Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy

Abstract

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green‐top Guideline No. 69)

“…Higher circulating levels of GDF15 and not hCG were found in hospitalised HG patients, patients taking medication for NVP, and patients with 2 nd trimester vomiting. 11 hCG is therefore unlikely to be causative. 11 Genetic variants associated with expression of GDF15 in families with HG have been identified as the greatest genetic risk factor for HG 12 and are associated with recurrence in subsequent pregnancies.…”

“…11 hCG is therefore unlikely to be causative. 11 Genetic variants associated with expression of GDF15 in families with HG have been identified as the greatest genetic risk factor for HG 12 and are associated with recurrence in subsequent pregnancies. 13…”

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

“…The circulating metabokine-cytokine growth differentiation factor 15 (GDF15) is among the most studied circulating proteins in biomedicine. Circulating GDF15 is produced by various somatic tissues and cell types, secreted and transported in the blood, to eventually reach the hindbrain (and possibly other tissues) where it signals energetic stress to alter behavior and whole-body energy expenditure [1][2][3][4][5] . GDF15 fulfills several criteria as a marker of systemic energetic stress: 1) GDF15 is the most robustly elevated circulating protein with aging 6,7 , 2) it is induced by some medications targeting mitochondria (e.g., metformin 8 ), and 3) it is elevated in several chronic physical and mental illnesses including cardiovascular disease 9 , cancer 10 , mood disorders 11 , Alzheimer's disease 12,13 autoimmune diseases 14 , and others.…”

“…GDF15 is also secreted in response to various non-disease states. Blood GDF15 increases with nutritional and physiological stressors such as exhaustive exercise 27,28 , pregnancy 2,29 , fasting 30 , and infectious challenges 31 . This secretion pattern aligns with the canonical, energy-mobilizing glucocorticoid and sympathetic hormonal pathways, with which GDF15 interacts 1,32 , and may contribute to GDF15-mediated increase in energy expenditure 1,33 .…”

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans

“…To measure GDF-15, we used two GDF-15 ELISAs. The first assay measures total GDF-15, which can detect GDF-15 irrespective of the presence of the H202D variant 22,23 . The second assay measures H-specific GDF-15, precisely and uniquely detecting the H amino acid at the 202 position in the GDF-15 sequence and does not detect genetic variants generated by the change of the H to D, called H202D; thus, it can detect only GDF-15 without the H202D variant 4,5,13,16 .…”