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Groei en ontwikkeling van
zwangerschap tot adolescentie:
GenerationR
Symposium Infantpsychiatrie
Nijmegen 28 juni 2016
Frank Verhulst
ErasmusMC
Fetal origins of adult disease
hypothesis
Fetal undernutrition in middle to
late gestation leads to
disproportionate fetal growth,
programmes later coronary heart
disease.
Not only coronary heart disease,
but also diabetes, obesity, stroke
and mental illness
Fetal programming Barker Hypothesis
Research Aims
To examine whether prospectively measured fetal growth
and intra-uterine influences are related to child
behavioral/emotional and cognitive problems
To understand mechanisms involved in the influence of
early postnatal factors on child behavioral/emotional and
cognitive problems
Prospective cohort design
From early foetal life
9.778 mothers and their children
Detailed measures in the Focus cohort (~1.000 mothers)
Urban, multi-ethnic population
Design Generation R
Data collection flowchart
Additional Assessments in Generation R Focus Cohort
12 20 weeks 30 weeks birth 2 months 6 months 12 months 24 months 3 yrs 4yrs
Fetal Ultrasound
Additional UltrasoundMeasures
Psychiatric Interview
Questionnaire 7
Questionnaire 10
Questionnaire 11
Questionaire 6
Neuromotorassessment
Homeobservation
Research Center visit 1e.g. Brainultrasound
Research Center visit 2Neuromotor assessment
Research Center visit 3e.g. Strange situation
Research Center visit 5e.g. Executive function
Fetal UltrasoundBlood
Fetal UltrasoundUrine
Questionnaire 12
Quest14
Father Quest.
Assessments in Generation R Cohort
Questionnaire 1
Questionnaire 3
Questionnaire 4
Cord bloodBirth weightComplications
FatherQuest.
Home Visit e.g. father-child interaction, compliance
Generation @ age 6 center visit: intelligence test + child interview
GenerationR@ age 10center visit: MRI, brain,heart,lungFam.interactionOstracism etc.
Question15
Question17
Father Quest.
Prenatal Influences
Maternal stress/depression
Maternal smoking
Maternal cannabis use
Maternal folic acid
Maternal thyroid hormone
Maternal diet
Maternal SSRI use
Maternal psychological distress and
fetal growth
The belief that the emotional state of the pregnant woman affects fetal
development is ancient and in all cultures
Maternal prenatal anxiety, depression, and stress related to birth
outcomes:
- spontaneous abortion and pre-eclempsia
- preterm delivery
- low birth weight
BUT
Birth outcomes are only summary measures of intrauterine growth and
cannot provide information about fetal growth
Gestational age at measurement
Early preg.: 12 weeks
Mid-preg. : 20 weeks
Late preg. : 30 weeks
Measures:
• abdominal circumference
• head circumference, biparietal diameter
• femur length
• estimated foetal weight
BPD
HC
LVAW
Does maternal stress in
pregnancy affect fetal growth?
Prenatal ultrasound measurements
Maternal psychological distress and foetal
growth trajectories
Difference in fetal weight gain (grams/week)
Beta 95% CI p-value
Depressive symptoms
-2.86
Anxious symptoms
-3.23
Family stress -1.78
Difference in head circumference growth (mm/week)
Depressive symptoms
-0.07 .13; -0.01 0.03
Anxious symptoms
-0.10 -0.17; -0.04 0.002
Family stress -0.06 -0.14; 0.01 0.11
Difference in foetal weight gain (grams/week)
Beta 95% CI p -value
Depressive symptoms
-2.86
Anxious symptoms
-3.23
Family stress -1.78
-4.48; -1.23 <0.001
-4.91; -1.55 0.002
-3.70; 0.13 0.07
-4.48; -1.23 <0.001
-4.91; -1.55 0.002
-3.70; 0.13 0.07
Difference in head circumference growth (mm/week)
Depressive symptoms
-0.07
Anxious symptoms
-0.10
Family stress -0.06
-0.13; -0.01 0.03
-0.17; -0.04 0.002
-0.14; 0.01 0.11
PhD student
J. Henrichs
Maternal distress: Growth trajectory of foetal weight
0
500
1000
1500
2000
2500
3000
3500
4000
20 wks 25 wks 30 wks 35 wks 40 wks
gestational duration
tota
l b
od
y w
eig
ht (in
gra
ms)
growth trajectory, mothers without symptoms (reference)
growth trajectory, mothers with family stress
growth trajectory, mothers with depressive symptomsHenrichs et al.,(2010) Psychol Med
Does Intrauterine growth affect infant problem
behavior?
Rosa S et al J Am Acad Child Adolesc Psychiatry. 2008,
47(3):264-72.
Copyright 2008 © American Academy of Child and Adolescent Psychiatry. Published by Lippincott Williams & Wilkins, Inc.
2
Associations Between Fetal Size and Infant Temperament
After controlling for several genetic and
socioeconomic status related factors, we found
little indication of an association between
intrauterine growth trajectories and temperamental
difficulties in infants.
J Am Acad Child Adolesc Psychiatry. 2008, 47(3):264-72.
Successive models Child internalizing problems at 3 yrs.
OR p OR p OR P
Prenatal depressive symptoms, per
Mother 1.18 <0.001 1.07 0.23 1.04 0.49
Father 1.07 0.22 1.05 0.33
Prenatal hostility
Mother 1.18 0.004 1.15 0.02
Father 1.15 0.008 1.14 0.02
Prenatal family functioning
Mother 1.28 <0.001
Father 0.99 0.92
SD
Successive models Child internalizing problems at 3 yrs.
OR p OR p OR P
Prenatal depressive symptoms, per
Mother 1.18 <0.001 1.07 0.23 1.04 0.49
Father 1.15 0.002 1.07 0.22 1.05 0.33
Prenatal hostility
Mother 1.18 0.004 1.15 0.02
Father 1.15 0.008 1.14 0.02
Prenatal family functioning
Mother 1.28 <0.001
Father 0.99 0.92
SD
Successive models Child internalizing problems at 3 yrs.
OR p OR p OR P
Prenatal depressive symptoms, per
Mother 1.18 <0.001 1.07 0.23 1.04 0.49
Father 1.15 0.002 1.07 0.22 1.05 0.33
Prenatal hostility, per
Mother 1.18 0.004 1.15 0.02
Father 1.15 0.008 1.14 0.02
Prenatal family functioning
Mother 1.28 <0.001
Father 0.99 0.92
Velders et al., ECAP, 2011
SD
SD
Successive models Child internalizing problems at 3 yrs.
OR p OR p OR P
Prenatal depressive symptoms, per
Mother 1.18 <0.001 1.07 0.23 1.04 0.49
Father 1.15 0.002 1.07 0.22 1.05 0.33
Prenatal hostility. per
Mother 1.18 0.004 1.15 0.02
Father 1.15 0.008 1.14 0.02
Prenatal family functioning
Mother 1.28 <0.001
Father 0.99 0.92
SD
SD
Successive models Child internalizing problems at 3 yrs.
OR p OR p OR P
Prenatal depressive symptoms
Mother 1.18 <0.001 1.07 0.23 1.04 0.49
Father 1.15 0.002 1.07 0.22 1.05 0.33
Prenatal hostility
Mother 1.18 0.004 1.15 0.02
Father 1.15 0.008 1.14 0.02
Prenatal family functioning
Mother 1.28 <0.001
Father 0.99 0.92
and postnatal symptoms ?
Successive models Child internalizing problems at 3 yrs.
OR p-value OR p-value
Prenatal depressive symptoms
Mother 1.0
1
0.75 1.06 0.36
Father 1.0
1
0.74 1.04 0.52
Prenatal hostility
Mother 1.1
2
0.07 1.04 0.52
Father 1.1
3
0.03 1.06 0.31
Prenatal family functioning
Mother 1.2
5
<0.001 1.23 <0.001
Father 0.9
7
0.65 0.96 0.51
Postnatal depressive symptoms
Mother 1.2 <0.001 1.07 0.28
Velders et al., ECAP, 2011
Prenatal and postnatal parental psychological
symptoms and family functioning and its impact
on child behavior at age 3
Prenatal depression in mothers and fathers are
associated with child problem behavior
However, this was accounted for by postnatal
parental hostility (mothers and fathers)
Prenatal family stress was independently
associated with child problem behavior
The role of maternal stress during pregnancy, maternal
discipline, and the child’s compliance at 3 years
Developmental Psychobiology
pages n/a-n/a, 21 MAY 2012 DOI: 10.1002/dev.21049
http://onlinelibrary.wiley.com/doi/10.1002/dev.21049/full#fig2
Conclusion
Prenatal psychological stress associated with fetal
development
Fetal development does not influence child
problem behavior
Prenatal depression associated with child behavior
through parental hostility
Prenatal family stress may indirectly affect child
development through spillover of prenatal stress
on parenting behavior
Smoking and Prenatal Head Growth
-3
-2.5
-2
-1.5
-1
-0.5
0
15 20 25 30 35
Gestational duration (in weeks)
Diffe
rence in f
oeta
l head
circum
fere
nce (
in m
m)
Non-smoking (reference)
Quit smoking when pregnancy known
Continued smoking
Children of mothers who continue smoking also have smaller cerebelli
and smaller cerebral ventricles
Adjusted for: maternal BMI, age, height, ethnicity, parity, SES, gender
child; maternal alcohol, prenatal anx, depression did not change
regression coeff for smoking Roza et al., Eur Neuroscience 2007
Smoking and Problem Behaviors at 18 Months
Parental smoking habits
CBCL Total Problems
Model 1 n OR (95% CI) P
No active or passive smoking 2205 Reference
Father smoked outside,
mother did not smoke
998 1.15 (0.86 – 1.52) 0.35
Father smoked indoors,
mother did not smoke
397 1.97 (1.40 – 2.76) < 0.001
Mother smoked 608 1.98 (1.48 – 2.64) < 0.001
CBCL Total Problems Fully Adjusted
Model 2 n OR (95% CI) P
No active or passive smoking 2205 Reference
Father smoked outside,
mother did not smoke
998 1.16 (0.87 – 1.56) 0.32
Father smoked indoors,
mother did not smoke
397 1.19 (0.82 – 1.71) 0.36
Mother smoked 608 1.22 (0.89 – 1.69) 0.22
Questionnaire self-reports in pregnancy
At 12 weeks
At 20 weeks
At 30 weeks
Pharmacy Records
Exposure in pregnancy was calculated using
date of delivery & gestational age at birth
calculation of last menstrual period and
conception date
Number of women per group in total GR-cohort
SSRI use at any time in pregnancy (n=99)
Depressive symptoms without SSRI use (n=570)
Control group, low depressive symptoms, no SSRI use
Outcome
Biparietal Diameter: the fetal cranium perpendicular to the midline
in the occipitofrontal plane
Transcerebellar diameter
Results
Association between SSRI exposure and fetal growth/fetal head growth
B + 95%CI P-value
Outcome: fetal weight gain in grams per week
SSRI use -2.0 (-6.6 to 2.5) .39
Depressive symptoms -4.4 (-6.4 to -2.5) <0.001
Control group Reference Reference
Outcome: fetal head growth in mm/week
SSRI use -0.18 (-0.31 to -0.06) .003
Depressive symptoms -0.08(-0.13 to -0.03) .003
Control group Reference Reference
All values were adjusted for maternal age, maternal Body Mass Index, parity, gender of the
child, maternal educational level and ethnicity, and maternal smoking and drinking habits.
Date of download: 9/16/2012Copyright © 2012 American Medical
Association. All rights reserved.
Arch Gen Psychiatry. 2012;69(7):706-714. doi:10.1001/archgenpsychiatry.2011.2333
Figure. The absolute (A) and relative (B) growth of fetal head circumference in 3 groups: fetuses exposed to selective serotonin
reuptake inhibitors (SSRIs) during pregnancy, fetuses exposed to high levels of depressive symptoms during pregnancy, and
fetuses in the control group. Estimates were obtained from fitting a fractional polynomial model adjusted for maternal age, maternal
body mass index, parity, sex of the child, maternal educational level and ethnicity, and maternal smoking habits and benzodiazepine
use.
Figure Legend:
SSRI and risk for autistic symptoms
Maternal SSRI use associated with increased risk
for autistic symptoms
Maternal depression associated with autistic
symptoms and affective problems in the child at
ages 1,5, 3 and 6 years
Risk of autistic traits was higher in those exposed
to SSRI versus those exposed to maternal
depression only
Conclusion
SSRIs in pregnancy is not without a risk for foetal
development.
In particular, head growth during foetal life appeared to be
affected by prenatal exposure to SSRIs.
Therefore, when prescribing SSRI treatment to depressive
pregnant women, clinicians should carefully consider the
expected risks for the child and the benefits for the pregnant
patient.
Vitamin D
• There is a growing body of evidence linking gestational vitamin D deficiency
with neurodevelopmental disorders such as schizophrenia and ASD
• No studies have examined the association between gestational vitamin D
deficiency and clinically diagnosed autism in general population samples.
Conclusion
Gestational vitamin D deficiency was
associated with two autism-related outcomes.
Because gestational vitamin D deficiency is
readily preventable with safe, cheap and
acceptable supplements, this candidate risk
factor warrants closer scrutiny.
Maternal thyroid hormones
Maternal thyroid hormones: a crucial role in child’s brain development
No fetal thyroid secretion before 12-14 weeks of gestation.
The fetus continues to rely on maternal thyroid hormones through the end
of pregnancy.
48
Maternal Hypothyroxemia and Language Delay
at 18 and 30 Months
0
0,5
1
1,5
2
*
*
Normal Mild Severe
risk of
language
delay
Models adjusted for maternal age, educational level,
psychopathology and prenatal smoking, birth weight, and
ethnicity of the child, and gestational age at the time of
thryoid sampling
Maternal Hypothyroxemia and Nonverbal
Cognitive Delay at 30 Months
0
0,5
1
1,5
2
2,5
*
Normal Mild Severe
risk nonverbal
cognitive delay
Association of gestational maternal hypothyroxinemia and increased autism risk at
age 6
Annals of Neurology
Volume 74, Issue 5, pages 733-742, 13 AUG 2013 DOI: 10.1002/ana.23976
http://onlinelibrary.wiley.com/doi/10.1002/ana.23976/full#ana23976-fig-0002
No associations with autism found for:
• Air Pollution exposure (Guxens et al., 2016, Env
Health Perspectives)
• Maternal folate (Steenweg-de Graaf et al., 2014,
Eur J Publ Health)
Conclusion
There is some evidence of associations of modifiable factors with
autistic problems in the general population for:
Vitamin D
Hypothyroxinemia
Uncertain: SSRI
No evidence: Folate, Air pollution
Postnatal Influences
Brain structure and problem behavior
Socioeconomic influences: ethnicity, poverty
Maternal depression and attachment
Breast feeding
Harsh parenting
TV watching
National Origin and Problem Behavior Pauline Jansen
Maternal National origin and Child Problems at age
18 months
* p-value <0.05, ** <0.01, *** <0.001.# Adjusted for parity, maternal age, marital status, maternal education, family income,
maternal psychopathology, and smoking habits during pregnancy.
Maternal national origin N CBCL Total Problems
Estimated means adjusted for family risk factors
Western
Dutch
European
Non-Western
Antillean
Cape Verdian
Indonesian
Moroccan
Surinamese
Turkish
Other Non-Western
All Non-Western
3190
406
84
110
190
164
278
301
220
1347
20.9 (20.0, 21.8)
24.3 (22.6, 26.0) ***
26.2 (22.8, 29.8) **
29.3 (26.2, 32.6) ***
23.7 (21.4, 26.0) *
23.4 (20.9, 26.0) *
22.7 (20.9, 24.5)
29.5 (27.3, 31.7) ***
29.3 (27.0, 31.7) ***
26.0 (24.9, 27.1) ***
Multiple Risk Factors
Amount of immigration risk factorsa
Ref.
Examples Risk factors:
-Poverty
-Does not speak Dutch
-Migrated >15 years
-Feels discriminated
-Poor education
-Psychopathology mother
DutchNumber of risks
….mechanisms underlying the effect of economic
disadvantage included maternal depressive symptoms,
along with parenting stress and harsh disciplining…..
Parental Behavior, Attachment and Child
Development
Attachment: Strange Situation Procedure (Ainsworth)
Attachment Classification: Secure (B) - Insecure (A,C)
Organized (D) - Disorganized (nonD) Anne
Tharner and
Rianne Kok
Infant attachment and maternal depression
Maternal history of depression and infant attachment
0
10
20
30
40
50
60
% insecure % disorganized
CIDI no, n = 550 CIDIyes, n = 77
Infant Attachment and Maternal
Depression
Maternal depressive symptoms and infant attachment security
0
10
20
30
40
50
60
no symptoms,
n = 310
prenatal symptoms,
n = 65
postnatal
symptoms, n = 94
pre- and postnatal
symptoms, n = 81
maternal depressive symptoms, assessed by BSI
% o
f in
fan
ts in
secu
re
Mother-child interaction at age 3
Father-child interaction at age 4
Teaching tasks
Do tasks
Don’t tasks
Duration of Breastfeeding and Maternal Sensitivity,
Attachment Security and Attachment Disorganization
Note: Scores for sensitivity, security and disorganization were z-standardized (Mean = 0, SD = 1).
Depicted are estimated marginal means taken from ANCOVA adjusted for parity and educational level.
Error bars represent standard errors of estimated means. Group differences in means are indicated: ** p < .01, * p < .05.
-0,5
-0,4
-0,3
-0,2
-0,1
0
0,1
0,2
0,3
0,4
0,5
never < 2 months 2-6 months at least 6months:
reference
Duration of breastfeeding
Att
ach
men
t secu
rity
, z-s
co
re* *
-0,5
-0,4
-0,3
-0,2
-0,1
0
0,1
0,2
0,3
0,4
0,5
never < 2 months 2-6 months at least 6months:
reference
Duration of breastfeeding
Mate
rnal sen
sit
ivit
y,
z-s
co
re
* *
-0,5
-0,4
-0,3
-0,2
-0,1
0
0,1
0,2
0,3
0,4
0,5
never < 2 months 2-6 months at least 6months:
reference
Duration of breastfeeding
Att
ach
men
t d
iso
rga
niz
ati
on
, z-s
co
re
* *
What we have learned from GenR
Large number of factors with each contributing relatively
small effects
Cumulative risk model: multiple risks are additive and
interact ( i.e. the child is at progressively greater risk,
despite the small impact any single factor is likely to have)
The most prominent factor is parental behavior (prenatal
and postnatal). Implications for intervention:
start early
67
Thank you for your
attention
Faculty
Frank C. Verhulst
Henning Tiemeier
Tonya White
Collaborators
Danielle Posthuma
Marinus van IJzendoorn
Marian Bakermans-Kranenburg
Wiro Niessen
Vince Calhoun
Ben Lahey
Philip Shaw
James J Hudziak/Alan Evans
Postdocs
Hanan El Marroun
Akghar Ghassabian
PhD Students
Sabine Mous
Laura Blanken
Ryan Muetzel
Andrea Wildeboer
Sandra Thijssen
Maja Radojči
Desana Kocevska
Philip Jansen