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Abstract Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways.

Abstract Background According to Norwegian registries, 91% of individuals ≥ 16 years had received ≥ 1 dose of COVID-19 vaccine by mid-July 2022, whereas less than 2% of children

In the mass-production of microfluidic devices through micro hot embossing/injection moulding, the longevity of mould inserts is influenced by elevated adhesion and friction between the polymer and the mould. Thus, accurate prediction of mould lifespan requires a comprehensive understanding of surface wettability and tribological performance during polymer contact. The current study addresses this gap by characterizing fabricated micro-structured Ni, Ni-WS2, and Ni-PTFE nanocomposite moulds (surface morphologies, crystal structures and microhardness) to investigate inherent lubrication mechanisms. Surface wettability of mould material was systematically studied by measuring the contact angles with eight different polymer melts. Pin-on-disk tests with polymer pins made of cyclic olefin copolymer (COC 8007), polypropylene (PP), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) were conducted to elucidate the wear resistance of the nanocomposite moulds. Pressure-dependent friction coefficient and wear resistance were further explored under increasing external loads, simulating the actual moulding processes where contact pressure may vary considerably depending on the part shape. Results indicate that Ni-WS2 exhibits the highest microhardness (532 Hv), followed by Ni-PTFE (465 Hv) and Ni (198 Hv). Notably, Ni-PTFE demonstrates exceptional hydrophobicity against all polymer melts, signifying low surface energy during polymer contact. Moreover, both nanocomposite moulds exhibit reduced friction coefficients and enhanced wear resistance across various polymers. Counterintuitively, despite its lower hardness, the Ni-PTFE mould displays superior wear resistance against the COC pin under higher loads, while the Ni-WS2 mould experiences severe adhesive wear, as observed from wear morphology and profile analysis. This finding establishes the Ni-PTFE as a promising alternative as a mould insert material for precision manufacturing.

Abstract Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Abstract 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

Abstract Background Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. Methods We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. Results All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. Conclusions Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. Funding Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Summary: Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2-ABCC2 and MDR1-ABCB1) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2-ABCC2 and MDR1-ABCB1 variants and antiseizure medication may impact neonatal birth weight.

Abstract Background Clear evidence of an increased risk for SARS-CoV-2 infection among smokers has not been established. We aimed to investigate associations between cigarette smoking or use of snus (snuff) and other nicotine-containing products and a positive SARS-CoV-2 test, taking test behavior into account. Methods Current tobacco use and testing behavior during the pandemic were recorded by adult participants from the Norwegian Mother, Father and Child Cohort Study and The Norwegian Influenza Pregnancy Cohort. SARS-CoV-2 infection status was obtained from The Norwegian Surveillance System for Communicable Diseases (MSIS) in May 2021 (n = 78,860) and antibody measurements (n = 5581). We used logistic regression models stratified by gender and adjusted for age, education, region, number of household members, and work situation. Results Snus use was more common among men (26%) than women (9%) and more prevalent than cigarette smoking. We found no clear associations between cigarette smoking or snus and a COVID-19 diagnosis among men. Associations among women were conflicting, indicating that cigarette smoke was negatively associated with a diagnosis (OR 0.51, 95% CI 0.35, 0.75), while no association was found for snus use (OR 1.07, 95% CI 0.86, 1.34). Compared with non-users of tobacco, both cigarette smokers and snus users had increased odds of being tested for SARS-CoV-2. Conclusions Cigarette smoking, but not snus use, was negatively associated with SARS-CoV-2 infection in women. The lack of an association between snus use and SARS-CoV-2 infection in this population with prevalent snus use does not support the hypothesis of a protective effect of nicotine.

Abstract Background Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother–father–newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian ‘Clinical review of the Health of adults conceived following Assisted Reproductive Technologies’ (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (‘XWASs’ hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. Results In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Conclusions Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

Abstract 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.

Digital Light Processing (DLP) is an advanced additive manufacturing technology which has garnered substantial recognition and has been extensively applications in various fields. This review focuses on the precision microfabrication process of DLP, providing an overview of the DLP 3D printing system, including the digital light engine, project lenses, motorised stage and resin vat for micro-structure fabrication. Additionally, this review paper comprehensively analyses commercially available DLP printers, covering resolution, cost and a detailed discussion on the importance of photopolymer resins, emphasising the monomer, photo-initiator, photo-absorber, etc. Based on the photopolymerisation theory, the DLP high-precision printing process is analysed, which is critical for producing complex microstructures. It also briefly discusses the application of DLP microfabrication including microfluidic chip printing. Finally, this paper summarises the advanced trends and challenges of DLP printing in high-precision, large-area, multi-material and high-speed printing; and it provides an in-depth understanding of DLP technology, highlighting its potential for various applications and addressing challenges that need to be overcome in future research.

Objectives: To identify factors associated with change in mental distress at the onset of the COVID-19 pandemic, relative to pre-pandemic levels, and with changes during the following 1.5 years.Methods: The prospective Norwegian Mother, Father and Child Cohort Study collected eight waves of data during the pandemic (March 2020–September 2021) in 105,972 adult participants used for this analyses. A piecewise latent growth model was fitted to identify initial level and longitudinal changes in mental distress.Results: Mental distress peaked at the beginning of the pandemic. Factors associated with initial increases were: medical conditions, living alone, history of psychiatric disorders, lower education, female sex, younger age, and obesity. Being quarantined or infected with SARS-CoV-2 were associated with increasing distress while being vaccinated was associated with reduced mental distress.Conclusion: Having a chronic disease and being quarantined or infected by the SARS-CoV-2 virus were associated with more mental distress during the pandemic. This knowledge is important for planning interventions to support individuals during future pandemics and other societal crises.

Abstract 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 ≤ P interaction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ P interaction ≤ 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 ≤ P interaction ≤ 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 ≤ P interaction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ P interaction ≤ 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.

Abstract Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Abstract Empirical evidence, primarily based on hospital-based or voluntary samples, suggests that current smokers have a lower risk of COVID-19 infection than never smokers. In this study, we used nationally representative data to examine the association between tobacco use and the risk of having a confirmed COVID-19 case. We explored several forms of tobacco use, contributing to separate the role of nicotine from smoking. We used data from 44,199 participants from three pooled national health surveys in Finland (FinSote 2018–2020). The primary outcome was a confirmed COVID-19 case. We examined current smoking, moist smokeless tobacco (snus), e-cigarettes with and without nicotine and nicotine replacement therapy products. Current daily smokers had a relative risk of 1.12 of a confirmed COVID-19 case (95% CI 0.65; 1.94) in fully adjusted models compared with never smokers. Current snus use was associated with a 68% higher risk of a confirmed COVID-19 case (RR 1.68, 95% CI 1.02; 2.75) than never users. We did not find conclusive evidence of associations between e-cigarettes with and without nicotine and nicotine replacement therapy products and the risk of confirmed COVID-19 cases. Our findings suggest that nicotine might not have a protective role in the risk of COVID-19 as previously hypothesized.

Abstract Background Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight. Methods We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks. Results In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting

The SARS-CoV-2 Omicron variant possess many mutations within the receptor binding domain of the Spike protein, which confer increased transmissibility and higher antibody escape. Here, the authors carry out analysis of the serological and cellular immune responses of individuals with Omicron breakthrough infection.

Abstract Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non‐European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans‐ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta‐analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. Results We show that in the absence of a well powered trans‐ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans‐ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans‐ethnic linkage disequilibrium reference panels. The ported trans‐ethnic scores outperform population specific‐PRS across all non‐European ancestry populations investigated including East Asians and three‐way admixed Brazilian cohort. Conclusions Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans‐ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three‐way admixed Brazilians.

Timing of assisted reproduction technology (ART) procedures coincides with extensive epigenetic remodeling early after conception. Here the authors identify 176 DNA methylation differences in cord blood of newborns conceived with ART. including genes related to growth, neurodevelopment, and cancer.

Assortative mating could violate the assumption of random mating used in many genetic studies. Here, the authors study more than 25,000 Norwegian families to find genetic similarity between partners, siblings, and in-laws in genetic factors related to educational attainment, height, and depression.

Abstract Background The overall aim of this study is to examine the effect of prenatal maternal anxiety on birthweight and gestational age, controlling for shared family confounding using a sibling comparison design. Methods The data on 77,970 mothers and their 91,165 children from the population-based Mother, Father and Child Cohort Study and data on 12,480 pairs of siblings were used in this study. The mothers filled out questionnaires for each unique pregnancy, at 17th and 30th week in pregnancy. Gestational age and birth weight was extracted from the Medical Birth Registry of Norway (MBRN). Associations between prenatal maternal anxiety (measured across the 17th and 30th weeks) and birth outcomes (birthweight and gestational age) were examined using linear regression with adjustment for shared-family confounding in a sibling comparison design. Results In the population level analysis the maternal anxiety score during pregnancy was inversely associated with new-born’s birthweight (Beta = -63.8 95% CI: -92.6, -35.0) and gestational age (Beta = -1.52, 95% CI: -2.15, -0.89) after adjustment for several covariates. The association of the maternal anxiety score with birthweight was no longer significant, but remained for maternal anxiety at 30th week with gestational age (Beta = -1.11, 95% CI: -1.82, -0.4) after further adjusting for the shared-family confounding in the sibling comparison design. Conclusion No association was found for maternal prenatal anxiety with birth weight after multiple covariates and family environment were controlled. However, there was an association between prenatal maternal anxiety at 30th week only with gestational age, suggesting a timing effect for maternal anxiety in third trimester.

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.

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

Objectives To examine employment status among adults bereaved by parental suicide at the time of bereavement and 2 and 5 years after the loss and to explore the importance of the gender of the adult child and the deceased parent.Design Population-based register study.Setting Norwegian population-based registries linked using unique personal identifiers.Participants Norwegian residents aged 25–49 years in the period 2000–2014. Participants were divided into three groups: bereaved by parental suicide, bereaved by parental death of other causes and non-bereaved population controls.Main outcome measures ORs for the risk of non-employment at the time of bereavement and 2 and 5 years after the loss.Results Those bereaved by parental suicide had a higher risk of non-employment already at the time of bereavement (OR 1.14, 95% CI 1.05 to 1.23). Stratified analyses showed that women accounted for this difference (OR 1.20, 95% CI 1.09 to 1.33), while no difference was found for men (OR 1.00, 95% CI 0.88 to 1.13). Looking at the gender of the parent, there was only a significant association of non-employment when losing a mother (OR 1.24, 95% CI 1.08 to 1.42), while not for losing a father (OR 1.09, 95% CI 0.99 to 1.20). Among those working at the time of bereavement, offspring bereaved by suicide were more likely to be non-employed at both 2 (OR 1.13, 95% CI 0.99 to 1.30) and 5 (OR 1.20, 95% CI 1.02 to 1.40) years after the loss compared with the general population.Conclusions Women bereaved by parental suicide and those losing a mother to suicide were found to have a weaker attachment to the labour market already before losing their parent. Those who were employed when bereaved by suicide were somewhat more likely to be non-employed 5 years after the event.

BackgroundInsomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW).Methods and findingsWe used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age 4,500 grams). We used data from women of European descent (N = 356,069, mean ages at delivery 25.5 to 30.0 years) from UK Biobank (UKB), FinnGen, Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Norwegian Mother, Father and Child Cohort (MoBa). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N = 11,745). IVW showed evidence of an association of genetic susceptibility to insomnia with miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17, p = 0.002), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54, p = 0.004), and LBW (OR 3.17, 95% CI: 1.69, 5.96, p < 0.001). IVW results did not support associations of insomnia with stillbirth, GD, HDP, PTB, and HBW, with wide CIs including the null. Associations of genetic susceptibility to insomnia with miscarriage, perinatal depression, and LBW were not observed in weighted median or MR-Egger analyses. Results from these sensitivity analyses were directionally consistent with IVW results for all outcomes, with the exception of GD, perinatal depression, and PTB in MR-Egger. Multivariable regression showed associations of insomnia at 18 weeks of gestation with perinatal depression (OR 2.96, 95% CI: 2.42, 3.63, p < 0.001), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24, p = 0.60). Multivariable regression with miscarriage and stillbirth was not possible due to small numbers in index pregnancies. Key limitations are potential horizontal pleiotropy (particularly for perinatal depression) and low statistical power in MR, and residual confounding in multivariable regression.ConclusionsIn this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important.

Abstract Background More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. Methods This study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. Results Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. Conclusions Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.

Abstract Background Maternal infections during pregnancy are common events that have been suggested to be risk factors for Attention‐deficit hyperactivity disorder (ADHD) in offspring. Only a few studies have been conducted to date and results are conflicting. The current study investigates the associations between specific groups of prenatal maternal infections and offspring ADHD, considering timing of exposure and the role of fever. Methods We used data from the prospective Norwegian Mother, Father and Child Cohort Study (MoBa), including more than 112,000 pregnancies, linked with data from the Medical Birth Registry of Norway and the Norwegian Patient Registry to estimate odds ratios for the likelihood that children develop ADHD after being exposed to maternal infections during gestation. Results Children exposed to any maternal infection during pregnancy showed increased risk of receiving an ADHD diagnosis (OR = 1.15, CI = 1.03–1.27). Specifically, increased ADHD risk was observed after exposure to genitourinary infections in second (OR = 1.42, CI = 1.06–1.90) or third trimester (OR = 2.04, CI = 1.19–3.49), and to respiratory infections in second trimester (OR = 1.31, CI = 1.12–1.54), provided these infections were accompanied by episodes of fever. Increased ADHD risk was also observed after exposure to diarrhea without fever in the third trimester (OR = 1.25, CI = 1.07–1.46). Conclusions Overall, our results suggest that prenatal exposure to maternal infections, particularly with co‐occurring episodes of fever, are risk factors for ADHD. Fever (or severity of the infection) appears to be more important in mid‐pregnancy associations. Our results indicate that type of infection and timing of exposure might influence the associations, but small effect sizes require careful interpretations. The association between infection and ADHD should be estimated using discordant siblings or other negative control designs that give better adjustment for unmeasured familial confounding.

Objectives To estimate the impact of being laid off from work, having to work from home or having been diagnosed with COVID-19 on self-reported satisfaction with life.Design Nationwide population-based cohort study.Setting Norway.Participants We followed more than 80 000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa), during the COVID-19 pandemic. We analysed current life satisfaction in April and again in September/October 2020 for subjects whose work situation and infection status had changed.Main outcome measures Self-reported satisfaction with life, using a scale from 0 (worst) to 10 (best). We analysed the scale both continuously and as a binary variable (

Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Abstract Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. Methods IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. Results Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model’s calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. Conclusions The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. Trial registration PROSPERO ID: CRD42015029349 .

Abstract Background Many studies detect associations between parent behaviour and child symptoms of anxiety and depression. Despite knowledge that anxiety and depression are influenced by a complex interplay of genetic and environmental risk factors, most studies do not account for shared familial genetic risk. Quantitative genetic designs provide a means of controlling for shared genetics, but rely on observed putative exposure variables, and require data from highly specific family structures. Methods The intergenerational genomic method, Relatedness Disequilibrium Regression (RDR), indexes environmental effects of parents on child traits using measured genotypes. RDR estimates how much the parent genome influences the child indirectly via the environment, over and above effects of genetic factors acting directly in the child. This ‘genetic nurture’ effect is agnostic to parent phenotype and captures unmeasured heritable parent behaviours. We applied RDR in a sample of 11,598 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) to estimate parental genetic nurture separately from direct child genetic effects on anxiety and depression symptoms at age 8. We tested for mediation of genetic nurture via maternal anxiety and depression symptoms. Results were compared to a complementary non-genomic pedigree model. Results Parental genetic nurture explained 14% of the variance in depression symptoms at age 8. Subsequent analyses suggested that maternal anxiety and depression partially mediated this effect. The genetic nurture effect was mirrored by the finding of family environmental influence in our pedigree model. In contrast, variance in anxiety symptoms was not significantly influenced by common genetic variation in children or parents, despite a moderate pedigree heritability. Conclusions Genomic methods like RDR represent new opportunities for genetically sensitive family research on complex human traits, which until now has been largely confined to adoption, twin and other pedigree designs. Our results are relevant to debates about the role of parents in the development of anxiety and depression in children, and possibly where to intervene to reduce problems.

Abstract Background Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age. Results We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set. Conclusions Our ABECs predicted adults’ chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.

IntroductionMaternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort.Material and methodsThe Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay.ResultsAmong mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different.ConclusionThis study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

Prenatal maternal anxiety has been associated with both short and long-term mental health problems in the child. The current study aims to examine the association between maternal and paternal prenatal anxiety and behaviour problems in the child at 1.5 and 5 years, using three different approaches; (1) adjusting for covariates, (2) using fathers' anxiety during pregnancy as a negative control, and (3) using a sibling-comparison design, controlling for unmeasured family factors. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) is used. MoBa is a cohort consisting of about 114 000 pregnancies (about 34000 siblings) recruited from 1999 to 2008. Self-reported measures on maternal anxiety were obtained twice in pregnancy and 6 months after birth, while paternal anxiety was reported prenatally at 17th weeks of gestation. Maternal reports on child behaviour problems were obtained at 1.5 and 5 years of age. Results suggests that prenatal exposure to maternal anxiety was associated with behaviour problems at 1.5 years: adjusted beta (β) = 0.13 (CI = 0.12, 0.15), and at 5 years: β = 0.11 (CI = 0.09, 0.14). However, paternal anxiety was also associated with behaviour problems at 1.5 years: β = 0.03 (CI = 0.01-0.03) and at 5 years β = 0.03 (CI = 0.02, 0.03). These associations were attenuated in the sibling comparison analyses: β = -0.02 (CI = -0.02-0.05) at 1.5 years and β = -0.05 (CI = -0.10, 0.02) at 5 years. In conclusions, the sibling analyses are not consistent with a direct effect of prenatal maternal anxiety on child behaviour problems. It is more likely that genetic or shared family environment explain this association.

BackgroundSchool free fruit and vegetable (FFV) policies are used to promote healthy dietary habits and tackle obesity; however, our understanding of their effects on weight outcomes is limited. We assess the effect of a nationwide FFV policy on childhood and adolescent weight status and explore heterogeneity by sex and socioeconomic position.Methods and findingsThis study used a quasi-natural experimental design. Between 2007 and 2014, Norwegian combined schools (grades 1-10, age 6 to 16 years) were obligated to provide FFVs while elementary schools (grades 1-7) were not. We used 4 nationwide studies (n = 11,215 children) from the Norwegian Growth Cohort with longitudinal or cross-sectional anthropometric data up to age 8.5 and 13 years to capture variation in FFV exposure. Outcomes were body mass index standard deviation score (BMISDS), overweight and obesity (OW/OB), waist circumference (WC), and weight to height ratio (WtHR) at age 8.5 years, and BMISDS and OW/OB at age 13 years. Analyses included longitudinal models of the pre- and post-exposure trajectories to estimate the policy effect. The participation rate in each cohort was >80%, and in most analyses ConclusionsIn this study we observed little evidence that the Norwegian nationwide FFV policy had any notable beneficial effect or unintended consequence on weight status among Norwegian children and adolescents.

Male sex and advanced age are associated with severe symptoms of COVID-19. Sex and age also exhibit substantial associations with genome-wide DNA methylation (DNAm) differences in humans. Using a random sample of Illumina EPIC-based genome-wide methylomes from peripheral whole blood of 1,976 parents, participating in The Norwegian Mother, Father and Child Cohort Study (MoBa), we explored whether DNAm in genes linked to SARS-CoV-2 host cell entry and to severe COVID-19 were associated with sex and age. This was carried out by testing 1,572 DNAm sites (CpGs) located near 45 genes for associations with age and sex. We found that DNAm in 281 and 231 of 1,572 CpGs were associated (pFDR

Abstract Background Severe iodine deficiency impacts fertility and reproductive outcomes. The potential effects of mild-to-moderate iodine deficiency are not well known. The aim of this study was to examine whether iodine intake was associated with subfecundity (i.e. > 12 months trying to get pregnant), foetal growth, and adverse pregnancy outcomes in a mild-to-moderately iodine-deficient population. Methods We used the Norwegian Mother, Father and Child Cohort Study (MoBa) and included 78,318 pregnancies with data on iodine intake and pregnancy outcomes. Iodine intake was calculated using an extensive food frequency questionnaire in mid-pregnancy. In addition, urinary iodine concentration was available in a subsample of 2795 pregnancies. Associations were modelled continuously by multivariable regression controlling for a range of confounding factors. Results The median iodine intake from food was 121 μg/day and the median urinary iodine was 69 μg/L, confirming mild-to-moderate iodine deficiency. In non-users of iodine supplements (n = 49,187), low iodine intake (

Abstract Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P

Changes in body mass index (BMI) during infancy and childhood follow a well-characterized pattern. Here, Helgeland et al. perform genome-wide association studies for BMI at 12 time points between birth and 8 years of age and find transient associations at the LEP and LEPR loci.

Abstract Background Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association. Methods We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis. Results Children exposed to acetaminophen up to 28 days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I. = 0.70‐1.08) for exposure 1 to 7 days, and 1.13 (95% C.I. = 0.82–1.49) for 8–28 days. Long‐term exposure (29 days or more) was associated with a two‐fold increase in risk of ADHD diagnosis (aHR = 2.02, 95% C.I = 1.17–3.25). In the sibling control model, the association between long‐term acetaminophen use and ADHD in the child was aHR = 2.77 (95% C.I. = 1.48–5.05) at the between‐family level, and aHR = 1.06 (95% C.I. = 0.51–2.05) at the within‐family level. Conclusions Both the exposed and the unexposed children of mothers with long‐term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long‐term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors.

Abstract Background Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. Methods We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. Results We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4–17.4) for underweight women, 14.5 kg (11.5–17.7) for normal weight women, 13.9 kg (10.1–17.9) for overweight women, and 11.2 kg (7.0–15.7), 8.7 kg (4.3–13.4) and 6.3 kg (1.9–11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. Conclusions Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

BackgroundFetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight.Methods and findingsWe performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations.ConclusionsWe observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

We present a process sequence for the fabrication of ultrathin perforated membranes suspended in polymer frames. Nanoimprint lithography was used to imprint high-density pillar arrays into a double layer consisting of 300 nm of water-soluble PVP and 2–3 μm COC sequentially spin coated onto a silicon wafer. After an RIE step to remove the residual layer and 3D-printing of PLA frames onto the structured COC film, the assemblies were released from the wafer by dissolving the sacrificial PVP bottom layer in water. The suspended membranes were developed as supports for serial protein crystallography, where small amounts of protein microcrystals are deposited onto a membrane and separated from most of their mother liquor through the sieving function of the membranes (blotting). After plunge freezing in liquid nitrogen crystallographic data are collected sequentially from the individual crystals, using X-rays from a synchrotron or femtosecond X-ray pulses of an X-ray free electron laser. Preliminary experiments confirmed that the supports allow for collection of good quality crystallographic data at high resolution, taking advantage of adequate liquid blotting, high stability and low X-ray interaction.

Long-term interfacing with neural tissue is key for the diagnosis and therapy of neurological disorder. Coatings with dedicated micro- and nanostructures have been proposed, such as gold nanowires, platinum nanostructured by electrochemical roughening, columnar and porous titanium nitride, carbon nanotubes, and conductive polymers. The performance of these coatings, however, is limited because of the mechanical mismatch between implant and neural tissue. Herein, we show that micro- and nanostructured, soft and conductive elastomer films can be obtained by depositing gold on nanometer-thin thiol-functionalized polydimethylsiloxane (PDMS) films. Additionally, microstructured polyether ether ketone (PEEK) films enable directional ordering in topology. The formation of soft and conductive PDMS films with oriented wrinkles on the macroscopic scale was controlled by the ratio between the metal/elastomter thicknesses and the depth of thermally imprinted trenches. Four-point probe measurements revealed that the electrical conductivity is one order of magnitude higher than that of recently presented hydrogel formulations. Nano-indentations proved that the submicrometer-thin conductive elastomer exhibit an average elastic modulus well below 10 MPa. This material system can be made tens of micrometers thin, and, therefore, has the potential to address several challenges of current implantable neural interfaces for the central nervous system, e.g. fabrication of softer and more flexible micrometer-thin spinal cord arrays.

Abstract Background An increasing number of children are exposed to road traffic noise levels that may lead to adverse effects on health and daily functioning. Childhood is a period of intense growth and brain maturation, and children may therefore be especially vulnerable to road traffic noise. The objective of the present study was to examine whether road traffic noise was associated with reported inattention symptoms in children, and whether this association was mediated by sleep duration. Methods This study was based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Parental reports of children’s inattention at age 8 were linked to modelled levels of residential road traffic noise. We investigated the association between inattention and noise exposure during pregnancy (n = 1934), noise exposure averaged over 5 years (age 3 to 8 years; n = 1384) and noise exposure at age 8 years (n = 1384), using fractional logit response models. The participants were children from Oslo, Norway. Results An association with inattention at age 8 years was found for road traffic noise exposure at age 8 years (coef = .0083, CI = [.0012, .0154]; 1.2% point increase in inattention score per 10 dB increase in noise level), road traffic noise exposure average for the last 5 years (coef = .0090, CI = [.0016, .0164]; 1.3% point increase/10 dB), and for pregnancy road traffic noise exposure for boys (coef = .0091, CI = [.0010, .0171]), but not girls (coef = −.0021, CI = [−.0094, .0053]). Criteria for doing mediation analyses were not fulfilled. Conclusion Results indicate that road traffic noise has a negative impact on children’s inattention. We found no mediation by sleep duration.

Abstract Background Cell phone use during pregnancy is a public health concern. We investigated the association between maternal cell phone use in pregnancy and child’s language, communication and motor skills at 3 and 5 years. Methods This prospective study includes 45,389 mother-child pairs, participants of the MoBa, recruited at mid-pregnancy from 1999 to 2008. Maternal frequency of cell phone use in early pregnancy and child language, communication and motor skills at 3 and 5 years, were assessed by questionnaires. Logistic regression was used to estimate the associations. Results No cell phone use in early pregnancy was reported by 9.8% of women, while 39%, 46.9% and 4.3% of the women were categorized as low, medium and high cell phone users. Children of cell phone user mothers had 17% (OR = 0.83, 95% CI: 0.77, 0.89) lower adjusted risk of having low sentence complexity at 3 years, compared to children of non-users. The risk was 13%, 22% and 29% lower by low, medium and high maternal cell phone use. Additionally, children of cell phone users had lower risk of low motor skills score at 3 years, compared to children of non-users, but this association was not found at 5 years. We found no association between maternal cell phone use and low communication skills. Conclusions We reported a decreased risk of low language and motor skills at three years in relation to prenatal cell phone use, which might be explained by enhanced maternal-child interaction among cell phone users. No evidence of adverse neurodevelopmental effects of prenatal cell phone use was reported.

BackgroundEarly identification and diagnosis is beneficial for children with autism spectrum disorder (ASD). Universal early screening is recommended by many experts, but disputed because evidence is limited, and sensitivity and specificity in general populations are largely unknown.AimsTo estimate the sensitivity and specificity of early population-based screening for ASDs.MethodThe study was based on the Norwegian Mother and Child Cohort Study. The 36-month cohort questionnaire included the Social Communication Questionnaire (SCQ), a 40-item screening instrument for ASD.ResultsA total of 58 520 mothers (58%) responded to the questionnaire. By the end of follow-up on 31 December 2015, 385 (0.7%) individuals with ASD had been identified among the responders' children. The distributions of SCQ scores in those with ASD and other children had large degrees of overlap. With the cut-off of 15 recommended in the SCQ manual, screening sensitivity was 20% (95% CI 16–24) for ASD overall. For children with ASD who had not developed phrase speech at 36 months, sensitivity was 46% (95% CI 35–57%), whereas it was 13% (95% CI 9–17) for children with ASD with phrase speech. Screening specificity was 99% (95% CI 99–99). With the currently recommended cut-off of 11, sensitivity increased to 42% for ASD overall (95% CI 37–47), 69% (95% CI 58–79) for ASD without phrase speech and 34% (95% CI 29–40) for ASD with phrase speech. Specificity was then reduced to 89% (95% CI 89–90).ConclusionsEarly ASD screening with a parent checklist had low sensitivity. It identified mainly individuals with ASD with significant developmental delay and captured very few children with ASD with cognitive skills in the normal range. Increasing sensitivity was not possible without severely compromising specificity.Declaration of interestC.L. receives royalty for the Social Communication Questionnaire, which she has co-authored.

Background Evidence linking individual‐level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996–2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000–2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non–folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80–1.22), 1.08 (95% CI, 0.93–1.25), and 1.07 (95% CI, 0.97–1.19), respectively. For initiation of folic acid in the preconception period weeks −4 to −1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI, 1.00–1.25), 1.09 (95% CI, 0.95–1.25), 0.98 (95% CI, 0.86–1.12), and 0.97 (95% CI, 0.78–1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.