Stress, glucocorticoids and liquorice in human pregnancy: Programmers of the offspring brain

Figures & data

Figure 1.  Mechanisms involved in the offspring programming. (Modified from Räikkönen et al. 2008b).

Table I.  Studies testing associations between prenatal maternal stress, anxiety and depression with offspring development.

Age of child	Measure or type of >prenatal exposure	Prenatal timing >weeks gestation	Outcome measure(s)	Reference(s)
2–3 days	Anxiety (state & trait); Stress (PSS)	20; 30	NBAS: habituation, social interaction, motor system, state organization, state regulation, autonomic system	Hernández-Reif et al. (2008)
3–5 days	Total distress	< 20; 30–34	Regulation problems (NBAS)	Rieger et al. (2004)
1 week	Perinatal depression	26	Cortisol level	Diego et al. (2004)
Neonate	Anxiety (general)	40^*	Auditory evoked responses (AER)	Harvison et al. (2009)
12 days	Depression	Not reported	Attentiveness (NBAS)	Hernández-Reif et al. (2006)
4–14 days	Life events stress	Mid gestation	Birth weight, head circumference, Prechtl's neurological observation	Lou et al. (1994)
Birth, 1 day, >3–4 weeks	Anxiety (state and trait)	≤ 16; 32–34	Medical records (e.g. Apgar scale), cardiac vagal tone (EKG Porges’ method)	Ponirakis et al. (1998)
6 weeks	Foetal reactivity to maternal stimulation (viewing of video)	32	Infant negative reactivity during a standardized lab procedure	DiPietro et al. (2008)
3 months	Depression	15–28; 29–40	Infant cortisol level pre and post infant stress test	Oberlander et al. (2008)
4 months	Anxiety (state) and depression	32	Behavioural reactivity (HIBRP)	Davis et al. (2004)
2, 6 months	Depression	Third trimester	Temperament ratings	McGrath et al. (2008)
3–5 months	Stress and depression	28–40	Face-to-face play interactions (CCTI)	Field et al. (1985)
3–6 months	Depressive symptoms, anxiety (pregnancy-specific), parenting stress; job strain	7–40	Excessive crying	van der Wal et al. (2007)
4–6 months	Anxiety (trait); depression, life events stress	Third trimester (32)	Difficult temperament (SITQ)	Austin et al. (2005)
6 months	Depression and anxiety	26	Infant cortisol level pre and post infant stress test	Brennan et al. (2008)
6 months	Stress experience	1st week postpartum	Temperament (IBQ); negative and overall temperamental reactivity	Pesonen et al. (2005)
6 months	Anxiety (pregnancy-specific; general)	12; 20	Temperament (IBQ-R); infant difficulties	Henrichs et al. (2009)
1 week, 12 weeks, >7 months	Anxiety (state and trait)	12–22; 23–31; 32–40	Prechtl's neurological observation, behavioural state observation, feeding score, mother–infant interaction (ITQ, ICQ, BSID)	Van den Bergh, (1990;1992)
7 months	Anxiety	36–39^*	Cortisol level of the child, pre and post still face procedure	Grant et al. (2009)
4–8 months	Anxiety (trait)	21; 26–34, 35	Temperament (ITQ-revised)	Vaughn et al. (1987)
8 months	Daily hassles	15–17, 27–28, 37–38	Mental development (BSID-MDI)	Huizink et al. (2002, 2003)
9 months	9/11	Not reported	Temperament (IBQ)	Brand et al. (2006)
9 months	9/11	28–40	Cortisol level of the child	Yehuda et al. (2005)
1.5 years	Life events stress (i.e. relationship problems)	14 months postpartum^*	Cognitive development (BSID-MDI), fear reactivity (Lab-TAB)	Bergman et al. (2007)
2 years	Anxiety (general: POMS and STAI), stress (DSI, PSS); depression (POMS, CES-D); pregnancy-specific stress (PES)	24, 28, 32	BSID: MDI, PDI; IBR	Dipietro et al. (2006)
3 weeks; 1 year; 2 years	Anxiety (state and trait)	32	Orientation (NBAS), Cognitive development (BSID-MDI), Task orientation and motor co-ordination (IBR)	Brouwers et al. (2001)
2 years	Perceived stress pregnancy-related anxiety	15–38	Behavioural problems (CBCL) temperament (ICQ), attention regulation (BSID)	Gutteling et al. (2005b)
13–15 and 42 months	Depression	Monthly, from >conception onwards	Frontal and parietal EEG asymmetry scores	Dawson and Ashman (2000); Dawson et al. (2001)
14–54 months	Anxiety, depression	Each trimester	Behavioural and emotional problems (CBCL); saliva cortisol after stressors	de Bruijn et al. (2009a,b)
6 months, 5 years	Psychological distress	1–16; 17–28; 29–40	Temperament (ITQ, PTQ)	Martin et al. (1999)
2 years	Ice storm	4–24	Cognitive development (BSID-MDI), language production (MCDI)	Laplante et al. (2004)
5.5 years		–	IQ (WISC)	Laplante et al. (2008)
6 months, 6 years	Pregnancy risks	16–20	Temperament (ITQ), school grades and marks	Niederhofer and Reiter (2004)
4–6 years	Daily hassles, anxiety, perceived stress, life events	16	Cortisol level of the child at first school day; after inoculation memory (TOMAL)	Gutteling et al. (2004, 2005a, 2006)
4 and 7 years	Anxiety	18, 32	Emotional and behavioural problems (SDQ)	O'Connor et al. (2002, 2003)
7–8 years	Perceived stress	10, 12, 20, 28, 32, 36	ADHD (DSM-IV)	Rodriguez and Bohlin (2005)
6–9 years	Anxiety (pregnancy specific)	19,25,31	Grey matter density (MRI study)	Buss et al. (2009)
10 years	Self rated anxiety	18, 32	Cortisol level of the child	O'Connor et al. (2005)
10 years →	Death of a close relative	0–12	Schizophrenia (ICD8/ICD10)	Khashan et al. (2008)
14 years	Chernobyl	14 →	Depression/MDD (C-SSAGA-A: DSM-III-R) ADHD	Huizink et al. (2007)
8–9 years, 14–15,>17 years	Anxiety (state and trait)	12–22	ADHD (CBCL, TRF), computerized encoding task and stop task, vocabulary and block design (WISC-R), sustained attention (CPT), depression (CDI), cued attention, N-back, Go/NoGo, dual task (ERP), response-shifting.	Van den Bergh and Marcoen (2004); >Van den Bergh et al. (2005, 2006, 2008), Mennes et al. (2006, 2009)
25 years	Severe life events	On average 25 years >postpartum^*	Cortisol and ACTH levels	Entringer et al. (2009)
–	Hurricane	24–40	Autism (DSM-II-R/DSM-IV)	Kinney et al. (2008)

Note: ADHD, attention deficit hyperactivity disorder; AER, Auditory Evoked Responses; BSID, Bayley Scales of Infant Development; CBCL, Child Behaviour Checklist; CCTI, Colorado Child Temperament Inventory; CDI, child depression inventory; CPT, continuous performance task; C-SSAGA-A-, child semi-structured assessment of genetics and alcoholism; DSI, Daily Stress Inventory; DSM-R, Diagnostic and Statistical Manual-revised; ECG, electrocardiogram; ERP, event-related potential; HIBRP, Harvard Infant Behavioural Reactivity Protocol; IBQ, Infant Behaviour Questionnaire; IBR, Infant Behaviour Record; ICD, International Classification of Diseases; ICQ, Infant Characteristics Questionnaire; ITQ, Infant Temperament Questionnaire; IQ, Intelligence Quotient; MCDI, MacArthur Communicative Development Inventory; MDD, Major Depressive Disorder; MDI, Mental Development Index; Lab-TAB, laboratory temperament assessment Battery; NBAS, Brazelton neonatal behavioural assessment scale; PES, Pregnancy Experience Scale; POMS, Profile of Moods Scale; PSS, Perceived Stress Scale; PDI, Psychomotor Development Index; PTQ, Preschool Temperament Questionnaire; SDQ, Strengths and Difficulties Questionnaire; SITQ: Short Infant Temperament Questionnaire; TOMAL, Test of Memory and Learning; TRF, Teacher's Report Form; WISC, Wechsler Intelligence Scale for Children; WPPSI, Wechsler Preschool and Primary Scale of Intelligence

* Retrospective.

Räikkönen K, Pesonen AK, Heinonen K, Kajantie E, Hovi P, Järvenpää AL, Eriksson JG, Andersson S. Depression in young adults with very low birth weight: The Helsinki study of very low-birth-weight adults. Arch Gen Psychiatry. 2008b; 65:290–296.

 PubMed Web of Science ®Google Scholar

Rieger M, Pirke KM, Buske-Kirschbaum A, Wurmser H, Papousek M, Hellhammer DH. 2004. Influence of stress during pregnancy on HPA activity and neonatal behavior. Ann N Y Acad Sci. 1032:228–230.

 PubMedGoogle Scholar

Diego MA, Field T, Hernandez-Reif M, Cullen C, Schanberg S, Kuhn C. 2004. Prepartum, postpartum, and chronic depression effects on newborns. Psychiatry. 67:63–80.

 PubMed Web of Science ®Google Scholar

Harvison KW, Molfese DL, Woodruff-Borden J, Weigel RA. 2009. Neonatal auditory evoked responses are related to perinatal maternal anxiety. Brain Cogn. 71:369–374.

 PubMedGoogle Scholar

Lou HC, Hansen D, Nordentoft M, Pryds O, Jensen F, Nim J, Hemmingsen R. 1994. Prenatal stressors of human life affect fetal brain development. Dev Med Child Neurol. 36:826–832.

 PubMed Web of Science ®Google Scholar

Ponirakis A, Susman EJ, Stifter CA. 1998. Negative emotionality and cortisol during adolescent pregnancy and its effects on infant health and autonomic nervous system reactivity. Dev Psychobiol. 33:163–174.

 PubMed Web of Science ®Google Scholar

DiPietro JA, Ghera MM, Costigan KA. 2008. Prenatal origins of temperamental reactivity in early infancy. Early Hum Dev. 84:569–575.

 PubMedGoogle Scholar

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.

 PubMed Web of Science ®Google Scholar

Davis EP, Snidman N, Wadhwa PD, Glynn LM, Schetter CD, Sandman CA. 2004. Prenatal maternal anxiety and depression predict negative behavioral reactivity in infancy. Infancy. 6:319–331.

 Web of Science ®Google Scholar

McGrath JM, Records K, Rice M. 2008. Maternal depression and infant temperament characteristics. Infant Behav Dev. 31:71–80.

 PubMed Web of Science ®Google Scholar

Field T, Sandberg D, Garcia R, Vega-Lahr N, Goldstein S, Guy L. 1985. Pregnancy problems, postpartum depression, and early mother–infant interactions. Dev Psychol. 21:1152–1156.

 Web of Science ®Google Scholar

van der Wal MF, van Eijsden M, Bonsel GJ. 2007. Stress and emotional problems during pregnancy and excessive infant crying. J Dev Behav Pediatr. 28:431–437.

 PubMedGoogle Scholar

Austin MP, Hadzi-Pavlovic D, Leader L, Saint K, Parker G. 2005. Maternal trait anxiety, depression and life event stress in pregnancy: Relationships with infant temperament. Early Hum Dev. 81:183–190.

 PubMed Web of Science ®Google Scholar

Brennan PA, Pargas R, Walker EF, Green P, Newport DJ, Stowe Z. 2008. Maternal depression and infant cortisol: Influences of timing, comorbidity and treatment. J Child Psychol Psychiatry. 49:1099–1107.

 PubMed Web of Science ®Google Scholar

Pesonen AK, Räikkönen K, Strandberg TE, Järvenpää AL. 2005. Continuity of maternal stress from the pre- to the postnatal period: Associations with infant's positive, negative and overall temperamental reactivity. Inf Behav Devel. 28:36–47.

 Web of Science ®Google Scholar

Henrichs J, Schenk JJ, Schimdt HG, Velders FP, Hofman A, Jaddoe VWV, Verhulst FC, Tiemeier H. 2009. Maternal pre- and postnatal anxiety and infant temperament. The generation R study. Inf Child Dev. 18:556–572.

 Web of Science ®Google Scholar

Van den Bergh BR. 1990. The influence of maternal emotions during pregnancy on fetal and neonatal behavior, Win, 1990. J Prenatal Perinatal Psychol Health. 5:119–130.

 Google Scholar

Van den Bergh BR. 1992. Maternal emotions during pregnancy and fetal and neonatal behavior. Oxford University Press: Oxford, UK.

 Google Scholar

Grant KA, McMahon C, Austin MP, Reilly N, Leader L, Ali S. 2009. Maternal prenatal anxiety, postnatal caregiving and infants' cortisol responses to the still-face procedure. Dev Psychobiol. 51:625–637.

 PubMed Web of Science ®Google Scholar

Vaughn B, Bradley C, Joffe L, Seifer R, Barglow P. 1987. Maternal characteristics measured prenatally are predictive of ratings of temperamental “difficulty” on the Carey Infant Temperament Questionnaire. Dev Psychol. 23:152–161.

 Web of Science ®Google Scholar

Huizink AC, de Medina PG, Mulder EJ, Visser GH, Buitelaar JK. 2002. Psychological measures of prenatal stress as predictors of infant temperament. J Am Acad Child Adolesc Psychiatry. 41:1078–1085.

 PubMed Web of Science ®Google Scholar

Huizink AC, Robles de Medina P, Mulder EJ, Visser GH, Buitelaar JK. 2003. Stress during pregnancy is associated with developmental outcome in infancy. J Child Psychol Psychiatry. 44:810–818.

 PubMed Web of Science ®Google Scholar

Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS. 2005. Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab. 90:4115–4118.

 PubMed Web of Science ®Google Scholar

Brouwers EPM, van Baar AL, Pop VJM. 2001. Maternal anxiety during pregnancy and subsequent infant development. Inf Behav Dev. 24:95–106.

 Web of Science ®Google Scholar

Dawson G, Ashman SB. 2000. On the origins of a vulnerability to depression: The influence of the early social environment on the development of psychobiological systems related to risk for affective disorder. Mahwah, NJ: Erlbaum.

 Google Scholar

Dawson G, Ashman SB, Hessl D, Spieker S, Frey K, Panagiotides H, Embry L. 2001. Autonomic and brain electrical activity in securely- and insecurely-attached infants of depressed mothers. Inf Behav Dev. 24:135–149.

 Google Scholar

de Bruijn ATCE, van Bakel HJA, van Baar AL. Sex differences in the relation between prenatal maternal emotional complaints and child outcome. Early Hum Dev. 2009a; 85:319–324.

 PubMed Web of Science ®Google Scholar

de Bruijn ATCE, van Bakel HJA, Wijnen H, Pop VJM, van Baar AL. Prenatal maternal emotional complaints are associated with cortisol responses in toddler and preschool aged girls. Dev Psychobiol. 2009b; 51:553–563.

 PubMed Web of Science ®Google Scholar

Martin RP, Noyes J, Wisenbaker J, Huttunen M. 1999. Prediction of early childhood negative emotionality and inhibition from maternal distress during pregnancy. Merrill-Palmer Q. 45:370–391.

 Web of Science ®Google Scholar

Laplante DP, Barr RG, Brunet A, Galbaud du Fort G, Meaney ML, Saucier JF, Zelazo PR, King S. 2004. Stress during pregnancy affects general intellectual and language functioning in human toddlers. Pediatr Res. 56:400–410.

 PubMed Web of Science ®Google Scholar

Laplante DP, Brunet A, Schmitz N, Ciampi A, King S. 2008. Project Ice Storm: Prenatal maternal stress affects cognitive and linguistic functioning in 5 1/2-year-old children. J Am Acad Child Adolesc Psychiatry. 47:1063–1072.

 PubMed Web of Science ®Google Scholar

Niederhofer H, Reiter A. 2004. Prenatal maternal stress, prenatal fetal movements and perinatal temperament factors influence behavior and school marks at the age of 6 years. Fetal Diagn Ther. 19:160–162.

 PubMedGoogle Scholar

Gutteling BM, de Weerth C, Buitelaar JK. 2004. Maternal prenatal stress and 4–6 year old children's salivary cortisol concentrations pre- and post-vaccination. Stress. 7:257–260.

 PubMed Web of Science ®Google Scholar

O'Connor TG, Heron J, Golding J, Beveridge M, Glover V. 2002. Maternal antenatal anxiety and children's behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br J Psychiatry. 180:502–508.

 PubMed Web of Science ®Google Scholar

O'Connor TG, Heron J, Golding J, Glover V. 2003. Maternal antenatal anxiety and behavioural/emotional problems in children: A test of a programming hypothesis. J Child Psychol Psychiatry. 44:1025–1036.

 PubMed Web of Science ®Google Scholar

Rodriguez A, Bohlin G. 2005. Are maternal smoking and stress during pregnancy related to ADHD symptoms in children?. J Child Psychol Psychiatry. 46:246–254.

 PubMed Web of Science ®Google Scholar

Buss C, Davis EP, Muftuler LT, Head K, Sandman CA. 2009. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6–9-year-old children. Psychoneuroendocrinology. 35:141–153.

 Google Scholar

O'Connor TG, Ben-Shlomo Y, Heron J, Golding J, Adams D, Glover V. 2005. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry. 58:211–217.

 PubMed Web of Science ®Google Scholar

Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, Kenny LC, Mortensen PB. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry. 2008a; 65:146–152.

 PubMed Web of Science ®Google Scholar

Van den Bergh BR, Marcoen A. 2004. High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev. 75:1085–1097.

 PubMed Web of Science ®Google Scholar

Van den Bergh BR, Mennes M, Oosterlaan J, Stevens V, Stiers P, Marcoen A, Lagae L. High antenatal maternal anxiety is related to impulsivity during performance on cognitive tasks in 14- and 15-year-olds. Neurosci Biobehav Rev. 2005a; 29:259–269.

 PubMed Web of Science ®Google Scholar

Van den Bergh BR, Mennes M, Stevens V, van der Meere J, Borger N, Stiers P, Marcoen A, Lagae L. 2006. ADHD deficit as measured in adolescent boys with a continuous performance task is related to antenatal maternal anxiety. Pediatr Res. 59:78–82.

 PubMed Web of Science ®Google Scholar

Van den Bergh BR, Van Calster B, Smits T, Van Huffel S, Lagae L. 2008. 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. 33:536–545.

 PubMed Web of Science ®Google Scholar

Mennes M, Stiers P, Lagae L, Van den Bergh BR. 2006. Long-term cognitive sequelae of antenatal maternal anxiety: Involvement of the orbitofrontal cortex. Neurosci Biobehav Rev. 30:1078–1086.

 PubMed Web of Science ®Google Scholar

Mennes M, Van den Bergh BR, Lagae L, Stiers P. 2009. Developmental brain alterations in 17 year old boys are related to antenatal maternal anxiety. Clin Neurophysiol. 120:1116–1122.

 PubMedGoogle Scholar

Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD, Wust S. 2009. Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav. 55:292–298.

 PubMed Web of Science ®Google Scholar

Kinney DK, Miller AM, Crowley DJ, Huang E, Gerber E. 2008. Autism prevalence following prenatal exposure to hurricanes and tropical storms in Louisiana. J Autism Dev Disord. 38:481–488.

 PubMed Web of Science ®Google Scholar