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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
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