Cumulative Febrile, Respiratory, and Diarrheal Illness among Infants in Rural Guatemala and their Association with Neurodevelopmental and Growth Outcomes

Objective We aimed to evaluate the association between cumulative illness with neurodevelopment and growth outcomes in a birth cohort of Guatemalan infants. Study Design 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 completed 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, six months, and one year. Results Out 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 of the mean). In multivariable analysis, greater cumulative weeks 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 weeks of diarrheal/vomiting illness alone (p=0.66). No association was shown between cumulative weeks 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 the inflammatory profile associated with these syndromic illnesses and their impact on neurodevelopment in the first years of life. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project has been funded in whole or in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services. Research was supported by a NIAID Division of Microbiology and Infectious Diseases (DMID) Vaccine and Treatment Evaluation Unit (VTEU) award to Baylor College of Medicine (Contract No. HHSN27220130015I funding the DMID 16-0057 study, PIs: Munoz, Asturias) and EMMES (Contract No. 75N93021C00012). Daniel Olson is supported by K23AI143967 and CTSI Grant Number UL1 TR001082. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was reviewed and approved by the Institutional Review Board at Baylor College of Medicine, the Colorado Multiple Institutional Review, the National Ethics Committee of the Guatemalan Ministry of Public Health and the local Community Advisory Board in Trifinio, Guatemala. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * ELC : Early Learning Composite LAZ : Length-for-age MSEL : Mullen Scales of Early Learning OFC : Occipital-frontal circumference RR : Relative risk SD : Standard deviations SE : Standard error