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Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study

  • E. C. Braithwaite (a1), J. Hill (a2), A. Pickles (a3), V. Glover (a4), K. O’Donnell (a5) (a6) and H. Sharp (a7)...


Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex-specific mechanisms that underpin fetal programming.


Corresponding author

*Address for correspondence: E. C. Braithwaite, School of Life Sciences and Education, Staffordshire University, Stoke-on-Trent ST4 2DE, UK.E-mail:


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1. Barker, DJ. In utero programming of chronic disease. Clin Sci (Lond). 1998; 95, 115128.
2. Barker, DJ. Fetal origins of cardiovascular disease. Ann Med. 1999; 31(Suppl. 1), 36.
3. O’Donnell, KJ, Meaney, MJ. Fetal origins of mental health: the developmental origins of health and disease hypothesis. Am J Psychiatry. 2017; 174, 319328.
4. Breslau, N. Psychiatric sequelae of low birth weight. Epidemiol Rev. 1995; 17, 96106.
5. Sucksdorff, M, Lehtonen, L, Chudal, R, et al. Preterm birth and poor fetal growth as risk factors of attention-deficit/hyperactivity disorder. Pediatrics. 2015; 136, e599e608.
6. Thomas, K, Harrison, G, Zammit, S, et al. Association of measures of fetal and childhood growth with non-clinical psychotic symptoms in 12-year-olds: the ALSPAC cohort. Br J Psychiatry. 2009; 194, 521526.
7. Abel, KM, Wicks, S, Susser, ES, et al. Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Arch Gen Psychiatry. 2010; 67, 923930.
8. Wiles, NJ, Peters, TJ, Leon, DA, Lewis, G. Birth weight and psychological distress at age 45-51 years: results from the Aberdeen Children of the 1950s cohort study. Br J Psychiatry. 2005; 187, 2128.
9. Mallen, C, Mottram, S, Thomas, E. Birth factors and common mental health problems in young adults: a population-based study in North Staffordshire. Soc Psychiatry Psychiatr Epidemiol. 2008; 43, 325330.
10. Raikkonen, K, Pesonen, AK, Roseboom, TJ, Eriksson, JG. Early determinants of mental health. Best Pract Res Clin Endocrinol Metab. 2012; 26, 599611.
11. Berle, JO, Mykletun, A, Daltveit, AK, Rasmussen, S, Dahl, AA. Outcomes in adulthood for children with foetal growth retardation. A linkage study from the Nord-Trondelag Health Study (HUNT) and the Medical Birth Registry of Norway. Acta Psychiatr Scand. 2006; 113, 501509.
12. Herva, A, Pouta, A, Hakko, H, et al. Birth measures and depression at age 31 years: the Northern Finland 1966 Birth Cohort Study. Psychiatry Res. 2008; 160, 263270.
13. Vasiliadis, HM, Gilman, SE, Buka, SL. Fetal growth restriction and the development of major depression. Acta Psychiatr Scand. 2008; 117, 306312.
14. Wojcik, W, Lee, W, Colman, I, Hardy, R, Hotopf, M. Foetal origins of depression? A systematic review and meta-analysis of low birth weight and later depression. Psychol Med. 2013; 43, 112.
15. Costello, EJ, Worthman, C, Erkanli, A, Angold, A. Prediction from low birth weight to female adolescent depression: a test of competing hypotheses. Arch Gen Psychiatry. 2007; 64, 338344.
16. Van Lieshout, RJ, Boylan, K. Increased depressive symptoms in female but not male adolescents born at low birth weight in the offspring of a national cohort. Can J Psychiatry. 2010; 55, 422430.
17. Van den Bergh, BR, Van Calster, B, Smits, T, Van Huffel, S, Lagae, L. Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology. 2008; 33, 536545.
18. Quarini, C, Pearson, RM, Stein, A, et al. Are female children more vulnerable to the long-term effects of maternal depression during pregnancy? J Affect Disord. 2016; 189, 329335.
19. Sandman, CA, Glynn, LM, Davis, EP. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. J Psychosom Res. 2013; 75, 327335.
20. Buss, C, Davis, EP, Shahbaba, B, et al. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proc Natl Acad Sci U S A. 2012; 109, E1312E1319.
21. Tibu, F, Hill, J, Sharp, H, et al. Evidence for sex differences in fetal programming of physiological stress reactivity in infancy. Dev Psychopathol. 2014; 26(Pt 1), 879888.
22. Vidal-Ribas, P, Pickles, A, Tibu, F, Sharp, H, Hill, J. Sex differences in the associations between vagal reactivity and oppositional defiant disorder symptoms. J Child Psychol Psychiatry 2017; 58, 988997.
23. Vidal-Ribas, P, Brotman, MA, Valdivieso, I, Leibenluft, E, Stringaris, A. The status of irritability in psychiatry: a conceptual and quantitative review. J Am Acad Child Adolesc Psychiatry. 2016; 55, 556570.
24. Rowe, R, Maughan, B, Pickles, A, Costello, EJ, Angold, A. The relationship between DSM-IV oppositional defiant disorder and conduct disorder: findings from the Great Smoky Mountains Study. J Child Psychol Psychiatry. 2002; 43, 365373.
25. Seckl, JR. Glucocorticoids, developmental ‘programming’ and the risk of affective dysfunction. Prog Brain Res. 2008; 167, 1734.
26. Braithwaite, EC, Pickles, A, Sharp, H, et al. Maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner. Physiol Behav. 2017; 175, 3136.
27. Braithwaite, EC, Murphy, SE, Ramchandani, PG, Hill, J. Associations between biological markers of prenatal stress and infant negative emotionality are specific to sex. Psychoneuroendocrinology. 2017; 86, 17.
28. Hinnant, JB, El-Sheikh, M. Codevelopment of externalizing and internalizing symptoms in middle to late childhood: sex, baseline respiratory sinus arrhythmia, and respiratory sinus arrhythmia reactivity as predictors. Dev Psychopathol. 2013; 25, 419436.
29. Morales, S, Beekman, C, Blandon, AY, Stifter, CA, Buss, KA. Longitudinal associations between temperament and socioemotional outcomes in young children: the moderating role of RSA and gender. Dev Psychobiol. 2015; 57, 105119.
30. Marsman, R, Swinkels, SH, Rosmalen, JG, et al. HPA-axis activity and externalizing behavior problems in early adolescents from the general population: the role of comorbidity and gender The TRAILS study. Psychoneuroendocrinology. 2008; 33, 789798.
31. Dietrich, A, Ormel, J, Buitelaar, JK, et al. Cortisol in the morning and dimensions of anxiety, depression, and aggression in children from a general population and clinic-referred cohort: an integrated analysis. The TRAILS study. Psychoneuroendocrinology. 2013; 38, 12811298.
32. Dorn, LD, Kolko, DJ, Susman, EJ, et al. Salivary gonadal and adrenal hormone differences in boys and girls with and without disruptive behavior disorders: contextual variants. Biol Psychol. 2009; 81, 3139.
33. Sharp, H, Pickles, A, Meaney, M, et al. Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes. PLoS One. 2012; 7, e45446.
34. Noble, M, Wright, G, Dibben, C, et al. The English Indices of Deprivation 2004 (revised). Report to the Office of the Deputy Prime Minister. Neighbourhood Renewal Unit: London; 2004.
35. Wehby, GL, Gili, JA, Pawluk, M, Castilla, EE, Lopez-Camelo, JS. Disparities in birth weight and gestational age by ethnic ancestry in South American countries. Int J Public Health. 2015; 60, 343351.
36. Moffitt, TE, Caspi, A, Krueger, R, et al. Do partners agree about abuse in their relationship?: A psychometric evaluation of interpartner agreement. Psychological Assessment. 1997; 9, 4756.
37. Spielberger, CD, Gorsuch, RL, Lushene, R, Vagg, PR, Jacobs, GA. Manual for the State-Trait Anxiety Inventory. 1983. Consulting Psychologists Press, Inc: Palo Alto.
38. Hill, J, Breen, G, Quinn, J, et al. Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks. Genes Brain Behav. 2013; 12, 388396.
39. Binder, DA. On the variances of asymptotically normal estimators from complex surveys. Int Stat Rev. 1983; 51, 279292.
40. Newcombe, R, Milne, BJ, Caspi, A, Poulton, R, Moffitt, TE. Birthweight predicts IQ: fact or artefact? Twin Res Hum Genet. 2007; 10, 581586.
41. Hayes, B, Sharif, F. Behavioural and emotional outcome of very low birth weight infants – literature review. J Matern Fetal Neonatal Med. 2009; 22, 849856.
42. McCormick, MC, Gortmaker, SL, Sobol, AM. Very low birth weight children: behavior problems and school difficulty in a national sample. J Pediatr. 1990; 117, 687693.
43. Banerjee, TD, Middleton, F, Faraone, SV. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr. 2007; 96, 12691274.
44. Sorensen, HT, Sabroe, S, Olsen, J, et al. Birth weight and cognitive function in young adult life: historical cohort study. BMJ. 1997; 315, 401403.
45. Leonard, H, Nassar, N, Bourke, J, et al. Relation between intrauterine growth and subsequent intellectual disability in a ten-year population cohort of children in Western Australia. Am J Epidemiol. 2008; 167, 103111.
46. van Mil, NH, Steegers-Theunissen, RP, Motazedi, E, et al. Low and high birth weight and the risk of child attention problems. J Pediatr. 2015; 166, 862869.e1-3.
47. Kim, DJ, Davis, EP, Sandman, CA, et al. Prenatal maternal cortisol has sex-specific associations with child brain network properties. Cereb Cortex. 2017; 27, 52305241.
48. Kivlighan, KT, DiPietro, JA, Costigan, KA, Laudenslager, ML. Diurnal rhythm of cortisol during late pregnancy: associations with maternal psychological well-being and fetal growth. Psychoneuroendocrinology. 2008; 33, 12251235.
49. Entringer, S, Buss, C, Andersen, J, Chicz-DeMet, A, Wadhwa, PD. Ecological momentary assessment of maternal cortisol profiles over a multiple-day period predicts the length of human gestation. Psychosomatic Med. 2011; 73, 469474.
50. Goedhart, G, Vrijkotte, TG, Roseboom, TJ, et al. Maternal cortisol and offspring birthweight: results from a large prospective cohort study. Psychoneuroendocrinology. 2010; 35, 644652.
51. Bale, TL. The placenta and neurodevelopment: sex differences in prenatal vulnerability. Dialogues Clin Neurosci. 2016; 18, 459464.
52. Bronson, SL, Bale, TL. The placenta as a mediator of stress effects on neurodevelopmental reprogramming. Neuropsychopharmacology. 2016; 41, 207218.
53. Elder, GJ, Wetherell, MA, Barclay, NL, Ellis, JG. The cortisol awakening response – applications and implications for sleep medicine. Sleep Med Rev. 2014; 18, 215224.
54. Clow, A, Thorn, L, Evans, P, Hucklebridge, F. The awakening cortisol response: methodological issues and significance. Stress. 2004; 7, 2937.


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Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study

  • E. C. Braithwaite (a1), J. Hill (a2), A. Pickles (a3), V. Glover (a4), K. O’Donnell (a5) (a6) and H. Sharp (a7)...


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