Attention-deficit/hyperactivity Disorder In Offspring Research Articles

Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: A prospective investigation

Early life predictors of attention-deficit/hyperactivity disorder (ADHD) are critically needed; they could inform etiological theory and may help identify new prevention targets. The current study examined prospectively whether maternal cytokine levels during pregnancy predict offspring ADHD symptoms at age 4–6 years. Secondarily, we evaluated maternal cytokine levels as a possible common pathway through which prenatal risks exert influence on child ADHD. Data came from a sample of women recruited during the 2nd trimester of pregnancy (N = 62) and followed postnatally until children were 4–6 years old. Maternal inflammation was assessed using 3rd trimester plasma concentrations of three indicators of nuclear factor kappa B signaling: interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 which were combined into a latent variable. Mothers and teachers reported on child ADHD symptoms, negative affect, and externalizing behaviors at 48–72 months of age. Maternal inflammation in the 3rd trimester predicted ADHD symptoms when children were 4–6 years old (β = 0.53, 95% CI = 0.154, 0.905, p = 0.006). Further, maternal inflammation mediated the effect of prenatal distress on child ADHD (β = 0.21, 95% CI = 0.007, 0.419, p = 0.04). The inflammation effect on ADHD was not explained by concurrent child negative affect, externalizing behavior, or familial ADHD status. This is the first human study to prospectively link maternal pregnancy cytokine levels and offspring ADHD symptoms, suggesting that cytokine levels are a possible marker of ADHD risk. Results also provide new evidence that maternal prenatal inflammation may be one common pathway by which prenatal risk factors influence offspring mental health outcomes.

Association of parental depression with offspring attention deficit hyperactivity disorder and autism spectrum disorder: A nationwide birth cohort study

BackgroundStudies have indicated that parental depression was slightly related to the increased risk of offspring attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the association between exposure to parental depression at different neurodevelopmental stages (i.e., perinatal or postnatal period) and subsequent ADHD and ASD development remained uncertain. Method708,515 children born between 2001 and 2008 were screened for ADHD and ASD based on ICD-9-CM codes of 314 and 299 given by psychiatrists from their birth to the end of 2011. Paternal and maternal depression was separately assessed during five periods, namely those before pregnancy (pre-pregnancy), during pregnancy (perinatal), and <1, 1–3, and >3 years after childbirth (postnatal). Cox regression analyses were performed. ResultsBoth paternal and maternal depression occurring in the pre-pregnancy, perinatal and postnatal periods were significantly associated with subsequent ADHD and ASD in the offspring, with hazard ratios between 1.42 (95% confidence interval [CI]: 1.35–1.49) and 2.25 (2.09–2.41). The chronicity and additive effect of paternal and maternal depression were related to increased risks of offspring ADHD and ASD. The effects of maternal depression were stronger than the effects of paternal depression for offspring ADHD (HR: 1.35, 95% CI: 1.27–1.45) and ASD (HR: 1.23, 95% CI: 1.05–1.46) risks. ConclusionBoth paternal depression and maternal depression in the pre-pregnancy, perinatal and postnatal periods increases offspring ADHD and ASD risks, and these risks increase further with increases in the duration of parental depression and with the additive effect of parental and maternal depression.

Obstetric oxytocin exposure and ADHD and ASD among Danish and Finnish children.

Some studies have indicated an increased risk of attention deficit hyperactivity disorder (ADHD) and a small, sex-specific association with autism spectrum disorder (ASD) among children prenatally exposed to obstetric oxytocin. Since oxytocin is widely used in the obstetric ward, these potentially deleterious effects are of concern. Thus, we aimed to examine whether obstetric oxytocin treatment for labour induction or augmentation is associated with ADHD and ASD in offspring born in a two-country design based on data from Denmark and Finland. This population-based study used data from national registers in Denmark and Finland. Singletons born in Denmark 2000-10 (n = 577380) and Finland 1991-2010 (n = 945543), who survived infancy, were followed until 31 December 2015. ADHD and ASD were defined using diagnostic codes. For ADHD, we also included information on prescribed and redeemed ADHD medication in the definition. Hazards ratios (HRs) with 95% confidence intervals (CI), modelled with age as the underlying time scale, were calculated to estimate the associations. Oxytocin was used in 31% and 46% of the included deliveries in Denmark and Finland, respectively. In crude analyses, prenatal oxytocin was associated with an approximately 20% increased risk of ADHD and ASD, but confounder adjustment attenuated the association. The adjusted HR was 1.03, 95% CI 1.01-1.05, for ADHD and 1.05, 95% CI 1.02-1.08, for ASD. The results were similar in across country and gender. We found an association between synthetic oxytocin and ADHD or ASD which is unlikely to reflect a causal association and thus should not support the concern of clinical use. Our results help to allay concerns of obstetric use of oxytocin causing ADHD or ASD.

The Association of Prenatal Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccination With Attention-Deficit/Hyperactivity Disorder.

As prenatal vaccinations become more prevalent, it is important to assess potential safety events. In a retrospective cohort study of Kaiser Permanente Southern California (Pasadena, California) mother-child pairs with birth dates during January 1, 2011-December 31, 2014, we investigated the association between prenatal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. Information on Tdap vaccination during pregnancy was obtained from electronic medical records. ADHD was defined by International Classification of Diseases codes (Ninth or Tenth Revision) and dispensed ADHD medication after age 3 years. Children were followed to the date of their first ADHD diagnosis, the end of Kaiser Permanente membership, or the end of follow-up (December 31, 2018). In Cox proportional hazards models, we estimated unadjusted and adjusted hazard ratios for the association between maternal Tdap vaccination and ADHD, with inverse probability of treatment weighting (IPTW) used to adjust for confounding. Of 128,756 eligible mother-child pairs, 85,607 were included in the final sample. The ADHD incidence rate was 3.41 per 1,000 person-years in the Tdap-vaccinated women and 3.93 per 1,000 person-years in the unvaccinated (hazard ratio=1.01, 95% confidence interval: 0.88, 1.16). The IPTW-adjusted analyses showed no association between prenatal Tdap vaccination and ADHD in offspring (hazard ratio=1.00, 95% confidence interval: 0.88, 1.14). In this study, prenatal Tdap vaccination was not associated with ADHD risk in offspring, supporting recommendations to vaccinate pregnant women.

Maternal spontaneous abortion and the risk of attention-deficit/hyperactivity disorder in offspring: a population-based cohort study.

Is a maternal history of spontaneous abortion (SA) associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring? Our results suggest an association between maternal history of SA and ADHD in offspring, with the risk increasing with the number of maternal SA and highest in the firstborn children whose mothers had had recurrent SAs after adjusting for a number of potential confounders. A history of SA has been associated with more complications in next pregnancies and adverse childbirth outcomes, which are risk factors for ADHD in the offspring. However, no previous study has investigated whether maternal SA increases risk of ADHD in the offspring. This population-based study included all live-born children in Denmark from 1 January 1995 to 31 December 2012 (n = 1 062 667). All children were followed from 3years of age until the day of ADHD diagnosis, death, emigration or 31 December 2016, whichever came first. There were 130 206 (12.2%) children born to mothers who had at least one SA. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 9.4years (interquartile range, 5.4-14.3), 25 747 children were diagnosed with ADHD. Overall, children of mothers with a history of SA had an increased rate of ADHD (HR, 1.11; 95% CI, 1.07 to 1.15). The HRs increased with the number of maternal SA, 1.09 (95% CI, 1.05 to 1.13) for one SA and 1.22 (95% CI, 1.12 to 1.33) for at least two SAs, respectively. These findings were consistent when we took into consideration a number of factors, such as maternal socioeconomic status, type of SA, birth order, parental history of psychiatric disorders, pregnancy characteristics and adverse birth outcomes. Misclassification of SA was possible as we used population-based register data to capture maternal history of SA. However, any misclassification of maternal history of SA would be non-differential with regard to the diagnosis of ADHD in offspring, which generally leads to underestimation of the associations. Furthermore, probabilistic sensitivity analysis suggested that only 1% of change in the estimate may have been due to misclassification of SA. SA is quite frequent (varying from 15 to 20%), and a small increase of neurodevelopmental problems in offspring could have major public health implications. This work was supported by grants from the National Natural Science Foundation of China (No. 81703237, No. 81530086 and No. 81761128035), National Key Research and Development Program (2018YFC1002801, 2016YFC1000505), Shanghai Municipal Commission of Health and Family Planning (No. 2017ZZ02026, No. 2017EKHWYX-02), the Novo Nordisk Foundation (NNF18OC0052029), the Danish Council for Independent Research (DFF-6110-00019), the Nordic Cancer Union (176673, 186200 and R217-A13234-18-S65), Karen Elise Jensens Fond (2016) and Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (2018YJRC03). All authors report no conflict of interest. NA.

Maternal pre-pregnancy overweight/obesity and the risk of attention-deficit/hyperactivity disorder in offspring: a systematic review, meta-analysis and quasi-experimental family-based study.

BackgroundPrevious studies are inconclusive concerning the association between maternal pre-pregnancy overweight/obesity and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. We therefore conducted a systematic review and meta-analysis to clarify this association. To address the variation in confounding adjustment between studies, especially inadequate adjustment of unmeasured familial confounding in most studies, we further performed cousin and sibling comparisons in a nationwide population-based cohort in Sweden.MethodsWe searched PubMed, Embase and PsycINFO during 1975–2018. We used random-effects models to calculate pooled risk ratios (RRs) with 95% confidence interval. In the population-based study, Cox proportional hazard models were used to calculate the unadjusted hazard ratios (HRs) and HRs adjusted for all confounders identified in previous studies. Stratified Cox models were applied to data on full cousins and full siblings to further control for unmeasured familial confounding.ResultsEight cohorts with a total of 784 804 mother–child pairs were included in the meta-analysis. Maternal overweight [RRoverweight = 1.31 (1.25–1.38), I2 = 6.80%] and obesity [RRobesity = 1.92 (1.84–2.00), I2 = 0.00%] were both associated with an increased risk of ADHD in offspring. In the population-based cohort of 971 501 individuals born between 1992 and 2004, unadjusted Cox models revealed similar associations [HRoverweight = 1.30 (1.28–1.34), HRobesity = 1.92 (1.87–1.98)]. These associations gradually attenuated towards the null when adjusted for measured confounders [HRoverweight = 1.21 (1.19–1.25), HRobesity = 1.60 (1.55–1.65)], unmeasured factors shared by cousins [HRoverweight = 1.10 (0.98–1.23), HRobesity = 1.44 (1.22–1.70)] and unmeasured factors shared by siblings [HRoverweight = 1.01 (0.92–1.11), HRobesity = 1.10 (0.94–1.27)].ConclusionPre-pregnancy overweight/obesity is associated with an increased risk of ADHD in offspring. The observed association is largely due to unmeasured familial confounding.

Association Between Maternal Exposure to Magnetic Field Nonionizing Radiation During Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Offspring in a Longitudinal Birth Cohort

An association between maternal exposure to magnetic field (MF) nonionizing radiation during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) has been reported in both animal and human studies. To determine whether maternal exposure to high levels of MF nonionizing radiation is associated with an increased risk of ADHD in offspring by using more accurate measurements of MF nonionizing radiation levels and physician-diagnosed ADHD, rather than self-reports, and to determine whether the association differs for the subtypes of ADHD with or without immune-related comorbidities. A longitudinal birth cohort study was conducted at Kaiser Permanente Northern California among 1482 mother-child pairs whose mothers were participants of an existing birth cohort and whose level of exposure to MF nonionizing radiation was captured during pregnancy in 2 studies conducted from October 1, 1996, to October 31, 1998, and from May 1, 2006, to February 29, 2012. The offspring were followed up from May 1, 1997, to December 31, 2017. All participating women wore a monitoring meter for 24 hours during pregnancy to capture the level of exposure to MF nonionizing radiation from any sources. Physician-diagnosed ADHD and immune-related comorbidities of asthma or atopic dermatitis up to 20 years of age in offspring captured in the Kaiser Permanente Northern California electronic medical record from May 1, 1997, to December 31, 2017. Confounders were ascertained during in-person interviews during pregnancy. Among the 1454 mother-child pairs (548 white [37.7%], 110 African American [7.6%], 325 Hispanic [22.4%], 376 Asian or Pacific Islander [25.9%], and 95 other or unknown [6.5%]; mean [SD] maternal age, 31.4 [5.4] years]), 61 children (4.2%) had physician-diagnosed ADHD. Using Cox proportional hazards regression to account for follow-up time and confounders, compared with children whose mothers had a low level of exposure to MF nonionizing radiation during pregnancy, children whose mothers were exposed to higher levels of MF nonionizing radiation had more than twice the risk of ADHD (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.06-3.81). The association was stronger for ADHD that persisted into adolescence (≥12 years of age), with an aHR of 3.38 (95% CI, 1.43-8.02). When the subtypes of ADHD were examined, the association existed primarily for ADHD with immune-related comorbidities (asthma or atopic dermatitis), with an aHR of 4.57 (95% CI, 1.61-12.99) for all ADHD cases and an aHR of 8.27 (95% CI, 1.96-34.79) for persistent cases of ADHD. Consistent with the emerging literature, this study suggests that in utero exposure to high levels of MF nonionizing radiation was associated with an increased risk of ADHD, especially ADHD with immune-related comorbidity. The findings should spur more research to examine the biological association of in utero MF exposure with risk of ADHD in offspring, given that almost everyone is exposed to it.

The associations of maternal polycystic ovary syndrome and hirsutism with behavioral problems in offspring

To study the associations between maternal polycystic ovary syndrome (PCOS) and hirsutism with offspring attention-deficit/hyperactivity disorder (ADHD), anxiety, conduct disorder, and behavioral problems. Prospective birth cohort study. Not applicable. A total of 1,915 mother-child dyads. None. Maternal report of offspring ADHD, anxiety, or conduct disorder diagnosis at 7 to 8 years; emotional symptoms, behavioral problems (including peer relationship, conduct, hyperactivity/inattention), and prosocial problems measured with the Strengths and Difficulties Questionnaire (SDQ) at 7 years. Prevalence of PCOS and hirsutism were 12.0% and 3.9%; 84% of women with hirsutism had PCOS. After adjustment for sociodemographic covariates, prepregnancy body mass index, and parental history of affective disorders, children born to mothers with PCOS had higher risk of anxiety (adjusted risk ratio [aRR] 1.62; 95% confidence interval [CI], 1.02-2.57) and borderline emotional symptoms (aRR 1.66; 95% CI, 1.18-2.33) compared with children born to mothers without PCOS. The associations between maternal PCOS and offspring ADHD were positive but imprecise. Maternal hirsutism was related to a higher risk of children's ADHD (aRR 2.33; 95% CI, 1.28-4.24), conduct disorder (aRR 2.54; 95% CI 1.18-5.47), borderline emotional symptoms, peer relationship problems, and conduct problems (aRRs 2.61; 95% CI, 1.69-4.05; 1.92; 95% CI, 1.16-3.17; and 2.22; 95% CI, 1.30-3.79, respectively). Maternal PCOS was associated with offspring anxiety, and hirsutism was related to other offspring behavioral problems. These findings should be interpreted with caution as replication is needed in prospective cohort studies that assess PCOS and hirsutism diagnoses using medical records.

Maternal Vitamin D Levels and the Risk of Offspring Attention-Deficit/Hyperactivity Disorder

Recent evidence has highlighted the importance of vitamin D in the development of the central nervous system. Some studies have shown an association between maternal vitamin D deficiency during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) symptoms based on parent or teacher ratings. There are no previous studies on early pregnancy 25-hydroxyvitamin D [25(OH)D] levels and the risk of diagnosed offspring ADHD. Our aim was to examine maternal 25(OH)D levels in early pregnancy and offspring ADHD. In this nationwide population-based case-control study, 1,067 ADHD cases (born between 1998 and 1999 and diagnosed according to the International Classification of Diseases) and 1,067 matched controls were identified from Finnish registers. Maternal 25(OH)D levels were measured using quantitative immunoassay from maternal sera, collected during the first trimester and archived in the national biobank. Conditional logistic regression was used to examine the association between maternal 25(OH)D and offspring ADHD. There was a significant association between decreasing log-transformed maternal 25(OH)D levels and offspring ADHD both in the unadjusted analyses (odds ratio 1.65; 95% CI 1.33-2.05; p< .001) and in the analyses adjusting for maternal socioeconomic status and age (odds ratio 1.45; 95% CI 1.15-1.81; p= .002). Analyses by quintiles of maternal 25(OH)D levels in the lowest versus highest quintile revealed an adjusted odds ratio for offspring ADHD of 1.53 (95% CI 1.11-2.12; p= .010). This study demonstrated an association between low maternal 25(OH)D during pregnancy and an elevated risk for offspring ADHD. If replicated in independent samples, this finding may have significant public health implications.

The affective temperament traits and pregnancy-related depression in mothers may constitute risk factors for their children with attention deficit and hyperactivity disorder

We investigated whether the affective temperaments of mothers and maternal depression before and during the index pregnancy are related to the development of Attention-Deficit Hyperactivity Disorder (ADHD) in their children. One hundred and twenty children were screened for the diagnosis of ADHD. After exclusion and inclusion criteria were applied for children and their mothers, we compared the mothers of children with (n = 63) and without ADHD (n = 60) in terms of affective temperament traits, depression before and during the index pregnancy, and some environmental risk factors. The rate of boys were significantly higher among children with ADHD compared to healthy controls. The mothers of children with ADHD had significantly lower education levels, more cigarette consumption during pregnancy, and more depression rates before the pregnancy than those of healthy children. Male gender (p = .002), Hamilton Depression Rating Scale (HDRS) (p = .002), cyclothymic (p = .022), irritable (p = .035) and anxious temperament scores (p = .016) significantly predicted the association between the mothers and their children with ADHD. Our findings might suggest that male child gender, the severity of depression at index pregnancy, higher cyclothymic, irritable, and anxious temperament scores in mothers may constitute as important risk factors for the development of ADHD in their children.Impact statementWhat is already known on this subject? Although the effects of maternal depression on ADHD were extensively investigated, the relationship between affective temperament traits of mothers and ADHD in their children has not been sufficiently examined. To investigate the roles of maternal affective temperament traits and pregnancy-related depression on offspring ADHD would help us to understand the etiopathogenic bases of ADHD.What do the results of this study add? Cyclothymic, irritable and anxious temperaments of mothers were significantly associated with the offspring ADHD after adjusting for the gender, maternal smoking, prepartum and antenatal depression.What are the implications of these findings for clinical practice and/or further research? These findings might demonstrate that some maternal affective temperaments and depression during pregnancy are suggestive of an inherited predisposition to ADHD in offsprings. Longitudinal studies are required to demonstrate the relationship between maternal affective temperament features and the development of affective illness in children with ADHD.

Controlled Antenatal Thyroid Screening II: Effect of Treating Maternal Suboptimal Thyroid Function on Child Behavior.

The Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children's behavior. Mothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, "overtreated") and child neurodevelopment were reported. There were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children. There was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of "overtreated" mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment.

Meta-analysis found that studies may have overestimated Caesarean section risks for attention-deficit hyperactivity disorder by ignoring confounding factors.

Epidemiological studies on associations between Caesarean sections (C-sections) and attention-deficit hyperactivity disorder (ADHD) have been inconsistent, and we performed a meta-analysis. We systematically searched PubMed and Embase to December 2018 and included nine hospital-based and population registry studies published in 2011-2018. These covered a total study cohort of more than 2.5 million people in eight countries: Australia, Brazil, Denmark, Finland, Germany, Sweden, Turkey and the UK. The analysis provided summary odds ratios (ORs) and 95% confidence intervals (CI) while taking heterogeneity into account. We found that that C-sections were associated with a small increase in the risk of ADHD (OR 1.14, 95% CI 1.11, 1.17, I2 0%) in offspring. In subgroup analyses, the association remained for both infants born after elective C-sections (OR, 1.15, 1.11, 1.19, I2 0%) and emergency C-sections (OR, 1.13, 1.1, 1.17, I2 45.4%). However, these were only marginally significant when we pooled data from siblings from other pregnancies (OR, 1.06, 1.00-1.13, I2 0%), implying that the association was due to confounding. The statistically significant association between C-sections and ADHD in children can be partially explained by unmeasured confounding. Further research controlling for important confounders is required before firm conclusions can be drawn.

Association of Prenatal Maternal Anemia With Neurodevelopmental Disorders

Given the critical role that iron plays in neurodevelopment, an association between prenatal iron deficiency and later risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), is plausible. To test the a priori hypothesis that anemia diagnosed in mothers during pregnancy is associated with an increased risk of ASD, ADHD, and ID in offspring and that the magnitude of the risk varies with regard to the timing of anemia in pregnancy. This cohort study used health and population register data from the Stockholm Youth Cohort to evaluate 532 232 nonadoptive children born from January 1, 1987, to December 31, 2010, in Sweden, with follow-up in health registers until December 31, 2016. Data analysis was performed from January 15, 2018, to June 20, 2018. Registered diagnoses of anemia during pregnancy. Gestational timing of the first recorded anemia diagnosis (≤30 weeks or >30 weeks) was considered to assess potential critical windows of development. Registered diagnoses of ASD, ADHD, or ID or co-occurring combinations of these disorders. The cohort included 532 232 individuals (272 884 [51.3%] male) between 6 and 29 years of age at the end of follow-up (mean [SD] age, 17.6 [7.1] years) and their 299 768 mothers. The prevalence of ASD, ADHD, and ID was higher among children born to mothers diagnosed with anemia within the first 30 weeks of pregnancy (4.9% ASD, 9.3% ADHD, and 3.1% ID) compared with mothers with anemia diagnosed later in pregnancy (3.8% ASD, 7.2% ADHD, and 1.1% ID) or mothers not diagnosed with anemia (3.5% ASD, 7.1% ADHD, and 1.3% ID). Anemia diagnosed during the first 30 weeks of pregnancy but not later was associated with increased risk of diagnosis of ASD (odds ratio [OR], 1.44; 95% CI, 1.13-1.84), ADHD (OR, 1.37; 95% CI, 1.14-1.64), and ID (OR, 2.20; 95% CI, 1.61-3.01) in offspring in models that included socioeconomic, maternal, and pregnancy-related factors. Early anemia diagnosis was similarly associated with risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) in a matched sibling comparison. Considering mutually exclusive diagnostic groups, we observed the strongest association between anemia and ID without co-occurring ASD (OR, 2.72; 95% CI, 1.84-4.01). Associations of these disorders with anemia diagnosed later in pregnancy were greatly diminished. In contrast to maternal anemia diagnosed toward the end of pregnancy, anemia diagnosed earlier in pregnancy was associated with increased risk of the development of ASD, ADHD, and particularly ID in offspring. Given that iron deficiency and anemia are common among women of childbearing age, our findings emphasize the importance of early screening for iron status and nutritional counseling in antenatal care.

Prenatal Exposure to Acetaminophen and the Risk of Attention-Deficit/Hyperactivity Disorder: A Nationwide Study in Taiwan.

Studies have suggested that a significant association exists between prenatal exposure to acetaminophen and the offspring's attention-deficit/hyperactivity disorder (ADHD) risk. However, this association has largely been unexplored among the Asian population, generally, and the Taiwanese population, specifically. In our study, 950 study pairs (children with ADHD [ICD-9-CM code: 314] and their mothers) and 3,800 control pairs (children without ADHD and their mothers) matched by demographic characteristics were identified between 1998 and 2008 from the Taiwan Longitudinal Health Insurance Database. Maternal use of acetaminophen was assessed in the first trimester, second trimester, and third trimester of pregnancy and over the period from 3 months before pregnancy to the date of last menstrual cycle. Logistic regression analysis with adjustments for demographic data, gestational infections, comorbid perinatal conditions, and maternal mental health disorders indicated that exposure to acetaminophen in the second trimester (odds ratio [OR] = 1.19; 95% CI, 1.00-1.40), both the first and second trimesters (OR = 1.28; 95% CI, 1.00-1.64), or in any trimester (OR = 1.20; 95% CI, 1.01-1.42) was associated with an increased risk of ADHD in offspring. Sensitivity analysis excluding gestational infections and maternal mental health disorders confirmed this association (OR = 1.33; 95% CI, 1.04-1.69). Prenatal exposure to acetaminophen was associated with an increased risk of ADHD in offspring, regardless of gestational infections and maternal mental health disorders. Additional studies are necessary to clarify the underlying mechanisms by which prenatal exposure to acetaminophen leads to neurodevelopmental risks.

Parental asthma occurrence, exacerbations and risk of attention-deficit/hyperactivity disorder

ObjectiveTo investigate whether intrauterine exposure to maternal asthma or asthma exacerbations increases the risk of attention-deficit/hyperactivity disorder (ADHD). MethodsUsing Danish register data, this cohort study comprised of 961,202 live singletons born in Denmark during 1997–2012. Children were followed to a maximum of 20.0 years from birth until the first of ADHD-diagnosis/prescription, emigration, death, or 31 December 2016. Cox regression models were used to evaluate the association between maternal or paternal asthma, asthma exacerbations and offspring ADHD. ResultsDuring 11.4 million person-years of follow-up, 27,780 (2.9%) children were identified as having ADHD. ADHD risk was increased among offspring born to asthmatic mothers (hazard ratio (HR) 1.41, 95% CI: 1.36–1.46) or asthmatic fathers (HR 1.13, 95% CI: 1.08–1.18). Antenatal antiasthma medication treatment did not increase offspring ADHD. However, higher risks were observed among offspring of mothers with asthma exacerbations compared with children of asthmatic mothers with no exacerbations: HR 1.12 (95% CI: 1.00–1.25) for pre-pregnancy exacerbations; 1.21 (95% CI: 1.00–1.47) for exacerbations during pregnancy; and 1.25 (95% CI: 1.08–1.44) for exacerbations after delivery. ConclusionsThese results support theories regarding shared genetic and environmental risk factors having a role in the development of ADHD.

Organophosphate pesticide metabolite concentrations in urine during pregnancy and offspring attention-deficit hyperactivity disorder and autistic traits

BackgroundPrenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings. ObjectiveThe objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. MethodMaternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18‐25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders. ResultsMedian DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18–25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: −0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected. ConclusionsIn this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.

Association between pharmacotherapy for ADHD in offspring and depression-related specialty care visits by parents with a history of depression

BackgroundPharmacotherapy is effective in reducing the core symptoms of attention-deficit/hyperactivity disorder (ADHD). We aimed to investigate the concurrent association between pharmacotherapy for ADHD in offspring and depression-related specialty care visits by the parents with a history of depression.MethodsUsing data from a variety of Swedish national registers, we conducted a cohort study with 8-year follow-up of 5605 parents (3872 mothers and 1733 fathers) who had a history of depression and an offspring diagnosed with ADHD. The hazard rate for parental depression-related specialty care visits during exposed periods when the offspring was on medication for treatment of ADHD was compared with the hazard rate during unexposed periods when the offspring was off medication. Within-individual comparisons were employed to control for time-constant confounding factors.ResultsAmong mothers, the crude rates of depression-related specialty care visits during exposed and unexposed periods were 61.33 and 63.95 per 100 person-years, respectively. The corresponding rates among fathers were 49.23 and 54.65 per 100 person-years. When the same parent was compared with him or herself, fathers showed a decreased hazard rate for depression-related visits during exposed periods when the offspring was on medication for treatment of ADHD as compared to unexposed periods (hazard ratio, 0.79 [95% confidence interval, 0.70 to 0.90]). No statistically significant associations were observed in mothers.ConclusionsAmong parents with a history of depression, pharmacotherapy for ADHD in offspring is concurrently associated with a decreased rate of depression-related specialty care visits in fathers but not in mothers. Future research with refined measures of parental depression and other time-varying familial factors is needed to better understand the mechanisms underlying the association.

Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD)

Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case–control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD (OR 1.05, 95% CI 0.96–1.15). No significant associations were seen in the highest quintile of CRP (OR 1.18, 95% CI 0.88–1.58). The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.

Maternal fever during pregnancy and offspring attention deficit hyperactivity disorder

Maternal fever during pregnancy is associated with several adverse child outcomes. We investigated associations between maternal fever and ADHD among offspring, as well as the sub-dimensions of ADHD - inattention and hyperactivity/impulsivity. Data came from the Norwegian Mother and Child Cohort Study, including more than 114,000 children. Information about children’s ADHD diagnoses was obtained from the Norwegian Patient Register. Mothers reported on inattention and hyperactivity/impulsivity symptoms in questionnaires at 8 years. Logistic regression analysis showed that children exposed to maternal fever in the first trimester received an ADHD diagnosis more often than unexposed children (Odds Ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06–1.61). For children exposed twice or more in the first trimester, the OR was 2.64 (CI = 1.36–5.14). Linear regression analysis showed elevated inattention symptoms among children exposed to fever in the first (Cohen’s d = 0.09, CI = 0.03–0.15) and second (Cohen’s d = 0.05, CI = 0.01–0.09) trimester. Results were similar whether the mother had taken acetaminophen for their fever or not. Hyperactivity/impulsivity symptoms were not related to maternal fever. The results indicate that maternal fever in early pregnancy may be a risk factor for ADHD, and particularly for inattention problems. This risk is neither mitigated nor inflated by use of acetaminophen.

Low-moderate prenatal alcohol exposure and offspring attention-deficit hyperactivity disorder (ADHD): systematic review and meta-analysis.

To evaluate the available evidence on the association between low-to-moderate prenatal alcohol exposure (PAE) and the development of attention-deficit hyperactivity disorder (ADHD) symptoms in the offspring. We systematically reviewed and meta-analysed studies reporting an association between low and/or moderate PAE and offspring ADHD symptoms (attention and/or hyperactivity). Systematic searches were performed in EMBASE, Pubmed, Medline, and PsycINFO and reviewed from selected references. Random effects modelling was conducted to pool adjusted odds ratios (OR) in different alcohol consumption levels (≤ 20g/week, ≤ 50g/week, and ≤ 70g/week). Stratified analysis by sex per alcohol level was conducted to investigate the difference on OR and the magnitude between-study heterogeneity. Ten studies were included in the systematic review and six in the meta-analysis. Eight studies found no association and two studies suggested an apparent protective effect of low PAE in hyperactivity/inattention symptoms in boys. These results were confirmed by the meta-analysis showing no association between ≤ 20g/week [OR 1.01 (0.68-1.49)], ≤ 50g/week [OR 0.94 (0.85-1.03)] and ≤ 70g/week [OR 0.94 (0.86-1.02)] and ADHD symptoms, with no evidence of publication bias. Stratified analysis by sex for a PAE ≤ 50g/week exposed less risk of ADHD symptoms in boys compared to girls [OR 0.89 (0.83-0.96)]. We found no increased risk of ADHD symptoms in offspring born to mothers who drank alcohol up to 70g/week.