Are the first 1,000 days of life a neglected vital period to prevent the impact on maternal and infant morbimortality of infectious diseases in Latin America? Proceedings of a workshop of experts from the Latin American Pediatric Infectious Diseases Society, SLIPE.

While the first 1,000 days of life are a critical period in child's development, limited information on the main determinants affecting this period in the Latin America and the Caribbean (LAC) region is available. Therefore, the Latin American Pediatric Infectious Diseases Society (SLIPE) held an ad hoc workshop in May 2022 with an expert panel designed to analyze the main factors impacting the development of childhood in the region during this period and the main causes of maternal infant morbimortality. The aim was to identify priorities, generate recommendations, and advise practical actions to improve this situation. Considerations were made about the challenges involved in bridging the gap that separates the region from more developed countries regarding an optimal early childhood and maternal care. Extensive discussion was conducted to reach consensus recommendations on general strategies intended to reduce maternal and infant mortality associated with infections and immune-preventable diseases during the first 1,000 days of life in LAC.

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

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.

Safety, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for systematic review and meta analysis.

INTRODUCTION: Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding the safety of these vaccines for the pregnant person and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, reactogenicity, immunogenicity, and efficacy of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review and meta-analysis of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide the information necessary to help guide vaccine policy decisions. METHODS AND ANALYSIS: We aim to conduct a living systematic review and meta-analysis based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety, efficacy, and effectiveness of COVID-19 vaccines in pregnant persons, including neonatal outcomes. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including prespecified subgroup and sensitivity analyses. We will use the grading of recommendations assessment, development, and evaluation approach to evaluate the certainty of evidence.

Incorporating COVID-19 into Acute Febrile Illness Surveillance Systems, Belize, Kenya, Ethiopia, Peru, and Liberia, 2020-2021.

Existing acute febrile illness (AFI) surveillance systems can be leveraged to identify and characterize emerging pathogens, such as SARS-CoV-2, which causes COVID-19. The US Centers for Disease Control and Prevention collaborated with ministries of health and implementing partners in Belize, Ethiopia, Kenya, Liberia, and Peru to adapt AFI surveillance systems to generate COVID-19 response information. Staff at sentinel sites collected epidemiologic data from persons meeting AFI criteria and specimens for SARS-CoV-2 testing. A total of 5,501 patients with AFI were enrolled during March 2020-October 2021; >69% underwent SARS-CoV-2 testing. Percentage positivity for SARS-CoV-2 ranged from 4% (87/2,151, Kenya) to 19% (22/115, Ethiopia). We show SARS-CoV-2 testing was successfully integrated into AFI surveillance in 5 low- to middle-income countries to detect COVID-19 within AFI care-seeking populations. AFI surveillance systems can be used to build capacity to detect and respond to both emerging and endemic infectious disease threats.

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.

During the course of the 2015-2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5-3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings.

A prospective cohort study of head circumference and its association with neurodevelopmental outcomes in infants and young children in rural Guatemala.

Microcephaly, an anthropometric marker of reduced brain volume and predictor of developmental disability, is rare in high-income countries. Recent reports show the prevalence of microcephaly to be much higher in lower resource settings. We calculated the prevalence of microcephaly in infants and young children (n = 642; age range = 0.1-35.9 months), examined trends in occipitofrontal circumference (OFC) growth in the year after birth and evaluated the relationship between OFC and performance on the Mullen Scales of Early Learning (MSEL) in rural Guatemala. Multivariable regression analyses adjusted for age were performed: (1) a model comparing concurrent MSEL performance and OFC at all visits per child, (2) concurrent OFC and MSEL performance by age group, and (3) OFC at enrollment and MSEL at final visit by age group. Prevalence of microcephaly ranged from 10.1% to 25.0%. OFC z-score decreased for most infants throughout the first year after birth. A significant positive association between continuous OFC measurement and MSEL score suggested that children with smaller OFC may do worse on ND tests conducted both concurrently and ∼1 year later. Results were variable when analyzed by OFC cutoff scores and stratified by 6-month age groups. OFC should be considered for inclusion in developmental screening assessments at the individual and population level, especially when performance-based testing is not feasible.

Epidemiological and Clinical Characteristics of Acute Dengue Virus Infections Detected through Acute Febrile Illness Surveillance, Belize 2020.

The Acute Febrile Illness (AFI) Surveillance Network in Belize is a country-wide active surveillance program aimed at diagnosing vector-borne, respiratory, and enteric pathogens among patients presenting to 11 participating hospitals and clinics with new onset fever. This study describes the epidemiology of dengue virus (DENV) infections in Belize diagnosed through AFI surveillance in 2020. Of the 894 patients enrolled and PCR-tested for DENV in this period, 44 DENV-positive cases (5%) were identified. All four DENV serotypes were detected, with two cases testing positive for DENV serotype 4, which is the first report of this serotype in Belize since 2004. The majority of DENV cases (66%) were diagnosed in the Belize District, which contains the largest urban center in the country (Belize City). Positive cases were detected between January 2020 and September 2020, with the majority (89%) diagnosed during the dry season between January and April, unlike years prior when cases were more often diagnosed during the wet season. Clinical signs and symptoms varied slightly between DENV serotypes. Active surveillance of DENV among AFI cases provides insight into the epidemiologic and clinical characteristics of DENV in Belize. This information is important for informing public health interventions to mitigate DENV transmission.

Caregiver rating of early childhood development: Reliability and validity of the ASQ-3 in rural Guatemala.

BACKGROUND: Although performance-based assessment of early childhood development is preferred, there are a number of limitations to this methodology in low resource settings (LRSs). Hence, clinicians and researchers often rely on caregiver report screening tools. The Ages and Stages Questionnaire 3 (ASQ) is one of the most widely used caregiver report measures globally. Adequate psychometric properties have been demonstrated in high income settings, especially when used in older children, high- risk children, or those with severe neurodevelopmental delays. However, its utility is more variable within very young children and for use in LRSs. METHODS: The reliability and validity of the ASQ was determined for children ages 0-5 years living in rural Guatemala. Internal consistency and test-retest reliability were assessed, as well as concurrent and predictive validity. Sensitivity, specificity, positive and negative predictive values related to performance-based developmental assessment (Mullen Scales of Early Learning; MSEL) and growth status (i.e. stunting) were also calculated. RESULTS: Internal consistency reliability for the ASQ was adequate, except when results were limited by small sample size. Test-retest reliability ranged from low to moderate (r = 0.08-0.43; p < 0.05-0.01). However, there was significant variability in mean scores over time across ASQ domain scores. In terms of validity, the ASQ did not discriminate adequately between children who performed within or below age-expectations on performance-based developmental testing or those with and without stunting. CONCLUSIONS: The ASQ did not demonstrate adequate psychometric properties in rural Guatemala, consistent with concerns documented in other LRSs. These results indicate that existing caregiver report screening measures of early childhood development should be utilized with caution in LRSs, and alternative methods for assessment or in the development and utilization of caregiver report measures should be considered.

Parent Report of Health Related Quality of Life in Young Children in Rural Guatemala: Implementation, Reliability, and Validity of the PedsQL in Stunting and Wasting.

In this study, we review the implementation, reliability, and validity of the Pediatric Quality of Life Inventory (PedsQL), a measure of health-related quality of life, in young children in rural Guatemala. Mothers of 842 children (age range = 1-60 months) completed the PedsQL Generic Core Scales 4.0 serially for 1 year. Low (Pearson's r = 0.28, P < .0001) to moderate (Pearson's r = 0.65, P < .0001) consistency in responding over time was shown. The PedsQL did not discriminate reliably between healthy children and those with stunting or wasting. PedsQL scores were not lower during the time of an acute illness. While we found low to moderate evidence for the reliability of the PedsQL in healthy children, it did not discriminate between healthy children and those with stunting, wasting or other acute illness.

Using maternal and neonatal data collection systems for coronavirus disease 2019 (COVID-19) vaccines active safety surveillance in low- and middle-income countries: an international modified Delphi study.

Background: Given that pregnant women are now included among those for receipt coronavirus disease 2019 (COVID-19) vaccines, it is important to ensure that information systems can be used (or available) for active safety surveillance, especially in low- and middle-income countries (LMICs). The aim of this study was to build consensus about the use of existing maternal and neonatal data collection systems in LMICs for COVID-19 vaccines active safety surveillance, a basic set of variables, and the suitability and feasibility of including pregnant women and LMIC research networks in COVID-19 vaccines pre-licensure activities. Methods: A three-stage modified Delphi study was conducted over three months in 2020. An international multidisciplinary panel of 16 experts participated. Ratings distributions and consensus were assessed, and ratings' rationale was analyzed. Results: The panel recommended using maternal and neonatal data collection systems for active safety surveillance in LMICs (median 9; disagreement index [DI] -0.92), but there was no consensus (median 6; DI 1.79) on the feasibility of adapting these systems. A basic set of 14 maternal, neonatal, and vaccination-related variables. Out of 16 experts, 11 supported a basic set of 14 maternal, neonatal, and vaccination-related variables for active safety surveillance. Seven experts agreed on a broader set of 26 variables. The inclusion of pregnant women for COVID-19 vaccines research (median 8; DI -0.61) was found appropriate, although there was uncertainty on its feasibility in terms of decision-makers' acceptability (median 7; DI 10.00) and regulatory requirements (median 6; DI 0.51). There was no consensus (median 6; DI 2.35) on the feasibility of including research networks in LMICs for conducting clinical trials amongst pregnant women. Conclusions: Although there was some uncertainty regarding feasibility, experts recommended using maternal and neonatal data collection systems and agreed on a common set of variables for COVID-19 vaccines active safety surveillance in LMICs.

Dengue Virus and Yellow Fever Virus Detection Using Reverse Transcription-Insulated Isothermal PCR and Comparison with Real-Time RT-PCR.

Real-time reverse transcriptase PCR (rRT-PCR) is the most accurate method for the detection of dengue virus (DENV) and yellow fever virus (YFV) in acute illness. However, performing rRT-PCR is not feasible for many laboratories in regions of endemicity. The current study compared new reverse transcription-insulated isothermal PCRs (the POCKIT DENV and YFV reagent sets) with laboratory-developed rRT-PCRs for both viruses using clinical samples and viral strains from different endemic regions. Sensitivity and specificity of the POCKIT DENV Reagent Set were 87.2% (68/78 samples) and 98.2% of samples (54/55), respectively. The YFV reagent set demonstrated sensitive detection of YFV RNA from six viral strains down to an estimated concentration of 2.5 log10 copies/mL and proved to be specific for YFV. Although the POCKIT assays require RNA extraction, they may provide accurate and less-complex options for molecular testing in laboratory settings where rRT-PCR is not practical.

Reliability and Validity of an Adapted and Translated Version of the Mullen Scales of Early Learning (AT-MSEL) in Rural Guatemala.

BACKGROUND: A growing literature base supports the use of tests developed in high-income countries to assess children in low resource settings when carefully translated, adapted, and applied. Evaluation of psychometric properties of adapted and translated measures within populations is necessary. The current project sought to evaluate the reliability and validity of an adapted and translated version of the Mullen Scales of Early Learning (AT-MSEL) in rural Guatelama. METHODS: The reliability and validity of the AT-MSEL in rural Guatemala were analyzed for children ages 0-5 years. RESULTS: Interrater reliability coefficients (ICC = 0.99-1.0) and internal consistency (Cronbach's alpha = 0.91-0.93) were excellent for all subscales. General linear models utilizing paired data showed consistency between standard scores (p < 0.0001). Mean raw scores increased with chronological age, as expected. Across age groups, subscales were significantly, positively correlated with one another (p < 0.05 - < 0.001) with one exception, visual reception and expressive language at the 0-10 month age range (p = 0.43). CONCLUSIONS: The AT- MSEL showed strong psychometric properties in a sample of young children in rural Guatemala. Findings demonstrate that the AT-MSEL can be used validly and reliably within this specific population of children. This work supports the concept that tests developed in high-income countries can be used to assess children in low resource settings when carefully translated, adapted and applied.

Receptive language skills among young children in rural Guatemala: The relationship between the Test de Vocabulario en Imagenes Peabody and a translated and adapted version of the Mullen Scales of Early Learning.

BACKGROUND: Children in low- and lower middle income countries (LMICs) often have poorer language skills compared with children from high-income countries. Limited availability of culturally and linguistically appropriate assessment measures in LMICs, especially for young children, can hinder early identification and prevention efforts. Here, we describe receptive language (RL) skills among young children in rural Guatemala and report on the validity of a translated and culturally adapted developmental measure of RL. METHODS: Children (n = 157; m = 53.6 months, range = 42-68 months) enrolled in a prospective cohort study of postnatally acquired Zika virus infection were administered the Test de Vocabulario en Imagenes Peabody (TVIP) and the RL scale from a translated and adapted version of the Mullen Scales of Early Learning (MSEL). Performance on the TVIP was compared with the Latin American normative sample. Correlational analysis examined the relationship between performance on the TVIP and the MSEL-RL. RESULTS: Mean scores were significantly below the normative sample mean on the TVIP, t(126) = -11.04, p < .001; d = 1.00. Performance on the TVIP among children who passed the practice items (n = 127) was significantly positively associated with performance on the MSEL-RL (r = .50, p < .001), but not significantly associated with age or gender. Older age (p < .0001) and female gender (p = .018) were associated with passing the TVIP practice items. CONCLUSIONS: Delays in RL vocabulary were identified among young children in rural Guatemala on the TVIP. The association between scores on the TVIP and the RL scale of the MSEL provides preliminary support for the construct validity of this translated and adapted version of the MSEL.

Clinical characteristics and outcomes of neonatal pertussis: a comparative study.

We describe the features and outcomes of neonatal pertussis and compare these with neonates with non-pertussis acute respiratory illness from July 2000 through December 2007. Patients with pertussis had a more severe course of disease as evidenced by the clinical presentation, length of hospitalization, and oxygen requirement. Clinicians should have a high index of suspicion so that appropriate supportive care can be initiated promptly.