We finally know the cause of severe morning sickness. A remedy could be next.

During her first pregnancy, Marlena Fejzo experienced nausea and vomiting so severe it landed her in the emergency room twice before giving birth. But her second pregnancy “was so much worse. I didn’t even think it could be worse, but it was,” recalls Fejzo, who is now a women’s health researcher at the Keck School of Medicine of USC.

During the second pregnancy, Fejzo was given IV fluids, seven different medications, and placed on a feeding tube. Nothing worked. At points she was so weak that she couldn’t speak, was bedridden, and needed round-the-clock care. Fejzo’s doctor told her he thought she was just trying to get attention from her husband. At 15 weeks, she miscarried.

Fejzo suffered from hyperemesis gravidarum (HG), a condition experienced by around 2 percent of pregnant individuals and characterized by severe, persistent nausea and vomiting that can be life-threatening. Despite that, HG research is consistently underfunded and those experiencing it are often dismissed. Fejzo’s miscarriage was in 1999. Shortly after, she returned to her postdoctoral researcher position at UCLA motivated to learn everything she could about HG.

Last month, Fejzo and her colleagues published breakthrough work on how the hormone GDF15 impacts a mother’s risk of developing HG. The work could lead to several effective treatments whose availability, some researchers say, feels imminent. But lack of awareness and acknowledgment of the severity of HG could stand in the way.

Morning sickness is an unpleasant pregnancy experience, but when HG—a far more extreme condition—is lumped together with morning sickness, the women suffering from it feel gaslit, says Kimber Wakefield MacGibbon, one of the study authors and the co-founder and executive director of the Hyperemesis Education and Research (HER) Foundation. HG feels like food poisoning, but with a very important difference: vomiting does not lead to relief. “It’s a continuous feeling that something's in your stomach that shouldn't be there," says MacGibbon, a registered nurse who experienced HG in both of her pregnancies.

Dehydration and weight loss are common symptoms of HG, but the most severe cases can lead to miscarriage and conditions in the mother such as Wernicke’s encephalopathy, a neurological disorder caused by vitamin B₁(thiamine) deficiency that can be fatal. A number of studies have shown that babies born to mothers with HG are at increased risk for preterm birth, low birth weight, and neurodevelopmental disorders including speech and language delay.

“It really is a dangerous exposure in pregnancy, and it should be considered that,” says Fejzo. “Unfortunately, it just isn’t.”

First-line treatments for HG, including anti-vomiting and nausea medications, are not effective for many women, says physician Jone Trovik, a professor in the department of clinical science at the University of Bergen who was not involved in Fejzo and MacGibbon’s study. And, even if a patient is given intravenous fluids to help relieve dehydration and electrolyte depletion or—in the most dire circumstances—is hooked up to a feeding tube, they may still need to terminate their pregnancy to survive.

“As a doctor I feel very incompetent when I do not manage to help these women avoid termination in an otherwise wanted pregnancy,” says Trovik.

Despite its severity, HG is overlooked, even by the medical community. Obstetrics and gynecology physician and HER Foundation medical advisor Aimee Brecht-Doscher will never forget the American College of Obstetricians and Gynecologists annual meeting she attended alongside thousands of other physicians in 2017, where only two presentations were given about HG, one by Fejzo. And as Brecht-Doscher and a few other attendees sat discussing the neglected condition, a male physician joined the conversation and announced: ‘I know what causes hyperemesis: it's hysteria.’ “And if you believe that,” says Brecht-Doscher, “then you don't believe that you really need to do anything to treat people.”

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Brecht-Doscher, who also was not involved in Fejzo and MacGibbon’s study, suffered from HG in two pregnancies, one of which led to a miscarriage. “The knee jerk reaction as a physician—especially to women who don't respond to standard therapies—is to assume that there's a psychological component and that's why they're not responding,” she says. “And I had learned that bias myself as a physician prior to having hyperemesis.” Brecht-Doscher says that, once she got HG, “I realized there was really nothing I could do to make myself better.”

Building an HG community

Following her miscarriage, one of the first things Fejzo did was create an online survey to get a sense of HG’s prevalence and the variables that influenced it. She was shocked by how many responses she received, including one from MacGibbon, who Fejzo remembers writing, “after I’m done with this pregnancy, I’m going to make a website on hyperemesis because there’s nothing out there.”

What began as a website became the HER Foundation in 2002, a non-profit that collaborates with universities and research studies; offers support to families; and provides resources on HG to patients and providers—such as information on medications and management strategies. MacGibbon says she has spoken to around 10,000 families across the globe since she launched the foundation.

Fejzo’s survey was soon posted on the HER website and, with that data, she, MacGibbon, and colleagues showed that HG was likely heritable. Fejzo then applied for NIH funding to study which gene(s) may be responsible but was denied. In 2010, her brother gave her a 23andMe genetic testing kit as a birthday gift. In addition to providing genetic information, 23andMe customers have the option of filling out health surveys. Fejzo had an idea. “I contacted them and asked them if they could include questions about hyperemesis, which they did.”

In 2018, using genetic and health survey data from 23andMe participants, Fejzo, MacGibbon, and colleagues were the first to show a link between hyperemesis and a hormone called GDF15. GDF15 levels were already known to increase in the first two trimesters of pregnancy and to be a driver of cachexia, a wasting syndrome often seen in cancer patients.

Around the same time, studies showed that GDF15 binds to cells in the brain stem, a structure responsible for basic functions like breathing and consciousness as well as vomiting, which reinforced its likely role in HG. But Fejzo was still perplexed as to why some people have HG in one pregnancy and not another.

What causes HG?

In the recent study, Fejzo and colleagues discovered that the majority of the GDF15 hormone comes from the baby, not the mother, and the amount produced can change from one pregnancy to the next, depending on the genetics of the baby, which is why mothers don’t always experience HG with all pregnancies. In addition, a mother’s level of nausea and vomiting during pregnancy is determined by her sensitivity to GDF15.

The researchers found that women who produce below average amounts of GDF15 before becoming pregnant are at higher risk for developing HG because they are hypersensitive to the typical rise of the GDF15 protein in early pregnancy. By comparison, women who produce high levels of GDF15 before becoming pregnant report very little nausea or vomiting.

To test the hypothesis that sensitivity to GDF15 influences risk of HG, researchers exposed mice to either a small dose of GDF15 followed by a high dose of GDF15—comparable to levels in women with HG—or to only a single high dose of GDF15. Mice given only one high dose began eating less and lost weight; by contrast, the mice given a small dose of GDF15 first, and thereby desensitized, were not impacted when given the larger dose.

Promising drugs in the pipeline 

Brecht-Doscher believes these findings will soon lead to treatments. But, she says, there is still valid concern about giving drugs to pregnant women. “There's a lot of history there, with other medications that were used specifically for nausea and pregnancy that did cause harm.” One of those was thalidomide which, in the early 1960s, was found to cause severe limb deformities in the children of mothers who took it to relieve nausea during pregnancy.

But Fejzo and others are optimistic because drugs that appear promising are already being tested, albeit for other conditions. Fejzo is hoping to evaluate drugs that increase GDF15 levels prior to pregnancy, preventing HG, as well as drugs that decrease GDF15 during pregnancy, further staving off or mitigating symptoms.

Fejzo is currently applying for a grant to test the diabetes drug metformin, which increases levels of GDF15 in the blood and is already used to increase fertility in patients with polycystic ovary syndrome (PCOS) and in some cases of gestational diabetes. There are also GDF15 blocking drugs in clinical trials for cancer patients with cachexia. Fejzo hopes that, once those drugs are shown to be safe in those trials as well as in pregnant animal models, they can be tested in pregnant women as well. On January 9, San Francisco biotech company NGM Bio announced that they are talking with the FDA about beginning clinical trials in HG patients with their GDF15-blocking drug, NGM120. Fejzo will serve as an advisor to NGM Bio in the process.