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Abstract

Background

Adverse childhood experiences (ACEs) are pernicious events (e.g., physical abuse) that occur before 18 years of age within the household. Mothers’ ACEs are associated intergenerationally with their preschool children’s (two-to-five-year-old) behavioural problems, impacting lifelong mental health trajectories. Mediators (e.g., mental health) may explain how mothers’ ACEs exert their influence on children's behavioural development whereas moderators (e.g., child sex) may affect the strength and direction of the association, revealing potential points of intervention. Therefore, this study aimed to: (1) identify mediators and moderators of this association; and (2) describe and compare moderation and mediation outcomes.

Methods

This review (#CRD42022307214) extracted data from peer-reviewed literature formally analyzing at least one moderating or mediating variable of the association between maternal ACEs and preschool children’s behavioural problems using MEDLINE, Embase, APA PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, SCOPUS, and Web of Science databases (n = 7). Validity was assessed using the Joanna Briggs Institute checklists.

Results

Thirteen full-text studies with moderate-to-high validity were identified. Most studies examined mediating variables, with unanimous support for mediation through maternal depression. The mediating roles of adult attachment styles and anxiety were conflicting. No studies examined environmental factors (e.g., neurotoxins).

Conclusions

Mothers’ depression is a significant contributor to children’s behavioural problems in the context of ACEs and should be a target of early intervention to prevent lifelong challenges. Future research should focus on examining more moderating variables and consider the roles of environmental factors. More research is needed on the moderating and mediating roles of genes.

Keywords

maternal adverse childhood experiences children’s behavioural problems mediators moderators child health

Background

Adverse childhood experiences (ACEs) were first identified by Felitti et al¹ in 1998, an overarching term that reflects stressful life events occurring within the household before 18 years of age including: physical, sexual, and/or emotional abuse or neglect; parental incarceration, loss, divorce, or separation; and parental substance use and mental health concerns. Since then, researchers have identified the pervasive and dose-response impacts of ACEs on developmental trajectories that persist into adulthood and result in poorer quality of life.¹ A report published by the Centers for Disease Control and Prevention determined that ACEs are associated with at least half of the top 10 leading causes of death in the US (e.g., strokes, cancer) and that prevalence of depression among adults could be reduced by 44% if ACEs were prevented.² Mothers (who are often the primary caregiver due to historically-rooted gender expectations) with mental and physical health problems subsequent to their ACEs are also at risk of providing less optimal care to their children.¹ Consequently, these children are more likely to develop behavioural problems which are associated with adverse developmental trajectories such as mental, physical, and psychosocial problems (e.g., unemployment), reflecting intergenerational transmission of negative impacts via ACEs.³ Understanding mediators and moderators of these troubling associations could help practitioners to intervene at appropriate timeframes to hinder the transmission of poor health outcomes intergenerationally.

Maternal Adverse Childhood Experiencess are Associated with their Children’s Behavioural Problems

Many studies provide evidence for the positive association between maternal ACEs and preschool children’s internalizing and externalizing behavioural problems.⁴ Internalizing behaviours (e.g., anxiety, depression, somatic complaints) are psychological in nature, inwardly focused, and related to the emotional state of the child.⁵ Conversely, externalizing behaviours are manifested in actions directed towards the external environment, and observed in aggressive forms such as yelling, hitting, or hyperactivity.⁶ McDonald et al⁷ reported that three or more maternal ACEs were associated with both internalizing and externalizing behaviours among three-year-old children. In a study on the same cohort, Hetherington et al⁸ found that four or more maternal ACEs were associated with internalizing and externalizing behavioural problems at five years of child age. Globally, studies reveal that an increasing number of preschool children are developing behavioural problems,⁹ including anxiety, depression, and conduct problems,¹⁰ which have been further exacerbated by restrictive measures during the COVID-19 pandemic.^10-12 The substantial evidence for the positive association between maternal ACEs and children’s behavioural problems, an increase in the prevalence of behavioural problems globally, and the compounding effects that have resulted from the COVID-19 pandemic calls for more clarity on how other factors (e.g., mediators, moderators) influence this association. Such information is needed to identify intervening strategies and to prevent and mitigate the development of behavioural problems among preschool children.^4,13

Potential Moderators and Mediators and their Importance

The impacts of maternal ACEs on children’s behavioural problems may begin as early as the prenatal period. For example, prenatally, ACEs may impact children’s socioemotional development, and subsequently, behavioural development, through epigenetic mechanisms involving mothers’ hypothalamic-pituitary-adrenal (HPA) axis.¹⁴ The HPA axis is a biological system governing the flight-or-fight system through the release of stress hormones and adaptive behavioural functioning.¹⁵ Acute stimulation of the HPA axis serves to assist individuals in moments of stress or discomfort; however, chronic stimulation is linked to toxic stress and maldevelopment of several physiological systems including the cardiovascular, metabolic, and immune systems.¹⁵ Mothers who have experienced ACEs may be more likely to have an overstimulated HPA axis,¹⁶ which may result in the transmission of cortisol to the developing fetus during pregnancy;¹⁴ studies show that high levels of cortisol during pregnancy may affect fetal development.¹⁴ Postnatally, maternal neglect stemming from unresolved ACEs trauma may result in poor caregiving, and in turn, hyperactivate their children’s own HPA axis;¹⁷ preschool children’s brains are particularly vulnerable to chronic activation of the HPA axis resulting from toxic stress.^18,19 When preschool children experience stress for prolonged periods of time due to neglect and abuse, they will likely adopt maladaptive behaviours (i.e., internalizing and externalizing behaviours) as an alternative means of regulating stress or expressing their needs.²⁰

Without intervention, behavioural problems are likely to persist into adolescence and adulthood, resulting in substance use disorders, crime, and health conditions associated with poorer quality of life.^5,21-24 Many negative behavioural outcomes for children are associated with maternal ACEs and potential moderators and mediators (defined and depicted in Table 1 and Figure 1, respectively) such as those related to the caregiving environment,²⁵ genetics, or educational settings,²⁶ warrant a need for further investigation both pre- and postnatally.

Table 1.

Definitions of moderators and mediators.

Term	Definition
Moderator	A variable which affects the strength or direction of the relationship between a focal predictor and the outcome of interest; the effect of the focal predictor on the outcome is conditional on the presence, absence, or level of the moderator²⁷
Mediator	A variable quantifying or representing the conduit through, or mechanism by which, the focal predictor transmits its effect of an outcome. A mediator is caused by the focal predictor and causes the outcome and therefore is causal between the focal predictor and outcome. The focal predictor causally affects the outcome indirectly through the mediator²⁷

Figure 1.

Illustration of moderation (Panel A) and mediation (Panel B). Maternal ACEs represent the focal predictor and children’s behavioural problems represents the outcome of interest.

A greater awareness of ACEs' conditional effects and pathways could highlight points of intervention to optimally promote healthy child growth and development (e.g., behaviour). Armed with this knowledge, healthcare professionals and policy/decision makers can be better prepared to intervene and adjust relevant programs and services. Therefore, systematically synthesizing existing knowledge and identifying gaps in the context of moderators and mediators is important to guide researchers in conducting future research studies, clinicians and healthcare providers on the front line, and policy makers focused on programs and services for at-risk children and families at local, regional, and national levels. Further, identifying null findings alongside those that are statistically significant are important to limit reporting bias when synthesizing literature and to ensure that time, energy, and money is funneled toward the most appropriate resources and services.²⁸

Purpose of the Study

The objectives of this systematic review were to: (1) identify all studies that formally examined at least one potential moderating and/or mediating variable on the association between maternal ACEs and preschool (two-to-five-year-old) children’s behavioural problems; and (2) describe and compare the effects of the moderating and mediating variables.

Methods

The systematic review protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Systematic Review Protocols (PRISMA-P) guidelines and the review is reported according to the PRISMA guidelines.²⁹ A PRISMA checklist is provided (See Supplementary Materials A). This review was registered on the PROSPERO database (ID# CRD42022307214).

Search Strategy and Selection Criteria

The following databases (n = 7) were searched to identify relevant articles: MEDLINE and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations and Daily (OVID); Embase (OVID); Cochrane Central Register of Controlled Trials (Cochrane Library, Wiley); APA PsycINFO (OVID); CINAHL Plus with Full Text; SCOPUS (Elsevier); and Web of Science Core Collection. An expert health sciences librarian (KAH) developed the search strategy in conjunction with the research team, consisting of two concepts: adverse childhood experiences and child behaviour. Keywords and subject headings were used for each concept and subject headings were adapted depending on the database’s indexing. All search strategies are provided (See Supplementary Materials).

Included studies: (1) were papers published in peer-reviewed journals; (2) were written in English, French, Spanish, Serbian, and Gujarati (languages that represent the fluency of our research team); (3) contained formal analysis related to at least one potential mediating and/or moderating effect on the association between maternal ACEs and preschool children’s behavioural problems; (4) were observational studies; and (5) examined mother-preschool child dyads where the mean age for children in the sample was between two-to-five-years of age. To limit reporting bias and overestimation of treatment effects (often more prevalent in meta-analyses), authors: did not use “moderator” and “mediator” as search concepts, broadening the search to capture more studies with potential moderators and mediators; included any studies reporting null findings (when provided) or any studies that used terminology synonymous to moderation and mediation analysis (e.g., interactions); and scanned through CENTRAL. Grey literature, qualitative studies, reviews, commentaries, dissertations, conference abstracts, and opinion papers were excluded. Though the inclusion of grey literature can provide valuable information in reviews, such sources were excluded as they require considerable resources (e.g., time, money) while lacking a peer-review process. Further, there is literature to suggest that the exclusion of grey literature does not usually affect the outcomes of reviews.³⁰ The exposure in this study was maternal ACEs and the outcome was preschool children’s behavioural problems (i.e., total, internalizing, externalizing). For this review, the term ACEs reflected any exposure that examined maternal history of childhood adversity to maintain consistency.

Study Selection and Data Extraction

Covidence, an online screening tool,³¹ was used to upload all database results and facilitate data management, duplicate removal, and screening of records. To ensure agreement amongst reviewers was met and clarity regarding inclusion and exclusion criteria were well-understood, a calibration exercise with 50 randomly selected studies was completed by two reviewers (SK, LA) through Excel. Once percent agreement was met (>90%), these two reviewers independently screened the titles/abstracts and then full texts using Covidence. After screening through the initial 2695 studies collected by the search, 13 studies were included in the full-text extraction (Figure 2). Reviewers were able to resolve disagreements in both title/abstract and full text screening phases via discussion and consensus. The same authors (SK, LA) then extracted data from the included studies. Data was extracted from a few studies to pilot the data extraction table and adjusted (NL, AD) prior to extraction from all studies.

Figure 2.

PRISMA Flow Diagram.

Critical Appraisal

To examine quality and validity of the included studies, critical appraisals were completed using Joanna Briggs Institute (JBI) checklists.³² Although not explicitly assessing risk of bias, the JBI checklists includes questions that assess some degree of risk of bias.³² As only observational studies (analytical cross-sectional and cohort studies) were included, a JBI checklist for analytical cross-sectional studies (number of questions = eight) and a checklist for cohort studies (number of questions = 11) were used. For both checklists, each item included the following options as responses: “yes”; “no”; “unclear”; and “not applicable”. Critical appraisal results were not used to exclude studies, but rather to allow for description of their rigor and impact. Two individuals critically appraised the studies (SK, SR) independently with at least 90% agreement and then subsequently met to review their results.

Data Analysis and Synthesis

Studies were described by identifying certain characteristics (e.g., demographics, moderators/mediators examined, moderation/mediation outcomes), providing sample characteristics (through percentages and frequencies), and identifying the presence of moderators and/or mediators to better synthesize results. A summary table was designed to compile and organize all the data (Table 3).

Table 2.

Study characteristics of all included studies (n = 13).

Criteria	Number of studies (n = 13)
Study design
Prospective cohort	10
Analytical cross-sectional	3
Date completed
2022	2
2021	5
2020	3
2019	2
2015	1
Country completed
United States	7
Canada	5
Israel	1
Language
English	13

Findings

Study Characteristics

General study characteristics and more specific information of each study are provided (Tables 2 and 3). The sample sizes for the three analytical cross-sectional study designs ranged from 121³³ to 152³⁴ and the sample sizes for the prospective cohort studies ranged from 45³⁵ to 1994.³⁶ Seven studies only examined mediating variables,^36-42 two only examined moderating variables,^33,43 and four examined both moderating and mediating variables.^34,35,44,45 Five studies described the effect of a moderator,^33,35,43-45 ten studies described the effect of a mediator,^35-42,44,45 and six studies employed more complex models.^{34,36,38,39,44,45}

Table 3.

Study information for all included studies (n = 13), categorized under analytical cross-sectional and prospective longitudinal cohort study designs.

Included study	Sample size (n)	Demographics	Study objective	Moderators and/or mediators examined	Results for moderators and/or mediators

Analytical cross-sectional study design
Dollberg & Hanetz-Gamliel,³⁴ Israel	152	- Mean age of Israeli mothers was 38.97 years (SD = 5.84)	To study “the mediated links between ACEs and mothers’ and children’s psychopathology symptoms during COVID-19 to determine whether maternal mentalization and the child’s age moderate these links.”^p1	Mediator(s) included	• Through moderated mediation, observed that among preschool children, the mediated association between maternal ACEs and children’s internalizing and externalizing problems through maternal depressive symptoms was significant only when mothers’ mind-mindedness was low or medium (postnatally)
		- Most (92.8%) lived with a spouse		- Postnatal maternal depressive symptoms	• There was support for the same outcomes when maternal anxiety symptoms was used as the mediator but only when mothers’ mind-mindedness was low (postnatally)
		- Most had an average or higher family income relative to population in Israel (97.3%)		- Postnatal maternal anxiety	• These effects were described as a medium effect size
		- Children’s mean age (acquired via email to authors) in the young group was 53.08 months (SD = 9.07)		Moderator(s) included
				- Postnatal maternal mind-mindedness
Hatch et al,³³ United States	121	- Mean age of mothers was 29.86 years (SD = 5.32)	“To examine family social support as a buffer to the intergenerational association between maternal adverse childhood experiences (ACEs) and preschool-aged children’s adjustment.” ^p3	Moderator(s) included: - Family social support (maternally perceived) postnatally	• Reported moderating effects by social support postnatally, where moderate to high family social support perceived by the mothers buffered the association between maternal ACEs and children’s externalizing problems, but not internalizing; this appeared to be a medium effect size.
		- 82% reported being single or never married
		- Low-to-moderate income
		- Children’s mean age was 51.88 months (SD = 9.06) when behaviour was assessed
Thomas-Giyer & Keesler,³⁷ United States-	140	- Mean age of mothers was 28.8 years (SD = 5.19) with low-income	“(1) to describe and compare relationships between individual and cumulative maternal adversity with childhood outcomes; and (2) to determine if mother-child attachment mediated the relationship between maternal adversity and childhood outcomes.” ^p1	ediator(s) included:	• Reported that harmonious (happy and obedient) or proximity-seeking attachment (needing to be close to caregiver) among children were not predicted by maternal trauma or physical and sexual abuse, therefore did not act as a mediating variable on the association between maternal ACEs and children’s behavioural problems.
		- Approximately 40% were single and 33% were married		- Children’s attachment style (harmonious and proximity-seeking attachment styles)
		- Children’s behaviour was assessed at an average age of 41.3 months (SD = 9.94)
Prospective longitudinal cohort study design
Alto et al,³⁸ United States	123	- Mean age of mothers was 25.1 years	“To investigate the links between mothers’ histories of childhood maltreatment, mothers’ current major depressive disorder (MDD) status, and the development of the mother-child attachment relationship, and to further investigate how this attachment relationship is associated with behavioral outcomes in early childhood.”^p6	Mediator(s) included:	• No mediating effects were observed through disorganized attachment among children.
		- Low-income mothers		Postnatal maternal depression	• Reported mediating effects of maternal depression on the association between maternal ACEs and their children’s behavioural problems, for both internalizing and externalizing behaviours; these appeared to be medium effect sizes.
		- 60% identified as Black, 22% as white, and 18% as other, and 84% identified as non-Hispanic		- Postnatal maternal sensitivity	• Observed no significant mediating effects through maternal sensitivity
		- Children’s behaviour was assessed at 36 months (49% of children were female)		- Children’s attachment style (disorganized versus organized)	• Using a sequential mediation model, maternal ACEs significantly predicted maternal depression in the positive direction, which in turn significantly predicted maternal sensitivity in the negative direction, ultimately predicting the outcome of interest in the negative direction; these appeared to be medium effect sizes.
Bouvette-Turcot et al,³⁹ Canada	239	- Mean age of mothers was 33.53 years (SD = 4.65)	To examine the importance of both maternal symptoms of depression and maternal sensitivity as candidate mediators in the relation between maternal childhood adversity and childhood outcomes.”^p2	Mediator(s) included:	• Reported mediating effects through maternal depression on the association between maternal ACEs and negative emotionality and behavioural dysregulation as the outcome in children, reflective of internalizing and externalizing behaviours.
		- Moderate income levels		- Postnatal maternal depressiony	• Observed no significant mediating effects through maternal sensitivity.
		- White individuals constituted 89% of the sample, with 8.1% having an African descent and 3.2% a Hispanic descent		- Postnatal maternal sensitivit	• Using a sequential mediation model, maternal ACEs significantly predicted maternal depression in the positive direction, which in turn significantly predicted maternal sensitivity in the negative direction, ultimately predicting the outcome of interest in the negative direction.
		- 19 mothers were single and 100 were primiparous			• Maternal ACEs did not directly predict maternal sensitivity.
	“	- Children’s behaviour was assessed at 36 months (48% female)			• Significant effects appeared to be small-to-medium
Bouvette‐Turcot et al,⁴³ Canada	154	- Mean age of mothers was 31.7 years for one group and 33.0 years for another	To examine “transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5-HTTLPR, in the serotonin-transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother–child dyads.”^p1	Moderator(s) included: - Children’s serotonin-transporter polymorphism (5-HTTLPR) genotype postnatally	• Observed moderation through children’s 5-HTTLPR genotype such that the association between maternal ACEs and children’s behavioural problems was conditional on the production of serotonin
		- Moderate income levels			• Appeared to be small effect sizes
		- White individuals constituted 89% of the sample, with 8.1% having an African descent and 3.2% of a Hispanic descent
		- Children’s behaviour was assessed at 36 months (48% female)
Cooke et al,³⁶ Canada	1994	- Mean age of mothers at pregnancy was 30.87 years	“To examine whether associations between maternal ACEs and child behavioral problems at five years of age were explained by mothers’ insecure adult attachment styles, symptoms of depression, and symptoms of anxiety.”^p3	Mediator(s) included	• Observed mediating effects on both externalizing and internalizing behaviours through maternal anxious attachment, but not avoidant
		- High-income group		- Postnatal maternal depressive symptoms	• Reported mediating effects of maternal depression on the association between maternal ACEs and their children’s behavioural problems, for both internalizing and externalizing behaviours
		- White individuals constituted 81.8% of the sample, whereas 17.7% constituted other and .6% was missing		- Postnatal maternal anxiety symptoms	• Maternal anxiety did not act as a significant mediator
		- Children’s behaviour was assessed at 60 months		- Postnatal maternal adult attachment style (avoidant and anxious attachment styles)	• Observed several different sequentially mediated pathways using anxious and avoidant attachment styles, maternal depression, and maternal anxiety; maternal ACEs were associated with both internalizing and externalizing behavioural problems via a mediated pathway of both maternal avoidant and anxious attachment styles operating through depression, but not through anxiety
					• Effect sizes appeared to be small.
Letourneau et al,⁴⁴ Canada	907	- Mean age of mothers was 32.16 years (SD = 4.03)	“To determine: (1) the association between ACEs and 2-year-old children’s behaviour, (2) whether maternal symptoms of prenatal and postnatal depression and anxiety mediate the relationship between maternal ACEs and 2-year-old children’s behaviour, and (3) whether the relationships observed in addressing objective 2 are moderated by child sex.”^p2	Mediator(s) included	• Observed that child sex moderated the association between maternal ACEs and children’s internalizing behaviours (not externalizing) with higher internalizing scores among girls compared to boys
		- 83% of the sample had a total annual household income of $70,000 or more		- Maternal depressive symptoms (prenatally and postnatally)	• Observed mediating effects through maternal depression in the postnatal period (and not the prenatal period) for both externalizing and internalizing behaviours
		- Caucasians constituted 87% of the sample		- Maternal anxiety symptoms (prenatally and postnatally)	• Observed mediating effects through anxiety only in the prenatal period and only for internalizing behaviours
		- Children’s behaviour was assessed at 24 months of age (47% female)		Moderator(s) included	• Observed a mediated effect of maternal ACEs on both internalizing and externalizing behavioural problems in both the prenatal and postnatal periods when combining the effects of maternal anxiety and maternal depression. Additional moderation through child sex revealed that: the combined effect was significant for boys’ externalizing behaviours prenatally; the mediated effect through anxiety was significant for boys’ internalizing behaviours prenatally; the combined effect was significant for both boys’ and girls’ internalizing behaviours prenatally; the mediated effect through depression and combined effect was significant for boys’ externalizing behaviours postnatally; and the combined effect was significant for boys’ internalizing behaviours postnatally
				- Child sex assigned at birth	• Appeared to have medium effect sizes
Roth et al,⁴⁰ United States	96	- Mean age of mothers was 32.32 years (SD = 4.83) at intake	To examine “the links among the severity of mothers’ experiences of childhood maltreatment, their attachment styles during pregnancy, and their offspring’s emotional and behavioral problems.”^p2	Mediator(s) included	• Only secure maternal attachment during pregnancy, as opposed to avoidant and anxious attachment styles, mediated the relationship between ACEs and children’s negative emotional and behavioural problems
		- White individuals constituted 60% of the population, 14% were of Asian descent, 8% were Hispanic, and 1% was Black		- Maternal adult attachment style (secure, avoidant, and anxious) prenatally	• Effect sizes appeared to be small-to-moderate
Roubinov et al,⁴¹ United States	1462	- Mean age of mothers not provided, but ranged from 16 to 40 years of age	“To identify the transactions and mechanisms that link maternal early life trauma, maternal depressive symptoms, and children's internalizing symptoms.”^p1	Mediator(s) included	• Observed mediation through maternal depressive symptoms when only considering internalizing behaviours as their outcome of interest in the postnatal period and not in the prenatal period; this effect was small
		- Black individuals constituted 66% of the population, followed by 32% being white and 2% other		- Maternal depressive symptoms (prenatally and postnatally)
		- Children’s behaviour was assessed at 24 months, 36 months, and 48 to 60 months of age (50.3% male)
Shih et al,42 United States	1030	- Mean age of mothers not provided	“To investigate longitudinal associations between maternal ACEs, postpartum anxiety, observed parenting behavior, and child internalizing behaviors (meanage = 4.31 years, S.D.age = .38) in a racially diverse (67% Black; 33% White/Other) sample.”^p1	Mediator(s) included	• Observed mediation through anxiety in the postnatal period when examining children’s internalizing behaviours as the outcome; this effect was small
		- Black individuals constituted 65% of the sample, with white individuals and others constituting the remainder		- Postpartum anxiety	• The PCI as a whole or the social-emotional growth fostering section alone did not act as mediating variables between maternal ACEs and children’s internalizing behaviours; however, the cognitive-growth fostering section alone did act as a significant mediating variable with a small effect
		- Children’s behaviour was assessed at a mean age of 4.31 years (SD = .38), with 50% being male		- Parenting behaviour via the NCAST Parent-child interaction (PCI) (further looked in to using the cognitive growth fostering section and the social-emotional growth fostering section)	• There was no significant statistical evidence for serial mediation from maternal ACEs to maternal anxiety to either PCI, cognitive-growth fostering, or social-emotional fostering factors
Thomas-Argyriou et al,⁴⁵ Canada	248	- Mean age of mothers was 32.2 years (SD = 3.7)	“To understand the mediating and/or moderating role of prenatal hypothalamic–pituitary–adrenal (HPA) axis function in the association between maternal adverse childhood experiences (ACEs) and child internalizing and externalizing behavior problems at age 4.”^p1	Mediator(s) included	• At T₁ (6 to 26 weeks gestation), Thomas-Argyriou et al (2021) only observed moderating effects by maternal diurnal slope, and not by maternal CAR or maternal total cortisol, on the association between maternal ACEs and externalizing problems in children (not internalizing); mothers with ACEs were more likely to have children with externalizing problems when maternal diurnal slopes were flatter at T₁. At T₂ (27 to 37 weeks gestation), maternal diurnal slope again demonstrated moderating effects, but for internalizing behaviours this time; mothers with ACEs were more likely to have children with internalizing problems when maternal diurnal slopes were flatter at T_2. maternal CAR and total cortisol did not have any moderating effects
		- High-income sample with ∼84% having a total annual household income of $100,000 or more		- Maternal cortisol awakening response (CAR) at T₁ and T₂	• Observed that maternal ACEs had a mediating effect on children’s internalizing, and not externalizing behaviours, through maternal CAR measured at 6 to 26 weeks gestation (T₁), whereas maternal diurnal slope and total cortisol did not mediate the association for either type of behavioural problem. At T₂ (27 to 37 weeks gestation), maternal CAR again served as a mediating variable only for internalizing behaviours, but maternal diurnal slope and total cortisol did not for either type of behavioural problem
				- Maternal diurnal slope at T₁ and T₂
		- White individuals constituted 87% of the population, with 4.4% being Latin American, 3.2% being 6.8% being Asian, and 2.1% other		- Maternal total cortisol output (AUCg) at T₁ and T₂	• Observed some moderated mediation through child sex in their study, such that an interaction existed between maternal ACEs and diurnal slope at 6 to 26 weeks gestation to predict internalizing behaviours among girls and to predict externalizing behaviours among boys; no moderated mediation was observed at either time point when examining child sex and either maternal CAR or total cortisol
		- Children’s behaviour was assessed around 48 months of age (50% female)		Moderator(s) included	• All effect sizes were medium
				- Maternal CAR at T₁ and T₂
				- Maternal diurnal slope at T₁ and T₂
				- Maternal diurnal slope at T₁ and T₂
				- Maternal total cortisol output (AUCg) at T₁ and T₂
				- Child sex
				(Maternal CAR, diurnal slope, and total cortisol output were different measures reflecting hypothalamus-pituitary-adrenal axis functioning)
van de Ven et al,³⁵ United States	45	- Average age of mothers was 30.0 years (SD = 4.49)	To “examine the role of [children’s frontal alpha asymmetry (FAA)] on the relationship between maternal childhood trauma and child behavior in a low resource, minority sample with high risk for childhood trauma.”^p3	Mediator(s) included	• Children’s FAA had moderating effects on the association between maternal ACEs and children’s total and externalizing problems (but not internalizing) such that only children with lower FAA of mothers with ACEs were likely to develop total and externalizing behavioural problems; these effects appeared to be small-to-medium effect sizes
		- Black individuals constituted 78% of the sample, followed by 13% being white, 2% being Asian, and the remainder (7%) as other		- Children’s FAA postnatally	• Did not observe any mediating effects through children’s FAA
		- Mean age of children was 57.9 months (SD = 3.13) with 36% being female		Moderator(s) included
				- Children’s FAA postnatally

Moderating Variables

The moderating effects of certain variables on maternal ACEs and children’s behavioural problems acting alone included: 1) child sex,⁴⁴ 2) maternal perceptions of family social support postnatally,³³ 3) frontal EEG alpha asymmetry (greater activity in the right frontal brain region relative to the left) postnatally,³⁵ 4) maternal HPA axis functioning during early or late gestation,⁴⁵ and 5) children’s serotonin transporter polymorphism (5-HTTLPR) genotype (expression of a gene coding for serotonin) postnatally.³⁹ Overall, maternal ACEs were more likely to: 1) result in internalizing behaviours when the child was female;⁴⁴ 2) not be associated with children’s externalizing behaviours when mothers’ perceived moderate to high family social support;³³ 3) be associated with total and externalizing behavioural problems when children had higher frontal EEG alpha asymmetry;³⁵ 4) be associated with externalizing behaviours in earlier gestational periods and internalizing behaviours in later gestational periods when maternal diurnal slope was flatter;⁴⁵ and 5) be associated with behavioural problems when children had variant alleles for the 5-HTTLPR serotonin-producing genotype.³⁹

Mediating Variables

Maternal adult attachment style was examined as a mediator in four studies both prenatally and postnatally,^36-38,40 maternal depression/depressive symptoms in five studies (more often examined postnatally),^{36,38,39,41,44} and maternal anxiety in three studies (with examination of prenatal and postnatal time periods).^36,42,44 One study examined parenting behaviour (cognitive growth fostering and social-emotional growth fostering behaviours) postnatally,⁴² another maternal HPA axis functioning during early and late gestation,⁴⁵ and a third examined frontal EEG alpha asymmetry postnatally.³⁵ When attachment was examined as the mediator, maternal secure attachment style (characterized by the ability to develop reliable and secure relationships)⁴⁶ during pregnancy demonstrated a protective mediating effect.⁴⁰ All studies examining maternal depressive symptoms or depression as a mediating variable reported significant effects;^{36,38,39,41,44} however, there were minor differences in terms of behavioural outcomes. Except in one study,³⁶ maternal anxiety mediated the association between maternal ACEs and children’s behavioural problems with some reported differences in effect through anxiety in the prenatal and postnatal periods.^42,44 Mothers’ capacity to foster cognitive-growth, as opposed to social-emotional growth,⁴² as well as maternal cortisol awakening response,⁴⁵ mediated the association between maternal ACEs and children’s internalizing behaviours.

Complex Model Variables

Some research involved the examination of multiple mediators linked in serial or models that combined mediation and moderation (conditional process models) to examine the impacts of mothers’ mind-mindedness, depression, anxiety, sensitivity, and adult attachment styles on the association between maternal ACEs and children’s behavioural problems. One study reported that maternal depression mediated the association between maternal ACEs and children’s internalizing and externalizing behaviours at low or medium maternal mind-mindedness postnatally, which encompasses mothers’ abilities to acknowledge that their child has a mind with their own thoughts, wants, and ambitions instead of simply someone requiring fulfillment of their needs.³⁴ Similar mediation outcomes were reported for anxiety but only at low levels of maternal mind-mindedness.³⁴ Maternal ACEs also acted through a sequential mediation mechanism via maternal depression followed by maternal sensitivity.^38,39 Boys, as opposed to girls, were more likely to develop both internalizing and externalizing behaviours when exposed to maternal depression and anxiety prenatally and postnatally.⁴⁴ Further, the influence of maternal cortisol diurnal slope in the earlier gestational period on the association between maternal ACEs and children’s behavioural problems was found to differ between boys (externalizing behaviours) and girls (internalizing behaviours).⁴⁵ Finally, both maternal avoidant (referred to as dismissive in adults and characterized by avoidant tendencies in intimate relationships)⁴⁶ and anxious (referred to as preoccupied in adults and characterized by heavy investments in and the need for copious amounts of reassurance from their intimate relationships)⁴⁶ attachment styles mediated the association between maternal ACEs and children’s behavioural problems, operating sequentially through postnatal maternal depression.³⁶

Critical Appraisal Results

The quality of the included studies is provided (Table 4). Using the JBI checklists for prospective cohort studies and analytical cross-sectional studies, most studies appeared to be of higher quality. For prospective cohort studies, measuring outcomes in a valid and reliable way and utilizing strategies to address incomplete follow-up were most often scored “no”. For analytical cross-sectional studies, measuring outcomes in valid/reliable ways always scored “no”.

Table 4.

Critical appraisal of included studies (n = 13) using the Joanna Briggs Institute (JBI) prospective longitudinal cohort and analytical cross-sectional study design checklists.

Prospective longitudinal cohort studies
	Alto, et al, 2021	Bouvette-Turcot, et al, 2020	Bouvette-Turcot, et al, 2015	Cooke, et al, 2019	Letourneau, et al, 2018	Roth, et al, 2021	Roubinov, et al, 2022	Shih, et al, 2021	Thomas-Argyriou, 2021	van de Ven, et al, 2019
Were the two groups similar and recruited from the same population?	✖	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were the exposures measured similarly to assign people to both exposed and unexposed groups?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Was the exposure measured in a valid and reliable way?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were confounding factors identified?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were strategies to deal with confounding factors stated?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were the outcomes measured in a valid and reliable way?	✖	✖	✖	✓	✓	✓	✓	✖	✓	✖
Was the follow up time reported and sufficient to be long enough for outcomes to occur?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Was follow up complete, and if not, were the reasons to loss to follow up described and explored?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Were strategies to address incomplete follow up utilized?	✖	✓	✓	✖	✖	✖	✓	✓	✖	✖
Was appropriate statistical analysis used?	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Analytical cross-sectional studies
	Dollberg and Hanetz-Gamliel, 2022	Hatch, et al, 2020	Thomas-Giyer and Keesler, 2021
Were the criteria for inclusion in the sample clearly defined?	✓	✓	✓
Were the study subjects and the setting described in detail?	✖	✓	✖
Was the exposure measured in a valid and reliable way?	✓	✓	✓
Were objective, standard criteria used for measurement of the condition?	✓	✓	✓
Were confounding factors identified?	✓	✓	✓
Were strategies to deal with confounding factors stated?	✓	✓	✓
Were the outcomes measured in a valid and reliable way?	✖	✖	✖
Was appropriate statistical analysis used?	✓	✓	✓

Discussion

The purpose of this systematic review was to summarize and synthesize existing peer-reviewed observational studies that have examined moderators, mediators, and more complex models of the association between maternal ACEs and preschool children’s behavioural problems. Included studies typically examined mediating, rather than moderating variables. Maternal mental health was predominantly examined in the included studies, with consistent support of mediation through maternal depression/depressive symptoms. Maternal attachment styles, maternal cortisol awakening response, and the ability for mothers to foster cognitive growth among their children were also key mediators. Sex-specific effects were noted, with boys’ behaviour more likely to be associated with maternal ACEs. However, the association between maternal ACEs and children’s behavioural problems was also conditional on maternal social support, diurnal cortisol slope, children’s serotonin genotype, and EEG frontal alpha functioning. Certain variables (e.g., maternal mind-mindedness, maternal sensitivity, maternal attachment styles) demonstrated significant effects when examined via more complex models. A similar review was recently conducted that examined the research question in the context of all children below the age of 18 years,⁴⁷ capturing less than half of the studies that this review included and also warranting caution when generalizing findings as development in preschool differs substantially from other developmental periods (i.e., teenage). Both reviews do however identify a pertinent role of maternal depressive symptoms/depression as a mediator of the association between maternal ACEs and children’s behavioural problems.

Attachment Styles

Mothers’ adult attachment style was found to be a prevalent mediator of the association between maternal ACEs and children’s behavioural problems, while children’s attachment style was not. However, the results were inconsistent among included studies. Cooke et al³⁶ observed effects postnatally through maternal anxious attachment style, but not avoidant attachment, for internalizing and externalizing behaviours. However, a more complex model that included depressive symptoms (but not anxiety) revealed that a sequential indirect mediation pathway through maternal anxious and avoidant attachment styles was associated with both externalizing and internalizing behaviours.³⁶ In contrast, maternal secure attachment in the prenatal period was the only significant mediator that Roth et al⁴⁰ observed. This suggests an interplay of environmental and temporal factors.

Securely attached mothers are more likely to respond to their children’s needs reliably, securely, and appropriately, resulting in better behavioural development trajectories.^48,49 However, anxiously attached pregnant mothers (compared to secure) may intergenerationally transmit stress hormones (e.g., cortisol) through placental transfer,^50,51 potentially resulting in behavioural problems during childhood.^52,53 In the postnatal period, maternal secure attachment may therefore be more significantly related to appropriate brain development in growing children whereas anxious attachment is more influential in the prenatal period. Lastly, maternal avoidant attachment styles alone may not be predictive of children’s behavioural problems and instead operate through mothers’ depression, potentially linked to their lack of social connections. While there is evidence that maternal attachment styles are associated with children’s behaviours, findings from this review suggest the need to examine the effects of maternal attachment styles temporally and via more complex (sequential) mediation pathways.

Maternal Mental Health

All studies included in this review that examined maternal depressive symptoms or depression as a mediator of the association between maternal ACEs and children’s internalizing and externalizing behaviours prenatally and postnatally observed significant mediating effects. Substantial literature provides evidence for a positive association between early childhood adversity and maternal mental health including depression later in life (see meta-analysis by Racine et al⁵⁴). Consequently, depressive symptoms during motherhood are associated with reduced maternal sensitivity to their children’s needs and cues, resulting in mothers’ withdrawn behaviours and hostile responses.^55,56 As this negative or lack of response continues, children’s stress response systems will remain stimulated, potentially manifesting in the display of behavioural problems to self-regulate.^56,57 In both cases, maternal neglect and maladaptive parenting skills arising from depressive symptoms, whether intentional or unintentional, suggests the potential for intergenerational transmission of ACEs.¹ Therefore, to prevent the development of behavioural problems among children, interventions should target mothers’ depression to encourage healthier parenting.

As opposed to Cooke et al,³⁶ Letourneau et al⁴⁴ and Shih et al⁴² observed significant effects through maternal anxiety but only on internalizing behaviours, suggesting that maternal ACEs act through maternal anxiety to predict inwardly focused, psychological impacts, rather than outwardly focused behaviours. Letourneau et al⁴⁴ examined the role of maternal anxiety in both the prenatal and postnatal period, with significant mediating effects only in the prenatal period, whereas Shih et al⁴² only examined postpartum anxiety symptoms, with significant results. These discrepancies could be attributable to temporal impacts of confounding factors and methodological differences as studies examining anxiety in the prenatal vs postnatal period often demonstrate conflicting results;⁵⁸ however, the co-morbid nature of maternal depressive symptoms and anxiety suggest that anxiety likely plays an important role in preschool children’s behavioural development, requiring clarity on how it exerts its influence.

In their meta-analysis, Racine et al⁵⁴ observed a significant positive association between maternal ACEs and maternal anxiety, suggesting that like the impacts of ACEs on maternal depressive symptoms, a heightened activation of the HPA axis during childhood may lead to anxiety-related symptoms in adolescence and adulthood without proper intervention.⁵⁴ Consequently, anxious mothers may not respond optimally to their children’s needs, resulting in the internalization of children’s emotions to self-regulate.⁵⁹ Temporally dependent effects of anxiety on children’s behaviour may also be present such that anxiety during pregnancy leads to internalizing behaviours in children, again attributable to stress hormone transfer through the placenta but also due to fetal programming, a biological phenomenon suggesting that children may develop internalizing behaviours in preparation for the environment that they are anticipated to grow up in.^50,51,53 As the negative effects of maternal anxiety on children’s behavioural outcomes may occur prenatally, health professionals should provide resources and interventions to buffer anxiety-inducing stress associated with pregnancy and parenthood.

Dollberg and Hanetz-Gamliel³⁴ observed interactions with maternal depressive symptoms and anxiety when examining mothers’ mind-mindedness as a moderating variable. In their study, the mediating effect of maternal ACEs on children’s behaviour through maternal depressive symptoms or anxiety was conditional on mothers’ mind-mindedness at low or medium levels.³⁴ This implies that mothers who acknowledge that their infant has desires, feelings, uncertainties, and needs (or in other words, a mind), rather than just needs, are more likely to respond successfully to their infants’ cues and engage in more dyadic synchrony.^34,60 Similarly, maternal sensitivity refers to the quality of response mothers provide to their children’s needs, with increased sensitivity characterized by the ability to respond quickly and adequately.⁶¹ In both studies that examined maternal sensitivity,^38,39 effects were only observed sequentially through maternal depression. As discussed, maternal depression was a significant mediating variable on the association between maternal ACEs and children’s behavioural problems, but these findings support that depression likely acts by impeding the ability of mothers to respond sensitively to their children. With this knowledge, education, support, and resources are recommended for depressed mothers that promote awareness of their children’s needs by highlighting important developmental cues as demonstrated in a review by Letourneau et al⁶².

Maternal Perception of Social Support

Social support is known to be a powerful predictor of mental and physical well-being, buffering the impacts of early childhood adversity.⁶³ In the postpartum period, maternal social support is also known to serve as a protective factor for maternal mental health.^64,65 In their study, Hatch, Swerbenski, and Gray³³ observed that the association between maternal ACEs and children’s behavioural problems postnatally was conditional on the level of maternal social support, where moderate to high levels buffered the negative impacts of maternal ACEs on children’s behaviour. Therefore, not only may social support act as a protective factor for maternal mental health, it can also prevent the intergenerational transmission of poor behavioural outcomes to children.⁶⁶

Maternal Parenting

Adults who experienced early adversity from their own parents are more likely to adopt similar parenting behaviours, resulting in the potential intergenerational transmission of ACEs.⁶⁷ Using the NCAST Parent-Child Interaction Teaching Scale (an assessment that examines parents’ sensitivity to their children’s cues and the responsiveness of both parents and children to each other),⁶⁸ Shih et al⁴² observed significant mediating effects through the cognitive-growth fostering subscale. This subscale focuses on parents’ use of rich, unambiguous language in their interactions with children, and their support of children’s learning, exploratory behaviour, and task performance.⁶⁸ Findings suggest that maternal ACEs may attenuate mothers’ ability to foster children’s cognitive development, and poor cognitive development is linked to the display of behavioural problems.⁶⁹ For this reason, when assisting mothers who have ACEs, interventions should focus on engaging caregivers in fostering an environment that promotes interactions which enhance cognition in children.⁷⁰

The Role of Mothers’ HPA Axis

Thomas-Argyriou et al⁴⁵ examined both the mediating and moderating effects of maternal HPA axis functioning during pregnancy, with a focus on cortisol awakening response, diurnal slope, and total cortisol output. Of these, cortisol awakening response during pregnancy appeared to be the sole mediating variable of maternal ACEs and children’s internalizing problems, suggesting that prenatally, maternal cortisol output in the mornings was more predictive of children’s psychological distress at four years of age relative to total daily cortisol secretion or cortisol change during the day.⁴⁵ McGuinn et al⁷¹ report conflicting results, such that only total cortisol output, and not cortisol awakening response, predicted children’s anxiety postnatally. However, that study did not examine the experiences of mothers’ early childhood, which is known to influence HPA axis functioning in adulthood including during pregnancy.⁷² These conflicting findings warrant the need for further examination of maternal HPA axis functioning with consideration of maternal ACEs and temporality to better understand their associations with child behaviour.

When examined as moderators, maternal diurnal cortisol slope in the earlier gestational period (six to 26 weeks) appeared to interact with maternal ACEs such that maternal ACEs were negatively associated with children’s externalizing behaviours when the diurnal slope was steeper and positively associated when the slope was flatter.⁴⁵ Further, adding child sex revealed a three-way interaction only in the earlier gestational period such that maternal ACEs interacted with diurnal slope to predict internalizing behaviours among girls and externalizing behaviours among boys.⁴⁵ The interaction changed in the latter gestational period (27 to 37 weeks), such that diurnal slope was associated with only internalizing behaviours among all children; no sex effects were observed.⁴⁵ Several studies support that maternal cortisol during pregnancy is more likely to result in internalizing behaviours among girls relative to boys, with some attributing this to the amygdala, a portion of the brain responsible for processing threats and fear-based responses.^73,74 Thomas-Argyriou et al.’s⁴⁵ study also highlights temporal effects of maternal cortisol such that sex-dependent behavioural outcomes were found to occur in the earlier gestational period, when brains and nervous systems of fetuses are beginning to develop.⁷⁵ Therefore, it is imperative that healthcare professionals provide women considering pregnancy or who are just transitioning into pregnancy with resources and support to reduce chronic stress and persistently high cortisol levels.

Genetic and Neurological Factors

van de Ven et al³⁵ examined if frontal EEG alpha asymmetry in children moderated and mediated the association between maternal ACEs and children’s behavioural problems. Only moderating effects were observed by increased asymmetry (more activity on the right frontal brain and less on the left), suggesting that decreased activation of the left frontal brain is associated with decreased capacity to buffer stress. This is supported in a study conducted by Lopez-Duran et al,⁷⁶ which revealed that increased activation of the left frontal brain (greater symmetry) among children at high risk for depressive symptoms residing in families with histories of depression moderated the association between stressful life events and internalizing behaviours. Therefore, for children with frontal EEG alpha asymmetry, the integration of certain tools, such as neurofeedback,⁷⁷ can help improve symmetry of the frontal brain region.

With a genetic focus, Bouvette-Turcot et al⁴³ observed that the association between maternal ACEs and children’s behavioural problems was moderated by the 5-HTTLPR genotype such that children with an S or L_G variant (rather than homozygous L_A/L_A functional genotypes) were more likely to develop behavioural problems as maternal ACEs increased due to lower amounts of serotonin.⁴³ Since serotonin is linked to better mood outcomes and psychological functioning, inadequate production of this neurotransmitter may be associated with worsened health outcomes, including poor behaviour.⁷⁸ More specifically, as this neurotransmitter plays a critical role in brain development, children with lower levels of serotonin may find it difficult to behave appropriately in stressful environments such as school settings.⁷⁹ Implementing activities (e.g., meditation) into children’s lives or pharmacotherapies that boost serotonin levels may prevent the development of behavioural problems among children lacking normal serotonin genotypes.⁷⁸

Limitations and Future Research

Some moderating and mediating variables were only identified in a single study, indicating the need for more research prior to suggesting causality. Almost all studies (12/13) were performed in North America and studies differed in terms of ethnicities and vulnerabilities, likely reducing generalizability to other countries or populations. While studies used validated tools to measure maternal ACEs, the tools that were used differed, potentially causing discrepancies in how mothers reported their own ACEs. No studies examined the role of environmental conditions (e.g., nutrition) on the association between maternal ACEs and children’s behavioural problems despite evidence for their effects on children’s development, suggesting a need for future research. Due to the important role of other caregivers (e.g., fathers, grandparents), studies should consider examining their individual and cumulative effects on preschool children’s behavioural problems.

Reporting bias is a prevalent issue in systematic reviews and meta-analyses which is characterized by researchers publishing only statistically significant, or desired, results.^28,80 Also termed the file drawer problem, it implies that researchers will be more likely to submit or successfully publish positive or statistically significant results.^28,80 In studies of moderators and mediators, this bias may be even more inflated as researchers may prefer to publish their findings only when significant interactions (i.e., moderation) and direct or indirect effects (i.e., mediation) are observed. It is likely that some of the studies captured in this review’s search initially sought to examine moderating and mediating effects, with no significant results. However, without explicitly stating this, it is impossible for authors to pinpoint studies that did complete such analyses. Therefore, authors of this review acknowledge the potentiality for reporting bias affecting findings of the review. Nonetheless, the authors of the review utilized a thorough search strategy, comprehensively identifying factors that are relevant to mother-child health and that can prevent intergenerational transmission of poor health outcomes. These factors are also supported by other literature, adding veracity to the findings.

Conclusion

As preschool children are rapidly developing, they are highly susceptible to the negative impacts that may be associated with maternal ACEs. This systematic review aimed to identify all studies that have formally examined at least one moderating and/or mediating variable on the association between maternal ACEs and preschool children’s behavioural problems. Most studies predominantly examined the role of maternal mental health and uniformly observed mediating effects through maternal depressive symptoms/depression. A lack of examination of moderation and of environmental factors such as nutrition,⁸¹ neurotoxicant exposure,⁸² and educational settings,²⁶ highlights the need for more research. Overall, the results of this review reinforce that maternal ACEs are associated with children’s behavioural problems and suggest certain factors that could be targeted as points of intervention to improve preschool children’s behavioural outcomes and quality of life and prevent the transmission of lifelong poor health outcomes intergenerationally.

Supplemental Material

Supplemental Material - Factors affecting the association between maternal adverse childhood experiences and preschool children’s behavioural problems: a systematic review of mediators and moderators

Supplemental Material for Factors affecting the association between maternal adverse childhood experiences and preschool children’s behavioural problems: a systematic review of mediators and moderators by Stefan Kurbatfinski, Nicole Letourneau, Deborah Dewey, Andrew F. Hayes, K. Alix Hayden, Lubna Anis, and Aliyah Dosani in Clinical Medicine Insights: Psychiatry

Footnotes

Acknowledgements

We thank all the authors of the included studies for their contributions to this area of research. Additionally, we thank Sharissa Robles (SR) for her assistance in critically appraising the included studies.

Author Contributions

SK conceived the idea of this paper (along with NL and AD), assisted with the search strategy, screened all studies using the inclusion/exclusion criteria via Covidence, critically appraised the studies, extracted data from the studies, and contributed substantially to the original drafting of the manuscript along with editing and review. In addition to the conception of this paper, NL and AD provided methodological guidance, supervision of the study, guidance on search strategies and studies that were included, support on data extraction approaches, and significant feedback and edits to the manuscript. LA also screened all studies using the inclusion and exclusion criteria via Covidence, extracted data from the studies, and reviewed and edited the manuscript. DD and AFH provided methodological guidance throughout the development of this paper and critically reviewed the manuscript. KAH developed the search strategy, performed the literature searches, placed all results onto Covidence, provided methodological guidance throughout, and critically reviewed the manuscript.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material:

Supplemental material for this article is available online.

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