Intergenerational transmission of depression: clinical observations and molecular mechanisms

Abstract

Maternal mental illness can have a devastating effect during the perinatal period, and has a profound impact on the care that the baby receives and on the relationships that the baby forms. This review summarises clinical evidence showing the effects of perinatal depression on offspring physical and behavioural development, and on the transmission of psychopathology between generations. We then evaluate a number of factors which influence this relationship, such as genetic factors, the use of psychotropic medications during pregnancy, the timing within the perinatal period, the sex of the foetus, and exposure to maltreatment in childhood. Finally, we examine recent findings regarding the molecular mechanisms underpinning these clinical observations, and identify relevant epigenetic and biomarker changes in the glucocorticoid, oxytocin, oestrogen and immune systems, as key biological mediators of these clinical findings. By understanding these molecular mechanisms in more detail, we will be able to improve outcomes for both mothers and their offspring for generations.

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References

  1. 1.

    Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry. 2004;49:726–35.

  2. 2.

    Biaggi A, Conroy S, Pawlby S, Pariante CM. Identifying the women at risk of antenatal anxiety and depression: a systematic review. J Affect Disord. 2016;191:62–77.

  3. 3.

    Stein A, Pearson RM, Goodman SH, Rapa E, Rahman A, McCallum M, et al. Effects of perinatal mental disorders on the fetus and child. Lancet. 2014;384:1800–19.

  4. 4.

    Murray L, Kempton C, Woolgar M, Hooper R. Depressed mothers’ speech to their infants and its relation to infant gender and cognitive development. J Child Psychol Psychiatry. 1993;34:1083–101.

  5. 5.

    Sit D, Rothschild AJ, Wisner KL. A review of postpartum psychosis. J Women’s Health (Larchmt). 2006;15:352–68.

  6. 6.

    Feldman R, Granat A, Pariente C, Kanety H, Kuint J, Gilboa-Schechtman E. Maternal depression and anxiety across the postpartum year and infant social engagement, fear regulation, and stress reactivity. J Am Acad Child Adolesc Psychiatry. 2009;48:919–27.

  7. 7.

    Murray L. The Impact of postnatal depression on infant development. J Child Psychol Psychiatry. 1992;33:543–61.

  8. 8.

    Leis JA, Heron J, Stuart EA, Mendelson T. Associations between maternal mental health and child emotional and behavioral problems: Does prenatal mental health matter? J Abnorm Child Psychol. 2014;42:161–71.

  9. 9.

    Evans J, Melotti R, Heron J, Ramchandani P, Wiles N, Murray L, et al. The timing of maternal depressive symptoms and child cognitive development: a longitudinal study. J Child Psychol Psychiatry. 2012;53:632–40.

  10. 10.

    Pearson RM, Evans J, Kounali D, Lewis G, Heron J, Ramchandani PG, et al. Maternal depression during pregnancy and the postnatal period: risks and possible mechanisms for offspring depression at age 18 years. JAMA Psychiatry. 2013;70:1312–9.

  11. 11.

    Barker ED, Jaffee SR, Uher R, Maughan B. The contribution of prenatal and postnatal maternal anxiety and depression to child maladjustment. Depress Anxiety. 2011;28:696–702.

  12. 12.

    Hanington L, Heron J, Stein A, Ramchandani P. Parental depression and child outcomes - is marital conflict the missing link? Child Care Health Dev. 2012;38:520–9.

  13. 13.

    Letourneau NL, Tramonte L, Willms JD. Maternal depression, family functioning and children’s longitudinal development. J Pediatr Nurs. 2013;28:223–34.

  14. 14.

    Naicker K, Wickham M, Colman I, Swartz M, Hemmingsson T. Timing of first exposure to maternal depression and adolescent emotional disorder in a national canadian cohort. PLoS ONE. 2012;7:e33422.

  15. 15.

    Galéra C, Côté SM, Bouvard MP, Pingault J-B, Melchior M, Michel G, et al. Early risk factors for hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years. Arch Gen Psychiatry. 2011;68:1267.

  16. 16.

    Velders FP, Dieleman G, Henrichs J, Jaddoe VWV, Hofman A, Verhulst FC, et al. Prenatal and postnatal psychological symptoms of parents and family functioning: the impact on child emotional and behavioural problems. Eur Child Adolesc Psychiatry. 2011;20:341–50.

  17. 17.

    Van Batenburg-Eddes T, Brion MJJ, Henrichs J, Jaddoe VWVW V, Hofman A, Verhulst FCC, et al. Parental depressive and anxiety symptoms during pregnancy and attention problems in children: a cross-cohort consistency study. J Child Psychol Psychiatry Allied Discip. 2013;54:591–600.

  18. 18.

    Tharner A, Luijk MPCM, van IJzendoorn MH, Bakermans-Kranenburg MJ, Jaddoe VWV, et al. Maternal lifetime history of depression and depressive symptoms in the prenatal and early postnatal period do not predict infant–mother attachment quality in a large, population-based Dutch cohort study. Attach Hum Dev. 2012;14:63–81.

  19. 19.

    Verbeek T, Bockting CLH, van Pampus MG, Ormel J, Meijer JL, Hartman CA, et al. Postpartum depression predicts offspring mental health problems in adolescence independently of parental lifetime psychopathology. J Affect Disord. 2012;136:948–54.

  20. 20.

    Kersten-Alvarez LE, Hosman CMH, Riksen-Walraven JM, van Doesum KTM, Smeekens S, Hoefnagels C. Early school outcomes for children of postpartum depressed mothers: comparison with a community sample. Child Psychiatry Hum Dev. 2012;43:201–18.

  21. 21.

    Hartley C, Pretorius K, Mohamed A, Laughton B, Madhi S, Cotton MF, et al. Maternal postpartum depression and infant social withdrawal among human immunodeficiency virus (HIV) positive mother–infant dyads. Psychol Health Med. 2010;15:278–87.

  22. 22.

    Noorlander Y, Bergink V, Van Den, Berg MP. Perceived and observed mother-child interaction at time of hospitalization and release in postpartum depression and psychosis. Arch Women’s Ment Health. 2008;11:49–56.

  23. 23.

    Hornstein C, Trautmann-Villalba P, Hohm E, Rave E, Wortmann-Fleischer S, Schwarz M. Maternal bond and mother-child interaction in severe postpartum psychiatric disorders: is there a link? Arch Women’s Ment Health. 2006;9:279–84.

  24. 24.

    Chandra PS, Bhargavaraman RP, VNGP Raghunandan, Shaligram D. Delusions related to infant and their association with mother-infant interactions in postpartum psychotic disorders. Arch Women’s Ment Health. 2006;9:285–8.

  25. 25.

    Pawlby S, Hay DF, Sharp D, Waters CS, O’Keane V. Antenatal depression predicts depression in adolescent offspring: Prospective longitudinal community-based study. J Affect Disord. 2009;113:236–43.

  26. 26.

    O'Donnell KJ, Glover V, Barker ED, O'Connor TG. The persisting effect of maternal mood in pregnancy on childhood psychopathology. 2017. https://doi.org/10.1017/S0954579414000029.

  27. 27.

    Plant DT, Pariante CM, Sharp D, Pawlby S. Maternal depression during pregnancy and offspring depression in adulthood: Role of child maltreatment. Br J Psychiatry. 2015;207:213–20.

  28. 28.

    Hay DF, Pawlby S, Waters CS, Sharp D. Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes. J Child Psychol Psychiatry. 2008;49:1079–88.

  29. 29.

    Capron LE, Glover V, Pearson RM, Evans J, O’Connor TG, Stein A, et al. Associations of maternal and paternal antenatal mood with offspring anxiety disorder at age 18 years. J Affect Disord. 2015;187:20–6.

  30. 30.

    Munhoz TN, Santos IS, Barros AJD, Anselmi L, Barros FC, Matijasevich A. Perinatal and postnatal risk factors for disruptive mood dysregulation disorder at age 11: 2004 Pelotas Birth Cohort Study. J Affect Disord. 2017;215:263–8.

  31. 31.

    Lovejoy MC, Graczyk PA, O’Hare E, Neuman G. Maternal depression and parenting behavior: a meta-analytic review. Clin Psychol Rev. 2000;20:561–92.

  32. 32.

    Jaser SS, Fear JM, Reeslund KL, Champion JE, Reising MM, Compas BE. Maternal sadness and adolescents’ responses to stress in offspring of mothers with and without a history of depression. J Clin Child Adolesc Psychol. 2008;37:736–46.

  33. 33.

    Brennan PA, Le Brocque R, Hammen C. Maternal depression, parent-child relationships, and resilient outcomes in adolescence. J Am Acad Child Adolesc Psychiatry. 2003;42:1469–77.

  34. 34.

    Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin L, et al. Preterm birth and psychiatric disorders in young adult life. Arch Gen Psychiatry. 2012;69:E1–8.

  35. 35.

    Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry. 2010;67:1012–24.

  36. 36.

    Jarde A, Morais M, Kingston D, Giallo R, MacQueen GM, Giglia L, et al. Neonatal outcomes in women with untreated antenatal depression compared with women without depression. JAMA Psychiatry. 2016;73:826.

  37. 37.

    O’Donnell KJ, Meaney MJ. Fetal origins of mental health: the developmental origins of health and disease hypothesis. Am J Psychiatry. 2017;174:319–28.

  38. 38.

    Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish National Twin Study of Lifetime Major Depression. Am J Psychiatry J Psychiatry. 2006;1631:109–14.

  39. 39.

    Reising MM, Watson KH, Hardcastle EJ, Merchant MJ, Roberts L, Forehand R, et al. Parental depression and economic disadvantage: the role of parenting in associations with internalizing and externalizing symptoms in children and adolescents. J Child Fam Stud. 2013;22. https://doi.org/10.1007/s10826-012-9582-4.

  40. 40.

    Couto TCE, Brancaglion MYM, Alvim-Soares A, Moreira L, Garcia FD, Nicolato R, et al. Postpartum depression: a systematic review of the genetics involved. World J Psychiatry. 2015;5:103–11.

  41. 41.

    Mahon PB, Payne JL, MacKinnon DF, Mondimore FM, Goes FS, Schweizer B, et al. Genome-wide linkage and follow-up association study of postpartum mood symptoms. Am J Psychiatry. 2009;166:1229–37.

  42. 42.

    Viktorin A, Meltzer-Brody S, Kuja-Halkola R, Sullivan PF, Landén M, Lichtenstein P, et al. Heritability of perinatal depression and genetic overlap with nonperinatal depression. Am J Psychiatry. 2016;173:158–65.

  43. 43.

    Rice F, Harold GT, Boivin J, van den Bree M, Hay DF, Thapar A. The links between prenatal stress and offspring development and psychopathology: disentangling environmental and inherited influences. Psychol Med. 2010;40:335–45.

  44. 44.

    Nomura Y, Wickramaratne PJ, Pilowsky DJ, Newcorn JH, Bruder-Costello B, Davey C, et al. Low birth weight and risk of affective disorders and selected medical illness in offspring at high and low risk for depression. Compr Psychiatry. 2007;48:470–8.

  45. 45.

    Pluess M, Velders FP, Belsky J, van IJzendoorn MH, Bakermans-Kranenburg MJ, Jaddoe VWV, et al. Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biol Psychiatry. 2011;69:520–5.

  46. 46.

    Wazana A, Moss E, Jolicoeur-Martineau A, Graffi J, Tsabari G, Lecompte V, et al. The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age. Dev Psychopathol. 2015;27:1145–61.

  47. 47.

    Qiu A, Shen M, Buss C, Chong Y-S, Kwek K, Saw S-M, et al. Effects of antenatal maternal depressive symptoms and socio-economic status on neonatal brain development are modulated by genetic risk. Cereb Cortex. 2017;27:3080–92.

  48. 48.

    Silveira PP, Pokhvisneva I, Parent C, Cai S, Rema ASS, Broekman BFP, et al. Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression. Dev Psychopathol. 2017;29:1601–17.

  49. 49.

    Belsky J, Pokhvisneva I, Rema ASS, Broekman BFP, Pluess M, O’Donnell KJ, et al. Polygenic differential susceptibility to prenatal adversity. Dev Psychopathol. 2018;7:1–3.

  50. 50.

    Cattaneo A, Cattane N, Malpighi C, Czamara D, Suarez A, Mariani N, et al. FoxO1, A2M, and TGF-β1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses. Mol Psychiatry. 2018;4:1.

  51. 51.

    Pawlby S, Hay D, Sharp D, Cerith SW, Pariante CM. Antenatal depression and offspring psychopathology: the influence of childhood maltreatment. Br J Psychiatry. 2011;199:106–12.

  52. 52.

    Plant DT, Barker ED, Waters CS, Pawlby S, Pariante CM. Intergenerational transmission of maltreatment and psychopathology: the role of antenatal depression. Psychol Med. 2013;43:519–28.

  53. 53.

    Lereya ST, Wolke D. Prenatal family adversity and maternal mental health and vulnerability to peer victimisation at school. J Child Psychol Psychiatry. 2013;54:644–52.

  54. 54.

    Paulzen M, Goecke TW, Stickeler E, Gründer G, Schoretsanitis G. Sertraline in pregnancy – therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood. J Affect Disord. 2017;212:1–6.

  55. 55.

    Koren G. SSRIs in pregnancy--are they safe? Pediatr Res. 2002;51:424–5.

  56. 56.

    Bakker MK, Kölling P, van den Berg PB, de Walle HEK, de Jong van den Berg LTW. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands. Br J Clin Pharmacol. 2008;65:600–6.

  57. 57.

    Cooper WO, Willy ME, Pont SJ, Ray WA, Pirraglia PA, Stafford RS, et al. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007;196:544.e1–5.

  58. 58.

    Mcallister-Williams RH, Baldwin DS, Cantwell R. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol Hampsh Perinat Ment Heal Serv. 2017. https://doi.org/10.1177/0269881117699361.

  59. 59.

    Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G, Dennis C-L, Koren G, et al. The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry. 2013;74:e321–41.

  60. 60.

    Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study. Br J Psychiatry. 2008;192:338–43.

  61. 61.

    Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005;293:2372–83.

  62. 62.

    Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med. 2006;160:173–6.

  63. 63.

    Galbally M, Lewis AJ, Lum J, Buist A. Serotonin discontinuation syndrome following in utero exposure to antidepressant medication: prospective controlled study. Aust N Z J Psychiatry. 2009;43:846–54.

  64. 64.

    Monk C, Fitelson EM, Werner E. Mood disorders and their pharmacological treatment during pregnancy: Is the future child affected? Pediatr Res. 2011;69:3R–10.

  65. 65.

    Van den Bergh BRH, Mulder EJH, Mennes M, Glover V. Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neurosci Biobehav Rev. 2005;29:237–58.

  66. 66.

    Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003;142:402–8.

  67. 67.

    Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatrics. 2010;125:e600–8.

  68. 68.

    Previti G, Pawlby S, Chowdhury S, Aguglia E, Pariante CM. Neurodevelopmental outcome for offspring of women treated for antenatal depression: a systematic review. Arch Women’s Ment Health. 2014;17:471–83.

  69. 69.

    Austin M-P, Karatas JC, Mishra P, Christl B, Kennedy D, Oei J. Infant neurodevelopment following in utero exposure to antidepressant medication. Acta Paediatr. 2013;102:n/a–n/a.

  70. 70.

    Nulman I, Koren G, Rovet J, Barrera M, Pulver A, Streiner D, et al. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012;169:1165–74.

  71. 71.

    Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499.

  72. 72.

    Robertson E, Grace S, Wallington T, Stewart DE. Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry. 2004;26:289–95.

  73. 73.

    Payne JL. Psychopharmacology in pregnancy and breastfeeding. Psychiatr Clin North Am. 2017;40:217–38.

  74. 74.

    Pariante CM. Depression and antidepressants in pregnancy: Molecular and psychosocial mechanisms affecting offspring’s physical and mental health. Neuropsychopharmacology. 2015;40:246–7.

  75. 75.

    Ornoy A. Neurobehavioral risks of SSRIs in pregnancy: comparing human and animal data. Reprod Toxicol. 2017. https://doi.org/10.1016/j.reprotox.2017.05.003.

  76. 76.

    Latendresse G, Elmore C, Deneris A. Selective serotonin reuptake inhibitors as first-line antidepressant therapy for perinatal depression. J Midwifery Womens Health. 2017. https://doi.org/10.1111/jmwh.12607.

  77. 77.

    Newman L, Judd F, Olsson CA, Castle D, Bousman C, Sheehan P, et al. Early origins of mental disorder - risk factors in the perinatal and infant period. BMC Psychiatry. 2016;16:270.

  78. 78.

    Champagne FA. Epigenetic mechanisms and the transgenerational effects of maternal care. Front Neuroendocrinol. 2008;29:386–97.

  79. 79.

    Bowers ME, Yehuda R. Intergenerational Transmission of Stress in Humans. Neuropsychopharmacology. 2016;41:232–44.

  80. 80.

    Essex MJ, Boyce WT, Hertzman C, Lam LL, Armstrong JM, Neumann SMA, et al. Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. Child Dev. 2013;84:58–75.

  81. 81.

    Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54.

  82. 82.

    Champagne FA, Weaver ICG, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006;147:2909–15.

  83. 83.

    Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010;68:408–15.

  84. 84.

    Szyf M, Bick J. DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev. 2013;84:49–57.

  85. 85.

    Sureshchandra S, Wilson RM, Rais M, Marshall NE, Purnell JQ, Thornburg KL, et al. Maternal pregravid obesity remodels the dna methylation landscape of cord blood monocytes disrupting their inflammatory program. J Immunol. 2017;199:2729–44.

  86. 86.

    van Otterdijk SD, Binder AM, Michels KB. Locus-specific DNA methylation in the placenta is associated with levels of pro-inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy. Epigenetics. 2017;12:875–85.

  87. 87.

    Schlinzig T, Johansson S, Gunnar A, Ekström T, Norman M. Epigenetic modulation at birth - altered DNA-methylation in white blood cells after Caesarean section. Acta Paediatr. 2009;98:1096–9.

  88. 88.

    Toth M. Mechanisms of non-genetic inheritance and psychiatric disorders. Neuropsychopharmacology. 2015;40:129–40.

  89. 89.

    Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75:324–31.

  90. 90.

    Seckl JR. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol. 2001;185:61–71.

  91. 91.

    Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol. 2004;151(Suppl 3):U49–62.

  92. 92.

    Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nat Clin Pract Endocrinol Metab. 2007;3:479–88.

  93. 93.

    Cottrell EC, Seckl J. Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci. 2009;3:19.

  94. 94.

    Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis – 2012 Curt Richter Award Winner. Psychoneuroendocrinology. 2013;38:1–11.

  95. 95.

    Moisiadis VG, Matthews SG. Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol. 2014;10:391–402.

  96. 96.

    Moisiadis VG, Matthews SG. Glucocorticoids and fetal programming part 2: mechanisms. Nat Rev Endocrinol. 2014;10:403–11.

  97. 97.

    Glover V. Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms. Adv Neurobiol. 2015;10:269–83.

  98. 98.

    Rich-Edwards JW, Mohllajee AP, Kleinman K, Hacker MR, Majzoub J, Wright RJ, et al. Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression. J Clin Endocrinol Metab. 2008;93:1946–51.

  99. 99.

    O’Connor TG, Tang W, Gilchrist MA, Moynihan JA, Pressman EK, Blackmore ER. Diurnal cortisol patterns and psychiatric symptoms in pregnancy: short-term longitudinal study. Biol Psychol. 2014;96:35–41.

  100. 100.

    O’Keane V, Lightman S, Marsh M, Pawlby S, Papadopoulos AS, Taylor A, et al. Increased pituitary-adrenal activation and shortened gestation in a sample of depressed pregnant women: a pilot study. J Affect Disord. 2011;130:300–5.

  101. 101.

    Gutteling BM, de Weerth C, Buitelaar JK. Short communicationmaternal prenatal stress and 4–6 year old children’s salivary cortisol concentrations pre- and post-vaccination. Stress. 2004;7:257–60.

  102. 102.

    Gutteling BM, Weerth C, de, Buitelaar JK. Prenatal stress and children’s cortisol reaction to the first day of school. Psychoneuroendocrinology. 2005;30:541–9.

  103. 103.

    O’Connor TG, Bergman K, Sarkar P, Glover V. Prenatal cortisol exposure predicts infant cortisol response to acute stress. Dev Psychobiol. 2013;55:145–55.

  104. 104.

    Huizink AC, Robles de Medina PG, Mulder EJH, Visser GHA, Buitelaar JK. Stress during pregnancy is associated with developmental outcome in infancy. J Child Psychol Psychiatry. 2003;44:810–8.

  105. 105.

    de Weerth C, van Hees Y, Buitelaar JK. Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Hum Dev. 2003;74:139–51.

  106. 106.

    DAVIS EP, Glynn LM, SCHETTER CD, Hobel C, CHICZ-DEMET A, SANDMAN CA. Prenatal exposure to maternal depression and cortisol influences infant temperament. J Am Acad Child Adolesc Psychiatry. 2007;46:737–46.

  107. 107.

    Davis EP, Sandman CA. The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development. Child Dev. 2010;81:131–48.

  108. 108.

    O’Donnell KJ, Glover V, Jenkins J, Browne D, Ben-Shlomo Y, Golding J, et al. Prenatal maternal mood is associated with altered diurnal cortisol in adolescence. Psychoneuroendocrinology. 2013;38:1630–8.

  109. 109.

    Weinstock M. The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav Immun. 2005;19:296–308.

  110. 110.

    Cottrell EC, Seckl JR. Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci. 2009;3:19.

  111. 111.

    Pariante CM. Depression during pregnancy: molecular regulations of mothers’ and children’s behaviour. Biochem Soc Trans. 2014;42:582–6.

  112. 112.

    Saif Z, Hodyl NA, Hobbs E, Tuck AR, Butler MS, Osei-Kumah A, et al. The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma. Placenta. 2014;35:260–8.

  113. 113.

    Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry. 2016;79:87–96.

  114. 114.

    Smart C, Strathdee G, Watson S, Murgatroyd C, McAllister-Williams RH. Early life trauma, depression and the glucocorticoid receptor gene – an epigenetic perspective. Psychol Med. 2015;45:3393–410.

  115. 115.

    Chen ES, Ernst C, Turecki G. The epigenetic effects of antidepressant treatment on human prefrontal cortex BDNF expression. Int J Neuropsychopharmacol. 2011;14:427–9.

  116. 116.

    Alt SR, Turner JD, Klok MD, Meijer OC, EAJF Lakke, DeRijk RH, et al. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed. Psychoneuroendocrinology. 2010;35:544–56.

  117. 117.

    McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12:342–8.

  118. 118.

    Ewald ER, Wand GS, Seifuddin F, Yang X, Tamashiro KL, Potash JB, et al. Alterations in DNA methylation of Fkbp5 as a determinant of blood–brain correlation of glucocorticoid exposure. Psychoneuroendocrinology. 2014;44:112–22.

  119. 119.

    Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33–41.

  120. 120.

    Walton E, Hass J, Liu J, Roffman JL, Bernardoni F, Roessner V, et al. Correspondence of DNA methylation between blood and brain tissue and its application to schizophrenia research. Schizophr Bull. 2016;42:406–14.

  121. 121.

    Mulligan C, D’Errico N, Stees J, Hughes D. Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics. 2012;7:853–7.

  122. 122.

    Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, et al. Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry. 2011;1:e21.

  123. 123.

    Katz ER, Stowe ZN, Newport DJ, Kelley ME, Pace TW, Cubells JF, et al. Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy. Psychol Med. 2012;42:943–56.

  124. 124.

    Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997;277:1659–62.

  125. 125.

    Laplante P, Diorio J, Meaney MJ. Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor. Brain Res Dev Brain Res. 2002;139:199–203.

  126. 126.

    Weaver ICG, D’Alessio AC, Brown SE, Hellstrom IC, Dymov S, Sharma S, et al. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J Neurosci. 2007;27:1756–68.

  127. 127.

    Anacker C, Cattaneo A, Luoni A, Musaelyan K, Zunszain PA, Milanesi E, et al. Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacology. 2013;38:872–83.

  128. 128.

    Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci. 2013;110:8708–13.

  129. 129.

    Seth S, Lewis AJ, Saffery R, Lappas M, Galbally M. Maternal prenatal mental health and placental 11β-hsd2 gene expression: initial findings from the mercy pregnancy and emotional wellbeing study. Int J Mol Sci. 2015;16:27482–96.

  130. 130.

    O’Donnell KJ, Bugge Jensen A, Freeman L, Khalife N, O’Connor TG, Glover V. Maternal prenatal anxiety and downregulation of placental 11β-HSD2. Psychoneuroendocrinology. 2012;37:818–26.

  131. 131.

    Mikelson C, Kovach MJ, Troisi J, Symes S, Adair D, Miller RK, et al. Placental 11β-Hydroxysteroid dehydrogenase type 2 expression: Correlations with birth weight and placental metal concentrations. Placenta. 2015;36:1212–7.

  132. 132.

    Holmes MC, Abrahamsen CT, French KL, Paterson JM, Mullins JJ, Seckl JR. The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci. 2006;26:3840–4.

  133. 133.

    Welberg LAM, Seckl JR, Holmes MC. Inhibition of 11β-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci. 2000;12:1047–54.

  134. 134.

    Montano MM, Wang MH. vom Saal FS. Sex differences in plasma corticosterone in mouse fetuses are mediated by differential placental transport from the mother and eliminated by maternal adrenalectomy or stress. J Reprod Fertil. 1993;99:283–90.

  135. 135.

    Lester BM, Marsit CJ, Giarraputo J, Hawes K, LaGasse LL, Padbury JF. Neurobehavior related to epigenetic differences in preterm infants. Epigenomics. 2015;7:1123–36.

  136. 136.

    Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP. Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab. 1996;81:1912–7.

  137. 137.

    Pariante CM, Nemeroff CB Unipolar depression. In: Handbook of clinical neurology. Elsevier, Amsterdam, The Netherlands 2012. pp 239–49.

  138. 138.

    Engineer N, Darwin L, Nishigandh D, Ngianga-Bakwin K, Smith SC, Grammatopoulos DK. Association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants and risk for depression during pregnancy and post-partum. J Psychiatr Res. 2013;47:1166–73.

  139. 139.

    Stergiakouli E, JAC Sterne, Smith GD. Letter toeditor: Failure to replicate the association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants with risk of depression during pregnancy and post-partum reported by Engineer et al. (2013). J Psychiatr Res. 2014;56:168–70.

  140. 140.

    Li XQ, Zhu P, Myatt L, Sun K. Roles of glucocorticoids in human parturition: a controversial fact? Placenta. 2014;35:291–6.

  141. 141.

    Sasaki A, Liotta AS, Luckey MM, Margioris AN, Suda T, Krieger DT. Immunoreactive corticotropin-releasing factor is present in human maternal plasma during the third trimester of pregnancy. J Clin Endocrinol Metab. 1984;59:812–4.

  142. 142.

    Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialog- Clin Neurosci. 2011;13:89–100.

  143. 143.

    Osborne S, Biaggi A, Chua TE, Du Preez A, Hazelgrove K, Nikkheslat N, et al. Antenatal depression programs cortisol stress reactivity in offspring through increased maternal inflammation and cortisol in pregnancy: The Psychiatry Research and Motherhood - Depression (PRAM-D) Study. Psychoneuroendocrinology. 2018. https://doi.org/10.1016/j.psyneuen.2018.06.017.

  144. 144.

    Sandman CA, Wadhwa P, Glynn L, Chicz-Demet A, Porto M, Garite TJ. Corticotrophin-releasing hormone and fetal responses in human pregnancy. Ann N Y Acad Sci. 1999;897:66–75.

  145. 145.

    Alves E, Fielder A, Ghabriel N, Sawyer M, Buisman-Pijlman FTA. Early social environment affects the endogenous oxytocin system: a review and future directions. Front Endocrinol (Lausanne). 2015;6:32.

  146. 146.

    Feldman R, Weller A, Zagoory-Sharon O, Levine A. Evidence for a neuroendocrinological foundation of human affiliation: plasma oxytocin levels across pregnancy and the postpartum period predict mother-infant bonding. Psychol Sci. 2007;18:965–70.

  147. 147.

    Eapen V, Dadds M, Barnett B, Kohlhoff J, Khan F, Radom N, et al. Separation anxiety, attachment and inter-personal representations: disentangling the role of oxytocin in the perinatal period. PLoS ONE. 2014;9:e107745.

  148. 148.

    Skrundz M, Bolten M, Nast I, Hellhammer DH, Meinlschmidt G. Plasma oxytocin concentration during pregnancy is associated with development of postpartum depression. Neuropsychopharmacology. 2011;36:1886–93.

  149. 149.

    Mileva-Seitz V, Steiner M, Atkinson L, Meaney MJ, Levitan R, Kennedy JL, et al. Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood. PLoS ONE. 2013;8:e61443.

  150. 150.

    Mah BL, Bakermans-Kranenburg MJ, Van IJzendoorn MH, Smith R. Oxytocin promotes protective behavior in depressed mothers: a pilot study with the enthusiastic stranger paradigm. Depress Anxiety. 2015;32:76–81.

  151. 151.

    Mah BL, Van Ijzendoorn MH, Out D, Smith R, Bakermans-Kranenburg MJ. The effects of intranasal oxytocin administration on sensitive caregiving in mothers with postnatal depression. Child Psychiatry Hum Dev. 2017;48:308–15.

  152. 152.

    Mah BL. Oxytocin, postnatal depression, and parenting. Harv Rev Psychiatry. 2016;24:1–13.

  153. 153.

    Kroll-Desrosiers AR, Nephew BC, Babb JA, Guilarte-Walker Y, Moore Simas TA, Deligiannidis KM. Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year. Depress Anxiety. 2017;34:137–46.

  154. 154.

    Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79:243–50.

  155. 155.

    Feldman R, Gordon I, Influs M, Gutbir T, Ebstein RP. Parental oxytocin and early caregiving jointly shape children’s oxytocin response and social reciprocity. Neuropsychopharmacology. 2013;38:1154–62.

  156. 156.

    Pratt M, Apter-Levi Y, Vakart A, Feldman M, Fishman R, Feldman T, et al. Maternal depression and child oxytocin response; moderation by maternal oxytocin and relational behavior. Depress Anxiety. 2015;32:635–46.

  157. 157.

    Feldman R, Gordon I, Influs M, Gutbir T, Ebstein RP. Parental oxytocin and early caregiving jointly shape children’s oxytocin response and social reciprocity. Neuropsychopharmacology. 2013;38:1154–62.

  158. 158.

    Atzil S, Hendler T, Feldman R. Specifying the neurobiological basis of human attachment: brain, hormones, and behavior in synchronous and intrusive mothers. Neuropsychopharmacology. 2011;36:2603–15.

  159. 159.

    Strathearn L, Fonagy P, Amico J, Montague PR. Adult attachment predicts maternal brain and oxytocin response to infant cues. Neuropsychopharmacology. 2009;34:2655–66.

  160. 160.

    Heim C, Young LJ, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol Psychiatry. 2009;14:954–8.

  161. 161.

    Smearman EL, Almli LM, Conneely KN, Brody GH, Sales JM, Bradley B, et al. Oxytocin receptor genetic and epigenetic variations: association with child abuse and adult psychiatric symptoms. Child Dev. 2016;87:122–34.

  162. 162.

    Kimmel M, Clive M, Gispen F, Guintivano J, Brown T, Cox O, et al. Oxytocin receptor DNA methylation in postpartum depression. Psychoneuroendocrinology. 2016;69:150–60.

  163. 163.

    Unternaehrer E, Bolten M, Nast I, Staehli S, Meyer AH, Dempster E, et al. Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Soc Cogn Affect Neurosci. 2016;11:1460–70.

  164. 164.

    Cecil CAM, Lysenko LJ, Jaffee SR, Pingault J-B, Smith RG, Relton CL, et al. Environmental risk, oxytocin receptor gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry. 2014;19:1071–7.

  165. 165.

    Unternaehrer E, Luers P, Mill J, Dempster E, Meyer AH, Staehli S, et al. Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF) after acute psychosocial stress. Transl Psychiatry. 2012;2:e150.

  166. 166.

    Henriques TP, Szawka RE, Diehl LA, de Souza MA, Corrêa CN, Aranda BCC, et al. Stress in neonatal rats with different maternal care backgrounds: monoaminergic and hormonal responses. Neurochem Res. 2014;39:2351–9.

  167. 167.

    Champagne FA, Meaney MJ. Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol Psychiatry. 2006;59:1227–35.

  168. 168.

    Sabihi S, Dong SM, Durosko NE, Leuner B. Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period. Front Behav Neurosci. 2014;8:258.

  169. 169.

    Bale TL, Davis AM, Auger AP, Dorsa DM, Mccarthy MM. CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior. http://www.jneurosci.org/content/jneuro/21/7/2546.full.pdf. Accessed 19 Mar 2017.

  170. 170.

    Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry. 2000;157:924–30.

  171. 171.

    Mehta D, Newport DJ, Frishman G, Kraus L, Rex-Haffner M, Ritchie JC, et al. Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling. Psychol Med. 2014;44:2309–22.

  172. 172.

    Guintivano J, Arad M, Gould TD, Payne JL, Kaminsky ZA. Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol Psychiatry. 2014;19:560–7.

  173. 173.

    Mccarthy MM, McDonald CH, Brooks PJ, Goldman D. An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav. 1996;60:1209–15.

  174. 174.

    Young LJ, Wang Z, Donaldson R, Rissman EF. Estrogen receptor alpha is essential for induction of oxytocin receptor by estrogen. Neuroreport. 1998;9:933–6.

  175. 175.

    Champagne F, Diorio J, Sharma S, Meaney MJ. Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci USA. 2001;98:12736–41.

  176. 176.

    Qiu A, Anh TT, Li Y, Chen H, Rifkin-Graboi A, Broekman BFP, et al. Prenatal maternal depression alters amygdala functional connectivity in 6-month-old infants. Transl Psychiatry. 2015;5:e508.

  177. 177.

    Soe NN, Wen DJ, Poh JS, Chong Y-S, Broekman BF, Chen H, et al. Perinatal maternal depressive symptoms alter amygdala functional connectivity in girls. Hum Brain Mapp. 2017. https://doi.org/10.1002/hbm.23873.

  178. 178.

    Buss C, Davis EP, Muftuler LT, Head K, Sandman CA. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6–9-year-old children. Psychoneuroendocrinology. 2010;35:141–53.

  179. 179.

    Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710.

  180. 180.

    Sandman CA, Buss C, Head K, Davis EP. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biol Psychiatry. 2015;77:324–34.

  181. 181.

    Field T, Diego M, Dieter J, Hernandez-Reif M, Schanberg S, Kuhn C, et al. Prenatal depression effects on the fetus and the newborn. Infant Behav Dev. 2004;27:216–29.

  182. 182.

    Belovicova K, Bogi E, Koprdova R, Ujhazy E, Mach M, Dubovicky M. Effects of venlafaxine and chronic unpredictable stress on behavior and hippocampal neurogenesis of rat dams. Neuro Endocrinol Lett. 2017;38:19–26.

  183. 183.

    Talati A, Odgerel Z, Wickramaratne PJ, Weissman MM. Brain derived neurotrophic factor moderates associations between maternal smoking during pregnancy and offspring behavioral disorders. Psychiatry Res. 2016;245:387–91.

  184. 184.

    Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, et al. candidate genes expression profile associated with antidepressants response in the GENDEP Study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology. 2013;38:377–85.

  185. 185.

    Van den Hove DLA, Steinbusch HWM, Scheepens A, Van de Berg WDJ, Kooiman LAM, Boosten BJG, et al. Prenatal stress and neonatal rat brain development. Neuroscience. 2006;137:145–55.

  186. 186.

    Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry. 2002;7:609–16.

  187. 187.

    Wang Q, Shao F, Wang W. Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats. Front Mol Neurosci. 2015;8:49.

  188. 188.

    Leff-Gelman P, Mancilla-Herrera I, Flores-Ramos M, Cruz-Fuentes C, Reyes-Grajeda JP, García-Cuétara MDP, et al. The immune system and the role of inflammation in perinatal depression. Neurosci Bull. 016;32:398–420.

  189. 189.

    Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37:137–62.

  190. 190.

    Krause D, Jobst A, Kirchberg F, Kieper S, Härtl K, Kästner R, et al. Prenatal immunologic predictors of postpartum depressive symptoms: a prospective study for potential diagnostic markers. Eur Arch Psychiatry Clin Neurosci. 2014;264. https://doi.org/10.1007/s00406-014-0494-8.

  191. 191.

    Danese A, Caspi A, Williams B, Ambler A, Sugden K, Mika J, et al. Biological embedding of stress through inflammation processes in childhood. Mol Psychiatry. 2011;16:244–6.

  192. 192.

    Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, et al. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013;148:136–40.

  193. 193.

    Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, et al. Transcriptomics in interferon-α-treated patients identifies inflammation-, neuroplasticity- and oxidative stress-related signatures as predictors and correlates of depression. Neuropsychopharmacology. 2016;41:2502–11.

  194. 194.

    Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:409–15.

  195. 195.

    Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.

  196. 196.

    Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–52.

  197. 197.

    Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci. 2007;104:1319–24.

  198. 198.

    Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2016;21:642–9.

  199. 199.

    Pace TWW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–3.

  200. 200.

    Du Preez A, Leveson J, Zunszain PA, Pariante CM. Inflammatory insults and mental health consequences: does timing matter when it comes to depression? Psychol Med. 2016;46:2041–57.

  201. 201.

    Christian LM. Effects of stress and depression on inflammatory immune parameters in pregnancy. Am J Obstet Gynecol. 2014;211:275–7.

  202. 202.

    Corwin EJ, Pajer K, Paul S, Lowe N, Weber M, McCarthy DO. Bidirectional psychoneuroimmune interactions in the early postpartum period influence risk of postpartum depression. Brain Behav Immun. 2015;49:86–93.

  203. 203.

    Walsh K, Basu A, Werner E, Lee S, Feng T, Osborne LM, et al. Associations among child abuse, depression, and interleukin-6 in pregnant adolescents. Psychosom Med. 2016;78:920–30.

  204. 204.

    Shelton MM, Schminkey DL, Groer MW. Relationships among prenatal depression, plasma cortisol, and inflammatory cytokines. Biol Res Nurs. 2015;17:295–302.

  205. 205.

    Edvinsson Å, Bränn E, Hellgren C, Freyhult E, White R, Kamali-Moghaddam M, et al. Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction. Psychoneuroendocrinology. 2017;80:15–25.

  206. 206.

    Graham AM, Rasmussen JM, Rudolph MD, Heim CM, Gilmore JH, Styner M, et al. Maternal systemic interleukin-6 during pregnancy is associated with newborn amygdala phenotypes and subsequent behavior at 2 years of age. Biol Psychiatry. 2018;83:109–19.

  207. 207.

    Mondelli V, Cattaneo A, Murri MB, Di Forti M, Handley R, Hepgul N, et al. Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis. J Clin Psychiatry. 2011;72:1677–84.

  208. 208.

    Mondelli V, Ciufolini S, Belvederi Murri M, Bonaccorso S, Di Forti M, Giordano A, et al. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr Bull. 2015;41:1162–70.

  209. 209.

    Bergink V, Burgerhout KM, Weigelt K, Pop VJ, de Wit H, Drexhage RC, et al. Immune system dysregulation in first-onset postpartum psychosis. Biol Psychiatry. 2013;73:1000–7.

  210. 210.

    Veen C, Myint AM, Burgerhout KM, Schwarz MJ, Schütze G, Kushner SA, et al. Tryptophan pathway alterations in the postpartum period and in acute postpartum psychosis and depression. J Affect Disord. 2016;189:298–305.

  211. 211.

    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

  212. 212.

    Wirleitner B, Neurauter G, Schröcksnadel K, Frick B, Fuchs D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem. 2003;10:1581–91.

  213. 213.

    Badawy AA-B. Tryptophan metabolism, disposition and utilization in pregnancy. Biosci Rep. 2015;35. https://doi.org/10.1042/BSR20150197.

  214. 214.

    Widner B, Ledochowski M, Fuchs D. Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences. Curr Drug Metab. 2000;1:193–204.

  215. 215.

    Cattaneo A, Macchi F, Plazzotta G, Veronica B, Bocchio-Chiavetto L, Riva MA, et al. Inflammation and neuronal plasticity: a link between childhood trauma and depression pathogenesis. Front Cell Neurosci. 2015;9:40.

  216. 216.

    Plant DT, Pawlby S, Sharp D, Zunszain PA, Pariante CM. Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study. Transl Psychiatry. 2016;6:e936.

  217. 217.

    Su K-P, Huang S-Y, Chiu T-H, Huang K-C, Huang C-L, Chang H-C, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69:644–51.

  218. 218.

    Mozurkewich EL, Clinton CM, Chilimigras JL, Hamilton SE, Allbaugh LJ, Berman DR, et al. The mothers, omega-3, and Mental Health Study: a double-blind, randomized controlled trial. Am J Obstet Gynecol. 2013;208:313.e1–313.e9.

  219. 219.

    Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, Ryan P, et al. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children. JAMA. 2010;304:1675.

  220. 220.

    Borsini A, Alboni S, Horowitz MA, Tojo LM, Cannazza G, Su K-P, et al. Rescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants. Brain Behav Immun. 2017;65:230–8.

  221. 221.

    Chlodzinska N, Gajerska M, Bartkowska K, Turlejski K, Djavadian RL. Lipopolysaccharide injected to pregnant mice affects behavior of their offspring in adulthood. Acta Neurobiol Exp (Wars). 2011;71:519–27.

  222. 222.

    Depino AM. Early prenatal exposure to LPS results in anxiety- and depression-related behaviors in adulthood. Neuroscience. 2015;299:56–65.

  223. 223.

    Bakos J, Duncko R, Makatsori A, Pirnik Z, Kiss A, Jezova D. Prenatal immune challenge affects growth, behavior, and brain dopamine in offspring. Ann N Y Acad Sci. 2004;1018:281–7.

  224. 224.

    Posillico CK, Schwarz JM. An investigation into the effects of antenatal stressors on the postpartum neuroimmune profile and depressive-like behaviors. Behav Brain Res. 2016;298:218–28.

  225. 225.

    Bronson SL, Bale TL. Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal anti-inflammatory treatment. Endocrinology. 2014;155:2635–46.

  226. 226.

    Diz-Chaves Y, Astiz M, Bellini MJ, Garcia-Segura LM. Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice. Brain Behav Immun. 2013;28:196–206.

  227. 227.

    Diz-Chaves Y, Pernía O, Carrero P, Garcia-Segura LM. Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice. J Neuroinflamm. 2012;9:580.

  228. 228.

    Vanbesien-Mailliot CCA, Wolowczuk I, Mairesse J, Viltart O, Delacre M, Khalife J, et al. Prenatal stress has pro-inflammatory consequences on the immune system in adult rats. Psychoneuroendocrinology. 2007;32:114–24.

  229. 229.

    Ślusarczyk J, Trojan E, Głombik K, Chamera K, Roman A, Budziszewska B, et al. Fractalkine attenuates microglial cell activation induced by prenatal stress. Neural Plast. 2016;2016:1–11.

  230. 230.

    Ślusarczyk J, Trojan E, Wydra K, Głombik K, Chamera K, Kucharczyk M, et al. Beneficial impact of intracerebroventricular fractalkine administration on behavioral and biochemical changes induced by prenatal stress in adult rats: possible role of NLRP3 inflammasome pathway. Biochem Pharmacol. 2016;113:45–56.

  231. 231.

    Barnes J, Mondelli V, Pariante CM. Genetic Contributions of Inflammation to Depression. Neuropsychopharmacology. 2016. https://doi.org/10.1038/npp.2016.169.

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Acknowledgements

KMS is supported by a Studentship from the Doctoral Training Programme, funded by the Medical Research Council. CMP’s research in perinatal psychiatry has been supported by the Psychiatry Research Trust, and PD’s research in perinatal psychiatry is supported by the Medical Research Foundation, the UK Medical Research Council’s independent charity. Professor Pariante is also supported by ‘Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome’ (MR/J002739/1) and by the grant ‘Immuno-psychiatry: A Consortium to test the Opportunity for Immunotherapeutics in Psychiatry’ (MR/L014815/1), from the Medical Research Council (UK). Additional support has been offered by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’ s College London.

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Correspondence to Carmine M. Pariante.

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Conflict of interest

CMP and PAZ have received research funding from Johnson & Johnson as part of a program of research on depression and inflammation, and research funding from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson& Johnson, GSK, and Lundbeck. The work presented in this paper is unrelated to this funding. KMS and PD declare that they have no conflict of interest.

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Sawyer, K.M., Zunszain, P.A., Dazzan, P. et al. Intergenerational transmission of depression: clinical observations and molecular mechanisms. Mol Psychiatry 24, 1157–1177 (2019). https://doi.org/10.1038/s41380-018-0265-4

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