Attention-deficit/hyperactivity Disorder In Offspring Research Articles

Maternal asthma and asthma exacerbation during pregnancy and attention-deficit/hyperactivity disorder in offspring: a population-based cohort study.

The link between inflammatory disorders, such as asthma, and attention deficit hyperactivity disorder (ADHD) is attracting increasing attention but few studies have examined cross-generational associations. We sought to examine associations of maternal asthma and asthma exacerbation during pregnancy, as well as paternal asthma, with the risk of ADHD in children. This population-based cohort study used data from the Taiwan National Health Insurance Research Database from 2004 to 2017. Cox regression models compared the risk of ADHD in children of parents with and without asthma, adjusting for parental sociodemographic, physical, and mental health conditions, as well as the child's birth weight, and number of births. A sibling control approach was employed to compensate for unmeasured confounders of asthma exacerbation during pregnancy. In the fully adjusted models, maternal and paternal asthma were both significantly associated with an increased risk of ADHD in offspring, with hazard ratios (HRs) of 1.36 (1.31-1.40) and 1.10 (1.05-1.14), respectively. Acute asthma exacerbation during pregnancy was not associated with the risk of further offspring ADHD (adjusted HR 1.00, 95% CI: 0.75-1.34). Both maternal and paternal asthma are associated with an increased risk of ADHD in offspring. The risk was higher from maternal asthma. However, no such association was found with maternal asthma exacerbation during pregnancy of sibling comparison.

The causal impact of maternal smoking around birth on offspring ADHD: A two-sample Mendelian randomization study

BackgroundThe previous literature highlights a relationship between maternal smoking around birth (MSAB) and offspring attention-deficit/hyperactivity disorder (ADHD). These studies have focused on the causal effects of MSAB on offspring ADHD. MethodA Mendelian randomization analysis was conducted using summary statistics. Data on MSAB were obtained from a recent study including 391,992 participants. ADHD data were obtained from six sources for 246,888 participants. The present study used five methods to examine the causal impact from outcomes on exposures. The inverse variance weighted (IVW) was the main method of analysis, while the other four methods were supplementary methods. ResultThe IVW revealed that MSAB was a risk factor for offspring ADHD (OR: 2.54; 95 % confidence interval [CI]: 1.61–4.00, p = 6.04 × 10−5). Concerning ADHD in both sexes, MSAB was associated with females (OR = 3.96, 95 % CI: 1.99–7.90, p = 8.98 × 10−5) and males (OR = 3.74, 95 % CI: 1.74–5.72, p = 1.48 × 10−4). In different diagnosis periods for ADHD, MSAB increased the risk of childhood (OR = 3.63, 95 % CI: 2.25–5.87, p = 1.31 × 10−7), late-diagnosed (OR = 2.99, 95 % CI: 1.74–5.14, p = 7.33 × 10−5), and persistent (OR = 4.77, 95 % CI: 1.88–12.14, p = 1.03 × 10−3) ADHD. The final analysis did not reveal heterogeneity. ConclusionsA causal impact of MSAB on offspring ADHD was observed. These findings highlight the need for careful consideration of prenatal exposure (MSAB) during the assessment of offspring ADHD. Additionally, it can provide targeted guidance for prenatal interventions. Future studies should analyze the effects of different doses of maternal smoking on ADHD.

Prenatal maternal PTSD as a risk factor for offspring ADHD: A register-based Swedish cohort study of 553 766 children and their mothers.

Attention-deficit hyperactivity disorder (ADHD) is highly heritable, though environmental factors also play a role. Prenatal maternal stress is suggested to be one such factor, including exposure to highly distressing events that could lead to post-traumatic stress disorder (PTSD). The aim of this study is to investigate whether prenatal maternal PTSD is associated with offspring ADHD. A register-based retrospective cohort study linking 553766 children born in Sweden during 2006-2010 with their biological parents. Exposure: Prenatal PTSD. Outcome: Offspring ADHD. Logistic regression determined odds ratios (ORs) with 95% confidence intervals (CIs) for ADHD in the offspring. Adjustments were made for potential covariates, including single parenthood and possible indicators of heredity measured as parental ADHD and maternal mental disorders other than PTSD. Subpopulations, excluding children with indicators of heredity, were investigated separately. In the crude results, including all children, prenatal PTSD was associated with offspring ADHD (OR: 1.79, 95% CI: 1.37-2.34). In children with indicators of heredity, the likelihood was partly explained by it. Among children without indicators of heredity, PTSD was associated with offspring ADHD (OR: 2.32, 95% CI: 1.30-4.14), adjusted for confounders. Prenatal maternal PTSD is associated with offspring ADHD regardless of indicators of heredity, such as parental ADHD or maternal mental disorder other than PTSD. The association is partly explained by heredity and socioeconomic factors. If replicated in other populations, preferably using a sibling design, maternal PTSD could be identified as a risk factor for ADHD.

Association of pre-existing maternal cardiovascular diseases with neurodevelopmental disorders in offspring: a cohort study in Sweden and British Columbia, Canada.

We aimed to investigate the associations of pre-existing maternal cardiovascular disease (CVD) with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) in offspring. This population-based cohort study included singletons live-born without major malformations in Sweden (n = 2 699 675) and British Columbia (BC), Canada (n = 887 582) during 1990-2019, with follow-up from age 1 year until the outcome, death, emigration or December 2020, whichever came first. The primary exposure was defined as a composite CVD diagnosed prior to conception: cerebrovascular disease, arrhythmia, heart failure, valvular and congenital heart diseases. The incidences of ADHD, ASD and ID, comparing offspring of mothers with versus without CVD, were calculated as adjusted hazard ratios (aHRs). These results were compared with models using paternal CVD as negative control exposure. Compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD [95% confidence interval (CI): 1.10-1.20] and ASD (95% CI 1.07-1.22). No association was found between maternal CVD and ID. Stratification by maternal CVD subtypes showed increased hazards of ADHD for maternal heart failure (HR 1.31, 95% CI 1.02-1.61), cerebrovascular disease (HR 1.20, 95% CI 1.08-1.32), congenital heart disease (HR 1.18, 95% CI 1.08-1.27), arrhythmia (HR 1.13, 95% CI 1.08-1.19) and valvular heart disease (HR 1.12, 95% CI 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (HR 1.25, 95% CI 1.04-1.46), congenital heart disease (HR 1.17, 95% CI 1.01-1.33) and arrythmia (HR 1.12, 95% CI 1.01-1.21). Paternal CVD did not show associations with ADHD, ASD or ID, except for cerebrovascular disease which showed associations with ADHD and ASD. In this large cohort study, pre-existing maternal CVD was associated with increased risk of ADHD and ASD in offspring.

Exposure to chlorpyrifos and pyrethroid insecticides and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in preschool children from the Odense Child Cohort

BackgroundAttention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings. ObjectivesTo investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort. MethodsSpot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported “ADHD scale” from the “Child Behavior Checklist 1½-5” (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex. ResultsMost pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 μg/L and 1.62 μg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 μg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5. ConclusionIn this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing.

Parental education, ADHD in family and ADHD diagnosis incidence in Finnish children and adolescents

Abstract Background Lower parental education is linked to higher incidence of attention-deficit hyperactivity disorder (ADHD) diagnosis in offspring, as is having ADHD in family, but these associations are rarely studied together. We examined whether parental education predicts offspring ADHD diagnosis differently for children and adolescents with or without ADHD family members. Methods We used Finnish total population register-based data on individuals born between 1994-2003 with non-migrant background. We followed 228,247 boys and 217,866 girls for first ADHD diagnosis, measured from health care or medication registers, in childhood (4-12) and adolescence (13-17), and identified ADHD for biological parents or full siblings. We used Poisson regression to examine differences in diagnoses separately by offspring sex and age group. Results Preliminary results show that boys are more often diagnosed for ADHD in childhood and girls in adolescence, but incidence is higher for boys in both age groups. Among boys and girls without ADHD family members, lower parental education is associated with higher incidence in both childhood and adolescence. Among those with ADHD family members, lower parental education predicts higher incidence in childhood, but in adolescence the differences by parental education even out for boys, and for girls, higher parental education predicts higher incidence. Conclusions While lower parental education predicts higher ADHD diagnosis incidence in general, for adolescents in ADHD families, higher parental education seems to increase the likelihood of getting diagnosed -particularly for girls. This suggests that adolescents in ADHD families with lower parental education may remain without ADHD diagnosis if they are not diagnosed as children. Support measures should be developed to ensure equal access to diagnosis and care irrespective of age, gender and family background. Key messages • Lower parental education predicts higher ADHD diagnosis incidence in general. Yet, adolescents in ADHD families with lower educated parents may remain underdiagnosed. • Support measures should be developed to guarantee equal access to ADHD diagnosis and care regardless of family background.

Prenatal sleep health and risk of offspring ADHD symptomatology and associated phenotypes: a prospective analysis of timing and sex differences in the ECHO cohort

Sleep difficulties are common in pregnancy, yet poor prenatal sleep may be related to negative long-term outcomes for the offspring, including risk for attention-deficit/hyperactivity disorder (ADHD). Existing studies are few and have not examined timing of exposure effects or offspring sex moderation. We thus aimed to test the hypotheses that poor sleep health in pregnancy is associated with increased risk for ADHD symptoms and offspring sleep problems at approximately 4 years of age. Participants were 794 mother-child dyads enrolled in the NIH Environmental Influences on Child Health Outcomes Study (ECHO). Participants self-reported on sleep duration, quality, and disturbances during pregnancy and on children's ADHD symptoms and sleep problems on the Child Behaviour Checklist. Pregnant participants were 32.30±5.50 years and children were 46% female. 44 percent of pregnant participants identified as Hispanic or Latine; 49% identified as White. Second-trimester sleep duration was associated with offspring ADHD symptoms (b=-0.35 [95% CI=-0.57,-0.13], p=0.026), such that shorter duration was associated with greater symptomatology. Poorer sleep quality in the second trimester was also associated with increased ADHD symptomatology (b=0.66 [95% CI=0.18, 1.14], p=0.037). Greater sleep disturbances in the first trimester were associated with offspring ADHD (b=1.03 [95% CI=0.32, 1.03], p=0.037) and in the second trimester with sleep problems (b=1.53 [95% CI=0.42, 2.92], p=0.026). We did not document substantial offspring sex moderation. Poor prenatal sleep health, particularly quality and duration in the second trimester, may be associated with offspring risk of neurodevelopmental disorders and sleep problems in early childhood. Further research is needed to understand mechanisms, yet our study suggests that prenatal maternal sleep may be a modifiable target for interventions aimed at optimizing early neurodevelopment. NIH grants U2COD023375, U24OD023382, U24OD023319, UH3OD023320, UH3OD023305, UH3OD023349, UH3OD023313, UH3OD023272, UH3OD023328, UH3OD023290, K08MH117452 and NARSAD Young Investigator Award28545.

Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study

Cumulative exposure to psychosocial adversity at an early age has been shown to be a risk factor for attention-deficit hyperactivity disorder (ADHD) and autism that often co-occur. However, it is not clear if this association reflects a causal effect or familial confounding. We aimed to assess whether cumulative psychosocial adversity in the family increases the risk for ADHD and autism in offspring while accounting for unmeasured familial confounding. We used a population-based cohort of 1,877,901 individuals born in Sweden between 1990 and 2009. Participants were followed from the age of 3 until 2013, with a median follow up time of 13.8 years. We created a cumulative index based on 7 psychosocial adversity factors. We used Cox regression to estimate the hazard ratios (HRs) relating neurodevelopmental conditions to cumulative psychosocial adversity. To address familial confounding, the analyses were repeated in groups of relatives of different kinship: siblings and half-siblings and cousins. A dose-response relationship was observed between cumulative exposure to psychosocial adversity and ADHD at a general population level (covariate adjusted HRs (aHRs) with 95% confidence intervals ranged from 1.55 [one adversity; 1.53–1.58] to 2.65 [ ≥ 4 adversities; 1.98–3.54]). No clear dose-response relation was seen for autism (aHRs ranged from 1.04 [.59–1.84] to 1.37 [1.30–1.45]). HRs of ADHD and autism decreased with increasing level of kinship in the analysis of relatives. Cumulative exposure to psychosocial adversity was associated with both ADHD and autism in the general population, these associations were partly explained by unmeasured familial confounding between relatives. This highlights the need for using family-based designs in studies of psychosocial adversity and ADHD and autism.

Effect of cesarean section on the risk of autism spectrum disorders/attention deficit hyperactivity disorder in offspring: a meta-analysis.

This study was conducted to investigate the relationship between cesarean section (CS) offspring and autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD). Searching of the databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies on the relationship between mode of delivery and ASD/ADHD until August 2022. The primary outcome was the incidence of ASD/ADHD in the offspring. This meta-analysis included 35 studies (12 cohort studies and 23 case-control studies). Statistical results showed a higher risk of ASD (oddsratio (OR) = 1.25, P < 0.001) and ADHD (OR = 1.11, P < 0.001) in CS offspring compared to the VD group. Partial subgroup analysis showed no difference in ASD risk between CS and VD offspring in sibling-matched groups (OR = 0.98, P = 0.625). The risk of ASD was higher in females (OR = 1.66, P = 0.003) than in males (OR = 1.17, P = 0.004) in the CS offspring compared with the VD group. There was no difference in the risk of ASD between CS under regional anesthesia group and VD group (OR = 1.07, P = 0.173). However, the risk of ASD was higher in the CS offspring under general anesthesia than in the VD offspring (OR = 1.62, P < 0.001). CS offspring developed autism (OR = 1.38, P = 0.011) and pervasive developmental disorder-not otherwise specified (OR = 1.46, P = 0.004) had a higher risk than VD offspring, but there was no difference in Asperger syndrome (OR = 1.19, P = 0.115). Offspring born via CS had a higher incidence of ADHD in different subgroup analyses (sibling-matched, type of CS, and study design). In this meta-analysis, CS was a risk factor for ASD/ADHD in offspring compared with VD.

Maternal cortisol in 3rd trimester is associated with traits of neurodevelopmental disorder in offspring. Odense Child Cohort.

BackgroundPrenatal cortisol exposure is essential for neurodevelopment. Maternal cortisol levels could be associated with offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). AimTo investigate associations between maternal 3rd trimester cortisol and offspring traits of ASD and ADHD. Material and methodsMother-child pairs were included from the prospective study Odense Child Cohort. Morning serum cortisol and 24-hour urine cortisol/cortisone were collected at gestational week 27–30. Offspring ASD and ADHD traits were assessed at age three and five years using the Child Behavior Checklist. Maternal cortisol measurements and offspring ASD and ADHD traits assessment were available in (n = 1131; 52% boys) mother-child pairs at age three and (n = 717; 54% boys) at five years of age. Maternal 24-hour urine measurement was available in a subset, at offspring three years of age (n = 300) and at five years of age (n = 217). Associations between maternal cortisol (continuous and tertiles) and offspring ASD or ADHD traits were examined in regression models adjusted for offspring sex, maternal age, pre-pregnancy BMI, parity, maternal education level, parental psychiatric disorders, and maternal smoking and stratified for offspring sex. ResultsMaternal mean age ( ± SD) was 30 years ( ± 4.4) and median BMI (25%; 75% percentiles) 23.5 kg/m2 (21.3; 26.6). Higher maternal serum cortisol levels were associated with higher prevalence of offspring ASD traits at three years of age in the total study cohort and in boys after stratifying for offspring sex. In the total population, tertiles of serum cortisol showed a significant dose-response relationship to ASD traits in unadjusted and adjusted models (p-values for linear trend, p < 0.01 and p = 0.02, respectively). In offspring at five years, associations between maternal cortisol and offspring ASD traits were non-significant (all p-values > 0.2). Maternal cortisol was not associated with offspring ADHD traits (all p-values > 0.07) in offspring at three and five years. Maternal 24-hour urine cortisol, cortisone, or cortisol/cortisone ratio were not associated with offspring ASD or ADHD traits. ConclusionHigher maternal serum cortisol in 3rd trimester was associated with offspring ASD traits at three years of age in the whole study cohort and in boys, but not in girls. This association was non-significant at five years of age.

Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder in Offspring

Two recent cohort studies, one from Norway and the other from Taiwan, examined for perhaps the first time whether gestational exposure to benzodiazepines and to z-hypnotics was associated with a clinical diagnosis of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring. The studies had important methodological strengths that are not often seen; these included actual assessment during pregnancy of whether drugs prescribed were used, and, if so, when; adjustment of analyses for postbaseline time-varying covariates; inclusion of discordant sibling pair and paternal exposure analyses; inclusion of pre-pregnancy vs intrapregnancy analyses; and others. The studies also had important limitations; these included inadequate statistical power resulting in a failure to identify potential associations in even unadjusted analyses; lack of information on intermittent use vs daily dosing; and others. The strengths and limitations are identified and explained to empower readers to identify similar issues in other studies. Important findings apparent in these studies are that benzodiazepine exposure may be associated with an increased risk of both ASD and ADHD, regardless of the trimester of exposure. The magnitude of increased risk is small and diminishes to statistical nonsignificance in adjusted analyses. The risks appear elevated in association with paternal exposure. In discordant sibling pair analyses, risks do not appear to be significantly higher in the exposed sib relative to the unexposed sib. These findings imply that observed associations, if any, between gestational exposure to benzodiazepines and ASD or ADHD in offspring may be due to maternal and paternal genetic factors, to family environmental variables, and to confounding by indication, rather than to benzodiazepine exposure itself. Nevertheless, decision-making should be tailored to individual context and shared between prescriber and patient. Finally, no conclusions can be drawn regarding the neurodevelopmental safety of z-drug exposure during pregnancy.

Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders

BackgroundPrevious studies have suggested that gestational weight gain (GWG) outside an optimal range increases the risks of neurodevelopmental disorders (NDDs) in offspring including autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). The sequential development of the fetal brain suggests that its vulnerability may vary depending on the timing of exposure. Therefore, we aimed to investigate the associations of not only gestational age-standardized total GWG (GWG z-scores) but also the rate of GWG (RGWG) in the second and third trimesters with risks of NDDs in offspring.MethodsIn this population-based cohort study, we used maternal weight data from antenatal care records collected for 57,822 children born to 53,516 mothers between 2007 and 2010 in the Stockholm Youth Cohort. Children were followed from 2 years of age to December 31, 2016. GWG z-scores and RGWG (kg/week) in the second and third trimesters were considered as continuous variables in cox regression models, clustered on maternal identification numbers. Nonlinear relationships were accommodated using restricted cubic splines with 3 knots. RGWG were also categorized according to the 2009 US Institute of Medicine (IOM) guidelines for optimal GWG. According to the IOM guidelines, the optimal rate of GWG for the second and third trimesters for underweight, normal weight, overweight, and obese categories were 0.44–0.58, 0.35–0.50, 0.23–0.33, and 0.17–0.27 kg/week, respectively.ResultsDuring a mean follow-up of 5.4 years (until children were on average 7.4 years old), 2205 (3.8%) children were diagnosed with NDDs, of which 1119 (1.9%) received a diagnosis of ASD, 1353 (2.3%) ADHD, and 270 (0.5%) ID. We observed a J-shaped association between total GWG z-score and offspring risk of NDDs, with higher total GWG (GWG z-score = 2) associated with 19% increased risk of any NDD (95% CI = 3–37%) and lower total GWG (GWG z-score = − 2) associated with 12% increased risk of any NDDs (95% CI = 2–23%), compared to the reference (GWG z-score = 0). In the second trimester, lower RGWG (0.25 kg/week) was associated with a 9% increased risk of any NDD diagnosis (95% CI = 4–15%) compared to the median of 0.57 kg/week, with no apparent relationship between higher RGWG and risk of NDDs. In the third trimester, there was no apparent association between lower RGWG and risk of NDDs, though higher RGWG (1 kg/week) was associated with a 28% increased risk of NDD diagnosis (95% CI = 16–40%), compared to the median (0.51 kg/week). When considering categorized RGWG, we found that slow weight gain in the second trimester followed by rapid weight gain in the third trimester most significantly increased the risk of ADHD (HRadjusted = 1.55, 1.13–2.13) and ID (HRadjusted = 2.53, 1.15–5.55) in offspring. The main limitations of our study are the relatively few years for which detailed GWG data were available and the relatively short follow-up for the outcomes, limiting power to detect associations and misclassifying children who receive an NDD diagnosis later in childhood.ConclusionsThe relationship between maternal weight gain and children’s risk of NDDs varied according to timing in pregnancy, with the greatest risks associated with slow weight gain in the second trimester and rapid weight gain in the third trimester.

Maternal age at childbirth and the risk of attention-deficit/hyperactivity disorder and learning disability in offspring.

Studies have shown that young maternal age at childbirth can increase the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, but a study of the U.S. population has not been reported. Moreover, there is no reported research on young and advanced maternal age at childbirth and whether it can contribute to the risk of learning disability (LD) in offspring. This study evaluated the association between young and advanced maternal age at childbirth and offspring risk of ADHD and LD in the U.S. population. Using data from 8,098 participants included in the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2004, we analyzed the association between maternal age at childbirth and ADHD and LD risk in offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) for maternal age at childbirth in association with ADHD and LD risk in offspring were estimated using multivariate logistic regression models after adjustment for age, sex, race, body mass index (BMI), poverty income ratio, smoking status during pregnancy, and NHANES cycle. Restricted cubic spline (RCS) models were used to evaluate potential non-linear relationships. Sensitivity analyses were performed to ensure the reliability of the results. Among all participants, the offspring of subjects with a maternal age at childbirth of 18-24 years had an increased risk of ADHD (OR = 1.34, 95% CI: 1.01, 1.79) and LD (OR = 1.36, 95% CI: 1.06, 1.79) or either ADHD or LD (OR = 1.48, 95% CI: 1.20, 1.81). Additionally, compared with subjects with a maternal age at childbirth of 25-29 years, subjects with a maternal age at childbirth of 35-39 years had lower odds of having offspring with ADHD (OR = 0.60, 95% CI: 0.36, 1.00) and higher odds of having offspring with LD (OR = 1.34, 95% CI: 1.01, 1.78). The relationship between maternal age at childbirth and LD risk presented a U-shaped curve. These results provide epidemiological evidence showing that young and advanced maternal age at childbirth are associated with ADHD and LD risk.

Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder.

As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR. We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected. Using data from the Norwegian Mother, Father and Child Cohort Study (n=2056) and Avon Longitudinal Study of Parents and Children (n=6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified. The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied. Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.

The Association between Prenatal Per- and Polyfluoroalkyl Substances Exposure and Neurobehavioral Problems in Offspring: A Meta-Analysis.

Exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy has been suggested to be associated with neurobehavioral problems in offspring. However, current epidemiological studies on the association between prenatal PFAS exposure and neurobehavioral problems among offspring, especially attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are inconsistent. Therefore, we aimed to study the relationship between PFAS exposure during pregnancy and ADHD and ASD in offspring based on meta-analyses. Online databases, including PubMed, EMBASE, and Web of Science, were searched comprehensively for eligible studies conducted before July 2021. Eleven studies (up to 8493 participants) were included in this analysis. The pooled results demonstrated that exposure to perfluorooctanoate (PFOA) was positively associated with ADHD in the highest quartile group. Negative associations were observed between perfluorooctane sulfonate (PFOS) and ADHD/ASD, including between perfluorononanoate (PFNA) and ASD. There were no associations found between total PFAS concentration groups and neurobehavioral problems. The trial sequential analyses showed unstable results. Our findings indicated that PFOA and PFOS exposure during pregnancy might be associated with ADHD in offspring and that prenatal PFOS and PFNA exposure might be associated with ASD in offspring. According to the limited evidence obtained for most associations, additional studies are required to validate these findings.

Association between maternal polycystic ovary syndrome and attention-deficit/hyperactivity disorder in offspring aged 3-6 years: A Chinese population-based study.

Maternal polycystic ovary syndrome (PCOS) may increase the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring; however, their association remains unexplored in Asian populations. Hence, this study aimed to investigate the association between maternal PCOS and ADHD in offspring aged 3-6 years and whether it differed by offspring sex. This was a district-wide population-based study of 87,081 preschoolers from 234 kindergartens in Longhua District, Shenzhen, China. The parents were invited to complete a self-administrated questionnaire covering information on socio-demographics, maternal disease history, and child behavior. ADHD symptoms were measured with the parent-rating 26-item Swanson, Nolan, and Pelham Rating Scale (SNAP-IV). Logistic regression was performed to examine the associations between maternal PCOS and ADHD symptoms in offspring. The response rate was 80% and 63,390 mother-child pairs were included. Of the mothers, 1,667 (2.6%) reported PCOS diagnoses. The mean age of children at ADHD assessment was 4.86 ± 0.84[SD] years, and 53.6% were boys. Children with maternal PCOS had a higher risk of developing ADHD symptoms than other children (12.0 vs. 9.4%, adjusted odds ratio [OR] = 1.32, 95% CI: 1.13-1.54). The risk estimate was significant in boys (adjusted OR = 1.38, 95% CI: 1.14-1.66) but not in girls (adjusted OR = 1.23, 95% CI: 0.94-1.57, P for interaction = 0.391). Treatment of PCOS tended to be associated with a lower risk of ADHD symptoms than untreated PCOS albeit risk confidence intervals were overlapped (treated: adjusted OR = 1.28, 95% CI: 1.06-1.54 vs. untreated: adjusted OR = 1.14, 95% CI: 1.08-1.83). Maternal PCOS increases the risk of developing ADHD in offspring, especially boys. Further studies are warranted to confirm our findings, and early neurodevelopmental screening may be needed in children born to mothers with PCOS.

Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study.

Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD). We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring. We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n=298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n=73). High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio 2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group. Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium.

In utero antidepressant exposure not associated with ADHD in the offspring: A case control sibling design.

Recent studies have reported an association between antidepressant (AD) use during pregnancy and the risk to develop attention-deficit/hyperactivity disorder (ADHD) in the offspring. However, the association might be confounded by risk factors in the pregnant parent. To control for unmeasured factors between pregnancies carried by the same parent, we set up a case-control sibling study using the University of Groningen prescription database IADB.nl. Children receiving medication for ADHD (cases) before the age of 16 years were matched to siblings not receiving such medication (controls). Exposure was defined as at least two prescriptions for any AD during pregnancy, i.e., the period of 39weeks before the birth date of the offspring. Secondary analyses were performed to assess the effects of the degree of exposure (the amount of Defined Daily Doses) and the type of AD exposed to. Univariate and multivariate logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI). In total, 2,833 children (1,304 cases and 1,529 controls) were included in the analysis. Exposure rate to ADs among cases and controls was 2.2% and 2.4%, respectively. After adjusting for the birth date of the child (as a proxy for the date of pregnancy), age of the pregnant parent at birth, use of psychostimulants, opioids, and antiepileptic drugs by the pregnant parent in the 15 months before birth of the child, an adjusted OR of 1.11 (95% CI 0.67-1.83) was found for the risk of ADHD in the offspring when exposed in utero to ADs. This indicates no increased risk of ADHD in offspring following in utero exposure to ADs. The secondary analyses revealed no statistically significant associations either. The present study provides further evidence that an association between in utero AD exposure and ADHD in offspring might not exist. This perceived association may be caused (at least partially) by confounding by indication. The extent to which depression in the pregnant parent could cause mental disorders such as ADHD in offspring, and the mechanisms involved, should be investigated in further studies.

Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study

BackgroundThe influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring.MethodsThis population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model.ResultsAmong 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD.ConclusionsThere is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy.

Parental smoking exposure before and during pregnancy and offspring attention-deficit/hyperactivity disorder risk: A Chinese child and adolescent cohort study.

BackgroundPrevious studies revealed that maternal smoking exposure during pregnancy was an essential risk factor for offspring developing attention-deficit/hyperactivity disorder (ADHD). The impact of paternal smoking exposure 1 year before pregnancy on offspring ADHD risk is still unclear.MethodsThe present study included 2,477 school-age children and their parents from the Shanghai Child and Adolescent Health Cohort who had complete data for offspring ADHD diagnosis and parents' smoking exposure before and during pregnancy information. A multivariate logistic regression model and Firth's logistic regression model were used to determine the associations of paternal smoking and parental smoke exposure patterns before and during pregnancy with offspring ADHD risk.ResultsChildren whose fathers smoked before pregnancy had a higher risk of developing ADHD [odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.35–4.98] compared to those whose fathers had never been exposed to smoking. Similarly, parents who were exposed to smoking or second-hand smoke before pregnancy had 1.96 times (OR = 1.96, 95% CI: 1.19–3.22) more likely to have offspring with ADHD. Moreover, children whose parents were exposed to smoking both before and during pregnancy were 2.01 times (OR = 2.01, 95% CI: 1.29–3.12) more likely to develop ADHD.ConclusionPaternal smoking before pregnancy and parental smoking exposure 1 year ahead of and throughout pregnancy were all risk factors for offspring developing ADHD.