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Background: Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Methods: Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Results: Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Conclusions: Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15's site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting. ; This work was supported by the Wellcome Trust [100574; Strategic Award]; and an unrestricted award from the Novo Nordisk Foundation (International Prize for Excellence in diabetes research) (both SOR). The Cambridge Baby Growth Study has been funded by the Medical Research Council (7500001180) (CLA), European Union Framework 5 (QLK4-1999-01422) (IAH), the Mothercare Foundation (RG54608) (IAH), Newlife Foundation for Disabled Children (07/20) (IAH), and the World Cancer Research Fund International (2004/03) (DBD). It is also supported by the National Institute for Health Research Cambridge Biomedical Research Centre. KKO and JRB are supported by the Medical Research Council (Unit Programme MC_UU_12015/2). The NIPTeR study was in part supported by an AMC-VUMC Alliance grant.