Groei en ontwikkeling van

zwangerschap tot adolescentie:

GenerationR

Symposium Infantpsychiatrie

Nijmegen 28 juni 2016

Frank Verhulst

ErasmusMC

f.verhulst@erasmusmc.nl

GenerationRBehavioral Research in a Cohort From Fetal Life

Onwards

f.verhulst@erasmusmc.nl

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

Prenatal risk

Fetal growth

Postnatal functioning

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

Does maternal psychological distress in

pregnancy affect 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

Associations Between fetal growth 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.

Maternal prenatal distress and

postnatal child behavior

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

Maternal smoking during pregnancy – is it

harming the mother or fetus most?

Prenatal Ultrasound Measurements

BPD

HC

LVAW

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

Antidepressant use during pregnancy

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

Estimated fetal weight, femur length and head

circumference

Head circumference

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

Prenatal SSRI & autistic symptoms

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.

Prevalence of deficiency in midgestation and

cord 25OHD samples

Association between midgestation and cord 25OHD

deficiency and Social Responsiveness Scale

Association between prenatal and cord 25OHD

deficiency and clinical Autism case-control status

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