11

Stress and Anxiety in Pregnancy Stress and Anxiety in Pregnancy and Child Developmentand Child Development

TThomas G. O’Connorhomas G. O’ConnorUniversity of Rochester Medical CenterUniversity of Rochester Medical Center

PNMC 21 October 2009

22

Theoretical and Public Health Context Theoretical and Public Health Context

The developmental programming/developmental origins of adult The developmental programming/developmental origins of adult disease model has influenced cardiovascular research, and it disease model has influenced cardiovascular research, and it may be relevant to psychological, immunological, and other may be relevant to psychological, immunological, and other phenotypesphenotypes

If a developmental programming model concerning prenatal If a developmental programming model concerning prenatal stress were applicable, then there would be important stress were applicable, then there would be important implications for prevention and public healthimplications for prevention and public health

Prenatal stress/anxiety is a compelling research paradigm:Prenatal stress/anxiety is a compelling research paradigm: a) there are animal and humans models that require translationa) there are animal and humans models that require translation b) a developmental perspective is requiredb) a developmental perspective is required c) consideration of inter-acting biological systems is neededc) consideration of inter-acting biological systems is needed d) findings have obvious potential for interventiond) findings have obvious potential for intervention

33

A Prenatal Stress Hypothesis and ModelA Prenatal Stress Hypothesis and Model

Stress/anxiety in pregnancy is associated with elevated Stress/anxiety in pregnancy is associated with elevated cortisol in the mom [this is unlikely the only meaningful cortisol in the mom [this is unlikely the only meaningful biological correlate/effect]biological correlate/effect]

Cortisol is transmitted to the fetus, either directly or Cortisol is transmitted to the fetus, either directly or indirectly, and notwithstanding placental functionindirectly, and notwithstanding placental function

Cortisol exposure during this [“sensitive”] period has a Cortisol exposure during this [“sensitive”] period has a direct effect on fetal brain and mediates the link between direct effect on fetal brain and mediates the link between prenatal stress/anxiety and infant outcomesprenatal stress/anxiety and infant outcomes

Early exposure may “program” certain systems, Early exposure may “program” certain systems, suggesting long-term effects on behavior (e.g., fear), suggesting long-term effects on behavior (e.g., fear), immune system, and stress physiologyimmune system, and stress physiology

Postnatal factors may moderate the effects of prenatal Postnatal factors may moderate the effects of prenatal exposure exposure

44

Translating from Animal to Human WorkTranslating from Animal to Human Work

Stress/anxiety in pregnancy is associated with elevated cortisol Stress/anxiety in pregnancy is associated with elevated cortisol in the momin the mom

Cortisol is transmitted to the fetus, either directly or indirectly, Cortisol is transmitted to the fetus, either directly or indirectly, and notwithstanding placental functionand notwithstanding placental function

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

Early exposure may “program” certain systems, suggesting Early exposure may “program” certain systems, suggesting long-term effects on behavior (e.g., fear), immune system, and long-term effects on behavior (e.g., fear), immune system, and stress physiologystress physiology

Postnatal factors may moderate the effects of prenatal exposure Postnatal factors may moderate the effects of prenatal exposure

Animal HumanYes ?

Yes Yes

Yes ?

Yes maybe

Yes ?

55

Imperial College StudyImperial College Study (March of Dimes funded; Glover, O’Connor, Bergman, Sarkar)(March of Dimes funded; Glover, O’Connor, Bergman, Sarkar)

Key features:Key features: Recruited from amniocentesis clinic Recruited from amniocentesis clinic

because amniotic fluid is a fairly direct because amniotic fluid is a fairly direct index of fetal exposure to prenatal index of fetal exposure to prenatal hormoneshormones

Only mothers with normal pregnancies Only mothers with normal pregnancies and babies were includedand babies were included

Children assessed at age 17 months: Children assessed at age 17 months: detailed assessments of childrearing, detailed assessments of childrearing,

HPA axis, cognitive ability, HPA axis, cognitive ability, temperamenttemperament

66

1. Stress/anxiety in pregnancy is associated with 1. Stress/anxiety in pregnancy is associated with elevated cortisol in the momelevated cortisol in the momState Anxiety is weakly associated with maternal cortisol (ln) in pregnancy r(254)=0.18, p<0.01

20 30 40 50 60 70 805

6

7

8

STAI state score

Pla

sm

a c

ort

iso

l (l

n)

nm

ol/

L

Source: Glover et al.; Data from Imperial College Study

77

2. Cortisol is transmitted to the fetus2. Cortisol is transmitted to the fetus

88

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

99

3. Cortisol exposure during this 3. Cortisol exposure during this [“sensitive”] period has a direct [“sensitive”] period has a direct

effect on fetal braineffect on fetal brain

1010

Human evidence suggests that there is Human evidence suggests that there is something something particularparticular about prenatal stress about prenatal stress

exposureexposure

0 2 4 6 8

75

100

125

Number Prenatal Stressful Life Events

Ba

yle

y S

ca

les

MD

I S

co

res

0 2 4 6 8 10

75

100

125

Number Postnatal Stressful Life Events

Ba

yle

y S

ca

les

MD

I S

co

res

NB: r’s -.39 and -.05, respectively

Source: Bergman et al., 2007

1111

0 10 20 30 40 5070

80

90

100

110

120

130

Amniotic fluid cortisol (ng/L)

Bay

ley

MD

I sc

ore

s

Prenatal Exposure to Cortisol Predicts Lower Cognitive Ability at ~17 Months

Source: Bergman et al., in press

1212

What about postnatal rearing?What about postnatal rearing?

1313

Post-natal Childrearing Assessment Post-natal Childrearing Assessment (~17 months)(~17 months)

Quality of child-parent attachment is assessed using Quality of child-parent attachment is assessed using the Strange Situationthe Strange Situation

Standardized assessment of child behavior during 7 3-Standardized assessment of child behavior during 7 3-minute episodes in which there are separations and minute episodes in which there are separations and reunions with the parentreunions with the parent

Attachment research has incorporated HPA-axis Attachment research has incorporated HPA-axis related findings, with some positive resultsrelated findings, with some positive results

The Strange Situation is used as both a relationship The Strange Situation is used as both a relationship assessment and as a context for assessing child assessment and as a context for assessing child HPA axis functioningHPA axis functioning

1414

0 1 2 3 4 570

80

90

100

110

120

Insecure:r(53)=-0.48**

Secure:r(70)=-0.04

amniotic fluid cortisol (ln)

BS

ID-I

I M

DI

sc

ore

Association between Prenatal Exposure to Cortisol and Lower Cognitive Ability is Moderated by Early Rearing

Source: Bergman et al., in press

1515

ALSPAC StudyALSPAC Study(NIMH funded; O’Connor, Glover, Golding)(NIMH funded; O’Connor, Glover, Golding)

Longitudinal prospective follow-up of Longitudinal prospective follow-up of ~6500 15 year-olds on whom prenatal ~6500 15 year-olds on whom prenatal stress/anxiety and detailed developmental stress/anxiety and detailed developmental data were collected from pregnancydata were collected from pregnancy

Age 15 assessments include in-person Age 15 assessments include in-person psychiatric assessments, diurnal cortisol psychiatric assessments, diurnal cortisol (n=1,000), and DNA(n=1,000), and DNA

1616Source: O’Connor et al., Biological Psychiatry, 2005

Prenatal stress is associated with elevated cortisol at age 10 ½ years

1717

1

1.3

1.6

1.9

2.2

2.5

2.8

Odds ratio

Hyper

activity

Conduct

Em

otio

nal

Tota

l

1

1.3

1.6

1.9

2.2

2.5

2.8

Odds ratio

Hyper

activity

Conduct

Em

otional

Tota

l

47 months 81 months

NB: Controlling for prenatal, obstetric, and psychosocial risks plus postnatal anxiety and depressionSource: O’Connor et al., 2002 Brit J Psychiatry, 2003 J Child Psychology & Psychiatry

Prenatal Anxiety Predicts Behavioural/Emotional Prenatal Anxiety Predicts Behavioural/Emotional ProblemsProblems

boys

1

1.3

1.6

1.9

2.2

2.5

2.8

Odds ratio

Hyper

activity

Conduct

Em

otio

nal

Tota

l

1

1.3

1.6

1.9

2.2

2.5

2.8

Odds ratio

Hyper

activity

Conduct

Em

otional

Tota

l

girls

1818

Rochester StudiesRochester Studies(NIMH funded: O’Connor, Glover et al.)(NIMH funded: O’Connor, Glover et al.)

NIMH-funded study of n=200 women from pregnancy to NIMH-funded study of n=200 women from pregnancy to infant age 16 monthsinfant age 16 months

Sampling from OB clinic serving population at high psychosocial Sampling from OB clinic serving population at high psychosocial riskrisk

Prenatal assessments, as above, plus infant assessments at 2, Prenatal assessments, as above, plus infant assessments at 2, 6, & 16 months involving behavior, saliva and blood samples6, & 16 months involving behavior, saliva and blood samples

Two distinct but interrelated components of adaptive immune Two distinct but interrelated components of adaptive immune function, the humoral (antibody) and T-cell mediated responsesfunction, the humoral (antibody) and T-cell mediated responses

Anxiety S ymptoms (P S WQ) and T rauma E xpos ure: Mid-preg nanc y

00.10.20.30.40.50.60.70.80.9

W ake 30 Min 2.5 Hrs . 8 Hrs . 12 HrsCo

rtiso

l co

nc.

(µ

g/d

L)

Neither

Trauma

A nx S x

B oth

1919

Review of General Findings on Human Research Review of General Findings on Human Research on Prenatal Anxiety/Stress and Child Outcomeson Prenatal Anxiety/Stress and Child Outcomes

Reliable associations between maternal (and not paternal) prenatal Anxiety/Stress Reliable associations between maternal (and not paternal) prenatal Anxiety/Stress and:and:

Pregnancy complicationsPregnancy complications Obstetric outcomesObstetric outcomes Cognitive developmentCognitive development Behavioral/emotional problemsBehavioral/emotional problems Indicators of neurodevelopment (e.g., atypical laterality, dermatoglyphic asymmetry of Indicators of neurodevelopment (e.g., atypical laterality, dermatoglyphic asymmetry of

finger ridge counts; autism & schizophrenia?)finger ridge counts; autism & schizophrenia?) Persistence of effect beyond middle childhood and controlling for postnatal Persistence of effect beyond middle childhood and controlling for postnatal

anxiety/stressanxiety/stress

But,But, Mechanisms of action are unclearMechanisms of action are unclear Studies have ignored postnatal rearing conditionsStudies have ignored postnatal rearing conditions Risk phenotype remains somewhat ambiguousRisk phenotype remains somewhat ambiguous Genetic factors have not been formally consideredGenetic factors have not been formally considered Maternal nutritional is status under-examinedMaternal nutritional is status under-examined

2020

Limitations of the model and methodLimitations of the model and method

There is an over-reliance on HPA axis and cortisol in There is an over-reliance on HPA axis and cortisol in particular as a candidate mechanism: particular as a candidate mechanism:

lack of attention to obvious confounders, including other systems & lack of attention to obvious confounders, including other systems & hormones, nutrition, and geneticshormones, nutrition, and genetics

persisting methodological variability in HPA assessmentpersisting methodological variability in HPA assessment Some uncertainty about the risk phenotypeSome uncertainty about the risk phenotype There are limits to what kinds of maternal and child/fetal There are limits to what kinds of maternal and child/fetal

data can be collected, e.g., re: placenta, prenatal exposuredata can be collected, e.g., re: placenta, prenatal exposure Questions about individual differences, timing, duration and Questions about individual differences, timing, duration and

severity of exposure are unresolvedseverity of exposure are unresolved Long-term follow-up assessments are still rareLong-term follow-up assessments are still rare Intervention designs are rarer stillIntervention designs are rarer still

2121

General ConclusionsGeneral Conclusions

The observation that child-parent attachment moderates The observation that child-parent attachment moderates the effect of prenatal cortisol exposurethe effect of prenatal cortisol exposure

replicates animal data in this paradigmreplicates animal data in this paradigm provides one of the few human examples that early caregiving provides one of the few human examples that early caregiving

quality alters biological risk vulnerabilityquality alters biological risk vulnerability

Intervention studies are needed not only to enact the Intervention studies are needed not only to enact the implications of human research but also to provide implications of human research but also to provide confirming causal evidenceconfirming causal evidence