Social cognition and behavioral outcomes in congenital heart disease: profiles and neuropsychiatric comorbidities.

Autism spectrum disorders are more prevalent in children with congenital heart disease (CHD) than in the general population. Children with CHD without diagnosed autism are also at increased risk for neurodevelopmental and psychiatric impairments. We characterized social and behavioral outcomes in children with CHD and examined neurodevelopmental and psychiatric comorbidities. Children without diagnosed autism who underwent infant open-heart surgery were eligible. Parent-reports assessed social communication, unusual behaviors, self-regulation, anxiety, and executive function (EF). Neuropsychological tests assessing theory of mind (ToM), working memory, and verbal comprehension were administered. Outcomes were compared to normative data. Linear regressions were estimated with parent-reported scores and ToM abilities as outcomes. Predictors were anxiety symptoms, parent-reported EF, and working memory scores. Covariates were age, parental education, ADHD diagnosis, and verbal comprehension. Clinically relevant comorbidities were identified (N children scoring ≥1SD below the norm). Fifty-six children (10.8 ± 1.8 years) participated virtually. Compared to norms, children with CHD had impaired ToM, more unusual behaviors (p = .002), and less self-regulation (p = .018), but better social communication (p = .014). "Autism-like" traits were positively associated with anxiety symptoms (ß(95% CI) = 0.28(0.08-0.49), p = .008) and worse working memory (ß(95% CI) = -0.36(-0.59-0.13), p = .003). Twenty-one out of 22 children who displayed clinically relevant social and behavioral scores also showed anxiety symptoms (n = 4), impaired EF (n = 7), or both (n = 10). Children with CHD without diagnosed autism have elevated unusual behaviors, lower self-regulation, and impaired ToM. There is a high risk of co-existing anxiety and impaired EF which may increase disease burden. Targeted therapeutic interventions are needed to reduce long-term psychosocial risks in these children.AbbreviationAttention deficit/hyperactivity disorder (ADHD), Autism Spectrum Rating Scale (ASRS), Behavior Rating Inventory of Executive Functions for school-aged children, 2nd Edition (BRIEF-2), cardiopulmonary bypass (CPB), congenital heart disease (CHD), Empathy/Systematizing Quotient Child Version (ESQ-C), Multidimensional Anxiety Scale for Children, 2nd Edition (MASC-2), Social Responsiveness Scale (School-age form), 2nd Edition (SRS-2), theory of mind (ToM), Theory of Mind Task Battery (ToM-TB), Wechsler Intelligence Scale for Children, 5th edition (WISC-V).

Childhood exposures to environmental chemicals and neurodevelopmental outcomes in congenital heart disease.

BACKGROUND: Children with congenital heart defects have an increased risk of neurodevelopmental disability. The impact of environmental chemical exposures during daily life on neurodevelopmental outcomes in toddlers with congenital heart defects is unknown. METHODS: This prospective study investigated the impacts of early childhood exposure to mixtures of environmental chemicals on neurodevelopmental outcomes after cardiac surgery. Outcomes were assessed at 18 months of age using The Bayley Scales of Infant and Toddler Development-III. Urinary concentrations of exposure biomarkers of pesticides, phenols, parabens, and phthalates, and blood levels of lead, mercury, and nicotine were measured at the same time point. Bayesian profile regression and weighted quantile sum regression were utilized to assess associations between mixtures of biomarkers and neurodevelopmental scores. RESULTS: One-hundred and forty infants were enrolled, and 110 (79%) returned at 18 months of age. Six biomarker exposure clusters were identified from the Bayesian profile regression analysis; and the pattern was driven by 15 of the 30 biomarkers, most notably 13 phthalate biomarkers. Children in the highest exposure cluster had significantly lower adjusted language scores by -9.41 points (95%CI: -17.2, -1.7) and adjusted motor scores by -4.9 points (-9.5, -0.4) compared to the lowest exposure. Weighted quantile sum regression modeling for the overall exposure-response relationship showed a significantly lower adjusted motor score (ß = -2.8 points [2.5th and 97.5th percentile: -6.0, -0.6]). The weighted quantile sum regression index weights for several phthalates, one paraben, and one phenol suggest their relevance for poorer neurodevelopmental outcomes. CONCLUSIONS: Like other children, infants with congenital heart defects are exposed to complex mixtures of environmental chemicals in daily life. Higher exposure biomarker concentrations were associated with significantly worse performance for language and motor skills in this population.

Portable HEPA filter air cleaner use during pregnancy and children's autistic behaviors at four years of age: The UGAAR randomized controlled trial.

BACKGROUND: Developmental exposure to airborne particulate matter (PM) may increase children's risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM2.5) concentrations during pregnancy and autistic traits. METHODS: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM2.5 concentrations and T-scores. RESULTS: We enrolled participants at a median of 11 weeks' gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: -2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m3) increase in indoor PM2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM2.5 concentrations by trimester were smaller and confidence intervals spanned no effect. CONCLUSION: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01741051.

Long-term cognitive and behavioral outcomes following early exposure to general anesthetics.

PURPOSE OF REVIEW: Nearly 100 clinical studies have been published evaluating neurodevelopmental outcomes in children following surgery and anesthesia. These studies have reported mixed results, likely attributable at least in part to significant heterogeneity in their study designs, types and numbers of exposures, patient populations evaluated, and most importantly, the outcomes that were assessed. This review aims to summarize the results from clinical studies evaluating behavioral outcomes in children exposed to surgery and anesthesia. RECENT FINDINGS: Children with early exposure to surgery and anesthesia were found to have limited to no differences in intelligence when compared with unexposed children. However, several studies have reported more behavioral problems in children exposed to general anesthesia. An increased incidence of attention-deficit hyperactivity disorder has also been reported in anesthetic exposed children, particularly after multiple exposures. SUMMARY: Nearly all clinical studies of anesthetic neurotoxicity are observational in nature, so the associations between anesthetic exposure and behavioral deficits cannot yet be directly attributed to the anesthetic medication. However, the finding of deficits in some neurodevelopmental domains and not others will help guide the selection of appropriate outcomes in future studies of anesthetic neurotoxicity that can further evaluate whether anesthetic medications have an impact on neurodevelopment in children.

Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry.

INTRODUCTION: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition. OBJECTIVE: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. METHODS: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models. RESULTS: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: ß = 0.20 (95 % CI: 0.02, 0.38)] and Block design [ß = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [ß = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [ß = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure. CONCLUSION: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.

Portable HEPA filter air cleaner use during pregnancy and children's behavior problem scores: a secondary analysis of the UGAAR randomized controlled trial.

BACKGROUND: Developmental exposure to particulate matter (PM) air pollution may impair children's behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children's behavior. METHODS: This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. RESULTS: We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. CONCLUSION: We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01741051.

Randomized Controlled Trial of Working Memory Intervention in Congenital Heart Disease.

OBJECTIVES: To evaluate the efficacy of Cogmed Working Memory Training compared with the standard of care to improve executive function and social outcomes in adolescents with congenital heart disease (CHD) who underwent open-heart surgery in infancy and to identify factors associated with changes in outcomes following the intervention. STUDY DESIGN: In a single-center, randomized controlled trial, adolescents (13-16 years) with CHD were randomly assigned to either Cogmed (home-based 45-minutes sessions for 5-8 weeks) or to a control group. The primary outcome was working memory. Secondary outcomes included inhibitory control and cognitive flexibility as well as parent-reported executive function, symptoms of attention deficit hyperactivity disorder, and social outcomes. All measures were assessed at baseline, post-treatment (1-3 weeks post-training) and at 3-month follow-up. Data were analyzed using an intention-to-treat approach. RESULTS: Sixty adolescents with CHD participated (28 assigned to Cogmed). No improvement at the post-treatment or 3-month follow-up assessments was found for the primary outcome measure of working memory. Compared with the control group, participants assigned to the intervention demonstrated benefits in inhibitory control and attention at the 3-month follow-up (P = .02) and in parent-reported cognitive regulatory skills at post-treatment and 3-month follow-up (P = .02 and P = .04, respectively). Preterm birth, biventricular CHD, and history of attention deficit hyperactivity disorder diagnosis were associated with improved response to the intervention. CONCLUSIONS: Cogmed intervention produced improvements in the self-regulatory control abilities of adolescents with CHD. The training did not enhance other areas of executive function or behavioral outcomes. Further studies are needed to evaluate the longer-term potential benefits to other domains. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02759263.

Modification of the effects of prenatal manganese exposure on child neurodevelopment by maternal anemia and iron deficiency.

BACKGROUND: We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4-6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects. METHODS: We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n = 571). McCarthy Scales of Children's Abilities were measured at 4-6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex. RESULTS: No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother's with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother's with low ferritin (-2.41 (-5.28, 0.47), interaction P value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed. CONCLUSIONS: Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.

The Bayley-III scale may underestimate neurodevelopmental disability after cardiac surgery in infants.

OBJECTIVES: Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery. METHODS: We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705). RESULTS: Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7-17.6; P < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14-0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14-0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4-6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment. CONCLUSIONS: The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

BACKGROUND: In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. METHODS: In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI -2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. INTERPRETATION: Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

Improving neurodevelopmental outcomes in children with congenital heart disease: protocol for a randomised controlled trial of working memory training.

INTRODUCTION: Executive function (EF) impairments are among the most prevalent neurodevelopmental morbidities in youth with congenital heart disease (CHD). To date, no studies have investigated the efficacy of cognitive interventions to improve EF outcomes in children with CHD. METHODS AND ANALYSIS: This is a single-centre, single-blinded, two-arm randomised controlled trial to test the efficacy of Cogmed Working Memory Training (Cogmed) versus standard of care in children with CHD after open-heart surgery in infancy. Participants will consist of 100 children with CHD aged 7-12 years who underwent open-heart surgery before the age of 12 months. Participants are randomly allocated to either an intervention group including training on the home-based Cogmed intervention for a duration of approximately 5 weeks or a control group who receive the standard of care. We will evaluate the efficacy of Cogmed at post-treatment and 3 months after completion of the intervention. Baseline, post-treatment and 3-month follow-up assessments will include specific measures of EF, cognitive and social functioning, and attention deficit hyperactivity disorder (ADHD) symptoms. The primary outcome of this study is the change in standardised mean score on the List Sorting Working Memory test from the National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function. Secondary outcomes include measures of social skills, inhibitory control, cognitive flexibility and behavioural EF as well as ADHD symptoms as measured by the Behavior Rating Inventory of Executive Function, Second Edition, and the Conners Third Edition. The efficacy of the intervention will be evaluated by comparing within-subject differences (baseline to post-treatment, baseline to 3-month follow-up) between the two groups using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has received Institutional Review Board (IRB) approval from Boston's Children's Hospital IRB (P00022440) and the Human Protection Agency from the US Department of Defense. TRIAL REGISTRATION NUMBER: NCT03023644; Pre-results.

Longitudinal Associations between Neurodevelopment and Psychosocial Health Status in Patients with Repaired D-Transposition of the Great Arteries.

OBJECTIVE: To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries. STUDY DESIGN: In the 16-year follow-up of the Boston Circulatory Arrest Study, 137 parents completed the Child Health Questionnaire-Parent Form-50, of whom 135 had completed the Child Health Questionnaire-Parent Form-50 when their child was age 8 years. Psychosocial and physical summary scores were used to assess change in health status from age 8 to 16 years. A comprehensive battery of neurodevelopmental testing was performed at ages 8 and 16 years to examine associations with adolescent health status. RESULTS: Lower psychosocial summary scores of 16 year old subjects with dextro-transposition of the great arteries were highly associated with numerous concurrent domains of neurodevelopmental function, most notably with higher (worse) scores on the Conners' Attention Deficit Hyperactivity Disorder/Diagnostic and Statistical Manual-4th Edition Scales (parent: r = -0.62, P < .001; adolescent: r = -0.43, P < .001) and the Behavior Rating Inventory of Executive Function Global Executive Composite (parent: r = -0.66, P < .001; adolescent: r = -0.39, P < .001). Psychosocial and physical summary scores tracked from ages 8 to 16 years (r = 0.44 and 0.47, respectively, P < .001 for each). Higher (worse) scores of multiple attention measures at age 8 years predicted worse psychosocial summary scores at age 16 years. CONCLUSIONS: Attention deficits at age 8 years were highly predictive of worse psychosocial health status in adolescence. Further studies are needed to assess whether treatment of childhood attention deficit hyperactivity disorder could improve adolescent well-being.

Perioperative Exposure to Suspect Neurotoxicants From Medical Devices in Newborns With Congenital Heart Defects.

BACKGROUND: Industrial chemicals are increasingly recognized as potential developmental neurotoxicants. Di(2-ethylhexyl) phthalate (DEHP), used to impart flexibility and temperature tolerance to polyvinylchloride, and bisphenol A (BPA), used to manufacture polycarbonate, are commonly present in medical devices. The magnitude of exposure in neonates during hospitalization for cardiac operations is unknown. METHODS: We quantified urinary concentrations of DEHP metabolites and BPA preoperatively and postoperatively in neonates undergoing cardiac operations and their mothers. Urinary concentrations of these biomarkers reflect recent exposures (half-lives are approximately 6 to 24 hours). Biomarker concentrations in mothers' and infants' preoperative and postoperative samples were compared. RESULTS: Operations were performed in 18 infants (mean age, 5 ± 4 [SD] days). The maternal sample was obtained on postpartum day 4 ± 4. The preoperative urine sample was obtained on day-of-life 4 ± 2 and the postoperative sample on day-of-life 6 ± 4. Mean maternal concentrations for DEHP metabolites and BPA were at the 50th percentile for females in the United States general population. Infant preoperative concentrations of 1 DEHP metabolite and BPA were significantly higher than maternal concentrations. Postoperative concentrations for all DEHP metabolites were significantly greater than preoperative concentrations. CONCLUSIONS: There is considerable perioperative exposure to DEHP and BPA for neonates undergoing cardiac operations. Infant concentrations for both BPA and DEHP metabolites were significantly higher than maternal concentrations, consistent with the infant's exposure to medical devices. Further study is needed to determine the potential role of these suspect neurotoxicants in the etiology of neurodevelopmental disability after cardiac operations.

Iron-processing genotypes, nutrient intakes, and cadmium levels in the Normative Aging Study: Evidence of sensitive subpopulations in cadmium risk assessment.

BACKGROUND: Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men. METHODS: In a longitudinal cohort of men age 51-97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates. RESULTS: HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (pinteraction = 0.021), as well as HFE H63D and vitamin C intake (pinteraction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries. CONCLUSIONS: These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide.

Visuospatial processing in adolescents with critical congenital heart disease: Organization, integration, and implications for academic achievement.

Among the most significant factors affecting quality of life in individuals with critical congenital heart disease (CCHD) are neurodevelopmental challenges, including deficits in visuospatial processing and academic achievement. Few studies have compared outcomes across CCHD subgroups, despite their significant differences in anatomy/physiology and medical/surgical courses. This study compared visuospatial processing abilities using the Developmental Scoring System for the Rey-Osterrieth Complex Figure (DSS-ROCF) across groups of adolescents with CCHD (d-transposition of the great arteries [TGA, n = 139], Tetralogy of Fallot [TOF, n = 68], single-ventricle cardiac anatomy requiring the Fontan operation [SVF, n = 145]) and a group of healthy controls (CTR, n = 111), and examined the validity of visuospatial processing in predicting concurrent academic outcomes. The CCHD subgroups were found to differ in Organization, ps < .001, Structural Accuracy, ps < .001, and Incidental Elements Accuracy scores, ps ≤ .008; the post hoc analyses show that the SVF group tended to underperform compared to the other CCHD groups. With respect to academic skills, all CCHD groups scored lower than the CTR group, ps ≤ .007; however, the CCHD groups were not different from each other, ps > .23. The regression results showed that the DSS-ROCF Style rating (reflecting integration) accounted for a small yet statistically significant portion of unique variance in "assembled" academic outcomes, over and above the variance already accounted for by DSS-ROCF Organization, p < .01. These findings support the need for comprehensive neuropsychological assessment and monitoring of children and adolescents with CCHD, as well as targeted intervention for organization and integration deficits that may increase their risk for academic underachievement.

Blood and Hair Aluminum Levels, Vaccine History, and Early Infant Development: A Cross-Sectional Study.

OBJECTIVE: To evaluate relationships between whole blood (B-Al) and hair aluminum (H-Al) levels in healthy infants and their immunization history and development. METHODS: We conducted a cross-sectional study of 9- to 13-month-old children recruited from an urban primary care center, excluding those with a history of renal disease or receipt of either aluminum-containing pharmaceuticals or parenteral nutrition. Aluminum levels were measured using inductively coupled plasma-mass spectrometry. Correlation with Bayley Scales of Infant and Toddler Development, Third Edition (BSID) and vaccine-related aluminum load was assessed via linear regression models. RESULTS: The median age of 85 participants was 287 days. B-Al (median, 15.4 ng/mL; range, 0.9-952 ng/mL) and H-Al (median 42,542 ng/g; range, 2758-211,690 ng/g) were weakly correlated (Spearman ρ = 0.26; P = .03). There was no significant correlation between B-Al or H-Al and estimated aluminum load from vaccines. B-Al was not correlated with BSID composite or subscale scores. Although H-Al was not correlated with BSID scores in models including all data (n = 85), it was inversely correlated with motor composite (P < .02; Wald = 5.88) and the gross motor subscale (P = .04; Wald = 4.38) in models that excluded an extreme outlying H-Al value. CONCLUSIONS: Infant B-Al and H-Al varied considerably but did not correlate with their immunization history. Likewise, there was no correlation between B-Al and infant development or between H-Al and language or cognitive development. An inverse correlation between H-Al and BSID motor scores deserves further investigation.

Neuropsychological and Psychiatric Outcomes in Dextro-Transposition of the Great Arteries across the Lifespan: A State-of-the-Art Review.

Advances in prenatal diagnosis, perioperative management, and postoperative care have dramatically increased the population of survivors of neonatal and infant heart surgery. The high survival rate of these patients into adulthood has exposed the alarming prevalence of long-term neuropsychological and psychiatric morbidities. Dextro-transposition of the great arteries (d-TGA) is one of the most extensively studied cyanotic congenital heart defect (CHD) with regard to neurodevelopmental outcomes. Landmark studies have described a common neurodevelopmental and behavioral phenotype associated with d-TGA. Children with d-TGA display impairments in key neurocognitive areas, including visual-spatial and fine motor abilities, executive functioning, processing speed, and social cognition. As they grow older, they may face additional challenges with a worsening of deficits in higher order cognitive skills, problems in psychosocial adjustment and a higher-than-expected rate of psychiatric disorders, such as attention-deficit hyperactivity disorder, depression, and anxiety. The aim of this review is to summarize the available recent data on neuropsychological and psychiatric outcomes in individuals with d-TGA after the arterial switch operation. We present findings within a life-span perspective, with a particular emphasis on the emerging literature on adolescent and young adult outcomes. Finally, we propose avenues for future research in the CHD adult neuropsychology field. Among these avenues, we explore the potential mechanisms by which pediatric neurodevelopmental impairments may have lifelong adverse effects as well as alternative interventions that could optimize outcomes.

White Matter Volume Predicts Language Development in Congenital Heart Disease.

OBJECTIVE: To determine whether brain volume is reduced at 1 year of age and whether these volumes are associated with neurodevelopment in biventricular congenital heart disease (CHD) repaired in infancy. STUDY DESIGN: Infants with biventricular CHD (n = 48) underwent brain magnetic resonance imaging (MRI) and neurodevelopmental testing with the Bayley Scales of Infant Development-II and the MacArthur-Bates Communicative Development Inventories at 1 year of age. A multitemplate based probabilistic segmentation algorithm was applied to volumetric MRI data. We compared volumes with those of 13 healthy control infants of comparable ages. In the group with CHD, we measured Spearman correlations between neurodevelopmental outcomes and the residuals from linear regression of the volumes on corrected chronological age at MRI and sex. RESULTS: Compared with controls, infants with CHD had reductions of 54 mL in total brain (P = .009), 40 mL in cerebral white matter (P <.001), and 1.2 mL in brainstem (P = .003) volumes. Within the group with CHD, brain volumes were not correlated with Bayley Scales of Infant Development-II scores but did correlate positively with MacArthur-Bates Communicative Development Inventory language development. CONCLUSIONS: Infants with biventricular CHD show total brain volume reductions at 1 year of age, driven by differences in cerebral white matter. White matter volume correlates with language development, but not broader developmental indices. These findings suggest that abnormalities in white matter development detected months after corrective heart surgery may contribute to language impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00006183.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE: Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE: To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS: Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES: A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS: Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE: Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.