Early life stress, MAOA, and gene-environment interactions predict behavioral disinhibition in children.

Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth-3 years) stressors to influence behavior in prepubertal children. The Avon Longitudinal Study of Parents and Children, UK, is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years. In both sexes, exposure to family adversity and stressful life events in the first 3 years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity. In a general population sample of prepubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR- stressful life event interactions specifically predicted hyperactivity.

Effects of early childhood lead exposure on academic performance and behaviour of school age children.

AIM: To determine whether early lead exposure at levels below 10 microg/dl has an impact on educational and behavioural outcomes at school. METHODS: Venous samples were taken from a subgroup of the Avon Longitudinal Study of Parents and Children (ALSPAC) attending a research clinic at 30 months of age (n = 582), and lead levels were measured by atomic absorption spectrometry. Developmental, behavioural and standardised educational outcomes (Standard Assessment Tests, SATs) were collected on these children at age 7-8 years. In the analysis, blood lead concentration was investigated both as a continuous covariate and as a categorical variable. RESULTS: 488 cases (84%) had complete data on confounders and outcomes. After adjustment for confounders and using a log dose-response model for lead concentration, blood lead levels showed significant associations with reading, writing and spelling grades on SATs, and antisocial behaviour. A doubling in lead concentration was associated with a 0.3 point (95% CI -0.5 to -0.1) decline in SATs grades. Treating lead levels categorically, with the reference group 0-2 microg/dl, no effects on outcomes were apparent at 2-5 microg/dl, but levels of 5-10 microg/dl were associated with a reduction in scores for reading (OR 0.51, p = 0.006) and writing (OR 0.49, p = 0.003). Lead levels >10 microg/dl were also associated with increased scores for antisocial behaviour (OR 2.9, p = 0.040) and hyperactivity (OR 2.82, p = 0.034). CONCLUSIONS: Exposure to lead early in childhood has effects on subsequent educational attainment, even at blood levels below 10 microg/dl. These data suggest that the threshold for clinical concern should be reduced to 5 microg/dl.

Developmental outcomes in early compared with delayed surgery for glue ear up to age 7 years: a randomised controlled trial.

OBJECTIVES: To investigate whether early versus delayed surgery for children severely affected by otitis media with effusion (OME) results in improved performance on developmental tests up to age 7 years. DESIGN: Follow-up of a randomised controlled trial. SETTING: University of Bristol. PARTICIPANTS: One hundred and eighty-two children (mean age 35 months) with persistent OME, hearing loss and speech, language or behaviour problems who were originally eligible and randomised to either early surgery or delayed surgery after a period of watchful waiting were followed-up as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 4 1/2 and 7-8 years. MAIN OUTCOME MEASURES: Measures included behaviour, language, educational attainment tests, hearing, reading, cognition and coordination. RESULTS: Of the original randomised trial, 88 of 92 of the early surgery and 74 of 90 of the watchful waiting group were still participating in ALSPAC. Analysis was by intention to treat. At age 4 1/2 years there were significant differences in teacher assessment of language (adj OR 3.45, 95% CI: 1.42-8.39) and writing (adj OR 3.74, 95% CI: 1.51-9.27), in favour of early surgery. At age 7-8 years, there was a significant difference on teacher report of emotional problems (adj OR 4.11, 95% CI: 1.15-14.64) in favour of early surgery. There were no other significant differences. CONCLUSIONS: Early surgery for the child severely affected by OME may be associated with subtle benefits at age 4 1/2 years. This may continue to 7-8 years but the small study size makes it difficult to distinguish these effects from chance. A larger study is recommended.

The variation in stool patterns from 1 to 42 months: a population-based observational study.

OBJECTIVE: To document the normal stool patterns of young children. DESIGN: Prospective population-based longitudinal study. SETTING: Avon Longitudinal Study of Parents and Children (ALSPAC). SUBJECTS: 12,984 children, whose parents completed questionnaires at 4 weeks, 6, 18, 30 and 42 months on their frequency of bowel movements and the consistency and colour of their stools. RESULTS: Stool frequency declined from a mean of 3.0 times/day (3rd centile 0.6, 97th centile 5.9) at 4 weeks to 1.3 times/day (0.6, 2.7) at 42 months. Stool consistency was soft in most babies with nearly half passing liquid or curdy stool at 4 weeks. 14% of babies usually passed a hard stool at 4 weeks, rising to 30% at 42 months. Stool colour was commonly yellow at 4 weeks and had changed to brown by 6 months. Black stools were extremely unusual at all ages. CONCLUSIONS: These data on the changes with age in the stool patterns of young children will be useful for clinicians.

Effect of an estrogen receptor-alpha intron 4 polymorphism on fat mass in 11-year-old children.

CONTEXT: Polymorphisms in the ESR1 gene encoding estrogen receptor (ER)-alpha may be associated with fat mass in adults. OBJECTIVES: The objective of the study was to establish whether ESR1 polymorphisms influence fat mass in childhood. DESIGN: This was a cross-sectional analysis after genotyping of rs9340799, rs2234693, and rs7757956 ESR1 polymorphisms. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC) was a population-based prospective study. PARTICIPANTS: Participants included 3097 11-yr-old children with results for ESR1 genotyping, puberty measures, and dual-energy x-ray absorptiometry results. OUTCOMES: Relationships between ESR1 polymorphisms and indices of body composition were measured. RESULTS: The rs7757956 polymorphism was associated with fat mass (P = 0.002). Total body fat mass (adjusted for height) was reduced by 6% in children with TA/AA genotypes, and risk of being overweight (> or =85th centile of fat mass) was decreased by 20%. This genetic effect appeared to interact with puberty in girls (P = 0.05 for interaction): in those with the TT genotype, total body fat mass (adjusted for height) was 18% higher in Tanner stages 3-5 vs. stages 1-2; the equivalent difference was 7% in those with TA/AA genotypes. Furthermore, the risk of being overweight was 36% lower in girls with TA/AA genotypes in Tanner stages 3-5, but no reduction was seen in those in stages 1-2. Neither rs9340799 nor rs2234693 polymorphisms were associated with body composition measures. CONCLUSIONS: Fat mass in 11-yr-old children was related to the rs7757956 ESR1 polymorphism. This association was strongest in girls in more advanced puberty, in whom the risk of being overweight was reduced by 36% in those with the TA/AA genotype.

Estrogen receptor alpha regulates area-adjusted bone mineral content in late pubertal girls.

CONTEXT: Whether the action of estrogen in skeletal development depends on estrogen receptor alpha as encoded by the ESR1 gene is unknown. OBJECTIVES: The aim of this study was to establish whether the gain in area-adjusted bone mineral content (ABMC) in girls occurs in late puberty and to examine whether the magnitude of this gain is related to ESR1 polymorphisms. DESIGN: We conducted a cross-sectional analysis. SETTING: The study involved the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective study. PARTICIPANTS: Participants included 3097 11-yr-olds with DNA samples, dual x-ray absorptiometry measurements, and pubertal stage information. OUTCOMES: Outcome measures included separate prespecified analyses in boys and girls of the relationship between ABMC derived from total body dual x-ray absorptiometry scans and Tanner stage and of the interaction between ABMC, Tanner stage, and ESR1 polymorphisms. RESULTS: Total body less head and spinal ABMC were higher in girls in Tanner stages 4 and 5, compared with those in Tanner stages 1, 2, and 3. In contrast, height increased throughout puberty. No differences were observed in ABMC according to Tanner stage in boys. For rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms, differences in spinal ABMC in late puberty were 2-fold greater in girls who were homozygous for the C and G alleles, respectively (P = 0.001). For rs7757956, the difference in total body less head ABMC in late puberty was 50% less in individuals homozygous or heterozygous for the A allele (P = 0.006). CONCLUSIONS: Gains in ABMC in late pubertal girls are strongly associated with ESR1 polymorphisms, suggesting that estrogen contributes to this process via an estrogen receptor alpha-dependent pathway.

Bone mass in childhood is related to maternal diet in pregnancy.

Evidence that birth weight is related to bone mass in later life suggests that the intrauterine environment programs the trajectory of subsequent bone development. To explore this hypothesis, we examined whether maternal diet in pregnancy, as assessed by the maternal food frequency questionnaire (FFQ) completed at 32 weeks gestation, is related to bone mass of the child, as measured by total body DXA carried out at age 9 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Diet records were linked to DXA scan results for the total body and spine sub-region and pooled between pre- and early pubertal boys and girls (n=4,451). Regression analysis was carried out between DXA values and dietary factors following adjustment for social and other confounding factors. Maternal magnesium intake was related to total body BMC (beta=4.9, 7.4-23.1; g) and BMD (beta=4.9, 2.5-7.3; g/cm2 x10(3)) (standardized regression coefficient with 95% confidence limits; P<0.001). An equivalent relationship was no longer observed after adjusting for the height of the child, to which magnesium intake was also related (beta=0.48, 0.20-0.77; cm; P=0.001). Maternal intake of potassium was related to spinal BMC (beta=1.8, 0.8-2.9; g) and BMD (beta=10.5, 4.9-16.0; g/cm2 x10(3)) (P=0.001), which was no longer observed after adjusting for the weight of the child, to which potassium intake was also related (beta=0.52, 0.16-0.88, P=0.005; kg). A significant association was also observed between maternal dietary folate intake and spinal BMC adjusted for bone area using a linear regression model (beta=0.55, 0.16-0.94; g; P=0.006), which persisted after adjusting for height and weight. Our observation that constituents of maternal diet are related to DXA measures at age 9 is consistent with the hypothesis that the trajectory of bone development in childhood is programmed by early life factors.