Next Article in Journal
Outcomes of a Near-Zero Fluoroscopy and Minimally Invasive Approach in Ablation of Right Free Wall Accessory Pathways in Children
Previous Article in Journal
Evaluating the Predictive Value of Clinical Factors for Pembrolizumab Efficacy and Safety in Advanced NSCLC with High PD-L1 Expression (TPS ≥ 50%)
Previous Article in Special Issue
Impact of COVID-19 on Pregnancy Outcomes: A Phase-Based Analysis from a Spanish Tertiary Hospital (2020–2023)
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 14
Issue 17
10.3390/jcm14176202
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review

by
Daniela Păcurar
1,2,
Alexandru Dinulescu
1,2,*,
Ana Prejmereanu
1,2,
Alexandru Cosmin Palcău
1,3,
Irina Dijmărescu
1,2 and
Mirela-Luminița Pavelescu
1,2
1
Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
2
Department of Pediatrics, Emergency Hospital for Children “Grigore Alexandrescu”, 011743 Bucharest, Romania
3
Department of General Surgery, University Emergency Hospital of Bucharest, 050098 Bucharest, Romania
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(17), 6202; https://doi.org/10.3390/jcm14176202
Submission received: 27 July 2025 / Revised: 24 August 2025 / Accepted: 1 September 2025 / Published: 2 September 2025
(This article belongs to the Special Issue New Advances in COVID-19 and Pregnancy)
Browse Figure
Versions Notes

Abstract

Background: The potential impact of maternal SARS-CoV-2 infection during pregnancy on the neurodevelopment of offspring has raised considerable concern. Emerging studies have evaluated various developmental domains in exposed infants, yet findings remain inconsistent. Objective: To synthesize current evidence regarding neurodevelopmental outcomes in infants born to mothers with confirmed SARS-CoV-2 infection during pregnancy. Methods: We conducted a narrative review following PRISMA guidelines. A literature search was performed in PubMed, Cochrane, and ScienceDirect using keywords including “COVID-19”, “pregnancy”, “neurodevelopment”, and “SARS-CoV-2”. Nineteen studies were included. Data were extracted regarding study design, sample size, timing of exposure, age at assessment, developmental tools used, and key findings. Study quality was assessed using the Newcastle–Ottawa Scale. Results: Among 19 included studies, 12 reported at least some neurodevelopmental delays, particularly in motor and language domains. However, these delays were generally mild, domain-specific, and often not statistically significant. Seven studies, most of which were high-quality and low-risk, reported no significant differences between exposed and unexposed groups. Assessment tools and follow-up durations varied widely, limiting comparability. Conclusions: Current evidence does not support a consistent association between in utero SARS-CoV-2 exposure and an unfavorable neurodevelopmental outcome up to 24 months. However, heterogeneity in methods and short-term follow-up warrant further high-quality longitudinal research.

1. Introduction

The intrauterine environment plays a pivotal role in fetal development, including the processes of brain growth and maturation [1,2,3]. Maternal infections during pregnancy are well-documented contributors to negative neurodevelopmental outcomes in offspring, as pathogens or the maternal immune response can disrupt fetal brain development at critical stages [1,4,5,6,7,8]. Among the diverse etiologies that may impair fetal and early neurodevelopment—including metabolic, genetic, endocrine, and structural disorders, congenital infections represent a significant and potentially preventable cause of adverse outcomes [9,10,11,12,13,14]. Numerous viral infections, such as cytomegalovirus (CMV), Epstein–Barr virus (EBV), Zika virus (ZIKV), and influenza, have been associated with a spectrum of neurodevelopmental sequelae, including sensorineural hearing loss, intellectual disability, motor dysfunction, and autism spectrum disorders (ASD) [15,16,17,18,19,20,21]. CMV, for instance, is the most common congenital viral infection and a leading cause of neurodevelopmental disability, while prenatal exposure to maternal influenza has been linked to increased risks of schizophrenia and neurocognitive impairments in later life, although this statement needs more reliable data [20,22,23,24].
In this context, the emergence of SARS-CoV-2 as a novel coronavirus with global reach has raised concerns about its potential impact on children’s neurodevelopment [25,26,27]. Although vertical transmission of SARS-CoV-2 appears to be rare, the maternal immune activation (MIA) associated with COVID-19, characterized by systemic inflammation, cytokine release, and placental pathology, may represent a mechanism by which SARS-CoV-2 prenatal exposure could affect the developing fetal brain [26,28,29,30,31,32]. Furthermore, the pandemic has brought additional stressors such as altered prenatal care, maternal mental health issues, and social isolation, all of which may compound neurodevelopmental risks [33,34,35].
COVID-19 infection in pregnancy is a known factor for preterm birth, especially if the infection occurs in the third trimester or is a severe one [36,37,38]. There were also other complications described in COVID-19 pregnancy, such as an increased risk of hypertensive disorders of pregnancy, gestational diabetes, or an increased rate of neonatal intensive care unit (NICU) admission [39,40,41,42]. One important aspect is that the mRNA COVID-19 vaccine administered before pregnancy was not associated with an increased risk of any of those complications [43,44].
While initial concerns focused on obstetric complications such as preterm birth and vertical transmission, attention has increasingly turned to potential long-term consequences for offspring, particularly in the domain of neurodevelopment [43,44,45]. Recent reviews have begun to explore the early neurodevelopmental trajectories of children born to mothers infected with SARS-CoV-2 during pregnancy, with some reports suggesting subtle delays in motor, language, or social-emotional development during infancy [26,46]. It remains critical to disentangle the direct effects of the virus from indirect influences such as maternal emotional dysregulation and psychosocial stress during the pandemic, including social isolation and healthcare disruption, which may have further contributed to altered mother–infant interactions and long-term neurodevelopmental impact [47,48,49]. However, findings remain inconclusive, and methodological heterogeneity, regarding timing of maternal infection, severity of disease, gestational age at exposure, and follow-up duration, limits the generalizability of available evidence.
This review aims to synthesize current evidence on neurodevelopmental outcomes in children with in utero exposure to SARS-CoV-2. By exploring current epidemiologic findings, we seek to highlight both the knowns and unknowns in this evolving field and underscore the need for long-term, high-quality follow-up studies to fully understand the impact of COVID-19 on the next generation.

2. Materials and Methods

This study was conducted as a narrative review, with elements of systematic methodology applied to ensure rigor and transparency. A comprehensive literature search was performed in databases such as PubMed and Cochrane using predefined keywords. The selection process followed PRISMA principles, and study quality was assessed using the Newcastle–Ottawa Scale (NOS).

2.1. Inclusion Criteria

  • Peer-reviewed observational studies (cohort or case–control).
  • Neurodevelopment assessed via standardized tools (e.g., ASQ 3, Bayley scales) or clinical examination during infancy or early childhood (≤24 months), standardized parent-reported questionnaires (e.g., Ages and Stages Questionnaire), or direct neurological clinical examination during infancy or early childhood (≤24 months).

2.2. Exclusion Criteria

  • Narrative reviews, animal studies (except mechanistic discussion), case reports without neurodevelopmental follow-up.
  • Studies reporting exclusively biological outcomes (e.g., cytokine profiles, epigenetic changes) without separate reporting of standardized neurodevelopmental assessments.

2.3. Search Strategy, Selection and Data Extraction

A comprehensive literature search was conducted using PubMed, Cochrane Library, and ScienceDirect databases up to July 2025. The following keywords were used: (“SARS-CoV-2” OR “COVID-19”) AND (“pregnancy” OR “maternal infection”) AND (“neurodevelopment” OR “neurodevelopmental outcomes” OR “infant development”). Data extraction included sample size, neurodevelopmental tools used, follow-up age, and key outcomes. The search yielded 1083 articles. After removing duplicates and screening titles and abstracts, the full texts of potentially relevant studies were reviewed. Borderline-eligible studies were excluded if they did not report standardized neurodevelopmental outcomes separately, if they focused exclusively on biological outcomes without clinical correlation, or if they involved animal models. A total of 21 studies met the final inclusion criteria and were included in the review (Figure 1).

2.4. Data Synthesis

Due to substantial heterogeneity across the included studies in terms of neurodevelopmental assessment tools, follow-up duration, outcome domains, and reporting formats, a meta-analysis was not feasible. Instead, a narrative synthesis was performed. Results were organized thematically according to developmental domains (e.g., motor, language, cognitive, and social-emotional) and by the type and timing of maternal SARS-CoV-2 exposure. Consistencies and discrepancies across studies were qualitatively assessed, with attention to study quality, sample size, and methodological rigor as evaluated by the Newcastle–Ottawa Scale, interpreted as low risk of bias: 7–9; moderate risk of bias: 4–6 and high risk of bias: 0–3 (Table 1) [50].
Among the 21 included studies, 9 were rated as low risk of bias, 11 as moderate, and 1 as high risk. Studies with high total scores (e.g., Jaswa et al., Vrantsidis et al., Shuffrey et al.) were typically large, prospective cohorts with appropriate comparators and robust outcome assessment [51,66,67]. Studies rated as moderate risk tended to have smaller sample sizes, limited follow-up durations, or used less validated assessment tools.

3. Results

A total of 21 studies met the inclusion criteria for this narrative review, evaluating neurodevelopmental outcomes in infants born to mothers infected with SARS-CoV-2 during pregnancy. The sample sizes of the exposed groups ranged from 9 to 555, and neurodevelopmental assessments were performed at ages ranging from 6 weeks to 24 months postpartum. The most frequently used assessment tool was the Ages and Stages Questionnaire (ASQ-3). Other instruments used were the Denver Developmental Screening Test, General Movement Assessment (GMA), Motor Optimality Scores Revised (MOS-R), Neonatal Behavioral Assessment Scale (NBAS), Age and Stage Questionnaire Social-Emotional (ASQ:SE-2), Van Wiechen Scheme, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), Survey of Well-Being of Young Children (SWYC), Baby Pediatric Symptom Checklist (BPSC), and various clinical or parent-report measures.
Based on Table 2, 13 out of 21 studies (62%) reported at least some neurodevelopmental delays among SARS-CoV-2-exposed infants. These delays were most frequently observed in motor, language, and socioemotional domains, though the clinical significance and persistence of these delays varied considerably across studies.

3.1. Motor Development Findings

Motor development was the most commonly affected domain, with 11 studies reporting motor-related concerns. Shuffrey et al. (2021) found that both exposed and unexposed infants born during the pandemic had significantly lower scores in gross motor and fine motor domains compared to pre-pandemic cohorts, suggesting broader pandemic-related effects beyond direct viral exposure [51]. Several studies specifically identified fine motor delays: Cheng et al. (2021) reported significantly lower fine motor scores (p = 0.03) in exposed infants at 8–10 months, while Liu et al. (2022) found higher rates of fine motor abnormalities in exposed versus unexposed groups (15.2% vs. 2.1%; p = 0.02) [53,60]. Studies utilizing more sensitive motor assessment tools detected subtle neuromotor differences. Martinez et al. (2023) and Aldrete-Cortez et al. (2022), both using the Motor Optimality Score-Revised (MOS-R), found significantly lower median scores in exposed infants (23 vs. 25, p < 0.001; and 21 vs. 25, p = 0.002, respectively) [59,62]. Martinez et al. additionally reported that 16 exposed infants had MOS-R scores < 20 versus 0 controls (p < 0.001), and 13 exposed versus 0 controls showed developmental delays at 6–8 months clinical examination [62]. Kehdi et al. (2025) observed that 40% had motor delays at 6 months, this percentage increasing to 64.3% at 24 months, with specific cord blood cytokines correlating with motor delays (IL-6, IL-8, IL-17, and IL-1β) [70].

3.2. Communication and Language Development Findings

Communication delays were reported in several studies, with varying degrees of severity. Silva et al. (2025) found that 22 of 41 exposed children (53%) performed below the cutoff value in communication domains at 18 months [69]. Hill et al. (2024) reported lower ASQ-3 scores in communication domains among children exposed to severe maternal SARS-CoV-2 infection (p < 0.005), with findings correlating with specific cytokine profiles and epigenetic markers [68]. Berg et al. (2025), in one of the largest cohorts (N = 1446, 555 exposed), found no group differences in total ASQ scores, but noted increased risk of scores below cutoff among those exposed to severe maternal COVID-19 (16.0% vs. 6.1%; OR 3.57; 95% CI, 1.14–11.24) [71]. Finally, the only study rated as high risk of bias, Rood et al. (2023), suggested a mild delay but lacked a control group and included only 14 infants, limiting its reliability [65].

3.3. Socioemotional and Behavioral Outcomes

Several studies examined socioemotional development with mixed findings. Silva et al. (2023) reported increased odds of socioemotional developmental delay (OR = 4.0; p = 0.02) and inflexibility (OR = 14.0; p = 0.02) in exposed infants [63]. Ayesa-Arriola et al. (2023) found lower affectionate response scores in exposed groups (p = 0.009), particularly among those exposed in the third trimester (p = 0.043) [64]. Roffman et al. (2021) noted high irritability in exposed infants (p = 0.015) [52].

3.4. Timing of Maternal Infection

The trimester of maternal infection showed variable associations with outcomes. Ayed et al. (2022) found a higher risk of developmental delays with first-trimester (OR: 8.2, p = 0.039) and second-trimester (OR: 8.1, p = 0.001) infections compared to third-trimester exposure, but Ayesa-Arriola et al. (2023) reported more pronounced effects in third-trimester exposures, particularly for affectionate response measures (p = 0.043) [57,64]. It should be noted that more than a quarter (6/21) of the studies included had subjects only from the 3rd trimester infection, and three studies did not report this variable.

3.5. Disease Severity

Disease severity appeared to influence outcomes in some studies. Berg et al. (2025) specifically found increased risk only among infants exposed to severe maternal COVID-19 [71]. Hill et al. (2024) focused exclusively on severe maternal infections and reported significant developmental impacts with biological correlates [68].

3.6. Studies Reporting No Significant Differences

Seven studies reported no significant neurodevelopmental differences between exposed and unexposed groups. These included some of the largest and highest-quality studies: Jaswa et al. (2024) with 2003 participants (217 exposed) followed to 12–24 months, Vrantsidis et al. (2024) with 896 participants (96 exposed) followed to 6–24 months, and Wu et al. (2021) with 135 participants (57 exposed) assessed at 3 months [54,66,67]. These studies were notable for their larger sample sizes, appropriate control groups, and adjustment for multiple confounders, including maternal comorbidities, socioeconomic status, gestational age, and infant characteristics.

3.7. Adjustment for Confounders

Adjustment for confounders varied substantially across studies. Higher-quality studies typically adjusted for key variables, including gestational age, birthweight, maternal age, education, socioeconomic status, and infection characteristics. Studies with limited or no confounder adjustment showed more pronounced associations, raising questions about residual confounding.

4. Discussion

This narrative review synthesizes current evidence regarding neurodevelopment in infants born to mothers infected with SARS-CoV-2 during pregnancy, incorporating quality assessment using the Newcastle–Ottawa Scale to contextualize findings. While methodological heterogeneity presents interpretive challenges, emerging patterns regarding gestational timing, infection severity, and biological mechanisms warrant deeper clinical and scientific consideration alongside careful evaluation of study design limitations.

4.1. Overall Pattern of Findings and Study Quality Considerations

While 67% of studies reported some neurodevelopmental concerns, this proportion requires careful interpretation within the context of study quality and design. The highest-quality studies with low risk of bias (Jaswa et al., Vrantsidis et al., Shuffrey et al.) consistently reported no major developmental differences between exposed and unexposed groups [51,66,67]. This pattern suggests that apparent associations in lower-quality studies may reflect methodological limitations rather than true causal relationships.
The domains most frequently affected, motor development, communication, and socioemotional function, align with areas particularly vulnerable to early disruption and most readily assessed in infancy. However, the transient and mild nature of most reported delays, combined with their absence in well-controlled studies, suggests these findings may not represent clinically significant or persistent developmental alterations in the majority of exposed infants.
Overall, this review supports the statement that SARS-CoV-2 infection during pregnancy is not consistently associated with clinically significant neurodevelopmental delays in early infancy, but it remains essential to distinguish between the effects of being born during the pandemic and direct intrauterine exposure to SARS-CoV-2. Some delays may reflect broader societal disruptions rather than biological effects of the virus.

4.2. Gestational Timing of SARS-CoV2 Infection

The timing of maternal SARS-CoV-2 infection during pregnancy emerges as a critical determinant of neurodevelopmental risk, with evidence suggesting trimester-specific vulnerabilities that align with established principles of fetal brain development.
First-trimester exposure shows the strongest association with developmental delays, consistent with this period’s critical role in neural tube closure, neurulation, and establishment of basic brain architecture [72,73]. Ayed et al. (2022) provided compelling evidence for this vulnerability window, reporting dramatically increased odds ratios for developmental delays with first-trimester exposure (OR: 8.2, p = 0.039) [57]. During the first trimester, the blood–brain barrier is still developing, potentially allowing greater cytokine penetration into fetal neural tissue [74]. Established literature describes that first-trimester maternal immune activation affects fundamental neurodevelopmental processes, including neurogenesis, neuronal migration, and synaptic pruning [75,76]. The motor and reflex deficits specifically associated with first-trimester exposure may reflect disruption of brainstem and spinal cord development, which occurs primarily during weeks 4–8 of gestation. These structures are particularly vulnerable to inflammatory insults during their critical formation periods [77].
Second-trimester findings present complex findings, with Ayed et al. similarly reporting elevated risk (OR: 8.1, p = 0.001), while other studies suggest more subtle effects [57]. This period (weeks 13–26) encompasses peak cortical neurogenesis and the establishment of fundamental cortical architecture [78]. The apparent inconsistency in second-trimester findings across studies may reflect the diverse nature of developmental processes occurring during this extended period.
Third-trimester exposure presents the most intriguing findings, with studies reporting both protective and adverse effects. Ayesa-Arriola et al. (2023) found reduced affectionate response specifically in third-trimester exposed infants (p = 0.043), while several studies focusing exclusively on third-trimester exposure reported relatively preserved outcomes [64]. This apparent paradox may reflect the dual nature of late pregnancy immune activation. While the fetal brain is more mature and potentially more resistant to inflammatory disruption, this period encompasses critical synaptogenesis, circuit refinement, and the establishment of neurotransmitter systems crucial for social-emotional development [79].

4.3. Infection Severity

Studies focusing on mild to moderate maternal infections generally report reassuring outcomes. Berg et al. (2025), in their large cohort study (N = 1446), found no group differences in overall ASQ scores when analyzing the full spectrum of infection severity [71]. This suggests that the typical maternal inflammatory response to mild SARS-CoV-2 infection may be insufficient to significantly disrupt fetal neurodevelopment. The predominance of mild infections in many cohorts (often 80–95% of cases) likely contributes to the generally reassuring overall findings.
Neurodevelopmental effects are more consistently reported in studies examining severe maternal infections. Berg et al. specifically identified increased risk of developmental concerns only among infants exposed to severe maternal COVID-19 (16.0% vs. 6.1%; OR 3.57; 95% CI, 1.14–11.24) [71]. This finding suggests a dose–response relationship between maternal inflammatory burden and fetal neurodevelopmental risk. Hill et al. (2024) provided crucial mechanistic insights by focusing exclusively on severe maternal infections and demonstrating correlations between infant DNA methylation patterns and neurodevelopmental outcomes with specific cytokine profiles. Their finding of lower ASQ-3 scores in multiple domains (communication, problem solving, and personal-social; p < 0.005) coupled with epigenetic evidence provides the strongest support for biologically mediated effects [68].

4.4. Maternal Immune Activation

The concept of MIA provides a unifying framework for understanding SARS-CoV-2 effects on fetal neurodevelopment. Rather than requiring direct viral invasion of fetal neural tissue, MIA suggests that the maternal inflammatory response itself, can disrupt fetal brain development through shared inflammatory pathways [80]. This mechanism has been demonstrated across diverse maternal infections, from influenza to bacterial infections, suggesting common downstream effects despite different initial triggers [18,81]. The MIA model explains why SARS-CoV-2 effects on neurodevelopment show similarities to those observed with other prenatal infections, despite the virus’s unique characteristics. The key mediators are pro-inflammatory cytokines (such as IL-6, TNF-α, and IL-1β) that can cross the placenta and blood–brain barrier, triggering neuroinflammation in the developing fetal brain [31]. This neuroinflammation can then disrupt critical developmental processes, including neurogenesis, neuronal migration, synaptic formation, and myelination, regardless of whether the original pathogen directly infected neural tissue [76].
Kehdi et al. (2025) provided direct evidence of cytokine-mediated mechanisms, demonstrating that specific cord blood cytokines (IFN-γ, TNF-α, IL-6, IL-8, IL-17, IL-1β, CXCL10) correlated with domain-specific developmental delays [70]. The specificity of these correlations suggests that different cytokine profiles may preferentially affect distinct neurodevelopmental domains. Pro-inflammatory cytokines like TNF-α and IL-6 have established roles in disrupting neurogenesis and synaptic development, while chemokines like CXCL10 may affect microglial activation and neuroinflammation [82,83,84,85].
Beyond direct cytokine effects, SARS-CoV-2 infection can cause placental pathology, including thrombosis, infarction, and chronic villitis [86]. Liu et al. (2022) specifically linked fine motor abnormalities in exposed infants to placental hypoxia and ischemia, suggesting that vascular-mediated effects may be as important as direct inflammatory mechanisms [60].
Hill et al. (2024) provided groundbreaking evidence of epigenetic changes in infants exposed to severe maternal SARS-CoV-2 infection [68]. These DNA methylation alterations correlated with specific neurodevelopmental deficits, suggesting that maternal immune activation may program persistent changes in gene expression that influence long-term neurodevelopmental trajectories [87,88,89].

4.5. Specific Areas of Development Affected

Motor delays represent the most frequently reported and consistent finding across studies, appearing in 11 of 21 included studies. This consistency may reflect both the early emergence and relatively straightforward assessment of motor skills, but also suggests genuine vulnerability of motor systems to prenatal inflammatory insults. The progression from gross motor delays detected by standard screening tools to fine motor deficits identified by more sensitive instruments (MOS-R, GMA) indicates that motor effects may be subtle but persistent. Martinez et al. (2023) and Aldrete-Cortez et al. (2022) both demonstrated that specialized motor assessment tools could detect deficits missed by standard screening instruments, with significantly lower median MOS-R scores in exposed groups (23 vs. 25, p < 0.001; and 21 vs. 25, p = 0.002, respectively) [59,62]. The basal ganglia and cerebellar systems, vulnerable to prenatal inflammatory insults, are integral to both motor control and higher-order cognitive functions, potentially predicting later learning difficulties and attention problems [90,91].
Communication delays, while less consistently reported across all studies, may represent more clinically significant long-term effects when present. Silva et al. (2025) found that 53% of exposed children performed below cutoff values in communication domains at 18 months, a proportion that substantially exceeds the typical population prevalence of language delays (10–15%) [69]. The correlation between communication delays and specific cytokine profiles (Kehdi et al., 2025) suggests that neuroinflammation may particularly affect perisylvian cortical regions critical for language development [70,92].
Social-emotional findings are reported in fewer studies. Ayesa-Arriola et al. (2023) documented reduced affectionate response, while Silva et al. (2023) reported increased inflexibility (OR = 14.0; p = 0.02) and socioemotional developmental delays (OR = 4.0; p = 0.02) [63,64]. These findings align with established research linking prenatal immune activation to autism spectrum disorders, social anxiety, and other social-emotional difficulties [93,94,95].

4.6. Methodological Heterogeneity Impact on Interpretation

4.6.1. Assessment Tools and Their Clinical Implications

The choice of neurodevelopmental assessment tool significantly influenced findings and their clinical interpretation. Parent-reported questionnaires such as the ASQ-3, while cost-effective and widely used, may be influenced by recall bias, parental stress, and pandemic-related anxiety [96]. These tools have known limitations in sensitivity for mild to moderate delays, and maternal education level significantly influences their accuracy [97]. The high prevalence of ASQ-3 use across studies (12 of 21) may contribute to apparent consistency of findings while actually reflecting shared methodological limitations rather than true developmental effects.
In contrast, studies using more sensitive, clinician-administered tools like the Motor Optimality Score-Revised (MOS-R) or General Movement Assessment (GMA) detected subtle neuromotor differences that may have greater clinical significance. However, these tools require specialized training and are resource-intensive, limiting their use to smaller cohorts and potentially introducing selection bias [98,99,100].
Direct neurological examination, while valuable for detecting overt abnormalities, may miss subtle cognitive or socioemotional delays that become apparent only with standardized developmental assessments [101]. This methodological diversity substantially contributes to the heterogeneity of findings and complicates direct comparison of results across studies.

4.6.2. Follow-Up Duration and Developmental Windows

The variation in follow-up duration (6 weeks to 24 months) represents another critical limitation with important clinical implications. Most studies focused on early infancy, when many neurodevelopmental domains are still emerging and may not yet manifest subtle deficits. Domains such as executive function, attention regulation, and complex social behaviors typically become measurable only in later childhood, meaning that current evidence may not capture the full spectrum of potential effects.
Furthermore, the timing of assessment relative to critical developmental windows varies across studies, making it difficult to determine whether observed differences represent persistent delays, transient perturbations, or normal developmental variation. This limitation is particularly important given that some prenatal exposures may have effects that only become apparent during school age or adolescence.

4.6.3. Distinguishing Viral Effects from Pandemic Context

A particularly important finding emerges from studies that attempted to distinguish direct viral effects from broader pandemic-related impacts. Shuffrey et al. (2021) [51] provided crucial insight by comparing three groups: pre-pandemic infants, pandemic-born unexposed infants, and pandemic-born exposed infants. Their finding that both pandemic-born groups showed lower developmental scores compared to pre-pandemic cohorts, regardless of maternal infection status, highlights the challenge of attributing developmental differences specifically to SARS-CoV-2 exposure [51]. This observation suggests that many reported developmental concerns may reflect broader pandemic-related disruptions, including altered prenatal care, maternal mental health impacts, reduced social stimulation, and disrupted healthcare access rather than direct viral effects [102,103]. The failure of many studies to account for these contextual factors represents a significant limitation in interpreting current literature.

4.6.4. Confounding and Study Quality Considerations

The inconsistent approach to confounder adjustment across studies represents a major limitation affecting interpretation. Key confounders, including preterm birth, small for gestational age status, maternal mental health, socioeconomic factors, and healthcare access disruption, were variably addressed. Large registry-based studies and well-funded cohorts generally provided more comprehensive adjustment, while smaller studies often presented unadjusted comparisons.
Where adjustment was limited or absent, observed associations, particularly modest developmental score differences, should be interpreted cautiously, given the potential for residual confounding. The observation that studies with more comprehensive confounder adjustment were less likely to report significant associations supports this concern.
Among the 21 included studies, the 9 studies rated as low risk of bias using the Newcastle–Ottawa Scale were predominantly large, prospective cohorts with appropriate control groups and robust outcome assessments. Notably, most studies rated as low risk (6 of 9) reported no significant neurodevelopmental differences, while studies reporting delays were more frequently rated as moderate or high risk due to limitations in sample size, control group quality, follow-up duration, or assessment methodology. The only study rated as high risk of bias, Rood et al. (2023), suggested a mild delay but lacked a control group and included only 14 infants, limiting its reliability [65].

4.7. Similar Studies

Our finding is in concordance with other studies: a meta-analysis comparing infants born during compared to those born before the pandemic published by Hessami et al. (2022) found no overall rise in neurodevelopmental impairment, except for communication delay regardless of maternal infection and among infants with confirmed prenatal SARS-CoV-2, only fine motor performance showed a notable increase in risk (OR ≈ 3.5) [104]. A systematic review conducted by Veloso et al. (2024) focusing on the first postnatal year reported that while most SARS-CoV-2-exposed infants achieved age-appropriate development, mild deficits emerged, particularly in gross and fine motor domains and early on, and language/social domains, especially by parental report tools such as ASQ 3, NBAS, and BPSC [105]. Another meta-analysis published by Jackson et al. (2024), which included four studies up to 11 months postpartum, found no statistically significant increased risk of delay in communication, motor, problem-solving, or social domains among term infants [106].

4.8. Limitations

This review has several limitations. First, there is a substantial heterogeneity among included studies regarding neurodevelopmental assessment tools, timing of evaluations, and definitions of delay. Second, most studies had short-term follow-up, typically ending before 24 months, precluding evaluation of later-emerging deficits in domains such as executive function, attention, and social behavior. Third, while some studies used standardized clinical assessments, many relied on parent-report tools, which may be subject to re-reporting bias.
Additionally, confounding factors such as maternal stress, preterm birth, or pandemic-related changes in healthcare access were variably controlled. Only one study distinguished between direct viral effects and indirect environmental consequences of the pandemic, by comparing 3 groups: pre-pandemic group and 2 pandemic groups exposed and non-exposed [51].

4.9. Future Directions

Future research should focus on large-scale, longitudinal cohort studies that follow children with in utero SARS-CoV-2 exposure into later childhood and adolescence, allowing for the assessment of cognitive, behavioral, and emotional outcomes beyond the early developmental window. Standardized neurodevelopmental assessment tools, consistent follow-up intervals, and appropriate control groups (including both pandemic-born but unexposed children and pre-pandemic cohorts) are essential to improving comparability across studies. Investigations should also explore potential modifiers such as the timing of maternal infection during pregnancy, maternal mental health, preterm birth, and infant sex.

5. Conclusions

Based on the Newcastle–Ottawa Scale analysis, current evidence does not indicate consistent neurodevelopmental harm from prenatal SARS-CoV-2 exposure. Most well-designed studies support normal developmental trajectories up to 24 months; however, emerging evidence suggests that specific subgroups, particularly those exposed to severe maternal illness or during vulnerable gestational periods, may be at increased risk for subtle developmental effects. Nonetheless, further high-quality longitudinal research is needed to track potential late-emerging outcomes, especially in cognitive, emotional, and behavioral domains during school age. While reassuring trends emerge from high-quality studies, the nuanced nature of prenatal exposures, direct viral effects versus indirect psychosocial or immunological impacts, underscores the complexity of this topic. Thus, continued surveillance and rigorous, harmonized research protocols remain essential.

Author Contributions

Conceptualization, D.P., A.D. and M.-L.P.; methodology, D.P., A.D. and M.-L.P.; software, A.D.; validation, D.P., I.D. and M.-L.P.; data curation, A.D., A.C.P. and A.P.; writing—original draft preparation, A.D., A.C.P. and A.P.; writing—review and editing, D.P., I.D. and M.-L.P.; visualization, A.D. and A.P.; supervision, D.P., I.D. and M.-L.P.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data are contained within the article.

Acknowledgments

Publication of this paper was supported by the University of Medicine and Pharmacy Carol Davila through the institutional program Publish not Perish.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
COVID 19Coronavirus disease 2019
SARS-CoV-2Severe acute respiratory syndrome coronavirus 2
PRISMAPreferred Reporting Items for Systematic reviews and Meta-Analyses
ASDAutism spectrum disorders
CMVCytomegalovirus
EBVEpstein–Barr virus
NOSNewcastle–Ottawa Scale
OROdds ratio
ASQ-3Ages and Stages Questionnaire
BPSCBaby Pediatric Symptom Checklist
GMAGeneral Movement Assessment
MOS-RMotor Optimality Scores Revised
NBASNeonatal Behavioral Assessment Scale
ICD-10International Statistical Classification of Diseases and Related Health Problems, Tenth Revision
SWYCSurvey of Well-Being of Young Children
ASQ:SE-2Age and Stage Questionnaire Social-Emotional
MIAMaternal Immune Activation
LBWLow birth weight
GAGestational age
OROdds ratio

References

  1. Fitzgerald, E.; Hor, K.; Drake, A.J. Maternal Influences on Fetal Brain Development: The Role of Nutrition, Infection and Stress, and the Potential for Intergenerational Consequences. Early Hum. Dev. 2020, 150, 105190. [Google Scholar] [CrossRef]
  2. Buss, C.; Entringer, S.; Wadhwa, P.D. Fetal Programming of Brain Development: Intrauterine Stress and Susceptibility to Psychopathology. A Presentation from the European Society for Paediatric Endocrinology (ESPE) New Inroads to Child Health (NICHe) Conference on Stress Response and Child Health in Heraklion, Crete, Greece, 18–20 May 2012. Sci. Signal 2012, 5, pt7. [Google Scholar] [CrossRef]
  3. Leibovitz, Z.; Lerman-Sagie, T.; Haddad, L. Fetal Brain Development: Regulating Processes and Related Malformations. Life 2022, 12, 809. [Google Scholar] [CrossRef]
  4. Kwon, H.-K.; Choi, G.B.; Huh, J.R. Maternal Inflammation and Its Ramifications on Fetal Neurodevelopment. Trends Immunol. 2022, 43, 230–244. [Google Scholar] [CrossRef]
  5. Goeden, N.; Velasquez, J.; Arnold, K.A.; Chan, Y.; Lund, B.T.; Anderson, G.M.; Bonnin, A. Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. J. Neurosci. 2016, 36, 6041–6049. [Google Scholar] [CrossRef] [PubMed]
  6. Sokou, R.; Lianou, A.; Lampridou, M.; Panagiotounakou, P.; Kafalidis, G.; Paliatsiou, S.; Volaki, P.; Tsantes, A.G.; Boutsikou, T.; Iliodromiti, Z.; et al. Neonates at Risk: Understanding the Impact of High-Risk Pregnancies on Neonatal Health. Medicina 2025, 61, 1077. [Google Scholar] [CrossRef] [PubMed]
  7. Lubrano, C.; Parisi, F.; Cetin, I. Impact of Maternal Environment and Inflammation on Fetal Neurodevelopment. Antioxidants 2024, 13, 453. [Google Scholar] [CrossRef]
  8. Lungu, N.; Popescu, D.-E.; Jura, A.M.C.; Zaharie, M.; Jura, M.-A.; Roșca, I.; Boia, M. Enhancing Early Detection of Sepsis in Neonates through Multimodal Biosignal Integration: A Study of Pulse Oximetry, Near-Infrared Spectroscopy (NIRS), and Skin Temperature Monitoring. Bioengineering 2024, 11, 681. [Google Scholar] [CrossRef]
  9. Sood, E.; Newburger, J.W.; Anixt, J.S.; Cassidy, A.R.; Jackson, J.L.; Jonas, R.A.; Lisanti, A.J.; Lopez, K.N.; Peyvandi, S.; Marino, B.S. Neurodevelopmental Outcomes for Individuals with Congenital Heart Disease: Updates in Neuroprotection, Risk-Stratification, Evaluation, and Management: A Scientific Statement From the American Heart Association. Circulation 2024, 149, e997–e1022. [Google Scholar] [CrossRef]
  10. Doi, M.; Usui, N.; Shimada, S. Prenatal Environment and Neurodevelopmental Disorders. Front. Endocrinol. 2022, 13, 860110. [Google Scholar] [CrossRef]
  11. De Felice, A.; Ricceri, L.; Venerosi, A.; Chiarotti, F.; Calamandrei, G. Multifactorial Origin of Neurodevelopmental Disorders: Approaches to Understanding Complex Etiologies. Toxics 2015, 3, 89–129. [Google Scholar] [CrossRef]
  12. Năstase, L.; Cristea, O.; Diaconu, A.; Stoicescu, S.-M.; Mohora, R.; Pascu, B.M.; Tala, S.T.; Roșca, I. Two Cases of Congenital Hypothyroidism Revealing Thyroid Agenesis. Medicina 2023, 59, 1887. [Google Scholar] [CrossRef]
  13. Rosca, I.; Turenschi, A.; Nicolescu, A.; Constantin, A.T.; Canciu, A.M.; Dica, A.D.; Bratila, E.; Coroleuca, C.A.; Nastase, L. Endocrine Disorders in a Newborn with Heterozygous Galactosemia, Down Syndrome and Complex Cardiac Malformation: Case Report. Medicina 2023, 59, 856. [Google Scholar] [CrossRef]
  14. Bratan, C.A.; Gheorghe, M.; Ispas, I.; Franti, E.; Dascalu, M.; Stoicescu, S.M.; Rosca, I.; Gherghiceanu, F.; Dumitrache, D.; Nastase, L. Dunstan Baby Language Classification with CNN. In Proceedings of the 2021 International Conference on Speech Technology and Human-Computer Dialogue (SpeD), Bucharest, Romania, 13–15 October 2021; IEEE: New York, NY, USA; pp. 167–171. [Google Scholar]
  15. Pesch, M.H.; Leung, J.; Lanzieri, T.M.; Tinker, S.C.; Rose, C.E.; Danielson, M.L.; Yeargin-Allsopp, M.; Grosse, S.D. Autism Spectrum Disorder Diagnoses and Congenital Cytomegalovirus. Pediatrics 2024, 153, e2023064081. [Google Scholar] [CrossRef]
  16. Wang, J.; Li, Y.; Geng, X.; Zhang, X.; Xiao, Y.; Wang, W. Associations of Epstein-Barr Virus Infection with Attention Deficit Hyperactivity Disorder, Learning Disability, and Special Education in U.S. Children. Int. J. Gen. Med. 2021, 15, 2187–2195. [Google Scholar] [CrossRef] [PubMed]
  17. Egorova, M.; Egorov, V.; Zabrodskaya, Y. Maternal Influenza and Offspring Neurodevelopment. Curr. Issues Mol. Biol. 2024, 46, 355–366. [Google Scholar] [CrossRef] [PubMed]
  18. Otero, A.M.; Connolly, M.G.; Gonzalez-Ricon, R.J.; Wang, S.S.; Allen, J.M.; Antonson, A.M. Influenza A Virus During Pregnancy Disrupts Maternal Intestinal Immunity and Fetal Cortical Development in a Dose- and Time-Dependent Manner. Mol. Psychiatry 2025, 30, 13–28. [Google Scholar] [CrossRef] [PubMed]
  19. Guardado, K.; Varela-Cardoso, M.; Pérez-Roa, V.O.; Morales-Romero, J.; Zenteno-Cuevas, R.; Ramos-Ligonio, Á.; Guzmán-Martínez, O.; Sampieri, C.L.; Ortiz-Chacha, C.S.; Pérez-Varela, R.; et al. Evaluation of Anomalies and Neurodevelopment in Children Exposed to ZIKV During Pregnancy. Children 2022, 9, 1216. [Google Scholar] [CrossRef]
  20. Pesch, M.H.; Lauer, C.S.; Weinberg, J.B. Neurodevelopmental Outcomes of Children with Congenital Cytomegalovirus: A Systematic Scoping Review. Pediatr. Res. 2024, 95, 418–435. [Google Scholar] [CrossRef]
  21. Seblany, H.T.; Dinu, I.S.; Safer, M.; Plesca, D.A. FACTORS THAT HAVE A NEGATIVE IMPACT ON QUALITY OF LIFE IN CHILDREN WITH ADHD. Farmacia 2014, 62, 350–357. [Google Scholar]
  22. Fung, S.G.; Fakhraei, R.; Condran, G.; Regan, A.K.; Dimanlig-Cruz, S.; Ricci, C.; Foo, D.; Sarna, M.; Török, E.; Fell, D.B. Neuropsychiatric Outcomes in Offspring after Fetal Exposure to Maternal Influenza Infection During Pregnancy: A Systematic Review. Reprod. Toxicol. 2022, 113, 155–169. [Google Scholar] [CrossRef]
  23. Moreno, J.L.; Kurita, M.; Holloway, T.; López, J.; Cadagan, R.; Martínez-Sobrido, L.; García-Sastre, A.; González-Maeso, J. Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT2A and MGlu2 Receptors in the Adult Offspring. J. Neurosci. 2011, 31, 1863–1872. [Google Scholar] [CrossRef] [PubMed]
  24. Selten, J.-P.; Termorshuizen, F. The Serological Evidence for Maternal Influenza as Risk Factor for Psychosis in Offspring Is Insufficient: Critical Review and Meta-Analysis. Schizophr. Res. 2017, 183, 2–9. [Google Scholar] [CrossRef] [PubMed]
  25. Shook, L.L.; Sullivan, E.L.; Lo, J.O.; Perlis, R.H.; Edlow, A.G. COVID-19 in Pregnancy: Implications for Fetal Brain Development. Trends Mol. Med. 2022, 28, 319–330. [Google Scholar] [CrossRef] [PubMed]
  26. Dubey, H.; Sharma, R.K.; Krishnan, S.; Knickmeyer, R. SARS-CoV-2 (COVID-19) as a Possible Risk Factor for Neurodevelopmental Disorders. Front. Neurosci. 2022, 16, 1021721. [Google Scholar] [CrossRef]
  27. Popescu, D.-E.; Cerbu, S.; Rosca, I.; Lungu, N.; Trușculescu, A.A.; Belengeanu, V.; Manea, A.M.; Dima, M.A.; Gorun, F.; Popa, Z.L.; et al. Comparative Analysis of Hematological and Biochemical Changes in Neonates among Women with and Without COVID-19 Infection During Pregnancy. Children 2023, 10, 1370. [Google Scholar] [CrossRef]
  28. De Luca, D.; Vauloup-Fellous, C.; Benachi, A.; Vivanti, A. Transmission of SARS-CoV-2 from Mother to Fetus or Neonate: What to Know and What to Do? Semin. Fetal Neonatal Med. 2023, 28, 101429. [Google Scholar] [CrossRef]
  29. Jeganathan, K.; Paul, A.B. Vertical Transmission of SARS-CoV-2: A Systematic Review. Obs. Med. 2022, 15, 91–98. [Google Scholar] [CrossRef]
  30. Lins, B. Maternal Immune Activation as a Risk Factor for Psychiatric Illness in the Context of the SARS-CoV-2 Pandemic. Brain Behav. Immun. Health 2021, 16, 100297. [Google Scholar] [CrossRef]
  31. Hofsink, N.; Groenink, L.; Plösch, T. The Fetal Programming Effect of Maternal Immune Activation (MIA) on the Offspring’s Immune System. Semin. Immunopathol. 2024, 46, 14. [Google Scholar] [CrossRef]
  32. Popescu, D.E.; Roșca, I.; Jura, A.M.C.; Cioca, A.; Pop, O.; Lungu, N.; Popa, Z.-L.; Rațiu, A.; Boia, M. Prompt Placental Histopathological and Immunohistochemical Assessment after SARS-CoV-2 Infection During Pregnancy—Our Perspective of a Small Group. Int. J. Mol. Sci. 2024, 25, 1836. [Google Scholar] [CrossRef]
  33. Kasaven, L.S.; Raynaud, I.; Jalmbrant, M.; Joash, K.; Jones, B.P. The Impact of the COVID-19 Pandemic on Perinatal Services and Maternal Mental Health in the UK. BJPsych Open 2023, 9, e13. [Google Scholar] [CrossRef] [PubMed]
  34. Kotlar, B.; Gerson, E.M.; Petrillo, S.; Langer, A.; Tiemeier, H. The Impact of the COVID-19 Pandemic on Maternal and Perinatal Health: A Scoping Review. Reprod. Health 2021, 18, 10. [Google Scholar] [CrossRef] [PubMed]
  35. Zhu, P.; Sun, M.; Hao, J.; Chen, Y.; Jiang, X.; Tao, R.; Huang, K.; Tao, F. Does Prenatal Maternal Stress Impair Cognitive Development and Alter Temperament Characteristics in Toddlers with Healthy Birth Outcomes? Dev. Med. Child. Neurol. 2014, 56, 283–289. [Google Scholar] [CrossRef] [PubMed]
  36. Perelli, F.; Vidiri, A.; Palomba, G.; Franco, R.; Gallitelli, V.; Parasiliti, M.; Bisanti, M.; Spanò, A.; Silvagni, A.; Lopez, A.; et al. Preterm Birth and SARS-CoV-2: Does a Correlation Exist? Biomedicines 2025, 13, 282. [Google Scholar] [CrossRef]
  37. Smith, L.H.; Dollinger, C.Y.; VanderWeele, T.J.; Wyszynski, D.F.; Hernández-Díaz, S. Timing and Severity of COVID-19 During Pregnancy and Risk of Preterm Birth in the International Registry of Coronavirus Exposure in Pregnancy. BMC Pregnancy Childbirth 2022, 22, 775. [Google Scholar] [CrossRef]
  38. Klein, A.Z.; Kunatharaju, S.; Golder, S.; Levine, L.D.; Figueiredo, J.C.; Gonzalez-Hernandez, G. Association Between COVID-19 During Pregnancy and Preterm Birth by Trimester of Infection: A Retrospective Cohort Study Using Longitudinal Social Media Data. J. Med. Internet Res. 2025, 27, e66097. [Google Scholar] [CrossRef]
  39. Zamparini, J.; Saggers, R.; Buga, C.E. A Review of Coronavirus Disease 2019 in Pregnancy. Semin. Respir. Crit. Care Med. 2023, 44, 050–065. [Google Scholar] [CrossRef]
  40. Metz, T.D.; Clifton, R.G.; Hughes, B.L.; Sandoval, G.J.; Grobman, W.A.; Saade, G.R.; Manuck, T.A.; Longo, M.; Sowles, A.; Clark, K.; et al. Association of SARS-CoV-2 Infection with Serious Maternal Morbidity and Mortality From Obstetric Complications. JAMA 2022, 327, 748. [Google Scholar] [CrossRef]
  41. Zanardo, V.; Tortora, D.; Sandri, A.; Severino, L.; Mesirca, P.; Straface, G. COVID-19 Pandemic: Impact on Gestational Diabetes Mellitus Prevalence. Diabetes Res. Clin. Pract. 2022, 183, 109149. [Google Scholar] [CrossRef]
  42. Murphy, C.A.; O’Reilly, D.P.; Edebiri, O.; Donnelly, J.C.; McCallion, N.; Drew, R.J.; Ferguson, W. The Effect of COVID-19 Infection During Pregnancy; Evaluating Neonatal Outcomes and the Impact of the B.1.1.7. Variant. Pediatr. Infect. Dis. J. 2021, 40, e475–e481. [Google Scholar] [CrossRef] [PubMed]
  43. Pinheiro, G.S.M.A.; de Souza, R.C.; de Oliveira Azevedo, V.M.G.; Guimarães, N.S.; Pires, L.G.; Lemos, S.M.A.; Alves, C.R.L. Effects of Intrauterine Exposure to SARS-CoV-2 on Infants’ Development: A Rapid Review and Meta-Analysis. Eur. J. Pediatr. 2023, 182, 2041–2055. [Google Scholar] [CrossRef] [PubMed]
  44. Yao, Y.; Sun, L.; Luo, J.; Qi, W.; Zuo, X.; Yang, Z. The Effect of Long-Term COVID-19 Infection on Maternal and Fetal Complications: A Retrospective Cohort Study Conducted at a Single Center in China. Sci. Rep. 2024, 14, 17273. [Google Scholar] [CrossRef] [PubMed]
  45. Goicea, L.; Buzoianu, E.; Davitoiu, A.M.; Chindris, S.; Zamfirescu, A.; Iancu, M.; Ghiorghiu, I.; Tincu, I.; Draganescu, A.; Dorobantu, A.; et al. Multisystemic Inflammatory Syndrome in Children Post-COVID-19: Clinical-Biological Characteristics of Patients in the First Year of the Pandemic. J. Pediatr. Neonatal Individ. Med. 2023, 12, e120210. [Google Scholar]
  46. Dunn, A.; Malhotra, A. Neurodevelopmental Risks of SARS-CoV-2 Infection in Utero. Pediatr. Res. 2025. [Google Scholar] [CrossRef]
  47. Buechel, C.; Friedmann, A.; Eber, S.; Behrends, U.; Mall, V.; Nehring, I. The Change of Psychosocial Stress Factors in Families with Infants and Toddlers During the COVID-19 Pandemic. A Longitudinal Perspective on the CoronabaBY Study from Germany. Front. Pediatr. 2024, 12, 1354089. [Google Scholar] [CrossRef]
  48. Nazzari, S.; Pili, M.P.; Günay, Y.; Provenzi, L. Pandemic Babies: A Systematic Review of the Association between Maternal Pandemic-Related Stress During Pregnancy and Infant Development. Neurosci. Biobehav. Rev. 2024, 162, 105723. [Google Scholar] [CrossRef]
  49. Penna, A.L.; de Aquino, C.M.; Pinheiro, M.S.N.; do Nascimento, R.L.F.; Farias-Antúnez, S.; Araújo, D.A.B.S.; Mita, C.; Machado, M.M.T.; Castro, M.C. Impact of the COVID-19 Pandemic on Maternal Mental Health, Early Childhood Development, and Parental Practices: A Global Scoping Review. BMC Public Health 2023, 23, 388. [Google Scholar] [CrossRef]
  50. Wells, G.; Shea, B.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available online: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed on 24 June 2025).
  51. Shuffrey, L.C.; Firestein, M.R.; Kyle, M.; Fields, A.; Alcántara, C.; Amso, D.; Austin, J.; Bain, J.M.; Barbosa, J.; Bence, M.; et al. Birth During the COVID-19 Pandemic, but Not Maternal SARS-CoV-2 Infection During Pregnancy, Is Associated with Lower Neurodevelopmental Scores at 6-Months. medRxiv 2021. [Google Scholar] [CrossRef]
  52. ACNP 60th Annual Meeting: Poster Abstracts P1–P275. Neuropsychopharmacology 2021, 46, 72–217. [CrossRef]
  53. Cheng, Y.; Teng, H.; Xiao, Y.; Yao, M.; Yin, J.; Sun, G. Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study. Front. Pediatr. 2021, 9, 762684. [Google Scholar] [CrossRef]
  54. Wu, T.; Chen, L.; Wang, Y.; Shi, H.; Niu, J.; Yin, X.; Li, M.; Tan, C.; Jiang, H.; Zheng, D.; et al. Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study. Front. Pediatr. 2021, 9, 750012. [Google Scholar] [CrossRef] [PubMed]
  55. Schuh, T.L.; Mithal, L.B.; Naureckas, S.; Miller, E.S.; Garfield, C.F.; Shah, M.D. Outcomes from Birth to 6 Months of Publicly Insured Infants Born to Mothers with Severe Acute Respiratory Syndrome Coronavirus 2 Infection in the United States. J. Perinat. Med. 2022, 50, 334–342. [Google Scholar] [CrossRef] [PubMed]
  56. Edlow, A.G.; Castro, V.M.; Shook, L.L.; Kaimal, A.J.; Perlis, R.H. Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy. JAMA Netw. Open 2022, 5, e2215787. [Google Scholar] [CrossRef] [PubMed]
  57. Ayed, M.; Embaireeg, A.; Kartam, M.; More, K.; Alqallaf, M.; AlNafisi, A.; Alsaffar, Z.; Bahzad, Z.; Buhamad, Y.; Alsayegh, H.; et al. Neurodevelopmental Outcomes of Infants Born to Mothers with SARS-CoV-2 Infections During Pregnancy: A National Prospective Study in Kuwait. BMC Pediatr. 2022, 22, 319. [Google Scholar] [CrossRef]
  58. Buonsenso, D.; Costa, S.; Giordano, L.; Priolo, F.; Colonna, A.T.; Morini, S.; Sbarbati, M.; Pata, D.; Acampora, A.; Conti, G.; et al. Short- and Mid-Term Multidisciplinary Outcomes of Newborns Exposed to SARS-CoV-2 in Utero or During the Perinatal Period: Preliminary Findings. Eur. J. Pediatr. 2022, 181, 1507–1520. [Google Scholar] [CrossRef]
  59. Aldrete-Cortez, V.; Bobadilla, L.; Tafoya, S.A.; Gonzalez-Carpinteiro, A.; Nava, F.; Viñals, C.; Alvarado, E.; Mendizabal-Espinosa, R.; Gómez-López, M.E.; Ramirez-Garcia, L.A.; et al. Infants Prenatally Exposed to SARS-CoV-2 Show the Absence of Fidgety Movements and Are at Higher Risk for Neurological Disorders: A Comparative Study. PLoS ONE 2022, 17, e0267575. [Google Scholar] [CrossRef]
  60. Liu, H.-Y.; Guo, J.; Zeng, C.; Cao, Y.; Ran, R.; Wu, T.; Yang, G.; Zhao, D.; Yang, P.; Yu, X.; et al. Transient Early Fine Motor Abnormalities in Infants Born to COVID-19 Mothers Are Associated with Placental Hypoxia and Ischemia. Front. Pediatr. 2022, 9, 793561. [Google Scholar] [CrossRef]
  61. Martenot, A.; Labbassi, I.; Delfils-Stern, A.; Deruelle, P.; Kuhn, P. Medical and Neurodevelopmental Outcomes at 10 Months of Age in Infants Born at 34 Weeks plus to Mothers with COVID-19. Acta Paediatr. 2023, 112, 296–297. [Google Scholar] [CrossRef]
  62. Fajardo Martinez, V.; Zhang, D.; Paiola, S.; Mok, T.; Cambou, M.C.; Kerin, T.; Rao, R.; Brasil, P.; Ferreira, F.; Fuller, T.; et al. Neuromotor Repertoires in Infants Exposed to Maternal COVID-19 During Pregnancy: A Cohort Study. BMJ Open 2023, 13, e069194. [Google Scholar] [CrossRef]
  63. Silva, P.Y.F.; Lima da Cruz, M.C.; Guerra Azevedo, I.; Moreira, R.S.; Sousa, K.G.; Pereira, S.A. Risk of Global Developmental Delay in Infants Born from Mothers with COVID-19: A Cross-Sectional Study. Int. J. Womens Health 2023, 15, 467–474. [Google Scholar] [CrossRef] [PubMed]
  64. Ayesa-Arriola, R.; Castro Quintas, Á.; Ortiz-García de la Foz, V.; Miguel Corredera, M.; San Martín González, N.; Murillo-García, N.; Neergaard, K.; Fañanás Saura, L.; de las Cuevas-Terán, I. Exploring the Impact of COVID-19 on Newborn Neurodevelopment: A Pilot Study. Sci. Rep. 2023, 13, 2983. [Google Scholar] [CrossRef]
  65. Rood, M.; ten Kate, L.; Boeddha, N.P.; van‘t Kruys, K. Clinical Characteristics, Transmission Rate and Outcome of Neonates Born to COVID-19-Positive Mothers: A Prospective Case Series From a Resource-Limited Setting. Pediatr. Infect. Dis. J. 2023, 42, 35–42. [Google Scholar] [CrossRef] [PubMed]
  66. Vrantsidis, D.M.; van de Wouw, M.; Hall, E.R.M.; Kuret, V.; Rioux, C.; Conrad, M.L.; Mesa, C.; Harris, A.; Lebel, C.; Tomfohr-Madsen, L.; et al. Neurodevelopment in the First 2 Years of Life Following Prenatal Exposure to Maternal SARS-CoV-2 Infection. JAMA Netw. Open 2024, 7, e2443697. [Google Scholar] [CrossRef] [PubMed]
  67. Jaswa, E.G.; Huddleston, H.G.; Lindquist, K.J.; Wu, A.H.B.; Bishop, S.L.; Kim, Y.-S.; Kaing, A.; Prahl, M.; Gaw, S.L.; Corley, J.; et al. In Utero Exposure to Maternal COVID-19 and Offspring Neurodevelopment Through Age 24 Months. JAMA Netw. Open 2024, 7, e2439792. [Google Scholar] [CrossRef]
  68. Hill, R.A.; Gibbons, A.; Suwakulsiri, W.; Taseska, A.; Darke, H.; Malhotra, A.; Yee, H.; Fahey, M.; Hunt, R.W.; Lim, I.; et al. Investigating the Impact of Severe Maternal SARS-CoV-2 Infection on Infant DNA Methylation and Neurodevelopment. Mol. Psychiatry 2025, 30, 1976–1984. [Google Scholar] [CrossRef]
  69. Silva, L.M.; Melo, M.L.dO.; Alpes, M.F.; Santos, C.M.D. Risk of Neurodevelopmental Changes in 18-Month-Old Children Born to Mothers Infected with SARS-CoV-2. Audiol. Commun. Res. 2025, 30, e2963. [Google Scholar] [CrossRef]
  70. Kehdi, R.C.; Silva, M.F.S.; Cavalcante, L.R.L.; Fiorenza, N.G.; Viana, M.; Leite, I.B.; dos Santos Silva, B.R.; de Assis, D.F.; Cortez, P.C.; Bezerra, D.L.; et al. Cord Blood Cytokines/Chemokines Linked to Delays in Toddlers Exposed to SARS-CoV-2 Prenatally. Pediatr. Res. 2025. [Google Scholar] [CrossRef]
  71. Berg, J.; Linden, K.; Zaigham, M.; Domellöf, M.; Ahlsson, F.; Elfvin, A.; Åden, U.; Abrahamsson, T.; Ohlin, A.; Berg, J.; et al. The Association between Antenatal SARS-CoV-2 Exposure and Infant Neurodevelopment at Four Months of Age: A Prospective Multicenter Cohort Survey within the COPE Study. Int. J. Infect. Dis. 2025, 158, 107973. [Google Scholar] [CrossRef]
  72. Yamaguchi, Y.; Miyazawa, H.; Miura, M. Neural Tube Closure and Embryonic Metabolism. Congenit. Anom. 2017, 57, 134–137. [Google Scholar] [CrossRef]
  73. Engelhardt, D.M.; Martyr, C.A.; Niswander, L. Pathogenesis of Neural Tube Defects: The Regulation and Disruption of Cellular Processes Underlying Neural Tube Closure. WIREs Mech. Dis. 2022, 14, e1559. [Google Scholar] [CrossRef] [PubMed]
  74. Goasdoué, K.; Miller, S.M.; Colditz, P.B.; Björkman, S.T. Review: The Blood-Brain Barrier; Protecting the Developing Fetal Brain. Placenta 2017, 54, 111–116. [Google Scholar] [CrossRef] [PubMed]
  75. Bergdolt, L.; Dunaevsky, A. Brain Changes in a Maternal Immune Activation Model of Neurodevelopmental Brain Disorders. Prog. Neurobiol. 2019, 175, 1–19. [Google Scholar] [CrossRef] [PubMed]
  76. McEwan, F.; Glazier, J.D.; Hager, R. The Impact of Maternal Immune Activation on Embryonic Brain Development. Front. Neurosci. 2023, 17, 1146710. [Google Scholar] [CrossRef]
  77. Chhetri, P.K.; Das, J.M. Neuroanatomy, Neural Tube Development and Stages. Available online: https://www.ncbi.nlm.nih.gov/books/NBK557414/ (accessed on 23 August 2025).
  78. Kostović, I.; Judaš, M. Embryonic and Fetal Development of the Human Cerebral Cortex. In Brain Mapping; Elsevier: Amsterdam, The Netherlands, 2015; pp. 167–175. [Google Scholar]
  79. National Research Council (US); Institute of Medicine (US). Committee on Integrating the Science of Early Childhood Development The Developing Brain. In From Neurons to Neighborhoods: The Science of Early Childhood Development; Shonkoff, J.P., Phillips, D.A., Eds.; National Academies Press (US): Washington, DC, USA, 2000. [Google Scholar]
  80. Jackson, R.; Cornish, R.; Daskalopoulou, Z.; Gale, C.; Hurd, M.; Johnson, S.; Knight, M.; Kurinczuk, J.J.; Woodward, K.; Chakkarapani, E.; et al. Association of Antenatal or Neonatal SARS-CoV-2 Exposure with Developmental and Respiratory Outcomes, and Healthcare Usage in Early Childhood: A National Prospective Cohort Study. EClinicalMedicine 2024, 72, 102628. [Google Scholar] [CrossRef]
  81. Hall, M.B.; Willis, D.E.; Rodriguez, E.L.; Schwarz, J.M. Maternal Immune Activation as an Epidemiological Risk Factor for Neurodevelopmental Disorders: Considerations of Timing, Severity, Individual Differences, and Sex in Human and Rodent Studies. Front. Neurosci. 2023, 17, 1135559. [Google Scholar] [CrossRef]
  82. Groh, J.; Feng, R.; Yuan, X.; Liu, L.; Klein, D.; Hutahaean, G.; Butz, E.; Wang, Z.; Steinbrecher, L.; Neher, J.; et al. Microglia Activation Orchestrates CXCL10-Mediated CD8+ T Cell Recruitment to Promote Aging-Related White Matter Degeneration. Nat. Neurosci. 2025, 28, 1160–1173. [Google Scholar] [CrossRef]
  83. Kummer, K.K.; Zeidler, M.; Kalpachidou, T.; Kress, M. Role of IL-6 in the Regulation of Neuronal Development, Survival and Function. Cytokine 2021, 144, 155582. [Google Scholar] [CrossRef]
  84. Gonzalez Caldito, N. Role of Tumor Necrosis Factor-Alpha in the Central Nervous System: A Focus on Autoimmune Disorders. Front. Immunol. 2023, 14, 1213448. [Google Scholar] [CrossRef]
  85. Zhang, W.; Xiao, D.; Mao, Q.; Xia, H. Role of Neuroinflammation in Neurodegeneration Development. Signal Transduct. Target. Ther. 2023, 8, 267. [Google Scholar] [CrossRef]
  86. Bicanin Ilic, M.; Nikolic Turnic, T.; Ilic, I.; Nikolov, A.; Mujkovic, S.; Rakic, D.; Jovic, N.; Arsenijevic, N.; Mitrovic, S.; Spasojevic, M.; et al. SARS-CoV-2 Infection and Its Association with Maternal and Fetal Redox Status and Outcomes: A Prospective Clinical Study. J. Clin. Med. 2025, 14, 1555. [Google Scholar] [CrossRef]
  87. LaSalle, J.M. DNA Methylation Biomarkers of Intellectual/Developmental Disability across the Lifespan. J. Neurodev. Disord. 2025, 17, 10. [Google Scholar] [CrossRef] [PubMed]
  88. Neumann, A.; Walton, E.; Alemany, S.; Cecil, C.; González, J.R.; Jima, D.D.; Lahti, J.; Tuominen, S.T.; Barker, E.D.; Binder, E.; et al. Association between DNA Methylation and ADHD Symptoms from Birth to School Age: A Prospective Meta-Analysis. Transl. Psychiatry 2020, 10, 398. [Google Scholar] [CrossRef] [PubMed]
  89. Trajkova, S.; Kerkhof, J.; Rossi Sebastiano, M.; Pavinato, L.; Ferrero, E.; Giovenino, C.; Carli, D.; Di Gregorio, E.; Marinoni, R.; Mandrile, G.; et al. DNA Methylation Analysis in Patients with Neurodevelopmental Disorders Improves Variant Interpretation and Reveals Complexity. Hum. Genet. Genom. Adv. 2024, 5, 100309. [Google Scholar] [CrossRef] [PubMed]
  90. Hikosaka, M.; Parvez, M.S.A.; Yamawaki, Y.; Oe, S.; Liang, Y.; Wada, Y.; Hirahara, Y.; Koike, T.; Imai, H.; Oishi, N.; et al. Maternal Immune Activation Followed by Peripubertal Stress Combinedly Produce Reactive Microglia and Confine Cerebellar Cognition. Commun. Biol. 2025, 8, 296. [Google Scholar] [CrossRef]
  91. Hagberg, H.; Mallard, C.; Ferriero, D.M.; Vannucci, S.J.; Levison, S.W.; Vexler, Z.S.; Gressens, P. The Role of Inflammation in Perinatal Brain Injury. Nat. Rev. Neurol. 2015, 11, 192–208. [Google Scholar] [CrossRef] [PubMed]
  92. Henry, M.L.; Beeson, P.M.; Stark, A.J.; Rapcsak, S.Z. The Role of Left Perisylvian Cortical Regions in Spelling. Brain Lang 2007, 100, 44–52. [Google Scholar] [CrossRef]
  93. Ellul, P.; Maruani, A.; Vantalon, V.; Humeau, E.; Amestoy, A.; Anchordoqui, A.; Atzori, P.; Baleyte, J.-M.; Benmansour, S.; Bonnot, O.; et al. Maternal Immune Activation During Pregnancy Is Associated with More Difficulties in Socio-Adaptive Behaviors in Autism Spectrum Disorder. Sci. Rep. 2023, 13, 17687. [Google Scholar] [CrossRef]
  94. Quagliato, L.A.; de Matos, U.; Nardi, A.E. Maternal Immune Activation Generates Anxiety in Offspring: A Translational Meta-Analysis. Transl. Psychiatry 2021, 11, 245. [Google Scholar] [CrossRef]
  95. Murlanova, K.; Begmatova, D.; Weber-Stadlbauer, U.; Meyer, U.; Pletnikov, M.; Pinhasov, A. Double Trouble: Prenatal Immune Activation in Stress Sensitive Offspring. Brain Behav. Immun. 2022, 99, 3–8. [Google Scholar] [CrossRef]
  96. Duggan, C.; Irvine, A.D.; O’B Hourihane, J.; Kiely, M.E.; Murray, D.M. ASQ-3 and BSID-III’s Concurrent Validity and Predictive Ability of Cognitive Outcome at 5 Years. Pediatr. Res. 2023, 94, 1465–1471. [Google Scholar] [CrossRef]
  97. Lockhart, M.; Chaux, R.; Chevin, M.; Celle, M.; Raia-Barjat, T.; Patural, H.; Chabrier, S.; Giraud, A. Classification Performance of the Ages and Stages Questionnaire: Influence of Maternal Education Level. Children 2023, 10, 449. [Google Scholar] [CrossRef]
  98. Crowle, C.; Jackman, M.; Webb, A.; Morgan, C. Use of the Motor Optimality Score-Revised (MOS-R) to Predict Neurodevelopmental Outcomes in Infants with Congenital Anomalies. Early Hum. Dev. 2023, 187, 105876. [Google Scholar] [CrossRef] [PubMed]
  99. Einspieler, C.; Bos, A.F.; Spittle, A.J.; Bertoncelli, N.; Burger, M.; Peyton, C.; Toldo, M.; Utsch, F.; Zhang, D.; Marschik, P.B. The General Movement Optimality Score-Revised (GMOS-R) with Socioeconomically Stratified Percentile Ranks. J. Clin. Med. 2024, 13, 2260. [Google Scholar] [CrossRef] [PubMed]
  100. Örtqvist, M.; Marschik, P.B.; Toldo, M.; Zhang, D.; Fajardo-Martinez, V.; Nielsen-Saines, K.; Ådén, U.; Einspieler, C. Reliability of the Motor Optimality Score-Revised: A Study of Infants at Elevated Likelihood for Adverse Neurological Outcomes. Acta Paediatr. 2023, 112, 1259–1265. [Google Scholar] [CrossRef] [PubMed]
  101. Ossmy, O.; Donati, G.; Kaur, A.; Sotoodeh, M.S.; Forrester, G. Towards Automatic Assessment of Atypical Early Motor Development? Brain Res. Bull. 2025, 224, 111311. [Google Scholar] [CrossRef]
  102. Kokkinaki, T.; Hatzidaki, E. COVID-19 Pandemic-Related Restrictions: Factors That May Affect Perinatal Maternal Mental Health and Implications for Infant Development. Front. Pediatr. 2022, 10, 846627. [Google Scholar] [CrossRef]
  103. Firestein, M.R.; Dumitriu, D.; Marsh, R.; Monk, C. Maternal Mental Health and Infant Development During the COVID-19 Pandemic. JAMA Psychiatry 2022, 79, 1040. [Google Scholar] [CrossRef]
  104. Hessami, K.; Norooznezhad, A.H.; Monteiro, S.; Barrozo, E.R.; Abdolmaleki, A.S.; Arian, S.E.; Zargarzadeh, N.; Shekerdemian, L.S.; Aagaard, K.M.; Shamshirsaz, A.A. COVID-19 Pandemic and Infant Neurodevelopmental Impairment. JAMA Netw. Open 2022, 5, e2238941. [Google Scholar] [CrossRef]
  105. Veloso, A.H.N.; Barbosa, A.d.M.; Ribeiro, M.F.M.; Gervásio, F.M. Neurodevelopment in the First Year of Children Exposed to SARS-CoV-2 During Intrauterine Period: Systematic Review. Rev. Gauch. Enferm. 2024, 45, e20240020. [Google Scholar] [CrossRef]
  106. Jackson, R.; Woodward, K.; Ireland, M.; Larkin, C.; Kurinczuk, J.J.; Knight, M.; Gale, C.; Johnson, S.; Cornish, R.; Chakkarapani, E. Antenatal and Neonatal Exposure to SARS-CoV-2 and Children’s Development: A Systematic Review and Meta-Analysis. Pediatr. Res. 2024, 96, 40–50. [Google Scholar] [CrossRef]
Jcm 14 06202 g001
Figure 1. Data extraction.
Figure 1. Data extraction.
Jcm 14 06202 g001
Table 1. Risk of Bias Assessment (Newcastle–Ottawa Scale).
Table 1. Risk of Bias Assessment (Newcastle–Ottawa Scale).
NumberStudySelection (Max 4)Comparability (Max 2)Outcome (Max 3)Total ScoreRisk Level
1Shuffrey et al., 2021 [51]4239Low
2Roffman et al., 2021 [52]3126Moderate
3Cheng et al., 2021 [53]3115Moderate
4Wu et al., 2021 [54]3126Moderate
5Schuh et al., 2021 [55]2114Moderate
6Edlow et al., 2022 [56]4228Low
7Ayed et al., 2022 [57]3227Low
8Buonsenso et al., 2022 [58]3115Moderate
9Aldrete-Cortez et al., 2022 [59]3126Moderate
10Liu et al., 2022 [60]3126Moderate
11Martenot et al., 2022 [61]3115Moderate
12Martinez et al., 2023 [62]4127Low
13Silva et al., 2023 [63]3126Moderate
14Ayesa-Arriola et al., 2023 [64]2125Moderate
15Rood et al., 2023 [65]2013High
16Vrantsidis et al., 2024 [66]4239Low
17Jaswa et al., 2024 [67]4239Low
18Hill et al., 2024 [68]4228Low
19Silva et al., 2025 [69]3126Moderate
20Kehdi et al., 2025 [70]4239Low
21Berg et al., 2025 [71]4239Low
Note: Risk levels were defined as Low (7–9), Moderate (4–6), or High (0–3).
Table 2. Consolidated characteristics of included studies.
Table 2. Consolidated characteristics of included studies.
StudyDesign/N (Exposed)Maternal Infection Timing (Trimester)Maternal Disease SeverityNeurodevelopment ToolFollow-Up AgeKey FindingsAdjustment for Confounders
Shuffrey et al., 2021 [51]Cohort/N = 317 (114 exposed)1st: n = 42, 2nd: n = 90, 3rd: n = 67;)34% asymptomatic, 62% mild/moderate, 4% severeASQ-3 6 monthsNo major neurodevelopmental differences in infants born during the pandemic (exposed vs. non-exposed), but those born during the pandemic had significantly lower scores on gross motor, fine motor, and personal-social subdomains when compared to a cohort born prior to the onset of the pandemic.Yes—adjusted for maternal education, race/ethnicity, infant sex, GA, mode of delivery, NICU admission
Roffman et al., 2021 [52]Cohort/N = 34 (19 exposed)Not reported (NR)NRASQ-3, BPSC12 monthsGross motor delay and high irritability (p = 0.015).NR
Cheng et al., 2021 [53]Cohort/N = 18 (9 exposed)All in the 3rd trimester100% mild/moderateASQ-38–10 monthsThe infants from SARS-CoV-2-exposed mothers had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains, but only fine motor movement was significantly lower (p = 0.03).NR
Wu et al., 2021 [54] Cohort/N = 135 (57 exposed)1st: n = 0, 2nd: n = 4, 3rd: n = 5386% mild/moderate, 14% severeASQ-3, ASQ:SE-23 monthsNo significant neurodevelopmental differences between exposed and unexposed groups.Yes—adjusted for mother–infant separation, low birth weight (LBW), infant sex, preterm birth, NICU admission, breastfeeding at 3 months
Schuh et al., 2021 [55]Cohort/N = 15 (15 exposed)NR100% severeASQ-36 monthsAll of them were reported as normal development.NR
Edlow et al., 2022 [56] Cohort/N = 7772 (222 exposed)1st: n = 1, 2nd: n = 61, 3rd: n = 160NRICD-10 codes 12 monthsMaternal SARS-CoV-2 positivity during pregnancy was associated with a greater rate of neurodevelopmental diagnoses (Odds ratio (OR) = 1.86, p = 0.04).Yes—adjusted for maternal age, race/ethnicity, insurance status, gestational age (GA), birthweight, infant sex,
Ayed et al., 2022 [57]Cohort/N = 298 (298 exposed)1st: n = 5, 2nd: n = 20, 3rd: n = 27339.5% asymptomatic, 53.6% mild/moderate, 6.9% severeASQ-310–12 monthsThe rate of development delays was 10%. The risk of developmental delays was higher with first-trimester (OR: 8.2, p  =  0.039) and second-trimester maternal SARS-CoV-2 infections (OR: 8.1, p  =  0.001) than with third-trimester.Yes—adjusted for maternal age, maternal infection timing, GA, birthweight, infant sex, parental education and type of feeding in the first 6 months
Buonsenso et al., 2022 [58]Cohort/N = 199 (199 exposed)1st: n = 6, 2nd: n = 6, 3rd: n = 18757.6% asymptomatic, 36.9% mild/moderate, 5.5% severeClinical exam3–6-9–12 monthsAll of them were reported as normal neurological development.NR
Aldrete-Cortez et al., 2022 [59]Cohort/N = 56 (28 exposed)All in 3rd trimester100% mild/moderateGMA3–5 monthsThe exposed group had a significantly reduced total MOS-R; the median was lower in the exposed group (21 vs. 25, p = 0.002).Yes—adjusted for maternal/infant characteristics differing between groups: maternal age, marital status, education level, preeclampsia, hypothyroidism, gestational diabetes, GA, infant sex, type of delivery, Hyperbilirubinemia, APGAR score, days of hospitalization, birthweight, length at birth, birth head circumference
Liu et al., 2022 [60]Cohort/N = 98 (31 exposed)All in the 3rd trimester100% mild/moderateDenver II9 monthsFine motor abnormalities higher in the exposed group (15.2% vs. 2.1%; p = 0.02).Yes—adjusted using for age, sex, infection status
Martenot et al., 2022 [61]Cohort/N = 24 (24 exposed)All in the 3rd trimester4% asymptomatic, 96% symptomatic (severity NR)ASQ-210 monthsAll of them were reported as normal neurological development.NR
Martinez et al., 2023 [62]Cohort/N = 239 (124 exposed)1st: n = 17, 2nd: n = 37, 3rd: n = 7014.5% asymptomatic, 67.7% mild/moderate, 17.7% severeGMA, MOS-R, clinical exam3–8 monthsSuboptimal neuromotor development in exposed infants. The median of MOS-R was lower in the exposed group (23 vs. 25, p < 0.001), and 16 exposed infants had MOS-R scores <20 vs. 0 controls (p < 0.001). At 6–8 months clinical exam, 13 exposed vs. 0 controls had developmental delay.Yes—adjusted for COVID-19 severity, trimester of infection, neonatal and maternal comorbidities, fetal sex, maternal age, maternal fever during COVID-19 and preterm birth
Silva et al., 2023 [63]Cross-sectional study, N = 54 (27 exposed); NRNRSWYCFrom 1 to 12 monthsMotor developmental delay in COVID-19-exposed infants (OR = 6.3, p = 0.01); socioemotional developmental delay (OR = 4.0; p = 0.02); Inflexibility (OR = 14.0; p = 0.02); Parental concerns about behavior, learning, or development of the infant (OR = 9.7; p = 0.01).Yes—adjusted for sex, GA and family context.
Ayesa-Arriola et al., 2023 [64]Cohort/N = 42 (21 exposed)1st: n = 3, 2nd: n = 8, 3rd: n = 1095.2% mild/moderate, 4.8% severeNBAS (0–3 mo)6 weeksLower affectionate response in the exposed group (p = 0.009), especially those exposed in the third trimester (p = 0.043).Yes—for maternal age, GA, trimester of infection, infant age at assessment and infant sex
Rood et al., 2023 [65] Cohort/N = 13 (13 exposed)All in 3rd trimester46% mild/moderate, 54% severeVan Wiechen Scheme 3 monthsFollow-up similar to children born to COVID-19-negative mothers, mild neurodevelopmental delay in 2 (15.3%).NR
Vrantsidis et al., 2024 [66]Cohort/N = 896 (96 exposed)1st: n = 21, 2nd: n = 45, 3rd: n = 301% asymptomatic, 74% mild/moderate, 25% severeASQ-36–24 monthsNo significant neurodevelopmental differences between the exposed and unexposed groupsYes—for maternal comorbidities and household socioeconomic status
Jaswa et al., 2024 [67]Cohort/N = 2003 (217 exposed)1st: n = 122, 2nd: n = 42, 3rd: n = 53NRASQ-3 12–24 monthsNo significant neurodevelopmental differences between exposed and unexposed groups, or by the trimester of infection in the exposed group.Yes—for maternal age, race, education level, income, maternal generalized anxiety and depression symptoms at baseline.
Hill et al., 2024 [68]Cohort/N= 30 (16 expoed)1st: n = 0, 2nd: n = 4, 3rd: n = 12100% severeASQ-312 monthsLower ASQ-3 scores in children exposed to severe SARS-CoV-2 maternal infection in communication, problem solving and personal-social domains (p < 0.005); correlations with cytokine profiles and epigenetic markers.NR
Silva et al., 2025 [69]Cohort/N = 41 (41 exposed)1st: n = 5, 2nd: n = 9, 3rd: n = 27NRASQ-318 months22 (53%) children performed below the cutoff value in communication and 19 (46%) in gross motor coordination.Yes—for maternal age, GA, type of delivery, sex, Apgar score, birth weight, the child’s need for prolonged hospitalization after birth, and trimester infection
Kehdi et al., 2025 [70]Cohort/N = 41 (18 exposed)All in 3rd trimester55% mild/moderate, 55% severeBayley-III6–24 monthsAt 6 and 24 months, up to 36% cognitive, 64% communication, and 57% motor delays were observed. Specific cord blood cytokines correlated with respective domain delays.No adjustment for confounders; BSID-III scores corrected for gestational age
Berg et al., 2025 [71]Cohort/N = 1446 (555 exposed)1st: n = 63, 2nd: n = 278, 3rd: n = 21495.5% mild/asymptomatic, 4.5% severeASQ-34 monthsThere was no group difference in ASQ total mean scores, but those exposed to severe maternal COVID-19 had an increased risk of total ASQ scores below the cutoff (exposed: 16.0% vs. unexposed: 6.1%; OR 3.57; 95% CI, 1.14–11.24).Yes—for mother BMI, education, country of origin, maternal age, pre-pregnancy comorbidity, GA, APGAR, type of delivery, birthweight, type of feeding
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Păcurar, D.; Dinulescu, A.; Prejmereanu, A.; Palcău, A.C.; Dijmărescu, I.; Pavelescu, M.-L. Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review. J. Clin. Med. 2025, 14, 6202. https://doi.org/10.3390/jcm14176202

AMA Style

Păcurar D, Dinulescu A, Prejmereanu A, Palcău AC, Dijmărescu I, Pavelescu M-L. Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review. Journal of Clinical Medicine. 2025; 14(17):6202. https://doi.org/10.3390/jcm14176202

Chicago/Turabian Style

Păcurar, Daniela, Alexandru Dinulescu, Ana Prejmereanu, Alexandru Cosmin Palcău, Irina Dijmărescu, and Mirela-Luminița Pavelescu. 2025. "Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review" Journal of Clinical Medicine 14, no. 17: 6202. https://doi.org/10.3390/jcm14176202

APA Style

Păcurar, D., Dinulescu, A., Prejmereanu, A., Palcău, A. C., Dijmărescu, I., & Pavelescu, M.-L. (2025). Neurodevelopmental Outcomes in Children Born to Mothers Infected with SARS-CoV-2 During Pregnancy: A Narrative Review. Journal of Clinical Medicine, 14(17), 6202. https://doi.org/10.3390/jcm14176202

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop