The three primary methods of communication in the human body (nervous system, immune system, and endocrine system) are interconnected in a number of ways, and exposures that take place during critical windows of fetal development can permanently impact how each system is “programmed” to function. Increasing amounts of research in both animal and human populations support the Fetal Programming Hypothesis, which asserts that experiences during pregnancy may modulate the normal course of development and that adverse experiences during this period may result in permanent alterations to the physiology, neurodevelopment, and behavior of the child that persist into adulthood (1).

Specific to a recent study from Plant and colleagues, prenatal maternal depression and childhood maltreatment are adverse experiences that may negatively impact development. The aims of this study were to determine whether these two forms of early adverse experiences could predict immune and endocrine dysfunction in adult offspring. Immune and endocrine dysfunction were measured by peripheral inflammation and HPA axis activation, respectively.  Inflammation and hypothalamic-pituitary-adrenal (HPA) axis dysregulation have both been proposed as different biological mechanisms through which depression can be transmitted between mother and child and how affective psychopathologies such as depression can emerge later in life (2-8).

This study used a population of mother-offspring dyads from the South London Child Development Study (SLCDS), a prospective longitudinal UK birth cohort study initially established in 1986. When the mothers were pregnant, maternal prenatal depression was assessed at 20 and 36 gestational weeks using the International Classification of Diseases, 9th revision. Assessments continued with the mother at 3 and 12 months postpartum; with the child and mother when the child was 4, 11, and 16 years old; and with the child at 25 years of age. While the study initially included 153 mothers at 36 gestational weeks, they were able to retain 103 offspring participants at the 25-year visit.  

At this 25-year visit, offspring participants provided blood and multiple saliva samples, from which peripheral inflammation was assessed through the measurement of hs-CRP (high sensitivity C-reactive protein) and HPA axis activation was assessed  through the cortisol-awakening response (CAR) in the period of time after waking up. At this visit, participants were also assessed for child maltreatment using the Child Experience of Care and Abuse Questionnaire (CECA.Q). These results were compared to the results of the Child and Adolescent Psychiatric Assessment (CAPA) which were used at the child’s 11-year and 16-year visits in order to understand the contribution of child maltreatment as a potential risk factor for depression later in life. Offspring depression was assessed at the 25-year visit using the SCID for DSM-IV Axis I disorders. Lastly, confounding variables such as body mass index, medications that could impact immune function, smoking, birth weight, gestational age, gender, ethnicity, and family social class were taken into consideration.

The researchers observed an association between prenatal depression and elevated offspring inflammation in early adulthood.  Overall, 16.7% of the offspring (SD=1.7, n=78) were categorized as having clinically high levels of inflammation (hs-CRP > 3.0 mg/L) and maternal prenatal depression predicted significantly elevated offspring hs-CRP levels ( P=0.005, 95% CI (0.3, 1.8), n=75). Surprisingly, inflammation as measured by hs-CRP, was negatively correlated with child maltreatment as measured with the CAR (P=-0.02, n=58).  Post-hoc analyses revealed that offspring exposed to maternal prenatal depression have significantly higher hs-CRP values compared to both the non-exposed offspring (P=0.02) and offspring exposed only to child maltreatment (P=0.03, n=75). There were no differences between those exposed to only child maltreatment and those not exposed to prenatal depression (P=0.7). Furthermore, there were no differences in inflammation between offspring exposed to both child maltreatment and maternal prenatal depression and those exposed to only maternal prenatal depression (P=0.4). An additional post-hoc comparison illustrated that offspring exposed to only child maltreatment (n=12) had significantly higher CAR levels and hs-CRP values in comparison with non-maltreated and non-depressed offspring (n=37, P=0.001; P<0.001, respectively) and maltreated and depressed offspring (n=14, P=0.02; P=0.002, respectively).

In summary, these results tell us that maternal prenatal depression had a persistent effect at age 25 on offspring inflammation that is independent of other subsequent adverse experiences (i.e., child maltreatment). Separately, offspring’s experience of child maltreatment  was predictive of higher awakening cortisol levels. Surprisingly maternal prenatal depression was not predictive of cortisol levels, which may seem contradictory to previous studies that have shown that adults with a history of child maltreatment have elevated inflammation (9-11). However, as the authors explain, many of the studies that have examined child maltreatment do not include maternal depression as a potential risk factor for adult inflammation, so it could have been a confounding variable that was misattributed to child maltreatment when looking at inflammation in previous experiments.

This 25-year longitudinal study in its length and depth goes beyond others in illustrating the importance of prenatal and childhood experiences in “programming” offspring, specifically in terms of their HPA axis and peripheral immune functioning.  This study is clearly strong due to the use of prospective data at multiple time points through both the mothers and their children’s lives. However, as the authors mention, only one measure of inflammation and HPA axis activation each were used, which does not give us a complete picture of the functioning of the neuroendocrineimmune system. Furthermore, the prenatal diagnosis of depression for the mothers was made in such a way that anxiety symptoms could have also been present alongside the prenatal depression, so the effects seen in offspring could also be a result of anxiety symptoms, which are very relevant for the HPA axis and inflammatory processes (12, 13).  In my opinion, a missed opportunity in this study was a further comparison of the measures of maternal postpartum depression to the measures of inflammation and depression in the offspring. Mothers were reported to have been interviewed at 3 and 12 months postpartum, and it could have added some additional dimensionality to compare the critical windows of maternal prenatal depression and postpartum depression (PPD) given the extensive body of research supporting the lasting effects of PPD on the child.

Overall this study provides valuable insight into potential biological mechanisms of depression and highlights the importance of early life experiences and prenatal depression in the development of children. As the field of developmental neuroimmunology grows, we need to continue investigating the crosstalk between the mechanisms of immune function and depression or other psychopathologies and their particular importance in development.

Lauren Claypoole, BA


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.


  1.  Bennett L, Gunn AJ. The Fetal Origins of Adult Mental Illness. Eurekah Bioscience 2005, 1(2), 154-161
  2.  Pariante C, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci 2008; 31: 464–468.
  3.  Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 2014;71: 1121–1128.
  4.  Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477–501.
  5.  Miller G, Chen E, Sze J, Marin T, Arevalo JMG, Doll R et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NFkappaB signaling. Biol Psychiatry 2008; 64: 266–272.
  6.  Miller G, Chen E, Zhou ES. If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull 2007; 133:25–45.
  7.  Miller A. Norman cousins lecture: mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun 2009; 23: 149–158.
  8.  Horowitz M, Zunszain P, Anacker C, Musaelyan K, Pariante CGlucocorticoids and Inflammation; a double-headed sword in depression? How do neuroendocrine and inflammatory pathways interact during stress to contribute to the pathogenesis of depression? In: Halaris A, Leonard Beds Inflammation in Psychiatry. Karger Publishers: Basel, 2013; 127–143.
  1.  Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci USA 2007; 104: 1319–1324.
  2. Slopen N, Lewis TT, Gruenewald TL, Mujahid MS, Ryff CD, Albert MA et al. Early life adversity and inflammation in African Americans and whites in the midlife in the United States survey. Psychosom Med 2010; 72: 694–701.
  3. Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand 2014; 129: 180–192.
  4. Van den Bergh BRH, 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: 536–545.
  5. Vogelzangs N,  Beekman ATF, de Jonge P, Penninx BWJH. Anxiety disorders and inflammation in a large adult cohort. Translational Psychiatry (2013) 3, e249; doi:10.1038/tp.2013.2. Published online 23 April 2013