Publications by authors named "Heidi Aase"

63 Publications

Gestational blood levels of toxic metal and essential element mixtures and associations with global DNA methylation in pregnant women and their infants.

Sci Total Environ 2021 Sep 8;787:147621. Epub 2021 May 8.

Norwegian Institute of Public Health, Oslo, Norway.

Background: Pregnant women and their fetuses are exposed to multiple toxic metals that together with variations in essential element levels may alter epigenetic regulation, such as DNA methylation.

Objectives: The aim of the study was to investigate the associations between gestational levels of toxic metals and essential elements and mixtures thereof, with global DNA methylation levels in pregnant women and their newborn children.

Methods: Using 631 mother-child pairs from a prospective birth cohort (The Norwegian Mother, Father and Child Cohort Study), we measured maternal blood concentration (gestation week ~18) of five toxic metals and seven essential elements. We investigated associations as individual exposures and two-way interactions, using elastic net regression, and total mixture, using quantile g-computation, with blood levels of 5-methylcytocine (5mC) and 5-hydroxymethylcytosine (5hmC) in mothers during pregnancy and their newborn children (cord blood). Multiple testing was adjusted for using the Benjamini and Hochberg false discovery rate (FDR) approach.

Results: The most sensitive marker of DNA methylation appeared to be 5mC levels. In pregnant mothers, elastic net regression indicated associations between 5mC and selenium and lead (non-linear), while in newborns results indicated relationships between maternal selenium, cobalt (non-linear) and mercury and 5mC, as well as copper (non-linear) and 5hmC levels. Several possible two-way interactions were identified (e.g. arsenic and mercury, and selenium and maternal smoking in newborns). None of these findings met the FDR threshold for multiple testing. No net effect was observed in the joint (mixture) exposure-approach using quantile g-computation.

Conclusion: We identified few associations between gestational levels of several toxic metals and essential elements and global DNA methylation in pregnant mothers and their newborn children. As DNA methylation dysregulation might be a key mechanism in disease development and thus of high importance for public health, our results should be considered as important candidates to investigate in future studies.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147621DOI Listing
September 2021

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study.

Environ Int 2021 Sep 25;154:106549. Epub 2021 Apr 25.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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.
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http://dx.doi.org/10.1016/j.envint.2021.106549DOI Listing
September 2021

Pregnancy exposure to common-detect organophosphate esters and phthalates and maternal thyroid function.

Sci Total Environ 2021 Aug 24;782:146709. Epub 2021 Mar 24.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Contemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health. In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa).

Methods: We included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004-2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR).

Results: We restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [-0.59, -0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (-1.99 ng/dL [-4.52, 0.53]) and TT4 (0.13 μg/dL [-0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (-0.48 [-0.96, 0.003]).

Conclusions: Maternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146709DOI Listing
August 2021

Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children.

Environ Int 2021 07 22;152:106468. Epub 2021 Mar 22.

Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, 0213 Oslo, Norway.

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.
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http://dx.doi.org/10.1016/j.envint.2021.106468DOI Listing
July 2021

The associations between maternal and child diet quality and child ADHD - findings from a large Norwegian pregnancy cohort study.

BMC Psychiatry 2021 03 8;21(1):139. Epub 2021 Mar 8.

Department of Environmental Health, Section of Environmental Exposure and Epidemiology, Norwegian Institute of Public Health, P.O. Box 222, Skøyen, 0213, Oslo, Norway.

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.
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http://dx.doi.org/10.1186/s12888-021-03130-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941947PMC
March 2021

Predictive validity of attention-deficit/hyperactivity disorder from ages 3 to 5 Years.

Eur Child Adolesc Psychiatry 2021 Mar 7. Epub 2021 Mar 7.

Division of Mental Health and Addiction, Oslo University Hospital, Pb. 4959 Nydalen, 0424, Oslo, Norway.

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.
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http://dx.doi.org/10.1007/s00787-021-01750-5DOI Listing
March 2021

Prenatal phthalate exposures and executive function in preschool children.

Environ Int 2021 04 29;149:106403. Epub 2021 Jan 29.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF.

Methods: Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks' gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding.

Results: Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: -0.63 [-2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: -0.15 [-1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT.

Conclusion And Relevance: Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures.
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http://dx.doi.org/10.1016/j.envint.2021.106403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945722PMC
April 2021

Child and Parental Characteristics of Medication Use for Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacol 2020 09 14;30(7):456-464. Epub 2020 Jul 14.

Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

To investigate child and parental characteristics of medication use for attention-deficit/hyperactivity disorder (ADHD). Participants were part of the prospective population-based Norwegian Mother, Father and Child Cohort study (MoBa) ( = 114,500 children, 95,000 mothers, and 75,000 fathers). This cohort was linked to the Norwegian Prescription Database (NorPD) and the Norwegian Patient Registry (NPR) to compare child and parental characteristics in children medicated and not medicated for ADHD during years 2008-2013. One thousand seven hundred and sixty-four children (74% boys) with ADHD (International Classification of Diseases [ICD-10]: F90 and F98.8) were identified. One thousand three hundred and sixty-two (77%) used medication. Boys and girls did not differ in the use of ADHD medication (both 77%). Mean age at first prescription was 9 years in both boys and girls, and age at ADHD diagnosis was 8 years in medicated and unmedicated children. Significantly more hyperkinetic conduct disorders (F90.1), and significantly fewer with attention-deficit disorder (F98.8) were found among the medicated children compared to the unmedicated children. The medicated children also had a significantly lower global functioning (Child Global Assessment Scale). Child disruptive symptoms reported in the MoBa child age 3 year questionnaire were significantly higher in children who used medication compared to the nonusers ( = 2.2,  = 0.03), and group differences in ADHD symptoms at age 3 years were close to significant ( = 1.8,  = 0.07). Other preschool child and parental characteristics were not significantly different in the two groups. In this large birth cohort study, where a great majority of children with ADHD used medication, only child characteristics were significantly associated with the use of medication. We could not replicate previous findings suggesting that "environmental factors," such as parental education and psychopathology, drive medication use. The small differences between medicated and unmedicated children in this cohort study, where a majority used medication, might be due to strong established clinical practices where medication is offered as a treatment option, particularly for hyperkinetic conduct disorder in an egalitarian high-income society.
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http://dx.doi.org/10.1089/cap.2019.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475088PMC
September 2020

Identifying a critical window of maternal metal exposure for maternal and neonatal thyroid function in China: A cohort study.

Environ Int 2020 06 4;139:105696. Epub 2020 Apr 4.

State Key Laboratory of Reproductive Medicine, School of Public Health, Nanjing Medical University, No. 101 Longmian Road, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, No. 101 Longmian Road, Nanjing 211166, China. Electronic address:

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 < 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.envint.2020.105696DOI Listing
June 2020

Neonatal thyroid-stimulating hormone and association with attention-deficit/hyperactivity disorder.

Paediatr Perinat Epidemiol 2020 09 18;34(5):590-596. Epub 2020 Feb 18.

Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.

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 (P = 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.
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http://dx.doi.org/10.1111/ppe.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431377PMC
September 2020

Associations between urine phthalate metabolites and thyroid function in pregnant women and the influence of iodine status.

Environ Int 2020 04 7;137:105509. Epub 2020 Feb 7.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina and Chapel Hill, Chapel Hill, NC, USA.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.envint.2020.105509DOI Listing
April 2020

Prenatal exposure to perfluoroalkyl substances and associations with symptoms of attention-deficit/hyperactivity disorder and cognitive functions in preschool children.

Int J Hyg Environ Health 2020 01 22;223(1):80-92. Epub 2019 Oct 22.

Norwegian Institute of Public Health, PO Box 222, Skøyen, N-0213, Oslo, Norway.

Background: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that are suspected to be neurodevelopmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We investigated the associations between prenatal exposure to PFASs and symptoms of attention-deficit/hyperactivity disorder (ADHD) and cognitive functioning (language skills, estimated IQ and working memory) in preschool children, as well as effect modification by child sex.

Material And Methods: This study included 944 mother-child pairs enrolled in a longitudinal prospective study of ADHD symptoms (the ADHD Study), with participants recruited from The Norwegian Mother, Father and Child Cohort Study (MoBa). Boys and girls aged three and a half years, participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview, Child Development Inventory and Stanford-Binet (5th revision). Prenatal levels of 19 PFASs were measured in maternal blood at week 17 of gestation. Multivariable adjusted regression models were used to examine exposure-outcome associations with two principal components extracted from the seven detected PFASs. Based on these results, we performed regression analyses of individual PFASs categorized into quintiles.

Results: PFAS component 1 was mainly explained by perfluoroheptane sulfonate (PFHpS), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA). PFAS component 2 was mainly explained by perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and perfluorononanoic acid (PFNA). Regression models showed a negative association between PFAS component 1 and nonverbal working memory [β = -0.08 (CI: -0.12, -0.03)] and a positive association between PFAS component 2 and verbal working memory [β = 0.07 (CI: 0.01, 0.12)]. There were no associations with ADHD symptoms, language skills or IQ. For verbal working memory and PFAS component 2, we found evidence for effect modification by child sex, with associations only for boys. The results of quintile models with individual PFASs, showed the same pattern for working memory as the results in the component regression analyses. There were negative associations between nonverbal working memory and quintiles of PFOA, PFNA, PFHxS, PFHpS and PFOS and positive associations between verbal working memory and quintiles of PFOA, PFNA, PFDA and PFUnDA, with significant relationships mainly in the highest concentration groups.

Conclusions: Based on our results, we did not find consistent evidence to conclude that prenatal exposure to PFASs are associated with ADHD symptoms or cognitive dysfunctions in preschool children aged three and a half years, which is in line with the majority of studies in this area. Our results showed some associations between PFASs and working memory, particularly negative relationships with nonverbal working memory, but also positive relationships with verbal working memory. The relationships were weak, as well as both positive and negative, which suggest no clear association - and need for replication.
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http://dx.doi.org/10.1016/j.ijheh.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922090PMC
January 2020

Bias from self selection and loss to follow-up in prospective cohort studies.

Eur J Epidemiol 2019 Oct 26;34(10):927-938. Epub 2019 Aug 26.

Norwegian Institute of Public Health, Oslo, Norway.

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.
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http://dx.doi.org/10.1007/s10654-019-00550-1DOI Listing
October 2019

Estimating the Strength of Associations Between Prenatal Diet Quality and Child Developmental Outcomes: Results From a Large Prospective Pregnancy Cohort Study.

Am J Epidemiol 2019 11;188(11):1902-1912

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.
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http://dx.doi.org/10.1093/aje/kwz166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825833PMC
November 2019

Evaluation of Maternal Exposure to PM and Its Components on Maternal and Neonatal Thyroid Function and Birth Weight: A Cohort Study.

Thyroid 2019 08;29(8):1147-1157

1State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

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 available data on the relationships among air pollution, thyroid function, and birth outcomes in pregnant women, particularly in China, are scarce. We aimed to evaluate the association between maternal exposure to PM and its components and maternal and neonatal thyroid function and to investigate whether thyroid function acts as a mediator between air pollution and birth weight. In this prospective birth cohort study, the levels of maternal exposure to PM and its components during the first trimester were assessed in 433 pregnant women in Nanjing, China, enrolled during 2014-2015. We evaluated the levels of maternal exposure to PM and its six main constituents-organic matter (OM), black carbon (BC), sulfate (SO), nitrate (NO), ammonium (NH), and soil dust-using the V4.CH.02 product of the Dalhousie University Atmospheric Composition Analysis Group. The maternal serum-free thyroxine (fT4), thyrotropin (TSH), and thyroid peroxidase antibody (TPOAb) levels during the second trimester were measured through electrochemiluminescent microparticle immunoassays. The neonatal TSH levels were detected using an AutoDELFIA Neonatal TSH kit within 72 hours after birth, and the birth weight Z-score of each newborn was estimated. Higher exposure to maternal PM and some components (BC and NH) decreased the maternal fT4 level ( < 0.05), and the birth weight Z-score was decreased ( < 0.05) by higher exposure to maternal PM and some components (OM, BC, NO, and NH). A mediation analysis clarified that the maternal fT4 levels explained 15.9%, 18.4%, and 20.9% of the associations of maternal PM, BC, and NH exposure with the birth weight Z-score, respectively ( < 0.05). After additional sensitivity analyses including only nonpreterm participants ( = 418) and non-TPOAb-positive participants ( = 415), the models remained stable. Our results suggest an inverse association between maternal exposure to PM and its components and the maternal fT4 levels. Maternal fT4 might act as a mediator between exposure to PM and its components and birth weight.
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http://dx.doi.org/10.1089/thy.2018.0780DOI Listing
August 2019

Maternal fever during pregnancy and offspring attention deficit hyperactivity disorder.

Sci Rep 2019 07 2;9(1):9519. Epub 2019 Jul 2.

Norwegian Institute of Public Health, Oslo, Norway.

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.
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http://dx.doi.org/10.1038/s41598-019-45920-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606630PMC
July 2019

Screening with an ADHD-specific rating scale in preschoolers: A cross-cultural comparison of the Early Childhood Inventory-4.

Psychol Assess 2019 Aug 8;31(8):985-994. Epub 2019 Apr 8.

Division of Mental Health and Addiction.

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).
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http://dx.doi.org/10.1037/pas0000722DOI Listing
August 2019

Diagnosis of hyperkinetic disorder among children in Norway.

Tidsskr Nor Laegeforen 2018 12 20;138(20). Epub 2018 Nov 20.

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.
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http://dx.doi.org/10.4045/tidsskr.18.0418DOI Listing
December 2018

Language delay and poorer school performance in children of mothers with inadequate iodine intake in pregnancy: results from follow-up at 8 years in the Norwegian Mother and Child Cohort Study.

Eur J Nutr 2019 Dec 12;58(8):3047-3058. Epub 2018 Nov 12.

Division of Infection Control and Environmental Health, Department of Exposure and Environmental Epidemiology, Norwegian Institute of Public Health, Skøyen, P.O. Box 222, 0213, Oslo, Norway.

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 non-iodine 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.
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http://dx.doi.org/10.1007/s00394-018-1850-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842354PMC
December 2019

Maternal Thyroid Function During Pregnancy or Neonatal Thyroid Function and Attention Deficit Hyperactivity Disorder: A Systematic Review.

Epidemiology 2019 01;30(1):130-144

From the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Background: Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in children, yet its etiology is poorly understood. Early thyroid hormone disruption may contribute to the development of ADHD. Disrupted maternal thyroid hormone function has been associated with adverse neurodevelopmental outcomes in children. Among newborns, early-treated congenital hypothyroidism has been consistently associated with later cognitive deficits.

Methods: We systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. We searched Embase, Pubmed, Cinahl, PsycInfo, ERIC, Medline, Scopus, and Web of Science for articles published or available ahead of print as of April 2018.

Results: We identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD.

Conclusions: The reviewed articles suggest an association between maternal thyroid function and ADHD, and possibly between early-treated congenital hypothyroidism and ADHD. Study limitations, however, weaken the conclusions in our systematic review, underlining the need for more research. Importantly, there was much variation in the measurement of thyroid hormone function and of ADHD symptoms. Recommendations for future research include using population-based designs, attending to measurement issues for thyroid hormones and ADHD, considering biologically relevant covariates (e.g., iodine intake), and assessing nonlinear dose-responses.
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http://dx.doi.org/10.1097/EDE.0000000000000937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359926PMC
January 2019

Meconium microbiome associates with the development of neonatal jaundice.

Clin Transl Gastroenterol 2018 09 20;9(9):182. Epub 2018 Sep 20.

State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Objective: Neonatal jaundice is a common disease that affects up to 60% of newborns. Gut microbiota mediated the excretion of bilirubin from the human body. However, the relationship between early gut microbiome and development of neonatal jaundice is not fully understood. Here we sought to characterize meconium microbiome of newborns and to clarify its association with risk of neonatal jaundice.

Methods: We conducted a nested case-control study with 301 newborns providing meconium samples from 2014 to 2015. The main outcome was the development of neonatal jaundice at 42 day follow-up. 16S rRNA gene sequencing was performed to profile the meconium microbiome. LEfSe was employed to identify different features between control and case groups. Logistic regression was used to estimate the risk effect of early gut microbiome on neonatal jaundice.

Results: Logistic regression models suggested that higher ɑ-diversity was significantly associated with lower risk of jaundice in cesarean infants (OR 0.72, 95% CI 0.52-0.98), but not in infants born naturally. Higher relative abundance of Bifidobacterium pseudolongum in newborn meconium was significantly associated with lower risk of jaundice both in cesarean-born infants and in the total subjects (OR 0.24, 95% CI 0.07-0.68; OR 0.55, 95% CI 0.31-0.95, respectively). Spearman's correlations showed that relative abundance of B. pseudolongum was significantly correlated with ɑ-diversity (P < 0.01).

Conclusion: Preventive and treatment methods implying early gut microbiome intervention could be promising for the management of neonatal jaundice.
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http://dx.doi.org/10.1038/s41424-018-0048-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147945PMC
September 2018

Dr. Øvergaard et al. Reply.

J Am Acad Child Adolesc Psychiatry 2018 09;57(9):701-702

Oslo University Hospital, Norway.

We appreciate that Rimvall et al. read our latest article with interest. Early and accurate screening of attention-deficit/hyperactivity disorder (ADHD) is important for the remediation of the disorder. Clinicians' lack of time has been identified as a barrier to screening for behavioral disorders. A short screener such as the Strengths and Difficulties Questionnaire (SDQ) hyperactivity-inattention (HI) subscale holds the potential to improve detection of ADHD in preschoolers. Rimvall et al. make the point that diagnosing children with ADHD requires a broader assessment that includes information from parents, teachers, and the child. We agree, except to say that 3-year-old children are too young to provide information.
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http://dx.doi.org/10.1016/j.jaac.2018.05.021DOI Listing
September 2018

Prenatal exposure to dental amalgam and risk of symptoms of attention-deficit and hyperactivity disorder (ADHD).

Community Dent Oral Epidemiol 2018 10 7;46(5):472-481. Epub 2018 Aug 7.

Dental Biomaterials Adverse Reaction Unit, Uni Research Health, Bergen, Norway.

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.
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http://dx.doi.org/10.1111/cdoe.12409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150829PMC
October 2018

Attention-Deficit/Hyperactivity Disorder in Preschoolers: The Accuracy of a Short Screener.

J Am Acad Child Adolesc Psychiatry 2018 06 7;57(6):428-435. Epub 2018 Apr 7.

Oslo University Hospital, Norway.

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.
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http://dx.doi.org/10.1016/j.jaac.2018.03.008DOI Listing
June 2018

Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort.

Environ Health Perspect 2018 05 10;126(5):057004. Epub 2018 May 10.

Norwegian Institute of Public Health, Oslo, Norway.

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1289/EHP2358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071976PMC
May 2018

Maternal air pollution exposure and preterm birth in Wuxi, China: Effect modification by maternal age.

Ecotoxicol Environ Saf 2018 Aug 12;157:457-462. Epub 2018 Apr 12.

State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing 211166, China. Electronic address:

Background: Numerous studies have investigated prenatal air pollution and shown that air pollutants have adverse effect on birth outcomes. However, which trimester was the most sensitive and whether the effect was related to maternal age is still ambiguous.

Objectives: This study aims to explore the association between maternal air pollution exposure during pregnancy and preterm birth, and if this relationship is modified by maternal age.

Methods: In this retrospective cohort study, we examine the causal relationship of prenatal exposure to air pollutants including particulate matters, which are less than 10 µm (PM), and ozone (O), which is one of the gaseous pollutants, on preterm birth by gestational age. A total of 6693 pregnant women were recruited from Wuxi Maternal and Child Health Care Hospital. The participants were dichotomized into child-bearing age group (< 35 years old) and advanced age group (> = 35 years old) in order to analyze the effect modification by maternal age. Logistic and linear regression models were performed to assess the risk for preterm birth (gestational age < 37 weeks) caused by prenatal air pollution exposure.

Results: With adjustment for covariates, the highest level of PM exposure significantly increased the risk of preterm birth by 1.42-fold (95% CI: 1.10, 1.85) compared those with the lowest level in the second trimester. Trimester-specific PM exposure was positively associated with gestational age, whereas O exposure was associated with gestational age in the early pregnancy. When stratified by maternal age, PM exposure was significantly associated with an increased risk of preterm birth only in the advanced age group during pregnancy (OR:2.15, 95% CI: 1.13, 4.07). The results suggested that PM exposure associated with preterm birth was modified by advanced maternal age (OR = 2.00, 95% CI: 1.02, 3.91, P = 0.032).

Conclusion: Prenatal air pollution exposure would increase risk of preterm birth and reduced gestational age. Thus, more attention should be paid to the effects of ambient air pollution exposure on preterm birth especially in pregnant women with advanced maternal age.
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http://dx.doi.org/10.1016/j.ecoenv.2018.04.002DOI Listing
August 2018

Early life exposure to air pollution particulate matter (PM) as risk factor for attention deficit/hyperactivity disorder (ADHD): Need for novel strategies for mechanisms and causalities.

Toxicol Appl Pharmacol 2018 09 14;354:196-214. Epub 2018 Mar 14.

Department of Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway.

Epidemiological studies have demonstrated that air pollution particulate matter (PM) and adsorbed toxicants (organic compounds and trace metals) may affect child development already in utero. Recent studies have also indicated that PM may be a risk factor for neurodevelopmental disorders (NDDs). A pattern of increasing prevalence of attention deficit/hyperactivity disorder (ADHD) has been suggested to partly be linked to environmental pollutants exposure, including PM. Epidemiological studies suggest associations between pre- or postnatal exposure to air pollution components and ADHD symptoms. However, many studies are cross-sectional without possibility to reveal causality. Cohort studies are often small with poor exposure characterization, and confounded by traffic noise and socioeconomic factors, possibly overestimating the study associations. Furthermore, the mechanistic knowledge how exposure to PM during early brain development may contribute to increased risk of ADHD symptoms or cognitive deficits is limited. The closure of this knowledge gap requires the combined use of well-designed longitudinal cohort studies, supported by mechanistic in vitro studies. As ADHD has profound consequences for the children affected and their families, the identification of preventable risk factors such as air pollution exposure should be of high priority.
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http://dx.doi.org/10.1016/j.taap.2018.03.015DOI Listing
September 2018

Early Predictors of ADHD: Evidence from a Prospective Birth Cohort.

J Atten Disord 2020 10 9;24(12):1685-1692. Epub 2017 Mar 9.

Oslo University Hospital, Norway.

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). 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 ( = 57,986) and 5 years ( = 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. 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]). The findings underline the importance of taking early parent-reported symptoms seriously. Both rating scales were useful for predicting ADHD.
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http://dx.doi.org/10.1177/1087054717696765DOI Listing
October 2020

Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study.

Nutrients 2017 Nov 13;9(11). Epub 2017 Nov 13.

Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, 0456 Oslo, Norway.

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.
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http://dx.doi.org/10.3390/nu9111239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707711PMC
November 2017

The importance of maternal diet quality during pregnancy on cognitive and behavioural outcomes in children: a systematic review and meta-analysis.

BMJ Open 2017 Sep 24;7(9):e016777. Epub 2017 Sep 24.

Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway.

Objectives: This systematic review and meta-analysis provides a quantitative summary of the literature exploring the relationship between maternal diet quality during pregnancy and child cognitive and affective outcomes. We investigate whether there are indications for robust associations and aim to identify methodological strengths and challenges of the current research to provide suggestions of improvement for future research.

Design And Participants: Relevant studies were identified through a systematic literature search in relevant databases. All studies investigating maternal diet quality during pregnancy in relation to child cognitive or affective functioning in children of elementary school age or younger were assessed for inclusion.

Results: 18 relevant studies, comprising 63 861 participants were identified. The results indicated a small positive association between better maternal diet quality during pregnancy and child functioning. We observed publication bias and significant heterogeneity between studies, where type of diet classification, publication year and outcome domain together accounted for about 30% of this heterogeneity. Trim and fill analysis substantiated the presence of publication bias for studies in the affective domain and showed an adjusted effect size of Hedge's g=0.088 (p=0.0018) (unadjusted g=0.093 (p=0.03)). We observed no publication bias in the cognitive domain, where results indicated a slightly larger effect size (g=0.14 (p<0.0001)) compared with that of the affective domain. The overall summary effect size was g=0.075 (p<0.0001) adjusted for publication bias (unadjusted g=0.112 (p=0.0001)). Child diet was not systematically controlled for in the majority of the studies.

Conclusion: The results indicated that a better maternal diet quality during pregnancy has a small positive association with child neurodevelopment, with more reliable results seen for cognitive development. These results warrant further research on the association between maternal diet quality during pregnancy and cognitive and affective aspects of child neurodevelopment, whereby it is crucial that future studies account for child diet in the analysis.
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http://dx.doi.org/10.1136/bmjopen-2017-016777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623570PMC
September 2017