Vomiting is normal. Until it isn't. 80% of pregnant women suffer from nausea during the first 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 disabling disease called hyperemesis gravidarum (HG). Until a few months ago, it was unknown what mechanism caused women to vomit during pregnancy. And this scientific gap was filled with prejudices. When they vomited little, it was not given importance. When they vomited too much, it was said that they wanted to have an abortion. That they were hysterical. That they did it to get attention. The latter was what they told Marlena Fejzo. When this American geneticist became pregnant with her first child in 1996, she did not give much importance to the vomiting, although it was so persistent and violent that it kept her bedridden for weeks. “It's normal,” she told him. “Aren't you exaggerating?” she asked. 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 mechanism to get the attention of her husband and her parents. She barely had the strength to refute anything. Most women gain about five kilos in the first 15 weeks of pregnancy. She lost seven weights, down to 41. Maybe she was less, she admits, but she reached 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.”
Recovering emotionally and physically took time, but when Fejzo returned to work, he decided to dedicate his career to discovering the true cause of his illness. This Wednesday, December 13 is published in the magazine Nature the last study in which you participated. A study that brings her a little closer to understanding what happened to her more than 20 years ago. What continues to happen to thousands of women.
The answer 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 typical of pregnancy, also in its most serious form, HG. “Our findings support a causal role of GDF15 of fetal origin in nausea and vomiting in human pregnancy,” summarizes the study, in which experts from the University of Cambridge also participated. Initially, it was thought that women who had high levels of this hormone before pregnancy could not handle the extra 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 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, both in its harmless version and in the most aggressive one. “We did the test with mice,” says the doctor. “We gave them this hormone at a low dose before exposing them to a higher, pregnancy-like dose.” It turned out that prior exposure makes them more tolerant. This can not only help solve the problem, but raise awareness of its existence. “I have been fighting hard to achieve this for two decades,” summarizes Fejzo.
Isolation to avoid oral abortion
In Spain, HG has historically been combated with rehydration treatment and anti-vomiting medication (antiemetics). And secluding the patient, she could not have contact with family and friends. “The practice of isolation, 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,” he explains. a study carried out by experts from the 12 de Octubre Hospital, the Universitario de Salamanca and the General Yagüe de Burgos. “By isolating them from their marital and family environment, the medical teams investigated the revelation of their abortion desire,” 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 first years of the 20th century. In the 1930s, pregnant women with “pernicious vomiting” They were denied access to a toilet or a basin and they were forced to lie down in their vomit.
Since there was no medical cause, a psychological one was sought. For the last century, doctors have claimed that hyperemesis is a subconscious attempt to “oral abortion”a rejection of femininity, a product of sexual frigiditya strategy for “to take a brake” or a way to get attention, as they told Dr. Fejzo.
Even today there is a debate, although increasingly minority, around the psychosomatic origins of excessive vomiting. The aforementioned study of October 12 was carried out in 2005. It then tried to investigate whether, with free abortion, the historical thesis of simulation made sense. And he concluded that these women were probably not malingerers, that their isolation was somewhat archaic. “But we find women facing a true ambivalence regarding their pregnancy,” the study clarified, before advising that they begin psychotherapy treatment, since “uncontrollable vomiting during pregnancy is a symptom fueled by a persistent somatic conflict.”
“It is true that medicine a few years ago did not pay attention to women,” concedes gynecologist Sara López, “but I have not experienced all these theories of rejection of pregnancy, I have not heard them.” López recalls that this disease has a very low prevalence, but it is serious. “I remember a patient, and I talk to you about assisted reproduction, that it is very difficult for us to get pregnant, that she had to abort due to hyperemesis gravidarum because she couldn't, she couldn't. And that impacted me.” Not all cases reach this extreme. Currently, when a woman presents symptoms of hyperemesis, what is usually done is a hospital admission, giving antiemetics and making sure that she is hydrated and cared for, explains López. It is not a treatment as such. Therefore, the advances made by Dr. Fejzo's team are a hope. “Anything that is research and looking for 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. He always has been, he regrets it. When he started researching the topic, it was difficult for him 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 was associated with the Hyperemesis Education and Research Foundation (HER) 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, published the results: Women who had sisters with hyperemesis had a 17 times greater risk of developing the disease than those who did not have it. It was one of the first clear 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 some genetic mutation that would explain the origin of the disease. She had the samples, but not the money to analyze them. But a strange birthday gift from her gave him the solution. It was a kit from 23andMe, the company that makes genetic profiles for individuals, 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 with more than 12 million genetic profiles. “I thought it was brilliant,” says the doctor. “So I decided to write to them.”
Fejzo partnered with the company, which began including some questions about nausea and vomiting during pregnancy in its tests. A few years later, the genetic data of tens of thousands of clients (who previously gave their consent) were scanned for genetic variations in those who suffered from nausea during pregnancy. The results are published in Nature in 2018. Three letters and two numbers were indicated: GDF15.
It was then that the psychosomatic approach began to lose strength compared to the genetic one. 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 her low tolerance to it during pregnancy. “The gene is like the recipe,” explains the expert, “and the hormone, the final dish. So, let's say that if you have the recipe written wrong, the cookies are not going to turn out well.
The next step may be to modify the recipe with gene editing. Or add some 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,” summarizes Fejzo. “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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