New Genotype Linked to Nausea and Vomiting during Pregnancy

New Genotype Linked to Nausea and Vomiting during Pregnancy
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A new genotype has been found that increases the recurrence of extreme nausea and vomiting during pregnancy, a condition called hyperemesis gravidarum (HG). HG can cause serious illness, including starvation, which affects both the mother and fetus. Some mothers with this condition even terminate wanted pregnancies and many decide not to have any more children. Current antiemetic treatments are not always effective, so novel approaches are needed.

One of the most common questions HG patients ask is “what are the chances I will have this again in my next pregnancy?” says Kimber MacGibbon, RN, Executive Director of the Hyperemesis Education and Research (HER) Foundation. “We now have information to help us answer that question.”

The research team included members from HER and the University of Southern California. They presented this work at the American College of Obstetrics and Gynecology (ACOG) in San Diego last week.

Most pregnancies are affected by nausea and vomiting, but some people develop very severe symptoms and are diagnosed with HG. These patients may have increased risk of suicidal ideation, PTSD, electrolyte disturbances, and nutritional deficiencies that can lead to cardiac arrest and maternal brain damage. Babies have increased risk of preterm birth and abnormal brain development resulting in an increased risk of neurodevelopmental delay and autism spectrum disorder.

In February, this team published a study in the British Journal of Obstetrics and Gynaecology (BJOG) confirming the placenta and appetite hormone gene GDF15 is the greatest genetic risk factor for HG. In that GWAS study, A common coding variant in GDF15 was the only exome-wide significant association, and a rare coding variant in GDF15 was the only predicted disease-causing variant occurring in 10 or more cases.

At the recent ACOG meeting, the team shared new findings that not only GDF15, but its co-receptor RET, may also play a role in causing the disease.

In one study, the researchers compared genotypes at the genetic risk locus PGR-TRPC6 in 125 patients who had HG in both their first and second pregnancy to 26 patients who only had HG in their first pregnancy, but not their second.

This study identified a genotype that was nine times more common in patients that did not have a recurrence. In the future, doctors may be able to test for this genotype and if patients have it, know that they are less likely to have HG again in their next pregnancy. “This may help patients with their family planning, which is of critical importance to people with HG,” says Marlena Fejzo, PhD, geneticist and coauthor of the study.

In a second study, also presented at ACOG, the researchers identified mutations in families affected by HG. In this study, using whole-exome sequencing, the researchers sequenced the DNA from 16 families with three or more members who had HG. Affected patients in two families had mutations within or near the RET gene.

“Some of the patients in the two families reported losing 30 pounds in their pregnancies due to severe nausea and vomiting,” said Fejzo, “and now we have identified a possible biological explanation for their extreme symptoms.

Medications to block the GDF15-GFRAL-RET pathway are currently in clinical trials to treat loss of appetite in cancer cachexia and may lead to novel treatments for HG. These studies also have implications for genetic testing and counseling of patients with HG.