Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-17T14:13:16.717Z Has data issue: false hasContentIssue false
  • English
  • Français

Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors

Published online by Cambridge University Press:  22 June 2015

K. Räikkönen ,
A.-K. Pesonen ,
J. R. O'Reilly ,
S. Tuovinen ,
M. Lahti ,
E. Kajantie ,
P. Villa ,
H. Laivuori ,
E. Hämäläinen  and
J. R. Seckl
...Show all authors
K. Räikkönen*
Affiliation:
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland
A.-K. Pesonen
Affiliation:
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland
J. R. O'Reilly
Affiliation:
Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK
S. Tuovinen
Affiliation:
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland
M. Lahti
Affiliation:
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland
E. Kajantie
Affiliation:
National Institute for Health and Welfare, Helsinki, Finland Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland Helsinki University Central Hospital and University of Helsinki, University of Helsinki, Helsinki, Finland
P. Villa
Affiliation:
Research Programmes Unit, Women's Health, University of Helsinki, Helsinki, Finland Department of Obstetrics and Gynaecology (PV), University of Helsinki and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
H. Laivuori
Affiliation:
Haartman Institute, Medical Genetics, University of Helsinki, Helsinki, Finland
E. Hämäläinen
Affiliation:
HUSLAB and Department of Clinical Chemistry, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
J. R. Seckl
Affiliation:
Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK
R. M. Reynolds
Affiliation:
Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK
*
* Address for correspondence: Professor K. Räikkönen, Institute of Behavioral Sciences, P.O Box 9 (Siltavuorenpenger 1 A), 00014 University of Helsinki, 00029 Helsinki, Finland. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background.

Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and ‘programming’ of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors.

Method.

Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days.

Results.

Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13–0.69, p = 0.005], HSD1B11 (0.30, 0.03–0.57, p = 0.03), NR3C1 (0.44, 0.19–0.68, p = 0.001) and SLC6A4 (0.26, 0.00–0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05).

Conclusions.

Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

Keywords

BehaviourinfantmothermRNAplacentapregnancyprospective
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 15 , November 2015 , pp. 3217 - 3226
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Benediktsson, R, Calder, AA, Edwards, CR, Seckl, JR (1997). Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clinical Endocrinology 46, 161–166.CrossRefGoogle ScholarPubMed
Bonnin, A, Goeden, N, Chen, K, Wilson, ML, King, J, Shih, JC, Blakely, RD, Deneris, ES, Levitt, P (2011). A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350.Google Scholar
Broussard, ER, Hartner, MSS (1971). Further considerations regarding maternal perception of the first born. In Exceptional Infant, Vol. 2, Studies in Abnormalities (ed. Hellmuth, J.), pp. 432–449. Brunner/Mazel: New York.Google Scholar
Conradt, E, Lester, BM, Appleton, AA, Armstrong, DA, Marsit, CJ (2013). The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8, 1321–1329.CrossRefGoogle ScholarPubMed
Cottrell, EC, Seckl, JR (2009). Prenatal stress, glucocorticoids and the programming of adult disease. Frontiers in Nehavioral Neuroscience 3, 19.Google ScholarPubMed
de Vries, A, Holmes, MC, Heijnis, A, Seier, JV, Heerden, J, Louw, J, Wolfe-Coote, S, Meaney, MJ, Levitt, NS, Seckl, JR (2007). Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. Journal of Clinical Investigation 117, 1058–1067.CrossRefGoogle ScholarPubMed
Edwards, CR, Benediktsson, R, Lindsay, RS, Seckl, JR (1993). Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet 341, 355–357.Google Scholar
Glover, V (2011). Annual research review: prenatal stress and the origins of psychopathology: an evolutionary perspective. Journal of Child Psychology and Psychiatry, and Allied Disciplines 52, 356–367.CrossRefGoogle ScholarPubMed
Hayes, AF (2009). Beyond Baron and Kenny: statistical mediation analysis in the new millennium. Communication Monographs 76, 408–420.Google Scholar
Hayes, AF, Preacher, KJ (2014). Statistical mediation analysis with a multicategorical independent variable. British Journal of Mathematical and Statistical Psychology 67, 451–470.Google Scholar
Hemmi, MH, Wolke, D, Schneider, S (2011). Associations between problems with crying, sleeping and/or feeding in infancy and long-term behavioural outcomes in childhood: a meta-analysis. Archives of Disease in Childhood 96, 622–629.Google Scholar
Holmes, MC, Abrahamsen, CT, French, KL, Paterson, JM, Mullins, JJ, Seckl, JR (2006). The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. Journal of Neuroscience 26, 3840–3844.CrossRefGoogle ScholarPubMed
Lindsay, RS, Lindsay, RM, Waddell, B, Seckl, JR (1996 a). Programming of glucose tolerance in the rat: role of placental 11ß-hydroxysteroid dehydrogenase. Diabetologia 39, 1299–1305.Google Scholar
Lindsay, RS, Lindsay, RM, Edwards, CR, Seckl, JR (1996 b). Inhibition of 11-beta-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension 27, 1200–1204.Google Scholar
Liu, L, Li, A, Matthews, SG (2001). Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. American Journal of Physiology, Endocrinology and Metabolism 280, E729–E739.Google Scholar
Moisiadis, VG, Matthews, SG (2014). Glucocorticoids and fetal programming part 2: mechanisms. Nature Reviews Endocrinology 10, 403–411.Google Scholar
Moss, TJ, Sloboda, DM, Gurrin, LC, Harding, R, Challis, JR, Newnham, JP (2001). Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 281, R960–R970.Google Scholar
Murphy, VE, Smith, R, Giles, WB, Clifton, VL (2006). Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocrine Reviews 27, 141–169.CrossRefGoogle ScholarPubMed
Oberlander, TF, Weinberg, J, Papsdorf, M, Grunau, R, Misri, S, Devlin, AM (2008). Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3, 97–106.CrossRefGoogle ScholarPubMed
O'Donnell, KJ, Bugge Jensen, A, Freeman, L, Khalife, N, O'Connor, TG, Glover, V (2012). Maternal prenatal anxiety and downregulation of placental 11beta-HSD2. Psychoneuroendocrinology 37, 818–826.Google Scholar
Pesonen, AK, Raikkonen, K, Lano, A, Peltoniemi, O, Hallman, M, Kari, MA (2009). Antenatal betamethasone and fetal growth in prematurely born children: implications for temperament traits at the age of 2 years. Pediatrics 123, e31–e37.Google Scholar
Ponder, KL, Salisbury, A, McGonnigal, B, Laliberte, A, Lester, B, Padbury, JF (2011). Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. Developmental Psychobiology 53, 711–723.Google Scholar
Radloff, LS (1977). The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1, 385–401.Google Scholar
Räikkönen, K, O'Reilly, JR, Pesonen, AK, Kajantie, E, Villa, P, Laivuori, H, Hämäläinen, E, Seckl, JR, Reynolds, RM (2014). Associations between maternal level of education and occupational status with placental glucocorticoid regeneration and sensitivity. Clinical Endocrinology 81, 175–182.Google Scholar
Räikkönen, K, Seckl, JR, Heinonen, K, Pyhälä, R, Feldt, K, Jones, A, Phillips, DIW, Pesonen, AK, Matthews, KA, Lahti, J, Eriksson, JG, Järvenpää, A-L, Strandberg, TE, Kajantie, E (2010). Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children. Psychoneuroendocrinology 35, 1587–1593.Google Scholar
Ressler, KJ, Nemeroff, CB (2000). Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depression and Anxiety 12 (Suppl. 1), 2–19.Google Scholar
Reynolds, RM, Labad, J, Buss, C, Ghaemmaghami, P, Räikkönen, K (2013). Transmitting biological effects of stress in utero: implications for mother and offspring. Psychoneuroendocrinology 38, 1843–1849.Google Scholar
Reynolds, RM, Pesonen, A, O'Reilly, J, Tuovinen, S, Lahti, M, Kajantie, E, Laivuori, H, Villa, P, Hämäläinen, E, Seckl, JR, Räikkönen, K (2015). Maternal depressive symptoms throughout pregnancy are associated with increased placental glucocorticoid sensitivity. Psychological Medicine 45, 2023–2030.CrossRefGoogle ScholarPubMed
Roseboom, T, de Rooij, S, Painter, R (2006). The Dutch famine and its long-term consequences for adult health. Early Human Development 82, 485–491.CrossRefGoogle ScholarPubMed
Schmid, G, Schreier, A, Meyer, R, Wolke, D (2010). A prospective study on the persistence of infant crying, sleeping and feeding problems and preschool behaviour. Acta Paediatrica 99, 286–290.Google Scholar
Seckl, JR (1998). Physiologic programming of the fetus. Clinics in Perinatology 25, 939–962.CrossRefGoogle ScholarPubMed
Seckl, JR, Holmes, MC (2007). Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nature Clinical Practice. Endocrinology & Metabolism 3, 479–488.CrossRefGoogle ScholarPubMed
Seckl, JR, Meaney, MJ (2004). Glucocorticoid programming. Annals of the New York Academy of Sciences 1032, 63–84.Google Scholar
Tuovinen, S, Räikkönen, K, Kajantie, E, Henriksson, M, Leskinen, JT, Pesonen, AK, Heinonen, K, Lahti, J, Pyhälä, R, Alastalo, H, Lahti, M, Osmond, C, Barker, DJ, Eriksson, JG (2012). Hypertensive disorders in pregnancy and cognitive decline in the offspring up to old age. Neurology 79, 1578–1582.Google Scholar
Villa, PM, Kajantie, E, Räikkönen, K, Pesonen, AK, Hämäläinen, E, Vainio, M, Taipale, P, Laivuori, H, PREDO Study group (2013). Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. British Journal of Obstetrics and Gynaecology 120, 64–74.CrossRefGoogle Scholar
Welberg, LA, Seckl, JR, Holmes, MC (2000). Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. European Journal of Neuroscience 12, 1047–1054.Google Scholar
Wolke, D, Rizzo, P, Woods, S (2002). Persistent infant crying and hyperactivity problems in middle childhood. Pediatrics 109, 1054–1060.Google Scholar
Wolke, D, Schmid, G, Schreier, A, Meyer, R (2009). Crying and feeding problems in infancy and cognitive outcome in preschool children born at risk: a prospective population study. Journal of Developmental and Behavioral Pediatrics 30, 226–238.Google Scholar
Wyrwoll, CS, Holmes, MC (2012). Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways. Neuroendocrinology 95, 47–55.Google Scholar