COVID-19 Pandemic and Infant Neurodevelopmental Impairment

This systematic review and meta-analysis evaluates whether the COVID-19 pandemic is associated with changes in neurodevelopmental outcomes during infancy.


Introduction
COVID-19, caused by SARS-CoV-2, persists as a global health emergency. 13][4] According to the results of a living systematic review and meta-analysis, 5 10% of pregnant women attending or admitted to hospitals for any reason, not only obstetrics-related issues, were suspected of having or had a diagnosis of COVID-19.At present, our understanding of the effects of maternal COVID-19 infection on short-term and long-term aspects of maternal-fetal health, including neurodevelopmental outcomes during infancy, remains limited. 2 Neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder, have heterogeneous causes associated with impaired cognition, communication, adaptive behavior, and psychomotor skills. 6][9][10][11] Maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies 8,9 supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders.
Fortunately, maternal-fetal vertical transmission of SARS-CoV-2 is rare, although the impact of maternal infection on fetal and postnatal neurodevelopment is still poorly understood. 12Recently, a few cohort studies [13][14][15][16] on this clinically important issue have been published with controversial results.Shuffrey et al, 15 as one of the largest cohorts, assessed 255 infants born during the pandemic, and exposure to maternal SARS-CoV-2 infection was not associated with differences in neurodevelopmental screening scores at age 6 months, regardless of infection timing or severity.
However, both infants with and without SARS-CoV-2 exposure born during that period had significantly lower scores on gross motor, fine motor, and personal-social subdomains compared with the prepandemic cohort. 15e net impact of the COVID-19 pandemic on potential risk of neurodevelopmental impairment (NDI) is of extreme importance.The current study aimed to determine whether (1) being born or raised during the COVID-19 pandemic and (2) gestational exposure to SARS-CoV-2 are associated with an increased risk of NDI during the first year of life using the Ages and Stages Questionnaires, Third Edition (ASQ-3), neurodevelopmental screening tool.

Methods
This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.The study protocol for this systematic review was registered in the PROSPERO international prospective register of systematic reviews (Registration number: CRD42022315849).

Search Strategy
A literature search was performed by 2 independent authors (K.H. and N.Z.) using PubMed, Web of

Eligibility Criteria
This review included only observational studies evaluating the risk of NDI among infants who had their neurodevelopmental screening during the COVID-19 pandemic.Only studies presenting data on infants undergoing neurodevelopmental screening up to 12 months corrected age follow-up were deemed eligible for inclusion.To be eligible for quantitative synthesis, studies were included if they defined "being at risk of NDI" as a composite or domain score at least 2 SDs below the established mean of the normal population reported by the standardized neurodevelopmental assessment tool of ASQ-3.Articles designed as case reports, narrative reviews, case series, dissertations, and letters or editorials were excluded.In terms of defining comparison groups, the risk of NDI was assessed among those who had screening during the pandemic vs those who had screening before the pandemic.As a secondary analysis, the risk of NDI was also assessed among those who were born during the pandemic with documented maternal SARS-CoV-2 infection vs those born during the pandemic with no maternal SARS-CoV-2 infection.

Study Selection
A total of 1880 articles were retrieved.Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility.Screening of the title and abstract resulted in 21 potentially eligible studies.Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).

Ages and Stages Questionnaires, Third Edition
The ASQ-3 is a parent-completed comprehensive neurodevelopmental screener with 30 items in 5 developmental domains: communication, gross motor, fine motor, problem-solving, and personalsocial.Each of the 30 items describes a skill, ability, or behavior to which the parent responds yes (10 points), sometimes (5 points), or not yet (0 points). 17For the quantitative meta-analysis, the score calculated for each domain was categorized as normal development (above cutoff) or at risk of NDI, if the score was 2 SDs below the mean, which indicates a possible delay that requires further follow-up or referral.

Primary and Secondary Outcomes
The primary outcome measure was the prevalence of infants (up to 12 months after birth) at risk of NDI who had their neurodevelopmental screening during the COVID-19 pandemic compared with the prevalence of infants at high risk of NDI who had their screening before the pandemic.The secondary outcome measure was to compare the risk of NDI among pandemic-born infants who had in utero exposure to SARS-CoV-2 vs those who were born during the same time frame but with no in utero exposure to SARS-CoV-2.

Quality Assessment
Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies and the risk of bias.NOS comprises participant selection, comparability of study groups, and assessment of outcome or exposure.A score of 7 or above was considered to be of high quality. 18Quality assessment selection was performed by 2 independent authors (K.H. and N.Z.), and discrepancies were resolved by the third investigator (A.A.S.).

Statistical Analysis
Statistical analysis was performed using Stata statistical software version 17 (StataCorp).Pooled effect sizes were presented as odds ratio (OR) with a 95% CI for categorical variables using DerSimonian and Laird method.Subgroup analysis was conducted to assess the risk of NDI according to the infantile age in which screening was performed (6 vs 12 months after birth).A 2-sided I 2 test was used to examine heterogeneity across the included studies; I 2 Ն 50% and P < .05indicate heterogeneity.A random-effects model was used due to the anticipated heterogeneity of included studies.Furthermore, publication bias was assessed using Egger and Begg tests.

Demographic Characteristics
The Table presents characteristics of the included studies, drawn from an initial search strategy inclusive of 1210 titles for screening.All included studies were published between 2021 and 2022.

Neurodevelopment Screening During the COVID-19 Pandemic vs Before Pandemic
Overall, there was no significant difference regarding the overall risk of NDI, adjusted for prematurity, among infants screened during the pandemic compared with those screened before the pandemic (OR, 1.12; 95% CI, 0.73- among infants who were born during the pandemic (Figure 3 and eFigure 1 in the Supplement).
Subgroup analysis was performed according to the infantile age in which neurodevelopmental screening was performed.At age 6 months, the risk of NDI was comparable between pandemic and

Quality Assessment
The overall score for the studies was between 6 and 8 out of a possible score of 9 (Table ).Three studies 20,22,23 had score of 6, 3 studies 16,19,21 had score of 7, and 2 studies 13,15 had score of 8.There was no publication bias for risk of overall NDI according to either the Egger test or the Begg test.

Discussion
This systematic review and meta-analysis reports the potential association of the COVID-19 pandemic during pregnancy with neurodevelopmental outcomes during infancy.For infants screened before and during the pandemic, we found no significant differences in the overall risk of NDI.However, analyses of individual domains of development revealed infants screened during the Odds ratio (95% CI) Neurodevelopmental impairments presenting during infancy can be secondary to genetic susceptibility, 6 preterm birth, 24 perinatal inflammation, infection, 7 diet, 25 socioeconomic factors, maternal and placental health, and congenital anomalies.Maternal infection with SARS-CoV-2 during pregnancy is associated with preterm birth 5 and inflammation 26 and can lead to mental health problems including anxiety and depression. 27Unlike Zika virus, which has a fairly high maternal-fetal vertical transmission rate associated with a well-described spectrum of congenital manifestations, including microcephaly, cerebral palsy, and developmental delays, 11,28 SARS-CoV-2 rarely crosses the placenta and is not associated with overt placental pathology. 14,29,30During the COVID-19 pandemic, financial strain, social isolation, and decreased family support have been associated with increased maternal depressive and anxiety symptoms in the perinatal period, 31 which are known to be associated with neurodevelopmental and behavioral disorders.Higher levels of COVID-19-related stress were reported for both mothers and fathers of infants aged 0 to 6 months and were associated with insensitive parenting practices, including decreased emotional in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood. 32,33Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.

Strengths and Limitations
Among the most important strengths of this study included not limiting our included studies to only English publications, incorporating a highly sensitive search strategy inclusive of 1210 titles for screening, and a novel question with unanticipated findings.Our study is also prone to limitations in the heterogeneity of outcome measures, including limitations of quantitative analyses in 5 studies.
An inherent limitation of the ASQ-3 questionnaire is its use as a screening instrument based on parent reports rather than objective assessment.Additionally, the sensitivity in detecting subtle but significant impairments in infancy is challenging compared with severe impairments or at later developmental stages.Given the novel finding of communication impairment as a result of being born during the COVID-19 pandemic, we were limited by a lack of data regarding the prevalence of social distancing among affected vs unaffected participants.Additionally, to better understand the subtle association of maternal SARS-CoV-2 infection during pregnancy with NDI warrants further investigation, with granular data on maternal-fetal COVID-19 illness and rigorous assessments of the potential for fetal SARS-CoV-2 exposures, which is beyond the scope of this review.
The ASQ-3 was administered by trained psychological evaluators in the Huang et al 21 study, whereas in other included studies, the ASQ-3 is completed by caregivers or mothers.This might introduce variability in the results which should be interpreted with caution.
Clearly, although our observations raise potential concerns regarding the early developmental trajectory of children born during the COVID-19 pandemic, long-term follow-up behavioral assessments would be necessary to see whether this is borne out during early childhood or indeed whether catch-up occurring after the follow-up period is limited to the first year of life, and to extrapolate further into early childhood.As such, we consider the principal value of our current metaanalysis lies in its importance in generating novel hypotheses warranting further study.
Science, and Embase from inception to March 25, 2022.The search was conducted from March 19 to March 25, 2022, with no language restriction using the following keywords: (COVID-19 OR Coronavirus OR Severe Acute Respiratory Syndrome OR Corona-virus OR 2019nCoV OR Corona Virus OR COVID OR COVID19 OR SARS CoV 2 OR SARS-CoV OR SARS-CoV-2) AND (neurodevelopment OR neurodevelopmental OR development disorder* OR developmental disorder* OR intellectual disability OR intellectual developmental disorder* OR mental retardation OR global developmental delay OR communication disorders OR gross motor OR fine motor OR personal social OR problem solving).The detailed search strategy is shown in eTable 1 in the Supplement.References of relevant articles were manually reviewed, and eligible studies were added to the results from the electronic literature search.Literature search and study selection were performed by 2 independent authors (N.Z. and A.N.), and discrepancies were resolved by consulting the third investigator (A.A.S.).

Figure 3 .
Figure 3. Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic

Figure 4 .
Figure 4. Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts

on 09/28/2023 pandemic
were more likely to be at risk of communication impairment compared with their prepandemic counterparts.Our findings suggest that known maternal SARS-CoV-2 infection was associated with a significantly greater risk of fine motor impairment but no increased risk of impairment in any other domain of neurodevelopment.