Scientists Find a Possible Explanation for Severe Morning Sickness

A recent study has identified a hormone released by growing fetuses that could contribute to the development of severe morning sickness, known as hyperemesis gravidarum. The research suggests that women who are more sensitive to this hormone, which surges during early pregnancy, may face an increased risk of experiencing debilitating nausea and vomiting. Tito Borner, a physiologist at the University of Pennsylvania, notes the significance of addressing hyperemesis gravidarum at its root cause rather than just treating symptoms. The study, published in Nature, not only sheds light on the potential cause but also offers new possibilities for treatment and prevention.

According to co-author Stephen O’Rahilly, a metabolism researcher at the University of Cambridge, women with high levels of the hormone GDF15 before pregnancy showed minimal reactions to it during gestation. This suggests that administering GDF15 to those at a high risk of hyperemesis gravidarum before pregnancy could potentially protect them from developing the condition. However, O’Rahilly acknowledges that while GDF15 appears to influence the risk of severe sickness, there may be other contributing factors.

Typically, around 70% of women experience nausea and vomiting during pregnancy, commonly referred to as morning sickness. However, approximately 0.3–2% of pregnant women endure hyperemesis gravidarum, characterized by severe symptoms that can impede daily activities, eating, and drinking. In extreme cases, it can lead to death from dehydration. O’Rahilly emphasizes the disabling nature of this condition and the potential impact of the study’s findings on understanding, treating, and preventing hyperemesis gravidarum.

The mechanism of protection

Research has demonstrated that GDF15, a hormone produced at low levels by various organs including the prostate, bladder, and kidneys, can induce nausea by binding to specialized receptors in the brainstem. Elevated levels of this hormone occur after ingesting toxic substances and during early pregnancy, contributing to nausea and vomiting. According to Stephen O’Rahilly, the lead researcher, this phenomenon is most pronounced in the first trimester of pregnancy and gradually diminishes over time. O’Rahilly proposes that GDF15 may have evolved as a protective mechanism, preventing individuals from consuming harmful substances and shielding developing fetuses from toxins. He suggests that in early pregnancy, it is advantageous to be cautious about dietary choices to safeguard the offspring.

Previous studies in 2018 identified certain variants of the GDF15 gene, responsible for encoding GDF15, as associated with an increased risk of developing hyperemesis gravidarum, the severe form of morning sickness.

In the latest study, O’Rahilly and his team observed significantly higher levels of GDF15 in the blood of nearly 60 pregnant women experiencing nausea and vomiting compared to approximately 60 women with minimal or no symptoms. By examining different variants of GDF15 produced by placental cells from both mothers and fetuses, the researchers determined that fetal cells were the primary source of the hormone. This contributes to a deeper understanding of how GDF15 levels influence the severity of nausea and vomiting during pregnancy.

The influence of genes on risk

Individuals with specific genetic variants of GDF15, previously associated with a heightened risk of hyperemesis gravidarum, displayed lower GDF15 levels in their bodies. The researchers analyzed genetic data from over 18,000 individuals and found that elevated GDF15 levels in non-pregnant individuals reduced the likelihood of developing hyperemesis gravidarum if they did become pregnant. This suggests that individuals with higher GDF15 levels are less responsive to the hormone during pregnancy, as explained by Stephen O’Rahilly.

To test this hypothesis, the researchers conducted experiments with mice that were not pregnant. The mice were injected with a prolonged form of GDF15 or a placebo. Subsequently, all mice received a dose of GDF15. The results showed that mice given the placebo ate less and lost weight, while those exposed to GDF15 consumed a normal amount of food and lost less weight.

Additionally, the team investigated mothers with the blood condition β-thalassaemia, characterized by lifelong elevated GDF15 levels, and inquired about their experience of sickness during pregnancy. Only 5% of these individuals reported experiencing symptoms, whereas over 60% of a matched sample from the general population, in terms of ethnicity and age, reported pregnancy-related sickness. These findings provide further support for the link between GDF15 levels and the severity of nausea and vomiting during pregnancy.

The way to stop the sickness

The findings of the study suggest potential interventions for individuals with generally low levels of GDF15 to reduce the risk of hyperemesis gravidarum during pregnancy. Stephen O’Rahilly proposes the administration of increasingly high doses of the hormone before conception to desensitize individuals to GDF15. This preventive approach aims to mitigate the severity of nausea and vomiting during pregnancy.

Alternatively, individuals with low GDF15 levels could be administered antibodies that block GDF15 or its receptors, offering a potential avenue for reducing pregnancy-related symptoms. Clinical trials are already underway testing such antibodies for the treatment of cachexia, a wasting syndrome.

However, further research is essential to explore these potential interventions and understand the role of GDF15 in normal pregnancy. Catherine Williamson, an obstetric clinician and researcher at Imperial College London, emphasizes the need to investigate whether altering the hormone’s activity might have unintended harmful effects.

Tito Borner echoes this sentiment, pointing out the historical challenges in addressing pregnancy sickness. He highlights the troubled past, such as the use of thalidomide in the 1950s and 1960s to treat the condition, which had severe developmental consequences for babies’ limbs.

Bart De Jonghe, a nutritional researcher at the University of Pennsylvania, emphasizes the significance of the study’s implications. If fetally derived GDF15 proves to be a primary driver of pregnancy-related nausea and vomiting, it highlights a powerful way in which the fetal environment can use a single chemical signal to significantly impact maternal health and behavior.

Resources

1. ^JOURNAL Wong, C. (2023). Extreme morning sickness? Scientists finally pinpoint a possible cause. Nature. [Nature]
2. ^JOURNAL Fejzo, M. S., Rocha, N., Cimino, I., Lockhart, S. M., Petry, C. J., Kay, R. G., Burling, K., Barker, P., George, A. L., Yasara, N., Premawardhena, A., Gong, S., Cook, E., Rimmington, D., Rainbow, K., Withers, D., Cortessis, V. K., Mullin, P., MacGibbon, K., . . . O’Rahilly, S. (2023). GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. [Nature]
3. ^JOURNAL Wischhusen, J., Melero, I., & Fridman, W. (2020). Growth/Differentiation factor-15 (GDF-15): From biomarker to novel targetable immune checkpoint. Frontiers in Immunology, 11. [Frontiers in Immunology]
4. ^JOURNAL O’Rahilly, S. (2017). GDF15—From biomarker to allostatic hormone. Cell Metabolism, 26(6), 807–808. [Cell Metabolism]
5. ^JOURNAL Fejzo, M. S., Sazonova, O. V., Sathirapongsasuti, J. F., Hallgrímsdóttir, I. B., Vacic, V., MacGibbon, K., Schoenberg, F. P., Mancuso, N., Slamon, D. J., & Mullin, P. (2018). Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications, 9(1). [Nature Communications]

Cite this page: