Skip to main content

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

  • K. Räikkönen (a1), A.-K. Pesonen (a1), J. R. O'Reilly (a2), S. Tuovinen (a1), M. Lahti (a1), E. Kajantie (a3) (a4) (a5), P. Villa (a6) (a7), H. Laivuori (a8), E. Hämäläinen (a9), J. R. Seckl (a2) and R. M. Reynolds (a2)...

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.


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.


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).


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.

Corresponding author
* 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:
Hide All
Benediktsson R, Calder AA, Edwards CR, Seckl JR (1997). Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clinical Endocrinology 46, 161166.
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, 347350.
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. 432449. Brunner/Mazel: New York.
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, 13211329.
Cottrell EC, Seckl JR (2009). Prenatal stress, glucocorticoids and the programming of adult disease. Frontiers in Nehavioral Neuroscience 3, 19.
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, 10581067.
Edwards CR, Benediktsson R, Lindsay RS, Seckl JR (1993). Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet 341, 355357.
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, 356367.
Hayes AF (2009). Beyond Baron and Kenny: statistical mediation analysis in the new millennium. Communication Monographs 76, 408420.
Hayes AF, Preacher KJ (2014). Statistical mediation analysis with a multicategorical independent variable. British Journal of Mathematical and Statistical Psychology 67, 451470.
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, 622629.
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, 38403844.
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, 12991305.
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, 12001204.
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, E729E739.
Moisiadis VG, Matthews SG (2014). Glucocorticoids and fetal programming part 2: mechanisms. Nature Reviews Endocrinology 10, 403411.
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, R960R970.
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, 141169.
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, 97106.
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, 818826.
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, e31e37.
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, 711723.
Radloff LS (1977). The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1, 385401.
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, 175182.
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, 15871593.
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), 219.
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, 18431849.
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, 20232030.
Roseboom T, de Rooij S, Painter R (2006). The Dutch famine and its long-term consequences for adult health. Early Human Development 82, 485491.
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, 286290.
Seckl JR (1998). Physiologic programming of the fetus. Clinics in Perinatology 25, 939962.
Seckl JR, Holmes MC (2007). Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nature Clinical Practice. Endocrinology & Metabolism 3, 479488.
Seckl JR, Meaney MJ (2004). Glucocorticoid programming. Annals of the New York Academy of Sciences 1032, 6384.
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, 15781582.
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, 6474.
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, 10471054.
Wolke D, Rizzo P, Woods S (2002). Persistent infant crying and hyperactivity problems in middle childhood. Pediatrics 109, 10541060.
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, 226238.
Wyrwoll CS, Holmes MC (2012). Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways. Neuroendocrinology 95, 4755.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 21
Total number of PDF views: 103 *
Loading metrics...

Abstract views

Total abstract views: 527 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd February 2018. This data will be updated every 24 hours.