Presentatie van dhr. prof. dr. Frank Verhulst op het Infantscongres Nijmegen op 28 juni 2016 over de verschillen in ontwikkeling van kinderen, het onderzoek GenerationR.

1. Groei en ontwikkeling van
zwangerschap tot adolescentie:
GenerationR
Symposium Infantpsychiatrie
Nijmegen 28 juni 2016
Frank Verhulst
ErasmusMC
f.verhulst@erasmusmc.nl

2. GenerationRBehavioral Research in a Cohort From Fetal Life
Onwards
f.verhulst@erasmusmc.nl

3. 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

4. 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

5.  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

6. 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
Ultrasound
Measures
Psychiatric
Interview
Question
naire 7
Question
naire 10
Question
naire 11
Questio
naire 6
Neuromotor
assessment
Home
observation
Research
Center visit 1
e.g. Brain
ultrasound
Research
Center visit 2
Neuromotor
assessment
Research Center
visit 3
e.g. Strange
situation
Research
Center visit 5
e.g. Executive
function
Fetal
Ultrasound
Blood
Fetal
Ultrasound
Urine
Question
naire 12
Quest
14
Father
Quest.
Assessments in Generation R Cohort
Question
naire 1
Question
naire 3
Question
naire 4
Cord blood
Birth weight
Complications
Father
Quest.
Home Visit
e.g. father-child
interaction,
compliance
Generation
@ age 6
center visit:
intelligence
test + child
interview
GenerationR
@ age 10
center visit: MRI,
brain,heart,lung
Fam.interaction
Ostracism etc.
Question
15
Question
17
Father
Quest.

7. Prenatal Influences
 Maternal stress/depression
 Maternal smoking
 Maternal cannabis use
 Maternal folic acid
 Maternal thyroid hormone
 Maternal diet
 Maternal SSRI use

8. Prenatal risk
Fetal growth
Postnatal functioning

9. 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

10. Does maternal psychological distress in
pregnancy affect fetal growth?

11. 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

12. 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

13. 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
totalbodyweight(ingrams)
growth trajectory, mothers without symptoms (reference)
growth trajectory, mothers with family stress
growth trajectory, mothers with depressive symptoms
Henrichs et al.,(2010) Psychol Med

14. Does Intrauterine growth affect infant problem
behavior?
Rosa S et al J Am Acad Child Adolesc Psychiatry. 2008,
47(3):264-72.

15. Copyright 2008 © American Academy of Child and Adolescent Psychiatry. Published by Lippincott Williams &
Wilkins, Inc.
2
Associations Between Fetal Size and Infant
Temperament

16. Associations Between fetal growth and Infant Temperament

17. 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.

18. Maternal prenatal distress and
postnatal child behavior

19. 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

20. 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

21. 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

22. 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

23. 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 ?

24. 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

25. 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

26. 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

27. 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

28. Maternal smoking during pregnancy – is it
harming the mother or fetus most?

29. Prenatal Ultrasound Measurements
BPD
HC
LVAW

30. Smoking and Prenatal Head Growth
-3
-2.5
-2
-1.5
-1
-0.5
0
15 20 25 30 35
Gestational duration (in weeks)
Differenceinfoetalhead
circumference(inmm)
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

31. 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

32. Antidepressant use during pregnancy

34.  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

35.  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

36. Outcome
 Estimated fetal weight, femur length and head
circumference
 Head circumference

37. Outcome
 Biparietal Diameter: the fetal cranium perpendicular to the midline
in the occipitofrontal plane
 Transcerebellar diameter

38. 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.

39. Date of download: 9/16/2012
Copyright © 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:

40. 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

41. Prenatal SSRI & autistic symptoms

42. 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.

43. 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.

44. Prevalence of deficiency in midgestation and
cord 25OHD samples

45. Association between midgestation and cord 25OHD
deficiency and Social Responsiveness Scale

46. Association between prenatal and cord 25OHD
deficiency and clinical Autism case-control status

47. 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.

48. 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

49. 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

50. 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

51. 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

52. 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)

53. 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

54. Postnatal Influences
 Brain structure and problem behavior
 Socioeconomic influences: ethnicity, poverty
 Maternal depression and attachment
 Breast feeding
 Harsh parenting
 TV watching

55. National Origin and Problem Behavior
Pauline Jansen

56. 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) ***

57. 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
Dutch
Number of risks

58.  ….mechanisms underlying the effect of economic
disadvantage included maternal depressive symptoms,
along with parenting stress and harsh disciplining…..

59. 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

60. 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

61. 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
%ofinfantsinsecure

62. Mother-child interaction at age 3
Father-child interaction at age 4
 Teaching tasks
 Do tasks
 Don’t tasks

64. 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 6
months:
reference
Duration of breastfeeding
Attachmentsecurity,z-score * *
-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 6
months:
reference
Duration of breastfeeding
Maternalsensitivity,z-score
* *
-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 6
months:
reference
Duration of breastfeeding
Attachmentdisorganization,z-score
* *

66. 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. 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