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Prenatal and perinatal factors associated with ADHD risk in schoolchildren: EPINED epidemiological study

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Joana Roigé-Castellví at Universitat Rovira i Virgili
Joana Roigé-Castellví
Paula Morales Hidalgo at Universitat Oberta de Catalunya
Paula Morales Hidalgo
Núria Voltas at Universitat Rovira i Virgili
Núria Voltas
Carmen Hernández-Martínez at Universitat Rovira i Virgili
Carmen Hernández-Martínez
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Abstract

The aim of this study is to assess the relationship between pre- and perinatal factors and ADHD in a sample of scholars exploring differences between ADHD presentations and spectrum of severity. A total of 6720 scholars (aged 3–4 and 10–11) participated in a double-phase epidemiologic cross-sectional study (Epidemiological Study of Neurodevelopmental Disorders, EPINED), and a sample of 646 scholars (ADHD risk, ASD risk and controls without risk) were individually assessed in the second phase of the study. The ADHD diagnosis, based on DSM-5 criteria, was performed with the Kiddie-Schedule for Affective Disorders & Schizophrenia, Present & Lifetime Version. Associations for the different ADHD presentations between prenatal, perinatal and postnatal factors and ADHD (n = 168), subclinical ADHD (n = 88) and non-ADHD (n = 310) were analysed. Logistic regression models showed that gestational diabetes (p = 0.012), instrumental delivery (p = 0.011), family history of psychopathology (p = 0.033) and maternal ADHD phenotype (p = 0.023) were associated with ADHD. These factors were related to the hyperactive–impulsive and combined presentations, but they were not related to the inattentive presentation. Maternal weight gain was associated with subclinical ADHD. In conclusion, metabolic disorder in the pregnancy, difficulties in childbirth and specific family phenotype were related to ADHD, specifically with hyperactive–impulsive presentation, but not in subclinical ADHD.
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Vol.:(0123456789)
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European Child & Adolescent Psychiatry (2021) 30:347–358
https://doi.org/10.1007/s00787-020-01519-2
ORIGINAL CONTRIBUTION
Prenatal andperinatal factors associated withADHD risk
inschoolchildren: EPINED epidemiological study
JoanaRoigé‑Castellví1 · PaulaMorales‑Hidalgo1· NúriaVoltas1· CarmenHernández‑Martínez1·
GeorgettevanGinkel1· JosefaCanals1
Received: 2 November 2019 / Accepted: 22 March 2020 / Published online: 2 April 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
The aim of this study is to assess the relationship between pre- and perinatal factors and ADHD in a sample of scholars
exploring differences between ADHD presentations and spectrum of severity. A total of 6720 scholars (aged 3–4 and 10–11)
participated in a double-phase epidemiologic cross-sectional study (Epidemiological Study of Neurodevelopmental Disor-
ders, EPINED), and a sample of 646 scholars (ADHD risk, ASD risk and controls without risk) were individually assessed
in the second phase of the study. The ADHD diagnosis, based on DSM-5 criteria, was performed with the Kiddie-Schedule
for Affective Disorders & Schizophrenia, Present & Lifetime Version. Associations for the different ADHD presentations
between prenatal, perinatal and postnatal factors and ADHD (n = 168), subclinical ADHD (n = 88) and non-ADHD (n = 310)
were analysed. Logistic regression models showed that gestational diabetes (p = 0.012), instrumental delivery (p = 0.011),
family history of psychopathology (p = 0.033) and maternal ADHD phenotype (p = 0.023) were associated with ADHD.
These factors were related to the hyperactive–impulsive and combined presentations, but they were not related to the inat-
tentive presentation. Maternal weight gain was associated with subclinical ADHD. In conclusion, metabolic disorder in the
pregnancy, difficulties in childbirth and specific family phenotype were related to ADHD, specifically with hyperactive–
impulsive presentation, but not in subclinical ADHD.
Keywords ADHD diagnosis· ADHD presentations· Risk factors· Family ADHD phenotype
Introduction
Attention deficit hyperactive disorder (ADHD) is a pervasive
neuropsychiatric disorder that manifests in inattention and/
or overactivity that significantly interferes with the child’s
functioning in family, social and/or academic settings [1–3].
According to clinical patterns, ICD-11 and DSM-5 criteria
distinguish between predominantly hyperactive–impulsive,
inattentive and combined presentations [4]. ADHD begins
in the early years of life, but usually persists until adoles-
cence or adulthood. It frequently co-occurs with other neu-
rodevelopmental or emotional and behavioural disorders,
which worsens the ADHD clinical course and prognosis
[5–7]. ADHD is a frequent disorder and its prevalence
has increased considerably in recent years [8, 9]. The lat-
est data suggest that the prevalence of ADHD in children
and adolescents is around 6–7% [10, 11]. In the Spanish
population, Canals, Morales-Hidalgo, Jané and Domènech
[12], and Ezpeleta, De La Osa and Doménech [13] found a
prevalence of 2–5% among pre-schoolers, while in the ado-
lescent population the prevalence was around 7% [14]. The
impaired behavioural and neuropsychological functioning of
ADHD children is associated with functional and morpho-
logical abnormalities in the fronto-striatal circuits. Specifi-
cally, several studies have observed a reduced volume and/or
activity of grey and white matter, and slower maturation of
the amygdala, nucleus accumbens, prefrontal cortex, caudate
and cerebellum, which underlies the reduced brain function-
ing and impaired communication in numerous neural tracts
[15–17]. In this sense, the results obtained by the ENIGMA
study indicate that the morphological abnormalities related
to ADHD reflect the existence of a family endophenotype,
linked to the symptomatology of ADHD in the population,
* Josefa Canals
josefa.canals@urv.cat
1 Department ofPsychology, Facultat de Ciències de
l’Educació i Psicologia, Research Center forBehavioral
Assessment (CRAMC), Universitat Rovira i Virgili,
Carretera de Valls, s/n, 43007Tarragona, Spain
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Evidence is emerging that an altered maternal metabolic state during pregnancy can increase a child's susceptibility to developing ADHD in childhood or adolescence. Type I diabetes in the mother is associated with an increased risk of ADHD in offspring [30] and higher rates of ADHD medication use in adolescents 13-19 years of age [31], and gestational diabetes mellitus is associated with increased likelihood of ADHD diagnosis in offspring aged 4-11 years [32]. Although the mechanisms linking in utero exposure to maternal diabetes and ADHD are not well understood, research in animal models suggests that epigenetic changes and oxidative stress in the mother and fetus, driven by high maternal glucose levels, may have detrimental effects on developing fetal neural tissues [33]. ...
... kg/m 2 ) may be more susceptible to developing ADHD by as much as 30% [34][35][36], and children whose mothers have obesity (BMI ≥ 30 kg/m 2 ) may be more susceptible by 60% [35]. Notably, excess weight gain during pregnancy is also associated with increased likelihood of subclinical ADHD presentation in children aged 4-11 years [32]. Epigenetic modifications, dysregulated leptin signaling, and increased levels of circulating pro-inflammatory cytokines as a result of chronic inflammation are posited to associate with maternal overweight and obesity, and may therefore be consequential for the developing fetal brain [37]. ...
Developmental Origins, Differential Susceptibility, and Resilience in Neurodevelopmental Disorders
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  • Feb 2023
Early life environments program developmental processes that determine later life disease risk and resiliency. To understand how early life circumstances shape health trajectories, it is critical to consider how environmental adversity and enrichment interact with constitutional factors, such as one’s genetic makeup, to produce lasting changes to the structure and function of biological systems. In this chapter, we illustrate how pre- and postnatal environments influence neurodevelopmental disorder emergence and trajectories, with a focus on Attention Deficit Hyperactivity Disorder (ADHD). We present evidence that prenatal exposure to nutritional insufficiency, altered maternal metabolic states, or excessive maternal stress and mental health challenges can make a child more susceptible to developing ADHD. We also explore how postnatal environmental enrichment may mitigate the consequences of adverse prenatal exposures and optimize developmental trajectories. Lastly, we present approaches for exploring gene-by-environment interactions, which have the potential to help identify those who are especially susceptible to adverse environments, as well as those who may benefit from enriched environments. The work highlighted supports a developmental approach for understanding the emergence of neurodevelopmental disorders, as well as evidence of continued susceptibility and resilience across the lifespan. Additionally, this work describes spaces where early intervention could modify long-term trajectories.
View
... Studies suggested that chronic exposure to hypoxia is more likely to be associated with neuropsychological impact, specifically ADHD (Brake et al., 2000;Hediger et al., 2013;Dunn et al., 2019;Roigé-Castellví et al., 2020) rather than acute insults. ...
... Moreover, there was a significant difference between the ADHD group and control group as regards the occurrence of maternal skin allergy during pregnancy (P=0.05), denoting that the inflammatory process plays an important role in association with ADHD (Brake et al., 2000;Trammell, 2012;Lu et al., 2013;Roigé-Castellví et al., 2020). ...
View
... The studies that were selected for inclusion quantified the relationship between prenatal tobacco exposure and diagnosed BDs in children aged 4 to 18 years old. We excluded studies from the meta-analysis if they (a) were not written in English (e.g., [65,66]); (b) were not a quantitative study of the relationship between prenatal tobacco exposure and BDs (e.g., [67,68]); (c) did not include a clear measure of a clinically diagnosed BD (e.g., [37,69]); (d) did not include a non-exposed comparison/control group that did not smoke during pregnancy (e.g., [70][71][72][73]); (e) had samples that were either less than 4 years of age, or greater than 18 years of age or included children that were below 4 or above 18 (e.g., [74][75][76]) or did not report child age at the time of diagnosis [77]; (f) did not report an unadjusted odds ratio, or information that could be meaningfully converted to an unadjusted odds ratio, such as a 2 × 2 frequency table that included the number of exposed vs. non-exposed participants and number diagnosed and not diagnosed within those categories (e.g., [78][79][80][81][82]); (g) had a sample that was not clearly independent (e.g., twin sample, large national samples covering several years of births where siblings were not clearly excluded [83][84][85]). ...
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Prenatal tobacco exposure has been implicated in increased risk of the development of behavioral disorders in children and adolescents. The purpose of the current study was to systematically examine the association between prenatal tobacco exposure and diagnoses of Attention Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, and Conduct Disorder in childhood and adolescence. We searched Medline, Psychinfo, ERIC, Proquest, Academic Search Complete, PsychArticles, Psychology and Behavioral Sciences Collection, Web of Science, CINAHL Plus, and Google Scholar databases through October 2022. The authors screened studies and extracted data independently in duplicate. Ten clinical studies examining diagnoses of Attention Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, and Conduct Disorder between the ages of 4 and 18 years old were included. There was insufficient evidence to synthesize outcomes related to Conduct Disorder and Oppositional Defiant Disorder. The meta-analysis found a significant effect of prenatal tobacco exposure in increasing the likelihood of an Attention Deficit/Hyperactivity Disorder diagnosis in childhood and adolescence. Implications for future research are discussed.
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... This result suggests that the pathways linking parental psychiatric history to these subgroups are similar and is consistent with findings in other studies. [39][40][41][42] That the association may reflect shared etiologic mechanisms is also consistent with reports of considerable genetic overlap across autism, ADHD, and other psychiatric conditions. [43][44][45] An alternative explanation is that this parental psychiatric diagnosis variable was nonspecific, given that it combined across psychiatric diagnoses. ...
Method for Testing Etiologic Heterogeneity Among Non-Competing Diagnoses, Applied to Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder
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  • Jul 2024
Background Testing etiologic heterogeneity – whether a disorder subtype is more or less impacted by a risk factor, is important for understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic sub-categorization because these disorders are heterogenous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for non-competing events in an open cohort of variable-length follow-up. Thus, we developed a new method. Methods We estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a co-diagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism+ADHD. To calculate the risk of a single diagnosis (e.g. autism alone), we subtracted the risk for autism+ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors. Results Urban residence was most strongly linked with autism+ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups. Conclusions Our method allowed the calculation of appropriate p values to test strength of association, informing etiologic heterogeneity wherein two of these three risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.
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... This result suggests that the pathways linking parental psychiatric history to these subgroups are similar, and is consistent with findings in other studies. [36][37][38][39] That the association may reflect shared etiologic mechanisms is also consistent with reports of considerable genetic overlap across autism, ADHD, and other psychiatric conditions. [40][41][42] An alternate explanation is that this parental psychiatric diagnosis variable was non-specific, given that it combined across psychiatric diagnoses. ...
Method to Test Etiologic Heterogeneity Among Non-Competing Diagnoses that Accrue Over Time: Application to Discriminating the Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder
Preprint
  • Aug 2023
Background: Testing etiologic heterogeneity, whether a disorder subtype is more or less impacted by a risk factor, is important toward understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic sub-categorization because these disorders are heterogenous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for non-competing events in an open cohort of variable-length follow-up. Thus, we developed a new method. Methods: We estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a co-diagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism+ADHD. To calculate the risk of a single diagnosis (e.g. autism alone), we subtracted the risk for autism+ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors. Results: Urban residence was most strongly linked with autism+ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups. Conclusions: Our method allowed the calculation of appropriate p values to test strength of association, showing etiologic heterogeneity wherein 2 of these 3 risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.
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Environmental Risk Factors for Attention-Deficit/Hyperactivity Disorder
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Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders and is accompanied by significant multidomain impairment. While genetic influences on the development of ADHD are strong (heritability of 0.70–0.80), there is increasing evidence suggesting that environmental factors may also play an etiological role. This chapter summarizes the literature investigating associations between various prenatal, perinatal/childbirth-related, and postnatal environmental risk factors and categorical ADHD diagnoses, as well as dimensionally measured ADHD symptoms. The complex interplay between genes and environment, as well as the role of protective factors, are also discussed. Overall, there appears to be stronger evidence for some factors (e.g., prematurity, low birth weight, parental age, maternal cigarette smoking, exposure to environmental toxins, and extreme early deprivation) than others (e.g., maternal diet, method of delivery, and screen time), and that certain protective factors such as family cohesion, community support, and maternal breastfeeding may play a role in promoting positive outcomes among individuals with ADHD, in some cases potentially reducing risk for ADHD. Methodological limitations and guidelines for future research are proposed. Examining the impact of environmental risk factors and protective factors, as well as gene–environment interactions, will be crucial to efforts aimed at uncovering etiological pathways to ADHD.
View
Preterm or Early Term Birth and Risk of Attention-Deficit/Hyperactivity Disorder: A National Cohort and Co-Sibling Study
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Introduction: The association between Bisphenol A (BPA) exposure and attention deficit hyperactivity disorder (ADHD) has been a controversial topic. Objective: To evaluate the connection between BPA exposure and ADHD. Content: We search Scopus, Web of Science, and Medline databases until August 2022. The meta-analysis was performed by using the software Stata 12.0 to calculate the combined effect value Odds ratios (OR) and 95% confidence interval (95%CI). A total of 8 studies were included in this meta-analysis, including 5,710 children. Using the random effect model, it was found that compared with the lowest level of BPA exposure, the OR (95%CI) value of urine BPA exposure and ADHD in the highest level of BPA exposure was 1.76 (1.13-2.74). Summary and outlook: Based on the current meta-analysis results, BPA exposure may be a significant contributing factor to the development of ADHD in children.
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Gestational Diabetes Mellitus (GDM) is the most common metabolic condition during pregnancy and may result in short- and long-term complications for both mother and offspring. The complexity of phenotypic outcomes seems influenced by genetic susceptibility, nutrient-gene interactions and lifestyle interacting with clinical factors. There are strong evidences that not only the adverse genetic background but also the epigenetic modifications in response to nutritional and environmental factors could influence the maternal hyperglycemia in pregnancy and the foetal metabolic programming. In this view, the correlation between epigenetic modifications and their transgenerational effects represents a very interesting field of study. The present review gives insight into the role of gene variants and their interactions with nutrients in GDM. In addition, we provide an overview of the epigenetic changes and their role in the maternal-foetal transmission of chronic diseases. Overall, the knowledge of epigenetic modifications induced by an adverse intrauterine and perinatal environment could shed light on the potential pathophysiological mechanisms of long-term disease development in the offspring and provide useful tools for their prevention.
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Psychiatric Disorders in Mothers of Children with Attention-Deficit/Hyperactivity Disorder: A Population-Based Perspective
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Full-text available
Objectives The purpose of this study was to conduct a long-term, population-based, epidemiologic study of psychiatric disorders in mothers of children with attention-deficit/hyperactivity disorder (ADHD). Methods Subjects included mothers of 306 childhood incident cases of ADHD and mothers of 617 age/gender matched controls from a 1976–1982 birth cohort. Results Compared to mothers of controls, mothers of children with ADHD were significantly more likely to be diagnosed prior to the child’s birth with a depressive disorder (adjusted odds ratio (aOR), 3.1; 95% confidence interval (CI), 1.3–7.7), an adjustment disorder (aOR, 8.1; 95% CI, 1.7–39.5), or any psychiatric disorder (aOR, 2.5; 95% CI, 1.61–4.7) and were likewise significantly more likely to be diagnosed with a de novo (i.e., first diagnosed after the child’s birth) depressive disorder (adjusted hazard ratio (aHR), 1.7; 95% CI, 1.2–2.4), de novo adjustment disorder (aHR, 2.0; 95% CI, 1.4–2.7), or any de novo psychiatric disorder (aHR, 1.7; 95% CI, 1.4–2.2) during the 21 years after the child’s birth. Conclusions This study provides an opportunity to study the natural occurrence of psychiatric disorders in mothers of children with ADHD and suggests that the likelihood of having a child with ADHD is associated with maternal psychopathology both before and after the birth. This adds to existing knowledge of maternal psychopathology for children with ADHD and has implications for screening and monitoring. Future research is needed to clarify the role that both genetic and environmental risk factors play in the increased rates of psychopathology in mothers of children with ADHD.
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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder
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Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
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  • Aug 2019
Objective: To evaluate the association between prematurity (by the gestational week [gw]) and ADHD during childhood. Method: Observational, matched cohort study using data from children born in a tertiary-level hospital (Hospital Universitari Vall d’Hebron, Catalonia, Spain) during 1995-2007 and data from the Information System for the Development of Research in Primary Health Care (SIDIAP database, Catalonia, Spain). Results: Prevalence of ADHD increases as gestational age decreases, 12.7% for those born ≤28 gw, compared to 3.2% for those born after the 37 gw. The risk of developing ADHD in the non-premature children tends to increase as the gw decreases (35-36 gw, hazard ratio [HR] = 1.70, 95% confidence interval [CI] [1.19, 2.44]; 33-34 gw, HR = 3.38, 95% CI [2.08, 5.50]; 29-32 gw, HR = 2.37, 95% CI [1.54, 3.63]; and ≤28 gw, HR = 5.57, 95% CI [2.49, 12.46]) Conclusion: Being born preterm is associated with a risk of developing ADHD, also in late preterm children (35-36 gw). Attention when taking care of these infants regarding their mental health must be made.
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Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples
Article
  • Apr 2019
Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. Methods: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). Results: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. Conclusions: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.
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Heritability of Attention-Deficit Hyperactivity Disorder Across The Lifespan
Article
  • Jan 2019
  • EUR NEUROPSYCHOPHARM
Attention-Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder affecting around 5-10% of children and 2.5-5% of adults worldwide. Research addressing the heritability of ADHD have yielded inconsistent findings, with studies in children suggesting higher heritability (75–90%) compared to studies in adults (30–50% )(Brikell, Kuja-Halkola, and Larsson 2015). To review the role of rater effects on the observed differences in heritability between children and adults, and to address the role of genetic and environmental influences on stability and change of ADHD over the life-span, we conducted a literature review of cross-sectional and longitudinal studies addressing the heritability of ADHD across ages, or in adulthood. We identified quantitative genetic studies published up until May 2017 by searching the NCBI's PubMed database using a combination of the keywords heritability, attention-deficit hyperactivity disorder, attention problems, ADHD, adult, genetic, self-report, twin, longitudinal and family studies. Based on the reviewed cross-sectional studies, the heritability of self-rated ADHD symptoms in adults ranged between 30%-44% and the heritability of self-rated symptoms in adolescent between 34%-54%. Cross-sectional studies including multiple informants showed that heritability estimates based on ratings from different informants (i.e., self-ratings and different parents/teachers rating each twin in a pair) consistently yield lower heritability estimates compared to studies based on ratings from a single informant. This effect appears to be independent of age. One study using cross-informant data in adults (combined parent and self-ratings) and two studies using register based clinical diagnoses in twin and family data reported the heritability of ADHD in adults to be 70–80%. The reviewed longitudinal twin studies suggest that stability in ADHD is largely due to genetic factors. In addition, longitudinal studies also provide evidence that new genetic effects for ADHD come online at different developmental stages and that these genetic factors are partly independent of those contributing to baseline symptoms. We identified one study assessing late-onset adult ADHD, which reported the heritability of both self-reported and co-informant (mother or co-twin) reported clinically relevant ADHD at age 18 to be around 35%. Together, the reviewed cross-sectional studies suggest that the reported lower heritability of ADHD in adults is likely to be at least partly explained by the switch from relying one rater (parent/teacher) in childhood, to relying on self-ratings (where each twin rates themselves) of ADHD symptoms in adulthood. When rater effects are addressed using cross-informant data or clinical diagnoses, the heritability of ADHD in adulthood appears to be comparable to the heritability of ADHD in childhood. Longitudinal studies show evidence for the role of genetic factors in both the stability and change in ADHD across ages. Emerging evidence suggest that the genes implicated in the onset of childhood ADHD are in part distinct from those associated with the developmental course of ADHD. Such findings raise new questions as to whether the heterogeneity in heritability estimates of ADHD across ages may be related to differential developmental trajectories of ADHD.
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Prenatal Cotinine Levels and ADHD Among Offspring
Article
  • Feb 2019
Objectives: An association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) has been shown across several studies based on self-reports. No previous studies have investigated the association of nicotine exposure measured by cotinine levels during pregnancy and offspring ADHD. Methods: In this population-based study, 1079 patients born between 1998 and 1999 and diagnosed with ADHD according to the International Classification of Diseases and 1079 matched controls were identified from Finnish nationwide registers. Maternal cotinine levels were measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank. Results: There was a significant association between increasing log-transformed maternal cotinine levels and offspring ADHD. The odds ratio was 1.09 (95% confidence interval [CI] 1.06-1.12) when adjusting for maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child's birth weight for gestational age. In the categorical analyses with cotinine levels in 3 groups, heavy nicotine exposure (cotinine level >50 ng/mL) was associated with offspring ADHD, with an odds ratio of 2.21 (95% CI 1.63-2.99) in the adjusted analyses. Analyses by deciles of cotinine levels revealed that the adjusted odds for offspring ADHD in the highest decile was 3.34 (95% CI 2.02-5.52). Conclusions: The study reveals an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD. Future studies incorporating maternal smoking and environmental, genetic, and epigenetic factors are warranted.
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Genetic risk factors and gene–environment interactions in adult and childhood attention-deficit/hyperactivity disorder
Article
  • Feb 2019
  • PSYCHIAT GENET
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the 'missing heritability' of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene-environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene-environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.
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The effect of prenatal smoke exposure on child neuropsychological function: a prospective mother–child cohort study
Article
  • Feb 2019
Objective: To study prospectively the effect of prenatal smoke exposure (PSE) on child neuropsychological function and intelligence quotient (IQ). Background: PSE has been associated with adverse effects on child neurodevelopment. However, some studies reported that these associations disappear after adjustment for potential confounders. Methods: A cohortof 248 mothers-child dyad was followed from the first trimester of pregnancy until children were 7.5 years old. PSE was recorded during pregnancy by questionnaire and plasma cotinine. The Wechsler Intelligence Scale for Children, the Neuropsychological Assessment of Executive Functions for Children (ENFEN) and the School Neuropsychological Maturity Questionnaire were administered at 7.5 years of age. The effect of PSE on child IQ and neuropsychological function was assessed with ANCOVA, adjusting for obstetric, neonatal and sociodemographic factors. Results: Children whose mothers smoked throughout pregnancy scored lower in interference (ENFEN) compared to unexposed children (F = 4.1; p = .008). The results showed no differences in other executive functions, verbal and visual memory and IQ between the PSE groups. Conclusion: PSE had little effect on child neuropsychological outcome and was limited to mental flexibility. Nevertheless, these findings support further efforts aimed at encouraging mothers to quit smoking in pregnancy.
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