Publications by authors named "Gun Peggy Knudsen"

68 Publications

Gestational Phthalate Exposure and Preschool Attention Deficit Hyperactivity Disorder in Norway.

Environ Epidemiol 2021 Aug 1;5(4):e161. Epub 2021 Jul 1.

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

Prenatal phthalate exposure has been linked to altered neurobehavioral development in both animal models and epidemiologic studies, but whether or not these associations translate to increased risk of neurodevelopmental disorders is unclear. We used a nested case-cohort study design to assess whether maternal urinary concentrations of 12 phthalate metabolites at 17 weeks gestation were associated with criteria for Attention Deficit Hyperactivity Disorder (ADHD) classified among 3-year-old children in the Norwegian Mother, Father and Child Cohort Study (MoBa). Between 2007 and 2011, 260 children in this substudy were classified with ADHD using a standardized, on-site clinical assessment; they were compared with 549 population-based controls. We modeled phthalate levels both linearly and by quintiles in logistic regression models adjusted for relevant covariates and tested for interaction by child sex. Children of mothers in the highest quintile of di-iso-nonyl phthalate (∑DiNP) metabolite levels had 1.70 times the odds of being classified with ADHD compared with those in the lowest quintile (95% confidence interval [CI] = 1.03 to 2.82). In linear models, there was a trend with the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP); each natural log-unit increase in concentration was associated with 1.22 times the odds of ADHD (95% CI = 0.99 to 1.52). In boys, but not girls, mono-n-butyl phthalate exposure was associated with increased odds of ADHD (odds ratio [OR] 1.42; 95% CI = 1.07 to 1.88). Additional adjustment for correlated phthalate metabolites attenuated estimates. These results suggest gestational phthalate exposure may impact the behavior of children as young as 3 years.
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http://dx.doi.org/10.1097/EE9.0000000000000161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367074PMC
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Alcohol Consumption, HDL-Cholesterol and Incidence of Colon and Rectal Cancer: A Prospective Cohort Study Including 250,010 Participants.

Alcohol Alcohol 2021 Oct;56(6):718-725

Norwegian Centre for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Pb 1171 Blinderen, 0318 Oslo, Norway.

Aims: Alcohol consumption has been linked to colorectal cancer (CRC) and also to the high-density lipoprotein cholesterol level (HDL-C). HDL-C has been associated with the incidence of CRC. The aim of this study was to investigate the association between self-reported alcohol consumption, HDL-C and incidence of CRC, separately for the two sites.

Methods: Altogether, 250,010 participants in Norwegian surveys have been followed-up for an average of 18 years with respect to a first-time outcome of colon or rectal cancer. During follow-up, 3023 and 1439 colon and rectal cancers were registered.

Results: For men, the HR per 1 drink per day was 1.05 with 95% confidence interval (0.98-1.12) for colon and 1.08 (1.02-1.15) for rectal cancer. The corresponding figures for women were 1.03 (0.97-1.10) and 1.05 (1.00-1.10). There was a positive association between alcohol consumption and HDL-C. HDL-C was inversely associated with colon cancer in men (0.74 (0.62-0.89) per 1 mmol/l) and positively associated with rectal cancer, although not statistically significant (1.15 (0.92-1.44). A robust regression that assigned weights to each observation and exclusion of weights ≤ 0.1 increased the HRs per 1 drink per day and decreased the HR per 1 mmol/l for colon cancer. The associations with rectal cancer remained unchanged.

Conclusion: Our results support a positive association between alcohol consumption and colon and rectal cancer, most pronounced for rectal cancer. Considering the positive relation between alcohol consumption and HDL-C, the inverse association between HDL-C and colon cancer in men remains unsettled.
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http://dx.doi.org/10.1093/alcalc/agab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557640PMC
October 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

Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents.

Eur J Hum Genet 2021 01 10;29(1):205-215. Epub 2020 Aug 10.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Recurrent copy number variations (CNVs) are common causes of neurodevelopmental disorders (NDDs) and associated with a range of psychiatric traits. These CNVs occur at defined genomic regions that are particularly prone to recurrent deletions and duplications and often exhibit variable expressivity and incomplete penetrance. Robust estimates of the population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders (NDD CNVs) are lacking. Here we perform array-based CNV calling in 12,252 mother-father-child trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and analyse the inheritance pattern of 26 recurrent NDD CNVs in 13 genomic regions. We estimate the total prevalence of recurrent NDD CNVs (duplications and deletions) in live-born children to 0.48% (95% C.I.: 0.37-0.62%), i.e., ~1 in 200 newborns has either a deletion or duplication in these NDDs associated regions. Approximately a third of the newborn recurrent NDD CNVs (34%, N = 20/59) are de novo variants. We provide prevalence estimates and inheritance information for each of the 26 NDD CNVs and find higher prevalence than previously reported for 1q21.1 deletions (~1:2000), 15q11.2 duplications (~1:4000), 15q13.3 microdeletions (~1:2500), 16p11.2 proximal microdeletions (~1:2000) and 17q12 deletions (~1:4000) and lower than previously reported prevalence for the 22q11.2 deletion (~1:12,000). In conclusion, our analysis of an unselected and representative population of newborns and their parents provides a clearer picture of the rate of recurrent microdeletions/duplications implicated in neurodevelopmental delay. These results will provide an important resource for genetic diagnostics and counseling.
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http://dx.doi.org/10.1038/s41431-020-00707-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852900PMC
January 2021

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Identification of Genetic Loci Shared Between Attention-Deficit/Hyperactivity Disorder, Intelligence, and Educational Attainment.

Biol Psychiatry 2020 06 29;87(12):1052-1062. Epub 2019 Nov 29.

Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address:

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown.

Methods: We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment (N = 842,499), and general intelligence (N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression, and biological processes.

Results: We identified 58 linkage disequilibrium-independent ADHD-associated loci (conditional FDR < 0.01), of which 30 were shared between ADHD and educational attainment or general intelligence (conjunctional FDR < 0.01) and 46 were novel risk loci for ADHD.

Conclusions: These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment, and general intelligence.
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http://dx.doi.org/10.1016/j.biopsych.2019.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255939PMC
June 2020

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

Transl Psychiatry 2019 10 17;9(1):258. Epub 2019 Oct 17.

deCODE genetics/Amgen, Reykjavík, Iceland.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5-BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.
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http://dx.doi.org/10.1038/s41398-019-0599-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797719PMC
October 2019

Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth.

Nat Commun 2019 10 1;10(1):4448. Epub 2019 Oct 1.

KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, NO-5020, Bergen, Norway.

Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6-12 months (rs2767486, P = 2.0 × 10, β = 0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P = 1.3 × 10, β = 0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.
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http://dx.doi.org/10.1038/s41467-019-12308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773698PMC
October 2019

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

The Norwegian Patient Registry and the Norwegian Registry for Primary Health Care: Research potential of two nationwide health-care registries.

Scand J Public Health 2020 Feb 9;48(1):49-55. Epub 2019 Jul 9.

Institute for Health Metrics and Evaluation and Department of Health Metrics Sciences, University of Washington, USA.

In Norway, the Directorate of Health is responsible for two nationwide registries - the Norwegian Patient Registry (NPR) and the Norwegian Registry for Primary Health Care (NRPHC) - which together cover all governmental-funded health care. The NPR (specialist health care) was established in 2008, while the NRPHC (primary health care) was established in 2017. Data from the NPR are extensively used in a large variety of studies. We expect that data from the NRPHC will increase in importance when the registry covers a longer time period. The NRPHC will be especially important for studying conditions mainly treated in primary care and for investigation of patient trajectories. The main aim of this paper is to give an overview of the history and content of the NPR and its research possibilities. In addition, we introduce the NRPHC as a possible future research tool and the potential for studying patient trajectories when combining data from the two registries.
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http://dx.doi.org/10.1177/1403494819859737DOI Listing
February 2020

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

Prenatal and perinatal risk factors for eating disorders in women: A population cohort study.

Int J Eat Disord 2019 06 20;52(6):643-651. Epub 2019 Mar 20.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Objective: The fetal programming model hypothesizes that developmental programming in utero and in early life induces adaptations that predetermine the adult phenotype. This study investigated whether prenatal/perinatal complications are associated with lifetime eating disorders in women.

Method: Participants included 46,373 adult women enrolled in the Norwegian Mother and Child Cohort Study (den norske Mor & barn-undersøkelsen [MoBa]). MoBa mothers and their mothers (MoBa grandmothers) were the focus of the current study. MoBa mothers with lifetime eating disorders were compared to a referent group.

Results: MoBa mothers who weighed more at birth (birth weight, adjusted odds ratio [OR] = 1.14; 95% confidence interval [CI]: 1.10-1.19) or were born large-for-gestational-age (adjusted OR = 1.39; 95% CI: 1.27-1.52) were more likely to develop binge-eating disorder in later life. MoBa mothers who weighed less at birth were more likely to develop anorexia nervosa (birth weight, adjusted OR = 0.88; 95% CI: 0.81-0.95). Bulimia nervosa and purging disorder (PD) were not significantly predicted by the prenatal and perinatal factors examined.

Discussion: Results of this study, which include the first known investigation of prenatal and perinatal factors in binge-eating disorder and PD, suggest that fetal programming may be relevant to the development of anorexia nervosa and binge-eating disorder. Future genetically informative research is needed to help disentangle whether these associations are a function of genetic influences or a true environmental fetal programming effect.
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http://dx.doi.org/10.1002/eat.23073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644683PMC
June 2019

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

A Twin Study of Normative Personality and DSM-IV Personality Disorder Criterion Counts: Evidence for Separate Genetic Influences.

Am J Psychiatry 2018 07 21;175(7):649-656. Epub 2018 Mar 21.

From the Department of Psychology and the Institute of Clinical Medicine, University of Oslo, Oslo; the Division of Mental Health, Norwegian Institute of Public Health, Oslo; the Virginia Institute for Psychiatric and Behavioral Genetics, the Department of Psychiatry, and the Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond; and the Department of Psychology, University of Minnesota, Minneapolis.

Objective: Both normative personality and DSM-IV personality disorders have been found to be heritable. However, there is limited knowledge about the extent to which the genetic and environmental influences underlying DSM personality disorders are shared with those of normative personality. The aims of this study were to assess the phenotypic similarity between normative and pathological personality and to investigate the extent to which genetic and environmental influences underlying individual differences in normative personality account for symptom variance across DSM-IV personality disorders.

Method: A large population-based sample of adult twins was assessed for DSM-IV personality disorder criteria with structured interviews at two waves spanning a 10-year interval. At the second assessment, participants also completed the Big Five Inventory, a self-report instrument assessing the five-factor normative personality model. The proportion of genetic and environmental liabilities unique to the individual personality disorder measures, and hence not shared with the five Big Five Inventory domains, were estimated by means of multivariate Cholesky twin decompositions.

Results: The median percentage of genetic liability to the 10 DSM-IV personality disorders assessed at wave 1 that was not shared with the Big Five domains was 64%, whereas for the six personality disorders that were assessed concurrently at wave 2, the median was 39%. Conversely, the median proportions of unique environmental liability in the personality disorders for wave 1 and wave 2 were 97% and 96%, respectively.

Conclusions: The results indicate that a moderate-to-sizable proportion of the genetic influence underlying DSM-IV personality disorders is not shared with the domain constructs of the Big Five model of normative personality. Caution should be exercised in assuming that normative personality measures can serve as proxies for DSM personality disorders when investigating the etiology of these disorders.
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http://dx.doi.org/10.1176/appi.ajp.2017.17050493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028291PMC
July 2018

Prevalence and stability of mental disorders among young adults: findings from a longitudinal study.

BMC Psychiatry 2018 03 12;18(1):65. Epub 2018 Mar 12.

Department of mental disorders, Norwegian Institute of Public Health, Oslo, Norway.

Background: Mental disorders often have onset early in life, contribute substantially to the global disease burden, and may interfere with young people's ability to complete age-relevant tasks in important developmental periods. However, knowledge about prevalence and course of mental disorders in young adulthood is sparse. The aim of the current study was to estimate prevalence and stability of mental disorders from the twenties to the thirties/forties.

Methods: DSM-IV mental disorders were assessed with the Composite International Diagnostic Interview in two waves (1999-2004 and 2010-2011) in 1623 young adult Norwegian twins (63.2% women, aged 19-29 years in wave 1).

Results: In wave 1, the 12-month prevalence of any mental disorder among people in the twenties was 19.8% (men) and 32.4% (women), anxiety disorders: 9.6% (men) and 26.7% (women), anxiety disorders excluding specific phobias: 2.5% (men) and 6.9% (women), major depressive disorder (MDD): 4.4% (men) and 7.2% (women), and alcohol use disorder (AUD): 8.7% (men) and 4.4% (women). The prevalence of any mental disorder decreased from the twenties to the thirties/forties. This was due to a decrease in AUD and specific phobias. Anxiety disorders in the twenties predicted anxiety disorders and MDD ten years later, even when controlling for the association between these disorders in the twenties. MDD in the twenties predicted MDD ten years later. At both ages, two-week and 12-month prevalence estimates differed markedly for MDD - indicating an episodic course.

Conclusions: Common mental disorders are highly prevalent among young adults in the twenties, and somewhat less prevalent in the thirties/forties. Those who suffer from one mental disorder in the twenties are at considerably increased risk for suffering from a disorder ten years later as well. This may have significant implications for young people's ability to attain education, establish a family, and participate in occupational life.
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http://dx.doi.org/10.1186/s12888-018-1647-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848432PMC
March 2018

Relationships Among Avoidant Personality Disorder, Social Anxiety Disorder, and Normative Personality Traits: A Twin Study.

J Pers Disord 2019 06 5;33(3):289-309. Epub 2018 Mar 5.

Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.

Avoidant personality disorder (AvPD) and social anxiety disorder (SAD) share risk factors to a substantial degree, and both are characterized by the experience of anxiety in social situations. The authors investigated whether these disorders are differentially related to the Big Five personality traits. They also examined the underlying genetic and environmental influences on these associations. A population-based sample of 1,761 female twins was interviewed at baseline, and 1,471 of these were re-interviewed 10 years later. Associations between AvPD, SAD, and personality traits were investigated with multivariate biometric analyses. The authors found that AvPD and SAD are differentially related to several personality traits at the phenotypic, genetic, and environmental level. The genetic and environmental liability to AvPD could be fully accounted for by the genetic and environmental factors influencing SAD and personality. The findings may increase current etiological understanding of these disorders and inform future classification and treatment efforts.
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http://dx.doi.org/10.1521/pedi_2018_32_341DOI Listing
June 2019

Associations between personality disorders and cannabis use and cannabis use disorder: a population-based twin study.

Addiction 2018 08 13;113(8):1488-1498. Epub 2018 Apr 13.

Department of Mental Disorders, Norwegian Institute of Public Health, Norway.

Background And Aims: Individual differences in DSM-IV personality disorders (PDs) are associated with increased prevalence of substance use disorders. Our aims were to determine which combination of PDs trait scores best predict cannabis use (CU) and cannabis use disorder (CUD), and to estimate the size and significance of genetic and environmental risks in PD traits shared with CU and CUD.

Design: Linear mixed-effects models were used to identify PD traits for inclusion in twin analyses to explore the genetic and environmental associations between the traits and cannabis use.

Setting: Cross-sectional data were obtained from Norwegian adult twins in a face-to-face interview in 1999-2004 as part of a population-based study of mental health.

Participants: Subjects were 1419 twins (μ  = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel with complete PD and cannabis data.

Measurements: PD traits were assessed using DSM-IV criteria. Life-time CU and CUD were based on DSM-IV abuse and dependence criteria, including withdrawal and craving.

Findings: After adjusting for age and sex, antisocial [β = 0.23, 95% confidence interval (CI) = 0.19-0.28] and borderline PDs (β = 0.20, 95% CI = 0.14-0.26) were associated strongly with CU. Antisocial (β = 0.26, 95% CI = 0.21-0.31) and borderline PDs (β = 0.12, 95% CI = 0.06-0.18) were also linked strongly to CUD. Genetic risks in antisocial and borderline PD traits explained 32-60% of the total variance in CU and CUD. Dependent and avoidant PDs explained 11 and 16% of the total variance in CU and CUD, respectively.

Conclusions: Individual differences in the liability to cannabis use and cannabis use disorder appear to be linked to genetic risks correlated with antisocial and borderline personality disorder traits.
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http://dx.doi.org/10.1111/add.14209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043378PMC
August 2018

Conserved DNA Methylation Signatures in Early Maternal Separation and in Twins Discordant for CO Sensitivity.

Sci Rep 2018 02 2;8(1):2258. Epub 2018 Feb 2.

Department of Psychiatry, the University of Toronto, Toronto, Canada.

Respiratory and emotional responses to blood-acidifying inhalation of CO are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field.
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http://dx.doi.org/10.1038/s41598-018-20457-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797081PMC
February 2018

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

NPJ Genom Med 2017 8;2:24. Epub 2017 Aug 8.

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa ( = 1.6 × 10, 4.3 × 10) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in , another is a missense variant in that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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http://dx.doi.org/10.1038/s41525-017-0027-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677966PMC
August 2017

Prenatal Exposure to Acetaminophen and Risk of ADHD.

Pediatrics 2017 Nov;140(5)

Norwegian Institute of Public Health, Oslo, Norway.

Objectives: To estimate the association between maternal use of acetaminophen during pregnancy and of paternal use before pregnancy with attention-deficit/hyperactivity disorder (ADHD) in offspring while adjusting for familial risk for ADHD and indications of acetaminophen use.

Methods: Diagnoses were obtained from the Norwegian Patient Registry for 112 973 offspring from the Norwegian Mother and Child Cohort Study, including 2246 with ADHD. We estimated hazard ratios (HRs) for an ADHD diagnosis by using Cox proportional hazard models.

Results: After adjusting for maternal use of acetaminophen before pregnancy, familial risk for ADHD, and indications of acetaminophen use, we observed a modest association between any prenatal maternal use of acetaminophen in 1 (HR = 1.07; 95% confidence interval [CI] 0.96-1.19), 2 (HR = 1.22; 95% CI 1.07-1.38), and 3 trimesters (HR = 1.27; 95% CI 0.99-1.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50-3.24). Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81-1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71-22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD.

Conclusions: Short-term maternal use of acetaminophen during pregnancy was negatively associated with ADHD in offspring. Long-term maternal use of acetaminophen during pregnancy was substantially associated with ADHD even after adjusting for indications of use, familial risk of ADHD, and other potential confounders.
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http://dx.doi.org/10.1542/peds.2016-3840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654387PMC
November 2017

Maternal eating disorders and perinatal outcomes: A three-generation study in the Norwegian Mother and Child Cohort Study.

J Abnorm Psychol 2017 Jul;126(5):552-564

Departments of Psychiatry and Nutrition, University of North Carolina at Chapel Hill.

Previous studies of the relationship between maternal eating disorders and adverse perinatal outcomes have failed to control for familial transmission of perinatal phenotypes, which may confound the reported association. In a unique design afforded by the Norwegian Mother and Child Cohort Study and Medical Birth Registry of Norway, we linked three generations through birth register records and maternal-reported survey data to investigate whether maternal eating disorders increase risk after parsing out the contribution of familial transmission of perinatal phenotypes. The samples were 70,881 pregnancies in grandmother-mother-child triads for analyses concerning eating disorder exposure during pregnancy and 52,348 for analyses concerning lifetime maternal eating disorder exposure. As hypothesized, eating disorders predicted a higher incidence of perinatal complications even after adjusting for grandmaternal perinatal phenotypes. For example, anorexia nervosa immediately prior to pregnancy was associated with smaller birth length (relative risk = 1.62; 95% CI [1.20, 2.14]), bulimia nervosa with induced labor (relative risk = 1.21; 95% CI [1.07, 1.36]), and binge-eating disorder with several delivery complications, larger birth length (relative risk = 1.25; 95% CI [1.17, 1.34]), and large-for-gestational-age (relative risk = 1.04; 95% CI [1.01, 1.06]). Maternal pregravid body mass index and gestational weight mediated most associations. Our results support that exposure to eating disorders increases the risk for negative health outcomes in pregnant women and their babies. (PsycINFO Database Record
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http://dx.doi.org/10.1037/abn0000241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505270PMC
July 2017

Stability and change in etiological factors for alcohol use disorder and major depression.

J Abnorm Psychol 2017 Aug 25;126(6):812-822. Epub 2017 May 25.

Department of Mental Disorders, Norwegian Institute of Public Health.

Alcohol use disorder (AUD) and major depressive disorder (MDD) are often comorbid. It is not understood how genetic risk factors for these disorders relate to each other over time and to what degree they are stable. Age-dependent characteristics of the disorders indicate that different genetic factors could be relevant at different stages of life, and MDD may become increasingly correlated with AUD over time. DSM-IV diagnoses of AUD and MDD were assessed by interviews of 2,801 young adult twins between 1999 and 2004 (T1) and 2,284 of the same twins between 2010 and 2011 (T2). Stability, change, and covariation were investigated in longitudinal biometric models. New genetic factors explained 56.4% of the genetic variance in AUD at T2. For MDD, there was full overlap between genetic influences at T1 and T2. Genetic risk factors for MDD were related to AUD, but their association with AUD did not increase over time. Thus, genetic risk factors for AUD, but not MDD, vary with age, suggesting that AUD has age-dependent heritable etiologies. Molecular genetic studies of AUD may therefore benefit from stratifying by age. The new genetic factors in AUD were not related to MDD. Environmental influences on the 2 disorders were correlated in middle, but not in young adulthood. The environmental components for AUD correlated over time (r = .27), but not for MDD. Environmental influences on AUD can have long-lasting effects, and the effects of preventive efforts may be enduring. Environment influences seem to be largely transient. (PsycINFO Database Record
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http://dx.doi.org/10.1037/abn0000280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546937PMC
August 2017

Maternal alcohol use during pregnancy and offspring attention-deficit hyperactivity disorder (ADHD): a prospective sibling control study.

Int J Epidemiol 2017 10;46(5):1633-1640

Norwegian Institute of Public Health, Oslo, Norway.

Background: Maternal alcohol use during pregnancy has repeatedly been associated with development of attention-deficit hyperactivity disorder (ADHD) in the offspring. It is, however not known whether this reflects a direct casual intra-uterine effect or a non-causal relationship due to confounding. We used three different approaches to control for measured and unmeasured confounding: statistical adjustment for covariates, negative control comparison against maternal pre-pregnancy alcohol use, and comparison among differentially exposed siblings.

Methods: The sample comprised 114 247 children (34 283 siblings) from 94 907 mothers, recruited to the Norwegian Mother and Child Birth Cohort Study between 1999 and 2008. Self-reported measurements of alcohol use were obtained in week 30 during the pregnancy. Mothers rated offspring ADHD symptoms at 5 years on two measures. Clinical ADHD diagnoses were obtained from the Norwegian Patient Registry.

Results: We found an overall positive association between maternal alcohol use during pregnancy and offspring ADHD symptoms, which was only marginally attenuated after inclusion of measured covariates. Both the negative control and the sibling comparison analysis further attenuated the estimated association, but it remained greater than zero [β = 0.017, 95% confidence interval (CI) = 0.005-0.030). No association was found between maternal alcohol use during pregnancy and offspring ADHD diagnosis.

Conclusions: For offspring ADHD symptoms we found a weak, but possibly causal association with maternal alcohol use during pregnancy, but no such effect was observed for clinical ADHD diagnosis.
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http://dx.doi.org/10.1093/ije/dyx067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837341PMC
October 2017

The quality of severe mental disorder diagnoses in a national health registry as compared to research diagnoses based on structured interview.

BMC Psychiatry 2017 03 14;17(1):93. Epub 2017 Mar 14.

Norwegian Center for Mental Health Research (NORMENT), Oslo University Hospital & University of Oslo, P.O. Box 4956, Nydalen, N-0424, Oslo, Norway.

Background: Utilization of diagnostic information from national patient registries rests on the quality of the registered diagnoses. We aimed to investigate the agreement and consistency of diagnoses of psychotic and bipolar disorders in the Norwegian Patient Registry (NPR) compared to structured interview-based diagnoses given as part of a clinical research project.

Methods: Diagnostic data from NPR were obtained for the period 01.01.2008-31.12.2013 for all patients who had been included in the Thematically Organized Psychosis (TOP) study between 18.10.2002 and 01.09.2014 with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of schizophrenia (n = 537), delusional disorder (n = 48), schizoaffective disorder (n = 118) or bipolar disorder (n = 408). Diagnostic agreement between the primary DSM-IV diagnosis in TOP and the International Classification of Diseases, 10th revision (ICD-10) diagnoses in NPR was evaluated using Cohen's unweighted nominal kappa (κ). Diagnostic consistency was calculated as the proportion of all registered severe mental disorder diagnoses in NPR that were equivalent to the primary diagnosis given in the TOP study.

Results: The proportion of patients registered with the equivalent ICD-10 diagnosis as the primary DSM-IV diagnosis given in TOP was 84.2% for the schizophrenia group, 68.8% for the delusional disorder group, 76.3% for the schizoaffective disorder group, and 78.4% for the bipolar disorder group. Diagnostic agreement was good for schizophrenia (κ = 0.74) and bipolar disorder (κ = 0.72), fair for schizoaffective disorder (κ = 0.63), and poor for delusional disorder (κ = 0.39). Among patients with DSM-IV schizophrenia, 4.7% were diagnosed with ICD-10 bipolar disorder, and among patients with DSM-IV bipolar disorder, 2.5% were diagnosed with ICD-10 schizophrenia. Diagnostic consistency was 84.9% for schizophrenia, 59.1% for delusional disorder, 65.9% for schizoaffective disorder, and 91.0% for bipolar disorder.

Conclusions: When compared to research-based diagnoses, clinical diagnoses of schizophrenia and bipolar disorder in the NPR are accurate and consistent, with minimal diagnostic overlap between the two disorders.
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http://dx.doi.org/10.1186/s12888-017-1256-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351165PMC
March 2017

Pre-pregnancy mental distress and musculoskeletal pain and sickness absence during pregnancy - a twin cohort study.

Eur J Public Health 2017 06;27(3):477-481

Department of Aging and Health, Norwegian Institute of Public Health, Norway.

Background: Sickness absence (SA) among pregnant women is high. The aim of this study was to examine whether factors known to predict SA in general also predict SA during pregnancy by estimating the association between prior mental distress and musculoskeletal pain and SA during pregnancy, and to assess the influence of familial (genetic and shared environmental) factors. In this prospective cohort study, data from 2076 female twins born 1967-79 who participated in a questionnaire study in 1998 were linked to register data on SA and childbirth during the years 1998-2008. Baseline measures included mental distress (symptoms of anxiety and depression; SCL-5) and musculoskeletal pain (lumbar spine, neck/shoulder and/or persisting muscular pain). SA was measured as a ratio of days on SA divided by potential working days. Negative binomial regression was performed for individual and within-pair effects. Musculoskeletal pain, but not mental distress, was prospectively associated with overall SA during pregnancy in the adjusted individual-level analyses. With each standard deviation increase in musculoskeletal pain, SA granted for any disorder increased with 12% (IRR 1.12, 95% CI = 1.07-1.17) and SA granted for pregnancy related disorders increased with 9% (IRR 1.09, 95% CI = 1.02-1.17). Within-pair estimates were similar, suggesting little or no familial confounding. Women with previous musculoskeletal pain are at increased risk of SA during pregnancy, whereas no increased risk in women with previous symptoms of mental distress could be demonstrated. SA during pregnancy seems partly to be associated with different factors than SA in general.
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http://dx.doi.org/10.1093/eurpub/ckw267DOI Listing
June 2017

Smoking in Pregnancy and Child ADHD.

Pediatrics 2017 Feb;139(2)

Norwegian Institute of Public Health, Oslo, Norway.

Background And Objective: There is a well-documented association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD). The degree to which this reflects causal intrauterine effects or is due to unmeasured confounding is not clear. We sought to compare the association between maternal smoking during pregnancy and offspring ADHD with the associations with paternal smoking, grandmother's smoking when pregnant with mother, and maternal smoking in previous pregnancies. Each of these exposures is expected to be influenced by much of the same confounding factors as maternal smoking during pregnancy, but cannot have direct intrauterine effects. A sibling control design was also used.

Methods: The current study used data from the Norwegian Mother and Child Cohort Study (n > 100 000 children). Mothers and fathers reported on smoking during pregnancy, and mothers reported on smoking in previous pregnancies and their mother's smoking when pregnant with them. Mothers reported on child ADHD symptoms at 5 years of age. Information about child ADHD diagnosis was obtained from the Norwegian Patient Registry.

Results: Maternal smoking during pregnancy was not more strongly associated with offspring ADHD diagnosis than was paternal smoking, grandmother's smoking when pregnant with mother, or maternal smoking in previous pregnancies. Sibling control analyses showed no association between maternal smoking in pregnancy and child ADHD symptoms among siblings discordant for maternal smoking.

Conclusions: These results suggest that the association between maternal smoking during pregnancy and offspring ADHD is not due to causal intrauterine effects, but reflects unmeasured confounding.
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http://dx.doi.org/10.1542/peds.2016-2509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260151PMC
February 2017
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