Around seven out of ten pregnant women suffer from nausea and vomiting during pregnancy. A study has now uncovered the mechanisms behind it: the main reason for the nausea is a hormone called GDF15, which is produced by the fetus. The less the mother had of this hormone before pregnancy and the more the fetus produces, the worse the nausea is - sometimes even leading to hospital admission. The findings could open up treatment options aimed at either getting at-risk women exposed to GDF15 before pregnancy or reducing the effects of the hormone during pregnancy.
Many women suffer from nausea and vomiting, especially at the beginning of pregnancy. For some, the symptoms are so severe that they threaten life-threatening dehydration. The so-called hyperemesis gravidarum, a particularly severe form of nausea during pregnancy, is one of the most common reasons for hospital admissions in the first trimester of pregnancy. The causes were unclear for a long time and treatment options were limited to giving those affected intravenous fluids and prescribing medication for general nausea.
Fetal hormone as a cause
A team led by Marlena Fejzo from the University of Southern California has now gotten to the bottom of the causes of pregnancy sickness. Previous studies had already provided evidence that the hormone GDF15 could play a role. This is a growth differentiation hormone that is produced in low concentrations in most organs of the body and is increasingly released from the fetus into the mother's organism during pregnancy. However, it was still unclear whether there was actually a causal connection between GDF15 and nausea during pregnancy.
Using a combination of methods - from blood tests and genetic studies to animal studies - Fejzo and her team have now proven that pregnancy sickness, including the severe form, is indeed caused by GDF15. The nausea is particularly severe in women who had a low GDF15 concentration before pregnancy. Apparently her body is hardly used to the hormone and therefore reacts particularly strongly when confronted with high concentrations of the hormone during pregnancy. “We now know that women experience nausea during pregnancy when they are exposed to higher levels of the hormone GDF15 than they are used to,” explains Fejzo.
Different sensitivity for GDF15
Genetic analysis showed that a rare mutation in the mother's GDF15 gene may increase the risk of hyperemesis gravidarum. This mutation causes GDF15 levels to be abnormally low outside of pregnancy. If the fetus carries the same mutation, the mother's risk of nausea is not increased. However, if the fetus produces GDF15 at normal levels, the mother has at least a tenfold increased risk of severe nausea during pregnancy. On the other hand, women who suffer from the hereditary disease beta-thalassemia, which, among numerous other symptoms, ensures that the GDF15 level is particularly high even outside of pregnancy, hardly have any problems with nausea during pregnancy - probably because their body is exposed to the hormone is used to.
To further test these relationships, the researchers administered high doses of GDF15 to mice to simulate concentrations during pregnancy. In response, the mice showed a loss of appetite, suggesting they were feeling nauseous. However, when the researchers started with low doses and slowly increased them, the mice that had been accustomed to the hormone in this way ate normally even at high concentrations. From the researchers' perspective, this result suggests that it could make sense for women who are particularly at risk of nausea and want to have children to take GDF15 before a planned pregnancy in order to prepare their bodies for the hormone.
Opportunities for new treatments
Another treatment approach could be to reduce GDF15 levels during pregnancy. Although it is not yet completely clear which processes the hormone is important for during embryonic development, the study provides initial evidence that even low GDF15 levels can be safe for mother and child. In pregnancies in which both the mother and the fetus had the mutation in the GDF15 gene, the babies developed normally and were born healthy.
In future studies, the research team plans to test various options that could help women with pregnancy sickness - including habituation to GDF15 before pregnancy, lowering levels during pregnancy, and a new group of drugs that block the docking sites for GDF15 in the mother's brain . “Now that we understand the root cause of hyperemesis gravidarum, we are hopefully one step closer to developing effective treatments,” says Fejzo.
Source: Marlena Fejzo (University of Southern California) et al., Nature, doi: 10.1038/s41586-023-06921-9