In a cohort study published in the journal Nature, researchers investigated the potential association of growth/differentiation factor 15 (GDF15), a fetal hormone, with nausea and vomiting in pregnancy (NVP) and its severe form, hyperemesis gravidarum (HG), and explored the mechanistic basis of this association. They found that a high level of GDF15 in the mother's blood is associated with an increased risk of vomiting and HG in pregnancy.
Study: GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Image Credit: christinarosepix / Shutterstock
Background
About 70% of pregnant women in the world face NVP. When the symptoms are too severe and hinder their appetite and daily activity, HG is diagnosed. The weight loss and electrolyte imbalance associated with HG can be debilitating for the mother and the baby, with long-term consequences for the health of both. Although HG is a leading cause of hospitalization during pregnancy, there's a limited understanding of the etiology and molecular pathogenesis of the condition.
GDF15 is a hormone affecting the brainstem, produced by the fetus and placental tissues in pregnancy. In non-pregnant individuals, GDF15 may be produced in response to stress. Elevated GDF15 levels in maternal circulation have been observed in previous studies in cases of HG, suggesting its potential role in the etiology of the condition. Genetic studies also support GDF15's involvement in HG susceptibility. Researchers in the present study aimed to reveal the less-understood mechanistic basis of the association between GDF15 levels, NVP, and HG in animal models as well as humans.
About the study
In the present study, blood samples were collected from pregnant women around 15 weeks of gestation, including those with NVP (n = 168) or presenting to the hospital with HG (n = 57), along with controls without significant symptoms. Immunoassays were used to measure GDF15 levels, those less susceptible to confounding by the H202D variant. The participants in the test and control groups had similar ages and body mass index. To distinguish between maternal and fetal GDF15, mass spectrometry-based assays, placental RNAseq (short for ribonucleic acid sequencing), and maternal DNA (short for deoxyribonucleic acid) genotyping studies were conducted.
Genetic variants associated with HG risk were identified and studied. Mendelian randomization (MR) analysis was conducted using data from genome-wide association studies to explore the causal relationship between GDF15 and HG.
As GDF15 levels are known to be increased in individuals with thalassemia, a survey was conducted among women having beta-thalassemia (with at least one previous pregnancy with live birth), comparing their pregnancy outcomes with ethnicity- and age-matched women without thalassemia.
Animal experiments involved the administration of a long-acting form of human GDF15 to wild-type mice, studying its effects on food intake. Additionally, mice congenitally lacking GDF15 (Gdf15-/-) were treated with human recombinant GDF15 to assess its impact on food intake.
Results and discussion
Compared to controls, GDF15 levels were significantly elevated in women with NVP or HG. While the maternal-origin GDF15 in maternal plasma was found to be <1%, its concentration in circulation was found to increase in some cases between trimesters one and two before declining in the later stages.
In mutation studies, the rare C211G variant and two common variants with single nucleotide mutations around the GDF15 locus associated with an increased HG risk were found to reduce the GDF15 levels in circulation. MR analysis showed that higher levels of circulating GDF15 in non-pregnant women lowered their risk of HG (odds ratio = 0.7), indicating a protective role for the molecule. This protection was also observed in animal studies. As compared to controls, the mice pre-exposed to GDF15 did not show a significant and acute lowering of food intake when injected with a long-acting form of human GDF15. Similarly, on GDF15 administration, Gdf15-/- mice showed food-intake suppression, while wild-type mice did not.
Survey results showed a strikingly lower prevalence of NVP among women with thalassemia (5%) as compared to controls (>60%, p<0.01).
However, the study is limited by the lack of consideration of fetal genotype in Mendelian randomization estimates. Further research is required to understand the desensitization effects of GDF15 and explore its additional roles in maternal and fetal health.
Conclusion
Combining experimental, genetic, and clinical approaches, the present study provides insights into the origin, regulation, and potentially causal role of GDF15 in NVP and HG. The findings provide evidence to show that the severity of NVP is influenced by the fetal production of GDF15 and the mother's sensitivity to the molecule, which in turn is influenced by her previous exposure to the hormone. Revealing a vital, mechanistic role for GDF15 in NVP and HG, insights from this study have opened new avenues in the prevention and treatment of HG with the potential to improve pregnancy outcomes.
New models identify pregnant women at risk of missing crucial prenatal care