Attention-deficit/hyperactivity Disorder In Offspring Research Articles

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.

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. 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. 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. 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. A measure of offspring ADHD symptoms at age 7-8years was derived by dichotomizing scores from questionnaires and parental self-reported prenatal substance use was measured at the second pregnancy trimester. 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. There appears to be no causal intrauterine effect of maternal prenatal substance use on offspring attention deficit hyperactivity disorder symptoms.

Maternal Thyroid Anomalies and Attention-Deficit Hyperactivity Disorder in Progeny.

Previous epidemiologic investigations suggested that maternal thyroid anomalies are a possible causal factor in attention-deficit hyperactivity disorder (ADHD) in progeny, yet clinical trials indicated that levothyroxine treatment was ineffective in preventing neurodevelopmental impairments. We used an Israeli cohort of 385,542 singleton births from 1999-2012 to explore the interrelated roles of maternal thyroid conditions, laboratory gestational thyroid hormone measurements, use of thyroid medications, and offspring ADHD. Analyses were performed using Cox proportional hazards models. Results indicated that maternal hypothyroidism diagnosis was associated with an elevated progeny ADHD hazard (adjusted hazard ratio= 1.14, 95% confidence interval= 1.10, 1.18). However, this association was unmitigated by gestational use of levothyroxine and was unexplained by maternal gestational thyroid hormone levels. Associations with gestational thyrotropin values and hypothyroxinemia were also observed but were robust only in mothers without other records indicative of a thyroid problem. Results indicated that maternal thyroid hypofunction was associated with progeny ADHD but possibly not due to a direct causal relationship. Instead, maternal thyroid hypofunction may serve as a proxy indicator for other factors that affect neurodevelopment through thyroid hormone independent pathways, which are thus unaffected by pharmaceutical treatments for thyroid hypofunction. Factors known to disrupt thyroid functioning should be examined for their independent ADHD-related effects.

Circulating levels of maternal vitamin D and risk of ADHD in offspring: results from the Vitamin D Antenatal Asthma Reduction Trial.

Low levels of circulating 25-hydroxy-vitamin D [25(OH)D] have been shown to associate with prevalent attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the association between 25(OH)D during fetal development and risk of childhood ADHD. Maternal plasma 25(OH)D was measured at 10-18 and 32-38 weeks of gestation, with sufficiency defined as 25(OH)D ≥ 30 ng/ml. Offspring ADHD status between ages 6-9 years was measured by parent report of clinical ADHD diagnosis among 680 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial. Association between maternal 25(OH)D and child ADHD was assessed using logistic regression, adjusting for maternal age, race and ethnicity. Effect modification by offspring sex was also assessed. No associations between maternal 25(OH)D at 10-18 weeks of gestation and offspring ADHD were observed. In the third trimester, we observed associations between maternal vitamin D sufficiency and offspring ADHD [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.26-0.84], in addition to maternal 25(OH)D sufficiency category, comparing the deficient (OR 0.34, 95% CI 0.12-0.94), insufficient (OR 0.41, 95% CI 0.15-1.10) and sufficient (OR 0.20, 95% CI 0.08-0.54) categories against highly deficient 25(OH)D, respectively. Stratified analyses revealed a protective association for sufficient maternal 25(OH)D and child ADHD among males (OR 0.47, 95% CI 0.23-0.94); the synergy index for additive effect modification of risk was 1.78 (95% CI 0.62-5.08). Higher levels of maternal vitamin D in the third trimester are associated with lower risk of ADHD in offspring, with modest evidence for a stronger effect among male offspring. However, larger studies will be necessary to confirm these findings.

Maternal polycystic ovary syndrome and attention deficit hyperactivity disorder in offspring at 3years of age: Odense Child Cohort.

Previous data suggested a link between maternal polycystic ovary syndrome (PCOS) and offspring attention deficit hyperactivity disorder (ADHD), which could be mediated by higher prenatal androgen exposure. The study was part of the prospective Odense Child Cohort and included 1776 pregnant women, 165 (9%) with PCOS and 1607 (91%) controls. ADHD symptoms at 3years of age were defined using the parent-reported questionnaire Child Behavior Checklist/1.5-5 (scores >90th centile of Danish national standard). Maternal blood samples were collected in the third trimester measuring total testosterone by mass spectrometry, sex hormone-binding globulin, and calculated free testosterone. Offspring anogenital distance was measured at 3months of age. Regression models were performed with presence of ADHD symptoms as the dependent variable and adjusted for maternal age, body mass index, parity, smoking status, educational level, and parental psychiatric diagnoses. ADHD symptoms were present in 105/937 (11%) boys and 72/839 (9%) girls. In boys, maternal PCOS was positively associated with ADHD symptoms (unadjusted odds ratio [OR] 1.91, 95% CI 1.07-3.43, p=0.03, adjusted OR 2.20, 95% CI 1.20-4.02, p=0.01), whereas maternal PCOS was not associated with ADHD symptoms in girls. Maternal total testosterone, free testosterone, and offspring anogenital distance were not associated with higher risk of ADHD symptoms in the offspring. Higher risk of ADHD in boys born of mothers with PCOS were not associated with maternal third-trimester testosterone levels or offspring anogenital distance.

Maternal and offspring genetic risk score analyses of fetal alcohol exposure and attention-deficit hyperactivity disorder risk in offspring.

BackgroundStudies investigating the effects of prenatal alcohol exposure on childhood attention‐deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7–8 years.MethodsWe used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (N ALSPAC = 8196; NMOBA = 13,614), fathers (N MOBA = 13,935), and offspring (N ALSPAC=8,237; N MOBA=14,112; N GENR=2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status.ResultsThe pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97–1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING = 0.98, 95% CI 0.94–1.02; ORNO DRINKING = 0.99, 95% CI 0.97–1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa.ConclusionsWe did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.

The link between attention deficit hyperactivity disorder (ADHD) symptoms and obesity-related traits: genetic and prenatal explanations

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with obesity, however, the potential causality between the traits remains unclear. We examined both genetic and prenatal evidence for causality using Mendelian Randomisation (MR) and polygenic risk scores (PRS). We conducted bi-directional MR on ADHD liability and six obesity-related traits using summary statistics from the largest available meta-analyses of genome-wide association studies. We also examined the shared genetic aetiology between ADHD symptoms (inattention and hyperactivity) and body mass index (BMI) by PRS association analysis using longitudinal data from Northern Finland Birth Cohort 1986 (NFBC1986, n = 2984). Lastly, we examined the impact of the prenatal environment by association analysis of maternal pre-pregnancy BMI and offspring ADHD symptoms, adjusted for PRS of both traits, in NFBC1986 dataset. Through MR analyses, we found evidence for bidirectional causality between ADHD liability and obesity-related traits. PRS association analyses showed evidence for genetic overlap between ADHD symptoms and BMI. We found no evidence for a difference between inattention and hyperactivity symptoms, suggesting that neither symptom subtype is driving the association. We found evidence for association between maternal pre-pregnancy BMI and offspring ADHD symptoms after adjusting for both BMI and ADHD PRS (association p-value = 0.027 for inattention, p = 0.008 for hyperactivity). These results are consistent with the hypothesis that the co-occurrence between ADHD and obesity has both genetic and prenatal environmental origins.

Maternal exposure to pesticides during pregnancy and risk for attention-deficit/hyperactivity disorder in offspring: A protocol for systematic review and meta-analysis.

Background:Attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric disorder in childhood. Studies explored the association of maternal exposure to pesticides during pregnancy with a risk of offspring developing ADHD, but have reported inconclusive results. Here, we will perform a systematic review and meta-analysis of observational studies to assess a possible association between them.Methods:This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. PubMed, Embase, Web of Science, the Cochrane Library, and the PsycINFO will be searched from inception to May 2021. Observational studies investigating the association of maternal exposure to pesticides during pregnancy with a risk of offspring developing ADHD will be considered. The Newcastle-Ottawa Scales or the scale of the Agency for Healthcare Research and Quality will be used to assess the methodological quality of the included studies according to their study design. A fixed or random-effect model will be used to synthesize data depend on the heterogeneity test. STATA version 12.0 will be used to conduct the meta-analysis.Results:This study will provide a high-quality evaluation of association between maternal exposure to pesticides during pregnancy and risk for ADHD in offspring.Conclusion:This study will present evidence on whether maternal exposure to pesticides during pregnancy is a risk factor for ADHD in offspring.

Acetaminophen use during pregnancy and offspring attention deficit hyperactivity disorder - a longitudinal sibling control study.

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

Attention-deficit/hyperactivity disorder and other neurodevelopmental disorders in offspring of parents with depression and bipolar disorder.

Offspring of parents with major mood disorders (MDDs) are at increased risk for early psychopathology. We aim to compare the rates of neurodevelopmental disorders in offspring of parents with bipolar disorder, major depressive disorder, and controls. We established a lifetime diagnosis of neurodevelopmental disorders [attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disabilities, specific learning disorders, and motor disorders] using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version in 400 participants (mean age 11.3 + s.d. 3.9 years), including 93 offspring of parents with bipolar disorder, 182 offspring of parents with major depressive disorder, and 125 control offspring of parents with no mood disorder. Neurodevelopmental disorders were elevated in offspring of parents with bipolar disorder [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.23-4.47, p = 0.010] and major depressive disorder (OR 1.87, 95% CI 1.03-3.39, p = 0.035) compared to controls. This difference was driven by the rates of ADHD, which were highest among offspring of parents with bipolar disorder (30.1%), intermediate in offspring of parents with major depressive disorder (24.2%), and lowest in controls (14.4%). There were no significant differences in frequencies of other neurodevelopmental disorders between the three groups. Chronic course of mood disorder in parents was associated with higher rates of any neurodevelopmental disorder and higher rates of ADHD in offspring. Our findings suggest monitoring for ADHD and other neurodevelopmental disorders in offspring of parents with MDDs may be indicated to improve early diagnosis and treatment.

Parental Age and the Risk of ADHD in Offspring: A Systematic Review and Meta-Analysis.

Evidence has suggested that parental age at birth is a risk factor of offspring attention deficit/hyperactivity disorder (ADHD). We conducted a meta-analysis of observational studies investigating the association between parental age and offspring ADHD. We conducted a systematic search that followed the recommended guidelines for performing meta-analyses on PUBMED, EMBASE, and Web of Science up to 8 April 2021. We calculated pooled risk estimates from individual age with and without adjusting for possible confounding factors. Dose–response analysis for parental age and ADHD risk was performed. Eleven studies were selected in this meta-analysis, which included 111,101 cases and 4,417,148 participants. Compared with the reference points, the lowest parental age category was associated with an increased risk of ADHD in the offspring, with adjusted odds ratios (ORs) of 1.49 (95% confidence intervals (95%CI) 1.19–1.87) and 1.75 (95%CI 1.31–2.36) for the mother and father, respectively. The highest parental age was statistically insignificant, with adjusted ORs of 1.11 (95%CI 0.79–1.55) and 0.93 (95%CI 0.70–1.23) for mother and father separately. Dose–response analysis indicated a non-linear relationship of parental age with offspring ADHD, with the lowest ADHD risk at 31–35 years old. The results of this meta-analysis support an association between young parental age and the risk of ADHD. More high-quality studies are needed to establish whether the association with parental age is causal.

Maternal hypertensive disorders and neurodevelopmental disorders in offspring: a population-based cohort in two Nordic countries

Maternal hypertensive disorders during pregnancy (HDP) have been associated with neuropsychiatric problems in offspring. We aim to investigate the associations between specific types of maternal HDP and offspring neurodevelopmental disorders and further examine whether the timing of onset and severity of HDP would affect these associations. The study population consisted of 4,489,044 live-born singletons in Denmark during 1978–2012 and Sweden during 1987–2010. Maternal HDP was categorized into chronic hypertension, gestational hypertension, and pre-eclampsia; pre-eclampsia was further stratified according to timing (early-onset, late-onset), or severity (moderate, severe) of the disease. Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), were defined by ICD-coded register diagnosis. Cox regression was used to calculate hazard ratios (HR) while adjusting for potential confounders, and sibling analyses assessed the influence of unmeasured shared familial factors. Maternal HDP was associated with increased risks of ADHD (HR, 1.24; 95% confidence interval [CI], 1.20–1.28), ASD (1.29 [1.24–1.34]), and ID (1.58 [1.50–1.66]) in offspring, respectively, which was mostly driven by pre-eclampsia. The strongest associations were observed for early-onset and severe pre-eclampsia, and the corresponding HRs for ADHD, ASD and ID were 1.93 [1.73–2.16], 1.86 [1.61–2.15], and 3.99 [3.42–4.65], respectively. The results were similar in the sibling analyses. The associations between maternal HDP and offspring neurodevelopmental disorders were consistent across the subgroups of sex, preterm status, parity, maternal age and psychiatric disorders. Maternal HDP, especially early-onset pre-eclampsia, are associated with increased risks of ADHD, ASD, and ID in particular, independent of shared familial factors.

Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring

Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear. To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring. This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020. Diagnoses of HDP, which were provided by the Medical Birth Register. Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings. The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08). The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.

Maternal depressive and anxiety symptoms and the risk of attention deficit hyperactivity disorder symptoms in offspring aged 17: Findings from the Raine Study

BackgroundWhile previous studies have suggested that maternal anxiety and depressive symptoms are associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in their offspring in early and late childhood, studies exploring the risk in late adolescence are however lacking. This study aims to examine the association between maternal anxiety and depressive symptoms and the risk of ADHD symptoms in late adolescence (at age 17). MethodsWe used data from the Raine Study. Maternal depressive and anxiety symptoms were measured when the child was 10 years of age using the Depression, Anxiety, and Stress Scale (DASS). Offspring ADHD symptoms at age 17 were assessed using the DSM-oriented scales of the child behavior checklist (CBCL). Log-binomial regression was used to explore the associations. ResultsWe found an increased risk of ADHD symptoms in offspring of mothers with comorbid anxiety and depressive symptoms when compared with offspring of mothers with no symptoms [RR 5.60 (95%CI 3.02-10.37)]. There was a nearly three-fold increase in the risk of ADHD symptoms in offspring of mothers with increased anxiety symptoms compared with offspring of mothers who were in the normal range [RR 2.84 (95%CI 1.18-6.83)]. No association was observed with maternal depressive symptoms. ConclusionThis study found an increased risk of ADHD symptoms in the offspring of mothers with anxiety as well as comorbid anxiety and depressive symptoms but not among the offspring of mothers with depressive symptoms. Early screening and intervention for ADHD symptoms in offspring with maternal anxiety and comorbid anxiety and depressive symptoms are warranted.

Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children

Maternal autoimmune disease has been associated with increased risk of neurodevelopmental disorders in offspring, but few studies have assessed the association with attention-deficit/hyperactivity disorder (ADHD). To examine the association between maternal autoimmune disease and ADHD within a population-based cohort and combine results in a subsequent systematic review and meta-analysis. A cohort study was conducted of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia, from July 1, 2000, to December 31, 2010, and followed up until the end of 2014; and a systematic review evaluated articles from the MEDLINE, Embase, and Web of Science databases to identify all studies published before November 20, 2019. A total of 12 610 children exposed to maternal autoimmune disease were propensity score matched (1:4) to 50 440 unexposed children, for a total cohort of 63 050. A child was considered to have ADHD if they had (1) an authorization or filled prescription for stimulant treatment for ADHD or (2) a hospital diagnosis of ADHD. Children linked to a first ADHD event before 3 years of age were excluded. Data were analyzed from January 13 to April 20, 2020. One or more maternal autoimmune diagnoses in linked hospital admission records between July 1, 2000, and December 31, 2012. Thirty-five conditions were considered together and individually. The main outcome was child ADHD identified from stimulant authorization or prescription data and diagnoses in linked hospital admission records. Multivariable Cox regression was used to assess the association between maternal autoimmune disease and ADHD adjusted for child sex. Pooled hazard ratios (HRs) were calculated using random-effects meta-analysis with inverse-variance weights for each exposure reported by 2 or more studies. In the population-based cohort analysis, 831 718 singleton, term infants born to 831 718 mothers (mean [SD] age, 29.8 [5.6] years) were assessed. Of 12 767 infants (1.5%) who were linked to a maternal autoimmune diagnosis, 12 610 were propensity score matched to 50 440 control infants, for a total study cohort of 63 050 infants. In this cohort, any autoimmune disease was associated with ADHD in offspring (HR, 1.30; 95% CI 1.15-1.46), as was type 1 diabetes (HR, 2.23; 95% CI, 1.66-3.00), psoriasis (HR, 1.66; 95% CI, 1.02-2.70), and rheumatic fever or rheumatic carditis (HR, 1.75; 95% CI, 1.06-2.89). Five studies (including the present study) were included in the meta-analysis. Any autoimmune disease (2 studies: HR, 1.20; 95% CI, 1.03-1.38), type 1 diabetes (4 studies: HR, 1.53; 95% CI, 1.27-1.85), hyperthyroidism (3 studies: HR, 1.15; 95% CI, 1.06-1.26), and psoriasis (2 studies: HR, 1.31; 95% CI, 1.10-1.56) were associated with ADHD. In this cohort study, maternal autoimmune diseases were associated with increased ADHD among children. These findings suggest possible shared genetic vulnerability between autoimmune disease and ADHD or a potential role for maternal immune activation in the expression of neurodevelopmental disorders in children. Future studies measuring disease activity, modifiers, and medication use are required to better understand the mechanisms underlying this association.

Sex differences in parent-offspring recurrence of attention-deficit/hyperactivity disorder.

BackgroundAttention‐deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison.MethodsIn a generation study linking data from several population‐based registries, all Norwegians born 1967–2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex.ResultsThe absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2–8.6 vs. RRpaternal 6.2, 6.0–6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5–21.7) vs. PDpaternal 14.8% (14.3–15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons.ConclusionsThe intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex‐ and diagnosis‐specific intergenerational recurrence risk in parents with ADHD.

Prescription Benzodiazepine Use During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring

IntroductionBenzodiazepine (BZD) prescribing rates during pregnancy have risen over the last two decades. There is little research into the potential relationship between in utero exposure to BZD and offspring risk of attention deficit/hyperactivity disorder (ADHD), although there is some evidence of negative neurodevelopmental outcomes.
 Objectives and ApproachWe used comprehensive linked administrative data to investigate the association between maternal use of prescription BZDs during pregnancy and ADHD in offspring. We included mother-newborn dyads in Manitoba born from 1996-2012, with follow-up through 2017. BZD exposure was defined as 2+ prescriptions between conception and delivery. We matched exposed children to unexposed children to account for differences in characteristics between women who used BZDs during pregnancy versus non-users. Several sensitivity analyses addressed the potential for residual confounding, including a negative control group and a group made entirely of recent users of BZDs. Cox Proportional Hazard Regression Models were used to estimate the risk of ADHD among offspring.
 ResultsAmong 495 children with at least two BZD exposures throughout pregnancy, 25.4% (n=452) had a diagnosis of ADHD compared with 18.0% (n=68) of children not exposed (adjusted HR 1.91, 95% CI 1.35-2.69). However, the association was unchanged in the negative control group analyses (aHR 1.76, 1.09-2.86), and not significant in the recent users of BZD (aHR 0.91, 0.63-1.30). Mother’s history of ADHD and teen births were also associated with ADHD in offspring.
 ConclusionsIn a large population-level analysis, in utero exposure to prescription BZDs during pregnancy appeared to increase risk of ADHD. However, sensitivity analyses suggest this relationship was likely due to residual confounding. The power to link data for the whole population and across generations enabled powerful sensitivity analyses that alter the initial inference.

Does exposure to organophosphate esters during pregnancy increase the risk of attention-deficit hyperactivity disorder in offspring?

Background. Elevated organophosphate esters (OPEs) during pregnancy has been associated with hyperactivity and attention problems in children. Such behaviors are often found in children with attention-deficit hyperactivity disorder (ADHD). However, no study has investigated OPEs in relation to clinically diagnosed ADHD.Aim. To evaluate associations between prenatal exposure to OPEs and ADHD diagnosis, in a case-cohort substudy of the Norwegian Mother, Father and Child Cohort.Methods. We identified 297 ADHD cases through the Norwegian patient registry and sampled a sub-cohort of 555 participants among the eligible population. Diphenyl phosphate (DPHP), di-n-butyl phosphate (DnBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in urine collected at 17 gestational weeks. Binary exposure indicators were created for DPHP (cutoff: sub-cohort median), DnBP (limit of quantification, LOQ), BBOEP and BDCIPP (limit of detection, LOD). We estimated ORs using logistic regression, adjusting for the season of urine collection, child sex, birth year, maternal depression, maternal ADHD, and phthalate metabolite concentrations. Missing covariates were multiply imputed and estimates were pooled using Rubin’s rules. Effect measure modification by child sex was investigated.Results. DPHP was detected in nearly all samples (98%>LOD), with a higher geometric mean among ADHD cases (0.70 ng/ml) as compared to the sub-cohort (0.52 ng/ml). DNBP was commonly detected as well (6%<LOD; 39% LOD-LOQ; 55%>LOQ), while BBOEP (51%>LOD) and BDCIPP (21%>LOD) were detected less frequently. Children whose mothers had above the median DPHP concentrations during pregnancy were more likely to be diagnosed with ADHD (aOR: 1.41 [95% CI: 1.00, 1.99]). Similar positive associations were observed for BDCIPP (1.47 [0.99, 2.17]), but near-null associations were observed for DnBP (0.93 [0.67,1.30]) and BBOEP (1.05 [0.75, 1.45]). We did not observe strong evidence of modification by child sex.Conclusions. DPHP and BDCIPP exposure during pregnancy may increase the risk of ADHD in offspring.

Parental age at childbirth and risk for attention-deficit/hyperactivity disorder in offspring

This study investigated the association between parental age at birth and attention-deficit/hyperactivity disorder (ADHD) symptoms in their children. A total of 30,552 children aged 6–12 years participated in the study. ADHD symptoms were rated using the Korean version of the ADHD Rating Scale (K-ARS) by parents. K-ARS scores and odds ratio (OR) for children with high-risk ADHD presented a U-shape curve depending on the age of both parents at birth. The total K-ARS scores and OR for high-risk ADHD were highest in children of fathers and mothers belonging to the youngest age group (aged ≤20) (K-ARS = 12.33, OR = 2.89 vs K-ARS = 10.98, OR = 2.63) and second highest in children whose father's or mother's age at birth was the oldest (K-ARS = 9.63, OR = 1.65 vs K-ARS = 9.95, OR = 1.95). Our study identified that both spectrums of age—young and old of either parent—were associated with ADHD in children. These are new findings considering that old age of parents as the correlates of offspring ADHD is the inconsistent finding with previous studies and warrant future studies in other cultures that include more detailed information on ADHD symptoms of children and their parents are needed to confirm the present findings.

Maternal serum Vitamin B12 and offspring attention-deficit/hyperactivity disorder (ADHD)

Maternal Vitamin B12 deficiency during pregnancy is associated with offspring neuropsychiatric disorders. Few previous studies examining this association with attention-deficit/hyperactivity disorder (ADHD) report inconsistent findings. The study examines the association between maternal serum Vitamin B12 levels and offsprings’ risk of ADHD. This study is based on the Finnish Prenatal Study of ADHD with a nested case–control design. All the singleton children born in Finland between January 1998 and December 1999 and diagnosed with ADHD were included in the study. A total of 1026 cases were matched with an equal number of controls on sex, date of birth and place of birth. Maternal Vitamin B12 levels were assessed using a chemiluminescence microparticle immunoassay and archived from maternal serum banks, collected during the first and early second trimester of pregnancy. Lower maternal Vitamin B12 levels when analyzed as a continuous variable was not associated with offspring ADHD (aOR 0.97, 95% CI 0.79–1.18, p = 0.75). No significant associations were seen in the lowest quintile of Vitamin B12 levels (aOR 0.96, 95% CI 0.73–1.27, p = 0.80). This is the first study examining maternal sera Vitamin B12 levels during early pregnancy and offspring ADHD. The result suggests that Vitamin B12 deficiency during early pregnancy has specificity for some disorders but not with offspring ADHD.

Neonatal and Childhood Outcomes in Offspring of Pregnant Women Using Antidepressant Medications: A Critical Review of Current Meta-Analyses.

This article reviewed the results of 21 recent meta-analyses examining the relationship between maternal use of antidepressants during pregnancy and negative outcomes in newborns and children. PubMed was searched for meta-analyses published in English between January 1, 2011, and November 30, 2019, by using combinations of the keywords pregnancy, antidepressants, review, meta-analysis, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, neonatal outcomes, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), preterm birth, low birth weight, spontaneous abortion, persistent pulmonary hypertension, infant, newborn, children, and offspring. The present review included a total of 21 relevant meta-analyses that met the inclusion criteria. Most of the meta-analyses reported that compared to non-users, the risks of preterm birth, low birth weight, spontaneous abortion, persistent pulmonary hypertension, autism spectrum disorders, and ADHD in offspring of antidepressant users were significantly higher. Some meta-analyses also noted that the elevated risks were no longer statistically significant when pregnant women with psychiatric diagnoses treated with an antidepressant were compared with control patients who remained untreated. Although this review of current meta-analyses suggests a moderately increased risk of neonatal and childhood outcomes assessed with maternal use of antidepressants, it is difficult to ascertain whether these outcomes are independent of underlying maternal psychiatric disorders.