Andrew J. O. Whitehouse

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia

BACKGROUND: Over the past decade, the safety of anesthetic agents in children has been questioned after the discovery that immature animals exposed to anesthesia display apoptotic neurodegeneration and long-term cognitive deficiencies. We examined the association between exposure to anesthesia in children under age 3 and outcomes in language, cognitive function, motor skills, and behavior at age 10. METHODS: We performed an analysis of the Western Australian Pregnancy Cohort (Raine) Study, which includes 2868 children born from 1989 to 1992. Of 2608 children assessed, 321 were exposed to anesthesia before age 3, and 2287 were unexposed. RESULTS: On average, exposed children had lower scores than their unexposed peers in receptive and expressive language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E]) and cognition (Colored Progressive Matrices [CPM]). After adjustment for demographic characteristics, exposure to anesthesia was associated with increased risk of disability in language (CELF-R: adjusted risk ratio [aRR], 1.87; 95% confidence interval [CI], 1.20–2.93, CELF-E: aRR, 1.72; 95% CI, 1.12–2.64), and cognition (CPM: aRR, 1.69; 95% CI, 1.13–2.53). An increased aRR for disability in language and cognition persisted even with a single exposure to anesthesia (CELF-R aRR, 2.41; 95% CI, 1.40–4.17, and CPM aRR, 1.73; 95% CI, 1.04–2.88). CONCLUSIONS: Our results indicate that the association between anesthesia and neuropsychological outcome may be confined to specific domains. Children in our cohort exposed to anesthesia before age 3 had a higher relative risk of language and abstract reasoning deficits at age 10 than unexposed children.

Friendship, loneliness and depression in adolescents with Asperger's Syndrome

This study investigated the relation between friendship, loneliness and depressive symptoms in adolescents with Aspergers Syndrome (AS). Thirty-five adolescents with AS and 35 controls matched on chronological age, school year and gender distribution, completed questionnaires designed to ascertain the quality of their best-friendship, motivation for developing friendships, feelings of loneliness and depressive symptomatology. Relative to the comparison group, the participants with AS reported poorer quality of best-friendship and less motivation to develop friendships. The individuals with AS displayed higher levels of loneliness and depressive symptoms, with loneliness being negatively correlated with the quality of their best-friendship. Increased levels of loneliness in the adolescents with AS was predicted by the extent to which their best-friendships were characterized by high levels of conflict/betrayal. Increased depressive symptoms in the adolescents with AS were also predicted by this factor. The findings indicate that increased levels of negative affect may be related to the poor quality of social relationships often reported in this population.

Maternal Serum Vitamin D Levels During Pregnancy and Offspring Neurocognitive Development

OBJECTIVES: To determine the association between maternal serum 25(OH)-vitamin D concentrations during a critical window of fetal neurodevelopment and behavioral, emotional, and language outcomes of offspring. METHODS: Serum 25(OH)-vitamin D concentrations of 743 Caucasian women in Perth, Western Australia (32°S) were measured at 18 weeks pregnancy and grouped into quartiles. Offspring behavior was measured with the Child Behavior Checklist at 2, 5, 8, 10, 14, and 17 years of age (n range = 412–652). Receptive language was assessed with the Peabody Picture Vocabulary Test—Revised at ages 5 (n = 534) and 10 (n = 474) years. Raw scores were converted to standardized scores, incorporating cutoffs for clinically significant levels of difficulty. RESULTS: χ2 analyses revealed no significant associations between maternal 25(OH)-vitamin D serum quartiles and offspring behavioral/emotional problems at any age. In contrast, there were significant linear trends between quartiles of maternal vitamin D levels and language impairment at 5 and 10 years of age. Multivariate regression analyses, incorporating a range of confounding variables, found that the risk of women with vitamin D insufficiency (≤46 nmol/L) during pregnancy having a child with clinically significant language difficulties was increased close to twofold compared with women with vitamin D levels >70 nmol/L. CONCLUSIONS: Maternal vitamin D insufficiency during pregnancy is significantly associated with offspring language impairment. Maternal vitamin D supplementation during pregnancy may reduce the risk of developmental language difficulties among their children.

CNTNAP2 variants affect early language development in the general population

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four‐marker haplotypes of rs2710102–rs759178–rs17236239–rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype GCAG, P = .0014). Our study suggests that common variants in the exon 13–15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.

Prenatal Maternal Stress Associated with ADHD and Autistic Traits in early Childhood

Research suggests that offspring of mothers who experience high levels of stress during pregnancy are more likely to have problems in neurobehavioral development. There is preliminary evidence that prenatal maternal stress (PNMS) is a risk factor for both autism and attention deficit hyperactivity disorder (ADHD), however most studies do not control for confounding factors and no study has investigated PNMS as a risk factor for behaviors characteristic of these disorders in early childhood. A population cohort of 2900 pregnant women were recruited before their 18th week of pregnancy and investigated prospectively. Maternal experience of stressful life events was assessed during pregnancy. When offspring were age 2 years, mothers completed the child behavior checklist. Multiple regression showed that maternal stressful events during pregnancy significantly predicted ADHD behaviors in offspring, after controlling for autistic traits and other confounding variables, in both males (p = 0.03) and females (p = 0.01). Similarly, stressful events during pregnancy significantly predicted autistic traits in the offspring after controlling for ADHD behaviors and confounding variables, in males only (p = 0.04). In conclusion, this study suggests that PNMS, in the form of typical stressful life events such as divorce or a residential move, show a small but significant association with both autistic traits and ADHD behaviors independently, in offspring at age 2 years, after controlling for multiple antenatal, obstetric, postnatal, and sociodemographic covariates. This finding supports future research using epigenetic, cross-fostering, and gene–environment interaction designs to identify the causal processes underlying this association.

Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure

Introduction:Immature animals exposed to anesthesia display apoptotic neurodegeneration and neurobehavioral deficits. The safety of anesthetic agents in children has been evaluated using a variety of neurodevelopmental outcome measures with varied results. Methods:The authors used data from the Western Australian Pregnancy Cohort (Raine) Study to examine the association between exposure to anesthesia in children younger than 3 yr of age and three types of outcomes at age of 10 yr: neuropsychological testing, International Classification of Diseases, 9th Revision, Clinical Modification–coded clinical disorders, and academic achievement. The authors’ primary analysis was restricted to children with data for all outcomes and covariates from the total cohort of 2,868 children born from 1989 to 1992. The authors used a modified multivariable Poisson regression model to determine the adjusted association of anesthesia exposure with outcomes. Results:Of 781 children studied, 112 had anesthesia exposure. The incidence of deficit ranged from 5.1 to 7.8% in neuropsychological tests, 14.6 to 29.5% in International Classification of Diseases, 9th Revision, Clinical Modification–coded outcomes, and 4.2 to 11.8% in academic achievement tests. Compared with unexposed peers, exposed children had an increased risk of deficit in neuropsychological language assessments (Clinical Evaluation of Language Fundamentals Total Score: adjusted risk ratio, 2.47; 95% CI, 1.41 to 4.33, Clinical Evaluation of Language Fundamentals Receptive Language Score: adjusted risk ratio, 2.23; 95% CI, 1.19 to 4.18, and Clinical Evaluation of Language Fundamentals Expressive Language Score: adjusted risk ratio, 2.00; 95% CI, 1.08 to 3.68) and International Classification of Diseases, 9th Revision, Clinical Modification–coded language and cognitive disorders (adjusted risk ratio, 1.57; 95% CI, 1.18 to 2.10), but not academic achievement scores. Conclusions:When assessing cognition in children with early exposure to anesthesia, the results may depend on the outcome measure used. Neuropsychological and International Classification of Diseases, 9th Revision, Clinical Modification–coded clinical outcomes showed an increased risk of deficit in exposed children compared with that in unexposed children, whereas academic achievement scores did not. This may explain some of the variation in the literature and underscores the importance of the outcome measures when interpreting studies of cognitive function.

Evaluating the twin testosterone transfer hypothesis: A review of the empirical evidence

In this paper we review the evidence that fetuses gestated with a male co-twin are masculinized in development, perhaps due to the influence of prenatal androgens: the so-called twin testosterone transfer (TTT) hypothesis. Evidence from studies of behavioral, perceptual, cognitive, morphological and physiological traits in same- and opposite-sex human twins is considered. Apart from two studies reporting increases in aspects of sensation-seeking for females with a male rather than a female co-twin, there is sparse evidence supporting the TTT hypothesis in behavioral studies. Outcomes from studies of perception (in particular otoacoustic emissions) and cognition (in particular vocabulary acquisition and visuo-spatial ability) provide more consistent evidence in support of masculinized performance in twins with a male co-twin compared to twins with a female co-twin. The outcomes favorable to the TTT hypothesis for otoacoustic emissions and visuo-spatial ability are restricted to females. Studies of physiology and morphology (e.g., brain volume, tooth size and 2D:4D ratio) also show some influence of co-twin sex, but again these effects are often restricted to female twins. Because females produce little endogenous testosterone, the effects of gestation with a male co-twin may be more pronounced in females than males. Thus, while uneven, the evidence for the TTT hypothesis is sufficient to warrant further investigation, ideally using large samples of same- and opposite-sex twins, along with control groups of same- and opposite-sex siblings when the characteristics assessed are potentially open to social influences.

Vitamin D in Fetal Development: Findings From a Birth Cohort Study

Birth cohort studies provide an invaluable resource for studies of the influence of the fetal environment on health in later life. It is uncertain to what extent maternal vitamin D status influences fetal development. Using an unselected community-based cohort of 901 mother-offspring pairs (the Western Australian Pregnancy Cohort [Raine] Study), we examined the relationship between maternal vitamin D deficiency at 18 weeks’ pregnancy and long-term health outcomes of offspring who were born in Perth, Western Australia (32° South), in 1989–1991. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 36% (323 of 901) of the pregnant women. After adjusting for relevant covariates, maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years. In summary, vitamin D may have an important, multifaceted role in the development of fetal lungs, brain, and bone. Experimental animal studies support an active contribution of vitamin D to organ development. Randomized controlled trials of vitamin D supplementation in pregnant women with long-term follow-up of offspring are urgently required to examine whether the correction of vitamin D deficiency in pregnant women is beneficial for their offspring and to determine the optimal level of maternal serum 25(OH)D for fetal development.

Do hypertensive diseases of pregnancy disrupt neurocognitive development in offspring

The current study sought to determine whether hypertensive diseases of pregnancy (gestational hypertension and pre-eclampsia) are associated with neurocognitive outcomes in middle childhood. Participants were members of the Western Australian Pregnancy Cohort (Raine) Study. Data were available for 1389 children (675 females; mean age = 10.59 years; SD = 0.19). Twenty-five per cent of these participants were offspring of pregnancies complicated by either gestational hypertension (n = 279), or pre-eclampsia (n = 34). Verbal ability at age 10 years was assessed with the Peabody Picture Vocabulary Test - Revised (PPVT-R), and non-verbal ability with Ravens Colored Progressive Matrices (RCPM). Separate multivariable regression analyses, incorporating sociodemographic, antenatal, obstetric and postnatal covariates, investigated the effect of a two- (normotensive pregnancy vs. hypertensive pregnancy) and three-level (normotensive pregnancy vs. gestational hypertension vs. pre-eclampsia) predictor variable on PPVT-R and RCPM scores. Offspring of pregnancies complicated by maternal hypertension (gestational hypertension or pre-eclampsia) had a mean PPVT-R score that was 1.83 ([95% confidence interval (CI) -3.48, -0.17], P = 0.03) points lower than children from normotensive pregnancies. Multivariable regression analysis also identified a significant inverse association between the three-level predictor variable and offspring PPVT-R scores (P = 0.02). Gestational hypertension (without pre-eclampsia) reduced offspring PPVT-R scores by 1.71 points [95% CI -3.39, -0.03] and pre-eclampsia led to a reduction of 3.53 points [95% CI -8.41, 1.35], although this latter association did not achieve statistical significance. There was no effect of the two- (P = 0.99) or three-level (P = 0.92) predictor variable on RCPM scores. Maternal hypertensive diseases of pregnancy are a risk factor for a small reduction in offspring verbal ability.

A Genome-Wide Approach to Children's Aggressive Behavior: The EAGLE consortium

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome‐wide approaches of aggressive behavior in children. We analyzed data from nine population‐based studies and assessed aggressive behavior using well‐validated parent‐reported questionnaires. This is the largest sample exploring childrens aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of childrens aggressive behavior based on genome‐wide SNP information, using genome‐wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi‐Poisson regression approach, capturing the highly right‐skewed distribution of aggressive behavior. Third, we performed meta‐analyses of genome‐wide associations for both the total age‐mixed sample and the two developmental stages. Finally, we performed a gene‐based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10–54%). The meta‐analysis of the total sample identified one region in chromosome 2 (2p12) at near genome‐wide significance (top SNP rs11126630, P = 5.30 × 10−8). The separate meta‐analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene‐based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning.