GDF15 linked to maternal risk of nausea and vomiting during pregnancy

Fejzo, M.; 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. J.; Cortessis, V.; Mullin, P. M.; MacGibbon, K. W.; Jin, E.; Kam, A.; Campbell, A.; Polasek, O.; Tzoneva, G.; Gribble, F. M.; Yeo, G. S. H.; Lam, B. Y. H.; Saudek, V.; Hughes, I. A.; Ong, K. K.; Perry, J. R. B.; Cole, A. Sutton; Baumgarten, M.; Welsh, P.; Sattar, N.; Smith, G. C. S.; Charnock-Jones, D. S.; Coll, A. P.; Meek, C. L.; Mettananda, S.; Hayward, C.; Mancuso, N.; O’Rahilly, S.

GDF15 linked to maternal risk of nausea and vomiting during pregnancy

M. Fejzo, N. Rocha, I. Cimino, S. M. Lockhart, C. J. Petry, R. G. Kay, K. Burling, P. Barker, A. L. George, N. Yasara, A. Premawardhena, S. Gong, E. Cook, D. Rimmington, K. Rainbow, D. J. Withers, V. Cortessis, P. M. Mullin, K. W. MacGibbon, E. Jin, A. Kam, A. Campbell, O. Polasek, G. Tzoneva, F. M. Gribble, G. S. H. Yeo, B. Y. H. Lam, V. Saudek, I. A. Hughes, K. K. Ong, J. R. B. Perry, A. Sutton Cole, M. Baumgarten, P. Welsh, N. Sattar, G. C. S. Smith, D. S. Charnock-Jones, A. P. Coll, C. L. Meek, S. Mettananda, C. Hayward, N. Mancuso and S. O’Rahilly ()
Additional contact information
M. Fejzo: University of Southern California
N. Rocha: University of Cambridge
I. Cimino: University of Cambridge
S. M. Lockhart: University of Cambridge
C. J. Petry: University of Cambridge
R. G. Kay: University of Cambridge
K. Burling: University of Cambridge
P. Barker: University of Cambridge
A. L. George: University of Cambridge
N. Yasara: University of Kelaniya, Thalagolla Road
A. Premawardhena: Adolescent and Adult Thalassaemia Care Center (University Medical Unit), North Colombo Teaching Hospital
S. Gong: University of Cambridge, NIHR Cambridge Biomedical Research Centre
E. Cook: University of Cambridge, NIHR Cambridge Biomedical Research Centre
D. Rimmington: University of Cambridge
K. Rainbow: University of Cambridge
D. J. Withers: University of Cambridge
V. Cortessis: University of Southern California
P. M. Mullin: University of Southern California
K. W. MacGibbon: Hyperemesis Education and Research Foundation
E. Jin: University of Southern California
A. Kam: University of Southern California
A. Campbell: University of Edinburgh
O. Polasek: University of Split
G. Tzoneva: Regeneron Genetics Center
F. M. Gribble: University of Cambridge
G. S. H. Yeo: University of Cambridge
B. Y. H. Lam: University of Cambridge
V. Saudek: University of Cambridge
I. A. Hughes: University of Cambridge
K. K. Ong: University of Cambridge
J. R. B. Perry: University of Cambridge
A. Sutton Cole: Cambridge University Hospitals NHS Foundation Trust
M. Baumgarten: Cambridge University Hospitals NHS Foundation Trust
P. Welsh: University of Glasgow
N. Sattar: University of Glasgow
G. C. S. Smith: University of Cambridge, NIHR Cambridge Biomedical Research Centre
D. S. Charnock-Jones: University of Cambridge, NIHR Cambridge Biomedical Research Centre
A. P. Coll: University of Cambridge
C. L. Meek: University of Cambridge
S. Mettananda: University of Kelaniya, Thalagolla Road
C. Hayward: University of Edinburgh
N. Mancuso: University of Southern California
S. O’Rahilly: University of Cambridge

Nature, 2024, vol. 625, issue 7996, 760-767

Abstract: Abstract GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1–4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Date: 2024
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DOI: 10.1038/s41586-023-06921-9

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