Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Fluoride and children's IQ: evidence of causation lacking.

DATA SOURCES: Human, animal, and in vitro studies. Extensive literature search of multiple bibliographic databases, trial registries, major grey literature sources and bibliographies of identified studies. STUDY SELECTION: The authors aimed to identify studies which could be used to determine the maximum safe level for fluoride in drinking water. To identify new studies published since a 2016 Australian review, the search period was 2016 to July 2021. Studies which evaluated the association between either naturally or artificially fluoridated water (any concentration) and any health outcomes were included. No restrictions on study design or publication status. Articles published in a 'non-Latin language' were excluded. Screening of abstracts and full texts was in duplicate. For IQ and dental fluorosis, a top-up search was conducted between 2021 and Feb 2023. DATA EXTRACTION AND SYNTHESIS: Extensive data extraction. Risk of bias assessment using the OHAT tool. A narrative synthesis of the results was carried out. RESULTS: The review included 89 studies in humans, 199 in animals and 10 reviews of in vitro studies. Where there was consistent evidence of a positive association, in relation to a water fluoride concentration of <20 ppm (mg F/L), and where studies were judged to be acceptable or high quality, health effects were taken forwards for further examination of causality using Bradford Hill's 9 criteria. Of the 39 health outcomes reviewed, 4 were further assessed for causality. The authors reported 'strong' evidence of causality for dental fluorosis and reductions in children's IQ scores, 'moderate' strength evidence for thyroid dysfunction, 'weak' for kidney dysfunction, and 'limited' evidence for sex hormone disruption. CONCLUSIONS: The authors conclude that moderate dental fluorosis and reductions in children's IQ scores are the most appropriate health outcomes to use when setting an upper safe level of fluoride in drinking water. For reductions in children's IQ, the authors acknowledge a biological mechanism of action has not been elucidated, and the dose response curve is not clear at lower concentrations, limiting the ability to set an upper safe threshold.

Arsenic and fluoride co-exposure through drinking water and their impacts on intelligence and oxidative stress among rural school-aged children of Lahore and Kasur districts, Pakistan.

Arsenic (As), and fluoride (F-) are potent contaminants with established carcinogenic and non-carcinogenic impacts on the exposed populations globally. Despite elevated groundwater As and F- levels being reported from various regions of Pakistan no biomonitoring study has been reported yet to address the co-exposure impact of As and F- among school children. We aimed to investigate the effects of these two contaminants on dental fluorosis and intelligence quotient (IQ) along with the induction of oxidative stress in rural children under co-exposed conditions. A total of 148 children (5 to 16 years old) from the exposed and control group were recruited in the current study from endemic rural areas of Lahore and Kasur districts, Pakistan having elevated As and F- levels in drinking water than permissible limits. We monitored malondialdehyde and its probable association with antioxidants activity (SOD, CAT, and GR) as a biomarker of oxidative stress. GSTM1/T1 polymorphisms were measured to find the impact of As on health parameters. Mean urinary concentrations of As (2.70 vs. 0.016 µg/L, P < 0.000) and F- (3.27 vs. 0.24 mg/L, P < 0.000) as well as the frequency of dental fluorosis were found elevated among the exposed group. The cases of children with lower IQ were observed high in the exposed group. Additionally, lower concentrations of antioxidants (SOD, CAT, and GR) were found suggesting high susceptibility to F- toxicity. The findings suggest that F- accounted for high variations in health parameters of children under the co-exposure conditions with As.

Maternal Intake of Lutein and Zeaxanthin during Pregnancy Is Positively Associated with Offspring Verbal Intelligence and Behavior Regulation in Mid-Childhood in the Project Viva Cohort.

BACKGROUND: Lutein and zeaxanthin are carotenoids associated with better cognition at older age. To our knowledge, no previous study has evaluated their cognitive implications in the prenatal period, when the brain undergoes its most rapid development. OBJECTIVE: The objective of this study was to examine associations of maternal lutein and zeaxanthin (L/Z) intake during pregnancy with child cognition. DESIGN: Among 1580 mother-child pairs in Project Viva, a prospective cohort, we assessed maternal intake of L/Z during pregnancy using food frequency questionnaires and offspring cognition by the Visual Recognition Memory paradigm in infancy, the Peabody Picture Vocabulary Test and the Wide Range Assessment of Visual Motor Abilities (WRAVMA) in early childhood, and the Kaufman Brief Intelligence Test (KBIT-II), the WRAVMA drawing subtest, and the Wide Range Assessment of Memory and Learning in mid-childhood. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and Strengths and Difficulties Questionnaire. RESULTS: Mothers consumed a daily mean (SD) of 2.6 (2.0) mg L/Z in the first and second trimesters of pregnancy. Mean mid-childhood KBIT-II verbal scores were higher with greater maternal L/Z intake [difference of Q4-Q1 means for first trimester: 2.67 (95% CI: 0.13, 5.20) and for second trimester: 3.55 (95% CI: 0.81, 6.28)], indicating better verbal intelligence. Secondary analyses on cognitive subtests showed that mean mid-childhood BRIEF Behavioral Regulation Index scores were lower with greater maternal L/Z intake [difference of Q4-Q1 means for first trimester: -1.63 (95% CI: -3.22, -0.04) and for second trimester: -1.89 (95% CI: -3.58, -0.21)], indicating better behavior regulation ability. CONCLUSIONS: Higher maternal L/Z intake during pregnancy was associated with better offspring verbal intelligence and behavior regulation ability in mid-childhood, suggesting a potential benefit during prenatal development. We did not find a benefit of higher maternal L/Z intake on other child cognitive or behavioral outcomes. Project Viva is registered at clinicaltrials.gov as NCT02820402.

Intelligence quotient decline following frequent or dependent cannabis use in youth: a systematic review and meta-analysis of longitudinal studies.

Previous systematic reviews and meta-analyses of cross-sectional data assessing the effect of cannabis on cognitive functioning and intelligence show inconsistent results. We hypothesized that frequent and dependent cannabis use in youth would be associated with Intelligence Quotient (IQ) decline. This study is a systematic review and meta-analysis. We searched Embase, PubMed and PsychInfo from inception to 24 January 2020. We included studies with non-treatment seeking samples and pre- and post-exposure measures of IQ. We requested data from authors if summary data was not available from published work. We preregistered our review with PROSPERO (ID no. CRD42019125624). We found seven cohort studies including 808 cases and 5308 controls. We found a significant effect for the association between frequent or dependent cannabis use in youth and IQ change, Cohen's d = -0.132 (95% CI -0.198 to -0.066) p < 0.001. Statistical heterogeneity between studies was also low at I2 = 0.2%. Study quality was moderate to high. This translates to an average decline of approximately 2 IQ points following exposure to cannabis in youth. Future studies should have longer periods of follow up to assess the magnitude of developmental impact.

Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis.

BACKGROUND: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. METHODS: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. RESULTS: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001). CONCLUSIONS: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Tyrosine supplementation for phenylketonuria.

BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. This is an update of previously published versions of this review. OBJECTIVES: To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references. Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 07 December 2020. SELECTION CRITERIA: All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. The trials were assessed as having a low to moderate risk of bias across several domains. AUTHORS' CONCLUSIONS: From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence. However, given this is not an active area of research, we have no plans to update this review in the future.

Brain activation patterns in medicated versus medication-naïve adults with attention-deficit hyperactivity disorder during fMRI tasks of motor inhibition and cognitive switching.

BACKGROUND: Adult-attention-deficit-hyperactive-disorder (ADHD) is often unrecognized condition. FMRI examination along with neuropsychological testing might strengthen the diagnosis. We hypothesized that ADHD-adults with and without medication would show different fMRI pattern compared to healthy controls while testing tasks of motor inhibition and cognitive switching. METHODS: 45 subjects in three age-matched groups: (1) controls, (2) ADHD-adults under medication (ADHD+) and (3) medication-naïve adults with ADHD (ADHD-) underwent fMRI and neuropsychological testing. Group analysis and population-based statistics were performed. RESULTS: DTVP-A, intellectual ability as well as attention capability, visual-perceptual and visual-motor abilities showed no significant differences between the groups. However, fMRI revealed statistically significant differences between the ADHD+, ADHD- and control groups on tasks of motor inhibition and cognitive switching on adults in bilateral fronto-striatal brain regions, inferior fronto-frontal, fronto-cingulate and fronto-parietal networks as well as in the parietal lobe (p < 0.05). CONCLUSIONS: fMRI offers the potential to differentiate between the ADHD+, ADHD- and control groups. FMRI possibly opens a new window for monitoring the therapeutic effect of ADHD medication. TRIAL REGISTRATION: NCT02578342, registered at August 2015 to clinical trial registry ( https://ichgcp.net/clinical-trials-registry/NCT02578342 ).

Fluoride exposure, dopamine relative gene polymorphism and intelligence: A cross-sectional study in China.

BACKGROUND: Excessive fluoride exposure is related to adverse health outcomes, but whether dopamine (DA) relative genes are involved in the health effect of low-moderate fluoride exposure on children's intelligence remain unclear. OBJECTIVES: We conducted a cross-sectional study to explore the role of DA relative genes in the health effect of low-moderate fluoride exposure in drinking water. METHODS: We recruited 567 resident children, aged 6-11 years old, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. Spot urine samples were tested for urinary fluoride concentration, combined Raven`s test was used for intelligence quotient test. Fasting venous blood were collected to analyze ANKK1 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 40 bp VNTR and MAOA uVNTR. Multivariable linear regression models were used to assess associations between fluoride exposure and IQ scores. We applied multiplicative and additive models to appraise single gene-environment interaction. Generalized multifactor dimensionality reduction (GMDR) was used to evaluate high-dimensional interactions of gene-gene and gene-environment. RESULTS: In adjusted model, fluoride exposure was inversely associated with IQ scores (ß = -5.957, 95% CI: -9.712, -2.202). The mean IQ scores of children with high-activity MAOA genotype was significantly lower than IQ scores of those with low-activity (P = 0.006) or female heterozygote (P = 0.016) genotype. We detected effect modification by four DA relative genes (ANKK1, COMT, DAT1 and MAOA) on the association between UF and IQ scores. We also found a high-dimensional gene-environment interaction among UF, ANKK1, COMT and MAOA on the effect of IQ (testing balanced accuracy = 0.5302, CV consistency: 10/10, P = 0.0107). CONCLUSIONS: Our study suggests DA relative genes may modify the association between fluoride and intelligence, and a potential interaction among fluoride exposure and DA relative genes on IQ.

The Effect of Lead Exposure on Autism Development.

Autism Spectrum Disorder (ASD) remains one of the most detrimental neurodevelopmental conditions in society today. Common symptoms include diminished social and communication ability. Investigations on autism etiology remain largely ambiguous. Previous studies have highlighted exposure to lead (Pb) may play a role in ASD. In addition, lead has been shown to be one of the most prevalent metal exposures associated with neurological deficits. A semi-systematic review was conducted using public databases in order to evaluate the extent of lead's role in the etiology of autism. This review examines the relationship between autistic comorbid symptoms-such as deterioration in intelligence scores, memory, language ability, and social interaction-and lead exposure. Specifically, the mechanisms of action of lead exposure, including changes within the cholinergic, dopaminergic, glutamatergic, gamma aminobutyric acid (GABA)ergic systems, are discussed. The goal of this review is to help illustrate the connections between lead's mechanistic interference and the possible furthering of the comorbidities of ASD. Considerations of the current data and trends suggest a potential strong role for lead in ASD.

Intelligence quotient (IQ) among children with epilepsy: National epidemiological study - Sudan.

BACKGROUND: Many studies of selected groups of children with epilepsy have demonstrated an association between epilepsy and cognitive deficits. The aim of this study was to assess the intellectual skills of children with epilepsy and to investigate the influence of gender, age at seizure onset, type of epilepsy, antiepileptic drug used, and control of epilepsy on their intellectual function. METHODS: This is a descriptive prospective study in which one hundred and eighty-seven patients at school age (6-14 years) were recruited. Epilepsy was classified using the International League Against Epilepsy (ILAE) Commission on Classification and Terminology 2005-2009 report. An intelligence quotient (IQ) test was conducted to all patients using Stanford-Binet Fifth Edition (SB5)/Arabic version. RESULTS: Eighty-eight (47.1%) patients had an average score on Full Scale IQ (FSIQ), 44 (23.5%) had low average, whereas 18 (9.6%) had borderline impaired or delayed score. In the nonverbal IQ (NVIQ) score, the majority 84 (44.9%) had average score. The performance of the patients in the nonverbal score is better than in the verbal score, which was found to be statistically significant (P-value = 0.01). The FSIQ score was negatively affected by younger age at onset of epilepsy, polytherapy, and uncontrolled seizures. CONCLUSIONS: Most of children with epilepsy had an average FSIQ; uncontrolled seizure had worse effect on overall FSIQ and memory. Interventions to support children with epilepsy should focus on epilepsy management and school psychosocial domains.

Biomarkers of environmental manganese exposure and associations with childhood neurodevelopment: a systematic review and meta-analysis.

BACKGROUND: Although prior studies showed a correlation between environmental manganese (Mn) exposure and neurodevelopmental disorders in children, the results have been inconclusive. There has yet been no consistent biomarker of environmental Mn exposure. Here, we summarized studies that investigated associations between manganese in biomarkers and childhood neurodevelopment and suggest a reliable biomarker. METHODS: We searched PubMed and Web of Science for potentially relevant articles published until December 31th 2019 in English. We also conducted a meta-analysis to quantify the effects of manganese exposure on Intelligence Quotient (IQ) and the correlations of manganese in different indicators. RESULTS: Of 1754 citations identified, 55 studies with 13,388 subjects were included. Evidence from cohort studies found that higher manganese exposure had a negative effect on neurodevelopment, mostly influencing cognitive and motor skills in children under 6 years of age, as indicated by various metrics. Results from cross-sectional studies revealed that elevated Mn in hair (H-Mn) and drinking water (W-Mn), but not blood (B-Mn) or teeth (T-Mn), were associated with poorer cognitive and behavioral performance in children aged 6-18 years old. Of these cross-sectional studies, most papers reported that the mean of H-Mn was more than 0.55 µg/g. The meta-analysis concerning H-Mn suggested that a 10-fold increase in hair manganese was associated with a decrease of 2.51 points (95% confidence interval (CI), - 4.58, - 0.45) in Full Scale IQ, while the meta-analysis of B-Mn and W-Mn generated no such significant effects. The pooled correlation analysis revealed that H-Mn showed a more consistent correlation with W-Mn than B-Mn. Results regarding sex differences of manganese associations were inconsistent, although the preliminary meta-analysis found that higher W-Mn was associated with better Performance IQ only in boys, at a relatively low water manganese concentrations (most below 50 µg/L). CONCLUSIONS: Higher manganese exposure is adversely associated with childhood neurodevelopment. Hair is the most reliable indicator of manganese exposure for children at 6-18 years of age. Analysis of the publications demonstrated sex differences in neurodevelopment upon manganese exposure, although a clear pattern has not yet been elucidated for this facet of our study.

Fluoride exposure and intelligence in school-age children: evidence from different windows of exposure susceptibility.

BACKGROUND: The intellectual loss induced by fluoride exposure has been extensively studied, but the association between fluoride exposure in different susceptibility windows and children's intelligence is rarely reported. Hence, we conducted a cross-sectional study to explore the association between fluoride exposure in prenatal and childhood periods and intelligence quotient (IQ). METHODS: We recruited 633 local children aged 7-13 years old randomly from four primary schools in Kaifeng, China in 2017. The children were divided into four groups, of which included: control group (CG, n = 228), only prenatal excessive fluoride exposure group (PFG, n = 107), only childhood excessive fluoride exposure group (CFG, n = 157), both prenatal and childhood excessive fluoride exposure group (BFG, n = 141). The concentrations of urinary fluoride (UF) and urinary creatinine (UCr) were determined by fluoride ion-selective electrode assay and a creatinine assay kit (picric acid method), respectively. The concentration of UCr-adjusted urinary fluoride (CUF) was calculated. IQ score was assessed using the second revision of the Combined Raven's Test-The Rural in China (CRT-RC2). Threshold and saturation effects analysis, multiple linear regression analysis and logistic regression analysis were conducted to analyze the association between fluoride exposure and IQ. RESULTS: The mean IQ score in PFG was respectively lower than those in CG, CFG and BFG (P < 0.05). The odds of developing excellent intelligence among children in PFG decreased by 51.1% compared with children in CG (OR = 0.489, 95% CI: 0.279, 0.858). For all the children, CUF concentration of ≥1.7 mg/L was negatively associated with IQ scores (ß = - 4.965, 95% CI: - 9.198, - 0.732, P = 0.022). In children without prenatal fluoride exposure, every 1.0 mg/L increment in the CUF concentration of ≥2.1 mg/L was related to a reduction of 11.4 points in children's IQ scores (95% CI: - 19.2, - 3.5, P = 0.005). CONCLUSIONS: Prenatal and childhood excessive fluoride exposures may impair the intelligence development of school children. Furthermore, children with prenatal fluoride exposure had lower IQ scores than children who were not prenatally exposed; therefore the reduction of IQ scores at higher levels of fluoride exposure in childhood does not become that evident.

Impact of low-level mercury exposure on intelligence quotient in children via rice consumption.

Wanshan is a city in southwest China that has several inactive mercury (Hg) mines. The local population are exposed to methylmercury (MeHg) due to the consumption of Hg contaminated rice. The relationship between Hg exposure and the cognitive functions of local children is unknown. This study investigated the relationship between hair Hg concentrations and the intelligence quotient (IQ) of 314 children aged 8-10 years, recruited from three local primary schools in Wanshan area in 2018 and 2019. IQ was evaluated using Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV). The average THg concentration in children's hair samples was 1.53 µg g-1 (range: 0.21-12.6 µg g-1), and 65.6% exceeded the United States Environment Protection Agency (USEPA) recommended value of 1 µg g-1. Results of logistic regression analysis showed that children with hair Hg ≥ 1 µg g-1 were 1.58 times more likely to have an IQ score <80, which is the clinical cut-off for borderline intellectual disability (R2 = 0.20, p = 0.03). Increasing of 1 µg g-1 hair Hg resulted in 1 point of IQ loss in Wanshan children, which was.much higher than that via fish consumption. The economical cost due to Hg exposure was estimated to be $69.8 million (9.43% of total GDP) in the Wanshan area in 2018.

Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study.

An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.

Impact of genetic subtypes of Prader-Willi syndrome with growth hormone therapy on intelligence and body mass index.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder characterized by infantile hypotonia with a poor suck and failure to thrive, hypogenitalism/hypogonadism, behavior and cognitive problems, hormone deficiencies, hyperphagia, and obesity. The Stanford Binet and Wechsler (WAIS-R; WISC-III) intelligence (IQ) tests were administered on 103 individuals with PWS from two separate cohorts [University of California, Irvine (UCI) (N = 56) and Vanderbilt University (N = 47)] and clinical information obtained including growth hormone (GH) treatment, PWS molecular classes, weight and height. Significantly higher IQ scores (p < .02) were found representing the vocabulary section of the Stanford Binet test in the growth hormone (GH) treated group when compared with non-GH treatment in the pediatric-based UCI PWS cohort with a trend for stabilization of vocabulary IQ scores with age in the GH treated maternal disomy (UPD) 15 subject group. Significant differences (p = .05) were also found in the adult-based Vanderbilt PWS cohort with 15q11-q13 deletion subjects having lower Verbal IQ scores compared with UPD 15. No difference in body mass index was identified based on the PWS molecular class or genetic subtype. Medical care and response to treatment with growth hormone may influence intelligence impacted by PWS genetic subtypes and possibly age, but more studies are needed.

Intelligence Test Scores Before and After Alcohol-Related Disorders-A Longitudinal Study of Danish Male Conscripts.

BACKGROUND: Existing studies on intellectual consequences of alcohol-related disorders are primarily cross-sectional and compare intelligence test scores of individuals with and without alcohol-related disorders, hence mixing the influence of alcohol-related disorders and predisposing factors such as premorbid intelligence. In this large-scale study, the primary aim was to estimate associations of alcohol-related disorders with changes in intelligence test scores from early adulthood to late midlife. METHODS: Data were drawn from a follow-up study on middle-aged men, which included a re-examination of the same intelligence test as completed in young adulthood at military conscription (total analytic sample = 2,499). Alcohol-related hospital diagnoses were obtained from national health registries, whereas treatment for alcohol problems was self-reported at follow-up. The analyses included adjustment for year of birth, retest interval, baseline intelligence quotient (IQ) score, education, smoking, alcohol consumption, and psychiatric and somatic comorbidity. RESULTS: Individuals with alcohol-related hospital diagnoses (8%) had a significantly lower baseline IQ score (95.0 vs. 100.5, p < 0.001) and a larger decline in IQ scores from baseline to follow-up (-8.5 vs. -4.8, p < 0.001) than individuals without such diagnoses. The larger decline in IQ scores with alcohol-related hospital diagnoses remained statistically significant after adjustment for all the covariates. Similar results were revealed when IQ scores before and after self-reported treatment for alcohol problems (10%) were examined. CONCLUSIONS: Individuals with alcohol-related disorders have a lower intelligence test score both in young adulthood and in late midlife, and these disorders, moreover, seem to be associated with more age-related decline in intelligence test scores. Thus, low mean intellectual ability observed in individuals with alcohol-related disorders is probably a result of both lower premorbid intelligence and more intellectual decline.

Evaluating the mediating role of executive functions for antiepileptic drugs' effects on IQ in children and adolescents with epilepsy.

Several studies suggest that antiepileptic drug (AED) treatment may permanently or reversibly affect intelligence (intelligence quotient [IQ]) in children and adolescents with epilepsy. Since AED treatment preferentially affects attention and executive functions, we evaluated the potentially mediating effect of executive functions in regard to the adverse effects of drug treatment on intelligence. In a retrospective observational study, 178 children and adolescents with refractory and mostly localization-related epilepsies were evaluated in regard to the interrelation of IQ (Wechsler Intelligence Scale for Children [WISC III] short-form), executive functions (EpiTrack-Junior®, a cognitive AED screening test), and drug treatment (drug load). The results indicate that a low IQ was evident in 23%, impaired executive functions in 59% of the patients. Executive functions correlated to IQ (r = 0.60) and the symbol digits and picture arrangement subtests (R2 = 0.46) in particular. Odds ratios for impaired executive functions compared to being off drug (33% impaired) increased from 2.0 with one drug (53% impaired) to 9.5 (83% impaired) with at least three drugs. A mediation analysis revealed that drug dependent differences in executive functions mediate the negative effect of the AED load on intelligence. Hence, executive functions appear to link adverse cognitive side effects of AED treatment to intelligence. Considering Catell's two factor model of intelligence, AEDs preferentially affect the aspects of fluid intelligence. The overall impact of AED on intelligence appears mild. It may become relevant, however, when drug-induced impairments persist over longer time intervals during sensitive developmental phases. This issue needs to be addressed in future longitudinal studies.

Prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and neurodevelopmental outcomes in children.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used during pregnancy. Findings that prenatal NSAID exposure may affect offspring neurodevelopment have been inconsistent. We investigated the effect of prenatal NSAID exposure on childhood neurodevelopment and explored the susceptibility of our effect estimates to forms of bias via negative exposure, negative outcome, and multi-informant analyses. METHODS: In a cohort of pregnant women (n = 6876), perinatal NSAID use was assessed by prescriptions and self-report. Primary neurodevelopmental outcomes included attention problems using maternal reports at 1½, 3, and 5 years. To explore potential systematic biases, we compared estimates from maternally reported attention problems to a teacher's report and a measure of nonverbal intelligence assessed at a clinic visit at age 6 years; we also used NSAID use before pregnancy and somatic problems as a "negative" exposure and outcome, respectively. RESULTS: Maternal reports suggested that prenatal exposure to NSAIDs was associated with more attention problems at younger ages (eg, at age 3: mean difference in attention problems score: 0.30; 95% CI 0.12, 0.48). However, no strong association with attention problems was found in the teacher report, and a similarly strong association between prenatal NSAID exposure and somatic complaints suggests residual confounding by indication likely remains. Moreover, prenatal exposure to NSAIDs was not associated with an observed measure of IQ (mean difference in IQ score: -0.32; 95% CI: -1.82, 1.19). CONCLUSIONS: Jointly, our results suggest that the observed associations between prenatal exposure to NSAIDs and child attention problems reflect systematic biases of a null or small effect.

Identifying periods of susceptibility to the impact of phthalates on children's cognitive abilities.

BACKGROUND: Early-life phthalate exposures may adversely affect children's neurodevelopment by disrupting thyroid function, reducing gonadal hormone levels, or altering fatty acid concentrations in the brain. This study aimed to identify periods of heightened susceptibility during gestation, infancy, and childhood to the impact of phthalates on children's cognitive abilities. METHODS: We used data from 253 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio), a longitudinal pregnancy and birth cohort. We quantified urinary concentrations of 11 phthalate metabolites in samples collected twice during gestation and 6 times during study visits when children were aged 1-8 years using a modified method of on-line solid phase extraction coupled with isotope dilution-high performance liquid chromatography-tandem mass spectrometry. We assessed children's intelligence (IQ) at ages 5 and 8 years using the Wechsler Preschool and Primary Scale of Intelligence-III and Wechsler Intelligence Scale for Children-IV, respectively. We estimated covariate-adjusted associations between a 1-standard deviation increase in log10-transformed urinary phthalate metabolite concentrations at each visit and children's IQ, adjusting for demographic, perinatal, and child factors; we tested for differences in these associations across visits using multiple informant models. RESULTS: Associations between some phthalate metabolites and IQ varied by visit (phthalate x visit interaction p-values<0.20). The sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), mono(3-carboxypropyl) phthalate, and monoethyl phthalate at age 3 years, and monobenzyl phthalate at 16 weeks gestation and child ages 3, 5, and 8 years were inversely associated with children's full-scale IQ. For example, each 1-standard deviation increase in ΣDEHP at age 3 was associated with a 1.9-point decrease in full-scale IQ (95% confidence interval: -3.7, -0.2). Mono-n-butyl phthalate and mono-isobutyl phthalate at age 4 years were positively associated with children's full-scale IQ. CONCLUSION: Urinary concentrations of several phthalate metabolites at age 3 years, compared to other time periods, were more strongly associated with decreased cognitive abilities in these children.