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Association of Parental Prenatal Mental Health on Offspring Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis

September 2024

DOI:10.1101/2024.09.12.24313571

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Thalia K Robakis

Icahn School of Medicine at Mount Sinai

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Objective: Parental prenatal mood and anxiety disorders (PMAD) are linked to child neurodevelopmental disorders (NDDs), but evaluations of the magnitude and mechanisms of this association are limited. This study estimates the strength of the association and whether it is impacted by genetic and environmental factors. Method: A systematic search of PubMed, CENTRAL, PsycINFO, OVID, and Google Scholar was performed for articles published from January 1988 to January 2024. Of 2,170 articles screened, 64 met the inclusion criteria. Meta-analyses were conducted on 20 studies, and 44 were included in the narrative synthesis. We conducted random-effects meta-analyses, along with tests for heterogeneity (I^2) and publication bias (Egger's test). The review followed PRISMA and MOOSE guidelines. Results: Maternal PMADs were associated with a significantly increased risk of ADHD (OR 1.91, 95% CI 1.45-2.52) and ASD (OR 1.57, 95% CI 1.37-1.81) in children. Paternal PMADs were also associated with the risk of NDDs, with combined odds for ASD and ADHD (OR 1.24, 95% CI 1.15-1.34). Several studies suggested that the link between parental PMADs and offspring NDDs might be impacted by both genetic and environmental factors, including the impact of ongoing parental depression on child behavior. Conclusions and Relevance: Parental PMADs are significantly associated with an increased risk of NDDs in children. These associations may be influenced by both genetic predispositions and environmental factors. Understanding these pathways is important for informing interventions aimed at mitigating mental health risks in families and supporting child development.

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Association of Parental Prenatal Mental Health on Offspring Neurodevelopmental

Disorders: A Systematic Review and Meta-Analysis

Authors: Adrianna P. K

ska, PhD, Shelby Smout, PhD, Thalia K. Robakis, MD, PhD,

Lily E. Cohen, BS, Ingrid Christina Gustavsson Mahjani, MSc, Alkistis Skalkidou, MD,

PhD, Veerle Bergink, MD, PhD, Behrang Mahjani, PhD

Drs. Adrianna P. K

ska, Shelby Smout, Ms. Lily E. Cohen, Ms. Ingrid Christina

Gustavsson Mahjani, and Dr. Behrang Mahjani are with the Seaver Autism Center for

Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Drs. Adrianna P. K

ska, Shelby Smout, Thalia K. Robakis, Ms. Lily E. Cohen, Ms. Ingrid

Christina Gustavsson Mahjani, and Drs. Veerle Bergink and Behrang Mahjani are with the

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Drs. Adrianna P. K

ska and Behrang Mahjani are with the Department of Genetics and

Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Dr.

Alkistis Skalkidou is with the Department of Women's and Children's Health, Uppsala

University, Uppsala, Sweden. Dr. Veerle Bergink is with the Department of Psychiatry,

Erasmus Medical Center, Rotterdam, The Netherlands. Dr. Behrang Mahjani is also with the

Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount

Sinai, New York, NY, USA; the Mindich Child Health and Development Institute, Icahn

School of Medicine at Mount Sinai, New York, NY, USA; the Department of Medical

Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and the

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Acknowledgments: This project was funded by the Beatrice and Samuel A. Seaver

Foundation (K

ska, Mahjani), Brain & Behavior Research Foundation (Mahjani), the

National Institute of Mental Health (NIMH) R01HD111117 (Robakis), R21MH131933

ska, Robakis, Bergink, Mahjani)

Correspondence to Behrang Mahjani, PhD, One Gustave L. Levy Place, Box 1230, New

York, NY 10029, Tel: 212-241-6500, behrang.mahjani@mssm.edu

Disclosure: None reported.

Keywords: anxiety disorders, obsessive-compulsive disorder, mood disorder, autism,

neurodevelopmental disorders, attention-deficit/hyperactivity disorder, intellectual disability,

maternal, paternal, prenatal

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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 13, 2024. ; https://doi.org/10.1101/2024.09.12.24313571doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Abstract

Objective: Parental prenatal mood and anxiety disorders (PMAD) are linked to child

neurodevelopmental disorders (NDDs), but evaluations of the magnitude and mechanisms of

this association are limited. This study estimates the strength of the association and whether it

is impacted by genetic and environmental factors.

Method: A systematic search of PubMed, CENTRAL, PsycINFO, OVID, and Google

Scholar was performed for articles published from January 1988 to January 2024. Of 2,170

articles screened, 64 met the inclusion criteria. Meta-analyses were conducted on 20 studies,

and 44 were included in the narrative synthesis. We conducted random-effects meta-analyses,

along with tests for heterogeneity (I²) and publication bias (Egger's test). The review followed

PRISMA and MOOSE guidelines.

Results: Maternal PMADs were associated with a significantly increased risk of ADHD (OR

1.91, 95% CI 1.45–2.52) and ASD (OR 1.57, 95% CI 1.37–1.81) in children. Paternal

PMADs were also associated with the risk of NDDs, with combined odds for ASD and

ADHD (OR 1.24, 95% CI 1.15–1.34). Several studies suggested that the link between

parental PMADs and offspring NDDs might be impacted by both genetic and environmental

factors, including the impact of ongoing parental depression on child behavior.

Conclusions and Relevance: Parental PMADs are significantly associated with an increased

risk of NDDs in children. These associations may be influenced by both genetic

predispositions and environmental factors. Understanding these pathways is important for

informing interventions aimed at mitigating mental health risks in families and supporting

child development.

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Introduction

As of 2021, 8.56% of children in the U.S. have a neurodevelopmental disorder (NDD),

including autism spectrum disorder (ASD), intellectual disability (ID), and attention-

deficit/hyperactivity disorder (ADHD). 1,2 Recognizing factors that predispose individuals to

NDDs and enhancing early detection can lead to interventions that reduce the severity of

NDD symptoms and improve the quality of life for neurodivergent individuals and their

families.3 Furthermore, timely interventions can help prevent the progression of these

conditions into other severe mental or medical complications in adulthood.

Recent research has demonstrated a significantly increased risk of NDDs in children born to

mothers who experienced mood or anxiety disorders during pregnancy.4,5 This finding

highlights the critical implications of maternal mental health on early neurodevelopmental

outcomes and underscores the importance of integrating maternal health considerations into

early pediatric care to support healthy developmental trajectories. Additionally, this body of

research suggests a genetic link between ASD, ADHD, anxiety, and mood disorders,

indicating that genes inherited from parents may predispose children to NDDs. It is also

possible that genetic predispositions could interact with environmental factors such as

maternal mental health to influence the development and severity of NDDs in children, thus

necessitating a multifaceted approach in research and intervention strategies that consider

both genetic and environmental contributions.

Despite extensive investigation into maternal mental health, such as pre and postnatal

depression, significant gaps remain in our understanding, particularly the magnitude of the

association and specific mechanisms through which prenatal mood and anxiety disorders

(PMADs) affect neurodevelopmental outcomes. Additionally, while maternal influences have

been extensively studied, the potential effects of paternal mental health remain largely

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unexplored. This oversight represents a critical gap in our knowledge, given the potential

influence of paternal mental health and genetic contribution on developmental trajectories.

To address these gaps, we conducted a systematic review and meta-analysis of studies

exploring the associations between both maternal and paternal PMADs—specifically prenatal

depression, anxiety disorders, and obsessive-compulsive disorder (OCD)—and the risk of

NDDs in offspring. This emphasis on the prenatal period is crucial, given its relatively

limited coverage in existing literature compared to the broader perinatal and early postnatal

periods. For NDDs, our focus was on three major conditions: ASD, ADHD, and ID, due to

their shared genetic and phenotypic overlaps. For studies not suitable for meta-analysis, we

performed narrative syntheses to provide a comprehensive overview of the existing literature.

For the purposes of this study, we define "maternal" as relating to the parent who carried the

pregnancy and "paternal" as relating to the other biological parent.

A crucial aspect of our study is analyzing whether the association between PMADs and

NDDs in offspring primarily stems from shared genetic variation. We consider the possibility

that this association may not be directly due to the environmental or behavioral influences of

having a parent with PMADs but could predominantly result from genetic predispositions

passed from parents to children. Understanding this potential genetic basis is critical for

discerning whether the observed association reflects modifiable risk factors or primarily

represents inherited genetic vulnerability.

Methods

This systematic review and meta-analysis followed recommendations of the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Supplement S1) and

of Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines.6 The study

protocol is registered with PROSPERO (ID=CRD42022370757).

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Search strategy and selection criteria

Figure 1 outlines our article selection process, including identification, screening, and

eligibility assessment. Two researchers completed searches (LEC and BM).

Inclusion Criteria: Studies on maternal/paternal PMADs and offspring NDDs were sought

from PubMed, Cochrane CENTRAL, OVID, and Google Scholar, covering January 1, 1988,

to January 16, 2024 (see Supplement S2 for search terms and details). We selected this study

period to ensure comprehensive coverage of recent literature. We included cohort, case-

control, and cross-sectional studies.

Exclusion Criteria: We excluded case studies, ecological/animal models, qualitative, and

psychometric studies of PMADs and NDDs due to organic brain syndrome, substance use, or

known physiological conditions. Since the goal of this study is to assess the relationship

between parental PMADs and offspring NDDs, these studies were excluded to limit the

number of confounding variables and pathophysiological mechanisms that could moderate

this relationship. We also excluded grey literature, unpublished, not English-language

research, and studies with fewer than 20 participants.

Screening: LEC and BM independently screened titles and abstracts to remove duplicates and

irrelevant studies using DistillerSR software (Evidence Partners, Ottawa, Canada).

Eligibility: Full texts from screening and references from review articles were assessed

independently by APK and LEC, with discrepancies resolved by discussion and random re-

screening by BM. Articles were categorized based on whether they had relevant data for

either the meta-analysis or narrative descriptive synthesis. The data required for inclusion in

the meta-analysis is described below.

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Data extraction

Data extractions were independently conducted by three researchers (APK, LEC, and BM),

with disagreements resolved through full-text review. Extracted data included: participant

numbers with and without parents with PMADs and with and without NDDs; where

available, reported measures of effect (odds ratios unadjusted for covariates, ORs; 95%

confidence intervals, CI) and directions of effect; publication year; parental exposure to

antidepressants; timing of parent exposure; parent age; parent exposure measures; offspring

outcome (NDD diagnosis or symptoms); offspring age; sample size; number of offspring per

sex/gender; setting; study/cohort/register name (where applicable); participant country of

origin, ethnicity, race, or ancestry (as reported).

While our study primarily addressed the association of PMADs and NDDs, several studies

examined the influence of prenatal antidepressant exposure. We only meta-analyzed or

reviewed findings where antidepressants were ascertained as a treatment for PMADs and not

other conditions, such as migraines and sleep disorders (Table S1).

Statistical analysis

Our meta-analysis included parents diagnosed with mood or anxiety disorders during

pregnancy or both prenatally and postnatally, excluding those diagnosed only postnatally.

Where multiple studies used the same cohort, we selected the largest one to avoid sample

overlap. We used a random-effects model for the meta-analyses to account for error variance

within and between studies.7,8 We conducted the meta-analyses using R packages meta and

dmetar. Effect sizes (OR) and variances were required for each study; for studies with counts

of exposed and unexposed participants, parameters were calculated using the meta metabin

function. When only unadjusted ORs and their confidence intervals (CIs) were available, the

variance was derived from these CIs using the standard formula to convert CI width to

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standard error.

Using the R package dmetar, we assessed study heterogeneity with Cochran's Q test, the I²

statistic, and checked for outliers with funnel plots. Publication bias was addressed with the

trim-and-fill method, which corrects for asymmetry in the funnel plot.9 We analyzed maternal

and paternal findings separately and stratified analyses by offspring NDD for maternal

studies only since the number of paternal PMAD studies was too low for stratification. A

sensitivity analysis was conducted by meta-analyzing the data after excluding potential

outlier studies.

Studies with information insufficient for meta-analysis were included in a narrative synthesis

(see Supplement S3 for methods). Two researchers (APK and BM) independently assessed

the risk of bias in all studies using the Newcastle-Ottawa scales and the Joanna Briggs

Institute (JBI) Critical Appraisal Checklists (Supplement S4).10–12 Authors resolved any

disagreements through discussion.

Results

A total of 2,170 studies initially met the inclusion criteria. We selected 64 studies for the

systematic review and 20 for meta-analysis (Figure 1).

Figure 1. PRISMA flow diagram.

Characteristics of meta-analyzed studies are detailed in Table 1. 27 studies reported

participant race, country of origin, and ancestry or ethnicity, but none specified how these

demographics were ascertained. The studies varied in their designs and implemented

measurement tools (Table 1; additional details in Table S1).

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Table 1.a Characteristics of meta-analyzed studies on maternal prenatal mood and anxiety

disorders and offspring neurodevelopmental disorders.

We additionally conducted a comprehensive narrative synthesis incorporating findings from

the remaining 40 studies that were unsuitable for meta-analysis due to insufficient data for

pooling. The findings from these studies are presented below.

Maternal PMAD and the risk of offspring NDDs

Our meta-analysis revealed a significant association between maternal PMADs and offspring

NDDs (OR 1.67, 95% CI 1.47–1.90, p<0.0001; Figure 2). Visual inspection of the funnel plot

(Figure S1) identified two studies as possible outliers.13,14 Removing these studies reduced

heterogeneity to low (Cochran's Q=187.64, p<0.001 to Q=20.63, p=0.19; I2=90.4% to

I2=22.5%) and OR to 1.59 (95% CI 1.50–1.68, p<0.0001; Figure S2).15

Figure 2. Forest plot of associations between maternal prenatal mood and anxiety disorders

and offspring neurodevelopmental disorders.

Square sizes reflect the weights attributed to each study. Diamonds denote the summary

effect sizes for the random-effect models.

OR=odds ratio. CI=confidence intervals NDD=neurodevelopmental disorders.

ADHD=attention-deficit/hyperactivity disorder. ASD=autism spectrum disorder.

aClements et al (2015) analyzed separate samples of individuals with diagnoses of autism

spectrum disorder and attention-deficit/hyperactivity disorder. The authors provided results

for three trimesters. The third trimester has been selected for this meta-analysis because it is

the most conservative estimate reported by Clements et al (2015).

bChien et al (2022) included the following disorders: major depressive disorder, persistent

depressive disorder, and depressive disorder, unspecified.

cHope et al (2024) analyzed a combined sample of individuals with any of the following

disorders: autism/autism spectrum disorder, attention-deficit/hyperactivity disorder,

intellectual disability, cerebral palsy, and epilepsy.

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The Egger's test indicated asymmetry in the funnel plot (p=0.03; Figure S1), which suggests

publication bias. In support of this result, the trim-and-fill method estimated at least nine

potentially missing studies (Figure S3).

Effects of maternal PMADs on offspring ADHD

Our meta-analysis revealed a significant association between maternal PMADs and an

increased risk of offspring ADHD (OR 1.91, 95% CI 1.45–2.52; Figure 2). Initially, the

ADHD model exhibited high heterogeneity (Cochran's Q=23.83, p<0.001; I2=74.8%). After

the exclusion of a single outlier study, heterogeneity decreased (Cochran's Q=9.90, p=0.08;

I2=49.5%), and OR changed to 1.70 (95% CI 1.34–2.14; Figure S1).15

Consistent with the meta-analysis, studies in the narrative synthesis reported associations

between maternal PMADs and offspring ADHD or elevated ADHD symptoms.16 However,

the literature presented mixed results for the mechanism underlying this finding. LM Chen

and colleagues employed polygenic risk scores (PRS) for ADHD and demonstrated that a

significant portion of the association between maternal prenatal depression and ADHD in

offspring could be attributed to shared genetic risk factors between these disorders.17 In

contrast, Eilertsen et al. demonstrated a persistent positive association between maternal

prenatal depression symptoms and the risk of ADHD in offspring, even after controlling for

shared genetic factors.18 Adding to this complexity, Olstad et al. investigated epigenetic

factors and found no association between cord blood DNA methylation, maternal prenatal

depression, and offspring ADHD symptoms.19Similar to maternal depression, maternal

anxiety has been associated with an increased risk of offspring ADHD, but studies remain

inconclusive on the critical exposure period. One study found only maternal anxiety at 12-22

weeks gestation, but not later, predicted offspring ADHD symptoms, while another

highlighted that interaction between maternal anxiety at 32 weeks and offspring genes

influences ADHD symptom severity.20,21 This discrepancy may be due to differing study

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designs, particularly the inclusion of genetic interactions in the latter study.21While individual

time points are informative, trajectory studies provide a more comprehensive picture of the

relationship between maternal PMADs and offspring ADHD. Trajectory studies of maternal

depression suggested that either persistently high or increasing levels of maternal depression

during pregnancy were associated with increased offspring ADHD symptoms.22–26 Similarly,

consistently low or decreasing levels of maternal depressive symptoms have been associated

with fewer offspring ADHD symptoms, with reductions in maternal symptoms corresponding

to decreases in offspring symptoms over time.22–24 This pattern indicates that both the timing

and the severity of maternal depression are important factors, although the precise

mechanisms are not yet fully understood.

Finally, research comparing the association of anxiety and depression found that increased

maternal anxiety correlated with higher child hyperactivity, while changes in maternal

depression were related to all ADHD symptoms except inattention.27 However, these patterns

have not been consistently reported across studies, possibly due to variations in sample sizes

and study designs.28–33

Effects of maternal PMADs on offspring ASD and ID

Our meta-analysis revealed an association between maternal PMADs and an increased risk of

offspring ASD (OR 1.57, 95% CI 1.37–1.81). Studies initially presented with high

heterogeneity (Cochran's Q=138.30, p<0.001; I2=92.8%), but upon removal of one study,

heterogeneity was low (I2=0%; Cochran's Q=6.96 p=0.64). OR increased to 1.61 (95% CI

1.54–1.69; Figure S2).14

Narrative synthesis largely corroborated the finding that maternal PMADs increase the risk of

ASD and autistic-like traits in offspring.34 One study found that children of mothers with

PMADs were significantly more likely than children of unaffected mothers to exhibit mild

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language and motor delays rather than severe developmental delays, with the risk intensifying

when mothers had both depression and anxiety pre-delivery. However, this finding should be

interpreted with caution, as anxiety was based on a self-reported questionnaire and the study

included controls with common comorbidities, such as bipolar disorder.34

Further supporting these associations, an analysis of cord blood from mothers with prenatal

depression or post-traumatic stress disorder found increased expression of genes associated

with ASD.35 These genes were linked to reduced cognitive performance in their two-year-old

infants. These findings suggest that maternal PMADs may influence infant brain

development through altered neurodevelopmental pathways beyond directly inherited genetic

risk.

Studies on OCD were rare. A single study addressed maternal OCD and reported a significant

association between maternal OCD within four years before delivery and offspring ASD

(adjusted OR = 3.42, 95% CI = 1.77–6.63).36,37 Although this study included the entire

Taiwanese population, it only involved 12 OCD cases and 36 controls, highlighting the need

for additional research with larger sample sizes to support these findings.

Several observational studies initially suggested an association between ASD and antenatal

antidepressant exposure, but these studies lacked adequate controls. 14,38,39 Conversely,

studies that included groups of siblings discordant for antidepressant exposure have

established that the association is not related to any direct pharmacological effect but, rather,

the shared genetic and environmental risk factors related to the indication for prescribing

antidepressants (i.e., maternal depression and related symptoms).40–42 Furthermore, one study

suggested potential parental rater bias in evaluating the severity of child developmental

problems among families with prenatal selective serotonin reuptake inhibitor (SSRI)

exposure.5 Findings indicated an association between SSRI exposure and autism symptoms in

children when both parents provided reports on child development. However, when only

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fathers reported, there was no significant association between maternal depression during

pregnancy and child developmental problems. This finding indicates that parental reports

might not always be reliable, potentially leading to biased estimates of children's behavioral

issues.

Paternal PMAD and the risk of offspring NDDs

Our meta-analysis identified a significant association between paternal PMADs and offspring

NDDs (OR 1.24, 95% CI 1.15–1.34, p<0.001; Figure 3). Given the few available studies, it

was not possible to conduct separate meta-analyses on the effects of paternal PMADs on

ADHD and ASD. Studies showed low heterogeneity (Cochran's Q=1.36, p=0.93; I2=0%)

with no outliers.

Table 1.b Characteristics of meta-analyzed studies on paternal prenatal mood and anxiety

disorders and offspring neurodevelopmental disorders.

The funnel plot (Figure S4) was asymmetrical, suggesting potential publication bias, but

Egger's test was non-significant (p=0.58). However, the number of studies may be too small

to test for small study effects. The trim-and-fill method (Figure S5) indicated at least one

missing study, suggesting unreported results that could affect the overall effect estimate.

Figure 3. Forest plot for the association between paternal prenatal mood and anxiety

disorders and the risk of neurodevelopmental disorders (NDDs) in offspring.

Square sizes reflect the weights attributed to each study. The diamond denotes the summary

effect size for the random-effect models.

CI=confidence intervals. ASD=autism spectrum disorder. ADHD=attention-

deficit/hyperactivity disorder.

aChien et al (2022) included the following disorders: major depressive disorder, persistent

depressive disorder, depressive disorder, unspecified, generalized anxiety disorder, panic

disorder, agoraphobia, social anxiety disorder, and specific phobia disorder.

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Effects of paternal PMAD on ADHD in offspring

Chen et al. showed that paternal prenatal depression increases offspring ADHD risk,

particularly in cases of chronic depression or when both parents are affected.17 In contrast,

Ramchandani et al. found no significant association between paternal depression during

pregnancy and offspring ADHD diagnoses.43 Other studies also reported limited evidence for

an association between prenatal paternal depression, anxiety, and risk of offspring

ADHD.21,25,31

Adding to this complexity, a single study found that, after controlling for shared genetics,

prenatal maternal depression was associated with a slightly elevated offspring ADHD risk,

while prenatal paternal depression showed a minor association with lowered offspring ADHD

risk.18 Nonetheless, researchers cautioned against drawing definitive conclusions from this

association, noting the lack of theoretical models that explain the effect of paternal prenatal

depression. In light of their findings, they also questioned the validity of selecting parents

with depression as negative controls for one another in future studies.

Effects of paternal PMADs on offspring ASD

Chen et al. found that offspring ASD risk was elevated when either parent was affected, with

a slightly greater risk for paternal than maternal prenatal depression. Additionally, a separate

study based on Taiwanese registers found no significant associations between paternal

prenatal OCD and offspring ASD, likely due to small sample sizes.36,37

Sex or gender differences

Few studies addressed interactions between offspring sex or gender, NDDs, and maternal

and/or paternal PMADs. Of these few, none qualified for meta-analysis. The influence of

prenatal maternal and paternal PMADs on NDDs appears to differ by sex, though the existing

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research is limited and yielded mixed results. The studies did not distinguish between sex and

gender.

Loomans et al. observed that maternal prenatal anxiety significantly correlated with increased

hyperactivity and inattention problems in boys but not in girls, suggesting potential sex-

specific vulnerabilities to prenatal anxiety.44 In contrast, Huhdanpää et al. found a similar

pattern, with maternal prenatal depressive symptoms linked to increased inattentiveness and

hyperactivity among boys at age five.25 These findings imply that boys might be particularly

susceptible to the neurodevelopmental influence of prenatal maternal affective symptoms.

Conversely, Bendiksen et al. reported that the higher prevalence of ADHD symptoms,

particularly the hyperactive/impulsive subtype in boys, does not reflect a differential

contribution of maternal distress between the sexes.30 This suggests that while boys generally

display more ADHD symptoms, the effects of maternal distress during pregnancy affect both

sexes similarly. Supporting this lack of sex-specific associations, Chen et al. found no sex

differences in the association between prenatal depression and child mental health

outcomes.45 They suggested that earlier findings indicating that prenatal maternal stress

predicts sex-specific child outcomes may vary depending on the particular behavior being

examined.

Studies found no sex/gender differences following exposure to maternal prenatal depression

and autism-related traits or behavioral problems in offspring.45 No studies specifically

addressed paternal PMADs.

Risk of bias

According to assessments conducted with the Newcastle-Ottawa scales, the majority of

studies on parental PMADs were at moderate risk of bias (36 studies, 59%), and five studies

(8%) were at low risk. Among studies assessed with JBI checklists, two out of three studies

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reported key information and used correct statistical analyses (Table S2).

Discussion

This systematic review and meta-analysis examined the relationship between PMADs in

parents and the risk of NDDs in their offspring. We found a stronger association for maternal

PMADs (OR 1.67, 95% CI 1.47–1.90) than paternal PMADs (OR 1.24, 95% CI 1.15–1.34).

Although not explored in this study, prior research suggests that this larger association with

maternal PMADs might be attributed to more direct biological and environmental effects

during pregnancy.46,47 Although our primary focus was on prenatal disorders, the observed

associations might also reflect the influence of postnatal maternal mental health, as many

women experience mood and anxiety disorders beyond childbirth.48,49

In the meta-analysis, we observed moderate heterogeneity after excluding two studies.13,14

Potential sources of heterogeneity include variation in sample sizes, diverse PMAD and NDD

measurement tools, diverse timeframes between conception and delivery, and few studies

accounting for prenatal treatment initiation.50

Our meta-analysis revealed a strong association between maternal depression and anxiety and

an increased risk of ADHD in offspring. The narrative synthesis underscored that specific

timing or trajectory of maternal disorder might have varying effects on offspring ADHD.

Notably, maternal anxiety during early pregnancy (12-22 weeks) significantly predicted

ADHD symptoms.20 This finding indicates the potential influence of factors beyond shared

genetics, as a purely genetic link would likely yield consistent effects irrespective of the

timing of maternal anxiety. Additionally, a single study highlighted a positive association

between maternal prenatal depression symptoms and offspring ADHD risk after adjusting for

genetic factors.18 Together, these findings suggest that prenatal environment may mediate the

association between PMADs and offspring ADHD. The meta-analysis also revealed a strong

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association between maternal depression and anxiety and an increased risk of offspring

ASD.17,51,52

Studies regarding prenatal OCD were limited and found an association between prenatal

maternal OCD and offspring ASD.36 Studies of offspring ID were also scarce and either

analyzed combined ID and NDDs, or ID-related symptoms. These studies reported that

offspring of mothers with PMADs were at greater risk of mild language and motor delay or

gross motor deficits.53,54

Finally, current research addressing the association of parental PMADs on sex/gender

differences in offspring NDDs is inconsistent. Some studies suggest a tentative association

with ADHD symptoms in boys, but not girls, and no significant gender/sex associations with

ASD or autism-related traits.25,30,44,55 These differences may stem from gender- or sex-

specific differences in how parental mental health influences child outcomes, methodological

differences between studies, or cultural patterns that influence diagnosis. For instance, the

ADHD symptom of hyperactivity may be more disruptive than inattention in certain

socioeconomic and healthcare environments, leading to higher diagnostic rates in boys.

Alternatively, diagnostic rates may be affected by gender role expectations or stereotypes of

neurodivergent presentations in individuals with different gender identities. Another

explanation may be that more recent studies used larger samples, including testing multiple

cohorts.16,55 Patterns of results may differ between diverse populations.

Multiple pathways are likely involved in the association between maternal PMADs and the

risk of NDDs in offspring. The first pathway (Figure 2, arrow 1) involves direct transmission

of genes from the mother to the offspring. The second and third pathways (arrows 3 & 4), are

known as maternal effect.56 Maternal effect refers to the impact of the mother's phenotype on

the offspring's phenotype, above and beyond the transmission of maternal genes: via

environmental pathways instead of directly transmitted genetic risk. Maternal effect can arise

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from maternal genotype (maternal genetic effect, also called maternal genetic nurture, arrow

3), and/or maternal environment (environmental maternal effect, arrow 4). Paternal PMADs

are also associated with the risk of offspring NDD via three analogous pathways (arrows 2, 5,

6).

Figure 4. Maternal and paternal effect on offspring phenotype (a neurodevelopmental

disorder). It includes three main pathways: the maternal/paternal genetic nurture effect,

showing transmission from maternal/paternal genotype to their respective phenotypes and

then to the offspring's phenotype (dashed arrows 3 & 5); the environmental maternal/paternal

effect, indicating the influence of the maternal or paternal environment on their phenotype

and consequently on the offspring's phenotype (dashed arrows 4 & 6); and the direct

maternal/paternal genetic effect, which traces direct transmission from maternal/paternal

genotype to the offspring's genotype and then to their phenotype (dashed arrows 1 & 2). This

figure omits child environment effects or gene-environment interactions.

Maternal/paternal effects have been defined as causal impacts of the maternal/paternal

genotype or phenotype on the offspring phenotype.56 However, statistical models used for

estimating parental effects may not always provide causal estimates due to several factors: (1)

Maternal/paternal effects could depend on offspring genotypes, such as an additive-by-

additive interaction between the maternal/paternal and the offspring genotype.56 For instance,

an interaction between maternal anxiety and the offspring gene may predict the severity of

ADHD symptoms, suggesting an additive-by-additive interaction between the maternal and

offspring genotypes.21 (2) Lack of blinding in observational family-based studies may lead to

diagnostic bias, as relatives of probands with psychiatric disorders may be more likely to be

diagnosed, due to family history being part of the diagnostic process. This could result in

overestimated genetic influence in family-based studies; (3) Assortative mating (non-random

mating) can influence population prevalence estimates and estimates of direct genetic effect;

(4) Selection bias due to differential access to healthcare, where individuals with milder

disorder forms or who do not seek or cannot access clinical services may be excluded from

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

research; (5) Gene-environment interactions can complicate causal inference (they were

omitted in Figure 1). Several studies reviewed here suggested such mechanisms, e.g., for

offspring ADHD, depression or anxiety interacting with smoking during pregnancy, prenatal

infection with prenatal anxiety, and short breastfeeding in mothers with prenatal depressive

mood or anhedonia;27,30,51,57 (6) Measurement errors can introduce uncertainties and biases

into the analysis; (7) Failure to achieve exchangeability between exposed and unexposed

groups may lead to confounding, undermining the validity of causal conclusions; and (8)

Retrograde effects, where the offspring phenotype may influence parental phenotype.

Examples include fetomaternal immune incompatibility, such as Rh factor incompatibility,

which could lead to maternal depressive symptoms and later cognitive effects in the

offspring.

Strengths and limitations

The primary strength of our study is its pre-registered analysis of multiple studies from

diverse regions, including Europe, North America, Asia, and Australia. However, the study

also has several limitations. Due to limited available findings, the meta-analysis of paternal

PMADs may have less statistical power than the findings on mothers. Furthermore, none of

the studies provided explicit definitions of mothers and fathers, making it difficult to

determine generalizability to transgender or non-binary parents, co-parents, or non-biological

partners. Moreover, several studies come from the same populations, predominantly

representing Western sites. Although we selected the largest sample sizes from studies with

the same cohorts for meta-analyses, the narrative synthesis included findings from different

studies that used the same cohorts. This approach may introduce unique limitations for each

cohort. For instance, the Norwegian cohort MoBa has a low response rate (43.5%) and may

suffer from self-selection of healthier participants into the cohort.58 Additionally, most

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

studies do not report detailed breakdowns of ethnicity, race, or ancestry, limiting our ability

to assess how globally representative the samples are.

Conclusion

Our comprehensive meta-analysis, reinforced by narrative synthesis, supports the association

between maternal and paternal PMADs and an increased likelihood of NDDs in offspring.

This association may not be entirely attributable to set genetic predispositions passed from

parents to children; rather, it could be partially moderated by the environmental or behavioral

impacts of having a parent with PMADs. To reduce the severity of neurodevelopmental

disorders (NDDs) and related symptoms, intervention strategies should consider both genetic

and environmental factors. These strategies could involve genetic counseling to identify

families who would benefit from early mental health screenings. This approach enables the

modification of environmental influences through timely mental health support and effective

stress management. Recognizing the importance of both genetic and environmental factors is

crucial for developing successful treatment strategies for NDDs.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Contributions:

Concept and design: Robakis, Bergink, Mahjani

Acquisition, analysis, or interpretation of data: K

ska, Robakis, Bergink, Mahjani

Drafting of the manuscript: K

ska, Mahjani

Critical revision of the manuscript for important intellectual content: All authors

Statistical analysis: K

ska, Mahjani

Obtained funding: K

ska, Robakis, Bergink, Mahjani

Supervision: Bergink, Mahjani

Role of the funders: The funders of the study had no role in study design, data collection, data

analysis, data interpretation, writing of the manuscript, or decision to submit the manuscript

for publication.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

References:

1. Boyle CA, Boulet S, Schieve LA, et al. Trends in the prevalence of developmental

disabilities in US children, 1997-2008. Pediatrics. 2011;127(6):1034-1042.

2. Zablotsky B, Ng A, Black L, Blumberg S. Diagnosed Developmental Disabilities in

Children Aged 3–17 Years: United States, 2019–2021. National Center for Health

Statistics (U.S.); 2023. doi:10.15620/cdc:129520

3. Aldharman SS, Al-Jabr KH, Alharbi YS, et al. Implications of early diagnosis and

intervention in the management of neurodevelopmental delay (NDD) in children: A

systematic review and meta-analysis. Cureus. 2023;15(5):e38745.

4. Kodesh A, Levine SZ, Khachadourian V, et al. Maternal health around pregnancy and

autism risk: a diagnosis-wide, population-based study. Psychol Med. Published online

March 26, 2021:1-9.

5. El Marroun H, White TJH, van der Knaap NJF, et al. Prenatal exposure to selective

serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-

based study of young children. Br J Psychiatry. 2014;205(2):95-102.

6. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items

for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg.

2010;8(5):336-341.

7. Viechtbauer W. Conducting meta-analyses in R with the metafor. J Stat Softw.

2010;36:1-48.

8. Companion R package for the guide Doing Meta-Analysis in R. Accessed March 8,

2024. http://dmetar.protectlab.org/.

9. Shi L, Lin L. The trim-and-fill method for publication bias: practical guidelines and

recommendations based on a large database of meta-analyses. Medicine (Baltimore).

2019;98(23):e15987.

10. Wells GA, Shea B, Connell O. The Newcastle-Ottawa Scale (NOS) for Assessing the

Quality If Nonrandomized Studies in Meta-Analyses.; 2011.

11. Aromataris E, Munn Z, eds. JBI Manual for Evidence Synthesis. JBI; 2020.

12. Barker TH, Stone JC, Sears K, et al. The revised JBI critical appraisal tool for the

assessment of risk of bias for randomized controlled trials. JBI Evid Synth.

2023;21(3):494-506.

13. Nidey NL, Momany AM, Strathearn L, et al. Association between perinatal depression

and risk of attention deficit hyperactivity disorder among children: a retrospective cohort

study. Ann Epidemiol. 2021;63:1-6.

14. Seebeck J, Sznajder KK, Kjerulff KH. The association between prenatal psychosocial

factors and autism spectrum disorder in offspring at 3 years: a prospective cohort study.

Soc Psychiatry Psychiatr Epidemiol. Published online August 9, 2023.

doi:10.1007/s00127-023-02538-5

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

15. Higgins JPT. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.

16. Shuffrey LC, Morales S, Jacobson MH, et al. Association of Gestational Diabetes

Mellitus and Perinatal Maternal Depression with Early Childhood Behavioral Problems:

An Environmental Influences on Child Health Outcomes ( ECHO ) Study. Child

Development. 2023;94(6):1595-1609.

17. Chen LC, Chen MH, Hsu JW, et al. Association of parental depression with offspring

attention deficit hyperactivity disorder and autism spectrum disorder: A nationwide birth

cohort study. J Affect Disord. 2020;277:109-114.

18. Eilertsen EM, Hannigan LJ, McAdams TA, et al. Parental Prenatal Symptoms of

Depression and Offspring Symptoms of ADHD: A Genetically Informed

Intergenerational Study. J Atten Disord. 2021;25(11):1554-1563.

19. Olstad EW, Nordeng HME, Sandve GK, Lyle R, Gervin K. Effects of prenatal exposure

to (es)citalopram and maternal depression during pregnancy on DNA methylation and

child neurodevelopment. Transl Psychiatry. 2023;13(1):149.

20. Van den Bergh BRH, Marcoen A. High antenatal maternal anxiety is related to ADHD

symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev.

2004;75(4):1085-1097.

21. O'Donnell KJ, Glover V, Lahti J, et al. Maternal prenatal anxiety and child COMT

genotype predict working memory and symptoms of ADHD. PLoS One.

2017;12(6):e0177506.

22. Wolford E, Lahti M, Tuovinen S, et al. Maternal depressive symptoms during and after

pregnancy are associated with attention-deficit/hyperactivity disorder symptoms in their

3- to 6-year-old children. PLOS ONE. 2017;12(12):e0190248.

doi:10.1371/journal.pone.0190248

23. Park M. Maternal Depression Trajectories from Pregnancy to 3 Years Postpartum Are

Associated with Children's Behavior and Executive Functions at 3 and 6 Years. Archives

of Women's Mental Health. Vol 21. #Pages#; 2018.

24. Lahti M, Savolainen K, Tuovinen S, et al. Maternal Depressive Symptoms During and

After Pregnancy and Psychiatric Problems in Children. J Am Acad Child Adolesc

Psychiatry. 2017;56(1):30-39.e7.

25. Huhdanpää H, Et Aronen P. Prenatal and Postnatal Predictive Factors for Children's

Inattentive and Hyperactive Symptoms at 5 Years of Age: The Role of Early Family-

Related Factors. Child Psychiatry and Human Development. Vol 52. #Pages#; 2021.

26. Kingston D, Kehler H, Austin MP, et al. Trajectories of maternal depressive symptoms

during pregnancy and the first 12 months postpartum and child externalizing and

internalizing behavior at three years. PLoS One. 2018;13(4):e0195365.

27. Koutra K, Roumeliotaki T, Kyriklaki A, et al. Maternal depression and personality traits

in association with child neuropsychological and behavioral development in preschool

years: Mother-child cohort (Rhea Study) in Crete, Greece. J Affect Disord. 2017;217:89-

98.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

28. MacKinnon N, Kingsbury M, Mahedy L, Evans J, Colman I. The Association Between

Prenatal Stress and Externalizing Symptoms in Childhood: Evidence From the Avon

Longitudinal Study of Parents and Children. Biol Psychiatry. 2018;83(2):100-108.

29. Teyhan A, Galobardes B, Henderson J. Child allergic symptoms and mental well-being:

the role of maternal anxiety and depression. J Pediatr. 2014;165(3):592-9.e5.

30. Bendiksen B, Aase H, Diep LM, Svensson E, Friis S, Zeiner P. The Associations

Between Pre- and Postnatal Maternal Symptoms of Distress and Preschooler’s

Symptoms of ADHD, Oppositional Defiant Disorder, Conduct Disorder, and Anxiety. J

Atten Disord. 2020;24(7):1057-1069.

31. Van Batenburg-Eddes T, Brion MJ, Henrichs J, et al. Parental depressive and anxiety

symptoms during pregnancy and attention problems in children: a cross



cohort

consistency study. J Child Psychol Psychiatry. 2013;54(5):591-600.

32. Betts KS, Williams GM, Najman JM, Alati R. Maternal depressive, anxious, and stress

symptoms during pregnancy predict internalizing problems in adolescence. Depress

Anxiety. 2014;31(1):9-18.

33. Betts KS, Williams GM, Najman JM, Alati R. The relationship between maternal

depressive, anxious, and stress symptoms during pregnancy and adult offspring

behavioral and emotional problems. Depress Anxiety. 2015;32(2):82-90.

34. Connor O, Ciesla TG, Sefair AA. Maternal prenatal infection and anxiety predict

neurodevelopmental outcomes in middle childhood. J Psychopathol Clin Sci.

2022;131:422-434.

35. Breen MS, Wingo AP, Koen N, et al. Gene expression in cord blood links genetic risk

for neurodevelopmental disorders with maternal psychological distress and adverse

childhood outcomes. Brain Behav Immun. 2018;73:320-330.

36. Yu T, Chang KC, Kuo PL. Paternal and maternal psychiatric disorders associated with

offspring autism spectrum disorders: A case-control study. J Psychiatr Res.

2022;151:469-475.

37. Chien YL, Wu CS, Chang YC, Cheong ML, Yao TC, Tsai HJ. Associations between

parental psychiatric disorders and autism spectrum disorder in the offspring-A response.

Autism Res. 2023;16(5):877-878.

38. Harrington RA, Lee LC, Crum RM, Zimmerman AW. Hertz-Picciotto I. Prenatal SSRI

use and offspring with autism spectrum disorder or developmental delay. Pediatrics.

2014;133:e1241-1248.

39. Siracusano M, Riccioni A, Gialloreti LE, et al. Maternal Perinatal Depression and risk of

neurodevelopmental disorders in offspring: Preliminary results from the SOS MOOD

project. Children (Basel). 2021;8(12):1150.

40. Sørensen MJ, Grønborg TK, Christensen J, et al. Antidepressant exposure in pregnancy

and risk of autism spectrum disorders. Clin Epidemiol. 2013;5:449-459.

41. Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN. Association Between

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in

Children. JAMA. 2017;317(15):1544-1552.

42. Zhou XH, Li YJ, Ou JJ, Li YM. Association between maternal antidepressant use during

pregnancy and autism spectrum disorder: an updated meta-analysis. Mol Autism.

2018;9(1). doi:10.1186/s13229-018-0207-7

43. Ramchandani PG, O'Connor TG, Evans J, Heron J, Murray L, Stein A. The effects of

pre- and postnatal depression in fathers: a natural experiment comparing the effects of

exposure to depression on offspring. J Child Psychol Psychiatry. 2008;49(10):1069-

1078.

44. Loomans EM, van der Stelt O, van Eijsden M, Gemke RJBJ, Vrijkotte T, Van den

Bergh BRH. Antenatal maternal anxiety is associated with problem behaviour at age

five. Early Hum Dev. 2011;87(8):565-570.

45. Chen LM, Pokhvisneva I, Lahti-Pulkkinen M, et al. Independent Prediction of Child

Psychiatric Symptoms by Maternal Mental Health and Child Polygenic Risk Scores.

Journal of the American Academy of Child & Adolescent Psychiatry. Published online

November 2023:S0890856723021858.

46. Le Bas G, Youssef G, Macdonald JA, et al. The role of antenatal and postnatal maternal

bonding in infant development. J Am Acad Child Adolesc Psychiatry. 2022;61(6):820-

829.e1.

47. Feldman R, Gordon I, Influs M, Gutbir T, Ebstein RP. Parental oxytocin and early

caregiving jointly shape children's oxytocin response and social reciprocity.

Neuropsychopharmacology. 2013;38(7):1154-1162.

48. Putnick DL, Sundaram R, Bell EM, et al. Trajectories of maternal postpartum depressive

symptoms. Pediatrics. 2020;146(5):e20200857.

49. Tucker JRD, Hobson CW. A systematic review of longitudinal studies investigating the

association between early life maternal depression and offspring ADHD. J Atten Disord.

2022;26(9):1167-1186.

50. Maselko J, Sikander S, Bhalotra S, et al. Effect of an early perinatal depression

intervention on long-term child development outcomes: follow-up of the Thinking

Healthy Programme randomised controlled trial. Lancet Psychiatry. 2015;2(7):609-617.

51. Say GN, Karabekiro

lu K, Babada

ı Z, Yüce M. Maternal stress and perinatal features

in autism and attention deficit/hyperactivity disorder. Pediatr Int. 2016;58(4):265-269.

52. Gao L, Xi QQ, Wu J, et al. Association between prenatal environmental factors and

child autism: A case control study in Tianjin, China. Biomed Environ Sci.

2015;28(9):642-650.

53. Lupattelli A, Chambers CD, Bandoli G, Handal M, Skurtveit S, Nordeng H. Association

of maternal use of benzodiazepines and Z-hypnotics during pregnancy with motor and

communication skills and attention-deficit/hyperactivity disorder symptoms in

preschoolers. JAMA Netw Open. 2019;2(4):e191435.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

54. Wiggins LD, Rubenstein E, Daniels J, et al. A phenotype of childhood autism is

associated with preexisting maternal anxiety and depression. J Abnorm Child Psychol.

2019;47(4):731-740.

55. Avalos LA, Chandran A, Churchill ML, et al. Prenatal depression and risk of child

autism-related traits among participants in the Environmental influences on Child Health

Outcomes program. Autism Res. 2023;16(9):1825-1835.

56. Wolf JB, Wade MJ. What are maternal effects (and what are they not)? Philos Trans R

Soc Lond B Biol Sci. 2009;364(1520):1107-1115.

57. Odonnell KJ, Glover V, Lahti J. Maternal prenatal anxiety and child COMT genotype

predict working memory and symptoms of ADHD. PLoS One. 2017;12(6).

58. Nilsen RM, Vollset SE, Gjessing HK, et al. Self-selection and bias in a large prospective

pregnancy cohort in Norway. Paediatr Perinat Epidemiol. 2009;23(6):597-608.

59. Grzeskowiak LE, Morrison JL, Henriksen TB, et al. Prenatal antidepressant exposure

and child behavioural outcomes at 7 years of age: a study within the Danish National

Birth Cohort. BJOG. 2016;123(12):1919-1928.

60. Lupattelli A, Mahic M, Handal M, Ystrom E, Reichborn-Kjennerud T, Nordeng H.

Attention-deficit/hyperactivity disorder in children following prenatal exposure to

antidepressants: Results from the Norwegian mother, father, and child cohort study.

Obstet Anesth Dig. 2022;42(3):123-123.

61. Bolea-Alamañac B, Davies SJC, Evans J, et al. Does maternal somatic anxiety in

pregnancy predispose children to hyperactivity? Eur Child Adolesc Psychiatry.

2019;28(11):1475-1486.

62. D'Souza S, Waldie KE, Peterson ER, Underwood L, Morton SMB. Antenatal and

postnatal determinants of behavioural difficulties in early childhood: Evidence from

growing up in New Zealand. Child Psychiatry Hum Dev. 2019;50(1):45-60.

63. Huhdanpää H, Morales-Muñoz I, Aronen ET, et al. Prenatal and postnatal predictive

factors for children's inattentive and hyperactive symptoms at 5 years of age: The role of

early family-related factors. Child Psychiatry Hum Dev. 2021;52(5):783-799.

64. Hagberg KW, Robijn AL, Jick SS. Maternal depression and antidepressant use during

pregnancy and the risk of autism spectrum disorder in offspring. Clin Epidemiol.

2018;10:1599-1612.

65. Clements CC, Castro VM, Blumenthal SR, et al. Prenatal antidepressant exposure is

associated with risk for attention-deficit hyperactivity disorder but not autism spectrum

disorder in a large health system. Mol Psychiatry. 2015;20(6):727-734.

66. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression,

maternal antidepressant use during pregnancy, and risk of autism spectrum disorders:

population based case-control study. BMJ. 2013;346:f2059.

67. Leis JA, Heron J, Stuart EA, Mendelson T. Associations between maternal mental

health and child emotional and behavioral problems: does prenatal mental health matter?

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

J Abnorm Child Psychol. 2014;42(1):161-171.

68. Nishigori T, Hashimoto K, Mori M, et al. Association between maternal prenatal

psychological distress and autism spectrum disorder among 3-year-old children: The

Japan Environment and Children's Study. J Dev Orig Health Dis. 2023;14(1):70-76.

69. Hope H, Pierce M, Gabr H, et al. The causal association between maternal depression,

anxiety, and infection in pregnancy and neurodevelopmental disorders among 410 461

children: a population study using quasi-negative control cohorts and sibling analysis.

Psychol Med. Published online January 11, 2024:1-9.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Table 1.a Characteristics of meta-analyzed studies on maternal prenatal mood and anxiety disorders and offspring neurodevelopmental

disorders.

Study

Maternal

exposure

Mother exposure

assessment time

xposure

measures

Offspring outcome

Outcome measures

Study design

Sample

size

Setting

Grzeskowiak et al

(2016)59

Antidepressants

; antenatal

mood

10, 17

32 weeks of

gestation

SCL

–

8d, self

reported use of

rugs from AT

code class

N06A

Behavioural

problems:

emotional; conduct; peer

relationship;

hyperactivity/inattention;

pro-social skills

SDQ >90th percentile

Nationwide

population-

based

48737

Denmark

Lupattelli et al

(2021)60

SSRI and SNRI

antidepressants;

depression or

anxiety

Week 17 and 30 of

pregnancy; offspring

age 6 months to

adolescence

Self

reported

symptoms;

SCL-5;

medication use

self-report;

NorPD filled

antidepressant

prescriptions

ADHD

ICD

10; dispensed

ADHD medications;

CPRS-R, z-scores,

higher scores indicate

greater ADHD

symptoms

Nationwide,

prospective

population-

based

pregnancy

6395

Norway

Bolea

Alamañac

et al (2019)61

Somatic anxiety

symptoms

Weeks 18 and 32 of

pregnancy

CCEI scores:

top 20% for

case status

Hypera

ctivity/inattention

symptoms; ADHD

diagnosis

SDQ scores > 2 SD

above mean; DAWBA

bands 4-5 high ADHD

probability

Population

based cohort

11029

United

Kingdom

D'Souza et al

(2018)62

Depression;

anxiety

Antenatal (exact

timing NR) and 9

months postnatal

EPDS

≥

13;

PSS; GAD-7

scores,

moderate to

severe anxiety

(10–21)

Emotional symptoms; peer

problems; hyperactivity-

inattention; conduct

problems; total difficulties

SDQ Preschool ranges:

top 10% "abnormal"

Longitudinal

prospective

6246

New Zealand

Nidey et al

(2021)13

Depression

One year prior to

pregnancy up to

delivery

ICD

9/10

ADHD

ICD

9/10

Popu

lation

based

retrospective

cohort

5635

United States

Huhdanpää et al

(2021)63

Depression

32nd pregnancy week

and at offspring age

CES

Inattentive and

hyperactive symptoms of

SDQ:

inattentive/hyperactive

Population

based birth

699

Finland

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

3, 8, and 24 months

ADHD

symptoms

≥

5 (75th

percentile); FTF:

inattention and

hyperactivity-

impulsivity domains

≥

(75th percentile)

Hagberg et al

(2018)64

Depression;

antidepressant

prescription

Within 1 year before

delivery

Read codes

from CPRD

(diagnostic

criteria NR)

ASD; Asperger

syndrome; PDD

Read diagnostic codes

Cohort

194494

United

Kingdom

Clements et al

(2015)65

Antidepressants

preconception

and during

pregnancy;

depression

Pregnancy trimesters

or at any time before

pregnancy

Outpatient EHR

prescriptions;

inpatient

pharmacy

dispenses; ICD-

ASD; ADHD

ICD

9; DSM

Cohort

13273

United States

Chien et al

(2022)37

Depressive,

anxiety, and

obsessive-

compulsive

disorders

Before childbirth;

between birth and

offspring ASD

diagnosis; after

offspring ASD

diagnosis

ICD

9/ICD

ASD

ICD

CM/10

Population

based case-

control study

121994

Taiwan

Kodesh et al

(2021)4

Depression

636 days prior to the

offspring's date of

birth

ICD

ASD

ICD

9/10

Exploratory

case-cohort,

population-

based

80187

Israel

Rai et al (2013)

Depression;

SSRIs and

NSMRIs during

pregnancy

Depression

onset/length NR;

SSRI/NSMRI use at

pregnancy median 10

weeks

ICD

diagnoses only

before

childbirth;

medications

with ATC code

N06AB and

N06AA

ASD (with and without

ID)

ICD

9/10; DSM

Population

nested case-

control

43277

Sweden

El Marroun et al

Depressive

Average 20.6 weeks

BSI >0.75;

Autistic symptoms:

CBCL 1.5

5: clinically

Population

5976

The

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

(2014)

symptoms;

prenatal SSRI

use

of pregnancy

CIDI; self

reported

medication use;

pharmacy

prescription

records

interpersonal

behaviour;

communication;

repetitive/stereotypic

behaviours

meaningful problems

>93rd percentile;

pervasive

developmental

problems >95th

percentile; affective

problems >89th

percentile; SRS

based cohort

Netherlands

Avalos et al

(2023)55

Depression

4 weeks

preconception to 8

weeks postpartum

Diagnosis self

report; ICD-

9/10; PROMIS-

D T-scores

(continuous and

≥

65.9 severe

depression)

ASD

related traits

SRS T

scores

(continuous and SRS T-

score

≥

66 moderate-to-

severe autism-related

traits)

Longitudinal

collaborative

cohort

5553

United States

Leis et al (2014)

Depression and

anxiety

18 and 32 weeks

pregnancy; 8 weeks,

8 months 21, 33, 61,

73 months, and 11

years postpartum

EPDS

≥

13;

CCEI

≥

Conduct problems,

emotional symptoms,

hyperactivity, peer

relationships, and

prosocial behaviour

SDQ, summed to

subscale scores, range 0

to 10

Prospective,

community-

based

2891

United

Kingdom

Nishigori et al

(2022)68

Psychological

distress;

depressive

moods and

anxiety

Median 15.1 (IQR

12.3–18.9); median

27.4 (IQR 25.3–30.1)

weeks of pregnancy

≥

ASD

ICD

Nationwide

prospective

birth cohort

78745

Japan

Seebeck et al

(2023)14

Depression;

antidepressants

Mean 35.2 (SD 1.5)

weeks of pregnancy

EPDS, higher

scores indicate

higher

depression

levels; self-

reported

antidepressant

use

ASD risk

SSI

T<45

Prospective

cohort

2388

United States

Siracusano et al

Depression;

1st or 2nd pregnancy

DSM

5; EPDS

ASD; hyperactiv

ity and

DQ of Griffiths III;

Cohort

Italy

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

(2021)

psychotropic

medications

during

pregnancy

trimester

≥

12;

psychotropic

medication

prescription

inattention

WISC

IV, standardised;

ABAS-II; DSM-5;

ADOS-2; CBCL, T

≥

for clinically

significant; Conners’

Parents Rating Scale-

Long Form, T

≥

70 for

clinically significant

Hope et al (2024)

Depression

Between minimum 2

years, 280 days and

280 days before birth

CPRD read

codes

ADHD/

ADD; ASD; ID;

cerebral palsy; epilepsy

CPRD prescriptions;

HES ICD CPRD read

codes; ICD-10

Population

410461

England

ATC=Anatomical Therapeutic Chemical Classification System. ADHD=attention deficit hyperactivity disorder. ICD-10=International Classification of Diseases, Tenth

Revision. SCL-8d=eight-item Symptom Checklist version. SDQ=Strengths and Difficulties Questionnaire. EHR=electronic health records. ASD=autism spectrum disorder.

ICD-9=International Classification of Diseases, Ninth Revision. DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. SSRI=selective serotonin

reuptake inhibitors. SNRI=serotonin-norepinephrine reuptake inhibitors. SCL-5=Symptom Checklist-5 five-item version. NorPD=Norwegian Prescription Database. CPRS-

R=Conners' Parent Rating Scale-Revised. CCEI=Crown-Crisp Experiential Index. DAWBA=Development and Well-Being Assessment. EPDS=Edinburgh Postnatal

Depression Scale. PSS=Perceived Stress Scale. GAD-7=General Anxiety Disorder-7. CPRD=Clinical Practice Research Datalink. PDD=Pervasive Developmental Disorder.

ICD-9-CM=International Classification of Diseases, Ninth Revision, Clinical Modification. ICD-10-CM=International Classification of Diseases, Tenth Revision, Clinical

Modification. PROMIS-D=Patient-Reported Outcomes Measurement Information System – Depression. SRS=Social Responsiveness Scale. BSI=Brief Symptom Inventory.

CIDI=Composite International Diagnostic Interview. CBCL=Child Behavior Checklist. K6=Kessler Psychological Distress Scale. SSI-T=Social Security Income-Test.

DQ=Developmental Quotient. WISC-IV=Wechsler Intelligence Scale for Children - Fourth Edition. ABAS-II=Adaptive Behavior Assessment System - Second Edition.

ADOS-2=Autism Diagnostic Observation Schedule - Second Edition. HES=Hospital Episode Statistics.

Participants are described as mothers to reflect the language used in meta-analyzed papers; a single study (Avalos et al, 2023) defined how parents were ascertained and

identified them as birthing parents.

aStudies by Bolea-Alamañac et al (2019) and Leis et al (2014) use the same sample but address different offspring outcomes. Consequently, data from these studies were

preserved for meta-analysis.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Table 1.b Characteristics of meta-analyzed studies on paternal prenatal mood and anxiety disorders and offspring neurodevelopmental disorders.

Study

Paternal

exposure

Parent

exposure

assessment

time

Exposure

mea sures

Offspring outcome

Outcome measures

Study desi

Sample

size

Setting

Van Batenburg

Eddes et al

(2013)20

Anxiety and

depression

Generation R:

20 weeks of

pregnancy;

ALSPAC: 18

weeks of

pregnancy; 33

months

postnatally

Generation R:

BSI;

ALSPAC:

EPDS; CCEI

Attention problems

Generation R: the Child

Behavior Checklist,

93rd percentile for

Attention Problems in

the borderline range;

ALSPAC: SDQ:

hyperactivity/inattention

subscale, in the

"abnormal" range

Cross

cohort

Generation

R: 2280;

ALSPAC:

3442

United

Kingdom;

The

Netherlands

Ramchandani et

al (2008)43

Depression

Week 18 of

their partners'

pregnancy; 8

weeks after

birth

EPDS

≥

Emotional problems;

conduct problems;

hyperactivity; prosocial

behaviour; DSM-IV

psychiatric diagnoses

Rutter Revised

Preschool Scales, top

10% for high-scorers;

DAWBA for DSM-IV

psychiatric diagnoses

Longitudinal

population

cohort

7601

United

Kingdom

Huhdanpää et al

(2021)63

Depression

32nd pregnancy

week and at

offspring age 3,

8, and 24

months

CES

Inattentive and

hyperactive symptoms of

ADHD

SDQ:

inattentive/hyperactive

symptoms

≥

5 (75th

percentile); FTF:

inattention and

hyperactivity-

impulsivity domains

≥

(75th percentile)

Population

based birth

699

Finland

Chien et al

(2022)37

Depressive,

anxiety, and

obsessive-

compulsive

disorders

Before

childbirth;

between birth

and offspring

ASD diagnosis;

after offspring

ASD diagnosis

ICD

9/ICD

10-CM

ASD

ICD

CM/10

Population

based case-

control study

121994

Taiwan

Rai et al (2013)

Depression;

SSRIs and

NSMRIs

during

Depression

onset/length

NR;

SSRI/NSMRI

ICD

diagnoses only

before

childbirth;

ASD (with and without

ID)

ICD

9/10; DSM

Population

nested case-

control

43277

Sweden

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

pregnancy

use at

pregnancy

median 10

weeks

medications

with ATC

code N06AB

and N06AA

ATC=Anatomical Therapeutic Chemical Classification System. ADHD=attention deficit hyperactivity disorder. ICD-10=International Classification of Diseases, Tenth Revision.

ALSPAC=Avon Longitudinal Study of Parents and Children. ICD-9=International Classification of Diseases, Ninth Revision. ICD-9-CM=International Classification of Diseases, Ninth

Revision Clinical Modification. ICD-10-CM=International Classification of Diseases, Tenth Revision Clinical Modification. DSM-IV=Diagnostic and Statistical Manual of Mental Disorders,

Fourth Edition. SSRI=selective serotonin reuptake inhibitors. SNRI=serotonin-norepinephrine reuptake inhibitors. SDQ=Strengths and Difficulties Questionnaire. ASD=autism spectrum

disorder. EPDS=Edinburgh Postnatal Depression Scale. DAWBA=Development and Well-Being Assessment. CCEI=Crown-Crisp Experiential Index. CES-D=Center for Epidemiologic Studies

Depression Scale.

Participants are described as fathers to reflect the language originally used in meta-analyzed papers.

aVan Batenburg-Eddes et al (2013) analyzed data from both mothers and fathers but only the data from the fathers were included in the meta-analysis as the study sample for mothers overlaps

with a larger study on maternal perinatal disorder by Bolea-Alamañac et al (2019).

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Figure 1. PRISMA flow diagram.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a

Figure 2. Forest plot of associations between maternal prenatal mood and anxiety disorders

and offspring neurodevelopmental disorders.

Square sizes reflect the weights attributed to each study. Diamonds denote the summary effect sizes for the random-effect

models.

OR=odds ratio. CI=confidence intervals NDD=neurodevelopmental disorders. ADHD=attention-deficit/hyperactivity

disorder. ASD=autism spectrum disorder.

aClements et al (2015) analyzed separate samples of individuals with diagnoses of autism spectrum disorder and attention-

deficit/hyperactivity disorder. Authors provided results for three trimesters. The third trimester has been selected for this

meta-analysis because it is the most conservative estimate reported.

bChien et al (2022) included the following disorders: major depressive disorder, persistent depressive disorder, and

depressive disorder, unspecified.

cHope et al (2024) analyzed a combined sample of individuals with any of the following disorders: autism/autism spectrum

disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy.

Figure 3. Forest plot for the association between paternal prenatal mood and anxiety

disorders and the risk of neurodevelopmental disorders (NDDs) in offspring.

Square sizes reflect the weights attributed to each study. The diamond denotes the summary effect size for the random-effect

models.

CI=confidence intervals. ASD=autism spectrum disorder. ADHD=attention-deficit/hyperactivity disorder.

aChien et al (2022) included the following disorders: major depressive disorder, persistent depressive disorder, depressive

disorder, unspecified, generalized anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, and specific phobia

disorder.