A breakthrough study from the University of Cambridge has uncovered a major cause of nausea and vomiting in pregnancy, the common condition known as morning sickness or hyperemesis gravidarum. The findings also point to a potential treatment approach currently under exploration.
CAMBRIDGE, England – A collaborative research effort by scientists at the University of Cambridge has identified sensitivity to high levels of the placental hormone GDF15 as a key factor determining a woman’s risk of developing nausea and vomiting during pregnancy.
This common condition, medically termed hyperemesis gravidarum and colloquially called morning sickness, is estimated to affect up to 70% of expecting mothers to some degree. While often manageable, moderate to severe cases can significantly diminish quality of life. In the most extreme instances, which impact 1-3% of pregnancies, persistent nausea and vomiting leads to dangerous weight loss and dehydration requiring hospitalization.
Despite the prevalence of pregnancy sickness, the underlying mechanisms behind it have remained poorly comprehended. This knowledge gap has stymied treatment development and added to the stigma surrounding the condition.
The new findings, represent a major step toward understanding why many women experience these unpleasant symptoms upon getting pregnant. They also provide a roadmap for exploring new therapeutic approaches.
The Culprit: GDF15
At the center of the Cambridge team’s work is the protein GDF15. Secreted by the placenta in high volumes during pregnancy, GDF15 is known to trigger nausea and vomiting when administered at elevated doses. Previous genetic studies have also linked variants in the GDF15 gene region to hyperemesis gravidarum risk.
“The fact that it develops in early pregnancy and invariably resolves when pregnancy ends strongly suggests that the cause of the sickness comes from the developing pregnancy,” said senior author Professor Stephen O’Rahilly, Co-Director of the Institute of Metabolic Science at Cambridge. “But the detail on how and why it happens has remained elusive.”
By conducting a series of human, animal, and cell culture studies, O’Rahilly, along with first author Sam Lockhart and colleagues, definitively established sensitivity to rising GDF15 levels as a major determinant of pregnancy sickness susceptibility.
Women hospitalized with hyperemesis gravidarum tended to exhibit higher blood concentrations of the hormone versus pregnant women hospitalized for other reasons. Additionally, genetic variants associated with increased sensitivity to GDF15 effects were linked to greater sickness severity.
Conversely, a rare mutation causing partial GDF15 deficiency was found to protect against nausea and vomiting symptoms during pregnancy. The researchers confirmed that this mutation, present in ~0.07% of the population, interferes with cellular GDF15 transport and secretion – resulting in chronically lower circulating levels.
“The conclusion of these studies is clear,” said Lockhart, a Wellcome Trust Clinical PhD Fellow at Cambridge. “Predisposition to higher levels of GDF15 when not pregnant reduces the risk of pregnancy sickness.”
A Sensitization Effect
At first glance, this finding seems counterintuitive. Why would higher lifetime exposures to a nausea-inducing hormone shield against sickness triggered by that same hormone during pregnancy?
The study authors posit that the protective effect stems from desensitization over time to GDF15’s pro-emetic properties. They found evidence for this theory in an animal experiment showing that mice with sustained elevated GDF15 levels were less responsive to acute spikes of the hormone.
O’Rahilly speculates that the rapid rise in GDF15 secreted by the placenta early in gestation overwhelms the body’s coping mechanisms in sensitized women. This placental surge likely explains why pregnancy sickness manifests transiently before dissipating later on.
“Our findings suggest that lower levels of GDF15 before pregnancy result in women being hypersensitive to the large amounts of GDF15 being released from the developing pregnancy,” O’Rahilly said. “This poses two obvious approaches to treatment of this condition.”
Toward New Treatments
The identification of GDF15 sensitization as pivotal in the genesis of nausea/vomiting during pregnancy provides two potential therapeutic avenues the Cambridge scientists aim to now pursue through continued research.
One is to raise GDF15 levels prior to conception to promote desensitization. The other is to interfere with GDF15 signaling pathways during early pregnancy stages when symptoms occur. Both tactics could theoretically mitigate sickness severity and improve outcomes.
“The challenge now is to develop and test strategies to achieve these aims that are safe and acceptable to women at risk from this debilitating condition,” said Lockhart.
With incidence hovering around 70% for general morning sickness – and up to 3% for the more dangerous hyperemesis gravidarum variant – effective new treatments could benefit millions of expecting mothers worldwide. For some pregnant women, just making it through the early phases of gestation without sustained agony remains a daily battle.
“This condition can affect pregnant women’s quality of life, even in so-called mild cases,” reiterated O’Rahilly, emphasizing the immense need for progress on this front. “Severe sickness is the most common reason women are admitted to hospital in the first trimester. It has been associated with poorer pregnancy outcomes, lasting psychological distress, and reluctance to have more children.”
Beyond mitigating individual maternal suffering, decreasing hyperemesis gravidarum severity could produce added societal dividends like lower healthcare costs. However, realizing lasting change first requires unraveling the science underpinning this vexing condition – a complex riddle Cambridge researchers now appear one step closer to solving.
The full study detailing these landmark findings can be accessed at the University of Cambridge’s repository. O’Rahilly and Lockhart were joined in this research by Ms. Eleanor Woodward and Ms. Neele Dellschaft, also affiliated with the Institute of Metabolic Science at Cambridge.
