Scientists Identify Cause of Morning Sickness, Potentially Ending Misery for Many

Some 70% of pregnant women experience morning sickness and up to 3% of pregnant women in the U.S. suffer from hyperemesis gravidarum, a severe and persistent form of nausea and vomiting that in extreme cases can cause maternal and fetal death. It is the leading cause in the U.S. of hospitalizations during the first half of pregnancy. Catherine, Princess of Wales, comedian Amy Schumer and singer Kelly Clarkson have spoken of their struggles with the condition.

For the Nature study, researchers built on work exploring a link between a hormone called GDF15 and hyperemesis gravidarum. Most of us, pregnant or not, have GDF15, which is produced by cells and at high levels can cause nausea, vomiting and reduced appetite. Cells produce a lot of it when they undergo stress.

“It’s a signal that tells our brain that bad stuff is happening in the body,” said Dr. Stephen O’Rahilly, an endocrinologist at the University of Cambridge and an author of the study.

GDF15 levels surge in the first trimester of pregnancy, but researchers didn’t know whether the primary source was the mother or the fetus. O’Rahilly and his colleagues analyzed the blood of pregnant women who produced a variant of GDF15 different from the variant produced by their fetus. The variants allowed them to pinpoint the source of the GDF15 increase. They discovered it was overwhelmingly coming from the fetal part of the placenta.

“It’s the baby who is making you sick,” O’Rahilly said.

He and his colleagues think humans might have evolved this mechanism to protect a developing fetus from potential toxins in food. “The placenta is sending a message to mom: Be careful of what you eat,” he said.

The researchers uncovered genetic factors that could explain why some pregnant women develop severe nausea and vomiting, while others don’t. Genetic variants associated with lower pre-pregnancy levels of GDF15 significantly increased the risk of hyperemesis gravidarum, the study found, suggesting that people who weren’t used to high levels of the hormone were more sensitive to sudden increases during pregnancy.

The reverse was also true: People with the inherited blood disorder beta thalassemia, which caused higher-than-normal levels of GDF15 before pregnancy, experienced little or no nausea and vomiting during pregnancy.

The findings suggest that women at higher risk of severe nausea and vomiting during pregnancy could be desensitized to the hormone’s surges with pre-emptive treatments of GDF15, said Marlena Fejzo, a co-author and a geneticist at the University of Southern California.

Researchers tested the desensitization idea by treating mice with a small, long-acting dose of the hormone before walloping them with a fast-acting dose. The rodents didn’t lose as much appetite or weight as mice given just a large dose.

The results brought Fejzo to tears.

“To get to this place where we might be able to prevent and treat this condition, it’s huge,” she said.

Fejzo suffered from hyperemesis gravidarum during both her pregnancies. It was so severe during her second pregnancy in 1999 that she couldn’t move, eat or drink without violently vomiting. Her doctors prescribed seven medications including anti-nausea drugs and antihistamines and put her on a feeding tube. Nothing helped. She lost her baby at 15 weeks.

“I was starving. I couldn’t even stand,” she said.

Fejzo turned her professional attention to hyperemesis gravidarum. Today, she is the chief scientific officer at Materna Biosciences, which is exploring treatments including some to block GDF15 or its receptors in the brain.

Dr. Samuel Breit, an immunologist who identified GDF15 in 1997, said blocking GDF15’s receptors instead of the hormone itself could be a safer way to treat pregnancy-related nausea and vomiting.

“It’s doing something and it’s probably important but we don’t know what that is,” said Breit, director of immunopathology at St. Vincent’s Hospital in Sydney.

Drastically reducing its levels could damage the pregnancy, he said. But using drugs that target GDF15 receptors in the mother’s brain could block the hormone’s effects without hurting the fetus.

Companies including  Pfizer are testing whether GDF15-targeting drugs could treat cachexia, a wasting syndrome characterized by major weight and muscle loss. Advanced cancer patients and people with serious chronic diseases can develop cachexia. Researchers are also exploring whether GDF15-targeting drugs could alleviate nausea in people undergoing chemotherapy.

About half of pregnant women who seek medical help for nausea and vomiting get significant relief from existing treatments, said Dr. Hyagriv Simhan, professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, who wasn’t involved in the new study.

Simhan said the research suggests opportunities to test for GDF15 and to treat nausea and vomiting in pregnancy more effectively. He said there are other potential causes of morning sickness, including the hormone progesterone, but targeting them could be more challenging and harmful to pregnancy.