Organic food consumption during pregnancy and symptoms of neurodevelopmental disorders at 8 years of age in the offspring: the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Partially driven by public concerns about modern food production practices, organic food has gained popularity among consumers. However, the impact of organic food consumption during pregnancy on offspring health is scarcely studied. We aimed to investigate the association between maternal intake of organic food during pregnancy and symptoms of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring at 8 years of age. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). The total study sample included 40,707 mother-child pairs (children born 2002-2009). Organic food consumption during pregnancy was assessed by six questions from a food frequency questionnaire in mid-pregnancy (sum score 0-18). Symptoms of ADHD and ASD in the offspring aged 8 years were measured by ADHD (0-54) and ASD (0-39) symptom scores based on the Parent/Teacher Rating Scale for Disruptive Behaviour disorders and the Social Communication Questionnaire. Associations between maternal intake of organic food during pregnancy and symptoms of ADHD and ASD in the offspring were analyzed using regression models with adjustment for covariates such as maternal anxiety and depression, including sibling analysis. RESULTS: Mean ADHD and ASD symptom scores in the offspring differed only slightly by maternal intake of organic food. The covariate-adjusted unstandardized regression coefficient (adjusted(Adj)beta) with 95% confidence interval for the ADHD symptom score with one unit increase in organic food sum score was 0.03 (0.01, 0.05). Similarly, Adjbeta for autism symptom score was 0.07 (0.04, 0.10). For ADHD, the adjusted estimates weakened when adjusting for maternal symptoms of ADHD. The sibling analyses showed no significant results with Adjbeta - 0.07 (- 0.15, 0.01) and - 0.001 (- 0.12, 0.12) for ADHD and ASD outcomes, respectively. CONCLUSIONS: We observed weak positive associations between frequent maternal organic food consumption during pregnancy and offspring ADHD and ASD symptom levels at 8 years of age. This trend weakened or disappeared after adjusting for maternal symptoms of ADHD, and in sibling analyses, suggesting that the associations mainly reflect genetic confounding. Our study indicates that consumption of organic food during pregnancy should neither be considered a risk factor nor protective against symptoms of ADHD and ASD in offspring.

Maternal diet in pregnancy and the risk of inflammatory bowel disease in the offspring: a prospective cohort study.

BACKGROUND: Diet has been hypothesized as a risk factor for development of inflammatory bowel disease (IBD). OBJECTIVE: To explore associations between maternal diet diversity and quality in pregnancy and the offspring's risk of IBD. METHODS: We used data from a nationwide cohort study on 85,129 Norwegian children followed from birth (1999-2009) with information on maternal diet in pregnancy from validated food frequency questionnaires. Hazard ratios (aHRs) for IBD, Crohn's disease (CD), and ulcerative colitis (UC) by maternal diet diversity, quality and intake amounts of individual food groups were adjusted for maternal body mass index, parental IBD, and socio-demographic factors. Sensitivity analyses adjusted for the child's early-life diet quality and antibiotic treatment. Dietary exposures were classified into tertiles, comparing low (reference) to medium, and high levels. RESULTS: During a mean follow-up time of 16.1 years (1,367,837 person-years of follow-up), 268 children developed IBD (CD, n=119; UC, n=76; IBD-unclassified, n=73). High compared with low diet diversity in pregnancy was associated with a lower risk of UC in the offspring (aHR 0.46, 95% confidence interval 0.25-0.87), with consistent findings after further adjustment for the child's early-life diet quality and antibiotic treatment. High compared with low diet diversity in pregnancy yielded aHRs of 0.81 for CD (0.51-1.28) and 0.75 for any IBD (0.55-1.02) in the offspring. A high compared with low diet quality in pregnancy or intakes of specific food groups were not associated with the offspring's risk of IBD or its subtypes. CONCLUSIONS: Our findings suggest that a higher maternal diet diversity in pregnancy may be associated with a lower risk of UC in the offspring.

Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders.

BACKGROUND: Symptoms related to mood and anxiety disorders (emotional disorders) often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for emotional disorders and related traits influence trajectories of childhood behavioral and emotional difficulties, and if specific developmental patterns are associated with higher genetic liability for these disorders. METHODS: This study uses data from a genotyped sample of children (n = 54,839) from the Norwegian Mother, Father, and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR). RESULTS: Associations between PGSDEP, PGSANX, and PGSNEUR, and emotional and behavioral difficulties in childhood were more persistent than age-specific across early childhood (1.5-5 years). Higher PGSANX and PGSDEP were associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles with different associations with emotional disorder diagnosis. All PGS were associated with the probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBD was uniquely associated with a single developmental profile. CONCLUSIONS: Genetic risk for mood disorders and related traits contribute to both a higher baseline level of, and a more rapid increase in, emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. Our findings may inform research on developmental pathways to emotional disorders and the improvement of initiatives for early identification and targeted intervention.

Eating Problems Among Adolescent Boys and Girls Before and During the Covid-19 Pandemic.

OBJECTIVE: Studies suggest that adolescents reported more eating problems during the pandemic. Using a population-based sample, we compared eating problems-and how they associate with a range of personal characteristics and genetic factors-among adolescents before (June 2017-April 2020) versus during (April 2020-December 2022) the pandemic. METHOD: Based on a preregistered analysis plan, we used cross-sectional data collected from 22,706 14-16-year-olds over 6 years (55% during the pandemic) in the Norwegian Mother, Father, and Child Cohort. We used measurement invariance analyses to compare the level of eating restraint and body concern before and during the pandemic, and multi-group structural equation models to estimate pre-pandemic and pandemic patterns of associations. RESULTS: Pandemic responders generally reported more eating problems than pre-pandemic responders, specifically on dieting and body dissatisfaction. However, after adjusting for a general linear increase in eating problems across all 6 years of data collection, the pandemic itself seems to be associated with more eating problems only among girls, reporting more eating restraints (meanΔ = 0.14 [CI: 0.07, 0.20]) and body concern (meanΔ = 0.17 [CI: 0.11, 0.23]). Associations between eating problems and a range of other characteristics did not differ across the pandemic and pre-pandemic groups. CONCLUSIONS: There was a general increase in eating problems among 14-16-year-olds over time. Adjusting for this trend, the pandemic seems to exacerbate problems among girls. Although the mechanisms are unclear, our results point to factors susceptible to change that could have been intensified during the pandemic (e.g., screen time, mental distress). Our results highlight the importance of recognizing sex-specific differences in eating problems.

Early-Life Diet Diversity and the Subsequent Risk of Inflammatory Bowel Disease: Findings From Two Scandinavian Birth Cohorts.

BACKGROUND: Diet diversity in early childhood promotes microbial diversity, influences the developing immune system, and has been linked to a reduced risk of immune-mediated diseases. This study aimed to determine the association between childhood diet diversity and later inflammatory bowel disease (IBD), for which data are limited. METHODS: Questionnaire data from the population-based birth cohorts All Babies in Southeast Sweden (ABIS) and the Norwegian Mother, Father, and Child Cohort (MoBa), including participants from Southeast Sweden and Norway, were used to estimate a diet diversity score at ages 1 and 3 years. This score represents the diversity of intakes across 5 food groups comprising 11 subgroups. A higher score signifies higher diet diversity. We used linked health registry data to identify IBD diagnoses up to the year 2021. Cox regression and random-effect models were used to estimate pooled hazard ratios (aHRs) adjusted for sociodemographics, breastfeeding, and early-life antibiotic use. RESULTS: Among 81 272 children with 1 304 325 person-years of follow-up, 307 developed IBD. Diet diversity at ages 1 and 3 years was in pooled analyses not associated with later IBD (per one-unit increase, aHR = 0.96 [95% CI = 0.81-1.14] and aHR = 0.96 [95% CI = 0.83-1.11]). In MoBa, but not ABIS, a higher diet diversity at 1 and 3 years of age was inversely associated with ulcerative colitis (UC) (per one-unit increase, aHR = 0.78 [95% CI = 0.66-0.94] and aHR = 0.78 [95% CI = 0.65-0.95]). Still, pooled aHRs for UC as well as Crohn's disease approximated one. CONCLUSIONS: In this prospective study of 2 Scandinavian birth cohorts, no association was observed between early-life diet diversity and the subsequent risk of IBD.

In this prospective study of over 80 000 children followed in 2 Scandinavian birth cohorts, early-life diet diversity was not associated with the subsequent risk of inflammatory bowel disease.

Testing maternal effects of vitamin-D and omega-3 levels on offspring neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. However, observational study designs cannot distinguish causal effects from confounding. METHODS: First, we conducted Mendelian randomisation (MR) using genetic instruments for vitamin-D and DHA identified in independent genome-wide association studies (GWAS). Outcomes were (1) GWAS for traits related to autism and ADHD, generated in the Norwegian mother, father, and child cohort study (MoBa) from 3 to 8 years, (2) autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa (1) to test causal effects through maternal nutrient levels, (2) to test effects of child nutrient levels, and (3) as a paternal negative control. RESULTS: Associations between higher maternal vitamin-D levels on lower ADHD related traits at age 5 did not remain after controlling for familial genetic predisposition using trio-MR. Furthermore, we did not find evidence for causal maternal effects of vitamin-D/DHA levels on other offspring traits or diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic predisposition on lower vitamin-D levels and of ADHD genetic predisposition on lower DHA levels. CONCLUSIONS: Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence that suggests that previous observational associations are likely biased by genetic confounding. Consequently, maternal supplementation is unlikely to influence these offspring neurodevelopmental traits. Notably, genetic predisposition to ADHD and autism was associated with lower DHA and vitamin-D levels respectively, suggesting previous associations might have been due to reverse causation.

Association Between Maternal Infections in Pregnancy and the Risk of Inflammatory Bowel Disease in the Offspring: Findings From Two Scandinavian Birth Cohorts.

BACKGROUND: The association of infections and antibiotic use in pregnancy and the risk of inflammatory bowel disease (IBD) development in the offspring have been scarcely investigated. We examined infection and antibiotic use in pregnancy and the risk of IBD in offspring. METHODS: We followed participants from the All Babies in Southeast Sweden (ABIS) and the Norwegian mother father and child cohort (MoBa) from birth (1997-2009) until 2020-2021. IBD diagnosis was classified as ≥2 records in national registers. Information on infections (any, gastrointestinal, and respiratory), their timing (early or late in pregnancy), and antibiotic use in pregnancy were collected from questionnaires. Cox proportional-hazard regression and meta-analytic methods were used to estimate pooled adjusted hazard ratios (aHRs) for IBD and its subtypes, adjusted for parental IBD, maternal smoking, and education. Sensitivity analyses accounted for exposure to antibiotics and infections 0-12 months of age. RESULTS: We followed 117 493 children for 2 024 299 person-years (follow-up 22.3 years in ABIS and 16.4 years in MoBa), including 451 IBD cases. The aHRs for any infection and respiratory infections in pregnancy and offspring IBD were close to one (aHR = 0.99 [95% CI = 0.73-1.33] and aHR = 1.00 [95% CI = 0.81-1.23], respectively). However, any versus no infection in early pregnancy was associated with IBD development (aHR = 1.26 [95% CI = 1.02-1.55]), particularly Crohn's disease (CD; aHR = 1.40 [95% CI = 1.01-1.93]). Any versus no gastrointestinal infection in late pregnancy was associated with offspring CD (aHR = 1.95 [95% CI = 1.34-2.84]). Antibiotic use in pregnancy was not associated with IBD in the child (aHR = 1.15 [95% CI = 0.93-1.44]). CONCLUSIONS: In this binational birth cohort study, the risk of offspring IBD varied by infection type and timing but not with maternal antibiotic use in pregnancy.

In this study, with over 117 000 participants from 2 Scandinavian birth cohorts, the type and timing of maternal infections in pregnancy were associated with the offspring's risk of inflammatory bowel disease.

Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.

Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.

Prenatal stress and gestational epigenetic age: No evidence of associations based on a large prospective multi-cohort study.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: "Bohlin", "EPIC overlap" and "Knight". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

Stability and change in maternal wellbeing and illbeing from pregnancy to three years postpartum.

PURPOSE: Motherhood affects women's mental health, encompassing aspects of both wellbeing and illbeing. This study investigated stability and change in wellbeing (i.e., relationship satisfaction and positive affect) and illbeing (i.e., depressive and anxiety symptoms) from pregnancy to three years postpartum. We further investigated the mutual and dynamic relations between these constructs over time and the role of genetic propensities in their time-invariant stability. DATA AND METHODS: This four-wave longitudinal study included 83,124 women from the Norwegian Mother, Father, and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway. Data were collected during pregnancy (30 weeks) and at 6, 18 and 36 months postpartum. Wellbeing and illbeing were based on the Relationship Satisfaction Scale, the Differential Emotions Scale and Hopkins Symptoms Checklist-8. Genetics were measured by the wellbeing spectrum polygenic index. Analyses were based on random intercept cross-lagged panel models using R. RESULTS: All four outcomes showed high stability and were mutually interconnected over time, with abundant cross-lagged predictions. The period of greatest instability was from pregnancy to 6 months postpartum, followed by increasing stability. Prenatal relationship satisfaction played a crucial role in maternal mental health postpartum. Women's genetic propensity to wellbeing contributed to time-invariant stability of all four constructs. CONCLUSION: Understanding the mutual relationship between different aspects of wellbeing and illbeing allows for identifying potential targets for health promotion interventions. Time-invariant stability was partially explained by genetics. Maternal wellbeing and illbeing develop in an interdependent way from pregnancy to 36 months postpartum.

Telomere length in relation to fecundability and use of assisted reproductive technologies: the Norwegian Mother, Father, and Child Cohort Study.

In women, shorter telomeres have been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, whereas other studies have reported the opposite. In men, studies mostly report associations between shorter telomeres and sperm quality. To our knowledge, no studies have thus far investigated the associations between TL and fecundability or the use of ART. This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1,054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated the associations between leukocyte TL and fecundability, infertility, and the use of ART. We also repeated the analyses using instrumental variables for TL, including genetic risk scores for TL and genetically predicted TL. Approximately 11% of couples had experienced infertility and 4% had used ART. TL was not associated with fecundability among women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility among women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing TL among men (OR, 1.22; CI, 1.03-1.46), but not among women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables. Our results indicate that TL is a poor biomarker of fecundability, infertility and use of ART in MoBa. Additional studies are required to replicate the association observed between TL and ART in men.

Prenatal exposure to benzodiazepine and z-hypnotics and fifth-grade scholastic skills - emulating target trials using data from the Norwegian Mother, Father and Child Cohort Study.

Evidence is limited regarding the effect of prenatal benzodiazepine and z-hypnotic exposure and long-term neurodevelopment in childhood. The objective of this study was to investigate the effects of initiating benzodiazepine or z-hypnotic treatment in early, mid and late pregnancy on fifth-grade numeracy and literacy scholastic skills in children, by emulating three target trials. The trials are identical except for the timing of enrollment and the number of eligible individuals. Eligibility to the trials required a history of anxiety and/or depression prior to pregnancy. We used data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, to emulate the trials. We adjusted for baseline covariates that were available at time 0 for each trial by inverse probability of treatment weighting using the propensity score. The findings of this study did not show any effect of mothers' initiation of treatment with benzodiazepines or z-hypnotics in early, mid or late pregnancy on the children's 5th grade test scores in numeracy and literacy. The study results provide reassurance for patients in need of benzodiazepines and z-hypnotics during pregnancy; however, these findings need to be interpreted with caution due to low study power in some of the analyses.

Mercury exposure in the Norwegian Mother, Father, and Child Cohort Study - measured and predicted blood concentrations and associations with birth weight.

Background: Blood total mercury concentration (BTHg) predominantly contains methyl Hg from seafood, and less inorganic Hg. Measured BTHg is often available only in a small proportion of large cohort study samples. Associations between estimated dietary intake of total Hg (THg) and lower birth weight within strata of maternal seafood intake was previously reported in the Norwegian Mother, Father, and Child Cohort Study (MoBa). However, maternal seafood consumption was associated with increased birth weight, indicating negative confounding by seafood in the association between THg intake and birth weight. Using predicted BTHg as a proxy for measured BTHg, we hypothesized that predicted BTHg would be associated with decreased birth weight. Objectives: To develop and validate a prediction model for BTHg in MoBa and to examine the association between predicted BTHg and birth weight in the MoBa population. Methods: Using linear regression, measured maternal BTHg (n = 1437) was used to build the best fitting model (highest R-squared value). Model validation (n = 1436) was based on correlation and weighted Kappa (Кw). Associations between predicted BTHg in the MoBa population (n = 86,775) or measured BTHg (n = 3590) and birth weight were assessed by multivariate linear regression models. Results: The best fitting model had R-squared = 0.3 and showed strong correlation (r = 0.53, p < 0.001) between predicted and measured BTHg. Cross-classification (quintiles) showed 73 % correctly classified and 3.3 % grossly misclassified, with Кw of 0.37. Measured BTHg was not associated with birth weight. Predicted BTHg was significantly associated with higher birth weight. There were no trends in birth weight with increasing quintiles of measured or predicted BTHg after stratification into high or low seafood consumption. Conclusions: The results indicate that prediction of BTHg did not overcome negative confounding of the association between Hg exposure and birth weight by seafood intake. Furthermore, effect on birth weight of toxicological concern is unexpected in our observed BTHg range.

Emotional analysis of multiplayer online battle arena games addiction.

Introduction: Multiplayer Online Battle Arena (MOBA) games have garnered widespread popularity as a form of recreational activity. The launch of League of Legends (LoL), a prominent MOBA game, has captivated the enthusiastic pursuit of gamers in the MOBA community. The surge in MOBA game fervor, coupled with the influence of personal emotions, can result in excessive engagement, ultimately leading to addiction. Objective: This study aimed to investigate the moderating effects of visceral perception, behavior, and reflection on game players' addiction within the framework of Leisure Theory (LT), Uses and Gratification Theory (UGT), and Emotional Design Theory (EDT). Methods: A hypothesized theoretical model was developed and empirically evaluated based on 236 self-reported validated responses from MOBA gamers. SPSS (version 26) was employed for demographic analysis and game duration analysis. The measurement model and structural model analyses were conducted in two stages using Partial Least Squares Structural Equation Modeling (PLS-SEM) with SmartPLS 4.1.0 to validate the nine theoretical hypotheses. Results: It has been observed that personal emotions significantly contributes to MOBA game addiction during gamers' leisure time or moments of gratification. Specifically, a noteworthy connection exists between two dimensions, namely gamers' behavior and reflection, demonstrating a positive correlation with gaming addiction. Without taking entertainment as a motivating factor, there is no significant relationship between gamers' leisure-time and visceral perception. Conclusion: This study enhances the theoretical model of gamers' behavioral motives in engaging with MOBA gaming and contributes to the expansion of research on game addiction theory. These findings offer valuable theoretical insights for emotional design in games and the design of mechanisms for preventing game addiction.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). CONCLUSION: Our results suggest that continued smoking during pregnancy causes higher placental weights.

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.

Tobacco Smoke Exposure in Early Childhood and Later Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study.

OBJECTIVES: To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease [IBD]. METHODS: We followed 115663 participants from the Norwegian Mother, Father and Child [MoBa] and All Babies in Southeast Sweden [ABIS] cohorts from birth [1997-2009] through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke [ETS] exposure during pregnancy, and child ETS exposure by ages 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios [aHRs] for sex, maternal age, education level, parental IBD, and origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: During 1 987 430 person-years of follow-up, 444 participants developed IBD [ABIS, 112; MoBa, 332]. Any vs no maternal smoking during pregnancy yielded a pooled aHR of 1.30 [95% CI = 0.97-1.74] for offspring IBD. Higher level of maternal smoking during pregnancy (compared with no smoking, average ≥6 cigarettes/day: pooled aHR = 1.60 [95% CI = 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR = 1.09 [95% CI = 0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs no ETS, pooled aHR = 1.32 [95% CI = 1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant. CONCLUSIONS: In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD.

Early or late menarche is associated with reduced fecundability in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is age at menarche associated with fecundability? SUMMARY ANSWER: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability. WHAT IS KNOWN ALREADY: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years. LIMITATIONS, REASONS FOR CAUTION: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate. WIDER IMPLICATIONS OF THE FINDINGS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Socioeconomic status and risk for child psychopathology: exploring gene-environment interaction in the presence of gene-environment correlation using extended families in the Norwegian Mother, Father and Child Birth Cohort Study.

BACKGROUND: Low socioeconomic status (SES) is associated with increased risk for emotional and behavioural problems among children. Evidence from twin studies has shown that family SES moderates genetic and environmental influences on child mental health. However, it is also known that SES is itself under genetic influence and previous gene-environment interaction (G×E) studies have not incorporated the potential genetic overlap between child mental health and family SES into G×E analyses. We applied a novel approach using extended family data to investigate the moderation of aetiological influences on child emotional and behavioural problems by parental socioeconomic status in the presence of modelled gene-environment correlation. METHODS: The sample comprised >28,100 children in extended-family units drawn from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported children's emotional and behavioural symptoms. Parents' income and educational attainment were obtained through linkage to administrative register data. Bivariate moderation Multiple-Children-of-Twins-and-Siblings (MCoTS) models were used to analyse relationships between offspring outcomes (emotional and behavioural symptom scores) and parental socioeconomic moderators (income rank and educational attainment). RESULTS: The aetiology of child emotional symptoms was moderated by maternal and paternal educational attainment. Shared environmental influences on child emotional symptoms were greater at lower levels of parents' education. The aetiology of child behavioural symptoms was moderated by maternal, but not paternal, socioeconomic factors. Genetic factors shared between maternal income and child behavioural symptoms were greater in families with lower levels maternal income. Nonshared environmental influences on child behavioural symptoms were greater in families with higher maternal income and education. CONCLUSIONS: Parental socioeconomic indicators moderated familial influences and nonshared environmental influences on child emotional and behavioural outcomes. Maternal SES and child mental health share aetiological overlap such that shared genetic influence was greater at the lower end of the socioeconomic distribution. Our findings collectively highlight the role that family socioeconomic factors play in shaping the origins of child emotional and behavioural problems.