Neurodevelopment in the first year of children exposed to SARS-CoV-2 during intrauterine period: systematic reviewABSTRACT
Objective: To identify, in the literature, the implications of gestational exposure to SARS-CoV-2 on neurodevelopment in the first postnatal year, focusing on changes in the motor, personal-social, socio-emotional, and communication and language domains.
Method: Systematic review with narrative synthesis, considering neurodevelopmental outcomes, categorized according to gross and fine motor skills, personal-social interaction, socio-emotional aspects, and communication and language. Searches were conducted in PubMed, LILACS/BIREME, and EMBASE databases between January 2020 and June 2023. Two independent researchers performed selection by reading the title and abstract and applying the inclusion and exclusion criteria. Cohort studies that evaluated children up to one year old, exposed to SARS-CoV-2 in utero, were included. The Newcastle-Ottawa scale was used to assess methodological quality.
Results: Seventeen articles were included, with methodological quality ranging from intermediate to good. The most frequently used instrument to characterize neurodevelopment was the Ages & Stages Questionnaires. Infants aged 0 to 3 months had lower scores for fine and gross motor skills. Infants aged 3 to 12 months had more fine motor, social and communication and language impairments.
Conclusion: Most infants exposed to SARS-CoV-2 showed development as expected, however delays were identified in the motor, personal-social, socio-emotional and communication and language domains according to the age group.
Descriptors: SARS-CoV-2; Pregnancy; Child development; Neurodevelopmental Disorders
RESUMEN
Objetivo: Identificar en la literatura las implicaciones de la exposición gestacional al SARS-CoV-2 sobre el neurodesarrollo en el primer año postnatal, enfocándose en los cambios en los dominios motor, personal-social, socioemocional y de comunicación y lenguaje.
Método: Revisión sistemática con síntesis narrativa, considerando los resultados del neurodesarrollo, categorizados en desarrollo de la motricidad gruesa y fina, interacción personal-social, aspectos socioemocionales y de comunicación y lenguaje. Las bases de datos utilizadas fueron PubMed, LILACS/BIREME y EMBASE entre enero de 2020 y junio de 2023. Dos investigadores independientes realizaron la selección inicial mediante la lectura del título y el resumen y la aplicación de los criterios de inclusión y exclusión. Se incluyeron estudios de cohortes prospectivos y retrospectivos que evaluaron a niños de hasta un año, expuestos al SARS-CoV-2 in utero. Se adoptó la escala Newcastle-Ottawa para evaluar la calidad metodológica.
Resultados: Se incluyeron 17 artículos cuya calidad metodológica fue intermedia a buena. El instrumento más utilizado para caracterizar el neurodesarrollo fue el Ages & Stages Questionnaires. Los bebés de 0 a 3 meses obtuvieron puntuaciones más bajas en habilidades motoras finas y gruesas. Los bebés de 3 a 12 meses mostraron más cambios motores finos, sociales y de comunicación y lenguaje.
Conclusión: La mayoría de los bebés expuestos al SARS-CoV-2 se desarrollaron como se esperaba, pero se pudieron identificar retrasos en los dominios motor, personal-social, socioemocional y de comunicación y lenguaje según el grupo de edad.
Descriptores: SARS-CoV-2; El embarazo; Desarrollo infantil; Trastornos del neurodesarrollo
RESUMO
Objetivo: Identificar, na literatura, implicações da exposição gestacional ao SARS-CoV-2 sobre o neurodesenvolvimento no primeiro ano pós-natal, com foco nos domínios motor, pessoal-social, socioemocional e de comunicação e linguagem.
Método: Revisão sistemática com síntese narrativa, considerando desfechos do neurodesenvolvimento, categorizados quanto à motricidade grossa e fina, interação pessoal-social, aspectos socioemocionais e de comunicação e linguagem. As buscas nas bases de dados Pubmed, LILACS/BIREME e EMBASE ocorreram entre janeiro/2020 e junho/2023. Dois pesquisadores independentes realizaram seleção pela leitura do título e resumo e a aplicação dos critérios de inclusão e exclusão. Foram incluídas coortes com crianças de até um ano, expostas ao SARS-CoV-2 in utero. Adotou-se a escala Newcastle-Ottawa para avaliar qualidade metodológica.
Resultados: Foram inclusos 17 artigos cuja qualidade metodológica apresentou-se de intermediária a boa. O instrumento mais utilizado para caracterização do neurodesenvolvimento foi o Ages & Stages Questionnaires. Bebês de 0 a 3 meses apresentaram menores pontuações para motricidade fina e grossa. Bebês de 3 a 12 meses apresentaram mais alterações motoras finas, sociais e na comunicação e linguagem.
Conclusão: A maioria dos bebês expostos ao SARS-CoV-2 apresentou desenvolvimento de acordo com o esperado, porém puderam ser identificados atrasos nos domínios motor, pessoal-social, socioemocional e comunicação e linguagem conforme faixa etária.
Descritores: SARS-CoV-2; Gravidez; Desenvolvimento Infantil; Transtornos do Neurodesenvolvimento
INTRODUCTION
Fetal brain development begins during the first trimester and occurs throughout gestation, being highly influenced by maternal and environmental humoral factors, due to the vulnerability of developing nerve cells1. This process is influenced by a series of epigenetic factors that may be involved in the origin of neurological developmental disorders in children2. Neurodevelopmental disorders comprise a spectrum of alterations resulting from the abnormal development of the nervous system, such as motor, socio-emotional, communication and language development disorders3.
The Severe Acute Respiratory Syndrome coronavirus, SARS-CoV-2, is the infectious agent responsible for COVID-14. SARS-CoV-2 shows, in astrocytes, a strong tropism in developing human cortical tissue, as evidenced by the high rate of infection and viral replication in these cells. After exposure to the virus, it was found that 90% of astrocytes located in the external subventricular zone exhibited infection markers. Astrocytes are essential for neurotransmitters regulation, maintenance of the blood-brain barrier, and neural metabolism control, which can significantly impact brain development5.
Maternal infections during pregnancy can alter the structure and function of the fetal brain by inducing an inflammatory cytokine cascade6. SARS-CoV-2 infection during pregnancy causes dysfunction in the renin-angiotensin (RA) system and vasoconstriction, due to the binding of the virus to angiotensin-converting enzyme 2 receptors, present in the placenta and uterus, which predisposes to preeclampsia and poor placental perfusion. For the fetus, epigenetic changes occur in organs, including the brain, mitochondrial dysfunction, and reactivity of macrophages and brain microglia. Increased pro-inflammatory cytokines implies adversities in neurodevelopment, including early cognitive and behavioral changes7,8.
Children represent a minority in lethal SARS-CoV-2 infections: 23 deaths per 1,000,000 children in Brazil in 20209,10. However, this group is indirectly affected when considering infection among pregnant women11. Gestational infection by SARS-CoV-2, as with other viral pathogens such as Chikungunya, Herpes simplex and Varicella Zoster, can cause encephalopathy, meningopathies and postnatal sequelae12.
Although maternal SARS-CoV-2 infection presents low neonatal mortality, it cannot be concluded that the infection does not bring complications to pregnancy and the child13. This is because changes in child development occur within complex systems, with many components that interact over time. Complex physical systems comprise interacting elements that span several levels, from the molecular (e.g., genes) to the neural, behavioral and social14. Therefore, motor development, by facilitating knowledge acquisition about the world, triggers cascades of changes in perceptual, cognitive, and social domains15. Genetic and environmental factors provide continuous modification of brain capacity through experience and stimuli, which favors learning and growth, but also highlights the sensitivity of the nervous system to pathological changes, as well as its capacity for recovery through neuronal plasticity16.
Due to the neurotropic potential of the SARS-CoV-2 virus and considering the intense process of neurodevelopment and neuroplasticity in the first year of extrauterine life, continuous monitoring of infants exposed to this pathogen in the prenatal period is necessary16. Thus, the objective of this study was to identify in the literature the implications of gestational exposure to SARS-CoV-2 on neurodevelopment in the first postnatal year, focusing on the motor, personal-social, socio-emotional, and communication and language domains.
METHOD
This is a systematic literature review, registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the identification CRD42023408029. The review was developed in compliance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)17.
The SPIDER strategy18 was adopted for research design, in which Sample consisted of: infants up to one year of age exposed to intrauterine SARS-CoV-2 infection; Phenomenon of Interest: neurodevelopment throughout the first postnatal year; Design: prospective and/or retrospective cohort studies; Evaluation: neurodevelopment measurement scales; Research Type: quantitative epidemiological research. The guiding question was: “What are the neurodevelopmental changes identified during the first postnatal year in the motor, personal-social, socio-emotional, and communication and language domains in children exposed to SARS-CoV-2 during the gestational period?”
To identify eligible articles, searches were conducted in the U.S. National Library of Medicine National Institutes of Health (PubMed), Latin American and Caribbean Literature in Health Sciences (LILACS/BIREME), and EMBASE (Elsevier) databases, from April to July 2023. A specific search strategy was used for each database, due to the particularities of each one. The descriptors in the English language were identified in the Health Sciences Descriptors (DeCS) of the Latin American and Caribbean Center on Health Sciences Information (BIREME) or in the terms from the Medical Subject Headings (MeSH) of PubMed, as well as their synonyms. The Boolean operator OR was used within categories and between term variations, and the operator AND was adopted between categories to combine them, as follows: (SARS-CoV-2) OR (coronavirus) OR (COVID-19) OR (Severe Acute Respiratory Syndrome) AND (embryogenesis) OR (fetal medicine) OR (maternal infection) OR (intrauterine) AND (Infant) OR (newborn) OR (toddler) OR (neonate) AND (follow-up) OR (neurodevelopmental disorders) OR (neurodevelopmental outcomes) OR (motor outcome) OR (motor development) OR (motor function assessment) OR (neural impairment).
The inclusion criteria were: studies with children up to one year old born to mothers exposed to SARS-CoV-2, at any gestational period, with positive PCR testing; studies that assessed aspects of motor, personal-social, socio-emotional, and communication and language neurodevelopment, using instruments clearly identified in the study methodology; prospective or retrospective cohort studies published from January 2020 to June 2023. The exclusion criteria were: review studies, protocols, letters, and editorials; ongoing research; studies that did not use standardized neurodevelopment assessment instruments; studies that assessed the consequences of maternal exposure to other viral pathogens; studies that assessed congenital or genetic childhood conditions that could affect neurodevelopment; studies that did not address neurodevelopmental conditions; studies that assessed children over one year old; and studies that presented low methodological quality.
Five stages of analysis were established18: 1) Selection by title and abstract; 2) Application of inclusion and exclusion criteria; 3) Selection of article by full-text reading; 4) Data extraction and 5) Qualitative synthesis.
Two independent researchers performed the initial selection by reading the title and abstract and applying the inclusion and exclusion criteria. Duplicate titles were eliminated using the Rayyan application19, ensuring reliability in information selection, and methodological accuracy and precision. Once the potentially eligible articles were identified, full-text reading was conducted to finalize the sample. In cases of disagreement, a third reviewer was consulted regarding article inclusion.
Data from the selected studies were extracted independently and entered into a Microsoft Excel spreadsheet. The following data were extracted: authors, year and country; study objective; methodology - including design, sample characteristics (age in months) and neurodevelopment assessment instrument - and outcomes.
The outcomes were categorized as: gross and/or fine motor development, personal-social interaction, socio-emotional aspects, and communication and language, in accordance with the domains used in the diagnostic concept of neurodevelopmental disorders3) and which are also presented according to the neurodevelopment assessment tools present in the included studies. The age of the children in months was considered, since the studies periodized reassessments in the third, sixth, and twelfth postnatal month.
The assessment of the methodological quality of the articles was performed using the Newcastle-Ottawa Scale20,21, which has specific questions for cohort studies divided into three sections: selection of study groups; comparability of groups; and exposure or outcome of interest. The questions are answered with a number of stars, with a maximum possible score of 9. The more stars, the better the study. Good quality is defined by 3 or 4 stars in the selection domain, 1 or 2 stars in the comparability domain, and 2 or 3 stars in the outcome/exposure domain. Reasonable/intermediate quality is indicated by 2 stars in the selection domain, 1 or 2 stars in the comparability domain, and 2 or 3 stars in the outcome/exposure domain. Poor quality is identified by 0 or 1 star in the selection domain, 0 stars in the comparability domain, or 0 or 1 star in the outcome/exposure domain20.
RESULTS
A total of 746 articles were found, 23 of which were selected after reading the title and abstract, and 17 articles were included after applying the inclusion and exclusion criteria and assessing methodological quality. Figure 1 represents the flowchart of the article selection process from the chosen database.
Flowchart of the process of identification, selection and eligibility of articles. Goiânia, Goiás, Brazil, 2023.
Sixteen prospective cohort studies and 1 retrospective cohort study were included, 1 published in 2020, 4 in 2021, 7 in 2022 and 5 in 2023, all in English.
The results were organized according to neurodevelopmental aspects: motor, personal-social, socio-emotional and communication and language. To facilitate the understanding of these aspects, this review describes the instruments used to characterize the outcomes.
All included studies considered, in the initial assessment of the newborn: gestational age; type of delivery; immediate health condition; diagnosis or non-diagnosis of COVID-19; immunization factor or immune sensitization; Apgar score at the first, fifth and tenth minutes; the need for ventilatory support and the major symptoms and complications during birth.
Regarding birth characteristics, although 11 articles identified the presence of preterm birth22-32, most infants presented weight, Apgar scores at the first and fifth minutes, and gestational age within normal parameters. Among preterm infants who presented alterations in neurodevelopment, these were associated with longer hospital stays and respiratory complications, which were related to severe forms of maternal COVID-19.
To minimize biases in the effect of prematurity and infection on development, four studies used multiple linear regression modeling, adjusting for preterm birth (yes or no), sex, neonatal intensive care unit admission, maternal SARS-CoV-2 infection status, maternal age (years), and ethnicity24,25,28,31. Another study mentioned linear mixed-effect models to determine whether age, sex, and SARS-CoV-2 infection status were able to predict infant development, but there was no statistical significance for the prematurity factor26.
For the other studies, there was also no statistical significance for the prematurity factor among the groups, and the analysis of covariance with maternal age, gestational age, and infant sex was adopted to compare the groups (exposed and unexposed to the virus),22) or the Student’s t-test and Mann-Whitney test23,29.
Regarding maternal characteristics, most mothers were diagnosed with SARS-CoV-2 in the third trimester of pregnancy22-24,29,31,33, with the majority being asymptomatic and fever being the main symptom, when present30,33. The disease was confirmed by laboratory testing.
Immune testing of babies was identified in 13 articles. The Polymerase Chain Reaction (RT-PCR) technique was used for both mothers and infants. Most of the babies tested were significantly negative for SARS-CoV-2 at birth23,26-28,30-37. In addition to the PCR evaluation, some studies also analyzed umbilical cord blood, amniotic fluid, breast milk, meconium and placenta, which identified the presence or absence of the virus31,32.
The instruments used to assess child development were: Ages & Stages Questionnaires Third Edition (ASQ-3)23,27,29-33,36,38, Age and Stage Questionnaire Social-Emotional (ASQ:SE- 2)31,32, Developmental Profile (DP-3)34, Amiel-Tison Method34, Denver Developmental Screening Test II (Denver II)26, General Movements Assessment (GMA) e Motor Optimality Score (MOS)28,35, Neonatal Behavioral Assessment Scale (NBAS)22, Baby Pediatric Symptom Checklist (BPSC)38, Van Wiechen Schem37) and Developmental Assessment of Young Children, 2nd edition (DAYC-2)25.
The ASQ-3, the main instrument used, is an easy-to-apply, low-cost and a sensitive tool for different cultural contexts, which makes it widely used39. The domains assessed are: communication, gross motor coordination, fine motor coordination, problem-solving, and personal-social skills. Although children exposed to SARS-CoV-2 are more likely to score below the normative averages38, most studies using the ASQ-3 reported that the neurodevelopment of infants born to mothers with SARS-CoV-2 infections was within the expected range27,30,32,33 or found no significant difference between those exposed and non-exposed to the virus23,36. In one study, developmental delays occurred significantly more frequently based on the trimester of SARS-CoV-2 infection: they were more common in infants born to mothers infected during the first and second trimesters (p<0.001)33.
Chart 1 presents a description of the articles included regarding the outcome for the motor domain. When assessed between eight and twelve months, newborns of mothers infected with SARS-CoV-2 during the gestational period had significantly lower scores in the fine motor domain (P = 0.03)23.
Infants of symptomatic mothers more frequently (compared to those of asymptomatic mothers) presented abnormal neurological examinations for age and ASQ-3 scores close to or below cutoff points for all domains. The differences were significant for fine motor (p = 0.01) and personal-social (p = 0.02) domains29.
The Amiel-Tison method detects warning signs of psychomotor development abnormalities, such as persistent primitive reflexes, changes in tone (decreased or increased) and posture, asymmetry, and cervical and axial hypotonia. Using this method, it was identified that 42.1% of the children in the cohort of mothers who tested positive for SARS-CoV-2 had below-average development, while the percentage was 25.9% among the negative cohort. However, there was no significant difference in growth, neurodevelopment, or hospital readmission rate among newborns34.
For the GMA and MOS instruments (from 3 to 6 months), the exposed group had a significantly reduced total motor optimization score compared to the unexposed group. Only atypical body symmetry was significantly different35. Another study using these instruments revealed that, compared to pre-pandemic control groups, infants exposed to SARS-CoV-2 in the prenatal phase had more frequent suboptimal neuromotor development28. These instruments are reliable and used for quantifying the quality of fidgety movements.
For the Denver II instrument, at 12 months, early fine motor alterations were identified with a higher incidence in the group exposed to SARS-CoV-2, compared to the unexposed group, and with a short-term neurological effect. The growth curve was similar between the two cohorts26.
In utero exposure was not associated with significant differences in any subdomain of the ASQ-3 instrument, although infants born during the pandemic had lower scores in the gross and fine motor and personal-social domains31.
For the ASQ:SE-2, which tracks social and emotional behaviors such as self-regulation, adaptive functioning, autonomy, affection, and interaction, the proportion of risk classification for infants exposed to SARS-CoV-2 reached 63.6%31.
Chart 2 presents the description of the included articles regarding outcomes for the personal-social and socio-emotional domains.
SARS-CoV-2 infection during pregnancy did not significantly increase the risk of socio-emotional delay, according to the ASQ-3 and ASQ:SE-232. When the BPSC instrument was used, 53% of the children in the cohort exposed to SARS-CoV-2 exceeded the threshold of clinical concern, with irritability being the most widespread behavior38.
Regarding the results for the NBAS instrument, the infants’ skills and performances were similar in the exposed and non-exposed groups to SARS-CoV-2. A significant difference was found in the less optimized response to affection, particularly in infants born to mothers exposed in the third trimester of pregnancy22.
Chart 3 presents the description of the included articles regarding the outcome for the communication and language domain. Diagnoses, based on the ICD-10, for neurodevelopmental disorders were significantly more common among children exposed to SARS-CoV-2 during the gestational period, particularly in the third trimester. Most diagnoses reflected motor function or speech and language developmental disorders24.
Regarding environmental aspects, there was a negative association between the days of mother-infant separation and the scores in the gross motor, communication, and personal-social domains of the ASQ-3, regardless of intrauterine exposure to the virus31,32.
The methodological quality scores of the articles, according to the Newcastle-Ottawa Quality Assessment Scale, ranged from 4 to 8, with a mean of 6, representing an overall quality considered from intermediate to good20, as expressed in Chart 4.
The most frequent methodological deficits were the lack of description or lack of clarity in the statistical presentation of sample representativeness and the inadequate description of participants lost throughout the research.
DISCUSSION
Most infants exposed to the SARS-CoV-2 virus during pregnancy presented development in line with what is expected for their age. However, studies have detected mild changes in the neurodevelopment of infants aged zero to one year born to mothers exposed to SARS-CoV-2 during pregnancy. Changes in the gross and fine motor skills domains were prominent up to six months, and in the social and language domains they emerged more frequently between six and twelve months.
Maternal immune activation is a signature of SARS-CoV-2 infection during pregnancy, regardless of the severity of the disease40. This activation causes placental changes, such as poor vascular perfusion, elevated cytokine production, increased abnormal mitochondria and high number of mitochondrial DNA copies, as well as decreased oxygen and nutrient transport capacity, contrasting with increased levels of IL-2, IL-6, TNF-α and IFN-γ in maternal blood trophoblastic cells26,29.
Activation of the anti-inflammatory cholinergic pathway (both maternal and fetal) and placental interactions may modulate the neuroimmune mechanisms employed to mitigate cytokine storm syndrome. This reduce tissue and cell damage, and the effects of SARS-CoV-2 infection on the fetus are minimized, implying births of babies negative for the virus41. Neonatal SARS-CoV-2 infection was found to be uncommon in the studies, and vertical transmission was considered unlikely, supporting international recommendations to avoid mother-infant separation42.
SARS-CoV-2 replicates in cells expressing angiotensin-converting enzyme-2 in the lungs, nasopharynx, and small intestine and can persist in tissues for extended periods43. Most infected newborns are asymptomatic at birth or present mild symptoms, such as rhinorrhea and fever. Adequate respiratory support, such as continuous positive airway pressure (CPAP), was necessary for newborns with anatomical and functional alterations of the respiratory system, regardless of the diagnosis of SARS-CoV-2 infection44.
Trunk hypotonia and changes in head control were found in the neurological examination of infants exposed to SARS-CoV-2 and were associated to lower scores in the motor domain29. Gross motor development is influenced by various factors, including muscle tone and the acquisition of stability to overcome the action of gravity and assume higher postures (sitting, standing, walking)45. Proper posture allows for limb movements and maintaining it provides the necessary conditions for looking around, handling objects, sustaining conversations, or moving around. Thus, most developmental skills, including those not directly related to posture, depend to some degree on the development of sufficient postural control. Increasing mobility skills and the ability to manipulate and explore objects can boost the cascade of learning opportunities and impact the development of language and social interactions15.
Increased prenatal maternal distress contributes to poorer socio-emotional development in children. Maternal pre and postnatal distress accounted for 13.7% of the variance in infants’ socio-emotional development. Anxiety and depressive symptoms during pregnancy have been associated with premature birth, low birth weight, and developmental delays. Impaired placental function in pregnant women with high stress levels increases the risk that the fetus - and potentially the baby through breastfeeding - will be exposed to inflammatory markers that may have deleterious effects on brain and behavioral development46.
Delays in communication and language are also correlated with maternal stress and decreased stimulation. There are a greater number of mothers with caregiving skills affected by psychological distress. Such distress, combined with measures to limit the spread of the SARS-CoV-2 virus, such as physical distancing and the use of masks, can deprive infants of interactions and their consequent opportunities to learn about communication and emotions46.
As a maternal stressor, the SARS-CoV-2 infection may imply fetal endocrine and neuroimmune sensitization, given that traumatic events in early life and childhood alter the dynamic gene-environment interaction and the programming of the neurological, immune, and endocrine systems47,48,41.
Although analyses of neurodevelopment are still inconclusive regarding the persistence of developmental delays after the first year of life, understanding early manifestations provides a parameter for designing long-term monitoring and early stimulation programs for children at risk. In this context, physicians, nurses, physical therapists, speech therapists and other healthcare professionals must be attentive to child development and maternal health conditions, monitoring them and intervening to prevent harm49. This not only impacts the quality of life of infants and families but also involves adopting care strategies with rigorous assessment of exposure to environmental factors, contributing to health system management.
Although the results of this study indicated that infants exposed to the SARS-CoV-2 virus during pregnancy may present neurodevelopmental delays, it is worth considering that there was a limitation of the small number of databases consulted in this review. Additionally, the variety of development assessment instruments used by the researchers made it difficult to compare and describe the results. It is also worth considering that there was little or no information about the expertise of the evaluators in applying the instruments and about the standardization in the assessment and interpretation of findings.
Additional studies with long-term follow-up of babies exposed to SARS-CoV-2 during the prenatal period are suggested, as the impact on neurodevelopment may be delayed and more sensitive to detection in older children, especially concerning disorders related to social interactions, behavior, cognition, and language.
CONCLUSION
Most studies identified that infants exposed to the SARS-CoV-2 virus during pregnancy presented development according to what is expected for their age. However, when infants with neurodevelopmental delays were identified, the proportion varied from 6.3% to 69%, according to the domain analyzed and the instrument used. Delays were particularly evident in the gross and fine motor domains among children up to six months of age and in the communication and personal-social domains among children aged six to twelve months.
Future exposures to SARS-CoV-2 during gestational period should be monitored and receive attention by healthcare professionals regarding neurodevelopmental milestones in the first year of life, to prevent delays evidenced in this review. For infants identified with deficits, it is suggested that they be referred to early intervention programs to encourage the achievement of expected motor, communication, and interactive skills, in line with age milestones of child development.
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Publication Dates
-
Publication in this collection
25 Nov 2024 -
Date of issue
2024
History
-
Received
06 Feb 2024 -
Accepted
07 June 2024
Source: Prepared by the authors, 2023.Legend: *Studies also included infants over 12 months of age.