Scientists finally pinpoint a possible cause
A protein released by fetal cells in the placenta influences the risk of experiencing severe nausea and vomiting during pregnancy.
Sickness during pregnancy can be so severe that it disrupts eating, drinking and everyday activities.
“For the first time, hyperemesis gravidarum could be addressed at the root cause, rather than merely alleviating its symptoms,” says Tito Borner, a physiologist at the University of Pennsylvania. The work was published on 13 December in Nature1.
The finding could also open avenues for treatment. “We now have a clear view of what may cause this problem and a route for both treatment and prevention,” says study co-author Stephen O’Rahilly, a metabolism researcher at the University of Cambridge, UK.
The researchers found that women who had high levels of the hormone GDF15 before they got pregnant had minimal reactions to it while carrying their baby. The findings suggest that giving GDF15 to those at high risk of hyperemesis gravidarum before pregnancy could protect them from the condition. O’Rahilly says that although their study suggests that GDF15 influences the risk of severe sickness, other factors might have a role.
Roughly 70% of women experience nausea and vomiting during pregnancy — colloquially termed morning sickness, even though it can occur at any time. Around 0.3–2% experience hyperemesis gravidarum: symptoms so severe that they have difficulty eating, drinking and doing everyday activities. In the worst cases, this can lead to death from dehydration. “It is extremely disabling,” says O’Rahilly.
Protective mechanism
Research has shown2 that GDF15, which is produced at low levels by organs including the prostate, bladder and kidneys, can trigger nausea by binding to specialized receptors in the brainstem. After ingesting toxic substances and during early pregnancy, levels of this hormone increase, causing sickness. “It’s usually worst in the first trimester and then it gradually fades,” says O’Rahilly.
On the basis of such studies, O’Rahilly proposed3 that GDF15 might have evolved to protect people from poisoning themselves and to shield a developing fetus from toxic substances. It’s not necessary to eat a lot and gain much mass in early pregnancy, says O’Rahilly. “It’s far better off being cautious about what you eat, to protect your offspring from toxins.”
In 2018, researchers linked some variants of the GDF15 gene, which encodes GDF15, to an increased risk of developing hyperemesis gravidarum4.
In the latest study, O’Rahilly and his colleagues found that GDF15 levels in the blood were substantially higher in nearly 60 pregnant women who experienced nausea and vomiting than in around 60 who had little or no sickness.
The researchers compared the levels of different variants of GDF15 produced by placental cells derived from the mothers and fetuses, and found that fetal cells produced most of the hormone.
Genetic risk
The team found that people with certain genetic variants of GDF15, which have previously been linked to a higher risk of developing hyperemesis gravidarum, had lower GDF15 levels in the body. By analysing genetic data from more than 18,000 people, the researchers found that higher levels of GDF15 in non-pregnant people reduced the risk that they would develop hyperemesis gravidarum if they did become pregnant. This suggests that people react less to the hormone during pregnancy if they have higher GDF15 levels beforehand, says O’Rahilly.
To test this idea, researchers injected mice that weren’t pregnant with either a long-lasting form of GDF15 or a placebo. Three days later, the team gave all the mice a dose of GDF15, and found that animals that had received the placebo ate less and lost weight, but those exposed to GDF15 ate normally and lost less weight.
The team also asked mothers with the chronic blood condition β-thalassaemia — who have lifelong elevated levels of GDF15 — whether they experienced sickness during pregnancy. Only 5% had, whereas more than 60% of those in a sample of the general population, matched for ethnicity and age, experienced these symptoms.
Stopping the sickness
The results suggest that people who have generally low levels of GDF15 could be given increasingly high doses of the hormone while trying to conceive, to desensitize them to it and reduce their chances of experiencing hyperemesis gravidarum during pregnancy, says O’Rahilly.
Alternatively, they could be given antibodies that block GDF15 or GDF15 receptors, to reduce nausea and vomiting. At least two antibodies against GDF15 are being tested in clinical trials to treat the wasting syndrome cachexia.
Further research is needed to explore these possibilities. “We don’t know anything about the role of GDF15 in normal pregnancy,” says obstetric clinician and researcher Catherine Williamson at Imperial College London. Studies should establish whether changing the hormone’s activity might have harmful side effects, she says.
Borner agrees. Attempts to tackle pregnancy sickness have a troubled past: in the 1950s and 1960s, the drug thalidomide was used to treat the condition, but turned out to affect the development of babies’ limbs.
“If fetally derived GDF15 is a primary driver of nausea and vomiting during pregnancy, then that’s a big deal,” says nutritional researcher Bart De Jonghe at the University of Pennsylvania in Philadelphia. “It shows us a powerful way the fetal environment can use a single chemical signal to dramatically impact maternal health and behaviour.”
doi: https://doi.org/10.1038/d41586-023-03982-8
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