Epilepsy in childhood and school performance: a nation-wide cohort study.

Childhood epilepsy has been linked to poor academic performance, but large-scale studies are lacking. In this nation-wide study of school-aged children, we examined the association between childhood epilepsy and school performance in standardized tests according to phenotypic and treatment-related characteristics. We performed a matched register-based cohort study of children born in Denmark (1997-2009) who participated in the Danish National School Test Programme between 2010 and 2019. We used population and health registers to identify children with epilepsy and a randomly sampled sex- and age-matched reference cohort without epilepsy (ratio 1:10). Norm-based test scores from language and mathematics reflecting performance as a percentile of the nation-wide distribution of scores (scale 1-100) were used to assess academic performance. Adjusted differences in mean standardized scores between children with and without epilepsy were estimated using linear regression models. Among 582 840 children participating in the School Test Programme, we identified 4659 (0.8%) children with epilepsy (52.8% males) and 46 590 matched reference children. Median age at epilepsy onset was 7.5 years (interquartile range: 4.0-10.6). Childhood epilepsy was associated with poorer school performance overall (mean score = 48.2 versus references = 56.7; adjusted difference = -6.7, 95% CI: -7.4 to -6.0), and worse performance was found in all epilepsy subgroups, including in 3534 children with uncomplicated epilepsy (i.e. no other pre-existing neurologic or intellectual disabilities and no identified possible cause for epilepsy; adjusted difference = -6.0, 95% CI: -6.8 to -5.2). No major variation by sex, age or subject was observed, but larger score differences were seen in children using antiseizure medication at time of testing (e.g. valproate monotherapy, adjusted difference = -9.3, 95% CI: -11.5 to -7.0 and lamotrigine monotherapy, adjusted difference = -13.1, 95% CI: -15.0 to -11.3) and in children with psychiatric comorbidity, especially epilepsy with comorbid intellectual disability (adjusted difference = -27.0, 95% CI: -30.0 to -23.9) and epilepsy with comorbid attention deficit/hyperactivity disorder (adjusted difference = -15.7, 95% CI: -19.0 to -12.4). Children with epilepsy scored significantly lower than their unaffected siblings (adjusted difference = -6.2, 95% CI: -7.1 to -5.4). In conclusion, childhood epilepsy was associated with impaired academic performance throughout schooling, which suggest that there is a widespread need for educational support of children with epilepsy, even when the child has no other comorbidities and when the epilepsy appears well-managed.

Cardiac morbidity and mortality associated with the use of lamotrigine.

OBJECTIVE: The US Food and Drug Administration recently issued a warning against the use of the antiseizure medication lamotrigine in people at risk of cardiac rhythm and conduction abnormalities. This study assessed the risk of cardiac morbidity and mortality in new users of lamotrigine. METHODS: In a Danish population-based cohort study, we followed cohort members aged ≥15 years for the first 2 years after they initiated lamotrigine therapy. The main outcomes were cardiac conduction disorders in people without pre-existing cardiac morbidity and all-cause mortality in people with pre-existing cardiac morbidity. Cox proportional hazards models provided hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for comparison of the risk in current versus past users of lamotrigine. RESULTS: There were 91 949 (36 618 males [39.8%]) new users of lamotrigine (median age = 45.7 years, interquartile range = 32.0-60.2 years). Among users without pre-existing cardiac disease (n = 86 769), 194 (.23%) developed a cardiac conduction disorder. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR of new onset cardiac conduction disorder of 1.03 (95% CI = .76-1.40). Among users with pre-existing cardiac disease (n = 5180), 1150 (22.2%) died. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR for all cause-mortality of 1.05 (95% CI = .93-1.19). SIGNIFICANCE: In this large population-based study, lamotrigine use was associated neither with a risk of cardiac conduction disorders in people without pre-existing cardiac morbidity nor with all-cause mortality in people with pre-existing cardiac morbidity.

Prenatal exposure to valproate and risk of congenital malformations-Could we have known earlier?-A population-based cohort study.

OBJECTIVE: Prenatal exposure to the antiseizure medication (ASM) valproate is associated with an increased risk of congenital malformations, but warnings against the use of valproate in pregnancy were not issued until 2009. The objective was to study how early administrative health registers could have identified the teratogenic risk associated with valproate. METHODS: This was a population-based cohort study of individual-linked data from Danish health care and socioeconomic registers including children born in Denmark between January 1, 1997 and December 31, 2014. Information on ASM use, including valproate, in pregnancy was obtained from the Danish National Prescription Registry. Children identified with major congenital malformations from the Danish National Patient Register and the Danish Register of Causes of Death were included. Using logistic regression models, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for major congenital malformations during the first year of life in children with and without prenatal exposure to ASMs adjusted for potential confounders. RESULTS: Among the 895 507 children (males, 51.3%), 31 790 (3.6%) were diagnosed with a major congenital malformation in the first year of life. In the analyses including children born in 1997, the risk of major congenital malformations among children prenatally exposed to valproate compared with children not exposed to ASMs was increased by a fully adjusted OR (aOR) of 3.95 (95% CI = 1.65-9.47). With the addition of data from the following years, the teratogenic effect of valproate was further substantiated, as the precision of the estimate improved (1997-2014: aOR = 2.44, 95% CI = 1.80-3.30). SIGNIFICANCE: Using Danish health care data, we were able to identify a teratogenic risk associated with prenatal valproate exposure in children born in 1997, which is much earlier than prospective clinical cohorts. Health registry data represent an important tool for early identification of risk associated with drugs in pregnancy.

Association of Maternal Antidepressant Prescription During Pregnancy With Standardized Test Scores of Danish School-aged Children.

Importance: Concerns exist about long-term neurodevelopmental consequences of prenatal exposure to antidepressants. Objective: To evaluate whether maternal prescription fill for antidepressants in pregnancy was associated with performance in standardized tests among Danish schoolchildren. Design, Setting, and Participants: Population-based retrospective cohort study of children born in Denmark between January 1, 1997, and December 31, 2009, attending public primary and lower secondary school. The children included had completed a language or mathematics test as part of the Danish National Test Program between January 1, 2010, and December 31, 2018. The age range of the eligible schoolchildren was 7 to 17 years. Exposures: Maternal prescription fill for antidepressants during pregnancy, obtained from the Danish Prescription Register. Main Outcomes and Measures: The difference in standardized scores between children with and without maternal prescription fill for antidepressants in mathematics and language tests (scale, 1-100; higher scores indicate better test results) was estimated using linear regression models, adjusted for relevant confounders. Ten sensitivity analyses were performed, including a sibling-controlled analysis. Results: Among the 575 369 children included (51.1% males), 10 198 (1.8%) were born to mothers filling an antidepressant prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antidepressants was significantly associated with a poorer performance in mathematics (mean test scores for the group exposed to maternal antidepressant fill: 52.1 [95% CI, 51.7-52.6] and for the group not exposed to maternal antidepressant fill: 57.4 [95% CI, 57.3-57.4]; adjusted difference, -2.2 [95% CI, -2.7 to -1.6]), but not in language (mean test scores for the exposed group: 53.4 [95% CI, 53.1-53.7] and for the not exposed group: 56.6 [95% CI, 56.5-56.6]; adjusted difference, -0.1 [95% CI, -0.6 to 0.3]). In the sibling-controlled analysis, the adjusted difference in mathematics (mean scores for the exposed group: 53.5 [95% CI, 52.7-54.3] and for the not exposed group: 59.0 [95% CI, 58.9-59.1]) was -2.8 (95% CI, -4.5 to -1.2) and in language (mean test scores for the exposed group: 53.9 [95% CI, 53.2-54.6] and for the not exposed group: 56.6 [95% CI, 56.5-56.7]) was -0.3 (95% CI, -1.9 to 1.2). Conclusions and Relevance: In this study of public schoolchildren in Denmark, children whose mothers had filled prescriptions for antidepressants during pregnancy, compared with children whose mothers did not fill prescriptions for antidepressants during pregnancy, had a 2-point lower standardized test score in mathematics, a difference that was statistically significant, but had no significant difference in language test scores. The magnitude of the difference in the mathematics test score was small and of uncertain clinical importance, and the findings must be weighed against the benefits of treating maternal depression during pregnancy.

Adolescent residential mobility, genetic liability and risk of schizophrenia, bipolar disorder and major depression.

BACKGROUND: Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear. AIMS: We used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder. METHOD: Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses. RESULTS: PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder). CONCLUSIONS: Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.

Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders.

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

Valproate Use During Spermatogenesis and Risk to Offspring.

Importance: Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis. Objective: To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders. Design, Setting, and Participants: This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024. Exposures: Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception). Main Outcomes and Measures: Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders. Results: Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points. Conclusions and Relevance: In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.

Utility of data from the Danish National School Test Program for health research purposes: Content and associations with sociodemographic factors and higher education.

The Danish National School Test Program is a set of nationwide tests performed annually since 2010 in all public schools in Denmark. To assess the utility of this data resource for health research purposes, we examined the association of school test performance with demographic and socioeconomic characteristics as well as correlations with ninth-grade exams and higher educational attainment. This nationwide descriptive register-based study includes children born between 1994 and 2010 who lived in Denmark at the age of six years. Norm-based test scores (range 1-100, higher scores indicate better performance) in reading (Danish) and mathematics from the Danish National School Test Program were obtained for children aged 6-16 attending public schools in Denmark from 2010 to 2019. Population registers were used to identify relevant demographic and socioeconomic variables. Mean test scores by demographic and socioeconomic variables were estimated using linear regression models. Among the full Danish population of 1,137,290 children (51.3% male), 960,450 (84.5%) children attended public schools. There were 885,360 children who completed one or more tests in reading or mathematics (test participation was 77.8% for the entire population, and 92.1% for children in public schools). Mean test scores varied by demographic and socioeconomic characteristics, most notably with education and labour market affiliation of parents. For every 1-point decrease in the test scores, there was a 0.95% (95% CI: 0.93%; 0.97%) lower probability of scoring B or higher in the ninth-grade exam and a 1.03% (95% CI: 1.00%; 1.05%) lower probability of completing high school within five years after graduating from lower secondary school. In this study of schoolchildren in Denmark, demographic and socioeconomic characteristics were associated with test scores from the Danish National School Test Program. Performance in school tests correlated closely with later educational attainment, suggesting that these early measures of school performance are good markers of subsequent academic potential.

Prenatal exposure to tap water containing nitrate and the risk of small-for-gestational-age: A nationwide register-based study of Danish births, 1991-2015.

BACKGROUND: Prenatal nitrate exposure from household tap water has been associated with increased risk of fetal growth restriction, preterm birth, birth defects, and childhood cancer. We aim to examine the association between maternal consumption of drinking-water nitrate during pregnancy and small-for-gestational-age (SGA) in a nationwide study of Danish-born children, as only one prior study has examined this association. METHODS: We linked individual-level household estimates of nitrate in tap water and birth registry data to all live singleton Danish births during 1991-2015 from Danish-born parents where the mother resided in Denmark throughout the pregnancy. Exposure was both binned into four categories and modeled as an ln-transformed continuous variable. SGA was defined as the bottom 10% of births by birth weight per sex and gestational week. Multiple logistic regression models with generalized estimating equations were used to account for siblings born to the same mother while controlling for relevant confounders. RESULTS: In the cohort of 1,078,892 births, the median pregnancy nitrate exposure was 1.9 mg/L nitrate. Compared to the reference group (≤2 mg/L), we found an increased risk of SGA in the second category (>2-5 mg/L) (OR = 1.04, 95% CI: 1.03-1.06) and third category (>5-25 mg/L) (OR = 1.02, 95% CI: 1.00-1.04) but not in the highest (>25 mg/L). There was strong (p = 0.002) evidence of an increase in SGA with nitrate in the model with continuous exposure (OR = 1.02, 95% CI: 1.01-1.04 per 10-fold increase in nitrate). Results were robust when restricting to households with nitrate levels at or below the current Danish and European Union regulatory drinking water standard (50 mg/L nitrate). CONCLUSIONS: Our findings suggest that exposure from nitrate in household tap water, even below current regulatory standards, may increase risk of SGA, raising concerns of whether current allowable nitrate levels in drinking water protect children from SGA.

Prenatal exposure to nitrate from drinking water and the risk of preterm birth: A Danish nationwide cohort study.

Evidence is emerging that preterm birth (PTB, birth before 37 completed weeks of gestation), a risk factor for neonatal mortality and future morbidity, may be induced by maternal nitrate ( N O 3 - ) exposure from drinking water. The objective of this study is to assess the association between maternal exposure to nitrate and the risk of PTB in a nationwide study of liveborn singletons. Methods: We estimated maternal nitrate exposure from household tap water for 1,055,584 births in Denmark to Danish-born parents during 1991-2015 by linkage of individual home address(es) with nitrate concentrations from a national monitoring database. Nitrate exposure during pregnancy was modeled using four categories and continuously. Logistic models adjusted for sex, birth year, birth order, urbanicity, and maternal age, smoking, education, income, and employment, with generalized estimating equations were used to account for sibling clusters. Results: A total of 1,009,189 births were included, comprising 51,747 PTB. An increase in the risk of PTB was seen across categories of exposure (P < 0.001) with an odds ratio (OR) in the uppermost category (>25 mg/L nitrate) of 1.05 (95% confidence interval [CI] = 1.00, 1.10). Evidence of an exposure-response relationship was observed in models using continuous nitrate (OR = 1.01 [95% CI = 1.00, 1.03] per 10 mg/L nitrate). In sensitivity analyses, results were robust to the addition of variables for short inter-pregnancy interval (<1 year between births), maternal pre-pregnancy body mass index, paternal socioeconomic status and age, season of birth, and inclusion of post-term births. Results were virtually unchanged when the analysis was restricted to women exposed to less than the current European Union standard of 50 mg/L. Conclusion: We observed an increasing risk of PTB with increases in nitrate in household tap water. These findings add to a growing body of evidence of adverse effects from nitrate in drinking water at levels below current regulatory levels.

Nitrate in drinking water and risk of birth defects: Findings from a cohort study of over one million births in Denmark.

BACKGROUND: A few studies have reported an increased risk of birth defects (BD) with maternal exposure to nitrate in drinking water. We examined this association in a large cohort study with well-characterized exposure. METHODS: Danish singletons liveborn to Danish-born parents from 1991-2013 were identified using civil and patient registries (n=1,018,914). Exposure to nitrate was estimated using a spatial model based on national data linked with individual addresses. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. FINDINGS: In total, 33,182 cases of BD were identified. Nitrate concentrations were generally well below US and EU standards. We observed an exposure-response relationship (p=0·004) between nitrate during pregnancy and eye BD, and increased risk in the highest exposure group (≥25 mg/L nitrate) (OR: 1·29; 95% CI: 1·00, 1·66). An interaction was observed between maternal age and continuous nitrate exposure for nervous system BD (p<0·001) indicating an increased risk among mothers <25 years-of-age (OR for 10 mg/L (OR10): 1·20; 95% CI: 1·06, 1·35). An interaction (p<0.01) with maternal age and continuous nitrate exposure was also observed for ear, face, and neck BD indicating an increased risk among babies born to mothers <25 years-of-age (OR10: 1·35; 95% CI: 1·11, 1·66). There was evidence of an inverse exposure-response relationship for any, digestive system, female genital, and urinary BD. INTERPRETATION: Our study is the first to report an association between nitrate and eye BD and BD of the ear, face, and neck. It also provides support to prior reports of increased risk of nervous system BD. FUNDING: This study was supported by a grant from the United States National Institute of Environmental Health Sciences (R01 ES027823-01A1).

Exposure to nitrate from drinking water and the risk of childhood cancer in Denmark.

BACKGROUND: There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark. METHODS: We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age. RESULTS: There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure-response in models of continuous nitrate exposure and CNC. CONCLUSIONS: Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.

Prenatal Exposure to Nitrate from Drinking Water and Markers of Fetal Growth Restriction: A Population-Based Study of Nearly One Million Danish-Born Children.

BACKGROUND: High levels of nitrate (NO3-) in drinking water cause methemoglobinemia in infants; however, few studies have examined the potential effects of low-level exposure on fetal growth, and the results have been inconsistent. OBJECTIVES: We sought to assess the association between maternal exposure to nitrate in drinking water during pregnancy and offspring size at birth in a nationwide study of full-term (≥37 wk gestation) live-born singletons. METHODS: We estimated maternal nitrate exposure for 898,206 births in Denmark during 1991-2011 by linkage of individual home address(es) with nitrate data from the national monitoring database. Maternal address during pregnancy, infant size at birth [i.e., birth weight, low birth weight (LBW), body length, and birth head circumference] and covariates were compiled from the Danish Civil Registration System, the Danish Medical Birth Register, and The Integrated Database for Longitudinal Labor Market Research. Linear and logistic models with generalized estimating equations were used to account for multiple births to an individual. Nitrate exposure was modeled using five categories and as a log-transformed continuous variable. RESULTS: There was evidence of a decreasing trend in models for term birth weight using categorical or continuous measures of exposure. Modeling exposure continuously, a difference of -9.71 g (95% confidence interval: -14.60, -4.81) was predicted at 25 mg/L (half the value of the European Union drinking water standard) compared with 0 mg/L NO3-. Body length also decreased as nitrate concentrations increased in categorical and continuous models. There was little evidence of an association between NO3- and head circumference or LBW. DISCUSSION: Although the estimated effects were small, our findings for live singleton births to Danish-born parents suggest that maternal intake of nitrate from drinking water may reduce term birth weight and length, which are markers of intrauterine growth. However, there was little evidence for an association between nitrate and head circumference or LBW. Future studies in other populations and with data on dietary sources of nitrate are encouraged to confirm or refute these findings. https://doi.org/10.1289/EHP7331.

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk. Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression. Design, Setting, and Participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs. Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses). Main Outcomes and Measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings. Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders. Conclusions and Relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.

ALS in Danish Registries: Heritability and links to psychiatric and cardiovascular disorders.

OBJECTIVE: To investigate the genetic contribution to amyotrophic lateral sclerosis (ALS) and the phenotypic and genetic associations between ALS and psychiatric and cardiovascular disorders (CVD) we used the national registry data from Denmark linked to first-degree relatives to estimate heritability and cross-trait parameters. METHODS: ALS cases and 100 sex and birth-matched controls per case from the Danish Civil Registration System were linked to their records in the Danish National Patient Registry. Cases and controls were compared for (1) risk of ALS in first-degree relatives, used to estimate heritability, (2) comorbidity with psychiatric disorders and CVD, and (3) risk of psychiatric disorders and CVD in first-degree relatives. RESULTS: 5,808 ALS cases and 580,800 controls were identified. Fifteen percent of cases and controls could be linked to both parents and full siblings, whereas 70% could be linked to children. (1) We estimated the heritability of ALS to be 0.43 (95% CI, 0.34-0.53). (2) We found increased rates of diagnosis of mental disorders (risk ratio = 1.18; 95% CI, 1.09-1.29) and CVD in those later diagnosed with ALS. (3) In first-degree relatives of those with ALS, we found increased rate of schizophrenia (1.17; 95% CI, 0.96-1.42), but no evidence for increased risk CVD. CONCLUSIONS: Heritability of ALS is lower than commonly reported. There is likely a genetic relationship between ALS and schizophrenia, and a nongenetic relationship between ALS and CVD.

Incidence Rates and Cumulative Incidences of the Full Spectrum of Diagnosed Mental Disorders in Childhood and Adolescence.

Importance: Knowledge about the epidemiology of mental disorders in children and adolescents is essential for research and planning of health services. Surveys can provide prevalence rates, whereas population-based registers are instrumental to obtain precise estimates of incidence rates and risks. Objective: To estimate age- and sex-specific incidence rates and risks of being diagnosed with any mental disorder during childhood and adolescence. Design: This cohort study included all individuals born in Denmark from January 1, 1995, through December 31, 2016 (1.3 million), and followed up from birth until December 31, 2016, or the date of death, emigration, disappearance, or diagnosis of 1 of the mental disorders examined (14.4 million person-years of follow-up). Data were analyzed from September 14, 2018, through June 11, 2019. Exposures: Age and sex. Main Outcomes and Measures: Incidence rates and cumulative incidences of all mental disorders according to the ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, diagnosed before 18 years of age during the study period. Results: A total of 99 926 individuals (15.01%; 95% CI, 14.98%-15.17%), including 41 350 girls (14.63%; 95% CI, 14.48%-14.77%) and 58 576 boys (15.51%; 95% CI, 15.18%-15.84%), were diagnosed with a mental disorder before 18 years of age. Anxiety disorder was the most common diagnosis in girls (7.85%; 95% CI, 7.74%-7.97%); attention-deficit/hyperactivity disorder (ADHD) was the most common in boys (5.90%; 95% CI, 5.76%-6.03%). Girls had a higher risk than boys of schizophrenia (0.76% [95% CI, 0.72%-0.80%] vs 0.48% [95% CI, 0.39%-0.59%]), obsessive-compulsive disorder (0.96% [95% CI, 0.92%-1.00%] vs 0.63% [95% CI, 0.56%-0.72%]), and mood disorders (2.54% [95% CI, 2.47%-2.61%] vs 1.10% [95% CI, 0.84%-1.21%]). Incidence peaked earlier in boys than girls in ADHD (8 vs 17 years of age), intellectual disability (5 vs 14 years of age), and other developmental disorders (5 vs 16 years of age). The overall risk of being diagnosed with a mental disorder before 6 years of age was 2.13% (95% CI, 2.11%-2.16%) and was higher in boys (2.78% [95% CI, 2.44%-3.15%]) than in girls (1.45% [95% CI, 1.42%-1.49%]). Conclusions and Relevance: This nationwide population-based cohort study provides a first comprehensive assessment of the incidence and risks of mental disorders in childhood and adolescence. By 18 years of age, 15.01% of children and adolescents in this study were diagnosed with a mental disorder. The incidence of several neurodevelopmental disorders peaked in late adolescence in girls, suggesting possible delayed detection. The distinct signatures of the different mental disorders with respect to sex and age may have important implications for service planning and etiological research.

Polygenic risk score, psychosocial environment and the risk of attention-deficit/hyperactivity disorder.

The objective of the present study was to investigate whether the polygenic liability for attention-deficit/hyperactivity disorder (ADHD) and the psychosocial environment impact the risk of ADHD in interaction or independently of each other. We conducted a register- and biobank-based cohort study of 13,725 individuals with ADHD and 20,147 randomly drawn population-based controls. These 33,872 cohort members were genotyped on the Infinium PsychChip v1.0 array (Illumina). Subsequently, we calculated the polygenic risk score (PRS) for ADHD and extracted register data regarding the following risk factors pertaining to the psychosocial environment for each cohort member at the time of birth: maternal/paternal history of mental disorders, maternal/paternal education, maternal/paternal work status, and maternal/paternal income. We used logistic regression analyses to assess the main effects of the PRS for ADHD and the psychosocial environment on the risk of ADHD. Subsequently, we evaluated whether the effect of the PRS and the psychosocial environment act independently or in interaction upon the risk of ADHD. We found that ADHD was strongly associated with the PRS (odds ratio: 6.03, 95%CI: 4.74-7.70 for highest vs. lowest 2% liability). All risk factors pertaining to the psychosocial environment were associated with an increased risk of ADHD. These associations were only slightly attenuated after mutual adjustments. We found no statistically significant interaction between the polygenic liability and the psychosocial environment upon the risk of ADHD. In conclusion, we found main effects of both polygenic liability and risk factors pertaining to the psychosocial environment on the risk of ADHD-in the expected direction.

Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication: A Danish Nationwide, Register-Based Study.

Importance: Microdeletions and duplications have been described at the 22q11.2 locus. However, little is known about the clinical and epidemiologic consequences at the population level. Objective: To identify indicators of deletions or duplications at the 22q11.2 locus and estimate the incidence rate ratios (IRRs) and absolute risk for psychiatric disorders in clinically identified individuals with 22q11.2 deletion or duplication. Design, Setting, and Participants: A Danish nationwide register study including all individuals recorded in the Danish Cytogenetic Central Register with a 22q11.2 deletion or duplication was performed. A total of 3 768 943 individuals born in Denmark from 1955 to 2012 were followed up during the study period (total follow-up, 57.1 million person-years). Indicators of 22q11.2 deletion or duplication and cumulative incidences were estimated using a nested case-control design that included individuals from the population-based cohort. Survival analysis was used to compare risk of disease in individuals with and without the 22q11.2 deletion or duplication. The study was conducted from May 7, 2015, to August 14, 2016. Exposure: The 22q11.2 deletion or duplication. Main Outcomes and Measures: Indicators for carrying a 22q11.2 deletion or duplication, IRR, and cumulative incidences for psychiatric diagnoses (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes F00-F99), including schizophrenia-spectrum disorders, mood disorders, neurotic stress-related and somatoform disorders, and a range of developmental and childhood disorders. Results: Among the 3 768 943 participants, 244 (124 [50.8%] male) and 58 (29 [50.0%] male) individuals were clinically identified with a 22q11.2 deletion or duplication, respectively. Mean (SD) age at diagnosis of any psychiatric disorder was 12.5 (8.3) years for individuals with deletions and 6.1 (0.9) years for duplication carriers. A parental diagnosis of schizophrenia-but not of other psychiatric diagnoses-was associated with a 22q11.2 deletion, and parental psychiatric diagnoses other than schizophrenia were associated with duplication carrier status. Both the 22q11.2 deletion (IRR, 4.24; 95% CI, 3.07-5.67) and duplication (IRR, 4.99; 95% CI, 1.79-10.72) was associated with increased risk of any psychiatric disorders. Furthermore, a highly increased risk of intellectual disability was found for the deletion (IRR, 34.08; 95% CI, 22.39-49.27) and duplication (IRR, 33.86; 95% CI, 8.42-87.87). Furthermore, individuals with the 22q11.2 deletion had an increased risk of several psychiatric disorders under study, for example, pervasive developmental disorders (IRR, 9.45; 95% CI, 5.64-14.69) and childhood autism (IRR, 8.94; 95% CI, 3.21-19.23). Conclusions and Relevance: Individuals with the 22q11.2 deletion or duplication have a significantly increased risk of developing psychiatric disorders. Survival analysis of persons carrying either the 22q11.2 deletion or duplication provides estimates of direct clinical relevance useful to assist clinical ascertainment, genetic counseling, guidance of symptomatic monitoring, and early clinical intervention.

Association of the polygenic risk score for schizophrenia with mortality and suicidal behavior - A Danish population-based study.

BACKGROUND: It is unknown whether an increased genetic liability to schizophrenia influences the risk of dying early. The aim of the study was to determine whether the genetic predisposition to schizophrenia is associated with the risk of dying early and experience a suicide attempt. METHOD: Case control study, Denmark. The main measure was the mortality rate ratios (MRR) for deaths and odds ratios (OR) for multiple suicide attempts, associated with one standard deviations increase of the polygenic risk-score for schizophrenia (PRS). RESULTS: We replicated the high mortality MRR=9.01 (95% CI: 3.56-22.80), and high risk of multiple suicide attempts OR=33.16 (95% CI: 20.97-52.43) associated with schizophrenia compared to the general population. However, there was no effect of the PRS on mortality MRR=1.00 (95% CI 0.71-1.40) in the case-control setup or in cases only, MRR=1.05 (95% CI 0.73-1.51). Similar, no association between the PRS and multiple suicide attempts was found in the adjusted models, but in contrast, family history of mental disorders was associated with both outcomes. CONCLUSIONS: A genetic predisposition for schizophrenia, measured by PRS, has little influence on the excess mortality or the risk of suicide attempts. In contrast there is a strong significant effect of family history of mental disorders. Our findings could reflect that the common variants detected by recent PRS only explain a small proportion of risk of schizophrenia, and that future, more powerful PRS instruments may be able to predict excess mortality within this disorder.

Influence of Polygenic Risk Scores on the Association Between Infections and Schizophrenia.

BACKGROUND: Several studies have suggested an important role of infections in the etiology of schizophrenia; however, shared genetic liability toward infections and schizophrenia could influence the association. We therefore investigated the possible effect of polygenic risk scores (PRSs) for schizophrenia on the association between infections and the risk of schizophrenia. METHODS: We conducted a nested case-control study on a Danish population-based sample born after 1981 comprising of 1692 cases diagnosed with schizophrenia between 1994 and 2008 and 1724 matched controls. All individuals were linked utilizing nationwide population-based registers with virtually complete registration of all hospital contacts for infections. PRSs were calculated using discovery effect size estimates weights from an independent meta-analysis (34,600 cases and 45,968 control individuals). RESULTS: A prior hospital contact with infection had occurred in 41% of the individuals with schizophrenia and increased the incidence rate ratio (IRR) of schizophrenia by 1.43 (95% confidence interval [CI] = 1.22-1.67). Adding PRS, which was robustly associated with schizophrenia (by an IRR of 1.46 [95% CI = 1.34-1.60] per standard deviation of the score), did not alter the association with infections and the increased risk of schizophrenia remained (IRR = 1.41; 95% CI = 1.20-1.66). Furthermore, there were no interactions between PRS and infections on the risk of developing schizophrenia (p = .554). Neither did PRS affect the risk of acquiring infections among patients with schizophrenia (odds ratio = 1.00; 95% CI = 0.89-1.12) nor among controls (odds ratio = 1.09; 95% CI: 0.96-1.24). CONCLUSIONS: PRS and a history of infections have independent effects on the risk for schizophrenia, and the common genetic risk measured by PRS did not account for the association with infection in this sample.