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

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

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

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

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

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

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

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

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

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)

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)

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)

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)

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

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

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

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)

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

Thank you! Contact me: terri.a.levine@gmail.com

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

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

PORTO-Associated Neurodevelopmental Assessment (PANDA) Study 7 major maternity hospitals in Ireland and Northern Ireland 1,100 women and their babies Follow-up to 2010-2011 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

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

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