Parental fecundability and neurodevelopmental delays and difficulties in offspring

Background: Impaired neurodevelopment is reported among children conceived by assisted reproductive technologies (ART). However, this might be explained by conditions underlying parental subfecundity, rather than the ART procedure. Methods: We examined associations of parental time-to-pregnancy (TTP) and conception by ART with neurodevelopmental traits up to 8 years of age, including motor and language skills, social delays and difficulties, and inattention-hyperactivity, among 92 142 singletons participating in the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported TTP and neurodevelopmental traits through questionnaires. Mean differences in standardized neurodevelopmental traits were estimated using linear regression, adjusting for maternal age, parity, educational level, body mass index and smoking, and paternal age. Results: A longer TTP was associated with decreased language skills and motor skills at 6, 18 and 36 months (P-values for trend ≤0.01), prosocial skills delay at 36 months (P-values for trend ≤0.001) and increased scores for inattention-hyperactivity traits at all ages up to 8 years (P-values for trend from 0.06 to 0.01). Effect sizes were small, ranging between 0.03 and 0.05 difference in the standardized neurodevelopmental scores. Estimates for ART were imprecise, but there were no differences between children conceived by ART and naturally conceived children of subfecund parents (TTP ≥12 months). Conclusions: Longer parental TTP is modestly but robustly associated with offspring neurodevelopmental delays and difficulties, with no added impact of ART. Future studies should investigate the underlying causes of—or aspects related to—parental subfecundity which might explain the association with offspring neurodevelopmental delays and difficulties

Prenatal Mercury Exposure and Neurodevelopment up to the Age of 5 Years:A Systematic Review

Neurodevelopmental delays can interfere with children’s engagement with the world and further development, and may have negative consequences into adulthood. Mercury is highly toxic and may negatively influence neurodevelopment because it can freely cross the placenta and accumulate in the fetal brain. We searched four publication databases (Embase, PsycINFO, PubMed/MEDLINE, Scopus) for studies examining the relationship between early life mercury exposure and scores on neurodevelopmental performance measures in children aged 0 to 5 years old. Study quality was assessed using the National Institutes of Health (NIH) Quality Assessment Tool. Thirty-two prospective studies were included in the review. Neurodevelopmental performance was measured using 23 different scales, most commonly the Bayley Scales of Infant and Toddler Development (BSID). In most cases, the evidence for an association between mercury and neurodevelopment was weak. There did not appear to be exceptions for particular childhood ages, outcome scales, or mercury levels. The small number of results to the contrary were more likely to be studies which did not meet our high-quality criteria, and could be a consequence of multiple testing, selection bias, or incomplete confounder adjustment. Based on current evidence, dietary mercury exposure during pregnancy is unlikely to be a risk factor for low neurodevelopmental functioning in early childhood

Mercury and Prenatal Growth: A Systematic Review

The intrauterine environment is critical for healthy prenatal growth and affects neonatal survival and later health. Mercury is a toxic metal which can freely cross the placenta and disrupt a wide range of cellular processes. Many observational studies have investigated mercury exposure and prenatal growth, but no prior review has synthesised this evidence. Four relevant publication databases (Embase, MEDLINE/PubMed, PsycINFO, and Scopus) were systematically searched to identify studies of prenatal mercury exposure and birth weight, birth length, or head circumference. Study quality was assessed using the NIH Quality Assessment Tool, and results synthesised in a narrative review. Twenty-seven studies met the review criteria, these were in 17 countries and used 8 types of mercury biomarker. Studies of birth weight (total = 27) involving populations with high levels of mercury exposure, non-linear methods, or identified as high quality were more likely to report an association with mercury, but overall results were inconsistent. Most studies reported no strong evidence of association between mercury and birth length (n = 14) or head circumference (n = 14). Overall, our review did not identify strong evidence that mercury exposure leads to impaired prenatal growth, although there was some evidence of a negative association of mercury with birth weight

Investigating causality in the association between vitamin D status and self-reported tiredness

Abstract Self-reported tiredness or low energy, often referred to as fatigue, has been linked to low levels of circulating 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status. Although it is uncertain if the association is causal, fatigue is a common indication for testing, and correcting, low 25OHD-levels. We used two-sample Mendelian randomization to test for genetic evidence of a causal association between low 25OHD-levels and fatigue. Genetic-25OHD associations were estimated from the largest genome-wide association study of vitamin D to date, and genetic-fatigue associations were estimated in 327,478 individuals of European descent in UK Biobank, of whom 19,526 (5.96%) reported fatigue (tiredness or low energy nearly every day over the past two weeks). Using seven genome-wide significant 25OHD-reducing genetic variants, there was little evidence for a causal effect of 25OHD on fatigue (odds ratio for fatigue was 1.05 with 95% confidence interval of 0.87–1.27 per 1-SD decrease in log-transformed 25OHD). There was also little evidence of association between any individual 25OHD-reducing variant and fatigue. Our results suggest that a clinically relevant protective effect of 25OHD-levels on fatigue is unlikely. Therefore, vitamin D supplementation of the general population to raise 25OHD-levels is not likely to be useful in preventing fatigue

Risk of miscarriage in women with psychiatric disorders

Background Some psychiatric disorders have been associated with increased risk of miscarriage. However, there is a lack of studies considering a broader spectrum of psychiatric disorders to clarify the role of common as opposed to independent mechanisms. Aims To examine the risk of miscarriage among women diagnosed with psychiatric conditions. Method We studied registered pregnancies in Norway between 2010 and 2016 (n = 593 009). The birth registry captures pregnancies ending in gestational week 12 or later, and the patient and general practitioner databases were used to identify miscarriages and induced abortions before 12 gestational weeks. Odds ratios of miscarriage according to 12 psychiatric diagnoses were calculated by logistic regression. Miscarriage risk was increased among women with bipolar disorders (adjusted odds ratio 1.35, 95% CI 1.26–1.44), personality disorders (adjusted odds ratio 1.32, 95% CI 1.12–1.55), attention-deficit hyperactivity disorder (adjusted odds ratio 1.27, 95% CI 1.21–1.33), conduct disorders (1.21, 95% CI 1.01, 1.46), anxiety disorders (adjusted odds ratio 1.25, 95% CI 1.23–1.28), depressive disorders (adjusted odds ratio 1.25, 95% CI 1.23–1.27), somatoform disorders (adjusted odds ratio 1.18, 95% CI 1.07–1.31) and eating disorders (adjusted odds ratio 1.14, 95% CI 1.08–1.22). The miscarriage risk was further increased among women with more than one psychiatric diagnosis. Our findings were robust to adjustment for other psychiatric diagnoses, chronic somatic disorders and substance use disorders. After mutual adjustment for co-occurring psychiatric disorders, we also observed a modest increased risk among women with schizophrenia spectrum disorders (adjusted odds ratio 1.22, 95% CI 1.03–1.44). Conclusions A wide range of psychiatric disorders were associated with increased risk of miscarriage. The heightened risk of miscarriage among women diagnosed with psychiatric disorders highlights the need for awareness and surveillance of this risk group in antenatal care.acceptedVersio

Genetic liability to schizophrenia is associated with exposure to traumatic events in childhood

Background There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene–environment correlation. Methods The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0–17 years; ALSPAC) and at age 8 years (MoBa). Results Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure. Conclusions Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment

Subdimensions of social-communication impairment in autism spectrum disorder

BACKGROUND: More refined dimensions of social-communication impairment are needed to elucidate the clinical and biological boundaries of autism spectrum disorders (ASD) and other childhood onset psychiatric disorders associated with social difficulties, as well as to facilitate investigations in treatment and long-term outcomes of these disorders. METHODS: The current study was intended to identify separable dimensions of clinician-observed, social-communication impairments by examining scores on a widely used autism diagnostic instrument. Participants included verbally fluent children ages 3 to 13 years, who were given a clinical diagnosis of ASD (n=120) or non-ASD (i.e., ADHD, language disorder, intellectual disability, mood or anxiety disorder; n=118) following a comprehensive diagnostic assessment. Exploratory and confirmatory factor analysis examined the factor structure of algorithm items from the Autism Diagnostic Observation Schedule (ADOS), Module 3. RESULTS: Results indicated that a three-factor model consisting of repetitive behaviors and two separate social-communication behavior factors had superior fit compared to a two-factor model that included repetitive behaviors and one social-communication behavior factor. In the three-factor model, impairments in ‘Basic Social-Communication’ behaviors (e.g., eye contact, facial expressions, gestures) were separated from impairments in ‘Interaction quality.’ Confirmatory factor analysis in an independent sample of children in the Simons Simplex Collection (SSC) further supported the division of social-communication impairments into these two factors. Scores in Interaction Quality were significantly associated with nonverbal IQ and male sex in the ASD group, and with age in the non-ASD group, while scores in basic social communication were not significantly associated with any of these child characteristics in either diagnostic group. CONCLUSIONS: Efforts to conceptualize level, or severity, of social-communication impairment in children with neurodevelopmental disorders might be facilitated by separating the most basic (or proximal) social-communication impairments, from those that could arise from a range of other phenotypic variables. Identification of social-communication subdimensions also highlights potential avenues for measuring different types of social-communication impairments for different purposes (e.g., for differential diagnosis vs. response to treatment)

Social and genetic associations with educational performance in a Scandinavian welfare state

Recent research has suggested that across Western developed societies, the influence of genetics on educational outcomes is relatively constant. However, the degree to which family environment matters varies, such that countries with high levels of intergenerational mobility have weaker associations of family background. Research in this vein has relied on twin-based estimates, which involve variance decomposition, so direct assessment of the association of genes and environments is not possible. In the present study, we approach the question by directly measuring the impact of child genotype, parental genetic nurture, and parental realized education on educational achievement in primary and secondary school. We deploy data from a social democratic context (Norway) and contrast our findings with those derived from more liberal welfare state contexts. Results point to genetics only confounding the relationship between parent status and offspring achievement to a small degree. Genetic nurture associations are similar to those in other societies. We find no, or very small, gene–environment interactions and parent–child genotype interactions with respect to test scores. In sum, in a Scandinavian welfare state context, both genetic and environmental associations are of similar magnitude as in societies with less-robust efforts to mitigate the influence of family background.publishedVersio

Prenatal smoking, alcohol and caffeine exposure and maternal-reported attention deficit hyperactivity disorder symptoms in childhood:triangulation of evidence using negative control and polygenic risk score analyses

Background and aims Studies have indicated that maternal prenatal substance use may be associated with offspring attention deficit hyperactivity disorder (ADHD) via intrauterine effects. We measured associations between prenatal smoking, alcohol and caffeine consumption with childhood ADHD symptoms accounting for shared familial factors. Design First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders), adjusted (including confounders) and mutually adjusted (including confounders and partner's substance use). The results were meta-analysed across the cohorts. Secondly, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for smoking, alcohol and coffee consumption were regressed against ADHD symptoms. We triangulated the results across the two approaches to infer causality. Setting We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. Participants Phenotype data available for children were: NALSPAC = 5455–7751; NGENR = 1537–3119; NMOBA = 28 053–42 206. Genotype data available for mothers was: NALSPAC = 7074; NMOBA = 14 583. Measurements A measure of offspring ADHD symptoms at age 7–8 years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. Findings The pooled estimate for maternal prenatal substance use showed an association with total ADHD symptoms [odds ratio (OR)SMOKING = 1.11, 95% confidence interval (CI) = 1.00–1.23; ORALCOHOL = 1.27, 95% CI = 1.08–1.49; ORCAFFEINE = 1.05, 95% CI = 1.00–1.11], while not for fathers (ORSMOKING = 1.03, 95% CI = 0.95–1.13; ORALCOHOL = 0.83, 95% CI = 0.47–1.48; ORCAFFEINE = 1.02, 95% CI = 0.97–1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD symptoms in MoBa). The PRS analyses were inconclusive for an association in ALSPAC or MoBa. Conclusions There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms