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Background Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder. Effective long-term treatment options are limited, which warrants increased focus on potential modifiable risk factors. The aim of this study was to investigate associations between maternal diet quality during pregnancy and child diet quality and child ADHD symptoms and ADHD diagnosis. Methods This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). We assessed maternal diet quality with the Prenatal Diet Quality Index (PDQI) and Ultra-Processed Food Index (UPFI) around mid-gestation, and child diet quality using the Diet Quality Index (CDQI) at 3 years. ADHD symptoms were assessed at child age 8 years using the Parent Rating Scale for Disruptive Behaviour Disorders. ADHD diagnoses were retrieved from the Norwegian Patient Registry. Results In total, 77,768 mother-child pairs were eligible for studying ADHD diagnoses and 37,787 for ADHD symptoms. Means (SD) for the PDQI, UPFI and CDQI were 83.1 (9.3), 31.8 (9.7) and 60.3 (10.6), respectively. Mean (SD) ADHD symptom score was 8.4 (7.1) and ADHD diagnosis prevalence was 2.9% (male to female ratio 2.6:1). For one SD increase in maternal diet index scores, we saw a change in mean (percent) ADHD symptom score of − 0.28 (− 3.3%) (CI: − 0.41, − 0.14 (− 4.8, − 1.6%)) for PDQI scores and 0.25 (+ 3.0%) (CI: 0.13, 0.38 (1.5, 4.5%)) for UPFI scores. A one SD increase in PDQI score was associated with a relative risk of ADHD diagnosis of 0.87 (CI: 0.79, 0.97). We found no reliable associations with either outcomes for the CDQI, and no reliable change in risk of ADHD diagnosis for the UPFI. Conclusions We provide evidence that overall maternal diet quality during pregnancy is associated with a small decrease in ADHD symptom score at 8 years and lower risk for ADHD diagnosis, with more robust findings for the latter outcome. Consumption of ultra-processed foods was only associated with increased ADHD symptom score of similar magnitude as for overall maternal diet quality, and we found no associations between child diet quality and either outcome. No causal inferences should be made based on these results, due to potential unmeasured confounding.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent. Objectives: We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). Methods: This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach. Results: Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]. Conclusion: Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.

Background 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. Objective 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). Methods 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. Results 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]. Conclusion 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.

Background 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. Objectives 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. Methods 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. Results 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. Conclusion 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.

Self-selection into prospective cohort studies and loss to follow-up can cause biased exposure-outcome association estimates. Previous investigations illustrated that such biases can be small in large prospective cohort studies. The structural approach to selection bias shows that general statements about bias are not possible for studies that investigate multiple exposures and outcomes, and that inverse probability of participation weighting (IPPW) but not adjustment for participation predictors generally reduces bias from self-selection and loss to follow-up. We propose to substantiate assumptions in structural models of selection bias through calculation of genetic correlations coefficients between participation predictors, outcome, and exposure, and to estimate a lower bound for bias due to self-selection and loss to follow-up by comparing effect estimates from IPP weighted and unweighted analyses. This study used data from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway. Using the example of risk factors for ADHD, we find that genetic correlations between participation predictors, exposures, and outcome suggest the presence of bias. The comparison of exposure-outcome associations from regressions with and without IPPW revealed meaningful deviations. Assessment of selection bias for entire multi-exposure multi-outcome cohort studies is not possible. Instead, it has to be assessed and controlled on a case-by-case basis.

Background: Particulate matter (PM) air pollution is an environmental risk to public health. The prevalence of thyroid disease during pregnancy has increased rapidly in recent decades, but the avai...

Maternal fever during pregnancy is associated with several adverse child outcomes. We investigated associations between maternal fever and ADHD among offspring, as well as the sub-dimensions of ADHD - inattention and hyperactivity/impulsivity. Data came from the Norwegian Mother and Child Cohort Study, including more than 114,000 children. Information about children’s ADHD diagnoses was obtained from the Norwegian Patient Register. Mothers reported on inattention and hyperactivity/impulsivity symptoms in questionnaires at 8 years. Logistic regression analysis showed that children exposed to maternal fever in the first trimester received an ADHD diagnosis more often than unexposed children (Odds Ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06–1.61). For children exposed twice or more in the first trimester, the OR was 2.64 (CI = 1.36–5.14). Linear regression analysis showed elevated inattention symptoms among children exposed to fever in the first (Cohen’s d = 0.09, CI = 0.03–0.15) and second (Cohen’s d = 0.05, CI = 0.01–0.09) trimester. Results were similar whether the mother had taken acetaminophen for their fever or not. Hyperactivity/impulsivity symptoms were not related to maternal fever. The results indicate that maternal fever in early pregnancy may be a risk factor for ADHD, and particularly for inattention problems. This risk is neither mitigated nor inflated by use of acetaminophen.

We investigated to what extent parent-rated attention-deficit/hyperactivity disorder (ADHD) and impairment at age 3 years predicted elevated ADHD symptoms at age 5 years, and whether teacher-rated ADHD symptoms improved these predictions. This study is part of the longitudinal, population-based Norwegian Mother, Father and Child Cohort Study. Parents of 3-year-old children (n = 1195) were interviewed about ADHD and impairment, and teachers rated child ADHD symptoms by the Strengths and Difficulties Questionnaire or the Early Childhood Inventory-4. At 5 years of age, the children (n = 957) were classified as ADHD-positive or -negative using Conners’ Parent Rating Scale. Relying solely on parent-rated ADHD or impairment at age 3 years did moderately well in identifying children with persistent elevation of ADHD symptoms, but gave many false positives (positive predictive values (PPVs): .40–.57). A small group of children (n = 20, 13 boys) scored above cut-off on both parent-rated ADHD and impairment, and teacher-rated ADHD symptoms, although adding teacher-rated ADHD symptoms slightly weakened the predictive power for girls. For this small group, PPVs were .76 for boys and .64 for girls. Limiting follow-up to these few children will miss many children at risk for ADHD. Therefore, we recommend close monitoring also of children with parent-reported ADHD symptoms and/or impairment to avoid delay in providing interventions. Clinicians should also be aware that teachers may miss ADHD symptoms in preschool girls.

Purpose Some studies indicate that mild-to-moderate iodine deficiency in pregnant women might negatively affect offspring neurocognitive development, including previous results from the Norwegian Mother and Child Cohort study (MoBa) exploring maternally reported child development at age 3 years. The aim of this follow-up study was to investigate whether maternal iodine intake in pregnancy is associated with language and learning at 8 years of age. Methods The study sample includes 39,471 mother–child pairs participating in MoBa with available information from a validated food frequency questionnaire covering the first half of pregnancy and a questionnaire on child neurocognitive development at 8 years. Multivariable regression was used to explore associations of iodine intake from food and supplements with maternally reported child outcomes. Results Maternal iodine intake from food less than ~ 150 µg/day was associated with poorer child language skills (p-overall = 0.013), reading skills (p-overall = 0.019), and writing skills (p-overall = 0.004) as well as poorer school test result in reading (p < 0.001), and increased likelihood of the child receiving special educational services (p-overall = 0.042) (in noniodine supplement users). Although significant, differences were generally small. Maternal use of iodine supplements in pregnancy was not significantly associated with any of the outcomes. Conclusions Low habitual iodine intake in pregnant women, i.e., lower than the recommended intake for non-pregnant women, was associated with mothers reporting poorer child language, school performance, and increased likelihood of special educational services. We found no indications of benefits or harm of using iodine-containing supplements in pregnancy. Initiating use in pregnancy might be too late. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/ NIEHS (contract no N01-ES-75558), NIH/NINDS (Grant no. 1 UO1 NS 047537-01 and Grant no. 2 UO1 NS 047537-06A1). MHA was supported by a 4 years Grant from the Norwegian Research Council (Grant no. 241430) and the Norwegian dairy company TINE SA.

Background Normal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid-stimulating hormone (TSH) 48-72 hours after birth screens for congenital hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub-clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD). Objectives To estimate the association between neonatal TSH below threshold for potential congenital hypothyroidism and subsequent ADHD diagnosis using a population-based birth cohort. Methods Children with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD-10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003-2008) with available neonatal TSH concentrations below 10 mU/L (cut-off for potential congenital hypothyroidism) measured in dried blood spots sampled 48-72 hours after birth. Results In multivariable, quintile models the relationship appeared to follow a U-shaped pattern with elevated odds ratios (OR) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5-fold higher than children in the middle quintile (OR 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (Pinteraction = 0.02; girls OR 3.10, 95% CI 1.53, 6.30; boys OR 1.16, 95% CI 0.73, 1.84). Conclusions ADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed.

The Early Childhood Inventory-4 (ECI-4) Hyperactivity-Impulsivity (HI) and Inattention (IA) subscales are screeners for attention-deficit/hyperactivity disorder (ADHD). There have been few studies of the screening properties of these subscales, particularly outside the United States. We investigated the classification accuracy of the parent and teacher versions of the HI and IA subscales and the cross-cultural validity of the cutoff values based on norms from a United States sample. The present study was part of the Norwegian Mother and Child Cohort Study. Parents and teachers rated boys (n = 332) and girls (n = 319) with the ECI-4 (mean Age 3.5 years). Interviewers who were blind to the ratings used the Preschool Age Psychiatric Assessment Interview to assign ADHD diagnoses. The ECI-4 HI and IA subscales showed acceptable accuracy in identifying ADHD in boys and girls (areas under the curve ranged from .67 to .85). In a multivariate regression analysis, the parent and teacher HI subscale scores significantly contributed to ADHD identification, but not the IA subscale scores. To achieve the necessary sensitivity to detect children with ADHD, lower cutoff levels than those specified by the United States ECI-4 norms were needed. For screening purposes, the parent and teacher ECI-4 showed acceptable accuracy in identifying preschoolers at risk for ADHD, and it may be sufficient to use the HI subscale scores. The suggested cutoff values provided by the United States ECI-4 norms had limited cross-cultural validity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Our aim in this study was to estimate the strength of associations between prenatal diet quality and child behavioral, language, and motor functions in the Norwegian Mother and Child Cohort Study (1999–2008). We created a prenatal diet quality index (PDQI) based on adherence to Norwegian dietary guidelines. Child outcomes were defined as sum scores on the Child Behavior Checklist, the Ages and Stages Questionnaire, and the Child Development Index at ages 18, 36, and 60 months. Using a longitudinal cohort study design and Bayesian hierarchical modeling, we estimated association strengths using inverse probability weighting to account for selection bias. In total, 27,529 mother-child pairs were eligible for inclusion. A 1–standard-deviation increase in PDQI score was associated with an absolute reduction in outcome sum scores of 0.02–0.21 and a 3%–7% relative decrease, with larger decreases seen for language and motor functions than for behavioral functions. PDQI scores were inversely associated with all child functions, but the estimated strength of each association was low. The results indicate that the observed variations in PDQI scores in an industrialized Western society may not profoundly influence the child functions studied. Estimating the Strength of Associations Between Prenatal Diet Quality and Child Developmental Outcomes: Results From a Large Prospective Pregnancy Cohort Study

Background: Polychlorinated dibenzo-p-dioxins/dibenzofurans (dioxins) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with potentially adverse impact on child neurodevelopment. Whether the potential detrimental effects of dioxins and PCBs on neurodevelopment are of specific or unspecific character is not clear. Objectives: The purpose of the current study was to examine the influence of maternal dietary exposure to dioxins and PCBs on ADHD symptoms and cognitive functioning in preschoolers. We aimed to investigate a range of functions, in particular IQ, expressive language, and executive functions. Material and methods: This study includes n = 1024 children enrolled in a longitudinal prospective study of ADHD (the ADHD Study), with participants recruited from The Norwegian Mother and Child Cohort Study (MoBa). Boys and girls aged 3.5 years participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview (PAPA), Stanford-Binet 5th revision (SB-5), Child Development Inventory (CDI), and Behavior Rating Inventory of Executive Function, Preschool version (BRIEF-P). Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl-PCBs). Generalized linear and additive models adjusted for confounders were used to examine exposure-outcome associations. Results: Exposure to PCB-153 or dl-compound was not significantly associated with any of the outcome measures when analyses were performed for boys and girls together. After stratifying by sex, adjusted analyses indicated a small inverse association with language in girls. An increase in the exposure variables of 1 SD was associated with a reduction in language score of −0.2 [CI −0.4, −0.1] for PCB-153 and −0.2 [CI −0.5, −0.1] for dl-compounds in girls. For boys, exposure to PCB-153 or dl-compounds was not associated with language skills. The difference between sex-specific associations was not statistically significant (p-value = 0.13). No sex-specific effects were observed for ADHD-symptoms, IQ scores, or executive functions. Conclusions: We found no indications that variation in current low-level exposure to PCB-153 or dl-compounds in Norway is associated with variation ADHD-symptoms, verbal/non-verbal IQ, or executive functions including working memory in preschoolers. However, our findings indicated that maternal dietary exposure to PCB-153 or dl-compounds during pregnancy was significantly associated with poorer expressive language skills in preschool girls, although the sex-specific associations were not significantly different. Keywords: Dioxin, PCB, Cognitive function, ADHD, The Norwegian Mother and Child Cohort Study, MoBa

Objective: Little is known about cognition in preschoolers with ADHD and language delay (LD). The objective was to investigate cognitive functions in preschoolers with ADHD symptoms and LD compared with children with ADHD symptoms only and to estimate the frequency of children with ADHD symptoms, co-occurring language delay, and delays on cognitive measures. Method: Participants were recruited from the Norwegian Mother and Child Cohort Study. The teacher report of expressive language and the cognitive tests from 119 3-year-old children with parent reported ADHD symptoms and LD were compared with those of 258 children with ADHD symptoms only. Results: The ADHD + LD group performed significantly worse than the ADHD group on most language-related measures. There were no differences between the groups on most nonverbal measures. Single measures had a limited potential of differentiating between the groups. Conclusion: ADHD symptoms and co-occurring LD in preschoolers were characterized by cognitive deficits associated with both disorders, not with global neurodevelopmental delay.

Background: 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. Methods: 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. Results: 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

Background ADHD is multifactorial, including both genetic and environmental factors. The safety of amalgam used in dental treatment has been discussed due to its content of mercury and potential risks for negative neurodevelopmental consequences in the offspring. The aim of the study was to investigate possible associations between symptoms related to ADHD in children of three and five years of age and prenatal exposure to mercury from mothers' amalgam fillings. Methods Data from the Norwegian Mother and Child Cohort Study (MoBa) were used. Data were collected by questionnaires sent to participating women in week 17 (Q1) and 30 (Q3) of pregnancy and when the child was three (Q6) and five years of age (Q7). Information about exposure to amalgam during pregnancy was obtained from Q3. Information about symptoms related to ADHD was obtained from Q6 and Q7. Valid data were obtained for 42 163 children at three years of age and 23 392 children at five years of age. Logistic regression models, including mothers' age, education, body mass index, parity, smoking and alcohol consumption during pregnancy, were used to estimate the association between ADHD symptoms and prenatal exposure to amalgam fillings. Results No significant associations between number of teeth with amalgam filling, amalgam fillings placed or removed during pregnancy, and symptoms related to ADHD in children of three and five years of age were found. Conclusions In a large, prospective cohort study, we found no indication of increased risk of ADHD-related symptoms in children prenatally exposed to mother's amalgam fillings.

Objective 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. Method 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. Results 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. Conclusion 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.

Background Hyperkinetic disorder is one of the most frequently used psychiatric diagnoses among children and adolescents in Norway. It has previously been shown that use of the diagnosis varies widely by county. Material and method We estimated the proportion of children with hyperkinetic disorder using patient data from the Norwegian Patient Registry and population data from the Norwegian Population Registry. The estimations were made for both Norway as a whole and by county. Assessment and documentation of the diagnosis were surveyed by linking the Norwegian Patient Registry and the Norwegian Mother and Child Cohort Study. We reviewed medical records from specialist mental health services for children and adolescents and assessed whether the diagnoses met the research criteria for hyperkinetic disorder. Results At 12 years of age, 5.4 % of Norwegian boys and 2.1 % of Norwegian girls had been diagnosed with hyperkinetic disorder by specialist health services. The proportion of children varied between 1.4 % and 5.5 % among the counties. A review of medical records for 549 children showed that 49 % of the diagnoses were reliably documented in the records. The main reasons that the diagnosis was not documented were a discrepancy between the information in the medical record and diagnostic criteria (38 %) and inadequate differential diagnostic assessment (46 %). Interpretation There was considerable geographic variation in the proportions of children and adolescents with hyperkinetic disorder. A large percentage of the diagnoses were not reliably documented in medical records. The guideline for evaluation, diagnostics and medical recordkeeping should be reviewed.

Objective: The aim of this study was to examine occurrence of emotional lability (EL) in preschoolers with ADHD symptoms versus controls. Method: The study was part of the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. In the present study, 495 preschoolers were clinically examined. Symptoms of ADHD, anxiety, and oppositional defiant disorder (ODD) were measured with the Preschool Age Psychiatric Assessment Interview. An EL measure was obtained from the Emotional Control subscale of the Behavior Rating Inventory of Executive Function–Preschool Version (BRIEF-P), which parents and teachers completed. Results: EL was significantly more frequent in the ADHD group compared with controls (25% vs. 7%, p < .001). By parent report, EL correlated significantly with ADHD-, anxiety-, and ODD symptoms. By teacher report, EL was significantly correlated only with hyperactivity-impulsivity. Conclusion: EL appears identifiable in young preschoolers and was particularly associated with ODD in children with ADHD symptoms.

Background Exposures to environmental phenols and parabens may be harmful, especially in utero. Prior studies have demonstrated high within-person variability of urinary concentrations across pregnancy. Objectives We sought to measure phenol and paraben biomarker concentrations for the Norwegian Mother and Child Cohort (MoBa) study, assess within-person variability, and investigate any possible external phenol or paraben contamination of specimens. Methods We collected three spot urine samples at approximately 17, 23, and 29 weeks gestation in a hospital setting and added a preservative containing ethyl paraben. We measured urinary concentrations and within-person variability for phenols and parabens in a MoBa sample (n = 45), including a subgroup of 15 participants previously randomly selected for a bisphenol A (BPA) exposure study who had unusually high total BPA concentrations. Additionally, we compared reliability results for total, conjugated, and free concentrations of phenolic compounds. Results We detected total and free BPA, butyl paraben, propyl paraben, and methyl paraben in 100% of samples, total benzophenone-3 in 95% of samples, and infrequently detected free benzophenone-3 and total and free 2,4-dichlorophenol and 2,5-dichlorophenol. Intraclass correlation coefficients (ICCs) for total, conjugated, and free concentrations ranged from relatively low for BPA to moderate for propyl paraben. ICCs were generally similar overall and by subgroup. Conclusions Using conjugated concentrations improved reliability estimates only for BPA. Measuring total and free concentrations, an approach that may be useful for future studies, allowed us to identify likely BPA and butyl paraben contamination of archived MoBa urine specimens. Citation Guidry VT, Longnecker MP, Aase H, Eggesbø M, Zeiner P, Reichborn-Kjennerud T, Knudsen GP, Bertelsen RJ, Ye X, Calafat AM, Engel SM. 2015. Measurement of total and free urinary phenol and paraben concentrations over the course of pregnancy: assessing reliability and contamination of specimens in the Norwegian Mother and Child Cohort Study. Environ Health Perspect 123:705–711; http://dx.doi.org/10.1289/ehp.1408325

Objective: To identify preschool predictors of registered ADHD diagnoses and compare two ADHD rating scales, Child Behavior Checklist (CBCL) and Conners’ Parent Rating Scale (CPRS-R:S). Method: The Norwegian Mother and Child Cohort study (MoBa) is a prospective population-based cohort study. The sample were singletons whose mothers responded to MoBa questionnaires at child age 3 years ( n = 57,986) and 5 years ( n = 32,377). ADHD diagnoses were obtained from the Norwegian Patient Register. Predictors were child gender, development and symptoms, and maternal ADHD symptoms. We used Cox proportional hazard regression analyses. Results: In all final models, ADHD symptoms at age 3 and 5 years predicted later ADHD: Age 3, CBCL: hazard ratio (HR) = 3.23 (CI [2.59, 4.02]); age 5, CBCL: HR = 10.30 (CI [7.44, 14.26]); and age 5 CPRS-R:S: HR = 5.92 (CI [4.95, 7.07]). Conclusion: The findings underline the importance of taking early parent-reported symptoms seriously. Both rating scales were useful for predicting ADHD.

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 (p = 0.89), while low iodine from food (

Background: Severe iodine deficiency in pregnancy has major effects on child neurodevelopment, but less is known about the potential consequences of mild-to-moderate deficiency and iodine supplement use. Objective: We explored the associations between maternal iodine intake and child neurodevelopment at 3 y of age and the potential impact of maternal intake of iodine from supplements on the same outcomes. Methods: This population-based prospective observational study included 48,297 mother-child pairs recruited during pregnancy from 2002 to 2008. Maternal iodine intake was calculated based on a validated food-frequency questionnaire answered during midpregnancy that covered mean intake since the beginning of pregnancy. Associations between iodine intake and maternal-reported child language and motor development and behavior problems were explored by multivariable regression analyses. Results: In 33,047 mother-child pairs, excluding iodine supplement users, maternal iodine intake was associated with child language delay (P = 0.024), externalizing and internalizing behavior problems (both P < 0.001), and fine motor skills (P = 0.002) but not gross motor skills or the risk of not walking unaided at 17 mo of age. In 74% of the participants who had an iodine intake 1.5 SD, and 16% (95% CI: 10%, 21%) of the cases of internalizing behavior problems >1.5 SD. In 48,297 mother-child pairs, including iodine supplement users, we found no protective effects of supplemental iodine during pregnancy on neurodevelopment. Conclusions: Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age. The results showed no evidence of a protective effect of iodine supplementation during pregnancy.

Background: Cohort studies often report findings on children with Attention Deficit Hyperactivity Disorder (ADHD) but may be biased by self-selection. The representativeness of cohort studies needs to be investigated to determine whether their findings can be generalised to the general child population. The aim of the present study was to examine the representativeness of child ADHD in the Norwegian Mother and Child Cohort Study (MoBa). Methods: The study population was children born between January 1, 2000 and December 31, 2008 registered with hyperkinetic disorders (hereafter ADHD) in the Norwegian Patient Registry during the years 2008–2013, and two groups of children with ADHD were identified in: 1. MoBa and 2. The general child population. We used the multiaxial International Classification of Diseases (ICD-10) and compared the proportions of comorbid disorders (axes I–III), abnormal psychosocial situations (axis V) and child global functioning (axis VI) between these two groups. We also compared the relative differences in the multiaxial classifications for boys and girls and for children with/without axis I comorbidity, respectively in these two groups of children with ADHD. Results: A total of 11 119 children were registered with ADHD, with significantly fewer in MoBa (1.45%) than the general child population (2.11%), p < 0.0001. The proportions of comorbid axis I, II, and III disorders were low, with no significant group differences. Compared with the general child population with ADHD, children with ADHD in MoBa were registered with fewer abnormal psychosocial situations (axis V: t = 7.63, p < .0001; d = -.18) and better child global functioning (axis VI: t = 7.93, p < 0.0001; d = .17). When analysing relative differences in the two groups, essentially the same patterns were found for boys and girls and for children with/without axis I comorbidity. Conclusions: Self-selection was found to affect the proportions of ADHD, psychosocial adversity and child global functioning in the cohort. However, the differences from the general population were small. This indicates that studies on ADHD and multiaxial classifications in MoBa, as well as other cohort studies with similar self-selection biases, may have reasonable generalisability to the general child population.

Early symptoms of attention deficit/hyperactivity disorder (ADHD) and oppositional-defiant disorder (ODD) are associated with deficits in cognitive self-regulatory processes or executive functions (EF)s. However, the hypothesis that neurocognitive deficits underlying the two disorders are already evident during early preschool years still has limited empirical support. The present study investigated associations between symptoms of ADHD and/or ODD and two core EFs, inhibition and working memory, in a large nonclinical sample of 3-year old children.Participants were 1045 children (554 boys, age 37-47 months), recruited from the population based Norwegian Mother and Child Cohort Study (MoBa). Relations between behavioral symptoms and measures of inhibition and working memory were studied both categorically and dimensionally.Children with co-occurring symptoms of ADHD and ODD performed at a significantly lower level than typically developing children in 4 out of 5 EF measures. Symptoms of ADHD, both alone and in combination with ODD, were associated with reduced performance on tests of inhibition in the group comparisons. Dimensional analyses showed that performance within both EF domains contributed to variance primarily in ADHD symptom load. The associations between test results and behavioral symptoms remained significant after gender and verbal skills had been controlled.Young preschoolers show the same pattern of relations between EF and behavioral symptoms of ADHD and/or ODD as previously described in older children diagnosed with ADHD and/or ODD. Effect sizes were generally small, indicating that measures of EF have limited clinical utility at this stage in development.

OBJECTIVE: The objective of this article is to examine the associations between pre- and postnatal maternal distress and preschooler's symptoms of ADHD, Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and anxiety, by timing and gender.METHOD: Children, aged 3.5 years (N = 1,195), recruited from the Norwegian Mother and Child Cohort Study, were assessed with a semistructured parental psychiatric interview. Perinatal maternal symptoms of distress were assessed by Symptom Checklist (SCL-5); Poisson regression was used to examine the associations.RESULTS: Mid-gestational maternal distress significantly increased the average number of child symptoms, ranging between 3.8% for ADHD hyperactive-impulsive (ADHD-HI) and 8.7% for anxiety. The combination of high maternal scores of distress both pre- and postnatally were associated with increased risk of child symptoms of anxiety (relative risk [RR] = 2.10; 95% confidence interval [CI] = [1.43, 3.07]), CD (RR = 1.83; 95% CI = [1.33, 2.51]), and ODD (RR = 1.30; 95% CI = [1.03, 1.64]), with minor sex differences.CONCLUSION: Maternal distress during mid-gestation was associated with ADHD, behavioral, and emotional symptoms in preschool children. Continued exposure into the postnatal period may further increase these risk associations .

The preschool period is an important developmental period for the emergence of cognitive self-regulatory skills or executive functions (EF). To date, evidence regarding the structure of EF in preschool children has supported both unitary and multicomponent models. The aim of the present study was to test the factor structure of early EF as measured by the Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P). BRIEF-P consists of five subscales and three broader indexes, hypothesized to tap into different subcomponents of EF. Parent ratings of EF from a nonreferred sample of children recruited from the Norwegian Mother and Child Cohort Study (N = 1134; age range 37–47 months) were subjected to confirmatory factor analyses (CFA). Three theoretically derived models were assessed; the second-order three-factor model originally proposed by the BRIEF-P authors, a “true” first-order one-factor model and a second-order one-factor model. CFA fit statistics supported the original three-factor solution. However, the difference in fit was marginal between this model and the second-order one-factor model. A follow-up exploratory factor analysis (EFA) supported the existence of several factors underlying EF in early preschool years, with a considerable overlap with the five BRIEF-P subscales. Our results suggest that some differentiation in EF has taken place at age 3 years, which is reflected in behavior ratings. The internal consistency of the BRIEF-P five clinical subscales is supported. Subscale interrelations may, however, differ at this age from those observed in the preschool group as a whole.

Epidemiological studies often use parent questionnaires to assess children's development and mental health. To date, few studies have investigated the validity of parent questionnaires with standardized clinical assessments as criterion. The current study examines discriminant and convergent validity of parent questionnaires for symptoms of Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiance Disorder (ODD), and Conduct Disorder (CD) as well as symptoms of Separation Anxiety employed in the Norwegian Mother and Child Cohort Study by using structured clinical interviews performed 5 months later in the Longitudinal ADHD Cohort Study as a criterion. The comparison of confirmatory factor analysis models and examination of factor correlations indicate convergent and discriminant validity of MoBa parent questionnaires for preschool children, especially for the assessment of ADHD and ODD/CD. Future research should attempt to further improve parent questionnaires, examine their validity in representative samples, and explicitly test their utility for screening.

Triclosan (TCS) is a synthetic antibacterial chemical that is used in personal care products and is measurable in urine. Urinary TCS has been associated with allergy in children in Norway and the United States. A reasonable degree of temporal reliability of TCS urinary concentrations has been reported among U.S. children as well as for Puerto Rican pregnant women. We examined the reliability of TCS measures in urine among Norwegian pregnant women. Triclosan was measured in spot urine samples collected in gestational weeks 17, 23, and 29 from 45 women in The Norwegian Mother and Child Cohort Study (MoBa) enrolled in 2007 and 2008. Spearman’s rank correlation coefficient (rs) and intraclass correlation coefficient (ICC) statistics were calculated. Fifty-six percent of the 45 women had a least one sample with a value above the method limit of detection (2.3 µg/L). The correlation coefficients were 0.61 for TCS concentrations at 17 and 23 weeks and 0.49 for concentrations at 17 and 29 weeks. For the three time points, the ICC was 0.49. The reliability of TCS concentrations in repeated urine samples from pregnant Norwegian women was reasonably good, suggesting a single urine sample can adequately represent TCS exposure during pregnancy.

Background: We have limited knowledge of the impact of attention-deficit/hyperactivity disorder (ADHD) symptoms on the daily functioning of young preschool children. Objective: This study investigated the level of impairment related to symptoms of ADHD in different functional domains. It also addressed how impairment caused by ADHD was related to ADHD subtype, symptom load, gender, and the co-occurrence of oppositional defiant disorder, conduct disorder, or both. Method: Participating children (N = 807) who were 3.5 years old were recruited from a population-based sample included in The Norwegian Mother and Child Cohort Study. Children who scored above the 90th percentile for ADHD symptoms were included in the present sample. The assessment of the symptoms and functional impairment described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision, was based on parental ratings and the semi-structured psychiatric interview entitled “The Preschool Age Psychiatric Assessment.” Results: Added burden and discord within family relationships were the areas that were most severely affected. All domain scores were strongly intercorrelated, and they were added to each child’s total score. Children with symptoms of ADHD, inattentive type (mean [M], 3.5; standard deviation [SD], 3.4), or ADHD, hyperactive/impulsive type (M, 2.9; SD, 2.7), were significantly less impaired than children with symptoms of ADHD, combined type (M = 6.4; SD = 3.8; p ` .001). Furthermore, co-occurring oppositional defiant disorder was associated with higher impairment scores (M, 6.1; SD, 4.3) than ADHD alone (M, 3.2; SD, 2.9; p ` .001. About 30% of the variance of impairment score of ADHD was explained by symptoms of ADHD and co-occurring symptoms of oppositional defiant disorder and conduct disorder. Few gender differences were observed. Conclusion: Overall, these non-referred young children with clinical symptoms of ADHD were only modestly impaired. Impairment related to ADHD occurred mainly in the areas of family functioning, and it was associated with ADHD subtype and comorbidity. Still, it is important to assess the impact of ADHD symptoms and coexisting difficulties among preschoolers to identify children and families who are in need of early intervention efforts.

Objective: The objective of this study was to examine co-occurrence of ADHD and anxiety in preschool children. Method: The data collection was part of the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. After a screening for ADHD symptoms at 36 months, participants were clinically assessed at age 36 to 44 months. Psychiatric symptoms of ADHD and anxiety were derived from the Preschool Age Psychiatric Assessment (PAPA) interview. Results: In preschoolers with ADHD symptoms, 33% were reported to have symptoms of anxiety. Children with symptoms of ADHD and anxiety had more severe ADHD symptomatology, and particularly more inattentive symptoms compared with children with ADHD symptoms and no anxiety. Conclusion: Clinicians should be aware of the frequent overlap between symptoms of anxiety and ADHD in preschoolers as different intervention strategies may be required.

Anxiety disorders and attention deficit/hyperactivity disorder (ADHD) develop before school age, but little is known about early developmental pathways. Here we test two hypotheses: first, that early signs of anxiety and ADHD at 18 months predict symptoms of anxiety and ADHD at age 3½ years; second, that emotional dysregulation at 18 months predicts the outcome of co-occurring anxiety and ADHD at age 3½ years. The study was part of the prospective Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. The 628 participants were clinically assessed at 3½ years. Questionnaire data collected at 18 months were categorized into early behavioural scales of anxiety, ADHD, and emotional dysregulation. We investigated continuity in features of anxiety and ADHD from 18 months to 3½ years of age through logistic regression analyses. Anxiety symptoms at 3½ years were predicted by early signs of anxiety (Odds ratio (OR) = 1.41, CI = 1.15–1.73) and emotional dysregulation (OR = 1.33, CI = 1.15–1.54). ADHD symptoms at 3½ years were predicted by early signs of ADHD (OR = 1.51, CI = 1.30–1.76) and emotional dysregulation (OR = 1.31, CI = 1.13–1.51). Co-occurring anxiety and ADHD symptoms at 3½ years were predicted by early signs of anxiety (OR = 1.43, CI = 1.13–1.84), ADHD (OR = 1.30, CI = 1.11–1.54), and emotional dysregulation (OR = 1.34, CI = 1.13–1.58). We conclude that there were modest continuities in features of anxiety and ADHD through early preschool years, while emotional dysregulation at age 18 months was associated with symptoms of anxiety, ADHD, and co-occurring anxiety and ADHD at age 3½ years.

Background Research has highlighted a series of persistent deficits in cognitive ability in preterm low-birth-weight children. Language and attention problems are among these deficits, although the nature of the relation between attention and language in early development is not well known. This study represents a preliminary attempt to shed light on the relations between attention problems and language development in preterm low-birth-weight children. Methods The aim of this study was to analyse reciprocal influences between language and attention problems from 18 to 36 months. We used maternal reports on attention problems and language ability referring to a sample of 1288 premature low-birth-weight infants, collected as part of the Norwegian Mother and Child Cohort Study (MoBa). A sample of children born full-term was used as the control group (N = 37010). Cross-lagged panel analyses were carried out to study reciprocal influences between attention problems and language. Results Language ability at 18 months did not significantly predict attention problems at 36 months, adjusting for attention problems at 18 months. Attention problems at 18 months significantly predicted changes in language ability from 18 to 36 months, pointing to a precursor role of attention in relation to language in children born preterm. Gender, age corrected for prematurity, and mother's education emerged as important covariates. Conclusions Preliminary evidence was found for a precursor role of early attention problems in relation to language in prematurity. This finding can contribute to a better understanding of the developmental pathways of attention and language and lead to better management of unfavourable outcomes associated with co-morbid attention and language difficulties.