Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study.

BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (ß = - 0.11, 95% CI [- 0.12, - 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (ß = - 0.07, 95% CI [- 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

Attainment and loss of early social-communication skills across neurodevelopmental conditions in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Delays and loss of early-emerging social-communication skills are often discussed as unique to autism. However, most studies of regression have relied on retrospective recall and clinical samples. Here, we examine attainment and loss of social-communication skills in the population-based Norwegian Mother, Father and Child Cohort Study (MoBa). METHODS: Mothers rated their child's attainment of 10 early-emerging social-communication skills at ages 18 and 36 months (N = 40,613, 50.9% male). Prospectively reported loss was defined as skill presence at 18 months but absence at 36 months. At 36 months, mothers also recalled whether the child had lost social-communication skills. The Norwegian Patient Registry was used to capture diagnoses of Autism Spectrum Disorder (autism) and other neurodevelopmental disabilities (NDDs). RESULTS: Delay in at least one skill was observed in 14% of the sample and loss in 5.4%. Recalled loss of social-communication skills was rare (0.86%) and showed low convergence with prospectively reported loss. Delay and especially loss were associated with elevated odds of an autism diagnosis (n = 383) versus no autism diagnosis (n = 40,230; ≥3 skills delayed: OR = 7.09[4.15,12.11]; ≥3 skills lost: OR = 30.66[17.30,54.33]). They were also associated with an increased likelihood of autism compared to some other NDDs. Delay (relative risk [RR] = 4.16[2.08, 8.33]) and loss (RR = 10.00[3.70, 25.00]) associated with increased likelihood of autism versus ADHD, and loss (RR = 4.35[1.28,14.29]), but not delay (RR = 2.00[0.78,5.26]), associated with increased likelihood of autism compared to language disability. Conversely, delay conferred decreased likelihood of autism versus intellectual disability (RR = 0.11[0.06,0.21]), and loss was not reliably associated with likelihood of autism versus intellectual disability (RR = 1.89[0.44,8.33]). CONCLUSIONS: This population-based study suggests that loss of early social communication skills is more common than studies using retrospective reports have indicated and is observed across several NDD diagnoses (not just autism). Nevertheless, most children with NDD diagnoses showed no reported delay or loss in these prospectively measured skills.

Measuring autism-associated traits in the general population: Factor structure and measurement invariance across sex and diagnosis status of the Social Communication Questionnaire.

LAY ABSTRACT: Using questionnaires in research relies on the expectation that they measure the same things across different groups of individuals. If this is not true, then interpretations of results can be misleading when researchers compare responses across different groups of individuals or use in it a group that differs from that in which the questionnaire was developed. For the questionnaire we investigated, the Social Communication Questionnaire (SCQ), we found that parents of boys and girls responded to questionnaire items in largely the same way but that the SCQ measured traits and behaviors slightly differently depending on whether the children had autism. Based on these results, we concluded that researchers using this questionnaire should carefully consider these differences when deciding how to interpret findings. SCQ scores as a reflection of "autism-associated traits" in samples that are mostly or entirely made up of individuals without an autism diagnosis may be misleading and we encourage a more precise interpretation of scores as a broader indication of social-communicative and behavioral traits.

Association between gestational levels of toxic metals and essential elements and cerebral palsy in children.

Introduction: Cerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children. Methods: In a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses. Results: The essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified. Conclusion: Using mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development.

Statistical methods to detect mother-father genetic interaction effects on risk of infertility: A genome-wide approach.

Infertility is a heterogeneous phenotype, and for many couples, the causes of fertility problems remain unknown. One understudied hypothesis is that allelic interactions between the genotypes of the two parents may influence the risk of infertility. Our aim was, therefore, to investigate how allelic interactions can be modeled using parental genotype data linked to 15,789 pregnancies selected from the Norwegian Mother, Father, and Child Cohort Study. The newborns in 1304 of these pregnancies were conceived using assisted reproductive technologies (ART), and the remainder were conceived naturally. Treating the use of ART as a proxy for infertility, different parameterizations were implemented in a genome-wide screen for interaction effects between maternal and paternal alleles at the same locus. Some of the models were more similar in the way they were parameterized, and some produced similar results when implemented on a genome-wide scale. The results showed near-significant interaction effects in genes relevant to the phenotype under study, such as Dynein axonemal heavy chain 17 (DNAH17) with a recognized role in male infertility. More generally, the interaction models presented here are readily adaptable to the study of other phenotypes in which maternal and paternal allelic interactions are likely to be involved.

No impact of prenatal paracetamol and folic acid exposure on cord blood DNA methylation in children with attention-deficit/hyperactivity disorder.

Pharmacoepigenetic studies are important to understand the mechanisms through which medications influence the developing fetus. For instance, we and others have reported associations between prenatal paracetamol exposure and offspring DNA methylation (DNAm). Additionally, folic acid (FA) intake during pregnancy has been associated with DNAm in genes linked to developmental abnormalities. In this study, we aimed to: (i) expand on our previous findings showing differential DNAm associated with long-term prenatal paracetamol exposure in offspring with attention-deficit/hyperactivity disorder (ADHD), and (ii) examine if there is an interaction effect of FA and paracetamol on DNAm in children with ADHD. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). We did not identify any impact of paracetamol or any interaction effect of paracetamol and FA on cord blood DNAm in children with ADHD. Our results contribute to the growing literature on prenatal pharmacoepigenetics, but should be replicated in other cohorts. Replication of pharmacoepigenetic studies is essential to ensure robust findings and to increase the clinical relevance of such studies.

Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites.

BACKGROUND: DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA. RESULTS: We applied a statistical approach called 'stability selection' to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns. CONCLUSION: We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.

Prenatal organophosphate ester exposure and executive function in Norwegian preschoolers.

Organophosphate esters (OPEs) are ubiquitous chemicals, used as flame retardants and plasticizers. OPE usage has increased over time as a substitute for other controlled compounds. This study investigates the impact of prenatal OPE exposure on executive function (EF) in preschoolers. Methods: We selected 340 preschoolers from the Norwegian Mother, Father, and Child Cohort Study. Diphenyl-phosphate (DPhP), di-n-butyl-phosphate (DnBP), bis(2-butoxyethyl) phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in maternal urine. EF was measured using the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P) and the Stanford-Binet fifth edition (SB-5). EF scores were scaled so a higher score indicated worse performance. We estimated exposure-outcome associations and evaluated modification by child sex using linear regression. Results: Higher DnBP was associated with lower EF scores across multiple rater-based domains. Higher DPhP and BDCIPP were associated with lower SB-5 verbal working memory (ß = 0.49, 95% CI = 0.12, 0.87; ß = 0.53, 95% CI = 0.08, 1.02), and higher BBOEP was associated with lower teacher-rated inhibition (ß = 0.34, 95% CI = 0.01, 0.63). DPhP was associated with lower parent-reported BRIEF-P measures in boys but not girls [inhibition: boys: 0.37 (95% CI = 0.03, 0.93); girls: -0.48 (95% CI = -1.27, 0.19); emotional control: boys: 0.44 (95% CI = -0.13, 1.26); girls: -0.83 (95% CI = -1.73, -0.00); working memory: boys: 0.49 (95% CI = 0.03, 1.08); girls: -0.40 (95% CI = -1.11, 0.36)]. Fewer sex interactions were observed for DnBP, BBOEP, and BDCIPP, with irregular patterns observed across EF domains. Conclusions: We found some evidence prenatal OPE exposure may impact EF in preschoolers and variation in associations by sex.

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

BACKGROUND: Prenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. OBJECTIVES: To examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. METHODS: We included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. RESULTS: We included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5-8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). CONCLUSIONS: In this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

Associations between health behaviours, fertility and reproductive outcomes: triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. METHODS: This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462-1,232,091) and controlled for education and ADHD liability using multivariable MR. RESULTS: In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. CONCLUSIONS: Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.

Maternal depression and the polygenic p factor: A family perspective on direct and indirect effects.

Within-family studies typically assess indirect genetic effects of parents on children, however social support theory points to a critical role of partners and children on women's depression. To address this research gap and account for the high heterogeneity of depression, we calculated a general psychiatric factor using eleven major psychiatric polygenic scores (polygenic p), in up to 25,000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa). Multilevel modeling of trio polygenic p was used to distinguish direct and indirect genetic effects on mothers depression during pregnancy (gestational age 17 and 30 weeks), infancy (6 months, 18 months) and early childhood (3 years, 5 years, and 8 years). We found mothers polygenic p predicts their depression symptoms (b = 0.092; 95 % CI [0.087,0.098]), outperforming prediction using a single major depressive disorder polygenic score (b = 0.070, 95 % CI [0.066,0.075]). Jointly modeling trio polygenic p revealed indirect genetic effects of fathers (b = 0.022, 95 % CI [0.014,0.030]) and children (b = 0.021, 95 % CI [0.010,0.037]) on mothers' depression. Our results support the generalizability of polygenic effects across mental health and highlight the role of close family members on women's depression.

Maternal prenatal cholesterol levels predict offspring weight trajectories during childhood in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Numerous intrauterine factors may affect the offspring's growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. METHODS: This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). RESULTS: Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99). CONCLUSIONS: Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.

Diet in Early Life Is Related to Child Mental Health and Personality at 8 Years: Findings from the Norwegian Mother, Father and Child Cohort Study (MoBa).

There is rising concern about population mental health. Personality and mental health traits manifest early. Sufficient nutrition is fundamental to early development. However, little is known about early life dietary impact on later mental health. The aim of this study was to investigate associations of exposure to a healthy and sustainable antenatal and early childhood diet with personality traits and symptoms of depression and anxiety measured at 8 years of age. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN) including 40,566 participants. Mental health measures and personality traits were assessed at 8 years. Dietary data from pregnancy, child age 6 and 18 months and 3 and 7 years were used. With few exceptions, inverse associations were observed between healthier diet at all time points and depression and anxiety symptom scores at age 8. We found positive associations between diet scores at almost all time points and extraversion, benevolence, conscientiousness and imagination. Inverse associations were observed between diet scores and neuroticism. Combined, these findings underpin a probable impact of both maternal pregnancy diet and early childhood diet on several aspects of child mental health.

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study.

Background: Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment. Methods: This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype. Results: Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child's own BMI increased their depressive symptoms (per 5 kg/m2 increase in BMI, beta = 0.26 S.D., CI = -0.01,0.52, p=0.06) and ADHD symptoms (beta = 0.38 S.D., CI = 0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child's depressive symptoms (per 5 kg/m2 increase in maternal BMI, beta = 0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents' BMI affected the child's ADHD symptoms, or that the child's or parents' BMI affected the child's anxiety symptoms. Conclusions: We found inconsistent evidence that a child's BMI affected their depressive and ADHD symptoms, and little evidence that a child's BMI affected their anxiety symptoms. There was limited evidence of an influence of parents' BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child's own BMI. Funding: This research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents' genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent's weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child's mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child's own weight. For older children and adolescents, this may not be the case, and the individual's own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.

Organophosphorus Pesticide Exposure at 17 Weeks' Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study.

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks' gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks' gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

An examination of mediation by DNA methylation on birthweight differences induced by assisted reproductive technologies.

BACKGROUND: Children born after assisted reproductive technologies (ART) differ in birthweight from those naturally conceived. It has been hypothesized that this might be explained by epigenetic mechanisms. We examined whether cord blood DNA methylation mediated the birthweight difference between 890 newborns conceived by ART (764 by fresh embryo transfer and 126 frozen thawed embryo transfer) and 983 naturally conceived newborns from the Norwegian Mother, Father, and Child Cohort Study (MoBa). DNA methylation was measured by the Illumina Infinium MethylationEPIC array. We conducted mediation analyses to assess whether differentially methylated CpGs mediated the differences in birthweight observed between: (1) fresh embryo transfer and natural conception and (2) frozen and fresh embryo transfer. RESULTS: We observed a difference in birthweight between fresh embryo transfer and naturally conceived offspring of - 120 g. 44% (95% confidence interval [CI] 26% to 81%) of this difference in birthweight between fresh embryo transfer and naturally conceived offspring was explained by differences in methylation levels at four CpGs near LOXL1, CDH20, and DRC1. DNA methylation differences at two CpGs near PTGS1 and RASGRP4 jointly mediated 22% (95% CI 8.1% to 50.3%) of the birthweight differences between fresh and frozen embryo transfer. CONCLUSION: Our findings suggest that DNA methylation is an important mechanism in explaining birthweight differences according to the mode of conception. Further research should examine how gene regulation at these loci influences fetal growth.

Adherence to a healthy and potentially sustainable Nordic diet is associated with child development in The Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: The rapid neurodevelopment that occurs during the first years of life hinges on adequate nutrition throughout fetal life and early childhood. Therefore, adhering to a dietary pattern based on healthy foods during pregnancy and the first years of life may be beneficial for future development. The aim of this paper was to investigate the relationship between adherence to a healthy and potentially sustainable Nordic diet during pregnancy and in early childhood and child development. METHODS: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). In 83,800 mother-child pairs, maternal pregnancy diet and child diet at 6 months, 18 months and 3 years were scored according to adherence to the New Nordic Diet (NND). NND scores were calculated both as a total score and categorized into low, medium, or high adherence. Child communication and motor development skills were reported by parents at 6 months, 18 months, 3 and 5 years, using short forms of the Ages and Stages Questionnaire and the Child Development Inventory. Associations of NND adherence with child development were estimated with linear and logistic regression in crude and adjusted models. RESULTS: When examining the NND and child developmental scores as percentages of the total scores, we found positive associations between the NND scores (both maternal pregnancy diet and child diet) and higher scoring on child development (adjusted [Formula: see text] s [95% confidence intervals] ranging from 0.007 [0.004, 0.009] to 0.045 [0.040, 0.050]). We further found that low and medium adherence to NND were associated with higher odds of later emerging developmental skills compared to high NND adherence at nearly all measured timepoints (odds ratios [95% CI] ranging from significant values 1.15 [1.03-1.29] to 1.79 [1.55, 2.06] in adjusted analyses). CONCLUSIONS: Our findings support that adherence to a healthy and potentially sustainable diet early in life is important for child development every step of the way from pregnancy until age 5 years.

Early childhood respiratory tract infections according to parental subfertility and conception by assisted reproductive technologies.

STUDY QUESTION: Are children conceived by ART or born to subfertile parents more susceptible to upper or lower respiratory tract infections (URTI, LRTI)? SUMMARY ANSWER: ART-conceived children had a higher frequency of and risk of hospitalization for respiratory infections up to age 3, which was only partly explained by parental subfertility. WHAT IS KNOWN ALREADY: Some studies report increased risks of infections in children conceived by ART. Results for URTIs and LRTIs are inconclusive, and the contribution of underlying parental subfertility remains unclear. STUDY DESIGN, SIZE, DURATION: We included 84 102 singletons of the Norwegian Mother, Father and Child Cohort Study (MoBa) born between 1999 and 2009. Mothers reported time-to-pregnancy at recruitment and child history of, frequency of and hospitalization for, respiratory infections when the child was 6, 18 and 36 months old by questionnaires. Subfertility was defined as having taken 12 or more months to conceive. The Medical Birth Registry of Norway (MBRN) provided information on ART. URTI included throat and ear infections, while LRTI included bronchitis, bronchiolitis, respiratory syncytial virus and pneumonia. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used log-binomial regression to estimate risk ratios (RR) and 95% CI of any respiratory tract infection and hospitalization, and negative-binomial regression to calculate incidence rate ratios (IRR) and 95% CI for number of infections. We compared children conceived by ART, and naturally conceived children of subfertile parents, to children of fertile parents (<12 months to conceive) while adjusting for maternal age, education, BMI and smoking during pregnancy and previous livebirths. We accounted for dependency between children born to the same mother. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 7334 (8.7%) singletons were naturally conceived by subfertile parents and 1901 (2.3%) were conceived by ART. Between age 0 and 36 months, 41 609 (49.5%) of children experienced any URTI, 15 542 (18.5%) any LRTI and 4134 (4.9%) were hospitalized due to LRTI. Up to age 3, children conceived by ART had higher frequencies of URTI (adjusted IRR (aIRR) 1.16; 95% CI 1.05-1.28) and hospitalizations due to LRTI (adjusted RR (aRR) 1.25; 95% CI 1.02-1.53), which was not seen for children of subfertile parents. Children conceived by ART were not at higher risks of respiratory infections up to age 18 months; only at age 19-36 months, they had increased risk of any LRTI (aRR 1.16; 95% CI 1.01-1.33), increased frequency of LRTIs (IRR 1.22; 95% CI 1.02-1.47) and a higher risk of hospitalization for LRTI (aRR 1.35; 95% CI 1.01-1.80). They also had an increased frequency of URTIs (aIRR; 1.19; 95% CI 1.07-1.33). Children of subfertile parents only had a higher risk of LRTIs (aRR 1.09; 95% CI 1.01-1.17) at age 19-36 months. LIMITATIONS, REASONS FOR CAUTION: Self-reported time-to-pregnancy and respiratory tract infections by parents could lead to misclassification. Both the initial participation rate and loss to follow up in the MoBa limits generalizability to the general Norwegian population. WIDER IMPLICATIONS OF THE FINDINGS: ART-conceived children might be more susceptible to respiratory tract infections in early childhood. This appears to be only partly explained by underlying parental subfertility. Exactly what aspects related to the ART procedure might be reflected in these associations need to be further investigated. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from the Swiss National Science Foundation (P2BEP3_191798), the Research Council of Norway (no. 262700), and the European Research Council (no. 947684). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures.

BACKGROUND: There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences. RESULTS: This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ([Formula: see text] 0.99), but low per-CpG correlations ([Formula: see text] ≈ 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5). CONCLUSION: The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.

Parents' age at birth and daughters' time to pregnancy: a study within the Norwegian Mother, Father and Child Cohort.

STUDY QUESTION: Is parents' age at birth associated with daughters' fecundability? SUMMARY ANSWER: Daughters born to mothers <25 years or fathers ≥35 years had slightly lower fecundability. WHAT IS KNOWN ALREADY: Two recent studies reported lower fecundability in women born to mothers <20 years, which may be partly due to daughters of young mothers being less likely to plan their pregnancies. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 58 496 pregnancy planners (4290 of whom conceived with treatment) and 14 194 non-planners enrolled in the Norwegian Mother, Father and Child Cohort Study (MoBa) between 2000 and 2008, linked with the Medical Birth Registry of Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were born in Norway between 1967 and 1990. We estimated fecundability ratios (FRs) and 95% CI as a function of both parents' (F1) age at the daughter's (F2) birth among non-treated planners and the relative risk of time to pregnancy (TTP) ≥12 months or treatment among all planners. We explored whether daughters of young mothers were under-represented among planners, compared with the underlying population. Finally, we estimated FRs after adding non-planners, randomly assigned to conceiving in the first cycle with probabilities of 0.60 and 0.70. MAIN RESULTS AND THE ROLE OF CHANCE: For both mother and father, the reference category was 25-29 years. Fecundability was slightly lower among daughters of older fathers (FRs (95% CI): 0.95 (0.92, 0.98) for F1 father's age 35-39 years and 0.93 (0.89, 0.97) for ≥40 years) and daughters of young mothers (0.92 (0.89, 0.96) for F1 mother's age <20 years and 0.97 (0.95, 0.99) for 20-24 years). Results were similar for the composite outcome TTP ≥ 12 months or treatment, although driven by TTP ≥ 12. Compared with Norwegian-born women with ≥1 pregnancy, planners born to mothers <20 years were underrepresented. Including non-planners with very high fecundability weakened the association with mother's age <20 years. LIMITATIONS, REASONS FOR CAUTION: This was a pregnancy cohort with retrospectively reported information on planning and TTP. Selection bias appears unlikely to fully explain the association with mother's age <20 years. WIDER IMPLICATIONS OF THE FINDINGS: Daughters of young mothers or older fathers may have slightly lower fecundability. If corroborated, the finding about older paternal age is relevant, given the widespread tendency to delay childbearing. STUDY FUNDING/COMPETING INTEREST(S): This work was partly funded by the Research Council of Norway (project no. 320656), and through its Centres of Excellence funding scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 947684). No competing interests. TRIAL REGISTRATION NUMBER: N/A.