GDF15 and Pregnancy Nausea

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), in a cohort study published in the journal Nature, and explored the mechanistic basis of this association. They discovered that high levels of GDF15 in the mother’s blood are linked to an increased risk of vomiting and HG during pregnancy.

Background

NVP affects around 70% of pregnant women worldwide. HG is diagnosed when the symptoms become too severe and interfere with their eating and everyday activities. The weight loss and electrolyte imbalance caused by HG can be debilitating for both the mother and the infant, with long-term health effects for both. Although HG is a leading cause of hospitalization during pregnancy, the etiology and molecular pathophysiology of the illness are poorly understood.

GDF15 is a brainstem hormone generated by the fetus and placental cells during pregnancy. GDF15 may be created in non-pregnant persons in response to stress. Previous research has found elevated GDF15 levels in maternal circulation in instances of HG, implying that it may have a role in the genesis of the illness. Genetic studies back up GDF15’s role in HG susceptibility. The current work sought to uncover the less-understood molecular underpinnings of the link between GDF15 levels, NVP, and HG in animal models and people.

About the Study

Blood samples were taken from pregnant women at 15 weeks of gestation in the current study, including those with NVP (n = 168) or presenting to the hospital with HG (n = 57), as well as controls with no notable symptoms. GDF15 levels were measured using immunoassays, which are less vulnerable to confounding by the H202D variation. Participants in the test and control groups were of comparable age and BMI. Mass spectrometry-based tests, placental RNAseq (short for ribonucleic acid sequencing), and maternal DNA (short for deoxyribonucleic acid) genotyping investigations were used to differentiate between maternal and fetal GDF15.

Genetic variations linked to HG risk were discovered and investigated. Mendelian randomization (MR) analysis was used to investigate the causal link between GDF15 and HG utilizing data from genome-wide association studies.

Because GDF15 levels are known to be elevated in thalassemia patients, a survey was done among women with beta-thalassemia (at least one previous pregnancy with live delivery), comparing their pregnancy outcomes to ethnicity- and age-matched women without thalassemia.

The researchers administered a long-acting version of human GDF15 to wild-type mice to evaluate its impact on food consumption. In addition, mice deficient in GDF15 (Gdf15-/-) were given human recombinant GDF15 to see how it affected their food consumption.

Results and Discussion

GDF15 levels in women with NVP or HG were considerably higher than in controls. While maternal-origin GDF15 was discovered to be 1% in maternal plasma, its concentration in circulation was observed to grow in some cases between trimesters one and two before decreasing in the later stages.

The rare C211G variant and two common variants with single nucleotide changes in the GDF15 gene associated with an increased HG risk were found to lower GDF15 levels in circulation in mutation studies. MR analysis revealed that greater levels of circulating GDF15 in non-pregnant women reduced their risk of HG (odds ratio = 0.7), indicating that the molecule plays a protective effect. Animal tests revealed the same level of protection. as injected with a long-acting version of human GDF15, mice pre-exposed to GDF15 did not display a substantial and acute decrease in food intake as compared to controls. Similarly, Gdf15-/- animals demonstrated food-intake inhibition after GDF15 treatment, whereas wild-type mice did not.

The prevalence of NVP was shown to be significantly lower in women with thalassemia (5%) compared to controls (>60%, p0.01).

However, the study is hampered by the absence of prenatal genotype consideration in Mendelian randomization calculations. More research is needed to understand GDF15’s desensitization effects and to investigate its other roles in maternal and fetal health.

Conclusion

The current investigation, which combines experimental, genomic, and clinical techniques, sheds light on the origin, regulation, and potentially causative involvement of GDF15 in NVP and HG. The findings reveal that the severity of NVP is determined by fetal GDF15 production and the mother’s sensitivity to the molecule, which is influenced by her past exposure to the hormone. Insights from this work have opened new pathways in the prevention and treatment of HG, with the potential to enhance pregnancy outcomes, by revealing a key, mechanistic function for GDF15 in NVP and HG.

For more information: GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Fejzo, M. et al., Nature (2023), DOI: https://doi.org/10.1038/s41586-023-06921-9