1 Stress and Anxiety in Pregnancy and Child Development Thomas G. O’Connor University of Rochester Medical Center PNMC 21 October 2009

2 Theoretical and Public Health Context  The developmental programming/developmental origins of adult disease model has influenced cardiovascular research, and it may be relevant to psychological, immunological, and other phenotypes  If a developmental programming model concerning prenatal stress were applicable, then there would be important implications for prevention and public health  Prenatal stress/anxiety is a compelling research paradigm: a) there are animal and humans models that require translation a) there are animal and humans models that require translation b) a developmental perspective is required b) a developmental perspective is required c) consideration of inter-acting biological systems is needed c) consideration of inter-acting biological systems is needed d) findings have obvious potential for intervention d) findings have obvious potential for intervention

3 A Prenatal Stress Hypothesis and Model  Stress/anxiety in pregnancy is associated with elevated cortisol in the mom [this is unlikely the only meaningful biological correlate/effect]  Cortisol is transmitted to the fetus, either directly or indirectly, and notwithstanding placental function  Cortisol exposure during this [“sensitive”] period has a direct effect on fetal brain and mediates the link between prenatal stress/anxiety and infant outcomes  Early exposure may “program” certain systems, suggesting long-term effects on behavior (e.g., fear), immune system, and stress physiology  Postnatal factors may moderate the effects of prenatal exposure

4 Translating from Animal to Human Work  Stress/anxiety in pregnancy is associated with elevated cortisol in the mom  Cortisol is transmitted to the fetus, either directly or indirectly, and notwithstanding placental function  Cortisol exposure during this [“sensitive”] period has a direct effect on fetal brain  Early exposure may “program” certain systems, suggesting long-term effects on behavior (e.g., fear), immune system, and stress physiology  Postnatal factors may moderate the effects of prenatal exposure AnimalHuman Yes ?Yes Yes maybe Yes ?

5 Imperial College Study (March of Dimes funded; Glover, O’Connor, Bergman, Sarkar)  Key features:  Recruited from amniocentesis clinic because amniotic fluid is a fairly direct index of fetal exposure to prenatal hormones  Only mothers with normal pregnancies and babies were included  Children assessed at age 17 months: detailed assessments of childrearing, HPA axis, cognitive ability, temperament detailed assessments of childrearing, HPA axis, cognitive ability, temperament

6 1. Stress/anxiety in pregnancy is associated with elevated cortisol in the mom State Anxiety is weakly associated with maternal cortisol (ln) in pregnancy r(254)=0.18, p<0.01 Source: Glover et al.; Data from Imperial College Study

7 2. Cortisol is transmitted to the fetus

8 Maternal plasma and amniotic fluid cortisol (ln) are moderately positively correlated (r(267)=0.32, p<0.001) Source: Sarkar et al., 2007; Glover et al., in press Correlation between maternal plasma and amniotic fluid cortisol (ln) according to gestation

9 3. Cortisol exposure during this [“sensitive”] period has a direct effect on fetal brain

10 Human evidence suggests that there is something particular about prenatal stress exposure NB: r’s -.39 and -.05, respectively Source: Bergman et al., 2007

11 Prenatal Exposure to Cortisol Predicts Lower Cognitive Ability at ~17 Months Source: Bergman et al., in press

12 What about postnatal rearing?

13 Post-natal Childrearing Assessment (~17 months)  Quality of child-parent attachment is assessed using the Strange Situation Standardized assessment of child behavior during 7 3- minute episodes in which there are separations and reunions with the parent Standardized assessment of child behavior during 7 3- minute episodes in which there are separations and reunions with the parent  Attachment research has incorporated HPA-axis related findings, with some positive results  The Strange Situation is used as both a relationship assessment and as a context for assessing child HPA axis functioning

14 Association between Prenatal Exposure to Cortisol and Lower Cognitive Ability is Moderated by Early Rearing Source: Bergman et al., in press

15 ALSPAC Study (NIMH funded; O’Connor, Glover, Golding)  Longitudinal prospective follow-up of ~ year-olds on whom prenatal stress/anxiety and detailed developmental data were collected from pregnancy  Age 15 assessments include in-person psychiatric assessments, diurnal cortisol (n=1,000), and DNA

16 Source: O’Connor et al., Biological Psychiatry, 2005 Prenatal stress is associated with elevated cortisol at age 10 ½ years

17 47 months 81 months NB: Controlling for prenatal, obstetric, and psychosocial risks plus postnatal anxiety and depression Source: O’Connor et al., 2002 Brit J Psychiatry, 2003 J Child Psychology & Psychiatry Prenatal Anxiety Predicts Behavioural/Emotional Problems boys girls

18 Rochester Studies (NIMH funded: O’Connor, Glover et al.)  NIMH-funded study of n=200 women from pregnancy to infant age 16 months Sampling from OB clinic serving population at high psychosocial risk Sampling from OB clinic serving population at high psychosocial risk Prenatal assessments, as above, plus infant assessments at 2, 6, & 16 months involving behavior, saliva and blood samples Prenatal assessments, as above, plus infant assessments at 2, 6, & 16 months involving behavior, saliva and blood samples Two distinct but interrelated components of adaptive immune function, the humoral (antibody) and T-cell mediated responses Two distinct but interrelated components of adaptive immune function, the humoral (antibody) and T-cell mediated responses

19 Review of General Findings on Human Research on Prenatal Anxiety/Stress and Child Outcomes  Reliable associations between maternal (and not paternal) prenatal Anxiety/Stress and: Pregnancy complications Pregnancy complications Obstetric outcomes Obstetric outcomes Cognitive development Cognitive development Behavioral/emotional problems Behavioral/emotional problems Indicators of neurodevelopment (e.g., atypical laterality, dermatoglyphic asymmetry of finger ridge counts; autism & schizophrenia?) Indicators of neurodevelopment (e.g., atypical laterality, dermatoglyphic asymmetry of finger ridge counts; autism & schizophrenia?)  Persistence of effect beyond middle childhood and controlling for postnatal anxiety/stress But,  Mechanisms of action are unclear  Studies have ignored postnatal rearing conditions  Risk phenotype remains somewhat ambiguous  Genetic factors have not been formally considered  Maternal nutritional is status under-examined

20 Limitations of the model and method  There is an over-reliance on HPA axis and cortisol in particular as a candidate mechanism: lack of attention to obvious confounders, including other systems & hormones, nutrition, and genetics lack of attention to obvious confounders, including other systems & hormones, nutrition, and genetics persisting methodological variability in HPA assessment persisting methodological variability in HPA assessment  Some uncertainty about the risk phenotype  There are limits to what kinds of maternal and child/fetal data can be collected, e.g., re: placenta, prenatal exposure  Questions about individual differences, timing, duration and severity of exposure are unresolved  Long-term follow-up assessments are still rare  Intervention designs are rarer still

21 General Conclusions  The observation that child-parent attachment moderates the effect of prenatal cortisol exposure replicates animal data in this paradigm replicates animal data in this paradigm provides one of the few human examples that early caregiving quality alters biological risk vulnerability provides one of the few human examples that early caregiving quality alters biological risk vulnerability  Intervention studies are needed not only to enact the implications of human research but also to provide confirming causal evidence