Neurodevelopment in preschool children exposed and unexposed to Zika virus in utero in Nicaragua: a prospective cohort study.

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero.

It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score < - 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social). Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5-30 months of age and 128 control children between 6-38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007. Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up.

Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review.

It was late 2015 when Northeast Brazil noticed a worrying increase in neonates born with microcephaly and other congenital malformations. These abnormalities, characterized by an abnormally small head and often neurological impairment and later termed Congenital Zika Syndrome, describe the severity of neurodevelopmental and nephrological outcomes in early childhood, and the implication of microcephaly at birth. The purpose of the study was to describe the neurodevelopmental outcomes in children exposed to Zika virus during fetal life, with and without microcephaly at birth. The systematic review included research studies about the neurodevelopmental outcomes with and without microcephaly, as well as nephrological outcomes in early childhood. We searched PubMed, Crossref, PsycINFO, Scopus, and Google Scholar publications and selected 19 research articles published from 2018 to 2021. Most studies have linked the severity of microcephaly in childbirth to the neurodevelopmental and urinary outcomes in early childhood. However, most children without microcephaly at birth develop typically, while others may be at risk for language impairment.

Desenvolvimento neuropsicomotor de crianças expostas à infecção congênita pelo Zika vírus / Neuropsychomotor development of children with congenital Zika virus infection

INTRODUÇÃO: A comprovação da associação de microcefalia no Brasil com a infecção congênita pelo Zika vírus, leva a necessidade de estudos sobre a repercussão no desenvolvimento das crianças decorrentes do comprometimento do sistema nervoso central (SNC). OBJETIVO: Avaliar o desenvolvimento neuropsicomotor (DNPM) de crianças expostas à infecção congênita pelo Zika vírus e sua associação com características e diagnósticos pré natais, neonatais e pós natais da mãe/criança. MÉTODOS: Estudo transversal com crianças de zero a três anos, nascidas entre 2015 e 2018, classificadas com infecção congênita pelo Zika vírus. Na coleta das características clínicas e sócio demográficas, utilizou-se um questionário semiestruturado e na avaliação do DNPM o Teste de Triagem de Denver II. Na associação, utilizou-se o teste exato de Fisher (p<0,05). RESULTADOS: Avaliou-se 30 crianças, 46,67% apresentavam alterações do DNPM, os maiores foram na linguagem (46,67%) e motricidade fina (43,33%). 23,33% tinham mais que 24 meses, idade que se associou a alterações do DNPM (p<0,012). A infecção predominou entre 4 e 12 semanas de gestação e obteve associação com os atrasos do DNPM (p<0,002). 46,67% das crianças apresentaram microcefalia e 40% calcificações cerebrais, ambos com associação a atrasos no DNPM (p<0,001). Em exame físico 36,7% apresentaram alterações de postura e persistência de reflexos primitivos, 40% hiperirritabilidade, 33,33% disfagia e deformidades articulares, todas com associação importante com as alterações no DNPM (p<0,001). CONCLUSÕES: Crianças expostas à infecção congênita pelo Zika vírus apresentaram atrasos no DNPM e quanto mais precoce a infecção na gravidez, maior o envolvimento do sistema nervoso central.

INTRODUCTION: The proof of the association of microcephaly in Brazil with congenital Zika virus infection leads to the need for studies on the impact on children's development resulting from the involvement of the central nervous system (CNS). OBJECTIVE: To evaluate the neuropsychomotor development (NPMD) of children exposed to congenital Zika virus infection and its association with prenatal, neonatal, and postnatal characteristics and diagnoses of the mother/child. METHODS: Cross-sectional study with children aged zero to three years, born between 2015 and 2018, classified with congenital Zika virus infection. In the collection of clinical and socio-demographic characteristics, a semistructured questionnaire was used, and the Denver II Screening Test was used to assess the DNPM. In the association, Fisher's exact test was used (p<0.05). RESULTS: Thirty children were evaluated; 46.67% had DNPM alterations, the greatest ones were in the language (46.67%) and fine motor skills (43.33%). 23.33% were older than 24 months, an age-associated with changes in DNPM (p<0.012). Infection predominated between 4 and 12 weeks of gestation and was associated with DNPM delays (p<0.002). 46.67% of children had microcephaly and 40% cerebral calcifications, both associated with DNPM delays (p<0.001). On physical examination, 36.7% had changes in posture and persistence of primitive reflexes, 40% hyperirritability, 33.33% dysphagia, and joint deformities, all with an important association with changes in DNPM (p<0.001). CONCLUSIONS: Children exposed to congenital Zika infection had developmental delays. It is noteworthy that the earlier the infection in pregnancy, the greater the involvement of the central nervous system of children.

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

Birth Defects and Long-Term Neurodevelopmental Abnormalities in Infants Born During the Zika Virus Epidemic in the Dominican Republic.

Background: When acquired during pregnancy, Zika virus (ZIKV) infection can cause substantial fetal morbidity, however, little is known about the long-term neurodevelopmental abnormalities of infants with congenital ZIKV exposure without microcephaly at birth. Methods: We conducted a cross sectional study to characterize infants born with microcephaly, and a retrospective cohort study of infants who appeared well at birth, but had possible congenital ZIKV exposure. We analyzed data from the Dominican Ministry of Health's (MoH) National System of Epidemiological Surveillance. Neurodevelopmental abnormalities were assessed by pediatric neurologists over an 18-month period using Denver Developmental Screening Test II. Results: Of 800 known live births from 1,364 women with suspected or confirmed ZIKV infection during pregnancy, 87 (11%) infants had confirmed microcephaly. Mean head circumference (HC) at birth was 28.1 cm (SD ± 2.1 cm) and 41% had a HC on the zero percentile for gestational age. Of 42 infants with possible congenital ZIKV exposure followed longitudinally, 52% had neurodevelopmental abnormalities, including two cases of postnatal onset microcephaly, during follow-up. Most abnormalities resolved, though two infants (4%) had neurodevelopmental abnormalities that were likely associated with ZIKV infection and persisted through 15-18 months. Conclusions: In the DR epidemic, 11% of infants born to women reported to the MoH with suspected or confirmed ZIKV during pregnancy had microcephaly. Some 4% of ZKV-exposed infants developed postnatal neurocognitive abnormalities. Monitoring of the cohort through late childhood and adolescence is needed.

Examining the Association of Socioeconomic Position with Microcephaly and Delayed Childhood Neurodevelopment among Children with Prenatal Zika Virus Exposure.

Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.

Neurological Findings in Children without Congenital Microcephaly Exposed to Zika Virus in Utero: A Case Series Study.

The Zika virus can induce a disruptive sequence in the fetal brain and is manifested mainly by microcephaly. Knowledge gaps still exist as to whether the virus can cause minor disorders that are perceived later on during the first years of life in children who are exposed but are asymptomatic at birth. In this case series, we describe the outcomes related to neurodevelopment through the neurological assessment of 26 non-microcephalic children who had intrauterine exposure to Zika virus. Children were submitted for neurological examinations and Bayley Scales-III (cognition, language, and motor performance). The majority (65.4%) obtained satisfactory performance in neurodevelopment. The most impaired domain was language, with 30.7% impairment. Severe neurological disorders occurred in five children (19.2%) and these were spastic hemiparesis, epilepsy associated with congenital macrocephaly (Zika and human immunodeficiency virus), two cases of autism (one exposed to Zika and Toxoplasma gondii) and progressive sensorineural hearing loss (GJB2 mutation). We concluded that non-microcephalic children with intrauterine exposure to Zika virus, in their majority, had achieved satisfactory performance in all neurodevelopmental domains. One third of the cases had some impairment, but the predominant group had mild alterations, with low occurrence of moderate to severe disorders, similar to other studies in Brazil.

Early Life Parechovirus Infection Neurodevelopmental Outcomes at 3 Years: A Cohort Study.

OBJECTIVE: To investigate the long-term developmental and behavioral outcomes in an established cohort of children hospitalized as infants with human parechovirus (HPeV) infection and sepsis-like illness. STUDY DESIGN: The HPeV cohort was composed of children 3 years of age after HPeV infection and hospitalization in early infancy that occurred during a well-documented HPeV genotype 3 outbreak in Australia. We assessed neurodevelopmental and behavioral outcomes using the Bayley Scales of Infant and Toddler Development-III and the Child Behavior Checklist. We compared their outcomes with a subsample of healthy control infants drawn from the independently sampled Triple B Pregnancy Cohort Study. RESULTS: Fifty children, with a mean age of 41 months, were followed for 3 years after hospital admission with HPeV infection. There were 47 children whose original illness was fever without source or sepsis-like illness and 3 who had encephalitis. All children in the HPeV cohort showed age-specific development within the population normal range on the Bayley Scales of Infant and Toddler Development-III. There was no difference in developmental attainment compared with 107 healthy control infants after adjusting for measured confounders. The HPeV cohort showed higher average scores on the Child Behavior Checklist and a higher frequency of clinical range scores compared with healthy controls. CONCLUSIONS: Although HPeV sepsis-like illness did not result in neurodevelopmental delay at 3 years of age, it was associated with increased behavioral problems compared with healthy controls. The behavioral problems reached a clinical threshold in a minority of children. Results inform clinical management and planning for children after severe HPeV infection in infancy.

Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018.

INTRODUCTION: Zika virus infection during pregnancy causes serious birth defects and might be associated with neurodevelopmental abnormalities in children. Early identification of and intervention for neurodevelopmental problems can improve cognitive, social, and behavioral functioning. METHODS: Pregnancies with laboratory evidence of confirmed or possible Zika virus infection and infants resulting from these pregnancies are included in the U.S. Zika Pregnancy and Infant Registry (USZPIR) and followed through active surveillance methods. This report includes data on children aged ≥1 year born in U.S. territories and freely associated states. Receipt of reported follow-up care was assessed, and data were reviewed to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection. RESULTS: Among 1,450 children of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and with reported follow-up care, 76% had developmental screening or evaluation, 60% had postnatal neuroimaging, 48% had automated auditory brainstem response-based hearing screen or evaluation, and 36% had an ophthalmologic evaluation. Among evaluated children, 6% had at least one Zika-associated birth defect identified, 9% had at least one neurodevelopmental abnormality possibly associated with congenital Zika virus infection identified, and 1% had both. CONCLUSION: One in seven evaluated children had a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both reported to the USZPIR. Given that most children did not have evidence of all recommended evaluations, additional anomalies might not have been identified. Careful monitoring and evaluation of children born to mothers with evidence of Zika virus infection during pregnancy is essential for ensuring early detection of possible disabilities and early referral to intervention services.

Neurodevelopment of 24 children born in Brazil with congenital Zika syndrome in 2015: a case series study.

OBJECTIVE: To describe the neurodevelopment of children with congenital Zika syndrome during the second year of life. DESIGN: Case series study. SETTING: Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Pernambuco, Brazil. PARTICIPANTS: 24 children with congenital Zika syndrome born with microcephaly during the Zika outbreak in Brazil in 2015 and followed up at the IMIP during their second year of life. MAIN OUTCOME MEASURE: Denver Developmental Screening Test II, head circumference and clinical neurological examination. RESULTS: All children presented neurodevelopmental delay: for an average chronological age of 19.9 months, language was equivalent to that of age 2.1 months, gross motor 2.7 months, fine motor/adaptive 3.1 months and personal/social 3.4 months. Head circumference remained below the third percentile for age and gender, and growth rate up to the second year of life was 10.3 cm (expected growth 13 cm). Muscle tone was increased in 23 (95.5%) of 24 children, musculotendinous reflexes were increased in the whole sample and clonus was present in 18 (77.3%) of 24 children. All children except one had epilepsy. CONCLUSION: Children born with microcephaly associated with congenital Zika virus have a significant neurodevelopmental delay.