In the first trimester of pregnancy, a majority of women will experience so-called morning sickness.
Unlike what its name suggests, morning sickness is not a condition where a pregnant woman just casually vomits in the morning and goes on with her day feeling fine. Even in its mildest of forms, it can be an all-consuming nausea, where the sight and smells of very specific foods result in gagging and vomiting. It’s like having the flu, or a really bad hangover, that lasts weeks or months. Sometimes, it can last the entire pregnancy.
In its most extreme form, a condition called hyperemesis gravidarum (HG), a pregnant person becomes so sick that even standing is intolerable. In this state, they are usually persistently vomiting and many times have to be hospitalized to be rehydrated with IV fluids. An estimated 2 percent of women who experience pregnancy will get hyperemesis gravidarum. Previous research has shown that women with hyperemesis gravidarum in one pregnancy have a high chance of recurrence for the next one. Yet, there’s never been a full understanding of it or the possibility of a treatment available until now.
In a new study published in the journal Nature, scientists say they have identified “extensive evidence” that the source of severe morning sickness is a hormone called GDF15 that’s produced by the placenta during pregnancy. A pregnant woman’s likelihood of getting HG depends on her sensitivity to the hormone before pregnancy, the research found.
“We found by looking at the levels of the hormone in blood during pregnancy that people with more severe nausea and vomiting had higher levels [of the hormone] than normal,” Marlena Fejzo, PhD, the paper’s lead author, told Salon. “So what we now know is that if you have lower levels before pregnancy, then you're more sensitive to the rapidly rising levels during pregnancy.”
Scientists used a variety of approaches to distinguish the link between GDF15 and extreme morning sickness, which included blood tests, genetic analyses and studying human and mice cells. One notable finding was that a genetic mutation in the female body that leads to abnormally low levels of GDF15 prior to pregnancy can put women at a greater risk of getting HG while pregnant. Another genetic analysis found that women with an inherited blood disorder called beta thalassemia, which produces chronically high levels of GDF15, can protect against morning sickness. Adding to their research, in an experiment on mice, scientists played with the dosages of GDF15 before and during pregnancy which seemed to affect the severity of morning sickness symptoms.
“If you give the mice a large dose similar to the dose that you have in pregnancy, the mice don't vomit, but the mice will lose their appetite and lose weight,” Fejzo said. “But if you give them a lower dose, prior to that high dose, they were desensitized to it and the mice were able to eat normally and not lose weight.”
Fejzo said this was an exciting finding because it suggests that HG, and maybe all morning sickness, can be prevented in pregnancy.
The next step for researchers is to test if exposure to GDF15 prior to pregnancy can reduce nausea and vomiting. Fejzo said she has already applied for funding to test whether metformin, a drug that increases GDF15 levels, could work.
Metformin is most commonly used to treat and prevent Type 2 diabetes by lowering blood sugar. Off label, it’s been used to treat prediabetes, gestational diabetes and polycystic ovary syndrome (PCOS). Researchers are also investigating whether it can help lower the risk of cancer, dementia and stroke, long COVID and even increase lifespan. Fejzo said since metformin is sometimes used to help women with PCOS conceive, and it’s a viable option as a contender to treat severe morning sickness, and then maybe even all nausea in pregnancy.
The role GDF15 and morning sickness plays in pregnancy remains unknown. But there are theories, Fejzo said, that date back to hunter-gatherer days. All humans have the GDF15 gene, not just pregnant people. Its levels increase in stressful situations, especially when the physical body is under a lot of stress. It’s what causes a lack of appetite and extreme levels of nausea, when for example, you're physically injured or have a viral infection.
“What we think is happening is that this hormone has evolved to tell the human or animal that they need to rest and recover more than they need food,” Fejzo said. "It's kind of a balance of risk-benefit, where the benefit to resting and recovering in some kind of adverse state is more important than going out and getting food.”
For example, if someone was injured in a hunter-gatherer community, it would be more beneficial for that person to rest than risk being attacked by another animal while finding food. In pregnancy, it’s been hypothesized that when a pregnant woman is in a more vulnerable state, it’s best to rest and avoid predators than eat. It could be that the hormone rises to keep pregnant women from eating foods that might be toxic to the mother or fetus, too.
Of course, the question on many peoples’ minds is how soon a possible treatment will go to market. Fejzo emphasized it’s important to take trials like this slowly. It's possible that with drug like metformin, women who are sensitive to high levels of GDF15 could get sick from being on the drug.
“We need to do this slowly, to figure out what the levels are, so we don't make these patients sick,” she said. “So we can really figure out the right dose, the right timeframe and the right formulation to really make this work.”
While she couldn’t specify a timeframe, Fejzo ended on a hopeful note. Instead of trying to figure out the cause, researchers can now move forward.
“The trials are imminent,” she said. “We can move forward now.”
