (HG) can present as much more than temporary discomfort, putting both mother and fetus at grave risk. Now, a new study led by investigators at UCLA has identified two genes associated with HG, whose cause has not been determined in previous studies.

Findings from the new study – published in Nature Communications in an article entitled “Placenta and Appetite Genes GDF15 and IGFBP7 Are Associated with Hyperemesis Gravidarum” – identified the genes known as GDF15 and IGFBP7, which are both involved in the development of the placenta and play important roles in early pregnancy and appetite regulation.

“It has long been assumed that the pregnancy hormones, human chorionic gonadotropin or estrogen, were the likely culprits of extreme nausea and vomiting, but our study found no evidence to support this,” explained lead study author Marlena Fejzo, Ph.D., an associate researcher at the David Geffen School of Medicine at UCLA. The two genes identified, she added, coincidentally are linked to cachexia, a weight loss and muscle-wasting condition that leads to death in about 20% of cancer patients and has similar symptoms to HG.

Dr. Fejzo has a personal connection to the study of this condition, as she experienced HG and sadly lost a pregnancy to the condition in 1999. The debilitating symptoms can include rapid weight loss, malnutrition, and dehydration due to persistent nausea and/or vomiting.

Current medications to treat the condition are largely ineffective and can lead to serious health consequences for both mother and baby. The condition is the second leading cause of hospitalization during pregnancy. Women often require intravenous fluids and, in the most severe cases, feeding tubes.

Previous research has shown that severe nausea and vomiting during pregnancy often runs in families, suggesting that genetics plays a role. For this study, the team compared the variation in DNA from pregnant women with no nausea and vomiting to those with HG to see what the differences were between the two groups. DNA variation around the genes GDF15 and IGFBP7 was associated with HG. The findings were then confirmed in an independent study of women with HG.

We conducted “a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications,” the authors wrote. “Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10⁻⁸) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia.”

Interestingly, in a separate follow-up study, researchers then proved the proteins GDF15 and IGFBP7 are abnormally high in women with HG. They presented these findings at the International Colloquium on Hyperemesis Gravidarum in 2017.

“While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease,” the authors remarked.

The next step is to determine whether GDF15 and IGFBP7 protein levels can be altered safely in pregnancy to minimize nausea and vomiting. These findings suggest a new avenue of research into a condition for which treatments have progressed little in the past.

“It is my hope that one day a medication that affects this pathway will be used to successfully treat and possibly cure HG,” Dr. Fejzo concluded.