Impact of Maternal Stress and COVID-19 Exposure During Pregnancy on Offspring Neurodevelopment: Signature Cohort 12 Month Follow-Up

Impact of Maternal Stress and COVID-19 Exposure During Pregnancy on Offspring Neurodevelopment: Signature Cohort 12 Month Follow-Up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Maternal Stress and COVID-19 Exposure During Pregnancy on Offspring Neurodevelopment: Signature Cohort 12 Month Follow-Up Nathalia Garrido-Torres, Andrés Román-Jarrín, Julia Rider, María Alemany-Navarro, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5442190/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Sep, 2025 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted 10 You are reading this latest preprint version Abstract The COVID-19 pandemic brought unprecedented global challenges. Amid the crisis, the potential impact of COVID-19 exposure on the neurodevelopment of offspring born to infected mothers emerged as a critical concern. This is a prospective cohort study of offspring exposed to mild or severe COVID-19 during pregnancy. Pregnant women who acquired SARS-CoV-2 were enrolled in the SIGNATURE project at Hospital Universitario Virgen del Rocio in Seville, Spain, between 01/01/2021 and 08/31/2022. Maternal stress was assessed through the Perceived Stress Scale; offspring neurodevelopment was screened through Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at 6 months and 12 months. Association between COVID-19 severity and neurodevelopmental outcomes were analyzed with univariate and multivariate analysis. The cohort included 689 women categorized into three distinct groups based on COVID-19 severity: non-infected mothers (N = 277), mothers with mild COVID-19 (N = 358), and mothers with severe COVID-19 (N = 54). In utero exposure to severe COVID-19 infection nearly tripled the risk of developmental concern in the ASQ-3 personal-social subdomain at 12 months follow-up [OR = 2.751 (95% CI 1.065–7.106), p = 0.037], independently of the timing of the infection and maternal stress. While this study did not yield statistically significant results, it highlights the need to further investigate the potential association between COVID-19 during pregnancy and offspring neurodevelopment to understand the potential long-term consequences of prenatal COVID-19 exposure. SARS-CoV-2 COVID-19 maternal stress pregnancy neurodevelopment Figures Figure 1 Introduction The declaration of the COVID-19 pandemic by the World Health Organization (WHO) in March 2020 marked a pivotal moment of global transformation. The emergence of the novel coronavirus disease (COVID-19), attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), brought profound changes across multiple dimensions of human life. ( 1 – 4 ). Beyond its characterization as a global health crisis, the pandemic introduced uncertainties, particularly regarding its potential impact on various facets of existence. SARS-CoV-2 is a novel RNA coronavirus with spike proteins aiding cell entry. Its infection often manifests in respiratory symptoms (e.g., cough, difficulty breathing), fever, and fatigue. ( 5 ) In relation to the potential consequences of SARS-CoV-2 infection and other viral infections in pregnant women, the immune adaptations that occur during pregnancy to support fetal growth may impact how this population responds to viral infections, though it remains uncertain whether these changes increase vulnerability or offer protective effects ( 6 ). While certain viruses, such as Influenza A (H1N1) and other coronaviruses like SARS and MERS (Middle East respiratory syndrome), have been associated with a higher risk of hospitalization, intensive care unit admission, and maternal mortality ( 7 ), most pregnant women infected with SARS-CoV-2 appear to remain asymptomatic with low mortality rates ( 8 ), ( 9 ). However, the stressors associated with the COVID-19 pandemic have led to increased stress, anxiety, and depressive symptoms in pregnant women, potentially upregulating inflammatory pathways and raising the risk of neuropsychiatric conditions in offspring ( 10 ), ( 11 ) Additionally, a notable issue emerged regarding the potential effects of SARS-CoV-2 on the neurodevelopment of offspring born to mothers with COVID-19 during pregnancy. This apprehension stemmed from documented instances of other viral infections affecting fetal brain development ( 12 – 15 ). Understanding the impact of SARS-CoV-2 on fetal neurodevelopment assumes paramount importance, given the substantial population exposed to the virus and its potential for harm. Physiologically, it can generate a complex inflammatory response leading to a maternal immune activation (MIA) resulting in elevation of pro-inflammatory cytokines in the mother that may produce fetal neuroinflammation and microglial activation, increasing the risks of neurodevelopmental disorders in the offspring ( 16 ). These immunological changes have been associated with the COVID-19 severity ( 17 ). Gestational timing of an infection during pregnancy is a pivotal determinant in the susceptibility of offspring to later disorders. For instance, Saatci et al. (2021) ( 18 ) found that maternal infection during pregnancy resulted in increased risk for non-affective psychosis. Similarly, a recent systematic review and meta-analysis concluded that exposure to infective agents and maternal infections were all significant risk factors for psychosis ( 19 , 20 ). Recent large-scale population-based cohort studies reinforce these findings, highlighting an augmented risk of autism in offspring born to mothers exposed to any maternal infection during pregnancy ( 21 ). These insights collectively emphasize the critical influence of maternal infection timing during pregnancy in shaping the long-term mental health outcomes of offspring. While a 12-month follow-up study, encompassing over 7000 deliveries, established an association between maternal SARS-CoV-2 infection during pregnancy and an increased risk for offspring neurodevelopmental diagnoses ( 22 ), existing research presents some inconsistencies. For instance, while Mulkey et al. (2020)( 23 ) identified differences in fine motor and personal-social domains measured by the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) in infants born to mothers with symptomatic COVID-19; Shuffrey et al. (2022)( 24 ) found no significant differences in neurodevelopment at six months assessed by the ASQ-3 among infants exposed to COVID-19 during pregnancy, regardless of the timing of infection or severity of maternal symptoms. Additionally, Firestein et al. (2023)( 25 ) showed that prenatal exposure to SARS-CoV-2 infection, did not appear to be associated with differences in neurodevelopment between ages 5 and 11 months. It is crucial to interpret these findings with caution because reliance on self-reported assessments of offspring neurodevelopment (Ages and Stages Questionnaire 3rd Edition or Developmental Assessment of Young Children 2nd Edition), retrospective data collection, and short follow-up durations, all of which may introduce biases affecting outcome accuracy. Furthermore, inconsistencies may stem from variability in study designs, sample sizes, demographic factors, and the timing and severity of maternal infection, as well as the vaccination status of participants for those studies for which sample recruiting was totally or partially done after vaccine safety in pregnancy was established. These discrepancies were attempted to be resolved in a systematic review and meta-analysis of eight articles (three and five articles, respectively) assessing both the effects of COVID-19 pandemic and SARS-CoV-2 infection exposures in offspring neurodevelopment using ASQ-3 ( 26 ). The authors found a higher odds ratio for fine motor impairment during the first year of life among infants with prenatal exposure to SARS-CoV-2 in comparison to those born during the pandemic but not exposed to the virus. Although no overall differences in neurodevelopmental impairment were found, this increased the risk of fine motor delays highlights a domain-specific vulnerability in SARS-CoV-2 exposed infants. Additionally, prenatal exposure to the pandemic environment – regardless of maternal infection status – was linked to an increase of communication impairment at any time during the first year, and communication and personal-social impairments at 12 months, suggesting that maternal stress during pregnancy may impact neurodevelopmental outcomes in offspring. While some of the limitations outlined above were addressed in this meta-analysis, such as increased sample size and inclusion of different populations, others remain. These included limited follow-up to the first years of life, heterogeneous outcome measures, and gaps in data in certain quantitative analyses. Additionally, the ASQ-3 tool, used across studies, is based on caregiver or trained assessor reports, which may overlook subtle developmental deficiencies and add variability to the findings. The lack of information on social distancing practices also complicates the assessment of pandemic effects on neurodevelopment. A critical aspect of this research is the role of maternal stress during pregnancy. Exposure to prenatal maternal anxiety and depression during this sensitive period can have long-term impacts on offspring, affecting gestational age and birth weight, which in turn may be linked with reduced brain connectivity. Evidence also suggest associations with reduced motor, communication, and problem-solving skills at 12 months, as well, as lower general cognitive function, executive function, and attention throughout childhood and adolescence ( 27 ). Maternal stress is also associated with an increased risk of psychopathological morbidity in offspring ( 28 ). The unique circumstances of the COVID-19 pandemic, with its lockdowns, uncertainties, and disrupted social support, may have heightened stress and anxiety among pregnant individuals ( 29 ). However, few studies have longitudinally examined the neurodevelopmental impact of both maternal stress and SARS-CoV-2 exposure during pregnancy. Notably, observed alterations in the regulatory capacity of 3-month-old infants whose mothers were pregnant during the COVID-19 pandemic compared to infants whose mother were pregnant previous to this period were found ( 30 ). Also, Werchan et al., 2023 described the negative effects of maternal psychosocial stress and COVID-19 during pregnancy on infant attention at 6 months. Similar work in differences in state regulation between exposed and non-exposed newborns has also been published ( 32 ). Most cohorts have focused either on measuring COVID-19 or maternal stress independently. Therefore, our research objective is to investigate the association between maternal stress and COVID-19 exposure during pregnancy, and how these factors impact neurodevelopmental outcomes in offspring at 6 and 12-month follow up. Our study aims to address this gap by examining the interplay between maternal stress and COVID-19 related risk. By addressing the limitations of prior studies, including sample size, COVID-19 severity, and gestational timing of infection during pregnancy, our research endeavors to provide a more nuanced understanding of these associations. Methods Study Design This prospective study aimed to investigate the association of maternal stress and COVID-19 exposure during pregnancy and developmental outcomes in offspring followed up at 6 and 12 months after birth. Approval for the project was obtained from the local institutional review board, specifically the Clinical Research Ethics Committee of Hospital Virgen del Rocío (Approval number: PECOVI-0195-2020; 1312-N-21). Participants meeting the defined inclusion criteria willingly provided written informed consent before being enrolled in the study. The detailed protocol for the study can be found in the Signature study protocol ( 33 ). Procedures The study was conducted at the Hospital Universitario Virgen del Rocío (HUVR) and the Institute of Biomedicine of Seville (IBiS), involving a multidisciplinary research team comprising medical specialists in pediatrics, psychiatry, gynecology, clinical psychology, primary care, as well as experts in basic and translational research, immunology, and infectious diseases. The study period for inclusion spanned from January 1, 2021, to August 31, 2022. The SARS-CoV-2 uninfected women were enrolled through primary care centers, while the SARS-CoV-2 infected women were enrolled through specific Gynecology consultations at HUVR. A comprehensive protocol for the care of pregnant women with SARS-CoV-2 infection was established at HUVR to manage both the infection and conduct neurodevelopmental assessments. Once a case has been identified, each patient was invited to participate, after confirming inclusion and exclusion criteria and signing the informed consent. Pregnant women meeting the following criteria were enrolled in the exposed group: i) experiencing or having experienced SARS-CoV-2 infection during the current pregnancy; ii) being of age 18 or older; iii) having a confirmed pregnancy via ultrasound examination; iv) presenting COVID-19 symptoms (meeting clinical criteria for a suspected case and testing positive on PCR), or v) being asymptomatic with a positive PCR result and negative Immunoglobulin G (IgG) assay. Exclusion criteria were: i) other concomitant causes of demonstrated risk for neurodevelopmental disorders; ii) under 18 years of age. In addition, a control group of non-exposed pregnant women was included to provide comparative data. For the non-exposed group, we selected pregnant women who meet the following inclusion criteria: i) pregnant women with no history of SARS-CoV-2 infection during the current pregnancy; ii) age 18 years or older; iii) confirmed pregnancy via ultrasound examination: iv) absence of COVID-19 symptoms and v) negative PCR test results. Exclusion criteria were: i) presence of other concomitant causes of demonstrated risk for neurodevelopmental disorders; ii) under 18 years of age. The type of PCR used to identify SARS-CoV-2 was a nasopharyngeal swab, utilizing the “SARS-CoV-2 RNA detection Kit” by Vitro Master Diagnóstica . All participants received COVID-19 vaccine during pregnancy. Measures and Core Variables The core variables of this study included the COVID-19 severity in mothers, measured during any trimester of pregnancy when the infection occurred, according to the WHO Clinical progression scale (WHO Working Group on the Clinical Characterization and Management of Covid-19 infection, 2020). The perceived maternal stress ( 35 ) was measured upon entry to the study and during the same trimester of the infection, and the developmental progress at 6 and 12 months was screened with the ASQ-3 ( 36 ) in the newborn. Women were assessed when the infection occurred by internal medicine specialists and classified according to the WHO clinical progression scale for SARS-CoV-2 infection. The WHO Clinical Progression Scale is a tool used to categorize and assess the clinical status of individuals infected with SARS-CoV-2. This scale provides a standardized framework for describing the severity of the disease and helps in clinical decision-making and communication. The scale consists of several levels, each representing a different stage of the disease, ranging from mild or asymptomatic cases to severe or critical conditions. The specific details of the scale may evolve based on updated clinical knowledge and research findings. The typical categories on the WHO Clinical Progression Scale include: Uninfected (Level 0); Asymptomatic (Level 1): Individuals infected with SARS-CoV-2 who do not exhibit any COVID-19 symptoms; Mild Illness (Level 2–3): Individuals with mild symptoms that do not require hospitalization, such as fever, cough, sore throat, malaise, headache, muscle pain, and loss of taste or smell; Moderate Illness (Level 4–5): Individuals with pneumonia, but not requiring supplemental oxygen; Severe Illness (Level 6–7): Individuals with pneumonia and requiring oxygen therapy. This category may also include other severe symptoms like acute respiratory distress syndrome (ARDS). Critical Illness (Level 8–9): Individuals with severe pneumonia, ARDS, sepsis, or other critical conditions. This category often involves the need for mechanical ventilation or admission to an intensive care unit (ICU). The symptomatology variable has been recoded to represent mild COVID-19 (severity scores from 1 to 3) and severe COVID-19 (severity scores from 4 to 8), which includes the categories Moderate illness, Severe illness and Critical illness, all collectively labeled as severe COVID-19. Maternal stress levels among pregnant participants were evaluated by the research team using the Perceived Stress Scale (PSS), a 14-item instrument initially developed by Cohen et al. in 1983 and later translated into Spanish by Remor in 2006. The PSS is designed to gauge participants' perceptions of stress and assess the impact of perceived stressful events on anxiety and stress levels. The scale measures the extent to which individuals perceive their lives as uncontrollable, unpredictable, and overwhelming. Each item is scored on a 5-point scale (0 = Never, 1 = Almost Never, 2 = Sometimes, 3 = Fairly Often, 4 = Very Often) and summed to create a total score. Elevated scores indicate increased levels of perceived stress. In adult studies, the PSS demonstrates strong internal consistency (α = 0.84–0.86) and solid test-retest reliability (r = 0.85 over two days, r = 0.55 over six weeks). Regarding concurrent validity, PSS scores show a positive correlation with both the quantity and perceived impact of life stressors (r = 0.17–0.35) ( 37 ). In the context of this study, the COVID-19 pandemic and the presence of a SARS-CoV-2 infection were considered as perceived stressors and “stressful events” measured by the scale. Participants self-reported their responses to the scale. High scores on the PSS indicate an increased risk of experiencing adverse health outcomes associated with elevated stress levels. The scale serves as a valuable tool for capturing the psychological impact of stressors, allowing for a comprehensive understanding of the participants’ stress experiences during the COVID-19 pandemic. The neurodevelopmental screening evaluation was conducted using the Ages and Stages Questionnaire, Third Edition (ASQ-3), which was completed by pregnant women across both groups. The ASQ-3 is a developmental screening tool intended to evaluate the developmental progress of children across multiple domains, including 30 items divided into five development domains, with six questions per domain (communication, gross motor skills, fine motor, problem-solving, and personal-social ), with scores ranging from 0 to 60 points in each domain, whether the skill or ability is achieved or not, and then classified in 3 areas for each domain: below expectation (2 SD below the mean); close to expectation (1 SD below the mean), and above expectation. This evaluation is administered by parents or caregivers and is widely utilized to identify potential developmental areas of concern in infants and young children. In our study, categories “close to expectation” and “above expectation” have been consolidated into a single category labeled as 0 for “typical” and category “below expectation” was labeled as 1 for “atypical”, to focus on children scoring clearly below expectation (2 SD below the mean). This approach allows for a more conservative analysis by identifying only those children with scores that fall distinctly below the developmental cutoff. The ASQ-3 has a strong test-retest reliability (r = 0.75–0.82); a robust interobserver reliability (r = 0.43–0.69); an acceptable internal consistency (α = 0.51–0.87); and a strong congruent validity (r = 0.85). The Social Determinant of Health (SDOH) screening questionnaire used in this study is part of the THRIVE program and assesses eight domains of social needs that may influence patient’s health. These domains include food insecurity, housing insecurity, difficulties affording medications, lack of transportation for medical appointment, needs related to basic services such as electricity or water, employment, education, and caregiving (( 38 )). Each domain is addressed with questions that identify whether the patient faces difficulties in any of these areas. The questionnaire is scored from 0 to 8, with each point corresponding to a specific social need identified by the patient. For the purposes of this study, we classified the scores into two groups: those with no needs and those with at least one identified need. Results from the SDOH screening are presented in Supplementary Table 1 and Supplementary Table 2. Statistics Descriptive statistics were utilized to characterize the demographic and clinical features of the study population. Continuous variables were expressed as mean ± standard deviation (SD), while categorical variables were presented as frequency (percentage). Categorical variables, such as education level, maternal occupational activity, racial group, substance use during pregnancy, prematurity and offspring sex, were analyzed for associations across the same three groups: non-infected mothers, mothers with mild COVID-19, and mothers with severe COVID-19. Additionally, the trimester of COVID-19 infection was assessed for its association with the two groups of infected mothers: those with mild COVID-19 and those with severe COVID-19. The Chi-square test or Fisher's exact test was employed, depending on appropriateness. Chi-square tests were conducted to investigate associations between categorical variables, including the association between ASQ-3 at 6 and 12 months and infection status (mothers with mild COVID-19, mothers with severe COVID-19, and non-infected mothers). The PSS variable was analyzed as a continuous measure. Analysis of Variance (ANOVA) was employed to assess differences in continuous variables between groups, such as comparing maternal age and perceived stress scores between non-infected mothers, mothers with mild COVID-19 and mothers with severe COVID-19. This non-parametric test was selected due to its ability to evaluate differences in medians across multiple groups when data did not adhere to the normality assumptions required for parametric tests. A significance level of p < 0.05 was set for all statistical analyses, with adjustments made for multiple comparisons using the Bonferroni correction to ensure robustness in the interpretation of results. In this analysis, COVID-19 severity served as the independent variable, or predictor, categorized in three groups; non-infected, mild COVID-19, and severe COVID-19. The ASQ-3 developmental domains were the dependent variables, or outcomes, which were dichotomized to indicate whether scores were below the mean (< 2SD) or not. For those ASQ-3 domains found to be significantly associated with the COVID-19 status based on Chi-square tests, logistic regression analyses were performed to further explore a possible association between COVID-19 severity and those ASQ-3 domains. Using the non-infected mothers as the reference group, we calculated odds ratios (OR) and 95% confidence intervals (CI) to assess the relationship between symptom severity (mild and severe COVID-19) and developmental outcomes in each ASQ-3 domain. The logistic regression was adjusted for variables found identified as statistically significant in the univariate analysis, and informed by findings from previous literature (e.g., offspring sex, prematurity). Data was analyzed with SPSS (Statistical Package for the Social Sciences) version 29.0. R Core Team (2023) was used to generate the graphics for this analysis. Results Description of Maternal Sample Table 1 shows that the total population (N = 689) was categorized into three distinct groups based on maternal COVID-19 severity: non-infected mothers (N = 277), mothers with mild COVID-19 (N = 358), and mothers with severe COVID-19 (N = 54). The analysis of maternal characteristics revealed a statistically significant difference in age across groups (ANOVA F = 4.564, gl = 2, p = 0.011). However, perceived stress scores during pregnancy did not differ significantly between the groups (ANOVA F = 0.729, gl = 2, p = 0.483). Regarding maternal education level, no significant differences were observed among the groups (χ 2 = 11.045, gl = 3, p = 0.087). Most participants across all groups had attained a university degree, with proportions ranging from 186 out of 358 mothers with mild COVID-19 (53.9%; one mother did not response), 22 out of 54 mothers with severe COVID-19 (41.5%) and to 161 out of 277 non-infected mothers (59.2%). Occupational activity varied significantly among the groups (χ 2 = 13.274, gl = 3, p = 0.039), with the majority of participants being employed or working for themselves across all groups. Analysis of racial groups showed no significant difference (χ 2 = 8.243, gl = 2, p = 0.083), with most participants identifying as Caucasian. Substance use during pregnancy did not significantly differ between the groups (χ 2 = 3.608, gl = 1, p = 0.165). The analysis of maternal factors. Including maternal comorbidities and the SDOH screening, on ASQ-3 developmental domains at 6 and 12 months revealed specific associations. At 6 months, only gestational diabetes during pregnancy was significantly associated with concerns in the gross motor domain (p = 0.026). At 12 months, perceived stress during pregnancy showed a significant association with concerns in the fine motor domain (p = 0.038). Additionally, maternal age at childbirth was associated with fine motor and personal-social concerns at 6 months and with gross motor and problem-solving concerns at 12 months. No significant associations were found between social determinants of health and any ASQ-3 at either 6 or 12 months. (Refer to Supplementary Tables 1 and 2 for comprehensive results). As for offspring characteristics, there was no significant difference in the distribution of sexes (χ 2 = 3.719, df = 2, p = 0.156), with approximately half of the offspring being female. Similarly, there was no significant differences regarding prematurity (F = 0.260, gl = 1, p = 0.878), with most preterm offspring (N = 27) born to mothers with mild COVID-19, Additionally, no significant differences were observed in the frequency of twin births across groups (F = 3.292, gl = 1, p = 0.212). These findings highlight the demographic characteristics of the study population and their association with maternal COVID-19 severity. The analysis of COVID-19 during pregnancy revealed significant differences in the distribution of infection trimesters among severity groups (χ 2 = 27.220, gl = 2, p < 0.001). Notably, a higher proportion of severe COVID-19 cases occurred in the third trimester (34 out of 53 mothers with severe infection; 63%) compared to the first (5 out of 53 mothers with severe infection; 9.3%) and second (15 out of 53 mothers with severe infection; 27.8%) trimesters. These findings underscore the potential impact of the timing of maternal infection on COVID-19 severity during pregnancy. Table 1. Sample description Total Non-infected mothers Mild COVID-19 Severe COVID-19 F gl P value n (%) 689 (100) 277 (40.2) 358 (52) 54 (7.8) Maternal age (mean +/- SD) 33.11 ± 5.36 33.53 ± 7.707 33.08 ± 5.081 31.21 ± 5.00 4.564 2 0.011 Maternal perceived stress score (mean +/- SD) 22.97 ± 7.76 22.68 ± 7.607 23.01 ± 7.612 24.25 ± 9.37 0.729 2 0.483 Educational level Reading and writing n (%) 3 (0.4) 0 (0.0) 2 (0.6) 1 (1.9) χ 2 =11.045 3 0.087 Elementary school n (%) 55 (8.2) 20 (7.4) 27 (7.8) 8 (15.1) High school n (%) 243 (36.3) 91 (33.5) 130 (37.7) 22 (41.5) University n (%) 369 (55.1) 161 (59.2) 186 (53.9) 22 (41.5) Occupational status Studying n (%) 15 (2.2) 7 (2.6) 8 (2.3) 0 (0.0) χ 2 =13.274 3 0.039 Looking for a job n (%) 78 (11.6) 38 (14.0) 29 (8.4) 11 (20.8) Employee n (%) 453 (67.6) 170 (62.5) 249 (72.2) 34 (64.2) Retired n (%) 124 (18.5) 57 (21) 59 (17.1) 8 (15.1) Ethnicity Caucasian n (%) 599 (89.3) 239 (87.9) 317 (91.6) 43 (81.1) χ 2 =8.243 2 0.083 N Caucasian n (%) 60 (8.9) 29 (10.7) 22 (6.4) 9 (17.0) No response n (%) 12 (1.8) 4 (1.5) 7 (2.0) 1 (1.9) Substance use during pregnancy n (%) 183 (32.0) 79 (33.8) 96 (32.5) 8 (19.0) χ 2 =3.608 1 0.165 Offspring characteristics N = 681 N = 277 N = 350 N = 54 Birth sex Female n (%) 350 (51.4) 144 (52) 185 (52.9) 21 (38.9) 3.719 1 0.156 Prematurity Yes n (%) 55 (8) 23 (8.3) 27 (7.5) 5 (9.3) 0.260 1 0.878 Twins n (%) 36 (5.2) 10 (3.6) 24 (6.7) 2 (3.7) 3.292 1 0.212 Infected women n (%) 399 (100) 346 (86.72) 53 (13.28) Trimester of SARS-CoV-2 Infection First trimester n (%) 95 (23.1) 90 (25.1) 5 (9.3) χ 2 =27.220 2 <0.001* Second trimester n (%) 184 (44.7) 169 (47.2) 15 (27.8) Third trimester n (%) 133 (32.3) 99 (27.7) 34 (63) * Significance was considered at p value < 0.01 after applying Bonferroni correction. When cell counts were less than 5, Fisher's exact p-value was used to ensure the accuracy of the results. Developmental Screening Results at 6 and 12 Months in relation to COVID-19 Severity The total sample of children evaluated in at least one of the two screening moments included 681 newborns (including 10 twin births). The distributions of scores across the different ASQ-3 domains in offspring born to non-infected mothers, mothers with mild COVID-19, and mothers with severe COVID-19 can be seen in Fig. 1 . The screening of neurodevelopmental outcomes using the ASQ-3 at 6 and 12 months provided insights into the developmental concerns present in infants in the three comparison groups (see Table 2 ). At 6 months, a total of 601 out of 681 children (88.25%) were assessed. No significant differences were observed in ASQ-3 scores for communication (χ 2 = 1.138, df = 2, p = 0.566), gross motor (χ 2 = 0.331, df = 2, p = 0.848), fine motor (χ 2 = 0.126, df = 2, p = 0.939), problem-solving (χ 2 = 0.135, df = 2, p = 0.935), or personal-social skills (χ 2 = 2.434, df = 2, p = 0.296) among the comparison groups. A total of 537 children out of the 681 children (78.85%) were assessed at 12 months. A total of 457 children were evaluated at both screening moments (6 and 12 months). No significant differences were found in ASQ-3 scores for communication (χ 2 = 3.211, df = 2, p = 0.201), gross motor (χ 2 = 0.574, df = 2, p = 0.751), fine motor (χ 2 = 1.022, df = 2, p = 0.600), or problem-solving (χ 2 = 0.936, df = 2, p = 0.626) at 12 months among the comparison groups. However, at 12 months, significant differences were observed in personal-social domain (χ2 = 8.282, df = 2, p = 0.016). Specifically, a higher proportion of infants born to mothers with severe COVID-19 exhibited personal-social concerns compared to those born to mothers with mild COVID-19 or non-infected mothers. In an exploratory analysis of offspring gender as a risk factor, we found no significance difference on developmental outcomes at 6-months follow up, however, male gender to be significant associated with developmental concerns at 12-month follow up in the following domains; communication (p < 0.001), fine motor (p = 0.011), and personal-social (p = 0.016) (Supplementary Table 3). Nonetheless, the significance did not persist in the multivariate analysis. Table 2 Proportion of children with developmental concernsa in the ASQ-3b scale at 6 and 12 months across COVID-19 severity groups. Total Non-infected mothers Mild COVID-19 Severe COVID-19 χ 2 P value ASQ-3 6 months n (%) 601 (88.25) 244 (35.83) 313 (45.96) 44 (6.46) Communication n (%) 14 (2.3) 6 (2.5) 8 (2.6) 0 (0.0) 1.138 0.566 Gross motor n (%) 50 (8.3) 22 (9.0) 25 (8.0) 3 (6.8) 0.331 0.848 Fine motor n (%) 19 (3.2) 8 (3.3) 10 (3.2) 1 (2.3) 0.126 0.939 Problem solving n (%) 18 (3.0) 7 (2.9) 10 (3.2) 1 (2.3) 0135 0.935 Socio-individual n (%) 16 (2.7) 5 (2.0) 11 (3.5) 0 (0.0) 2.434 0.296 ASQ-3 12 months n (%) 537 (78.85) 222 (32.60) 275 (40.38) 40 (5.87) Communication n (%) 49 (9.1) 23 (10.4) 20 (7.3) 6 (15.0) 3.211 0.201 Gross motor n (%) 66 (12.3) 30 (13.5) 31 (11.3) 5 (12.5) 0.574 0.751 Fine motor n (%) 26 (4.9) 9 (4.1) 14 (5.1) 3 (7.7) 1.022 0.600 Problem solving n (%) 82 (15.3) 37 (16.7) 38 (13.8) 7 (17.5) 0.936 0.626 Socio-individual n (%) 91 (16.9) 31 (14.0) 47 (17.1) 13 (32.5) 8.282 0.016 a Developmental concerns (atypical): children scoring clearly below expectation (2 SD below the mean). b ASQ-3, Ages & Stages Questionnaire, 3rd Edition * Significance was considered at p value < 0.01 after applying Bonferroni correction. The total number of children assessed at any assessment point was 681. Given the found difference in the personal-social domain at 12 months, we performed a univariate logistic regression analysis, exploring the correlation between COVID-19 severity as the predictor (independent variable) and personal-social developmental concerns, identified in the ASQ-3 as the outcome (dependent variable). This analysis included groups of infected mothers (mothers with mild COVID-19 and with severe COVID-19, using non-infected mothers as the reference group. We found a significant association between severe COVID-19 and personal-social developmental concerns at 12 (Table 3 ; p = 0.005). Specifically, severe COVID-19 during pregnancy was associated with nearly a threefold increase in the risk of personal-social concerns, with an odds ratio (OR) of 2.967 (95% CI [1.384, 6.361]). Subsequently, in a multivariate logistic regression analysis adjusting for COVID-19 vaccine, offspring sex, mother's age at birth, prematurity, and preeclampsia, severe COVID-19 (Table 3 ; p = 0.037) did not remain significantly associated with personal-social developmental concerns at 12 months follow up-. The odds ratio (OR) for COVID-19 severity in this adjusted model was 2.751 (95% CI [1.065, 7.106]). Additionally, trimester of infection, offspring sex, prematurity, infections, perceived, and drug consumption during pregnancy did not exhibit significant associations with personal-social skills at 12 months. As these variables did not show significant associations, they were not included in the final model, with the exception of prematurity and offspring sex, which have been previously reported as associated with offspring developmental delay. Table 3 Univariate and Multivariate Logistic Regression of Socio-Individual ASQ3 Outcome with COVID-19 Severity Univariate analysis Multivariate analysis OR adjusted by COVID-19 vaccine, maternal age, sex, preeclampsia and prematurity. SARS-COV-2 severity Crude OR (CI 95%) P value OR (CI 95%) P value Non infected (Ref) COVID-19 mild 1.270 (0.776–2.078) 0.341 1.329 (0.794–2.223) 0.279 COVID-19 severe 2.967 (1.384–6.361) 0.005* 2.751 (1.065–7.106) 0.037* * Significance was considered at p value < 0.01 after applying Bonferroni correction. Discussion Our study examines maternal stress during pregnancy, measured upon entry to the study and during the same trimester of the infection, as well as COVID-19 exposure within a birth cohort followed up for 12 months. This investigation focuses on COVID-19 severity and the timing of infection during gestation. Descriptively, we observed significant differences in age among the three groups of mothers (non-infected mothers, mothers with mild COVID-19 and mothers with severe COVID-19, with a p value of 0.011 (Table 1). Although these differences were statistically significant, the variation in means was modest, potentially limiting their impact on the outcome analyzed. In addition, we found significant differences between the three groups of mothers regarding their usual activity. Remarkably, none of the mothers with severe COVID-19 were students, which might be explained by their potentially lower exposure to SARS-CoV-2 due to the possibility of studying from home. In contrast, among mothers with severe COVID-19, we observed a relatively higher percentage of those searching for a job (20.8% compared to 8.4% in mothers with mild COVID-19 and 14.0% in non-infected mothers), which could be related to greater exposure through job interviews or other social interactions associated with actively seeking employment. The analysis of maternal comorbidities showed that gestational diabetes during pregnancy was significantly associated with concerns in the gross motor developmental area. This finding aligns with existing literature suggesting that inflammatory conditions during pregnancy, such as gestational diabetes, may increase the risk neurodevelopment impairment ( 39 ). Additionally, while socioeconomic status (SES) has been linked to developmental delays in prior studies ( 40 ), our analysis using the SDOH screening questionnaire, which examines factors such as family income, food insecurity, housing instability, and employment changes, did not find any significant associations between these SES-related factors and developmental outcomes in any ASQ-3 domains at the 6- or the 12-months follow-up. Our exploratory analysis examining offspring sex as a potential risk factor for developmental concerns showed that male offspring exhibited increased developmental concerns in communication, fine motor, and personal-social domains compared to female offspring. This finding aligns with prior research suggesting that females generally achieve developmental milestones earlier than males ( 41 ). Regarding COVID-19 severity as a predictor for developmental concern, despite the p-values in our results did not achieve statistical significance after applying the Bonferroni correction, they remained below the conventional threshold of 0.05. We recognize that the Bonferroni adjustment is highly conservative, especially in studies with multiple comparisons, which can substantially reduce statistical power and increase the risk of Type II errors, Consequently, while these results do not meet the stringent criteria set by the Bonferroni method, the observed p-valued suggest a potential significant association between COVID-19 severity in mothers and developmental outcomes in offspring. Specifically, offspring of mothers with severe COVID-19 showed a higher likelihood of personal-social concerns at 12 months, even after adjusting for relevant covariates. Notably, the timing of infection during pregnancy did not have any impact on any of the outcomes. These findings suggest that maternal health during the pandemic may influence early childhood development. Although not definitive, they highlight a potential area of concern that warrants further investigation in future studies with larger sample sizes. Our findings align with existing literature, highlighting the vulnerability of the developing fetal brain to maternal health conditions, infectious diseases, and pregnancy-related stressors. In this sense, our data replicates previous studies ( 23 ), that also found that SARS-CoV-2 in utero exposure in offspring born to symptomatic mothers may be associated with generally lower ASQ-3 scores, with significant differences in fine motor and personal-social domains in comparisons to offspring of asymptomatic mothers or offspring with postnatal infections, what aligns with our findings of delay in personal-social domain in infants born to infected mothers with severe symptoms. A recent meta-analysis indicated lower scores in fine motor and problem-solving domains among infants exposed to SARS-CoV-2 ( 42 ). However, the ages of the offspring at the time of assessment varied across the three studies included in the meta-analysis, with heterogeneity ranging from moderate (problem-solving domain) to high (fine motor domain). In our study, we divided the sample into mothers with severe COVID-19, and mothers with mild COVID-19 and non-infected mothers to explore the varying impact of COVID-19 severity on developmental outcomes. This stratification aimed to clarify if COVID-19 severity correlates with offspring developmental outcomes, allowing us to assess potential severity effect associations. The complex interplay between COVID-19 severity and personal-social skills in offspring at 12 months underscores the need to explore other vulnerability factors, such as epigenetics, as some studies reveal potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the offspring epigenome ( 43 ). Our study adds significant evidence to the growing body of research ( 22 , 32 , 44 , 45 ) on the potential impact of COVID-19 during pregnancy on offspring neurodevelopment, emphasizing the importance of considering maternal well-being in public health strategies and prenatal care. However, it is important to consider the limitations outlined in the introduction regarding previous research on this topic. Additional studies with larger sample sizes, more rigorous neurodevelopmental assessments (beyond screening and self-reported measures), and longitudinal approaches that track neurodevelopmental trajectories over time are necessary to draw conclusive associations between prenatal SARS-CoV-2 exposure and neurodevelopmental delays. Further investigation into the mechanisms underlying these effects and the development of tailored interventions for at-risk groups are warranted. Longitudinal studies can provide insights into developmental trajectories, while exploring potential mediators and moderators of the observed associations can inform targeted strategies to enhance neurodevelopment in offspring exposed to COVID-19 during pregnancy. This study has various strengths such as including a prospective design, comparison with non-infected mothers, mild and severe symptomatic mothers (mild and severe COVID-19), and consideration of covariates such as maternal stress and substance use. However, some limitations should be acknowledged such as the potential for bias introduced by self-reporting of certain variables. For instance, while the ASQ3 is a commonly utilized screening tool, a recent diagnostic accuracy study indicated that its sensitivity was below 70% across all levels of delay ( 46 ). Long-term follow-up studies that include structured tools for assessing neurodevelopment in children and clinical diagnosis are needed to validate the findings and gain a more comprehensive understanding of developmental outcomes beyond the 12-month assessment. In addition, despite our large sample size, the subgroup of mothers with severe COVID-19 and offspring with Personal-social concerns in the ASQ-3 is small, particularly for those children whose mothers had severe COVID-19 and exhibited atypical ASQ results. This results in a wide confidence interval for the odds ratio, limiting the precision of the estimate and warranting cautious interpretation of the findings. In conclusion, our study sheds light on the association between COVID-19 severity during pregnancy and personal-social concerns in their 12-month-old offspring, emphasizing the potential of lasting impact of maternal health during the COVID-19 pandemic and early childhood development. Declarations Acknowledgements and fundings Dr. Nathalia Garrido-Torres received funds under Juan Rodes Contract (JR22/00075). Dr. María Alemany-Navarro received funds under Juan de la Cierva Contract (FJC2021-047538-I). Dr. Luis Alameda thanks the Foundation Adrian and Simone Frutiger and Carigest SA Foundation for their support. Dr. Andrés Román-Jarrín received funds under Alicia Koplowitz Foundation research grant. Dr. Miguel Ruiz-Veguilla received funds from Carlos III Health Institute. Grant ID: PI22-0678. This work has received funds from the Consejería de Salud y Familias para financiación de la investigación, desarrollo e innovación en ciencias de la salud de Andalucía (CSyF 2021-FEDER), grant number PECOVID -01952020; and also received support from the Alicia Koplowitz Foundation to realize the clinical assessment to the children. Author contribution NGT, ARJ, MRV, and BCF conceived and designed the study; NGT, ARJ, BCF, APG, JR, and ERM collected the data; NGT, MRV, JR, ARJ, LA, and MAN contributed data or analysis tool; JR, MAN and MRV performed the analysis; NGT, ARJ, MAN, JR, BdF, LC, CDS, and BAG wrote the first draft; all authors reviewed the final version of the manuscript. Data sharing statement The data generated in this study will be shared upon request. References Boelig RC, Manuck T, Oliver EA, Di Mascio D, Saccone G, Bellussi F et al (2020) Labor and delivery guidance for COVID-19. Am J Obstet Gynecol MFM 2(2):100110 Wastnedge EAN, Reynolds RM, van Boeckel SR, Stock SJ, Denison FC, Maybin JA et al (2021) Pregnancy and COVID-19. Physiol Rev 101(1):303–318 World Health Organization (2020) Coronavirus disease (COVID-19) Wu Z, McGoogan JM (2020) Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 323(13):1239–1242 Hu B, Guo H, Zhou P, Shi ZL (2021) Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 19(3):141–154 Wastnedge EAN, Reynolds RM, Van Boeckel SR, Stock SJ, Denison FC, Maybin JA et al (2021) Pregnancy and COVID-19. Physiol Rev 101(1):303–318 Mosby LG, Rasmussen SA, Jamieson DJ (2011) 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol 205(1):10–18 Khalil A, Hill R, Ladhani S, Pattisson K, O’Brien P (2020) Severe acute respiratory syndrome coronavirus 2 in pregnancy: symptomatic pregnant women are only the tip of the iceberg. Am J Obstet Gynecol 223(2):296–297 Sutton D, Fuchs K, D’Alton M, Goffman D (2020) Universal Screening for SARS-CoV-2 in Women Admitted for Delivery. N Engl J Med 382(22):2163–2164 Xu K, Zhang Y, Zhang Y, Xu Q, Lv L, Zhang J (2021) Mental health among pregnant women under public health interventions during COVID-19 outbreak in Wuhan, China. Psychiatry Res 301:113977 Abdoli A, Falahi S, Kenarkoohi A, Shams M, Mir H, Jahromi MAM (2020) The COVID-19 pandemic, psychological stress during pregnancy, and risk of neurodevelopmental disorders in offspring: a neglected consequence. J Psychosom Obstet Gynecol 41(3):247–248 Cordeiro CN, Tsimis M, Burd I, Infections, Brain Development, Obstetrical (2015) & Gynecological Survey [Internet]. ;70(10). https://journals.lww.com/obgynsurvey/fulltext/2015/10000/infections_and_brain_development.19.aspx Doyle TJ, Goodin K, Hamilton JJ (2013) Maternal and neonatal outcomes among pregnant women with 2009 pandemic influenza A(H1N1) illness in Florida, 2009–2010: a population-based cohort study. PLoS ONE 8(10):e79040 Fell DB, Savitz DA, Kramer MS, Gessner BD, Katz MA, Knight M et al (2017) Maternal influenza and birth outcomes: systematic review of comparative studies. BJOG 124(1):48–59 Shook LL, Sullivan EL, Lo JO, Perlis RH, Edlow AG (2022) COVID-19 in pregnancy: implications for fetal brain development. Trends Mol Med 28(4):319–330 Reyes-Lagos JJ, Abarca-Castro EA, Echeverría JC, Mendieta-Zerón H, Vargas-Caraveo A, Pacheco-López G (2021) A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway. Front Psychol 12:614451 Pedersen SF, Ho YC (2020) SARS-CoV-2: a storm is raging. J Clin Invest 130(5):2202–2205 Saatci D, Van Nieuwenhuizen A, Handunnetthi L (2021) Maternal infection in gestation increases the risk of non-affective psychosis in offspring: a meta-analysis. J Psychiatr Res 139:125–131 Davies C, Segre G, Estrade A, Radua J, De Micheli A, Provenzani U et al (2020) Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry 7(5):399–410 Rodriguez V, Alameda L, Trotta G, Spinazzola E, Marino P, Matheson SL et al (2021) Environmental Risk Factors in Bipolar Disorder and Psychotic Depression: A Systematic Review and Meta-Analysis of Prospective Studies. Schizophr Bull 47(4):959–974 Al-Haddad BJS, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R et al (2019) Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry 76(6):594–602 Edlow AG, Castro VM, Shook LL, Kaimal AJ, Perlis RH (2022) Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy. JAMA Netw Open 5(6):e2215787 Mulkey SB, Williams ME, Jadeed N, Zhang A, Israel S, DeBiasi RL (2022) Neurodevelopment in infants with antenatal or early neonatal exposure to SARS-CoV-2. Early Hum Dev 175:105694 Shuffrey LC, Firestein MR, Kyle MH, Fields A, Alcántara C, Amso D et al (2022) Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection. JAMA Pediatr. ;e215563 Firestein MR, Shuffrey LC, Hu Y, Kyle M, Hussain M, Bianco C et al (2023) Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy. JAMA Netw Open 6(4):e237396 Hessami K, Norooznezhad AH, Monteiro S, Barrozo ER, Abdolmaleki AS, Arian SE et al (2022) COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis. JAMA Netw Open 5(10):e2238941 Davis EP, Narayan AJ (2020) Pregnancy as a period of risk, adaptation, and resilience for mothers and infants. Dev Psychopathol 32(5):1625–1639 Class QA, Abel KM, Khashan AS, Rickert ME, Dalman C, Larsson H et al (2014) Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress. Psychol Med 44(1):71–84 Lebel C, MacKinnon A, Bagshawe M, Tomfohr-Madsen L, Giesbrecht G (2020) Elevated depression and anxiety symptoms among pregnant individuals during the COVID-19 pandemic. J Affect Disord 277:5–13 Provenzi L, Grumi S, Giorda R, Biasucci G, Bonini R, Cavallini A et al (2020) Measuring the Outcomes of Maternal COVID-19-related Prenatal Exposure (MOM-COPE): study protocol for a multicentric longitudinal project. BMJ Open 10(12):e044585 Werchan DM, Hendrix CL, Hume AM, Zhang M, Thomason ME, Brito NH (2023) Effects of prenatal psychosocial stress and COVID-19 infection on infant attention and socioemotional development. Pediatr Res Ayesa-Arriola R, Castro Quintas A, de la Ortiz-Garcia V, Miguel Corredera M, San Martin Gonzalez N, Murillo-Garcia N et al (2023) Exploring the impact of COVID-19 on newborn neurodevelopment: a pilot study. Sci Rep 13(1):2983 Garrido-Torres N, Cerrillos L, García Cerro S, Pérez Gómez A, Canal-Rivero M, de Felipe B et al (2022) Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study. Front Pediatr 10:899445 WHO Working Group on the Clinical Characterisation and Management of Covid-19 infection (2020) A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis 20(8):e192–e197 Chan SF, La Greca AM (2013) Perceived Stress Scale (PSS). In: Gellman MD, Turner JR, editors. Encyclopedia of Behavioral Medicine [Internet]. New York, NY: Springer New York; pp. 1454–5. https://doi.org/10.1007/978-1-4419-1005-9_773 Squires J, Potter L, Bricker D (1995) The ASQ user’s guide for the Ages & Stages Questionnaires: A parent-completed, child-monitoring system. Baltimore, MD, US: Paul H Brookes Publishing; xvi, 156 p. (The ASQ user’s guide for the Ages & Stages Questionnaires: A parent-completed, child-monitoring system.) Cohen S, Kamarck T, Mermelstein R (1983) A Global Measure of Perceived Stress. J Health Soc Behav 24(4):385 De La Buitron P, Losi S, Sprague Martinez L, Bovell-Ammon A, Garg A, James T et al (2019) Implementing an EHR-based Screening and Referral System to Address Social Determinants of Health in Primary Care. Med Care 57(Suppl 2):S133–S139 Croen LA, Ames JL, Qian Y, Alexeeff S, Ashwood P, Gunderson EP et al (2024) Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders. Biol Psychiatry Global Open Sci 4(1):39–50 Correia LL, Rocha HAL, Sudfeld CR, Rocha SGMO, Leite ÁJM, Campos JS et al (2019) Prevalence and socioeconomic determinants of development delay among children in Ceará, Brazil: A population-based study. Busija L, editor. PLoS ONE. ;14(11):e0215343 Flensborg-Madsen T, Grønkjær M, Mortensen EL (2019) Predictors of early life milestones: Results from the Copenhagen Perinatal Cohort. BMC Pediatr 19(1):420 Pinheiro GSMA, de Souza RC, de Oliveira Azevedo VMG, Guimarães NS, Pires LG, Lemos SMA et al (2023) Effects of intrauterine exposure to SARS-CoV-2 on infants’ development: a rapid review and meta-analysis. Eur J Pediatr 182(5):2041–2055 Kocher K, Bhattacharya S, Niforatos-Andescavage N, Almalvez M, Henderson D, Vilain E et al (2023) Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic. BMC Med Genomics 16(1):268 Ayed M, Embaireeg A, Kartam M, More K, Alqallaf M, AlNafisi A et al (2022) Neurodevelopmental outcomes of infants born to mothers with SARS-CoV-2 infections during pregnancy: a national prospective study in Kuwait. BMC Pediatr 22(1):319 Huang P, Zhou F, Guo Y, Yuan S, Lin S, Lu J et al (2021) Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19. Front Pediatr 9:662165 Sheldrick RC, Marakovitz S, Garfinkel D, Carter AS, Perrin EC (2020) Comparative Accuracy of Developmental Screening Questionnaires. JAMA Pediatr 174(4):366 Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterialFINAL.docx Cite Share Download PDF Status: Published Journal Publication published 10 Sep, 2025 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted Editorial decision: Revision requested 08 Apr, 2025 Reviews received at journal 24 Feb, 2025 Reviewers agreed at journal 06 Feb, 2025 Reviews received at journal 03 Feb, 2025 Reviewers agreed at journal 13 Jan, 2025 Reviewers agreed at journal 06 Jan, 2025 Reviewers invited by journal 06 Jan, 2025 Editor assigned by journal 14 Nov, 2024 Submission checks completed at journal 14 Nov, 2024 First submitted to journal 12 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5442190","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":378162810,"identity":"d6be0a89-05b7-402b-9baf-63ece382485e","order_by":0,"name":"Nathalia Garrido-Torres","email":"","orcid":"","institution":"Virgen del Rocio University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nathalia","middleName":"","lastName":"Garrido-Torres","suffix":""},{"id":378162811,"identity":"9811dd1f-ef33-44a0-b064-f5bc9be99528","order_by":1,"name":"Andrés Román-Jarrín","email":"","orcid":"","institution":"Spanish Network for Research in Mental Health (CIBERSAM), ISCIII","correspondingAuthor":false,"prefix":"","firstName":"Andrés","middleName":"","lastName":"Román-Jarrín","suffix":""},{"id":378162812,"identity":"644c1295-0647-4eb3-ae08-4636a35ab67c","order_by":2,"name":"Julia Rider","email":"","orcid":"","institution":"Seville Biomedical Research Institute (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Rider","suffix":""},{"id":378162813,"identity":"a2115061-cf45-49be-8490-3dae243da69c","order_by":3,"name":"María Alemany-Navarro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYFAC5gYozcNwgKGCKC2MyFrOkKSFgQfIbiNCg277wcZHN2ruJDaw8x48+HPeYXsG9vYHeLWYnUlsNs459iyxgZkv4TDvtsOJDTxnDPBrOZDYJp3Ddjhx/2Eeg8OM2w4nMEjk4HeY2fmH7b9z/gENZ+YxOPhzDtBh8s8JOOxGYhtzbhtEywHehsOMDRIMBBx242GzdG7fYWOwX3iOpSe28eQQ0HI++eDnnG+HZRv4zx7++KPG2p6f/Th+h8GAYwOMxUaUeiCwJ1bhKBgFo2AUjEAAAFvsTFaBPadJAAAAAElFTkSuQmCC","orcid":"","institution":"Spanish Network for Research in Mental Health (CIBERSAM), ISCIII","correspondingAuthor":true,"prefix":"","firstName":"María","middleName":"","lastName":"Alemany-Navarro","suffix":""},{"id":378162814,"identity":"c8910317-36ae-42c2-9489-4e600dd50f78","order_by":4,"name":"Blake A. 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Each column represents the proportion of offspring scoring within the \"Typical\" or \"Atypical\" ranges for each developmental domain.\u003c/p\u003e\n\u003cp\u003eFigure 1.a: There was no significant concern in all ASQ-3 domains in offspring at the 6-month follow-up screening evaluation in either the control or infected groups, irrespective of infection severity.\u003c/p\u003e\n\u003cp\u003eFigure 1.b: A higher percentage of offspring born to mothers who experienced severe COVID-19 during pregnancy scored in the 'Atypical' range (\u0026lt;2SD below the mean) in the ASQ-3 Personal-Social domain, compared to the other ASQ-3 domains. This suggests a potential association between severe COVID-19 and developmental concerns in the Personal-Social domain.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5442190/v1/a7143acfd0ecf5fcef24b77f.png"},{"id":91359063,"identity":"da93a253-a460-4c8e-9b5a-4b58f9868560","added_by":"auto","created_at":"2025-09-15 16:04:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1330577,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5442190/v1/d4b57f78-7743-4f67-9159-54b0b66dfe8f.pdf"},{"id":70317192,"identity":"296815b3-daf1-4adf-b53a-e6b9f69e77ab","added_by":"auto","created_at":"2024-12-02 06:00:11","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":30201,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialFINAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-5442190/v1/ba7a882f4d7181ccb068f142.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Maternal Stress and COVID-19 Exposure During Pregnancy on Offspring Neurodevelopment: Signature Cohort 12 Month Follow-Up","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe declaration of the COVID-19 pandemic by the World Health Organization (WHO) in March 2020 marked a pivotal moment of global transformation. The emergence of the novel coronavirus disease (COVID-19), attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), brought profound changes across multiple dimensions of human life. (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Beyond its characterization as a global health crisis, the pandemic introduced uncertainties, particularly regarding its potential impact on various facets of existence. SARS-CoV-2 is a novel RNA coronavirus with spike proteins aiding cell entry. Its infection often manifests in respiratory symptoms (e.g., cough, difficulty breathing), fever, and fatigue. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn relation to the potential consequences of SARS-CoV-2 infection and other viral infections in pregnant women, the immune adaptations that occur during pregnancy to support fetal growth may impact how this population responds to viral infections, though it remains uncertain whether these changes increase vulnerability or offer protective effects (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). While certain viruses, such as Influenza A (H1N1) and other coronaviruses like SARS and MERS (Middle East respiratory syndrome), have been associated with a higher risk of hospitalization, intensive care unit admission, and maternal mortality (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), most pregnant women infected with SARS-CoV-2 appear to remain asymptomatic with low mortality rates (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, the stressors associated with the COVID-19 pandemic have led to increased stress, anxiety, and depressive symptoms in pregnant women, potentially upregulating inflammatory pathways and raising the risk of neuropsychiatric conditions in offspring (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAdditionally, a notable issue emerged regarding the potential effects of SARS-CoV-2 on the neurodevelopment of offspring born to mothers with COVID-19 during pregnancy. This apprehension stemmed from documented instances of other viral infections affecting fetal brain development (\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Understanding the impact of SARS-CoV-2 on fetal neurodevelopment assumes paramount importance, given the substantial population exposed to the virus and its potential for harm. Physiologically, it can generate a complex inflammatory response leading to a maternal immune activation (MIA) resulting in elevation of pro-inflammatory cytokines in the mother that may produce fetal neuroinflammation and microglial activation, increasing the risks of neurodevelopmental disorders in the offspring (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). These immunological changes have been associated with the COVID-19 severity (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGestational timing of an infection during pregnancy is a pivotal determinant in the susceptibility of offspring to later disorders. For instance, Saatci et al. (2021) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) found that maternal infection during pregnancy resulted in increased risk for non-affective psychosis. Similarly, a recent systematic review and meta-analysis concluded that exposure to infective agents and maternal infections were all significant risk factors for psychosis (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Recent large-scale population-based cohort studies reinforce these findings, highlighting an augmented risk of autism in offspring born to mothers exposed to any maternal infection during pregnancy (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). These insights collectively emphasize the critical influence of maternal infection timing during pregnancy in shaping the long-term mental health outcomes of offspring.\u003c/p\u003e \u003cp\u003eWhile a 12-month follow-up study, encompassing over 7000 deliveries, established an association between maternal SARS-CoV-2 infection during pregnancy and an increased risk for offspring neurodevelopmental diagnoses (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), existing research presents some inconsistencies. For instance, while Mulkey et al. (2020)(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) identified differences in fine motor and personal-social domains measured by the Ages \u0026amp; Stages Questionnaire, 3rd Edition (ASQ-3) in infants born to mothers with symptomatic COVID-19; Shuffrey et al. (2022)(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) found no significant differences in neurodevelopment at six months assessed by the ASQ-3 among infants exposed to COVID-19 during pregnancy, regardless of the timing of infection or severity of maternal symptoms. Additionally, Firestein et al. (2023)(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) showed that prenatal exposure to SARS-CoV-2 infection, did not appear to be associated with differences in neurodevelopment between ages 5 and 11 months. It is crucial to interpret these findings with caution because reliance on self-reported assessments of offspring neurodevelopment (Ages and Stages Questionnaire 3rd Edition or Developmental Assessment of Young Children 2nd Edition), retrospective data collection, and short follow-up durations, all of which may introduce biases affecting outcome accuracy. Furthermore, inconsistencies may stem from variability in study designs, sample sizes, demographic factors, and the timing and severity of maternal infection, as well as the vaccination status of participants for those studies for which sample recruiting was totally or partially done after vaccine safety in pregnancy was established.\u003c/p\u003e \u003cp\u003eThese discrepancies were attempted to be resolved in a systematic review and meta-analysis of eight articles (three and five articles, respectively) assessing both the effects of COVID-19 pandemic and SARS-CoV-2 infection exposures in offspring neurodevelopment using ASQ-3 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The authors found a higher odds ratio for fine motor impairment during the first year of life among infants with prenatal exposure to SARS-CoV-2 in comparison to those born during the pandemic but not exposed to the virus. Although no overall differences in neurodevelopmental impairment were found, this increased the risk of fine motor delays highlights a domain-specific vulnerability in SARS-CoV-2 exposed infants. Additionally, prenatal exposure to the pandemic environment \u0026ndash; regardless of maternal infection status \u0026ndash; was linked to an increase of communication impairment at any time during the first year, and communication and personal-social impairments at 12 months, suggesting that maternal stress during pregnancy may impact neurodevelopmental outcomes in offspring.\u003c/p\u003e \u003cp\u003eWhile some of the limitations outlined above were addressed in this meta-analysis, such as increased sample size and inclusion of different populations, others remain. These included limited follow-up to the first years of life, heterogeneous outcome measures, and gaps in data in certain quantitative analyses. Additionally, the ASQ-3 tool, used across studies, is based on caregiver or trained assessor reports, which may overlook subtle developmental deficiencies and add variability to the findings. The lack of information on social distancing practices also complicates the assessment of pandemic effects on neurodevelopment.\u003c/p\u003e \u003cp\u003eA critical aspect of this research is the role of maternal stress during pregnancy. Exposure to prenatal maternal anxiety and depression during this sensitive period can have long-term impacts on offspring, affecting gestational age and birth weight, which in turn may be linked with reduced brain connectivity. Evidence also suggest associations with reduced motor, communication, and problem-solving skills at 12 months, as well, as lower general cognitive function, executive function, and attention throughout childhood and adolescence (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Maternal stress is also associated with an increased risk of psychopathological morbidity in offspring (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The unique circumstances of the COVID-19 pandemic, with its lockdowns, uncertainties, and disrupted social support, may have heightened stress and anxiety among pregnant individuals (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). However, few studies have longitudinally examined the neurodevelopmental impact of both maternal stress and SARS-CoV-2 exposure during pregnancy. Notably, observed alterations in the regulatory capacity of 3-month-old infants whose mothers were pregnant during the COVID-19 pandemic compared to infants whose mother were pregnant previous to this period were found (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Also, Werchan et al., 2023 described the negative effects of maternal psychosocial stress and COVID-19 during pregnancy on infant attention at 6 months. Similar work in differences in state regulation between exposed and non-exposed newborns has also been published (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMost cohorts have focused either on measuring COVID-19 or maternal stress independently. Therefore, our research objective is to investigate the association between maternal stress and COVID-19 exposure during pregnancy, and how these factors impact neurodevelopmental outcomes in offspring at 6 and 12-month follow up. Our study aims to address this gap by examining the interplay between maternal stress and COVID-19 related risk. By addressing the limitations of prior studies, including sample size, COVID-19 severity, and gestational timing of infection during pregnancy, our research endeavors to provide a more nuanced understanding of these associations.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eThis prospective study aimed to investigate the association of maternal stress and COVID-19 exposure during pregnancy and developmental outcomes in offspring followed up at 6 and 12 months after birth. Approval for the project was obtained from the local institutional review board, specifically the Clinical Research Ethics Committee of Hospital Virgen del Roc\u0026iacute;o (Approval number: PECOVI-0195-2020; 1312-N-21). Participants meeting the defined inclusion criteria willingly provided written informed consent before being enrolled in the study. The detailed protocol for the study can be found in the \u003cem\u003eSignature\u003c/em\u003e study protocol (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003e The study was conducted at the Hospital Universitario Virgen del Roc\u0026iacute;o (HUVR) and the Institute of Biomedicine of Seville (IBiS), involving a multidisciplinary research team comprising medical specialists in pediatrics, psychiatry, gynecology, clinical psychology, primary care, as well as experts in basic and translational research, immunology, and infectious diseases. The study period for inclusion spanned from January 1, 2021, to August 31, 2022. The SARS-CoV-2 uninfected women were enrolled through primary care centers, while the SARS-CoV-2 infected women were enrolled through specific Gynecology consultations at HUVR. A comprehensive protocol for the care of pregnant women with SARS-CoV-2 infection was established at HUVR to manage both the infection and conduct neurodevelopmental assessments. Once a case has been identified, each patient was invited to participate, after confirming inclusion and exclusion criteria and signing the informed consent. Pregnant women meeting the following criteria were enrolled in the exposed group: i) experiencing or having experienced SARS-CoV-2 infection during the current pregnancy; ii) being of age 18 or older; iii) having a confirmed pregnancy via ultrasound examination; iv) presenting COVID-19 symptoms (meeting clinical criteria for a suspected case and testing positive on PCR), or v) being asymptomatic with a positive PCR result and negative Immunoglobulin G (IgG) assay. Exclusion criteria were: i) other concomitant causes of demonstrated risk for neurodevelopmental disorders; ii) under 18 years of age. In addition, a control group of non-exposed pregnant women was included to provide comparative data. For the non-exposed group, we selected pregnant women who meet the following inclusion criteria: i) pregnant women with no history of SARS-CoV-2 infection during the current pregnancy; ii) age 18 years or older; iii) confirmed pregnancy via ultrasound examination: iv) absence of COVID-19 symptoms and v) negative PCR test results. Exclusion criteria were: i) presence of other concomitant causes of demonstrated risk for neurodevelopmental disorders; ii) under 18 years of age. The type of PCR used to identify SARS-CoV-2 was a nasopharyngeal swab, utilizing the \u0026ldquo;SARS-CoV-2 RNA detection Kit\u0026rdquo; by \u003cem\u003eVitro Master Diagn\u0026oacute;stica\u003c/em\u003e. All participants received COVID-19 vaccine during pregnancy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasures and Core Variables\u003c/h3\u003e\n\u003cp\u003eThe core variables of this study included the COVID-19 severity in mothers, measured during any trimester of pregnancy when the infection occurred, according to the WHO Clinical progression scale (WHO Working Group on the Clinical Characterization and Management of Covid-19 infection, 2020). The perceived maternal stress (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) was measured upon entry to the study and during the same trimester of the infection, and the developmental progress at 6 and 12 months was screened with the ASQ-3 (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) in the newborn.\u003c/p\u003e \u003cp\u003eWomen were assessed when the infection occurred by internal medicine specialists and classified according to the WHO clinical progression scale for SARS-CoV-2 infection. The WHO Clinical Progression Scale is a tool used to categorize and assess the clinical status of individuals infected with SARS-CoV-2. This scale provides a standardized framework for describing the severity of the disease and helps in clinical decision-making and communication. The scale consists of several levels, each representing a different stage of the disease, ranging from mild or asymptomatic cases to severe or critical conditions. The specific details of the scale may evolve based on updated clinical knowledge and research findings. The typical categories on the WHO Clinical Progression Scale include: Uninfected (Level 0); Asymptomatic (Level 1): Individuals infected with SARS-CoV-2 who do not exhibit any COVID-19 symptoms; Mild Illness (Level 2\u0026ndash;3): Individuals with mild symptoms that do not require hospitalization, such as fever, cough, sore throat, malaise, headache, muscle pain, and loss of taste or smell; Moderate Illness (Level 4\u0026ndash;5): Individuals with pneumonia, but not requiring supplemental oxygen; Severe Illness (Level 6\u0026ndash;7): Individuals with pneumonia and requiring oxygen therapy. This category may also include other severe symptoms like acute respiratory distress syndrome (ARDS). Critical Illness (Level 8\u0026ndash;9): Individuals with severe pneumonia, ARDS, sepsis, or other critical conditions. This category often involves the need for mechanical ventilation or admission to an intensive care unit (ICU). The symptomatology variable has been recoded to represent mild COVID-19 (severity scores from 1 to 3) and severe COVID-19 (severity scores from 4 to 8), which includes the categories Moderate illness, Severe illness and Critical illness, all collectively labeled as severe COVID-19.\u003c/p\u003e \u003cp\u003eMaternal stress levels among pregnant participants were evaluated by the research team using the Perceived Stress Scale (PSS), a 14-item instrument initially developed by Cohen et al. in 1983 and later translated into Spanish by Remor in 2006. The PSS is designed to gauge participants' perceptions of stress and assess the impact of perceived stressful events on anxiety and stress levels. The scale measures the extent to which individuals perceive their lives as uncontrollable, unpredictable, and overwhelming. Each item is scored on a 5-point scale (0\u0026thinsp;=\u0026thinsp;Never, 1\u0026thinsp;=\u0026thinsp;Almost Never, 2\u0026thinsp;=\u0026thinsp;Sometimes, 3\u0026thinsp;=\u0026thinsp;Fairly Often, 4\u0026thinsp;=\u0026thinsp;Very Often) and summed to create a total score. Elevated scores indicate increased levels of perceived stress. In adult studies, the PSS demonstrates strong internal consistency (α\u0026thinsp;=\u0026thinsp;0.84\u0026ndash;0.86) and solid test-retest reliability (r\u0026thinsp;=\u0026thinsp;0.85 over two days, r\u0026thinsp;=\u0026thinsp;0.55 over six weeks). Regarding concurrent validity, PSS scores show a positive correlation with both the quantity and perceived impact of life stressors (r\u0026thinsp;=\u0026thinsp;0.17\u0026ndash;0.35) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). In the context of this study, the COVID-19 pandemic and the presence of a SARS-CoV-2 infection were considered as perceived stressors and \u0026ldquo;stressful events\u0026rdquo; measured by the scale. Participants self-reported their responses to the scale. High scores on the PSS indicate an increased risk of experiencing adverse health outcomes associated with elevated stress levels. The scale serves as a valuable tool for capturing the psychological impact of stressors, allowing for a comprehensive understanding of the participants\u0026rsquo; stress experiences during the COVID-19 pandemic.\u003c/p\u003e \u003cp\u003eThe neurodevelopmental screening evaluation was conducted using the Ages and Stages Questionnaire, Third Edition (ASQ-3), which was completed by pregnant women across both groups. The ASQ-3 is a developmental screening tool intended to evaluate the developmental progress of children across multiple domains, including 30 items divided into five development domains, with six questions per domain (communication, gross motor skills, fine motor, problem-solving, and personal-social ), with scores ranging from 0 to 60 points in each domain, whether the skill or ability is achieved or not, and then classified in 3 areas for each domain: below expectation (2 SD below the mean); close to expectation (1 SD below the mean), and above expectation. This evaluation is administered by parents or caregivers and is widely utilized to identify potential developmental areas of concern in infants and young children. In our study, categories \u0026ldquo;close to expectation\u0026rdquo; and \u0026ldquo;above expectation\u0026rdquo; have been consolidated into a single category labeled as 0 for \u0026ldquo;typical\u0026rdquo; and category \u0026ldquo;below expectation\u0026rdquo; was labeled as 1 for \u0026ldquo;atypical\u0026rdquo;, to focus on children scoring clearly below expectation (2 SD below the mean). This approach allows for a more conservative analysis by identifying only those children with scores that fall distinctly below the developmental cutoff. The ASQ-3 has a strong test-retest reliability (r\u0026thinsp;=\u0026thinsp;0.75\u0026ndash;0.82); a robust interobserver reliability (r\u0026thinsp;=\u0026thinsp;0.43\u0026ndash;0.69); an acceptable internal consistency (α\u0026thinsp;=\u0026thinsp;0.51\u0026ndash;0.87); and a strong congruent validity (r\u0026thinsp;=\u0026thinsp;0.85).\u003c/p\u003e \u003cp\u003eThe Social Determinant of Health (SDOH) screening questionnaire used in this study is part of the THRIVE program and assesses eight domains of social needs that may influence patient\u0026rsquo;s health. These domains include food insecurity, housing insecurity, difficulties affording medications, lack of transportation for medical appointment, needs related to basic services such as electricity or water, employment, education, and caregiving ((\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e)). Each domain is addressed with questions that identify whether the patient faces difficulties in any of these areas. The questionnaire is scored from 0 to 8, with each point corresponding to a specific social need identified by the patient. For the purposes of this study, we classified the scores into two groups: those with no needs and those with at least one identified need. Results from the SDOH screening are presented in Supplementary Table\u0026nbsp;1 and Supplementary Table\u0026nbsp;2.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eDescriptive statistics were utilized to characterize the demographic and clinical features of the study population. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), while categorical variables were presented as frequency (percentage).\u003c/p\u003e \u003cp\u003eCategorical variables, such as education level, maternal occupational activity, racial group, substance use during pregnancy, prematurity and offspring sex, were analyzed for associations across the same three groups: non-infected mothers, mothers with mild COVID-19, and mothers with severe COVID-19. Additionally, the trimester of COVID-19 infection was assessed for its association with the two groups of infected mothers: those with mild COVID-19 and those with severe COVID-19. The Chi-square test or Fisher's exact test was employed, depending on appropriateness. Chi-square tests were conducted to investigate associations between categorical variables, including the association between ASQ-3 at 6 and 12 months and infection status (mothers with mild COVID-19, mothers with severe COVID-19, and non-infected mothers). The PSS variable was analyzed as a continuous measure. Analysis of Variance (ANOVA) was employed to assess differences in continuous variables between groups, such as comparing maternal age and perceived stress scores between non-infected mothers, mothers with mild COVID-19 and mothers with severe COVID-19. This non-parametric test was selected due to its ability to evaluate differences in medians across multiple groups when data did not adhere to the normality assumptions required for parametric tests. A significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was set for all statistical analyses, with adjustments made for multiple comparisons using the Bonferroni correction to ensure robustness in the interpretation of results.\u003c/p\u003e \u003cp\u003eIn this analysis, COVID-19 severity served as the independent variable, or predictor, categorized in three groups; non-infected, mild COVID-19, and severe COVID-19. The ASQ-3 developmental domains were the dependent variables, or outcomes, which were dichotomized to indicate whether scores were below the mean (\u0026lt;\u0026thinsp;2SD) or not. For those ASQ-3 domains found to be significantly associated with the COVID-19 status based on Chi-square tests, logistic regression analyses were performed to further explore a possible association between COVID-19 severity and those ASQ-3 domains. Using the non-infected mothers as the reference group, we calculated odds ratios (OR) and 95% confidence intervals (CI) to assess the relationship between symptom severity (mild and severe COVID-19) and developmental outcomes in each ASQ-3 domain. The logistic regression was adjusted for variables found identified as statistically significant in the univariate analysis, and informed by findings from previous literature (e.g., offspring sex, prematurity). Data was analyzed with SPSS (Statistical Package for the Social Sciences) version 29.0. R Core Team (2023) was used to generate the graphics for this analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDescription of Maternal Sample\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;1 shows that the total population (N\u0026thinsp;=\u0026thinsp;689) was categorized into three distinct groups based on maternal COVID-19 severity: non-infected mothers (N\u0026thinsp;=\u0026thinsp;277), mothers with mild COVID-19 (N\u0026thinsp;=\u0026thinsp;358), and mothers with severe COVID-19 (N\u0026thinsp;=\u0026thinsp;54). The analysis of maternal characteristics revealed a statistically significant difference in age across groups (ANOVA F\u0026thinsp;=\u0026thinsp;4.564, gl\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.011). However, perceived stress scores during pregnancy did not differ significantly between the groups (ANOVA F\u0026thinsp;=\u0026thinsp;0.729, gl\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.483). Regarding maternal education level, no significant differences were observed among the groups (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;11.045, gl\u0026thinsp;=\u0026thinsp;3, p\u0026thinsp;=\u0026thinsp;0.087). Most participants across all groups had attained a university degree, with proportions ranging from 186 out of 358 mothers with mild COVID-19 (53.9%; one mother did not response), 22 out of 54 mothers with severe COVID-19 (41.5%) and to 161 out of 277 non-infected mothers (59.2%). Occupational activity varied significantly among the groups (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;13.274, gl\u0026thinsp;=\u0026thinsp;3, p\u0026thinsp;=\u0026thinsp;0.039), with the majority of participants being employed or working for themselves across all groups. Analysis of racial groups showed no significant difference (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;8.243, gl\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.083), with most participants identifying as Caucasian. Substance use during pregnancy did not significantly differ between the groups (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3.608, gl\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;=\u0026thinsp;0.165). The analysis of maternal factors. Including maternal comorbidities and the SDOH screening, on ASQ-3 developmental domains at 6 and 12 months revealed specific associations. At 6 months, only gestational diabetes during pregnancy was significantly associated with concerns in the gross motor domain (p\u0026thinsp;=\u0026thinsp;0.026). At 12 months, perceived stress during pregnancy showed a significant association with concerns in the fine motor domain (p\u0026thinsp;=\u0026thinsp;0.038). Additionally, maternal age at childbirth was associated with fine motor and personal-social concerns at 6 months and with gross motor and problem-solving concerns at 12 months. No significant associations were found between social determinants of health and any ASQ-3 at either 6 or 12 months. (Refer to Supplementary Tables\u0026nbsp;1 and 2 for comprehensive results). As for offspring characteristics, there was no significant difference in the distribution of sexes (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3.719, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.156), with approximately half of the offspring being female. Similarly, there was no significant differences regarding prematurity (F\u0026thinsp;=\u0026thinsp;0.260, gl\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;=\u0026thinsp;0.878), with most preterm offspring (N\u0026thinsp;=\u0026thinsp;27) born to mothers with mild COVID-19, Additionally, no significant differences were observed in the frequency of twin births across groups (F\u0026thinsp;=\u0026thinsp;3.292, gl\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;=\u0026thinsp;0.212). These findings highlight the demographic characteristics of the study population and their association with maternal COVID-19 severity. The analysis of COVID-19 during pregnancy revealed significant differences in the distribution of infection trimesters among severity groups (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;27.220, gl\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Notably, a higher proportion of severe COVID-19 cases occurred in the third trimester (34 out of 53 mothers with severe infection; 63%) compared to the first (5 out of 53 mothers with severe infection; 9.3%) and second (15 out of 53 mothers with severe infection; 27.8%) trimesters. These findings underscore the potential impact of the timing of maternal infection on COVID-19 severity during pregnancy.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Sample description\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"869\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eNon-infected mothers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003cp\u003eCOVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003cp\u003eCOVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003egl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e689 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e277 (40.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e358 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e54 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eMaternal age (mean +/- SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e33.11 \u0026plusmn; 5.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e33.53 \u0026plusmn; 7.707\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e33.08 \u0026plusmn; 5.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e31.21 \u0026plusmn; 5.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e4.564\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eMaternal perceived stress score (mean +/- SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e22.97 \u0026plusmn; 7.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e22.68 \u0026plusmn; 7.607\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e23.01 \u0026plusmn; 7.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e24.25 \u0026plusmn; 9.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" rowspan=\"4\" style=\"width: 110px;\"\u003e\n \u003cp\u003eEducational level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eReading and writing n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=11.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eElementary school n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003cp\u003e(8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eHigh school n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e243\u003c/p\u003e\n \u003cp\u003e(36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003cp\u003e(33.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003cp\u003e(37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e(41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eUniversity n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e369\u003c/p\u003e\n \u003cp\u003e(55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e161\u003c/p\u003e\n \u003cp\u003e(59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e186\u003c/p\u003e\n \u003cp\u003e(53.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e(41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" rowspan=\"4\" style=\"width: 110px;\"\u003e\n \u003cp\u003eOccupational status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eStudying n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=13.274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 89px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eLooking for a job n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003cp\u003e(11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003cp\u003e(14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003cp\u003e(8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eEmployee n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e453\u003c/p\u003e\n \u003cp\u003e(67.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003cp\u003e(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e249\u003c/p\u003e\n \u003cp\u003e(72.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003cp\u003e(64.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eRetired n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003cp\u003e(18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003cp\u003e(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003cp\u003e(17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" rowspan=\"3\" style=\"width: 110px;\"\u003e\n \u003cp\u003eEthnicity\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eCaucasian n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e599\u003c/p\u003e\n \u003cp\u003e(89.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003cp\u003e(87.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e317\u003c/p\u003e\n \u003cp\u003e(91.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003cp\u003e(81.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=8.243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 89px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eN Caucasian n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003cp\u003e(8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003cp\u003e(10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e(6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eNo response n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eSubstance use during pregnancy\u003c/p\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e183\u003c/p\u003e\n \u003cp\u003e(32.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003cp\u003e(33.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003cp\u003e(32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=3.608\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eOffspring characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eN = 681\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eN = 277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eN = 350\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eN = 54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 105px;\"\u003e\n \u003cp\u003eBirth sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 95px;\"\u003e\n \u003cp\u003eFemale n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e350\u003c/p\u003e\n \u003cp\u003e(51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003cp\u003e(52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e185 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e(38.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3.719\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 105px;\"\u003e\n \u003cp\u003ePrematurity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 95px;\"\u003e\n \u003cp\u003eYes n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003cp\u003e(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003cp\u003e(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e0.260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.878\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eTwins n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003cp\u003e(5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e3.292\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 201px;\"\u003e\n \u003cp\u003eInfected women n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e399 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e346 (86.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e53 (13.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003eTrimester of SARS-CoV-2\u003c/p\u003e\n \u003cp\u003eInfection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003eFirst trimester n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e95 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e90 (25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e5 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=27.220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 89px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003eSecond trimester n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e184 (44.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e169 (47.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e15 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003eThird trimester n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e133 (32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e99 (27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e34 (63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e* Significance was considered at p value \u0026lt; 0.01 after applying Bonferroni correction. When cell counts were less than 5, Fisher\u0026apos;s exact p-value was used to ensure the accuracy of the results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e\u003cem\u003eDevelopmental Screening Results at 6 and 12 Months in relation to COVID-19 Severity\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe total sample of children evaluated in at least one of the two screening moments included 681 newborns (including 10 twin births). The distributions of scores across the different ASQ-3 domains in offspring born to non-infected mothers, mothers with mild COVID-19, and mothers with severe COVID-19 can be seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The screening of neurodevelopmental outcomes using the ASQ-3 at 6 and 12 months provided insights into the developmental concerns present in infants in the three comparison groups (see Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At 6 months, a total of 601 out of 681 children (88.25%) were assessed. No significant differences were observed in ASQ-3 scores for communication (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;1.138, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.566), gross motor (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.331, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.848), fine motor (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.126, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.939), problem-solving (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.135, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.935), or personal-social skills (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;2.434, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.296) among the comparison groups. A total of 537 children out of the 681 children (78.85%) were assessed at 12 months. A total of 457 children were evaluated at both screening moments (6 and 12 months). No significant differences were found in ASQ-3 scores for communication (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3.211, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.201), gross motor (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.574, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.751), fine motor (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;1.022, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.600), or problem-solving (χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.936, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.626) at 12 months among the comparison groups. However, at 12 months, significant differences were observed in personal-social domain (χ2\u0026thinsp;=\u0026thinsp;8.282, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.016). Specifically, a higher proportion of infants born to mothers with severe COVID-19 exhibited personal-social concerns compared to those born to mothers with mild COVID-19 or non-infected mothers. In an exploratory analysis of offspring gender as a risk factor, we found no significance difference on developmental outcomes at 6-months follow up, however, male gender to be significant associated with developmental concerns at 12-month follow up in the following domains; communication (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fine motor (p\u0026thinsp;=\u0026thinsp;0.011), and personal-social (p\u0026thinsp;=\u0026thinsp;0.016) (Supplementary Table\u0026nbsp;3). Nonetheless, the significance did not persist in the multivariate analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eProportion of children with developmental concernsa in the ASQ-3b scale at 6 and 12 months across COVID-19 severity groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-infected mothers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003cp\u003eCOVID-19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003cp\u003eCOVID-19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASQ-3 6 months n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e601 (88.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e244 (35.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e313 (45.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44 (6.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommunication n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.566\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross motor n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.848\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFine motor n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.939\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProblem solving n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.935\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocio-individual n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASQ-3 12 months n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e537 (78.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e222 (32.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e275 (40.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 (5.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommunication n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross motor n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.751\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFine motor n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProblem solving n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (17.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.626\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocio-individual n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Developmental concerns (atypical): children scoring clearly below expectation (2 SD below the mean).\u003c/p\u003e \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e ASQ-3, Ages \u0026amp; Stages Questionnaire, 3rd Edition\u003c/p\u003e \u003cp\u003e* Significance was considered at p value\u0026thinsp;\u0026lt;\u0026thinsp;0.01 after applying Bonferroni correction.\u003c/p\u003e \u003cp\u003eThe total number of children assessed at any assessment point was 681.\u003c/p\u003e\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the found difference in the personal-social domain at 12 months, we performed a univariate logistic regression analysis, exploring the correlation between COVID-19 severity as the predictor (independent variable) and personal-social developmental concerns, identified in the ASQ-3 as the outcome (dependent variable). This analysis included groups of infected mothers (mothers with mild COVID-19 and with severe COVID-19, using non-infected mothers as the reference group. We found a significant association between severe COVID-19 and personal-social developmental concerns at 12 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e; p\u0026thinsp;=\u0026thinsp;0.005). Specifically, severe COVID-19 during pregnancy was associated with nearly a threefold increase in the risk of personal-social concerns, with an odds ratio (OR) of 2.967 (95% CI [1.384, 6.361]). Subsequently, in a multivariate logistic regression analysis adjusting for COVID-19 vaccine, offspring sex, mother's age at birth, prematurity, and preeclampsia, severe COVID-19 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e; p\u0026thinsp;=\u0026thinsp;0.037) did not remain significantly associated with personal-social developmental concerns at 12 months follow up-. The odds ratio (OR) for COVID-19 severity in this adjusted model was 2.751 (95% CI [1.065, 7.106]). Additionally, trimester of infection, offspring sex, prematurity, infections, perceived, and drug consumption during pregnancy did not exhibit significant associations with personal-social skills at 12 months. As these variables did not show significant associations, they were not included in the final model, with the exception of prematurity and offspring sex, which have been previously reported as associated with offspring developmental delay.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and Multivariate Logistic Regression of Socio-Individual ASQ3 Outcome with COVID-19 Severity\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003cp\u003eOR adjusted by COVID-19 vaccine, maternal age, sex, preeclampsia and prematurity.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSARS-COV-2 severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCrude OR (CI 95%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eOR (CI 95%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon infected\u003c/p\u003e \u003cp\u003e(Ref)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOVID-19 mild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.270 (0.776\u0026ndash;2.078)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.329 (0.794\u0026ndash;2.223)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOVID-19 severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.967 (1.384\u0026ndash;6.361)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.751 (1.065\u0026ndash;7.106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.037*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* Significance was considered at p value\u0026thinsp;\u0026lt;\u0026thinsp;0.01 after applying Bonferroni correction.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study examines maternal stress during pregnancy, measured upon entry to the study and during the same trimester of the infection, as well as COVID-19 exposure within a birth cohort followed up for 12 months. This investigation focuses on COVID-19 severity and the timing of infection during gestation. Descriptively, we observed significant differences in age among the three groups of mothers (non-infected mothers, mothers with mild COVID-19 and mothers with severe COVID-19, with a p value of 0.011 (Table\u0026nbsp;1). Although these differences were statistically significant, the variation in means was modest, potentially limiting their impact on the outcome analyzed. In addition, we found significant differences between the three groups of mothers regarding their usual activity. Remarkably, none of the mothers with severe COVID-19 were students, which might be explained by their potentially lower exposure to SARS-CoV-2 due to the possibility of studying from home. In contrast, among mothers with severe COVID-19, we observed a relatively higher percentage of those searching for a job (20.8% compared to 8.4% in mothers with mild COVID-19 and 14.0% in non-infected mothers), which could be related to greater exposure through job interviews or other social interactions associated with actively seeking employment.\u003c/p\u003e \u003cp\u003eThe analysis of maternal comorbidities showed that gestational diabetes during pregnancy was significantly associated with concerns in the gross motor developmental area. This finding aligns with existing literature suggesting that inflammatory conditions during pregnancy, such as gestational diabetes, may increase the risk neurodevelopment impairment (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Additionally, while socioeconomic status (SES) has been linked to developmental delays in prior studies (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), our analysis using the SDOH screening questionnaire, which examines factors such as family income, food insecurity, housing instability, and employment changes, did not find any significant associations between these SES-related factors and developmental outcomes in any ASQ-3 domains at the 6- or the 12-months follow-up. Our exploratory analysis examining offspring sex as a potential risk factor for developmental concerns showed that male offspring exhibited increased developmental concerns in communication, fine motor, and personal-social domains compared to female offspring. This finding aligns with prior research suggesting that females generally achieve developmental milestones earlier than males (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding COVID-19 severity as a predictor for developmental concern, despite the p-values in our results did not achieve statistical significance after applying the Bonferroni correction, they remained below the conventional threshold of 0.05. We recognize that the Bonferroni adjustment is highly conservative, especially in studies with multiple comparisons, which can substantially reduce statistical power and increase the risk of Type II errors, Consequently, while these results do not meet the stringent criteria set by the Bonferroni method, the observed p-valued suggest a potential significant association between COVID-19 severity in mothers and developmental outcomes in offspring. Specifically, offspring of mothers with severe COVID-19 showed a higher likelihood of personal-social concerns at 12 months, even after adjusting for relevant covariates. Notably, the timing of infection during pregnancy did not have any impact on any of the outcomes. These findings suggest that maternal health during the pandemic may influence early childhood development. Although not definitive, they highlight a potential area of concern that warrants further investigation in future studies with larger sample sizes.\u003c/p\u003e \u003cp\u003eOur findings align with existing literature, highlighting the vulnerability of the developing fetal brain to maternal health conditions, infectious diseases, and pregnancy-related stressors. In this sense, our data replicates previous studies (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), that also found that SARS-CoV-2 in utero exposure in offspring born to symptomatic mothers may be associated with generally lower ASQ-3 scores, with significant differences in fine motor and personal-social domains in comparisons to offspring of asymptomatic mothers or offspring with postnatal infections, what aligns with our findings of delay in personal-social domain in infants born to infected mothers with severe symptoms. A recent meta-analysis indicated lower scores in fine motor and problem-solving domains among infants exposed to SARS-CoV-2 (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). However, the ages of the offspring at the time of assessment varied across the three studies included in the meta-analysis, with heterogeneity ranging from moderate (problem-solving domain) to high (fine motor domain).\u003c/p\u003e \u003cp\u003eIn our study, we divided the sample into mothers with severe COVID-19, and mothers with mild COVID-19 and non-infected mothers to explore the varying impact of COVID-19 severity on developmental outcomes. This stratification aimed to clarify if COVID-19 severity correlates with offspring developmental outcomes, allowing us to assess potential severity effect associations.\u003c/p\u003e \u003cp\u003eThe complex interplay between COVID-19 severity and personal-social skills in offspring at 12 months underscores the need to explore other vulnerability factors, such as epigenetics, as some studies reveal potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the offspring epigenome (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Our study adds significant evidence to the growing body of research (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) on the potential impact of COVID-19 during pregnancy on offspring neurodevelopment, emphasizing the importance of considering maternal well-being in public health strategies and prenatal care. However, it is important to consider the limitations outlined in the introduction regarding previous research on this topic. Additional studies with larger sample sizes, more rigorous neurodevelopmental assessments (beyond screening and self-reported measures), and longitudinal approaches that track neurodevelopmental trajectories over time are necessary to draw conclusive associations between prenatal SARS-CoV-2 exposure and neurodevelopmental delays.\u003c/p\u003e \u003cp\u003eFurther investigation into the mechanisms underlying these effects and the development of tailored interventions for at-risk groups are warranted. Longitudinal studies can provide insights into developmental trajectories, while exploring potential mediators and moderators of the observed associations can inform targeted strategies to enhance neurodevelopment in offspring exposed to COVID-19 during pregnancy.\u003c/p\u003e \u003cp\u003eThis study has various strengths such as including a prospective design, comparison with non-infected mothers, mild and severe symptomatic mothers (mild and severe COVID-19), and consideration of covariates such as maternal stress and substance use. However, some limitations should be acknowledged such as the potential for bias introduced by self-reporting of certain variables. For instance, while the ASQ3 is a commonly utilized screening tool, a recent diagnostic accuracy study indicated that its sensitivity was below 70% across all levels of delay (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Long-term follow-up studies that include structured tools for assessing neurodevelopment in children and clinical diagnosis are needed to validate the findings and gain a more comprehensive understanding of developmental outcomes beyond the 12-month assessment. In addition, despite our large sample size, the subgroup of mothers with severe COVID-19 and offspring with Personal-social concerns in the ASQ-3 is small, particularly for those children whose mothers had severe COVID-19 and exhibited atypical ASQ results. This results in a wide confidence interval for the odds ratio, limiting the precision of the estimate and warranting cautious interpretation of the findings. In conclusion, our study sheds light on the association between COVID-19 severity during pregnancy and personal-social concerns in their 12-month-old offspring, emphasizing the potential of lasting impact of maternal health during the COVID-19 pandemic and early childhood development.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements and fundings\u003c/p\u003e\n\u003cp\u003eDr. Nathalia Garrido-Torres received funds under Juan Rodes Contract (JR22/00075). Dr. Mar\u0026iacute;a Alemany-Navarro received funds under Juan de la Cierva Contract (FJC2021-047538-I). Dr. Luis Alameda thanks the Foundation Adrian and Simone Frutiger and Carigest SA Foundation for their support. Dr. Andr\u0026eacute;s Rom\u0026aacute;n-Jarr\u0026iacute;n received funds under Alicia Koplowitz Foundation research grant. Dr. Miguel Ruiz-Veguilla received funds from Carlos III Health Institute. Grant ID: PI22-0678.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis work has received funds from the Consejer\u0026iacute;a de Salud y Familias para financiaci\u0026oacute;n de la investigaci\u0026oacute;n, desarrollo e innovaci\u0026oacute;n en ciencias de la salud de Andaluc\u0026iacute;a (CSyF 2021-FEDER), grant number PECOVID -01952020; and also received support from the Alicia Koplowitz Foundation to realize the clinical assessment to the children.\u003c/p\u003e\n\u003cp\u003eAuthor contribution\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNGT, ARJ, MRV, and BCF conceived and designed the study; NGT, ARJ, BCF, APG, JR, and ERM collected the data; NGT, MRV, JR, ARJ, LA, and MAN contributed data or analysis tool; JR, MAN and MRV performed the analysis; NGT, ARJ, MAN, JR, BdF, LC, CDS, and BAG wrote the first draft; all authors reviewed the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eData sharing statement\u003c/p\u003e\n\u003cp\u003eThe data generated in this study will be shared upon request.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBoelig RC, Manuck T, Oliver EA, Di Mascio D, Saccone G, Bellussi F et al (2020) Labor and delivery guidance for COVID-19. Am J Obstet Gynecol MFM 2(2):100110\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWastnedge EAN, Reynolds RM, van Boeckel SR, Stock SJ, Denison FC, Maybin JA et al (2021) Pregnancy and COVID-19. Physiol Rev 101(1):303\u0026ndash;318\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization (2020) Coronavirus disease (COVID-19)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Z, McGoogan JM (2020) Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 323(13):1239\u0026ndash;1242\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu B, Guo H, Zhou P, Shi ZL (2021) Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 19(3):141\u0026ndash;154\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWastnedge EAN, Reynolds RM, Van Boeckel SR, Stock SJ, Denison FC, Maybin JA et al (2021) Pregnancy and COVID-19. Physiol Rev 101(1):303\u0026ndash;318\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMosby LG, Rasmussen SA, Jamieson DJ (2011) 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol 205(1):10\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalil A, Hill R, Ladhani S, Pattisson K, O\u0026rsquo;Brien P (2020) Severe acute respiratory syndrome coronavirus 2 in pregnancy: symptomatic pregnant women are only the tip of the iceberg. Am J Obstet Gynecol 223(2):296\u0026ndash;297\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSutton D, Fuchs K, D\u0026rsquo;Alton M, Goffman D (2020) Universal Screening for SARS-CoV-2 in Women Admitted for Delivery. N Engl J Med 382(22):2163\u0026ndash;2164\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu K, Zhang Y, Zhang Y, Xu Q, Lv L, Zhang J (2021) Mental health among pregnant women under public health interventions during COVID-19 outbreak in Wuhan, China. Psychiatry Res 301:113977\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdoli A, Falahi S, Kenarkoohi A, Shams M, Mir H, Jahromi MAM (2020) The COVID-19 pandemic, psychological stress during pregnancy, and risk of neurodevelopmental disorders in offspring: a neglected consequence. J Psychosom Obstet Gynecol 41(3):247\u0026ndash;248\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCordeiro CN, Tsimis M, Burd I, Infections, Brain Development, Obstetrical (2015) \u0026amp; Gynecological Survey [Internet]. ;70(10). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://journals.lww.com/obgynsurvey/fulltext/2015/10000/infections_and_brain_development.19.aspx\u003c/span\u003e\u003cspan address=\"https://journals.lww.com/obgynsurvey/fulltext/2015/10000/infections_and_brain_development.19.aspx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoyle TJ, Goodin K, Hamilton JJ (2013) Maternal and neonatal outcomes among pregnant women with 2009 pandemic influenza A(H1N1) illness in Florida, 2009\u0026ndash;2010: a population-based cohort study. PLoS ONE 8(10):e79040\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFell DB, Savitz DA, Kramer MS, Gessner BD, Katz MA, Knight M et al (2017) Maternal influenza and birth outcomes: systematic review of comparative studies. BJOG 124(1):48\u0026ndash;59\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShook LL, Sullivan EL, Lo JO, Perlis RH, Edlow AG (2022) COVID-19 in pregnancy: implications for fetal brain development. Trends Mol Med 28(4):319\u0026ndash;330\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReyes-Lagos JJ, Abarca-Castro EA, Echeverr\u0026iacute;a JC, Mendieta-Zer\u0026oacute;n H, Vargas-Caraveo A, Pacheco-L\u0026oacute;pez G (2021) A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway. Front Psychol 12:614451\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePedersen SF, Ho YC (2020) SARS-CoV-2: a storm is raging. J Clin Invest 130(5):2202\u0026ndash;2205\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaatci D, Van Nieuwenhuizen A, Handunnetthi L (2021) Maternal infection in gestation increases the risk of non-affective psychosis in offspring: a meta-analysis. J Psychiatr Res 139:125\u0026ndash;131\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies C, Segre G, Estrade A, Radua J, De Micheli A, Provenzani U et al (2020) Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry 7(5):399\u0026ndash;410\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodriguez V, Alameda L, Trotta G, Spinazzola E, Marino P, Matheson SL et al (2021) Environmental Risk Factors in Bipolar Disorder and Psychotic Depression: A Systematic Review and Meta-Analysis of Prospective Studies. Schizophr Bull 47(4):959\u0026ndash;974\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Haddad BJS, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R et al (2019) Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry 76(6):594\u0026ndash;602\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdlow AG, Castro VM, Shook LL, Kaimal AJ, Perlis RH (2022) Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy. JAMA Netw Open 5(6):e2215787\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMulkey SB, Williams ME, Jadeed N, Zhang A, Israel S, DeBiasi RL (2022) Neurodevelopment in infants with antenatal or early neonatal exposure to SARS-CoV-2. Early Hum Dev 175:105694\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShuffrey LC, Firestein MR, Kyle MH, Fields A, Alc\u0026aacute;ntara C, Amso D et al (2022) Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection. JAMA Pediatr. ;e215563\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFirestein MR, Shuffrey LC, Hu Y, Kyle M, Hussain M, Bianco C et al (2023) Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy. JAMA Netw Open 6(4):e237396\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHessami K, Norooznezhad AH, Monteiro S, Barrozo ER, Abdolmaleki AS, Arian SE et al (2022) COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis. JAMA Netw Open 5(10):e2238941\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavis EP, Narayan AJ (2020) Pregnancy as a period of risk, adaptation, and resilience for mothers and infants. Dev Psychopathol 32(5):1625\u0026ndash;1639\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClass QA, Abel KM, Khashan AS, Rickert ME, Dalman C, Larsson H et al (2014) Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress. Psychol Med 44(1):71\u0026ndash;84\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLebel C, MacKinnon A, Bagshawe M, Tomfohr-Madsen L, Giesbrecht G (2020) Elevated depression and anxiety symptoms among pregnant individuals during the COVID-19 pandemic. J Affect Disord 277:5\u0026ndash;13\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProvenzi L, Grumi S, Giorda R, Biasucci G, Bonini R, Cavallini A et al (2020) Measuring the Outcomes of Maternal COVID-19-related Prenatal Exposure (MOM-COPE): study protocol for a multicentric longitudinal project. BMJ Open 10(12):e044585\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWerchan DM, Hendrix CL, Hume AM, Zhang M, Thomason ME, Brito NH (2023) Effects of prenatal psychosocial stress and COVID-19 infection on infant attention and socioemotional development. Pediatr Res\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAyesa-Arriola R, Castro Quintas A, de la Ortiz-Garcia V, Miguel Corredera M, San Martin Gonzalez N, Murillo-Garcia N et al (2023) Exploring the impact of COVID-19 on newborn neurodevelopment: a pilot study. Sci Rep 13(1):2983\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarrido-Torres N, Cerrillos L, Garc\u0026iacute;a Cerro S, P\u0026eacute;rez G\u0026oacute;mez A, Canal-Rivero M, de Felipe B et al (2022) Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study. Front Pediatr 10:899445\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO Working Group on the Clinical Characterisation and Management of Covid-19 infection (2020) A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis 20(8):e192\u0026ndash;e197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan SF, La Greca AM (2013) Perceived Stress Scale (PSS). In: Gellman MD, Turner JR, editors. Encyclopedia of Behavioral Medicine [Internet]. New York, NY: Springer New York; pp. 1454\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/978-1-4419-1005-9_773\u003c/span\u003e\u003cspan address=\"10.1007/978-1-4419-1005-9_773\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSquires J, Potter L, Bricker D (1995) The ASQ user\u0026rsquo;s guide for the Ages \u0026amp; Stages Questionnaires: A parent-completed, child-monitoring system. Baltimore, MD, US: Paul H Brookes Publishing; xvi, 156 p. (The ASQ user\u0026rsquo;s guide for the Ages \u0026amp; Stages Questionnaires: A parent-completed, child-monitoring system.)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen S, Kamarck T, Mermelstein R (1983) A Global Measure of Perceived Stress. J Health Soc Behav 24(4):385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe La Buitron P, Losi S, Sprague Martinez L, Bovell-Ammon A, Garg A, James T et al (2019) Implementing an EHR-based Screening and Referral System to Address Social Determinants of Health in Primary Care. Med Care 57(Suppl 2):S133\u0026ndash;S139\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCroen LA, Ames JL, Qian Y, Alexeeff S, Ashwood P, Gunderson EP et al (2024) Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders. Biol Psychiatry Global Open Sci 4(1):39\u0026ndash;50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorreia LL, Rocha HAL, Sudfeld CR, Rocha SGMO, Leite \u0026Aacute;JM, Campos JS et al (2019) Prevalence and socioeconomic determinants of development delay among children in Cear\u0026aacute;, Brazil: A population-based study. Busija L, editor. PLoS ONE. ;14(11):e0215343\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlensborg-Madsen T, Gr\u0026oslash;nkj\u0026aelig;r M, Mortensen EL (2019) Predictors of early life milestones: Results from the Copenhagen Perinatal Cohort. BMC Pediatr 19(1):420\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePinheiro GSMA, de Souza RC, de Oliveira Azevedo VMG, Guimar\u0026atilde;es NS, Pires LG, Lemos SMA et al (2023) Effects of intrauterine exposure to SARS-CoV-2 on infants\u0026rsquo; development: a rapid review and meta-analysis. Eur J Pediatr 182(5):2041\u0026ndash;2055\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKocher K, Bhattacharya S, Niforatos-Andescavage N, Almalvez M, Henderson D, Vilain E et al (2023) Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic. BMC Med Genomics 16(1):268\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAyed M, Embaireeg A, Kartam M, More K, Alqallaf M, AlNafisi A et al (2022) Neurodevelopmental outcomes of infants born to mothers with SARS-CoV-2 infections during pregnancy: a national prospective study in Kuwait. BMC Pediatr 22(1):319\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang P, Zhou F, Guo Y, Yuan S, Lin S, Lu J et al (2021) Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19. Front Pediatr 9:662165\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheldrick RC, Marakovitz S, Garfinkel D, Carter AS, Perrin EC (2020) Comparative Accuracy of Developmental Screening Questionnaires. JAMA Pediatr 174(4):366\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"SARS-CoV-2, COVID-19, maternal stress, pregnancy, neurodevelopment","lastPublishedDoi":"10.21203/rs.3.rs-5442190/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5442190/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe COVID-19 pandemic brought unprecedented global challenges. Amid the crisis, the potential impact of COVID-19 exposure on the neurodevelopment of offspring born to infected mothers emerged as a critical concern. This is a prospective cohort study of offspring exposed to mild or severe COVID-19 during pregnancy. Pregnant women who acquired SARS-CoV-2 were enrolled in the SIGNATURE project at Hospital Universitario Virgen del Rocio in Seville, Spain, between 01/01/2021 and 08/31/2022. Maternal stress was assessed through the Perceived Stress Scale; offspring neurodevelopment was screened through Ages \u0026amp; Stages Questionnaire, 3rd Edition (ASQ-3) at 6 months and 12 months. Association between COVID-19 severity and neurodevelopmental outcomes were analyzed with univariate and multivariate analysis. The cohort included 689 women categorized into three distinct groups based on COVID-19 severity: non-infected mothers (N\u0026thinsp;=\u0026thinsp;277), mothers with mild COVID-19 (N\u0026thinsp;=\u0026thinsp;358), and mothers with severe COVID-19 (N\u0026thinsp;=\u0026thinsp;54). In utero exposure to severe COVID-19 infection nearly tripled the risk of developmental concern in the ASQ-3 personal-social subdomain at 12 months follow-up [OR\u0026thinsp;=\u0026thinsp;2.751 (95% CI 1.065\u0026ndash;7.106), p\u0026thinsp;=\u0026thinsp;0.037], independently of the timing of the infection and maternal stress. While this study did not yield statistically significant results, it highlights the need to further investigate the potential association between COVID-19 during pregnancy and offspring neurodevelopment to understand the potential long-term consequences of prenatal COVID-19 exposure.\u003c/p\u003e","manuscriptTitle":"Impact of Maternal Stress and COVID-19 Exposure During Pregnancy on Offspring Neurodevelopment: Signature Cohort 12 Month Follow-Up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 06:00:06","doi":"10.21203/rs.3.rs-5442190/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-08T06:34:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-24T22:11:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314039784068572333470837562345013331448","date":"2025-02-06T13:57:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-03T23:06:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315471102755668829651097319754532966578","date":"2025-01-13T14:06:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326131105195417500057715444482445010989","date":"2025-01-06T15:50:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-06T10:35:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-14T13:25:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-14T13:22:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Child \u0026 Adolescent Psychiatry","date":"2024-11-12T20:57:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4ca8b3bd-3df1-432f-9fa6-a6819db9d100","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-15T16:01:39+00:00","versionOfRecord":{"articleIdentity":"rs-5442190","link":"https://doi.org/10.1007/s00787-025-02848-w","journal":{"identity":"european-child-and-adolescent-psychiatry","isVorOnly":false,"title":"European Child \u0026 Adolescent Psychiatry"},"publishedOn":"2025-09-10 15:57:17","publishedOnDateReadable":"September 10th, 2025"},"versionCreatedAt":"2024-12-02 06:00:06","video":"","vorDoi":"10.1007/s00787-025-02848-w","vorDoiUrl":"https://doi.org/10.1007/s00787-025-02848-w","workflowStages":[]},"version":"v1","identity":"rs-5442190","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5442190","identity":"rs-5442190","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}