•Exposure to metals/elements may be a risk factor for neurodevelopmental disorders.•We examined gestational levels of metals/elements and ADHD and autism in children.•Several metals and elements ...appeared to increase ADHD or autism risk.•Population levels of these chemicals may adversely affect neurodevelopment.
Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring.
We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD.
This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach.
For ASD, we identified positive associations (increased risks) in the second quartile of arsenic OR = 1.77 (CI: 1.26, 2.49) and the fourth quartiles of cadmium and manganese OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59), respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium OR = 1.59 (CI: 1.15, 2.18); OR = 1.42 (CI: 1.06, 1.91). There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses.
Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals’ and elements’ impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.
•The urinary detection rate of radioactive cesium in Chinese pregnant women is 100%.•Mercury, cadmium and cesium may influence maternal and neonatal thyroid function.•First trimester is a critical ...window for maternal metal exposure to thyroid function.
China, a developing country, has a particularly serious problem with metal pollution. We evaluated the association of metal exposure during pregnancy with maternal and neonatal thyroid function, and identified the critical window for maternal metal exposure effects on maternal and neonatal thyroid functions.
The maternal urinary concentrations of mercury (Hg), cadmium (Cd), arsenic (As) and cesium (Cs) were determined in pregnant women during their first (n = 389) or third (n = 257) trimesters in a prospective cohort from 2014 to 2015 in Nanjing, China, using an inductively coupled plasma mass spectrometry (ICP-MS) instrument. Maternal serum-free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured by electrochemiluminescent microparticle immunoassays in the second and third trimesters. Neonatal TSH levels were detected 72 h after birth.
Hg (>0.162 µg/L), Cd (>0.084 µg/L), As (>0.348 µg/L) and Cs (>0.093 µg/L) were detectable in 76.9%, 90.1%, 100% and 100% of maternal urine samples from women in the first trimester of pregnancy. In the multiple adjusted linear regression models, maternal exposures to Hg and Cd in the first trimester were positively associated with maternal TSH levels in the second trimester (P < 0.01, P = 0.02). Moreover, maternal exposures to Cd and Cs in the first trimester were positively associated with neonatal TSH levels (P = 0.04, P = 0.02). In the Bayesian kernel machine regression (BKMR) model, the results were stable and consistent with the linear regression model.
Maternal exposure to Hg, Cd and Cs in the first trimester was related to TSH levels in mothers and newborns. Efforts to identify maternal and neonatal thyroid disruptors should carefully consider the effects of exposure to these metals.
There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning ...defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype.
We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.
Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (
=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (
=553) from the MoBa population was obtained.
In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest OR=2.99 (95% CI: 1.47, 5.49). When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% OR=1.47 (95% CI: 1.09, 1.94). We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.
In this population-based case-control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358.
Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Inattentiveness, overactivity, and ...impulsiveness are presently regarded as the main clinical symptoms. The dynamic developmental behavioral theory is based on the hypothesis that altered dopaminergic function plays a pivotal role by failing to modulate nondopaminergic (primarily glutamate and GABA) signal transmission appropriately. A hypofunctioning mesolimbic dopamine branch produces altered reinforcement of behavior and deficient extinction of previously reinforced behavior. This gives rise to delay aversion, development of hyperactivity in novel situations, impulsiveness, deficient sustained attention, increased behavioral variability, and failure to "inhibit" responses ("disinhibition"). A hypofunctioning mesocortical dopamine branch will cause attention response deficiencies (deficient orienting responses, impaired saccadic eye movements, and poorer attention responses toward a target) and poor behavioral planning (poor executive functions). A hypofunctioning nigrostriatal dopamine branch will cause impaired modulation of motor functions and deficient nondeclarative habit learning and memory. These impairments will give rise to apparent developmental delay, clumsiness, neurological "soft signs," and a "failure to inhibit" responses when quick reactions are required. Hypofunctioning dopamine branches represent the main individual predispositions in the present theory. The theory predicts that behavior and symptoms in ADHD result from the interplay between individual predispositions and the surroundings. The exact ADHD symptoms at a particular time in life will vary and be influenced by factors having positive or negative effects on symptom development. Altered or deficient learning and motor functions will produce special needs for optimal parenting and societal styles. Medication will to some degree normalize the underlying dopamine dysfunction and reduce the special needs of these children. The theory describes how individual predispositions interact with these conditions to produce behavioral, emotional, and cognitive effects that can turn into relatively stable behavioral patterns.
Although early and accurate screening is required for the remediation of attention-deficit/hyperactivity disorder (ADHD), possible gender differences have not been extensively studied. We examined ...the classification accuracy of the parent and preschool teacher version of the Strengths and Difficulties Questionnaire (SDQ) hyperactivity−inattention (HI) subscale in girls and boys.
The study was part of the Norwegian Mother and Child Cohort Study (MoBa). Parents and preschool teachers rated a total of 238 girls and 276 boys (mean age 3.5 years) with the SDQ HI subscale. Blinded to the parent and teacher ratings, interviewers classified the children by ADHD diagnoses with the Preschool Age Psychiatric Assessment Interview.
Areas under the curves for the parent HI subscale scores were good for both girls and boys (0.87 and 0.80, respectively). Preschool teacher classifications were fair (0.76) for girls and poor (0.62) for boys, a significant difference (p = .017). The subscale accurately identified children without ADHD at low parent scores (≤4), and fairly accurately identified ADHD at high scores (≥9), with maximum probabilities of finding true cases of 0.75 in girls and 0.55 in boys. Intermediate scores gave the best balance between sensitivity and specificity with low probabilities of correctly identifying children with ADHD.
The parental SDQ HI subscale was useful for screening for ADHD in preschool girls and boys. For preschool teachers, the subscale was useful for screening girls.
Attention Deficit Hyperactivity Disorder (ADHD) is associated with deficits in different functional domains. It remains unclear if deficits in different domains are equally strong in early childhood, ...and which deficits are specific to ADHD. Here, we describe functional domains in preschoolers and assess deficits in children with ADHD problems, by comparing them to preschoolers with other mental health problems or who develop typically.
The ADHD Study assessed 1195 ca. 3.5 years old preschoolers through a semi-structured parent interview, parent questionnaires, and with neuropsychological tests. We determined functional domains by applying factor analytic methods to a broad set of questionnaire- and test-scales. Using resulting factor scores, we employed a Bayesian hierarchical regression to estimate functional deficits in children with ADHD.
We found that preschoolers' functioning could be described along the seven relatively independent dimensions activity level and regulation, executive function, cognition, language, emotion regulation, introversion, and sociability. Compared to typically developing preschoolers, those with ADHD had deficits in all domains except introversion and sociability. Only deficits in activity level regulation and executive functions were larger than 0.5 standardised mean deviations and larger than deficits of children with other mental health problems.
Preschoolers with ADHD have deficits in multiple functional domains, but only impairments in activity level and regulation and executive functions are specific for ADHD and large enough to be clinically significant. Research on functioning in these domains will be important for understanding the development of ADHD, and for improving treatment and prevention approaches.
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•Elevated DPHP and BDCIPP during mid-pregnancy increased ADHD risk in offspring.•Simultaneously decreasing joint exposure to OPEs and phthalates may reduce ADHD risk.•The link between ...prenatal DPHP and ADHD was stronger among girls than boys.•Suggestive modification by maternal paraoxonase1 Q192R genotype was present for DPHP.•DPHP-ADHD association was partly mediated via pregnancy maternal thyroid function.
Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD.
To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa).
We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals 95% CI using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation.
DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 95% CI: 0.96, 1.99), which was slightly higher among girls (2.04 1.03, 4.02) and children of mothers with PON1 Q192R genotype QR (1.69 0.89, 3.19) or PON1 Q192R genotype RR (4.59 1.38, 15.29). The relationship between DPHP and ADHD (total risk ratio: 1.34 0.90, 2.02) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 0.87, 1.94; natural indirect effect: 1.04 1.00, 1.10; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 0.98, 2.28). We did not observe notable differences in ADHD by DNBP (0.88 0.62, 1.26) or BBOEP (1.03 0.73, 1.46) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 0.64, 0.72.
Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.
•We investigated the relations between phthalates and thyroid function mid-pregnancy.•We accounted for the urinary phthalate metabolite mixture by factor analyses.•We found relationships between ...phthalate factors and thyroid function, mainly T3.•Dietary iodine intake in pregnancy influenced some of these relationships.
Human populations, including susceptible subpopulations such as pregnant women and their fetuses, are continuously exposed to phthalates. Phthalates may affect the thyroid hormone system, causing concern for pregnancy health, birth outcomes and child development. Few studies have investigated the joint effect of phthalates on thyroid function in pregnant women, although they are present as a mixture with highly inter-correlated compounds. Additionally, no studies have investigated if the key nutrient for thyroid health, iodine, modifies these relationships.
In this study, we examined the cross-sectional relationships between concentrations of 12 urinary phthalate metabolites and 6 plasma thyroid function biomarkers measured mid-pregnancy (~17 week gestation) in pregnant women (N = 1072), that were selected from a population-based prospective birth cohort, The Norwegian Mother, Father and Child Cohort study (MoBa). We investigated if the phthalate metabolite-thyroid function biomarker associations differed by iodine status by using a validated estimate of habitual dietary iodine intake based on a food frequency questionnaire from the 22nd gestation week. We accounted for the phthalate metabolite mixture by factor analyses, ultimately reducing the exposure into two uncorrelated factors. These factors were used as predictors in multivariable adjusted linear regression models with thyroid function biomarkers as the outcomes.
Factor 1, which included high loadings for mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and monobenzyl phthalate (MBzP), was associated with increased total triiodothyronine (TT3) and free T3 index (fT3i). These associations appeared to be driven primarily by women with low iodine intake (<150 µg/day, ~70% of our sample). Iodine intake significantly modified (p-interaction < 0.05) the association of factor 1 with thyroid stimulating hormone (TSH), total thyroxine (TT4) and free T4 index (fT4i), such that only among women in the high iodine intake category (≥150 µg/day, i.e. sufficient) was this factor associated with increased TSH and decreased TT4 and FT4i, respectively. In contrast, factor 2, which included high loadings for di-2-ethylhexyl phthalate metabolites (∑DEHP) and di-iso-nonyl phthalate metabolites (∑DiNP), was associated with a decrease in TT3 and fT3i, which appeared fairly uniform across iodine intake categories.
We find that phthalate exposure is associated with thyroid function in mid-pregnancy among Norwegian women, and that iodine intake, which is essential for thyroid health, could influence some of these relationships.
Current knowledge about the relationship between mild to moderately inadequate maternal iodine intake and/or supplemental iodine on child neurodevelopment is sparse. Using information from 77,164 ...mother-child pairs in the Norwegian Mother and Child Cohort Study, this study explored associations between maternal iodine intake and child attention-deficit/hyperactivity disorder (ADHD) diagnosis, registered in the Norwegian Patient Registry and maternally-reported child ADHD symptoms at eight years of age. Pregnant women reported food and supplement intakes by questionnaire in gestational week 22. In total, 1725 children (2.2%) were diagnosed with ADHD. In non-users of supplemental iodine (53,360 mothers), we found no association between iodine intake from food and risk of child ADHD diagnosis (
= 0.89), while low iodine from food (<200 µg/day) was associated with higher child ADHD symptom scores (adjusted difference in score up to 0.08 standard deviation (SD),
< 0.001,
= 19,086). In the total sample, we found no evidence of beneficial effects of maternal use of iodine-containing supplements (
= 23,804) on child ADHD diagnosis or symptom score. Initiation of iodine supplement use in gestational weeks 0-12 was associated with an increased risk of child ADHD (both measures). In conclusion, insufficient maternal iodine intake was associated with increased child ADHD symptom scores at eight years of age, but not with ADHD diagnosis. No reduction of risk was associated with maternal iodine supplement use.
Childhood anxiety and depressive symptoms may be influenced by symptoms of attention deficit/hyperactivity disorder (ADHD). We investigated whether parent- and teacher-reported anxiety, depressive ...and ADHD symptoms at age 3 years predicted anxiety disorders and/or depression in children with and without ADHD at age 8 years. This study is part of the longitudinal, population-based Norwegian Mother, Father and Child Cohort Study. Parents of 3-year-olds were interviewed, and preschool teachers rated symptoms of anxiety disorders, depression and ADHD. At age 8 years (n = 783), Child Symptom Inventory-4 was used to identify children who fulfilled the diagnostic criteria for anxiety disorders and/or depression (hereinafter: Anx/Dep), and ADHD. Univariable and multivariable logistic regression analyses were used. In the univariable analyses, parent-reported anxiety, depressive and ADHD symptoms, and teacher-reported anxiety symptoms at age 3 years all significantly predicted subsequent Anx/Dep. In the multivariable analyses, including co-occurring symptoms at age 3 years and ADHD at 8 years, parent-reported anxiety and depressive symptoms remained significant predictors of subsequent Anx/Dep. At age 3 years, regardless of ADHD symptoms being present, asking parents about anxiety and depressive symptoms, and teachers about anxiety symptoms, may be important to identify children at risk for school-age anxiety disorders and/or depression.
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