Challenges and lessons learned from the rapid operationalization of a prospective cohort to study the natural history and neurodevelopmental outcomes of postnatal Zika virus infection among infants and children in rural Guatemala

Paniagua-Ávila, Alejandra; Olson, Daniel; Connery, Amy K.; Calvimontes, Diva M; Bolaños, Guillermo Antonio; Lamb, Molly M.; Bauer, Desiree; Ralda, Aida; Rojop, Neudy; Barrios, Eduardo; Chacon, Andrea; Gomez, Melissa; Arroyave, Paola; Hernández, Sara B.; Martínez, María Alejandra; Bunge-Montes, Saskia; Colbert, Alison M.; Arias, Kareen; Brazeale, Garret; Holliday, Andrea; Tomashek, Kay M.; Sahly, Hana M. El; Keitel, Wendy A.; Muñoz, Flor M.; Asturias, Edwin J.

doi:10.1371/journal.pntd.0010480

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…From June 2017 to July 2018, 499 infants and their mothers were enrolled at 0–3 months of age into the parent study, which leveraged an existing maternal-child health program to identify a convenience sample of mothers/infants in the community. Per study design, 18 there were no exclusion criteria other than living outside the study catchment area and inappropriate age, though children who were acutely unwell at the time of study screening were referred for medical evaluation and enrollment deferred. Gestational age and intrauterine growth are typically unknown in this community, though the cohort 19 and community 20 have a high prevalence of microcephaly.…”

Section: Methodsmentioning

confidence: 99%

Cumulative Febrile, Respiratory, and Gastrointestinal Illness Among Infants in Rural Guatemala and Association With Neurodevelopmental and Growth Outcomes

Olson

Lamb

Connery

et al. 2023

Pediatric Infectious Disease Journal

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Background: Infectious disease exposures in early life are increasingly recognized as a risk factor for poor subsequent growth and neurodevelopment. We aimed to evaluate the association between cumulative illness with neurodevelopment and growth outcomes in a birth cohort of Guatemalan infants. Methods: From June 2017 to July 2018, infants 0–3 months of age living in a resource-limited region of rural southwest Guatemala were enrolled and underwent weekly at-home surveillance for caregiver-reported cough, fever, and vomiting/diarrhea. They also underwent anthropometric assessments and neurodevelopmental testing with the Mullen Scales of Early Learning (MSEL) at enrollment, 6 months, and 1 year. Results: Of 499 enrolled infants, 430 (86.2%) completed all study procedures and were included in the analysis. At 12–15 months of age, 140 (32.6%) infants had stunting (length-for-age Z [LAZ] score < –2 SD) and 72 (16.7%) had microcephaly (occipital-frontal circumference [OFC] < –2 SD). In multivariable analysis, greater cumulative instances of reported cough illness (beta = –0.08/illness-week, P = 0.06) and febrile illness (beta = –0.36/illness-week, P < 0.001) were marginally or significantly associated with lower MSEL Early Learning Composite (ELC) Score at 12–15 months, respectively; there was no association with any illness (cough, fever, and/or vomiting/diarrhea; P = 0.27) or with cumulative instances of diarrheal/vomiting illness alone (P = 0.66). No association was shown between cumulative instances of illness and stunting or microcephaly at 12–15 months. Conclusions: These findings highlight the negative cumulative consequences of frequent febrile and respiratory illness on neurodevelopment during infancy. Future studies should explore pathogen-specific illnesses, host response associated with these syndromic illnesses, and their association with neurodevelopment.

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Section: Methodsmentioning

confidence: 99%

Cumulative Febrile, Respiratory, and Gastrointestinal Illness Among Infants in Rural Guatemala and Association With Neurodevelopmental and Growth Outcomes

Olson

Lamb

Connery

et al. 2023

Pediatric Infectious Disease Journal

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Postnatal Zika and Dengue Infection and their Effects on Neurodevelopment Among Children Living in Rural Guatemala

Asturias,

Connery,

Olson

et al. 2024

Pediatric Infectious Disease Journal

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Background: Prenatal Zika virus (ZIKV) infection leads to microcephaly and adverse neurodevelopment. The effects of postnatal ZIKV infection on the developing brain are unknown. We assessed the neurodevelopmental outcomes of children exposed postnatally during the ZIKV epidemic. Methods: A prospective study enrolled infants 0–3 months of age and their mothers, and children 1.5–3.5 years of age in rural Guatemala from 2017 and were followed for 12 months until 2019. Neurodevelopment was evaluated using the Mullen Scales of Early Learning (MSEL). ZIKV and dengue virus (DENV) infections were identified by polymerase chain reaction (PCR) using active surveillance. Serological analyses, stratified by age group flavivirus serostatus at enrollment, were conducted using a focus reduction neutralization test. Results: Of 1371 enrolled participants, 1187 (86.6%) completed the study. No PCR-confirmed ZIKV infections were identified during the study period. One-third of 1.5–3.5-year-old children were ZIKV-seropositive at enrollment (likely postnatal infection). Twenty participants (5.8%) tested positive for DENV by PCR (11 infants, 5 children and 4 mothers); 15 (75%) were DENV-3 infections and 5 were DENV-2. The incidence of DENV infection in infants was 2.6%. No significant differences in MSEL scores were found between infants born seropositive versus seronegative for ZIKV or DENV. DENV seropositivity at enrollment in 1.5–5-year-old children was associated with lower MSEL scores for fine motor, visual reception and language, and microcephaly at 12 months versus seronegative children (all P < 0.05). Conclusions: Postnatal ZIKV infection in children from rural Guatemala was not associated with worse neurodevelopmental outcomes. DENV seropositivity was associated with a higher risk of microcephaly in infants and worse neurodevelopmental outcomes in children.

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Association between biomarkers of environmental enteric dysfunction and growth and neurodevelopment in Guatemalan infants

Connery,

Calvimontes,

Bucardo

et al. 2024

Preprint

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BACKGROUND. There is growing evidence that environmental enteric dysfunction (EED) is a driver of poor growth and neurodevelopment (ND) in early childhood. To further investigate this, we measured the associations between biomarkers reflecting various domains of EED and growth and ND in Guatemalan infants. METHODS. A subset of 114 cohort infants were randomly selected for inclusion from a 2017-2019 population-based cohort study of 499 young infants in rural southwest Guatemala. Growth and neurodevelopmental performance using the Mullen Scales of Early Learning (MSEL) were assessed at a household visit around 12 months of age. Serum samples collected at the visit were analyzed for concentrations of α-1 acid glycoprotein (AGP), glucagon-like peptide-2 (GLP-2), and anti-flagellin IgA (Anti-FliC IgA), Multivariable regression analyses adjusted for relevant confounders were conducted to define associations between these EED biomarkers and length-for-age z-score (LAZ) and neurodevelopmental performance. We planned a priori to conduct analyses with and without excluding infants who had acute infectious disease symptoms (fever, cough, vomiting, diarrhea) at the 12-month visit. RESULTS. No significant association between biomarkers representing different domains of EED and LAZ or MSEL scores at 12-14 months of age was found. However, removing children with acute infectious symptoms uncovered an association between Anti-FliC IgA and MSEL. Specifically, an increase in 10ng/L in Anti-FliC IgA concentration was associated in a decrease in the MSEL Early Learning Composite (ELC) raw score of 3.2 points, which equates to approximately a 9-point decrease in the ELC standard score. CONCLUSIONS. In this study, having increased levels of Anti-FliC IgA was associated with lower ND in the first year of life and may represent an important risk to long-term health and development.

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Challenges and lessons learned from the rapid operationalization of a prospective cohort to study the natural history and neurodevelopmental outcomes of postnatal Zika virus infection among infants and children in rural Guatemala

Cited by 4 publications

References 23 publications

Cumulative Febrile, Respiratory, and Gastrointestinal Illness Among Infants in Rural Guatemala and Association With Neurodevelopmental and Growth Outcomes

Cumulative Febrile, Respiratory, and Gastrointestinal Illness Among Infants in Rural Guatemala and Association With Neurodevelopmental and Growth Outcomes

Postnatal Zika and Dengue Infection and their Effects on Neurodevelopment Among Children Living in Rural Guatemala

Association between biomarkers of environmental enteric dysfunction and growth and neurodevelopment in Guatemalan infants

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