The association between impaired fetal growth and neurodevelopment in childhood

Murray, E

Abstract:: Impaired fetal growth is associated with an increased risk of negative neurodevelopmental outcomes. The majority of research to date, however, has relied on birth weight as an index of fetal growth impairment. Furthermore, few studies have included samples from low- and middle-income countries (LMICs). The objective of this thesis was to examine the association between impaired fetal growth, using a range of birth indices, and neurodevelopment in childhood.

A systematic review showed that cognitive development and attention are two domains particularly affected by impaired fetal growth and thus was the focus of this thesis. Cognitive development and attention were assessed in three large, prospective birth cohorts drawn from high-, middle- and low-income countries: Pelotas (Brazil) 2004 (N=3579), ALSPAC (UK) (N=7354) and INTERGROWTH-21^st (UK, Italy, Brazil, India and Kenya) (N=1073). INTERGROWTH-21^st only enrolled low-risk mothers, whereas Pelotas and ALSPAC were not selective. In all three cohorts, indices of birth weight, stunting, wasting and asymmetry were collected at birth. Attention was assessed using subscales of the Child Behaviour Checklist or the Strengths and Difficulties Questionnaire; and cognition was assessed using the Wechsler Preschool and Primary Scales of Intelligence-Revised or INTERGROWTH-21^st Neurodevelopmental Assessment (INTER-NDA). Each cohort measured these outcomes at one time point (range = 2-6 years of age). As part of this thesis the INTER-NDA was validated against the Bayley Scales of Infant Development.

Associations between birth anthropometric indices and both cognitive and attention outcomes were assessed using hierarchical ordinal logistic regression. Attention impairment was associated with stunted birth length (BL) but only in females (OR=1.21-1.69, p<.05), across cohorts drawn from high-, middle- and low-income countries. In contrast, cognitive impairment was associated with stunted head circumference (HC) and low ponderal index (PI) in both sexes, although predominantly in LMIC settings (HC: OR=1.73-1.91, p<.05; PI: OR=1.46-4.91, p<.05).

Identification of a female-specific association between stunted BL and poor attention across cohorts from different settings, suggests the association is robust to differential confounding effects. In contrast, the stronger association in LMICs between cognitive impairment and stunted HC and low PI suggests confounding structures (e.g. maternal and neonatal health care) may modify the effect of fetal growth on cognitive development. Birth indices (specifically BL, HC and PI) may be particularly helpful in identifying children at risk of neurodevelopmental impairment for early intervention.

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APA Style

Murray, E. (2015). The association between impaired fetal growth and neurodevelopment in childhood [PhD thesis]. University of Oxford.

MLA Style

Murray, E. The Association between Impaired Fetal Growth and Neurodevelopment in Childhood. 2015. University of Oxford, PhD thesis.

Chicago Style

Murray, E. 2015. “The Association between Impaired Fetal Growth and Neurodevelopment in Childhood.” PhD thesis, University of Oxford.
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Authors

+ Murray, E More by this author

Institution:: University of Oxford
Division:: MSD
Department:: Psychiatry
Oxford college:: University College
Role:: Author

Contributors

+ Stein, A

Institution:: University of Oxford
Division:: MSD
Department:: Psychiatry
Role:: Supervisor

+ Fernandes, M

Institution:: University of Oxford
Division:: MSD
Department:: Women's & Reproductive Health
Role:: Supervisor

DOI:: 10.5287/ora-dmygnje7m
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Language:: English
Keywords:: cognitive development

fetal growth

anthropometry

neurodevelopment

attention development
Subjects:: Neurodevelopment

Attention

Cognition in children

Fetus--Growth

Fetal brain--Growth
UUID:: uuid:f3a12dd8-868b-4e13-99f6-20b8f4b5adba
Deposit date:: 2016-06-26
ARK identifier:: ark:/29072/ora_f3a12dd8868b4e1399f620b8f4b5adba

Related item:: Sex differences in the association between foetal growth and child attention at age four: specific vulnerability of girls
Description:: Background Recent evidence suggests that impaired foetal growth may provide an early indication of increased risk of child attention problems. However, despite both foetal growth and child attention problems differing by sex, few studies have examined sex differences in this association. Furthermore, no studies have been conducted in low- and middle-income countries, where there are higher rates of perinatal problems. This study aimed to test for sex differences in the association between foetal growth indices and attention problems at age four, in a large, prospective birth cohort from a middle-income country.MethodsA total of 3,749 neonates from the 2004 Pelotas birth cohort (Brazil) with foetal growth indices collected at birth [low birthweight (LBW), small-for-gestational age (SGA), head circumference (HC), head circumference-to-abdominal circumference ratio (HC/AC) and ponderal index (PI)], were assessed for attention problems using the Child Behaviour Checklist at age four. Ordinal logistic regression with successive adjustment for maternal, demographic, gestational, perinatal and child nutrition/mother–child morbidity, was conducted separately for girls and boys.ResultsIn girls, attention difficulties were associated with being born SGA (OR = 1.40, CI = 1.08–1.82, p = .012), with a small HC (OR = 1.52, CI = 1.11–2.08, p = .009), or with a low PI (OR = 1.29, CI = 1.08–1.54, p = .005). There were no associations identified between attention difficulties and any foetal growth indices in boys.ConclusionsOur results show that girls with impaired foetal growth may be particularly at risk of attention difficulties in childhood. This is consistent with emerging research that female foetuses may be more vulnerable to certain suboptimal intrauterine environments, inducing epigenetic changes that lead to disturbed growth and long-term developmental impairment.
Related item:: Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison of high- and middle-income cohorts
Description:: Background Cross-cohort comparison is an established method for improving causal inference. This study compared 2 cohorts, 1 from a high-income country and another from a middle-income country, to (1) establish whether birth exposures may play a causal role in the development of childhood attention problems; and (2) identify whether confounding structures play a different role in parent-reported attention difficulties compared with attention deficit hyperactivity disorder (ADHD) diagnoses.Methods Birth exposures included low birth weight (LBW), small-for-gestational age (SGA), small head circumference (HC) and preterm birth (PTB)). Outcomes of interest were attention difficulties (Strengths and Difficulties Questionnaire, SDQ) and ADHD (Development and Well-Being Assessment, DAWBA). Associations between exposures and outcomes were compared between 7-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK (N=6849) and the 2004 Pelotas cohort in Brazil (N=3509).Results For attention difficulties (SDQ), the pattern of association with birth exposures was similar between cohorts: following adjustment, attention difficulties were associated with SGA (OR=1.59, 95% CI 1.20 to 2.19) and small HC (OR=1.64, 95% CI 1.11 to 2.41) in ALSPAC and SGA (OR=1.35, 95% CI 1.04 to 1.75) in Pelotas. For ADHD, however, the pattern of association following adjustment differed markedly between cohorts. In ALSPAC, ADHD was associated with LBW (OR=2.29, 95% CI 1.09 to 4.80) and PTB (OR=2.33, 95% CI 1.23 to 4.42). In the Pelotas cohort, however, ADHD was associated with SGA (OR=1.69, 95% CI 1.02 to 2.82).Conclusions The findings suggest that fetal growth impairment may play a causal role in the development of attention difficulties in childhood, as similar associations were identified across both cohorts. Confounding structures, however, appear to play a greater role in determining whether a child meets the full diagnostic criteria for ADHD.
Related item:: Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review
Description:: Background Neurodevelopmental disorders are increasingly believed to originate from intrauterine growth restriction (IUGR). Current reviews exploring the neurodevelopmental effects of IUGR, however, are mostly based on birthweight, an inadequate proxy.ObjectiveWe aimed to examine the association between IUGR documented in utero, and neurodevelopmental outcomes during childhood.Search strategyMedline, CINAHL, PsycInfo and Scopus were searched for relevant studies published after 1970.Selection criteriaThe analysis included studies that identified IUGR in utero, with follow-up assessments between 1 month and 12 years of age.Data collection and analysisData was extracted for cognitive, behavioural, language, motor, hearing, vision or sleep outcomes. Studies were summarised separately for children born at <35 and ≥35 weeks gestation.Main resultsOf 28 876 titles identified, 38 were suitable for inclusion. IUGR children born ≥35 weeks gestation scored on average 0.5 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children born <35 weeks of gestation scored approximately 0.7 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children with evidence of fetal circulatory redistribution (preferential perfusion of the brain) had more severe neurodevelopmental impairments than those born IUGR alone.ConclusionsIUGR increases the risk of neurodevelopmental impairment during childhood differentially across domains. IUGR children born preterm or with evidence of fetal circulatory redistribution are more severely affected.

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