Pregnancy sickness, or hyperemesis gravidarum, is common and is thought to affect seven out of ten women at some point during pregnancy. But until recently there was very little information about why this happens.

New research from our team has identified sensitivity to GDF15, a hormone produced in abundance during pregnancy, as a contributor to pregnancy disease risk.

This condition can affect the quality of life of pregnant women, even in so-called mild cases. 1% to 3% of women suffer from severe pregnancy sickness, when nausea and vomiting are so severe that they lose weight or become dehydrated, or both. In one study, this condition was the most common cause of hospitalization for women in the first three months of pregnancy.

It has been linked to worse pregnancy outcomes and its effects last well into the pregnancy, with some women reporting psychological distress and becoming reluctant to conceive again.

The fact that it develops in early pregnancy and always resolves when the pregnancy ends strongly suggests that the cause of the disease comes from the developing pregnancy. But the details of how and why this happens remain unclear. This lack of understanding makes the development of treatments difficult and arguably contributes to the considerable stigma associated with the condition.

GDF15

GDF15 is a hormone that suppresses food intake in mice by acting specifically on a small group of cells at the base of the brain, which is also known to induce nausea and vomiting. Thus, GDF15 is being investigated as an obesity therapy.

Early trials have confirmed that it suppresses appetite in people, but it also causes nausea and vomiting. It has long been known that it is abundant in the human placenta and is present in very high concentrations in the blood of healthy pregnant women. These factors make it a plausible cause, but there is a lack of detailed understanding of whether GDF15 affects disease severity in pregnancy.

We used different methods to study how GDF15 increases the risk of pregnancy disease. We measured GDF15 in the blood of pregnant women who came to the hospital due to illness and pregnant women who came to the hospital for other reasons.

We found that women with pregnancy sickness had higher levels of GDF15. Although this was in keeping with the contribution of GDF15 to the condition, GDF15 levels in each group overlapped significantly. This suggests that factors other than the absolute amount of GDF15 from the developing pregnancy may determine disease risk.

Natural variation in expectant mothers’ DNA contributes to pregnancy disease risk. Previous studies have identified changes in DNA near GDF15 as the largest determinant of pregnancy disease risk. In particular, a rare genetic mutation (present in about one in 1,500 people) that affects the structure of the GDF15 protein in the blood has a big impact on that risk.

To understand the potential impact of this genetic variant on the levels of GDF15 in the bloodstream, we studied its effects on the protein in cells grown in the laboratory. We found that this mutated GDF15 molecule gets trapped inside cells. Furthermore, it stuck to “normal” GDF15 and became trapped – this creates a double hit that interferes with the transport of GDF15 out of the cells. Healthy people with this mutation have significantly lower levels of GDF15 in their blood, which is consistent with these findings.

We found that a DNA mutation near GDF15, prevalent in about 15 to 30% of people, reduces hormone levels. These changes increase the risk of pregnancy sickness by a small amount. In contrast, women with the blood disorder thalassemia, who have very high levels of GDF15 throughout life, are less likely to have nausea and vomiting during pregnancy.