They told her that the vomiting that ended her pregnancy was fake. More than 20 years later, this geneticist has discovered what caused it

Vomiting is normal. Until it isn’t. About 80% of pregnant women suffer from nausea during the first few months of pregnancy. But between 1% and 2% of them vomit up to 50 times a day, lose weight, become dehydrated and in the most serious cases, end up hospitalized. It is a debilitating disease called hyperemesis gravidarum (HG). Until a few months ago, the mechanism that caused women to vomit during pregnancy was unknown. And this gap in medical knowledge was filled with prejudices. When expectant mothers vomited little, it was not given importance. When they vomited too much, it was said that they wanted to have an abortion, they were hysterical, or they did it to get attention. That was what they told Marlena Fejzo. When the American geneticist became pregnant with her first child in 1996, she did not pay the vomiting much mind, although it was so persistent and violent that it kept her bedridden for weeks. “It’s normal,” they told her. “Aren’t you exaggerating?” they asked her. So she continued vomiting in silence.

When the situation worsened with her second pregnancy in 1999, she began to worry. “I couldn’t move without vomiting. I couldn’t eat or drink anything,” she explains in a video call. “They gave me seven different medications at once. But towards the end nothing worked anymore.” The doctor told her that it was a ploy to get the attention of her husband and parents. She barely had the strength to refute anything. Most women gain about 11 pounds in the first 15 weeks of pregnancy. She lost 15, and her weight dropped to 90 pounds. Maybe it was less, she admits, but there came a point where she was too weak to stand on a scale. “It was torture,” she remembers now. By the third month she ended up in a wheelchair and they finally started feeding her through an intravenous tube. “But it was too late, my baby died.”

The emotional and physical recovery took time, but when Fejzo returned to work, she decided to focus her career on discovering the true cause of her illness. This Wednesday, December 13, the latest study in which she participated was published in the journal Nature. It is a study that brings her a little closer to understanding what happened to her more than 20 years ago and continues to happen to thousands of women.

The cause has three letters and two digits. GDF15 is a hormone that acts on the brain stem. It is secreted by the embryo in its first stages of growth, and it is responsible for the nausea and vomiting that is typical of pregnancy, including HG, its most serious form. The study, in which experts from the University of Cambridge also participated, summarizes, “Our findings support a putative causal role for fetally-derived GDF15 in the nausea and vomiting of human pregnancy.” Initially, it was thought that women who had high levels of this hormone before pregnancy could not manage the increase that it entailed, and that is why they developed excessive vomiting. But this recent analysis suggests just the opposite.

“It was very surprising,” admits Dr. Fejzo. “What we discovered is that there are women who generate very little of the hormone or less than normal. And during pregnancy, this increases a lot. Not being used to it, these women are hypersensitive to the increase.” This idea opens the door to creating a medicine to prevent nausea, in both its most harmless and most aggressive versions. “We tested our theory on mice,” says the doctor. “We gave them the hormone at a low dose before exposing them to a higher, pregnancy-like dose.” It turned out that prior exposure makes them more tolerant. Not only can this help solve the problem, but also raise awareness of its existence. “I have been fighting hard to achieve this for two decades,” says Fejzo.

Isolation to avoid oral abortion

In Spain, HG has historically been combated with rehydration treatment and anti-vomiting medication (antiemetics) and isolating the patient, who could not have contact with family and friends. “The practice of confinement, instituted more or less around 1914, is in line with the belief that these women were malingerers who hoped for the right to an abortion thanks to this symptom,” explains a study carried out by experts from the Hospital 12 de Octubre, the Hospital Universitario de Salamanca, and the Hospital General Yagüe in Burgos (Spain). “By isolating them from their marital and family environment, the medical teams investigated whether the women revealed their desire for an abortion,” he adds. The idea of isolating the patient to analyze her psychologically may seem extreme, but it is not unique, neither to Spain nor to the early 20th century. In the 1930s, pregnant women with “pernicious vomiting” were denied access to a toilet bowl or basin and were forced to lie in their vomit.

Since there was no medical cause, the medical establishment sought a psychological one. For the last century, doctors have claimed that hyperemesis is a subconscious attempt at “oral abortion,” a rejection of femininity, a product of sexual frigidity, a strategy to “take a break,” or a way to get attention, as they told Dr. Fejzo.

Even today there is an increasingly minority debate around the psychosomatic origins of excessive vomiting. The study by the Hospital 12 de Octubre was carried out in 2005. It aimed to investigate whether the historical thesis that women were simulating illness made sense in a time when abortion is freely available. And it concluded that these women were probably not malingerers and isolating them was somewhat archaic. “But we find women facing a true ambivalence regarding their pregnancy,” the study noted, before advising that these women begin psychotherapy treatment, since “uncontrollable vomiting during pregnancy is a symptom fueled by a persistent somatic conflict.”

“It is true that a few years ago medicine did not pay attention to women,” gynecologist Sara López concedes, “but I have not experienced all these theories of rejecting pregnancy. I have not heard them.” López recalls that the disease has a very low prevalence, but it is serious. “I remember a patient, and I’m talking about assisted reproduction, who was very difficult for us to get pregnant, and who had to abort due to hyperemesis gravidarum because she couldn’t go on. She just couldn’t. And that had an impact on me.” Not all cases reach this extreme. Currently, when a woman presents symptoms of hyperemesis, she is usually admitted to hospital, where she is given antiemetics and medical staff make sure she is hydrated and cared for, López explains. It is not a treatment as such. Therefore, the advances made by Dr. Fejzo’s team are a hope. “Anything that is research and seeks to find the reason is something positive,” says the gynecologist, “but of course, there is a step from here to it finally reaching clinical practice. And giving it also depends on interest.”

Fejzo is aware that this interest is limited. She regrets that that is the way it has always been. When she started researching the topic, she found it difficult to find funding. In 2005, she saw that women who suffered from HG often had mothers or sisters with the same condition, and she began to suspect there might be a genetic component. She partnered with the Hyperemesis Education and Research (HER) Foundation and with obstetricians and gynecologists at the University of Southern California. Together, they conducted an online survey with patients who had suffered from HG. In 2011, they published the results: women who had sisters with hyperemesis had a risk of developing the disease 17 times higher than those who did not have it. It was one of the first clear pieces of evidence that the disease had a hereditary component.

The doctor also requested biological samples from patients so she could analyze them and see what they had in common. She was looking for a genetic mutation that would explain the origin of the disease. She had the samples, but not the money to analyze them. But an unusual birthday gift gave her the solution. It was a kit from 23andMe, the company that makes genetic profiles for individuals by analyzing 600,000 regions of the genome to tell the customer how much of a Viking they are, whether they have distant cousins in Australia, or what diseases they could develop. This company has a bank of more than 12 million genetic profiles. “I thought it was awesome,” says the doctor. “So I decided to write them.”

Fejzo partnered with the company, which began including questions about nausea and vomiting during pregnancy in its tests. A few years later, the genetic data of tens of thousands of clients (who had previously given their consent) were scanned for genetic variations in those who suffered from nausea during pregnancy. The results were published in Nature in 2018. The cause finally had a name, and it had three letters and two digits: GDF15.

It was then that the psychosomatic theory began to lose strength compared to the genetic approach. Subsequent studies, culminating in this week’s study, corroborated and expanded this idea. People with a mutation in the GDF15 gene produced less of the homonymous protein. This could explain their low tolerance to it during pregnancy. “The gene is like the recipe,” explains the expert, “and the hormone is the final dish. So, let’s say that if you have the recipe written wrong, the dish is not going to turn out right.

The next step may be to modify the recipe with gene editing. Or add an extra ingredient to the final result to avoid vomiting during pregnancy. The options are many, and so are the doubts. “There are always more questions to ask in science,” Fejzo says in summary. “But I would say this is a very exciting time. It’s been a long road to get here, but I think we now have a great understanding of the main mechanism.” The next phase is to find a way to treat and prevent this disease. But for now, Fejzo is satisfied with having proven that it is real.

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