Child Cohort Study Research Articles

Low perceived social support in mothers during pregnancy and early childhood; associations with anxiety and ADHD symptoms in children at 3 and 8 years.

Low perceived social support is associated with adverse effects on maternal mental health, and often coexists with other risk factors for offspring anxiety and attention-deficit/hyperactivity disorder (ADHD). We aimed to investigate whether low maternal social support during pregnancy and early childhood predicted anxiety and ADHD symptoms in children at ages 3.5 and 8 years. This study is part of the longitudinal, population-based Norwegian Mother, Father, and Child Cohort Study. Mothers were queried about perceived social support twice during pregnancy, and again at child ages 18 months and 3 years. They were interviewed about their children's symptoms of anxiety and ADHD at 3.5 years. At 8 years (n = 781), the Child Symptom Inventory-4 was used to identify children who fulfilled the criteria for anxiety disorders and ADHD. Logistic regression models estimated the risk of child anxiety and ADHD, depending on maternal social support. Low maternal social support predicted child anxiety symptoms at both ages 3.5 and 8 years as well as ADHD symptoms at 8 years. When including other maternal stressors and child risk factors, low maternal social support remained a significant predictor for child anxiety symptoms at 3.5 years, and there was a trend towards also predicting child anxiety and ADHD symptoms at 8 years. The associations between low maternal social support and child symptoms of anxiety and ADHD found in the present study, suggest that focusing on mothers with low social support may hold significance for child symptoms years later.

Bayesian additive regression trees for predicting childhood asthma in the CHILD cohort study

BackgroundAsthma is a heterogeneous disease that affects millions of children and adults. There is a lack of objective gold standard diagnosis that spans the ages; instead, diagnoses are made by clinician assessment based on a cluster of signs, symptoms and objective tests dependent on age. Yet, there is a clear morbidity associated with chronic asthma symptoms. Machine learning has become a popular tool to improve asthma diagnosis and classification. There is a paucity of literature on the use of Bayesian machine learning algorithms to predict asthma diagnosis in children. This paper develops a prediction model using the Bayesian additive regression trees (BART) and compares its performance to various machine learning algorithms in predicting the diagnosis of childhood asthma.MethodsClinically relevant variables collected at or before 3 years of age from 2794 participants in the CHILD Cohort Study were used to predict physician-diagnosed asthma at age 5. BART and six other commonly used machine learning algorithms, namely adaptive boosting, logistic regression, decision tree, neural network, random forest, and support vector machine were trained. Measures of performance including sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve were calculated. The confidence intervals were calculated using Bootstrapping samples. Important predictors and interaction effects associated with asthma were also identified using BART.ResultsBART, logistic regression and random forest showed the highest area under the ROC curve compared to other machine learning algorithms. Based on BART, recurrent wheeze, respiratory infection and food sensitization at 3 years of age were the most important predictors. The three most important interaction effects were found to be interaction terms of respiratory infection at 3 years and recurrent wheezing at 3 years, maternal asthma and paternal asthma, and maternal wheezing and inhalant sensitization of child at 3 years.ConclusionsBART demonstrated promising prediction performance when compared to other machine learning algorithms. Future research could validate the BART in an external cohort to evaluate its reliability and generalizability.

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

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

Epigenetic aging and fecundability: the Norwegian Mother, Father and Child Cohort Study.

Is there an association between male or female epigenetic age acceleration (EAA) or deceleration (EAD) and fecundability? We do not find compelling evidence of an association between EAA or EAD and fecundability. Prior research has shown that female accelerated epigenetic aging is associated with unfavorable clinical fecundity outcomes and use of in vitro fertilization, and that epigenetic aging in sperm cells is associated with unfavorable sperm parameters. Studies of epigenetic aging and fecundability among individuals who conceive naturally are lacking. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based pregnancy cohort which recruited pregnant couples between 1999 and 2008. We used data from 1657 couples (women and men) with planned naturally conceived pregnancies and available blood samples. Methylation levels were measured in DNA from blood samples taken recruitment (at ∼18 gestational weeks) from pregnant women and their partners using the Illumina Methylation EPIC Array. To obtain a measure of EAA/EAD, we performed a linear regression of each of seven different established epigenetic biomarkers (DNAmAge by Horvath, DNAmAge by Hannum et al., PhenoAge by Levine et al., DunedinPoAm by Belsky et al., DunedinPACE by Belsky et al., DNAmTL by Lu et al., and GrimAge by Lu et al.) against chronological age. We fitted proportional probability regression models to obtain fecundability ratios (FRs) for each standard deviation increase in epigenetic aging, and obtained crude and adjusted (for body mass index, smoking, and education level) estimates. Results were evaluated at a false discovery rate (FDR) of 5%. We evaluated all models for non-linear associations using categories of epigenetic age where appropriate. Although the DunedinPACE clock in males demonstrated slightly increasing fecundability with increasing EAA (adjusted FR 1.05 per one standard deviation increase in EAA, 95% CI 1.00-1.10), this was not robust when evaluated at an FDR of 5%. We found evidence of non-linearity between biological aging and fecundability in two models in females and three models in males, but non-linear associations were weak and conflicting. As MoBa is a pregnancy cohort, our findings may not be generalizable to all couples attempting conception. Fecundability is a couple-level measure, and any impacts of epigenetic aging in each partner may be obscured by effects of the other partner. Our findings contrast with those of prior studies, which have indicated an association between EAA and unfavorable clinical fertility outcomes in populations using fertility treatments, possibly due to less important effects of epigenetic aging among couples who conceive naturally. More research is needed on the association between blood-based EAA and clinical fertility parameters in both sexes. The study was supported by the Research Council of Norway through its Medical Student Research Program funding scheme (project number 271555/F20), its Centres of Excellence funding scheme (project number 262700), and a grant from the Women's Health Program (320656). Co-funding was also received from the Strategic Research Council (SRC), FLUX consortium, decision numbers 345130 and 345131; the National Institute on Aging (R01AG075208); grants to the Max Planck-University of Helsinki Center from the Max Planck Society (decision number 5714240218), Jane and Aatos Erkko Foundation, Faculty of Social Sciences at the University of Helsinki, and Cities of Helsinki, Vantaa, and Espoo; and the European Research Council; and the European Research Council (ERC Synergy, BIOSFER, grant number 101071773, and the Horizon 2020 research and innovation program, grant number 947684). The authors declare no conflicts of interest. N/A.

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

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

Incidence and genetic risk of juvenile idiopathic arthritis in Norway by latitude.

We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographical regions of Norway, and whether potential regional incidence differences are explained by environmental or genetic factors across regions. We conducted a register-based cohort study including all Norwegian children born 2004-2019, with follow-up throughout 2020. The JIA diagnosis defined by ≥ 2 ICD-10 codes for JIA was validated against medical records. The incidence rate (IR) and hazard ratio (HR) for JIA were estimated for all Norway, and for the regions North, Mid, and South. In a sub-sample from the Norwegian Mother, Father, and Child Cohort Study (MoBa), the genetic risk for JIA was assessed in the three regions. After median 9.1 (range 0.3-16.0) years of follow-up, we identified 1184 JIA cases and 910058 controls. The IR for JIA/100 000 person-years was 14.4 in all of Norway; 25.9 in region North, 17.9 in region Mid and 12.5 in region South. The HR (95% CI) of JIA in region North was 2.07 (1.77-2.43) and in region Mid 1.43 (1.23-1.67) compared to region South. Adjustments for perinatal factors, socioeconomic status, and early antibiotic exposure did not change our estimates substantially. In MoBa (238 cases, 57392 controls), the association between JIA and region of birth was no longer significant when adjusting for genetic factors. We found a higher incidence of JIA with increasing latitude, without evidence for available environmental factors explaining the observed gradient. In contrast, genetic factors modified the association, but further studies are warranted.

From Fetus to Eight: the CHILD Cohort Study.

The CHILD Cohort Study is an active multi-center longitudinal, prospective, population pregnancy cohort study following Canadian infants from fetal life until adulthood. We hypothesized that early life physical and psychosocial environments interact with biological factors (e.g. immunologic, genetic, physiologic, and metabolic) influencing burdensome non-communicable disease outcomes, including asthma and allergic disorders, growth and development, cardio-metabolic health, and neurodevelopmental outcomes that manifest during the life-course. Detailed clinical and physiologic phenotyping at strategic intervals was complemented by environmental sampling, actigraphy and global positioning system measures, biological sampling including gut, breastmilk and nasal microbiome, nutritional studies, genetics, and epigenetic profiling. Of 3,454 families recruited from 2008 to 2012, study retention was 96.0% at 1-year, 93.2% at 5-years and 90.7% at 8-years. Data collection during the SARS-2 COVID-19 pandemic was partially completed via virtual visits. A sub-cohort was implemented, capturing detailed information on the prevalence and predictors of SARS-CoV-2 infection and the health and psychosocial impact of the pandemic on Canadian families. The 13-year clinical assessment launched in 2022 will be completed in 2025. Ultimately, the CHILD Cohort Study provides a data science platform designed to enable a deep understanding of early life factors associated with the development of chronic non-communicable diseases and multimorbidity.

Sex differences in DNA methylation variations according to ART conception-evidence from the Norwegian mother, father, and child cohort study

Previous studies have shown cord-blood DNA methylation differences in newborns conceived using assisted reproductive technologies (ART) compared to those conceived naturally. However, whether these ART-related DNA methylation differences vary with children’s sex is unknown. We hypothesize that the DNA methylation differences in cord blood between ART-conceived and naturally conceived newborns also varies by the sex of the child, with distinct patterns of differential methylation present in males and females. We investigated sex differences in cord-blood DNA methylation variation according to conception by ART using the Illumina MethylationEPIC platform, comparing 456 ART-conceived versus 507 naturally-conceived girls, and 503 ART-conceived and 473 naturally-conceived boys. We identified 37 differentially methylated CpGs according to ART-conception among girls, and 70 differentially methylated CpGs according to ART-conception among boys, when we used a 1% false discovery rate to account for multiple testing. Ten CpGs were differentially methylated according to conception by ART in both sexes. Among the genes that were associated with these CpGs, we found the BRCA1; NBR2 gene (two CpGs) was hypermethylated in girls while the APC2 (two CpGs) and NECAB3;ACTL10, (four CpGs) related to cellular signaling were hypomethylated in boys. These findings confirm the presence of sex-specific epigenetic differences, illustrating the nuanced impact of ART on the fetal epigenome. There is a need for further explorations into the implications for sex-specific developmental trajectories and health outcomes in ART-conceived children.

Feeding Method, Nicotine Exposure, and Growth during Infancy

ObjectiveTo answer three questions: 1) Are infants breastfed by smokers at risk of rapid weight and length gain? 2) Is rapid growth during infancy partially attributable to ingestion of smokers’ breastmilk? 3) If so, what are the implications for breastfeeding by smokers? Study DesignUsing data from the Norwegian Mother, Father and Child Cohort Study and Medical Birth Registry of Norway (N=54,522) we examined changes in weight, length, weight-for-length z-score (WFLZ) during infancy in the context of maternal smoking (0, 1-10, >10 cigarettes/day) and feeding method during the first 6 months (breastfed, formula-fed, mixed-fed). We fit generalized linear models, adding a smoking by feeding method interaction term to evaluate the effect of ingesting smokers’ breastmilk. ResultsBreastfed infants of both light and heavy smokers experienced WFLZ gains of 0.05 (95% CI: 0.01, 0.09), and 0.13(95% CI: 0.07, 0.18) respectively. Among mixed-fed infants, only heavy maternal smoking predicted WFLZ gain (0.10; 95% CI: 0.05, 0.16). Among exclusively formula-fed infants maternal smoking did not predict rapid growth. Interaction models suggest that infants ever-breastfed (i.e., breastfed and mixed-fed groups combined) by heavy smokers gained weight (100 grams; 95%CI: 30, 231) and length (2.8 mm; 95%CI:0.1, 5.6) attributable to ingesting smoker’s breastmilk. ConclusionsInfants breastfed by smokers experience rapid growth, some of these gains are attributable to ingesting smokers’ breastmilk. Among infants breasted by light smokers, these gains are within the range of normative growth patterns for healthy, breastfed infants.

Antenatal anti-D prophylaxis and D antigen negativity in pregnant women of the UAE: a cross-sectional analysis from the Mutaba’ah Study

ObjectiveThis study aimed to determine the prevalence of the negative D antigen phenotype, adherence to routine antenatal anti-D immunoglobulin prophylaxis (RAADP) administration and D antigen sensitisation among pregnant women in...

Associations of Pregnancy Dietary Quality and Diversity with Childhood Celiac Disease

BackgroundHigh gluten and low dietary fiber in pregnancy intake is associated with an increased risk of celiac disease (CeD) in the child. Early life higher dietary quality is suggested to reduce the subsequent risk of CeD. ObjectivesThe aim was to investigate associations of pregnancy dietary quality and diversity with child risk of CeD. MethodsIn The Norwegian Mother, Father and Child Cohort Study, 85,122 mother-child pairs had available data from a validated pregnancy food frequency questionnaire. Pregnancy dietary quality and diversity were estimated by a Pregnancy Healthy Eating Index [mean 99.3, standard deviation (SD) 9.9, range 48.8–128.3], and a Diet Diversity Score (mean 7.0, SD 1.0, range 1.6–9.8), respectively. Child CeD was captured by ≥2 diagnostic codes in the Norwegian Patient Registry. Logistic regression was used to estimate associations between pregnancy dietary quality, diversity and child CeD, adjusted for socioeconomic factors, and parents CeD [adjusted odds ratio (aOR), 95% confidence intervals (CI)]. CeD-susceptible human leukocyte antigen haplotypes (DQ2/DQ8) were present in 30,718 (45.5%). ResultsUp to mean age 16.0 (SD 1.8, 12.4–19.8) y, 1363 (1.6%) children were diagnosed with CeD. Lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD in the child (<5th percentile aOR = 0.67, 95% CI: 0.48, 0.93, >95th percentile aOR = 0.71, 95% CI: 0.52, 0.98, respectively, nonlinear squared term P = 0.011). Analyses on genetically susceptible children, adjustments for pregnancy iron supplementation, gluten, and dietary fiber intake, and child early life dietary quality, gluten intake and iron supplementation, supported the finding. Pregnancy dietary diversity was not associated with child CeD (aOR = 1.00, 95% CI: 0.94, 1.07/score). ConclusionsIn this population-based study, lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD diagnosis in the child. In contrast, no such association was observed with maternal dietary diversity.

Human milk feeding practices and serum immune profiles of one-year-old infants in the CHILD birth cohort study

Breastfeeding and human milk consumption are associated with immune system development; however, the underlying mechanisms and the impact of different infant feeding practices are unclear. This study aimed to investigate how current human milk feeding (HMF) status is related to infant immune biomarker profiles, and explore relationships with HMF history (i.e., duration, exclusivity, and method: directly from the breast, or pumped and bottled). This observational birth cohort study involved 605 infants from the Canadian CHILD Cohort Study. Infant feeding was captured from hospital birth records and parent questionnaires. Ninety-two biomarkers reflecting immune system activity and development were measured in serum collected at one year (12.6±1.4 months) using the Olink Target 96 Inflammation panel. Associations were determined using multivariable regression (adjusted for sex, time until blood sample centrifugation, and study site). Nearly half (42.6%) of infants were still HMF at the time of blood sampling. Compared to non-HMF infants, HMF infants had higher levels of serum Fibroblast Growth Factor 21 (FGF-21, adjusted standardized β-coefficient=0.56; 95%CI=0.41,0.72), Cluster of Differentiation 244 (CD244, β=0.35; 0.19,0.50), Chemokine Ligand 6 (CXCL6, β=0.34; 0.18,0.50), and Chemokine Ligand 20 (CCL20, β=0.26; 0.09,0.42), and lower Extracellular Newly Identified Receptor for Advanced Glycation End-Products Binding Protein (EN-RAGE, β=-0.16; -0.29,-0.03). Among non-HMF infants, serum Interleukin 7 (IL-7) had a marginally positive association with past HMF duration (β=0.05; 0.02,0.08) that persisted for up to five months post-HMF cessation. Exclusive HMF duration and HMF method (at three months of age) were not associated with any biomarkers. Current HMF status and (to a lesser extent) HMF history are associated with several inflammation-associated biomarkers in one-year-old infants. These results provide new evidence that HMF impacts immune activity and development and suggest hypotheses about the underlying mechanisms. They also highlight the importance of including current HMF status in immune-system-focused infant serum proteomic studies.

Psychological and social difficulties in young non-help-seeking adolescents at risk for psychosis: insights from a large cohort study.

This study used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), and explored the psychological and social challenges of 14-year-olds who report psychotic symptoms. Research on help-seeking youths indicates comorbid symptoms of depression, anxiety, and social deterioration, but less is known about non-help-seeking individuals who may not use healthcare services, possibly skewing comorbidity profiles. Also, findings suggest that adolescents manifesting psychotic symptoms refrain from pursuing help. This gap underscores the necessity of studying non-help-seeking adolescents to better understand their needs and the risks they face without intervention. We analyzed responses from adolescents who completed the 14-year questionnaire in MoBa (N = 127), identifying those as at risk by their high scores on psychosis-risk items, within the top 0.4% (N = 58). Comparative analyses were conducted against matched controls to assess differences in psychological and social functioning (N = 69). Results indicated that the at-risk adolescents experience significantly more depression and anxiety and have lower self-esteem and poorer social functioning than controls. Social functioning parameters, including leisure activities, social competence, quality of parental relationship, and sense of school belonging, were significantly worse than those observed in controls. The results indicate a pronounced vulnerability among non-help-seeking adolescents at-risk, similar to issues seen in help-seeking youths. These findings highlight the importance of early identification and intervention strategies that reach beyond traditional clinical settings, suggesting the efficacy of population or community-based screenings to prevent long-term adverse outcomes. The study proposes a broader understanding of psychosis risk, stressing the importance of inclusive approaches to support at-risk adolescents effectively.

Networks of human milk microbiota are associated with host genomics, childhood asthma, and allergic sensitization

The human milk microbiota (HMM) is thought to influence the long-term health of offspring. However, its role in asthma and atopy and the impact of host genomics on HMM composition remain unclear. Through the CHILD Cohort Study, we followed 885 pregnant mothers and their offspring from birth to 5 years and determined that HMM was associated with maternal genomics and prevalence of childhood asthma and allergic sensitization (atopy) among human milk-fed infants. Network analysis identified modules of correlated microbes in human milk that were associated with subsequent asthma and atopy in preschool-aged children. Moreover, reduced alpha-diversity and increased Lawsonella abundance in HMM were associated with increased prevalence of childhood atopy. Genome-wide association studies (GWASs) identified maternal genetic loci (e.g., ADAMTS8, NPR1, and COTL1) associated with HMM implicated with asthma and atopy, notably Lawsonella and alpha-diversity. Thus, our study elucidates the role of host genomics on the HMM and its potential impact on childhood asthma and atopy.

Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children

Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e–118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6′-sialyllactose (P = 2.2e–9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P < 0.01). Thus, we report novel genetic factors associated with HMOs, some of which may protect the respiratory health of children.

Mendelian randomization analysis of maternal coffee consumption during pregnancy on offspring neurodevelopmental difficulties in the Norwegian Mother, Father and Child Cohort Study (MoBa).

Previous observational epidemiological studies have suggested that coffee consumption during pregnancy may affect fetal neurodevelopment. However, results are inconsistent and may represent correlational rather than causal relationships. The present study investigated whether maternal coffee consumption was observationally associated and causally related to offspring childhood neurodevelopmental difficulties (NDs) in the Norwegian Mother, Father and Child Cohort Study. The observational relationships between maternal/paternal coffee consumption (before and during pregnancy) and offspring NDs were assessed using linear regression analyses (N = 58694 mother-child duos; N = 22 576 father-child duos). To investigate potential causal relationships, individual-level (N = 46 245 mother-child duos) and two-sample Mendelian randomization (MR) analyses were conducted using genetic variants previously associated with coffee consumption as instrumental variables. We observed positive associations between maternal coffee consumption and offspring difficulties with social-communication/behavioral flexibility, and inattention/hyperactive-impulsive behavior (multiple testing corrected p < 0.005). Paternal coffee consumption (negative control) was not observationally associated with the outcomes. After adjusting for potential confounders (smoking, alcohol, education and income), the maternal associations attenuated to the null. MR analyses suggested that increased maternal coffee consumption was causally associated with social-communication difficulties (individual-level: beta = 0.128, se = 0.043, p = 0.003; two-sample: beta = 0.348, se = 0.141, p = 0.010). However, individual-level MR analyses that modelled potential pleiotropic pathways found the effect diminished (beta = 0.088, se = 0.049, p = 0.071). Individual-level MR analyses yielded similar estimates (heterogeneity p = 0.619) for the causal effect of coffee consumption on social communication difficulties in maternal coffee consumers (beta = 0.153, se = 0.071, p = 0.032) and non-consumers (beta = 0.107, se = 0.134, p = 0.424). Together, our results provide little evidence for a causal effect of maternal coffee consumption on offspring NDs.

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

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

Machine learning approach to investigate pregnancy and childbirth risk factors of sleep problems in early adolescence: Evidence from two cohort studies

BackgroundThis study aimed to predict early adolescent sleep problems using pregnancy and childbirth risk factors through machine learning algorithms, and to evaluate model performance internally and externally. MethodsData from the China Jintan Child Cohort study (CJCC; n=848) for model development and the US Healthy Brain and Behavior Study (HBBS; n=454) for external validation were employed. Maternal pregnancy histories, obstetric data, and adolescent sleep problems were collected. Several machine learning techniques were employed, including least absolute shrinkage and selection operator, logistic regression, random forest, naïve bayes, extreme gradient boosting, decision tree, and neural network. The area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, and root mean square of residuals were used to evaluate model performance. ResultsKey predictors for CJCC adolescents’ sleep problems include gestational age, birthweight, duration of delivery, and maternal happiness during pregnancy. In HBBS adolescents, the duration of postnatal depressive emotions was the primary perinatal predictor. The prediction models developed in the CJCC had good-to-excellent internal validation performance but poor performance in predicting the sleep problems in HBBS adolescents. ConclusionThe identification of specific perinatal risk factors associated with adolescent sleep problems can inform targeted interventions during and after pregnancy to mitigate these risks. Health providers should consider integrating these predictive factors into routine pre- and postnatal assessments to identify at-risk populations. The variability in model performance across different cohorts highlights the need for context-specific models and the cautious application of predictive analytics across diverse populations. Future research should focus on refining predictive models to account for such variations, potentially through the incorporation of additional socio-cultural factors and genetic markers. This study emphasizes the importance of personalized and culturally sensitive approaches in the prediction and management of adolescent sleep problems, leveraging advanced computational methods to enhance maternal and child health outcomes.

Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common. To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR). This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024. Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices. Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control. The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP. The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

Growth Restriction in the Offspring of Mothers With Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, characterized by subfertility, increased risk of metabolic diseases, and pregnancy complications. Previous studies diverge regarding the association between maternal PCOS and newborn anthropometrics. To explore the association between maternal PCOS and newborn anthropometrics and the modifying effects of maternal body mass index, PCOS phenotype, and gestational diabetes. This cohort study followed up women from the first half of pregnancy to birth and combined data from 3 clinical trials of pregnant women with PCOS and a reference population consisting of participants in the Norwegian Mother, Father, and Child Cohort (MoBa) Study, with data from the Medical Birth Registry of Norway. The recruitment period for the clinical trials was between October 1, 2000, and August 31, 2017, and for MoBa, between July 1, 1999, and December 31, 2008. Participants included women with singleton pregnancies and live-born children. Data were analyzed from January 1 to June 15, 2023. Maternal PCOS status. Newborn birth weight, birth length, and head circumference as continuous variables and z scores, and ponderal index (calculated as the birth weight in grams × 100 divided by the birth length in centimeters cubed), placenta weight, and ratio of birth weight to placenta weight (BWPW). The cohort included 390 pregnant women with PCOS (mean [SD] age, 29.6 [4.2] years) and 68 708 women in the reference group (mean [SD] age, 30.4 [4.5] years). Offspring in the PCOS group had lower birth weight, birth length, and head circumference than in the reference group offspring. The estimated mean differences in z scores were -0.26 (95% CI, -0.38 to -0.14) for birth weight, -0.19 (95% CI, -0.33 to -0.05) for birth length, and -0.13 (95% CI, -0.26 to -0.01) for head circumference. The PCOS group also had a lower ponderal index (-0.04 [95% CI, -0.07 to -0.004] g × 100/cm3) and placenta weight (-24 [95% CI, -43 to -5)] g), and higher BWPW ratio (0.4 [95% CI, 0.3 to 0.5]). The association between growth restriction and PCOS was more apparent when additionally adjusting for body mass index. Neither PCOS phenotype nor gestational diabetes diagnosis was associated with neonatal anthropometry in women with PCOS. In this cohort of mother-infant pairs, maternal PCOS status was associated with lower birth weight, shorter birth length, and smaller head circumference in the offspring. This growth restriction was more pronounced when adjusting for BMI, providing insight into the association between PCOS and body mass index. The study contributed to the understanding of how PCOS affects the offspring.