prenatal stress, anxiety and depression: effects on the...
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Prenatal stress, anxiety and
depression: effects on the fetus and
the child across the generations
Vivette Glover
Imperial College London
MMHA September 2017
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The mother’s emotional state in pregnancy
and in the early postnatal period
can have a long lasting effect on her child
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Effects of prenatal stress in guinea pigs
(Matthews personal communication)
Generation 1
Generation 2
Generation 3
Generation 4
Females Males
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Sex differences in effects of
prenatal stress on offspring
• Females more anxious
• Males more aggressive and more
cognitive deficits
• Sex differences being found in human
infants
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Fetal programming
Environment in the womb,
during different sensitive periods
for specific outcomes,
can alter the development
of the fetus,
with a long lasting effect
on the child.
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Sensitive early mothering helps attachment,
and can counteract some of what happens
in the womb
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From fetus
To child
From fetus
To child
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The Fetal Brain is “Under
Construction”
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Long term effects of prenatal
stress on neurodevelopment
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Examples of prenatal stress reported to be
associated with changes in development and
behavior
➢ Maternal anxiety and depression
➢ Maternal daily hassles
➢ Pregnancy specific anxiety
➢ Partner or family discord, interpersonal violence
➢ Distress caused by 6 day war in Israel, 1967
➢ Experience of acute disasters, e.g. freezing ice storm,
hurricane or 9/11
➢ It’s not just extreme or toxic stress or diagnosed mental
illness
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Pregnancy specific anxiety
been found to be associated with
• having an unintended pregnancy,
• first birth,
• higher medical risk,
• higher perceived risk of complications
• job stress
lower income
lower self-esteem
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Causes of antenatal maternal
anxiety /depression
( New ALSPAC study in prepn)
• Early childhood trauma-adverse childhood
experiences (ACES)
• Maternal history of sexual abuse predicts
elevated anxiety/depression from pregnancy to
33months.
• This effect is significantly stronger for women
who knew the perpetrator.
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• Interpersonal violence
• War
• Refugees/migrants
• Natural disasters
(e.g earthquake in
Tibet)
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➢Anxiety and Depression
➢Behavioural problems-ADHD, conduct disorder
➢ Impaired cognitive development
➢Sleep problems in infants
➢Neonatal behaviour
➢More difficult infant temperament
➢Victimisation in childhood
➢Schizophrenia, Autism
Prenatal stress associated with increased :
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Prenatal stress associated
with
increased :
➢Reduced birthweight and gestational age
➢Mixed handedness
➢Altered finger print pattern
➢Decreased telomere length
➢Asthma
➢Altered immune function
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Altered microbiome
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•Is it causal?
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ALSPACAvon Longitudinal Study of Parents and Children
• Large prospective birth cohort
~14,000 pregnant women
recruited around Bristol in
1990-1991
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Multivariate Analysis
Cohort with complete data
n = 7, 363
• Maternal Postnatal anxiety and depression
• Paternal pre and postnatal anxiety
• Parenting
• Maternal age
• Birthweight
• Gestational age
• Smoking
• Alcohol
• Psychosocial factors: crowding (SES)
• Maternal education
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ALSPAC. Predicted population prevalence of a probable
mental health disorder in children born to high (top 15%: open
bars) and low prenatal anxiety (full bars) mothers. Based on
SDQ scores. Results similar with prenatal depression
0.0
2.5
5.0
7.5
10.0
12.5
15.0Low prenatal anxiety (n=6,731)
High prenatal anxiety (n=1,213)
4 7 9 11.5 13
Age (yrs)
Po
pu
lati
on
pre
vale
nce %
(O’Donnell et al 2014)
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• Why are some children affected
and not others?
• Why are they affected in different
ways?
• Gene-environment interactions?
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COMTC
COMT
COMT
COMT inactivates catecholamines
–dopamine, adrenaline and
noradrenaline-
gene variants associated with
working memory and ADHD
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Working memory at age 8Birthweight, gestational age, maternal education, maternalage,
household crowding, maternal smoking, alcohol consumption,
postnatal mood and parenting controlled for GG: N=1126
AG: N=2310
AA: N=1259
P<0.01
COMT
rs4680
(O’ Donnell et al 2017)
Maternal anxiety at 32 weeks gestation
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Child ADHD (DAWBA) at age
15GG: N=761
AG: N=1543
AA: N=857
P<0.05
Maternal anxiety at 32 weeks gestation
COMT
rs4680
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Underlying mechanisms
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Maternal stress/anxiety/mental illness
cortisol
transplacental passage
cortisolcortisol?
?
Cortisol
NR3C1
Proinflammatory cytokines
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The feto-placental unit
Shams et al., 1999
Placental 11β-HSD2
CORTISONE
CORTISOL
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1/11β-HSD2 ΔCT
Maternal Trait anxiety
r= 0. 40, p<0.01**
Males r = -0.39
p = 0.040
n = 28
Females r = -0.40
p = 0.034
n = 28
0 10 20 30 40 50 60 70 80-7.5
-5.0
-2.5
0.0
significant correlation with State
anxiety
trend with depressionO’Donnell et al 2011
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11-βHSD2
cortisol
cortisol
11
-βH
SD
2
cortisone
Maternal Placenta Fetal
stress
cortisol
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New Placental studyCapron, Ramchandani, Glover submitted
• Women(n=81) recruited day before elective caesarean. Filled in self rating psychometric questionnaires EPDS (depression) and Spielberger(anxiety) and Life Events.
• N=48 Caucasian n= 33 Non Caucasian ( mainly Indian, Pakistani, Bangladeshi)
• Analysed for 11β-HSD2, NR3C1 (GR receptor) expression
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ΔC
t 11
β-
HS
D2
ge
ne
ex
pre
ss
ion
ΔC
t 11
β-H
SD
2 g
en
e
ex
pre
ss
ion
Interaction between the number of
maternal antenatal life events,
11b-HSD2 and ethnicity
β= -.385, p=.020
11b-HSD2
Antenatal life events
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PCA of genetic variation (SNPs) in GUSTO Cohort
Teh et al., 2014 Genome Research
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Questions for the future
• Are there ethnic differences in the effects
of prenatal stress on the placenta?
• Which ethnic groups differ from
Caucasians and how?
• Are there different effects of prenatal
stress on the fetus and the child among
different ethnic groups?
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Maternal stress/anxiety/mental illness
cortisol
transplacental passage
cortisolcortisol?
?
Cortisol
NR3C1
Proinflammatory cytokines
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Blood sample
Spielberger state and trait Anxiety questionnaire
Amniotic fluid
cortisol
cortisol
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Bayley Scales of Infant Development (BSID-
II)
Study child’s
cognitive
(MDI)
development
at
17 months
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Correlation between amniotic fluid cortisol and
cognitive development
r= - 0.245 n=125 p=0.006
0 10 20 30 40 50 6060
80
100
120
amniotic fluid cortisol
MD
I
Bergman et al 2010
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Effect of Maternal Attachment on association
between AF cortisol and Cognitive Development
1.00 2.00 3.00 4.00 5.00
70
80
90
100
110
120
Bayle
y M
en
tal D
evelo
pm
en
t In
dex
1.00 2.00 3.00 4.00 5.00
Insecure Secure
Ln AF cortisol
Bergman et al 2010
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Antenatal in utero cortisol and fMRI
sustained attention response in
children age 6-9 years n=32 (areas
with a significant correlation p<0.01)
Sarkar et al (in prepn)
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Epigenetic modifications-basis for
fetal programming
Epigenetic
changes are
functionally
relevant
modifications
to the genome
that do not
involve a
change in
nucleotide
sequence.
Can persist to
grandchild
generation
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What should be done?
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Role of Professionals
• Detect and treat anxiety and depression both in pregnancy and postnatally– Psychological interventions (eg CBT)
– Pharmacological intervention if needed
• Help with relationship problems or domestic abuse
• Help to create more social support
• Practical help with housing etc
• Help to teach sensitive mothering – video feedback
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Ask about ACES at booking
• hree Types of ACEs
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bas
elin
e
Wee
k 4
Wee
k 8
Wee
k 12
25
30
35
40
45
time
Tra
it a
nxie
ty
relax
lullaby
Spielberger Trait
P<0.01
N=20
N=16
***
Effect of listening to Jennnie Muskett lullabies
or control relaxation on anxiety in pregnant women
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Public health implications of
reducing stress/anxiety/depression
in pregnancy
• More than one million children in UK suffer from emotional, behavioural, and cognitive developmental problems
• Attributable load of such problems due to prenatal stress ~10 %
• Potential to reduce number of affected children in the UK by 100,000