1. Early Childhood Neurodevelopment after IUGR: a Systematic Review
Terri Levine
Professor Ruth Grunau
Dr. RagaMallika Pinnameneni
Professor Fionnuala McAuliffe
Dr. Adrienne Foran
Professor Fiona Alderdice

2. Intrauterine Growth Restriction (IUGR)
Significant reduction in fetal growth resulting in birth weight in lowest 10th percentile for GA
Occurs in 5-7% of all pregnancies
Can be associated with abnormal Doppler ultrasound
5-10% of IUGR pregnancies result in stillbirth or neonatal death

3. IUGR: Placental Insufficiency
Most common identifiable cause of IUGR
Can be associated with hypoxia, hypoglycemia, lactic acidosis
Factors include
abnormal trophoblast invasion
placental infarcts
placenta previa
circumvallate placenta
umbilical-placental vascular anomalies

4. IUGR: Outcomes
Poorest outcomes follow severe or early-onset IUGR, prematurity, impaired fetal umbilical artery flow
Majority of IUGR infants show increased postnatal growth velocity
Catch-up growth by 2-3 years
IUGR infants often have decreased nutritional stores
~10% remain susceptible to sustained growth delay
Increased risk of diabetes, hypertension, stroke, heart disease
Several early childhood neurodevelopment follow-up studies conducted; not systematically reviewed or assessed for quality

5. Aim of Systematic Review
Examine associations between IUGR and neurodevelopment in first three years of life

6. Methods: Database Search
Conducted comprehensive literature search to identify studies through March 2014
Databases
PubMed
Embase
PsycINFO
Maternity and Infant Care
CINAHL
Search terms
Intrauterine, growth restriction, child development, neurodevelopment, early childhood, cognitive, motor, speech, language

7. Methods: Inclusion Criteria
Study participants met specified criteria for IUGR
Birth weight <10th percentile for GA
Follow-up from 6 months to 3 years
Study methods adequately described
Non-IUGR comparison group(s) included
Full English text of the article available

8. Methods: Study Selection
731 articles returned in database search
579 articles excluded by title
152 abstracts reviewed
35 articles excluded by abstract
117 full-text articles analysed
101 articles excluded by full-text
16 studies included in review

9. Methods: Quality Assessment
Suitable outline for assessing quality of evidence on prognostics and health outcomes
Evaluates 6 areas of potential bias
Study participation
Study attrition
Prognostic factor measurement
Outcome measurement
Confounding factor analysis
Data analysis
Used ISPOR retrospective database checklist to evaluate data source quality in 1 included retrospective study

10. Results: 6 months to 1 year (2/4)
4 studies
2 defined IUGR by LBW or FAC
Higher rates of neuromotor/neurological abnormalities, mostly mild (Fernandez-Carrocera 2003)
No significant differences between IUGR and SGA (Roth 1999)
2 defined IUGR by abnormal Doppler parameters
Preterm asymmetric IUGR infants scored lower on NBAS compared to controls and symmetric IUGR (Figueras 2011)
No significant differences between preterm children with and without IUGR on the Hammersmith Infant Neurological Examination or Bayley-II (Padilla 2010)

11. Results: 1 to 2 Years (8/9) 9 studies 4 defined IUGR by LFW or FAC
IUGR children scored lower on Bayley-II Mental Development Index (MDI) at 18 months (Amin 1997)
Cognitive, linguistic, and motor deficits using Bayley-II (Batalle 2012)
Only girls with most severe IUGR were at increased risk of neurodevelopmental impairment using Bayley-II (Streimish 2012)
Both SGA and AGA VLBW infants with and without severe IUGR were neurodevelopmentally delayed, but not significantly related to severe IUGR (Procianoy 2009)

12. Results: 1 to 2 Years 9 studies
5 studies defined IUGR using abnormal Doppler
53% IUGR children had linguistic/motor delays (Baschat 2009)
Motor deficits using Bayley-II (Esteban 2010, Padilla 2011)
Lower scores on adaptive behaviour subscale: health, safety, self-care, self-direction (Esteban 2010)
Increased risk of cognitive, linguistic, motor delays on Bayley-II (von Beckerath 2013)
Abnormal neurodevelopmental outcome predicted by LBW, fetal acidosis, and placental villitis (Torrance 2010)

13. Results: 2 to 3 Years (2/4) 4 studies 3 defined IUGR by LBW
IUGR children more delayed (Fattal-Valevski 1999)
Cephalisation index, neonatal risk score, birth weight most significantly correlated with developmental outcomes
Asymmetric IUGR children scored lower on Composite Infant Scale (Villar 1984)
Children with symmetric IUGR scored lower on mental items
No significant neurodevelopmental differences (Amin 1997)
Persistence of microcephaly associated with more adverse outcomes
1 defined IUGR using abnormal Doppler
Did not find difference in Stanford-Binet scores (Llurba 2013)

14. Results: Summary 12/16 report poorer neurodevelopment after IUGR
9 found cognitive delay
7 found language delay
10 found motor delay
Reduced adaptive behaviour skills also reported
Neonatal risk factors associated with delay after IUGR:
LBW
Fetal acidosis
Placental villitis
Persistent microcephaly

15. Results: Quality Assessment
Non-standardised outcome measures
Increases measurement bias, complicates study comparison
11/16 inadequately describe study attrition
2/16 inadequately describe adjustment for confounders
1 retrospective study, did not outline quality assessment of data sources

16. Review Limitations
Heterogeneity of primary outcome, assessment choices, adjustment for confounding variables, IUGR definition
Limits synthesis and interpretation of current research
Neglecting to include abnormal Doppler in definition of IUGR conflates IUGR with SGA
Many studies examine preterm IUGR infants without including term IUGR or term AGA comparison groups
Significant reliance on Bayley-II and –III
Acton 2011, Anderson 2010, Chinta 2014, Lowe 2012
Small sample sizes
Low power to detect meaningful differences
3 studies with >100 IUGR children, all found significant deficits

17. Definition of IUGR
8 studies used fetal or birth weight or FAC to define IUGR
8 required abnormal Doppler parameters
6/8 found neurodevelopmental delay
Difficult to determine from this review whether including Doppler parameters allows for more sensitivity
Stricter definition requiring abnormal Doppler and EFW<3rd centile may be important
In study of 1116 fetuses, abnormal Doppler associated with adverse obstetric, neonatal outcomes, regardless of EFW, FAC (Unterscheider 2013)
Additional research into neurodevelopmental outcomes following asymmetric growth restriction
“Brain-sparing” phenomenon, considered protective
Two studies in review found asymmetric IUGR preceded more adverse neurodevelopmental outcomes (Figueras 2011, Villar 1984)

18. Conclusions IUGR is a major public health problem
16 studies reviewed indicate IUGR often results in neurodevelopmental delay
IUGR inconsistently defined and often conflated with SGA
Follow-up studies would be helpful
Essential to standardise definitions, study design, and outcome measures
Great need for additional neuroimaging data and development of interventional strategies

19. Thank you!
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20. Neuroimaging
Hippocampal grey matter volume reduction (Lodygensky 2008)
Intracranial volume and cerebral cortical grey matter reduction (Tolsa 2004)
Reorganisation of white matter circuitry (Batalle 2012)
Neuroimaging results correlate with lower Bayley scores
Baschat 2009, Esteban 2010, Batalle 2012

21. Later Childhood Neurodevelopment after IUGR
Preterm IUGR children scored lower on verbal and full-scale IQ tests at 5-8 years than preterm or term AGA (Morsing 2011)
Significant differences in growth, neurodevelopment, and IQ scores at 6 years (Leitner 2000)
Spatial orientation, coordination problems, lower academic achievement at 9-10 years (Leitner 2005)
Lower IQs, difficulties with language, creativity, executive functioning, short-term memory (Geva 2006, 2008)
Learning disabilities, difficulties with verbal knowledge, decoding and comprehension, arithmetic

22. PORTO-Associated Neurodevelopmental Assessment (PANDA) Study
7 major maternity hospitals in Ireland and Northern Ireland
1,100 women and their babies
Follow-up to PORTO study
Detailed ultrasound measurements taken at 2-weekly intervals
Babies’ medical status and condition following delivery recorded
Found highest risk EFW <3rd centile, abnormal UA Doppler (Unterscheider 2013)
Neurodevelopmental, psychosocial, and anthropometric assessments of these children at age 3
Examine predictive value of abnormal UA Doppler, AEDF, and low-growth trajectory modelling

23. Gender Differences in Streimish et al. 2012
Assessed at 24 months
Used Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley-II
Split children into B-SGA (SGA based on birth weight curves) and F- SGA (SGA based on fetal weight curves)—B-SGA more severe IUGR
B-SGA, not F-SGA girls had lower PDI
B-SGA and F-SGA boys did not have lower indices
Neurosensory limitations diminished associations among girls of B- SGA with low MDI, and among B-SGA and F-SGA boys with low PDI
Summary: only girls with most severe growth restriction (B-SGA) were at increased risk
Neurosensory limitations interfere with assessing FGR in preterms

24. Bayley-II v. -III Acton 2011 Anderson 2010 Chinta 2014 Lowe 2012
Compared Bayley-II and –III scores of children after early complex cardiac surgery
Bayley-III scores on average 6.1 points higher
Greatest difference 10-point increase in mean cognitive scores
Anderson 2010
Extremely preterm or VLBW children
Extremely preterm/VLBW significantly lower Bayley-III scores than controls but approached normative mean
Controls’ scores higher than normative mean
Proportions of children with developmental delay grossly underestimated using reference values, within expected range using controls’ mean
Chinta 2014
Term healthy newborn control infants from prospective Development after Infant Surgery study at 3 years
Mean scores compared with standardised norms
Mean scores were higher than standardised norms on 4 subscales (not gross motor)
Recommend re-standardising for Australian children
Lowe 2012
Bayley-III cognitive scores significantly higher than Bayley-II MDI scores for term and preterm toddlers combined and separately
Calculated a conversion formula to convert Bayley-II MDI to Bayley-III cognitive scores
At-risk children who previously qualified for early developmental intervention may no longer