The Impact of Exposure to Iodine and Fluorine in Drinking Water on Thyroid Health and Intelligence in School-Age Children: A Cross-Sectional Investigation.

Iodine and fluorine, as halogen elements, are often coexisting in water environments, with nearly 200 million people suffering from fluorosis globally, and, in 11 countries and territories, adolescents have iodine intakes higher than that required for the prevention of iodine deficiency disorders. It has been suggested that excess iodine and/or fluorine can affect thyroid health and intellectual development, especially in children, but their combined effect has been less studied in this population. This study investigated 399 school-age children in Tianjin, China, collected drinking water samples from areas where the school-age children lived, and grouped the respondents according to iodine and fluorine levels. Thyroid health was measured using thyroid hormone levels, thyroid volume, and the presence of thyroid nodules; intelligence quotient (IQ) was assessed using the Raven's Progressive Matrices (CRT) test; and monoamine neurotransmitter levels were used to explore the potential relationship between thyroid health and intelligence. Multiple linear regression and restricted cubic spline (RCS) analyses showed that iodine and fluorine were positively correlated with thyroid volume and the incidence of thyroid nodules in school-age children, and negatively correlated with IQ; similar results were obtained in the secondary subgroups based on urinary iodine and urinary fluoride levels. Interaction analyses revealed a synergistic effect of iodine and fluorine. A pathway analysis showed that iodine and fluorine were negatively associated with the secretion of free triiodothyronine (FT3) and free tetraiodothyronine (FT4), which in turn were negatively associated with the secretion of thyroid-stimulating hormone (TSH). Iodine and fluorine may affect IQ in school-aged children through the above pathways that affect thyroid hormone secretion; of these, FT3 and TSH were negatively correlated with IQ, whereas FT4 was positively correlated with IQ. The relationship between thyroid hormones and monoamine neurotransmitters may involve the hypothalamic-pituitary-thyroid axis, with FT4 hormone concentrations positively correlating with dopamine (DA), norepinephrine (NE), and 5-hydroxytryptophan (5-HT) concentrations, and FT3 hormone concentrations positively correlating with DA concentrations. Monoamine neurotransmitters may play a mediating role in the effects of iodine and fluoride on intelligence in schoolchildren. However, this study has some limitations, as the data were derived from a cross-sectional study in Tianjin, China, and no attention was paid to the reciprocal effects of iodine and fluorine at different doses on thyroid health and intelligence in schoolchildren in other regions.

Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Impact of antenatal exposure to a mixture of persistent organic pollutants on intellectual development.

OBJECTIVE: Strong experimental evidence exists that several endocrine disrupting chemicals (EDCs) have neurobehavioral toxicity. However, evidence of associations between prenatal exposure and child's cognitive development is inconsistent. Moreover, toxicants are generally analyzed one by one without considering aggregate effects. We examined here the impact of a prenatal exposure to a mixture of persistent organic pollutants (POPs) on intellectual abilities in preschool children, and compared their effects to those described in the literature. METHODS: Sixty-two children were included in a longitudinal cohort. Four organochlorine pesticides, four polychlorinated biphenyls (PCBs) and seven perfluorinated compounds (PFCs) were measured in cord blood. Intellectual abilities were assessed at 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence 4th ed. (WPPSI-IV). We examined the associations between a mixture of POPs and cognitive performances using principal components approach (PCA) and weighted quantile sum (WQS) regression taking sex difference into account. RESULTS: No negative correlation was found when analyses were performed on boys and girls together. In sex-stratified analyses, lower scores in full scale intelligence quotient (FSIQ) and fluid reasoning index (FRI) were observed in boys most exposed to a mixture of POPs. Increase of the WQS index was also associated with lower verbal comprehension index (VCI) scores in girls only. No other negative correlation was found using both WQS and PCA models. CONCLUSION: Our study suggests deleterious associations between antenatal exposure to a mixture of POPs and sex-specific cognitive level, clarifying some trends described in the literature.

Association between maternal metal exposure during early pregnancy and intelligence in children aged 3-6 years: Results from a Chinese birth cohort.

OBJECTIVE: Maternal environmental metal exposure is common, but long-term prospective epidemiological evidence of its impact on children's intellectual development is still insufficient. METHODS: Data on maternal plasma metal levels and child intelligence were obtained for 211 3-6-year-old children from Guangxi Zhuang Birth Cohort. ICP-MS was employed to detect 17 metals, including 7 essential metals (Mn, Fe, Co, Ni, Cu, Zn, Mo) and 10 non-essential metals (As, Rb, Sr, Cd, Sb, Cs, Ba, W, Pb, U), in maternal plasma samples obtained before 13 weeks of gestation during the initial maternity checkup. Child intelligence was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition. The GLM, RCS and mixture models were used to assess the associations of maternal plasma metal levels with child intelligence quotient (IQ) scores. RESULTS: The GLM analysis revealed that U had a significant adverse effect on child IQ scores in high-dose exposure groups (-9.236 [-18.644, -4.936], p = 0.006) after adjusting for covariates, while Sb showed a linear adverse effect on children's intelligence in the adjusted model (-4.028 [-7.432, -0.626], p = 0.021). BKMR modeling indicated that overall IQ scores decreased as concentrations of non-essential metals mixtures increased after adjusting for essential metal mixtures, consistent with findings from the WQS (ß [95% CI], -8.463 [-14.449, -2.476], p = 0.007) and Qgcomp models (-7.003 [-12.928, -1.078], p = 0.022). Among the non-essential metals, U had the highest negative weight at 37.96%, followed by Pb (23.35%) and Sb (16.91%). Furthermore, potential interactions were observed between metals (Pb and U) and Sb in the study findings. CONCLUSION: Reducing exposure to non-essential metal mixtures, especially U, Sb and Pb, during early pregnancy and ensuring adequate intake of specific essential metal elements could be a critical intervention in addressing childhood intellectual impairment.

Trends of hair Hg accumulation in reproductive-age women living in Central Russia and the calculated costs of Hg-induced IQ loss in the period between 2005 and 2021.

The objective of the present study was to retrospectively evaluate hair mercury (Hg) content in reproductive-age women living in Central Russia (Moscow and Moscow region), and to calculate the potential costs of the potential Hg-induced IQ loss in a hypothetical national birth cohort. MATERIALS AND METHODS: A total of 36,263 occupationally non-exposed women aged between 20 and 40 years living in Moscow (n = 30,626) or Moscow region (n = 5637) in the period between 2005 and 2021 participated in this study. Hair Hg content was evaluated with inductively coupled plasma-mass spectrometry (ICP-MS). Hair Hg levels in reproductive-age women were used for assessment of the potential IQ loss and its costs. RESULTS: The results demonstrate that hair Hg content in the periods between 2010 and 2015, and 2016-2021 was significantly lower than that in 2005-2009 by 26 % and 51 %, respectively. The highest hair Hg level was observed in women in 2005 (0.855 µg/g), being more than 2.5-fold higher than the lowest value observed in 2020 (0.328 µg/g). Multiple regression analysis revealed a significant inverse association between the year of analysis and hair Hg content (ß = -0.288; p < 0.001). The calculations demonstrate that in 2005 the costs of IQ loss in children exceeded 1.0 (1.6) billion USD, whereas in 2020 the costs of IQ loss accounted to approximately 0.15 (0.28) billion USD. CONCLUSION: Taken together, our data demonstrate that Hg accumulation in reproductive-age women reduced significantly in Russia from 2005 to 2021 resulting in predicted economic benefits by decreasing the costs of Hg-induced IQ loss.

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.

Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive. OBJECTIVES: This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function. METHODS: The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function. RESULTS: The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (ß = -6.21, 95 % confidence interval [CI]: -12.21, -0.21), with more pronounced associations observed among girls (ß = -9.57, 95 % CI: -18.33, -0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ. CONCLUSIONS: Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.

Infant Behaviors, Prenatal Cocaine Exposure, and Adult Intelligence.

Importance: Linking prenatal drug exposures to both infant behavior and adult cognitive outcomes may improve early interventions. Objective: To assess whether neonatal physical, neurobehavioral, and infant cognitive measures mediate the association between prenatal cocaine exposure (PCE) and adult perceptual reasoning IQ. Design, Setting, and Participants: This study used data from a longitudinal, prospective birth cohort study with follow-up from 1994 to 2018 until offspring were 21 years post partum. A total of 384 (196 PCE and 188 not exposed to cocaine [NCE]) infants and mothers were screened for cocaine or polydrug use. Structural equation modeling was performed from June to November 2023. Exposures: Prenatal exposures to cocaine, alcohol, marijuana, and tobacco assessed through urine and meconium analyses and maternal self-report. Main Outcomes and Measures: Head circumference, neurobehavioral assessment, Bayley Scales of Infant Development, Fagan Test of Infant Intelligence score, Wechsler Perceptual Reasoning IQ, Home Observation for Measurement of the Environment (HOME) score, and blood lead level. Results: Among the 384 mothers in the study, the mean (SD) age at delivery was 27.7 (5.3) years (range, 18-41 years), 375 of 383 received public assistance (97.9%) and 336 were unmarried (87.5%). Birth head circumference (standardized estimate for specific path association, -0.05, SE = 0.02; P = .02) and 1-year Bayley Mental Development Index (MDI) (standardized estimate for total of the specific path association, -0.05, SE = 0.02; P = .03) mediated the association of PCE with Wechsler Perceptual Reasoning IQ, controlling for HOME score and other substance exposures. Abnormal results on the neurobehavioral assessment were associated with birth head circumference (ß = -0.20, SE = 0.08; P = .01). Bayley Psychomotor Index (ß = 0.39, SE = 0.05; P < .001) and Fagan Test of Infant Intelligence score (ß = 0.16, SE = 0.06; P = .01) at 6.5 months correlated with MDI at 12 months. Conclusions and Relevance: In this cohort study, a negative association of PCE with adult perceptual reasoning IQ was mediated by early physical and behavioral differences, after controlling for other drug and environmental factors. Development of infant behavioral assessments to identify sequelae of prenatal teratogens early in life may improve long-term outcomes and public health awareness.

Prenatal exposure to pyrethroids and chlorpyrifos and IQ in 7-year-old children from the Odense Child Cohort.

BACKGROUND: Organophosphates and pyrethroids are two major groups of insecticides used for crop protection worldwide. They are neurotoxicants and exposure during vulnerable windows of brain development may have long-term impact on human neurodevelopment. Only few longitudinal studies have investigated associations between prenatal exposure to these substances and intelligence quotient (IQ) at school age in populations with low, mainly dietary, exposure. OBJECTIVE: To investigate associations between maternal urinary concentrations of insecticide metabolites at gestational week 28 and IQ in offspring at 7-years of age. MATERIALS AND METHODS: Data was derived from the Odense Child Cohort (OCC). Metabolites of chlorpyrifos (TCPy) and pyrethroids (3-PBA, cis- and trans-DCCA, 4-F-3PBA, cis-DBCA) were measured in maternal urine collected at gestational week (GW) 28. An abbreviated version of the Danish Wechsler Intelligence Scale for Children fifth edition (WISC-V) consisting of four subtests to estimate full scale IQ (FSIQ) was administered by trained psychologists. Data were analyzed by use of multiple linear regression and adjusted for confounders. RESULTS: 812 mother/child-pairs were included. Median concentrations were 0.21 µg/L for 3-PBA, 1.67 µg/L for TCPy and the mean IQ for children were 99.4. Null association between maternal 3-PBA and child IQ at 7 years was seen, but with trends suggesting an inverse association. There was a significant association for maternal TCPy and child IQ at mid-level exposure. Trans-DCCA above the level of detection (LOD) was also associated with slightly lower child IQ, but the association was also not statistically significant. CONCLUSIONS: We found no significant associations between maternal 3-PBA metabolites and child IQ at 7 years, but with trends suggesting an inverse association. A non-significant trend between maternal TCPy exposure and child IQ in 7-year-children was seen even in this low exposed population. Given the widespread exposure and increasing use of insecticides, this should be elaborated in future studies.

Effects of saturated and monounsaturated fatty acids on cognitive impairment: evidence from Mendelian randomization study.

BACKGROUND: Prior observational studies have suggested correlations between saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) with cognitive function. However, causal relationships remains unclear. METHODS: We assessed the causal impact of two SFAs (palmitic acid [PA] and stearic acid [SA]) and two MUFAs (oleic acid [OA] and palmitoleic acid [POA]) on cognitive function-related traits, and dementia-related traits by univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) analyses. RESULTS: UVMR indicated ß of 0.060 (P = 4.05E-06) for cognitive performance score and 0.066 (P = 4.21E-04) for fluid intelligence per standard deviation (SD) increase in OA level. MVMR indicated: (i) ß of -0.608 (P = 8.37E-05) for fluid intelligence score per SD increase in POA; (ii) ß of 0.074 (P = 0.018) for fluid intelligence score per SD increase in OA; (iii) ß of 0.029 (P = 0.033) for number of incorrect matches in round per SD increase in PA; and (iv) ß of 0.039 (P = 0.032) for number of incorrect matches in round per SD increase in SA. In addition, a secondary MVMR analysis after excluding the effect of polyunsaturated fatty acids suggested that: (i) ß of -0.043 (P = 1.97E-02) for cognitive performance score per SD increase in PA and (ii) ß of -0.079 (P = 1.79E-03) for cognitive performance score per SD increase in SA. CONCLUSIONS: Overall, UVMR and MVMR suggest that OA may be beneficial for cognitive function, while POA, PA, and SA may have detrimental effects on cognitive function.

Flawed MIREC fluoride and intelligence quotient publications: A failed attempt to undermine community water fluoridation.

OBJECTIVE: To assess the evidence presented in a set of articles that use the Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study database to claim that community water fluoridation (CWF) is associated with harm to foetal and infant cognitive development. METHODS: Critical appraisal of measurements and processes in the MIREC database, and articles derived therefrom. MIREC's cohort is approximately 2000 pregnant women recruited in 10 centres across Canada, 2008-2011, leading to measuring 512 children aged 3-6 years in six cities. Fluoride exposure was measured by city fluoridation status, self-reports and maternal spot urine samples. Intelligence Quotient (IQ) was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) by different assessors in each city. RESULTS: MIREC's fluoride and IQ measurements are invalid and therefore cannot support the claim that CWF is associated with IQ decline in children. CONCLUSIONS: The MIREC fluoride-IQ articles' results should be considered unacceptable for legal and policy purposes; other water fluoridation studies and systematic reviews show no effect of fluoridation on cognition.

Association of prenatal exposure to perfluorinated and polyfluoroalkyl substances with childhood neurodevelopment: A systematic review and meta-analysis.

BACKGROUND: Although previous studies have shown an association between prenatal exposure to perfluorinated and polyfluoroalkyl substances (PFAS) and neurodevelopmental disorders in children, the results have been inconsistent. We summarize studies on the association between prenatal PFAS exposure and neurodevelopment in children in order to better understand the relationship. OBJECTIVE: We conducted a meta-analysis of prenatal PFAS exposure and developmental outcomes associated with intellectual, executive function and behavioral difficulty in children to explore the relationship between prenatal exposure to perfluorinated and polyfluoroalkyl substances (PFAS) and neurodevelopmental disorders in children. METHODS: We searched for articles published up to August 3, 2023, included and quantified original studies on PFAS and child Intelligence Quotient (IQ), executive function and behavioral difficulty during pregnancy, and systematically summarized articles that could not be quantified. CONCLUSION: There is evidence of sex-specific relationship between PFAS exposure and children's PIQ. We found that PFOS [ß = -1.56, 95% CI = -2.96, - 0.07; exposure = per 1 ln (ng/ml) increase], PFOA [ß = -1.87, 95% CI = -3.29, - 0.46; exposure = per 1 ln (ng/ml) increase], PFHxS [ß = -2.02, 95% CI = -3.23, - 0.81; exposure = per 1 ln (ng/ml) increase] decreased performance IQ in boys, but PFOS [ß = 1.56, 95% CI = 0.06, 3.06; exposure = per 1 ln (ng/ml) increase] increased performance IQ in girls. PFAS are associated with executive function impairments in children, but not related to behavioral difficulty in children.

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.).

Gestational Exposure to Antidepressant Drugs and Neurodevelopment: An Examination of Language, Mathematics, Intelligence, and Other Cognitive Outcomes.

During the past decade, nearly a dozen small and large, prospective and retrospective observational studies examined cognitive neurodevelopmental outcomes in childhood after gestational exposure to antidepressant drugs. Many of the studies found that exposure was associated with poorer outcomes on measures of language, cognition, intellectual skills, and academic performance, but, in most instances, the association appeared to be more related to maternal depression during pregnancy and other confounds than to antidepressant use during pregnancy. A large new population-based observational study specifically examined language and mathematics performance in serial, nationally standardized tests. The study found that, in fully adjusted analyses, in children and adolescents aged 9-15 years, a history of gestational exposure to antidepressant drugs was associated with a small (by about 2 out of 100 points) but statistically significantly poorer performance in mathematics but not in language. The findings were consistent though attenuated in a large number of important and appropriate sensitivity analyses, some of which adjusted for confounding in additional ways. The body of literature reviewed suggests that prenatal antidepressant exposure is indeed associated with cognitive neurodevelopmental deficits and that the deficits are attenuated or eliminated by adjustment for maternal depression and other confounds. It is suggested that the deficits that remain despite adjustment may be due to residual confounding from unmeasured behavioral and internal environment variables associated with untreated maternal depression. Thus, prenatal antidepressant exposure may merely be a marker rather than the cause of cognitive neurodevelopmental deficits. Whereas the literature in the field does not drive a case for withholding antidepressants from depressed pregnant women, decision-making must remain a shared process.

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.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation.

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown. Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years. Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021. Exposures: Amino acid intake at 7 days after birth. Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study. Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; ß = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; ß = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; ß = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; ß = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; ß = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort. Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.

Prenatal exposure to a mixture of organophosphate esters and intelligence among 8-year-old children of the HOME Study.

Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children's cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior.

Hearing loss and intellectual outcome in children treated for embryonal brain tumors: Implications for young children treated with radiation sparing approaches.

PURPOSE: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. METHODS: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard-dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced-dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. RESULTS: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). CONCLUSIONS: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

Maternal smoking during pregnancy and intelligence quotient in offspring: A systematic review and meta-analysis.

BACKGROUND: Exposure to tobacco during pregnancy may disrupt fetal brain development and impact offspring cognitive development. AIMS: To perform a systematic review and meta-analysis on maternal smoking during pregnancy and intelligence quotient (IQ) in childhood, adolescence, and adulthood. METHODS: We searched PubMed, Lilacs, PsycINFO, and Web of Science. Original articles evaluating tobacco use/exposure during pregnancy and the offspring's IQ as the outcome. The review protocol is registered in PROSPERO (number CRD 42,019,116,257). For the meta-analysis, we included studies with information on the regression coefficient and its confidence interval (CI) or standard error. Random effects model was used for pooling the estimates. RESULTS: 25 studies were included in the review, and of these 14 met the inclusion criteria for the meta-analysis. The overall pooled estimate showed that subjects who were exposed to maternal smoking during pregnancy presented lower IQ scores, compared to those not exposed to maternal smoking (ß -1.30; 95 % CI -1.74, -0.86; I2 = 87.8 %); IQ scores were also lower in crude (ß -5.46; 95 % CI -7.31, -3.60; I²: 79.0 %) and adjusted pooled estimates (ß =-0.45; 95 % CI -0.76, -0.13; I2 = 80.4 %), for the group exposed to maternal smoking. In the stratified analysis, an inverse association was also observed in studies with large sample size (n≥1000 participants) (ß=-0.49; 95 % CI -0.96, -0.02), among those performed with adolescents (ß=-1.16; 95 % CI -2.18, -0.14), and among those adjusted for maternal education (ß=-0.57; 95 % CI -1.05, -0.08). CONCLUSIONS: Our findings suggest that exposure to tobacco during pregnancy may have negative effects on IQ. However, the findings of this meta-analysis should be interpreted with caution.

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 ).