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Abstract
Introduction Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition prevalent in both children and adults. With growing awareness of the importance of the preconception period in health, it is essential to understand whether preconception parental mental health and related factors are related to onset of offspring ADHD. This protocol presents the methodology for undertaking a systematic review to investigate associations between parental mental health and/or psychotropic use during the preconception years and offspring ADHD.
Methods and analysis Peer-reviewed literature will be identified by searching relevant electronic databases including Medline complete, Embase, PsycINFO and CINAHL; reference lists of eligible articles will be hand searched and grey literature considered. Eligible study designs include population-based and/or clinically based cohort or case–control studies. The primary exposure and outcome of interest is parental history of mental health conditions in the preconception period and offspring ADHD, respectively (ie, according to semistructured interviews/confirmed diagnosis by a relevant health professional or screening instruments). Critical appraisal will be undertaken. A descriptive synthesis will be presented including characteristics of the included studies, critical appraisal scores and a summary of main findings (eg, presented in tables, text and figures). A meta-analysis will be conducted, if possible, and statistical techniques will be employed if heterogeneity is detected.
Ethics and dissemination Ethical permissions are not required for this systematic review since the study will only use published data. Findings from this systematic review will be published in a peer-reviewed scientific journal/presented at national and international conferences relevant to the field.
PROSPERO registration number CRD42023460379.
- mental health
- psychiatry
- child & adolescent psychiatry
- adult psychiatry
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Our systematic review is a novel attempt to determine whether parental mental health and/or psychotropic use during the preconception years is associated with offspring ADHD.
Two independent reviewers will confirm study selection, perform data extraction and assessment of methodological quality.
No studies will be excluded based on year of publication or nationality.
Potential limitations include scarcity of data in the area of interest and heterogeneity of the available evidence.
Introduction
Attention Deficit Hyperactivity Disorder (ADHD) as described in the fifth Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is characterised by a ‘persistent pattern of inattention and hyperactivity or impulsivity that interferes with functioning to a degree that is inconsistent with developmental levels’.1 According to the Global Burden of Disease (GBD) study, it is estimated that ADHD is a leading cause of disability adjusted life years (DALY) with ADHD being responsible for 491 500 DALYs in 2010.2 3 ADHD is believed to have a global prevalence of between 5.9% and 7.1% in children, and among adults, an estimated range of between 1.2% and 7.3%.4 5 The nature of ADHD can be explained in terms of childhood-onset, persistent, remitted and young-onset adult ADHD. Based on its symptom presentation, ADHD can be subdivided into three subtypes according to the DSM criteria and it is estimated that the inattentive type of ADHD is the most common in population-based studies, followed by the combined and the hyperactive subtypes.6 However, in clinical studies, greater prevalence can be seen for the combined subtype followed by the inattentive and hyperactive subtypes, respectively.7 The aetiology of ADHD is hypothesised to be vast and diverse.8 The biopsychosocial model of health and disease assumes ADHD has its own developmental, psychological and environmental factors that contribute to and magnify symptoms.9 To date, no single factor has been identified as causal, rather a combination of, and interactions between a number of factors are thought to be more likely.10
Several epidemiological studies have set out to investigate the role of exposures, in particular during the prenatal and postnatal periods in influencing long-term disease risk.11 Psychiatric disorders are one of such exposures that have been increasingly investigated. A recent meta-analysis revealed that maternal and paternal depression both prenatally and postnatally affect child outcomes, and more specifically, increases the risk of ADHD.12 Similarly, another meta-analysis revealed that parental depression during the prepregnancy, antenatal and postnatal time windows is associated with increased ADHD risk in offspring.13 Furthermore, there is some evidence to suggest that parental history of psychiatric disorders including substance use, personality and anxiety disorders are also associated with increased risk of offspring ADHD.12 14 In terms of substance use disorders, a recent systematic review revealed that the risk for offspring ADHD was higher when parents identified as using alcohol prior to the child’s birth, suggesting the possibility of germ cell mutation in increasing the risk for ADHD.15 The use of psychotropic medications during the preconception period, especially antidepressant use prior to pregnancy has been shown to influence ADHD risk in the offspring.16
To summarise, it is not well understood whether maternal and paternal mental health histories may differentially influence the risk of offspring ADHD, including age of onset, recency and type of mental health condition. Therefore, we present a protocol of the methodology to undertake a systematic review with an aim of evaluating whether parental mental health and/or psychotropic use during the preconception years is associated with ADHD in the offspring. This review would essentially provide a starting point for further research in the current area.
Objectives
This systematic review will do the following:
Investigate the association between parental mental health conditions and/or psychotropic use during preconception years and the risk of offspring ADHD.
Evaluate the methodological quality for all studies eligible for inclusion in this review.
Collate available evidence including any potential confounding and/or mediating factors in the link between parental mental health and/or psychotropic use and offspring ADHD.
Methods and analysis
Design
Inclusion criteria
The inclusion criteria according to the population, exposure and outcome framework are as follows:
Population
Studies will be eligible if they examine population-based and/or clinically based samples.
Exposure
The exposure(s) of interest include parental history of mental health conditions preconception (yes/no) as defined by criteria based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) and assessed by structured/semistructured interviews or confirmed diagnosis by a relevant health professional including:
Mood disorders.
Anxiety disorders.
Substance use/related disorders.
Eating disorders.
Neurodevelopmental or neurocognitive disorders.
Personality disorders.
Trauma/stressor-related disorders.
Disruptive/impulse-control/conduct disorders.
In addition, studies that examine the use of prenatal preconception psychotropic use (ever/current) will also be considered. The current study will focus on both mothers and fathers. Only biological parents will be considered for this review.
Outcome
Studies will be eligible if they examine ADHD in offspring based on DSM or ICD criteria, structured/semistructured interviews (yes/no) or screening instruments or self-report questionnaires (continuous).
The DSM-V Criterion A for diagnosing ADHD requires the presence of at least five inattentive or the hyperactive/impulsivity symptoms for older adolescents and adults (age 17 or older), whereas for children, any six out of the nine symptoms are required. With the latest revision of the DSM-IV to DSM-V, the age of onset criterion has been changed from ‘the symptoms to be present before age 7 years’ to ‘the symptoms to be present before age 12 years’. For this review, ADHD symptoms diagnosed prior to age 12 years will be classified as Child ADHD, symptoms diagnosed after 17 years as Adult ADHD and the period in-between as Adolescent ADHD. If relevant, ADHD as measured at single and/or several timepoints will be included.
Study designs
Relevant cohort or case controls studies will be considered eligible.
Language
Assistance will be sought to interpret articles written in languages other than English, where possible.
Exclusion criteria
Studies with a non-eligible design (eg, cross-sectional).
Studies diagnosing ADHD not according to the inclusion criteria.
Exposures not defined as per the inclusion criteria (eg, other medical conditions).
Information sources
Relevant peer-reviewed literature will be identified via electronic searching of research databases in the disciplines of medical, health and social sciences (eg, Embase, PsycINFO, CINAHL and Medline Complete). Reference lists of eligible articles will be hand searched to pick out relevant additional studies that might not have been identified from the database searching. In addition, grey literature will be considered and searched, such as published theses from ProQuest Dissertations and Theses Global.
Search strategy
First, a preliminary search strategy was developed by listing and mapping keywords according to the major themes of this project, which was guided by the literature.12 15 Next, the search was implemented for Medline Complete via the EBSCOhost platform on 7 March 2023 to scope the existing literature on the topic of preconception mental health and ADHD. This included potentially existing longitudinal studies and reviews on this topic. A liaison librarian will be consulted to further refine the preliminary search and translate it for the other databases including, Embase, PsycINFO and CINAHL. No restrictions regarding the year of publication will be applied.
Record management
One reviewer (DAJ) will apply the search strategy and manage the records using a citation management application.
Selection process
Screening
Two reviewers will independently screen and review full-text articles for inclusion. The supervising author will provide consensus where necessary (eg, if discrepancies cannot be resolved by the two reviewers at either stage).
Data collection process
Critical appraisal of individual studies
The included studies will undergo critical appraisal using the JBI critical appraisal tools for epidemiological study designs by two reviewers, independently. Potential disagreements arising out of the rigorous appraisal by the two reviewers will be solved by consensus from the supervising author, if necessary.
The JBI critical appraisal tools17 were selected as they are helpful in assessing the methodological quality of case–control and cohort studies and to determine the extent to which the possibility of bias in the design, conduct and analysis has been introduced in a study.
Sum scores will be calculated according to each relevant study design: 0–9 for case–control studies and 0–11 for cohort studies. The critical appraisal score will be reported in a table and discussed in the results/discussion section(s) of the ensuing review.
Data extraction
A preliminary data extraction form has been developed; the final version of the form will be further refined with guidance from a statistician and pilot tested by the review team. The planned data items for extraction are presented in online supplemental appendix A. A data validation process will be implemented to ensure accuracy of the data collected and coded. Further details will be provided in the ensuring review.
Supplemental material
Presenting and reporting results
A narrative synthesis will be used to present the major findings including characteristics of the included studies, critical appraisal scores and summary of main findings in text and tables/figures. The narrative synthesis will present the findings according to each exposure, if possible.
Meta-analyses will be performed, where appropriate. For categorical outcomes (eg, diagnosed categorical ADHD: yes/no), the OR will be considered the main effect size; if relevant, risk ratios from eligible studies will be transformed into ORs. Where possible, the outcome will be grouped according to the DSM-V criterion for ADHD (ie, child, adolescent and/or adult).
Adjusted ORs from the most fully adjusted models from each study will be used in a pooled analysis. For continuous outcomes (eg, ADHD symptoms determined from screening instruments or self-report questionnaires), regression coefficients and p-values will be considered as the main measure of effect.
As potential heterogeneity is anticipated, all the analysis will be carried out in Stata V.17 using random-effect models. Heterogeneity or the presence of variation in true effect sizes of the studies included will be calculated using the I2 statistic where appropriate. If significant heterogeneity is expected, the ‘leave one out’ approach to sensitivity analysis will be applied where the overall effect against which heterogeneity is measured changes each time a study is excluded. A subgroup analysis will be performed to assess the stability of results and potential sources of heterogeneity. This subgroup analysis may also be conducted according to the study design, sex (father/mother) and/or adjustment for important confounding factors.
Separately, a comprehensive search strategy will be developed, which is anticipated to minimise the potential for publication bias. The issue of publication bias will be resolved by visually inspecting the funnel plot and looking for funnel plot asymmetry. The funnel plot is a scatter plot which helps in identifying publication bias in the form of missing studies, which specifically targets small study bias, in which these studies show greater variability and larger effect estimates when compared with larger studies.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be adhered to with regard to the conduct and presentation of findings of this review. A meta-analysis will be undertaken, if possible.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Anticipated or actual start date
1 August 2024
Anticipated completion date
20 December 2025
Discussion
The growing body of literature shows that genetics play a large role in ADHD and that genetic risks can increase susceptibility to ADHD by altering individual sensitivity towards environmental risks or protective factors.18 ADHD runs in families and can be transmitted from one generation to another which can be coined as the term ‘inherited risk or liability’, even though not all genetic risks need not be inherited. Heritability estimates in ADHD aetiology not only accounts for genetic risks but rather an interplay of gene-environment interaction.19
Thus, the role of genetics and heritability is a strong predictor in the aetiology of ADHD. Any observable association found in the study might also be because of the genetic factors and for the same reason, genetically sensitive study designs will be included in the current study.
Ethics and dissemination
Given that this systematic review will only use published data, we do not require ethical permissions. However, our research processes will strictly adhere to ethical and governance standards in matters of data management and in the presentation and discussion of our results.
Findings from this systematic review will be published in a peer-reviewed scientific journal and will be presented at national and international conferences relevant to the field of neuropsychiatric disorders or ADHD.
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors DAJ, SQ and LW conceived the research idea. All authors including DAJ, SQ, JP, NKH and LW edited and contributed to writing the manuscript and approved the final version. DAJ is the guarantor of this review.
Funding DAJ is supported by the Deakin university postgraduate research scholarship (DUPRS). LJW is supported by a NHMRC Emerging Leadership Fellowship (1174060). The funding providers played no role in the design or conduct of the study; in the collection, management, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.