Growth Faltering Research Articles

Effect of high calorie formula on head circumference and body length on young children with stunted due to feeding problems

Background: Feeding is a complex process which requires the coordination of several organ systems. However, special conditions lead to feeding problems which increase risk of nutrition problems and growth retardation, resulting in undernutrition. Objectives: This study was performed to investigate young children's length and head circumference. More specifically, this study investigated children stunted due to feeding problems in their first two years and with over three months of nutritional and medicative intervention. Methods: A cross-sectional study was conducted from January 2019-December 2020 on healthy young children. These children were aged 6 to 24 months and brought in by their parents for nutritional consultations due to constant body weight or feeding problems. Subject numbers were determined using total sampling during the study period. The feeding problem diagnosis and physical examination were done by a pediatrician specialized in nutrition and metabolic syndromes. Results: There were 139 infants and young children recruited, of which 65 were boys and 74 were girls. Their mean age was 15.11, give or take 0.53 months. There were 32 subjects selected based on their experience with at least three months of nutritional intervention and medication. Microcephaly was detected in three subjects (23.08%). Nutritional intervention increased the head circumference-for-age z-score (HCAZ) from -0.77 + 1.19 to -0.27 + 1.05 (p = 0.012). After 90 days of intervention, there was no microcephaly detected despite no significant difference. Nutritional intervention also increased the height-for-age z-score. Conclusion: Feeding problems contributes to constant body weight gain and feeding problems. Nutritional intervention can be done by giving children high calorie formula to prevent growth faltering and restore growth during the first two years of life. Nutritional intervention improved the growth parameters, including head circumference z-scores.

Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy

Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia-mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors.

The long view of vaccination to secure the future

The long view of vaccination to secure the future

Projecting the long-term economic benefits of reducing Shigella-attributable linear growth faltering with a potential vaccine: a modelling study

Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to linear growth faltering (LGF). However, benefits from potential reductions in LGF are rarely included in economic analyses of enteric infections. We aimed to quantify the economic benefits of vaccination related to reduced Shigella-attributable disease and associated LGF compared with the net costs of a vaccine programme. In this benefit-cost analysis, we modelled productivity benefits in 102 low-income and middle-income countries that had recent stunting estimates available, at least one Shigella-attributable death annually, and available economic data, particularly on gross national income and growth rate projections. We modelled benefits strictly related to linear growth improvements and no other benefits associated with reducing diarrhoeal burden. The effect size in each country was calculated as shifts in height-for-age Z score (HAZ), representing population average changes for preventing Shigella-attributable less-severe diarrhoea and moderate-to-severe diarrhoea separately for children younger than 5 years. Benefits data were calculated per country and combined with estimated net costs of the vaccine programme in the form of benefit-cost ratios (BCRs); BCRs above parity, or $1 in benefits per $1 in costs (with a 10% margin representing borderline results: 1·10:1), were considered cost-beneficial. Countries were aggregated for analysis by WHO region, World Bank income category, and eligibility for support from Gavi, the Vaccine Alliance. In the base-case scenario, all regions exhibited cost-beneficial results, with the South-East Asia region and Gavi-eligible countries exhibiting the highest BCRs (21·67 for the South-East Asia region and 14·45 for Gavi-eligible countries), and the Eastern Mediterranean region yielding the lowest BCRs (2·90). All regions exhibited cost-beneficial results from vaccination, except in more conservative scenarios (eg, those assuming early retirement ages and higher discount rates). Our findings were sensitive to assumed returns for increased height, assumptions about vaccine efficacy against linear growth detriments, the anticipated shift in HAZ, and discount rate. Incorporating the productivity benefits of LGF reduction into existing cost-effectiveness estimates resulted in longer-term cost-savings in nearly all regions. LGF is a secondary outcome of Shigella infection and reduction in LGF is not often quantified as a health or economic benefit of vaccination. However, even under conservative assumptions, a Shigella vaccine only moderately effective against LGF could pay for itself from productivity gains alone in some regions. We recommend that LGF be considered in future models assessing the economic and health impacts of interventions preventing enteric infections. Further research is needed on vaccine efficacy against LGF to inform such models. Bill & Melinda Gates Foundation, Wellcome Trust.

Potential impact and cost-effectiveness of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 years or younger: a modelling study

Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea. We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes. We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions. Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis. Bill & Melinda Gates Foundation and Wellcome Trust.

Modulating the early-life gut microbiota using pro-, pre-, and synbiotics to improve gut health, child development, and growth.

In children exposed to poor hygiene and sanitation, invasion of the gut by pathogenic microbes can result in a subclinical enteropathy termed "environmental enteric dysfunction" (EED) that contributes to undernutrition, growth faltering, and impaired organ development. EED may already be present by age 6-12 weeks; therefore, interventions that can be started early in life, and used alongside breastfeeding, are needed to prevent or ameliorate EED. A healthy gut microbiota is critical for intestinal development and repair, nutrient digestion and absorption, and resisting colonization or overgrowth by pathogens. However, its development can be impaired by several environmental factors. Dietary supplementation with pro-, pre-, or synbiotics may be a pragmatic and safe means of building the resilience of the developing gut microbiota against adverse environmental factors, thereby preventing EED.

The Systemic Availability of Indispensable Amino Acids from Orally Ingested Algal and Legume Protein in Young Children at Risk of Environmental Enteric Dysfunction

BackgroundThe digestion and absorption of ingested protein may be reduced in children with environmental enteric dysfunction (EED), reducing systemic amino acid availability for protein synthesis with resultant growth faltering. This has not been directly measured in children with EED and associated growth faltering. ObjectivesTo evaluate the systemic availability of algal (spirulina) and legume (mung bean) indispensable amino acids (IAAs) in children with EED. MethodsIndian children (18–24 mo) from urban slums were assigned to EED (n = 24) or no-EED (control, n = 17) groups based on the lactulose rhamnose test, where the lactulose rhamnose ratio cutoff for diagnosing EED (≥0.068) was the mean + 2SD of its distribution in healthy, age-, and sex-matched children of high socioeconomic status. Fecal biomarkers of EED were also measured. Systemic IAA availability was calculated from the plasma: meal IAA enrichment ratio for each protein. True ileal mung bean IAA digestibility was measured by the dual isotope tracer method using spirulina protein as reference. Co-administration of free 13C6-phenylalanine allowed for estimating true ileal phenylalanine digestibility of both proteins, and a phenylalanine absorption index. ResultsThere was no significant difference (independent t-test) in the systemic IAA availability from spirulina or mung bean protein between EED and no-EED groups. There was no between-group difference in true ileal phenylalanine digestibility and its absorption index, or in mung bean IAA digestibility. ConclusionsThe systemic IAA availability of algal and legume protein, or the latter’s IAA/phenylalanine digestibility, is not significantly reduced in children with EED and does not correlate with linear growth.This study was registered in Clinical Trials Registry of India (CTRI) with registration number: CTRI/2017/02/007921.

Leaky gut mechanisms in giardiasis

Abstract Giardia duodenalis is a common intestinal pathogen transmitted via consumption of contaminated water. In addition to causing intestinal distress symptoms, Giardia infection is one of the top 5 infectious causes of growth stunting in children under two. Growth faltering is a complex pathology facilitated by changes in the intestinal barrier and enzymatic deficiencies. While infection is widely associated with barrier damage in vitro, in animal models, and in patient studies, the mechanisms behind this process are not well understood. Since PAR2 has a prominent role in increased intestinal permeability in Celiac disease, we are focusing on the involvement of the protease activated receptor 2 (PAR2) in giardiasis-facilitated intestinal defects. We are using human intestinal cell lines, murine intestinal organoids, and a mouse infection model to address the role of PAR2. Co-culture of Giardia and Caco2 cells results in altered tight junction morphology as revealed by staining for ZO-1; these changes are reduced by treatment with a PAR2 antagonist. Effects of PAR2 signaling on barrier function are being assessed by measuring transepithelial electrical resistance (TEER) in Caco2 cells and PAR2+/− and PAR2−/− organoids cultured on transwell filters. Additionally, while C57BL/6 mice fed a low-protein diet exhibit reduced weight gain when infected with Giardia, mice lacking PAR2 gain weight normally when infected. These data indicate that PAR2 signaling contributes to intestinal permeability defects and growth faltering. Identifying parasite factors that activate PAR2 will provide novel targets for development of pharmaceuticals and vaccines to improve child growth. AI166467

Порівняльна характеристика різних способів збагачення грудного молока для дітей, які народилися передчасно. Що найкраще? (систематичний огляд)

Human milk is the preferred feeding for all infants, including those of very low birth weight and vulnerable groups. However, mother’s milk is generally likely has insufficient protein to promote appropriate growth. That's why fortification of human milk is required to meet nutrient requirements for growth and development for these preterm infants who are at high risk for growth faltering during the hospital stay. There are multiple strategies and products that may be employed to support desired growth rates. Purpose - Conduct comparative analysis the current literature on the fortification own mothers’ milk and influence of this fortification on the outcomes for preterm and sick infant’s health. Materials and methods. Search Strategy: A systematic search of the literature was conducted using search strategy was based on MeSH terms/subject headings and separate keywords. The study designs included were randomized or quasi-randomized controlled trials in the English, Ukrainian and Russian languages. Study Selection: Published literature was searched from January 2010 up to July, 1, 2022 using five databases (PubMed, Ovid Medline, Web of Science, Ovid Embase, and the Cochrane Library). The search resulted in 75 articles, and an additional article was identified by an expert in the field; 20 were used for review. Data Extraction: Data from the full-text articles was extracted into a Table. The manuscripts were organised in the table as follows: first Cochrane reviews and systematic reviews, followed by individual research studies that were not cited in any of the systematic reviews. Results and conclusions. The primary outcomes of this review were influence of different types fortification of mother's milk and time of starting fortification in short term growth parameters (length, head growth, and weight gain), feeding intolerance (defined as clinical signs only and/or cessation of feeding), length of hospital stay (number of days that the baby remained in the neonatal unit), and post menstrual age (i.e., gestational age plus chronological age) at discharge. Secondary outcomes were narcotising enterocolitis and sepsis. The study results suggested that early human milk fortification appears to positively affect growth for infants whose human milk feedings are fortified with a fortifier without adverse effects. Implications for Practice: Adequate nutrition in the early weeks of life is rarely achieved in premature infants, resulting in extrauterine growth restriction. The use of fortified human milk produces adequate growth in premature infants and satisfies the specific nutritional requirements of these infants. The use of individualised fortification is recommended but with proper protocols. No conflict of interests was declared by the authors.

Etiologies of Poor Weight Gain and Ultimate Diagnosis in Children Admitted for Growth Faltering

Growth faltering (GF) (previously failure to thrive) is a common reason for hospital admission, but there is little data on whether diagnoses made during initial admission remain accurate in follow-up. We sought to characterize infants admitted for isolated GF and identify diagnoses at discharge and ultimate diagnoses determined over 2 years of follow-up, to determine how diagnoses changed. We also sought to identify patient factors on admission associated with ultimate diagnosis. We conducted a retrospective study of children aged 2 weeks to 2 years with index admissions for GF from 2013 to 2017. We reviewed clinical data and documentation to determine discharge and ultimate diagnosis, and identify factors associated with ultimate diagnosis. Of 497 patients, 292 (59%) had insufficient intake, 103 (20%) had organic disease including 36 genetic disorders, 52 (11%) had mechanical feeding difficulties, and 50 (10%) had mixed or unknown diagnoses 2 years after admission. Over 90% of cases of insufficient intake were diagnosed during admission. Sixty-five percent of organic diseases, and only 39% of genetic disorders, were diagnosed during admission. Patient factors associated with genetic disorders included previous NICU stay, low birth weight, dysphagia, hypotonia, and dysmorphisms. Insufficient intake remains the most common diagnosis, and this diagnosis was accurately made during admission. Organic disease, especially genetic disease, was often not diagnosed during admission. Better tools are needed to identify patients with organic disease. We identified patient factors on admission associated with ultimate diagnosis, which could be used to prioritize evaluation and expedite follow-up.

Clinical and Epidemiologic Features of Cryptosporidium-Associated Diarrheal Disease Among Young Children Living in Sub-Saharan Africa: The Vaccine Impact on Diarrhea in Africa (VIDA) Study

As part of the Vaccine Impact on Diarrhea in Africa (VIDA) Study, we examined the prevalence, clinical presentation, and seasonality of Cryptosporidium in children to understand its relative burden after the introduction of rotavirus vaccine. VIDA was a 3-year, age-stratified, matched case-control study of medically attended acute moderate-to-severe diarrhea (MSD) in children aged 0-59 months residing in censused populations at sites in Kenya, Mali, and The Gambia. Clinical and epidemiologic data were collected at enrollment, and a stool sample was tested for enteropathogens by quantitative PCR. An algorithm was created based on the organism's cycle threshold (Ct) and association with MSD to identify the subset of Cryptosporidium PCR-positive (Ct <35) cases most likely to be attributed to MSD. Clinical outcomes were assessed at 2-3 months after enrollment. One thousand one hundred six (22.9%) cases of MSD and 873 controls (18.1%) were PCR positive for Cryptosporidium; 465 cases (42.0%) were considered attributable to Cryptosporidium, mostly among children 6-23 months. Cryptosporidium infections peaked in The Gambia and Mali during the rainy season, while in Kenya they did not have clear seasonality. Compared with cases with watery MSD who had a negative PCR for Cryptosporidium, cases with watery MSD attributed to Cryptosporidium were less frequently dehydrated but appeared more severely ill using a modified Vesikari scale (38.1% vs 27.0%; P < 0.001), likely due to higher rates of hospitalization and intravenous fluid administration, higher prevalence of being wasted or very thin very thin (23.4% vs 14.7%; P < 0.001), and having severe acute malnutrition (midupper arm circumference <115 mm, 7.7% vs 2.5%; P < 0.001). On follow-up, Cryptosporidium-attributed cases had more prolonged and persistent episodes (43.2% vs 32.7%; P <0 .001) and linear growth faltering (change in height-for-age z score between enrollment and follow-up: -0.29 vs -0.17; P < 0.001). The burden of Cryptosporidium remains high among young children in sub-Saharan Africa. Its propensity to cause illness and further impact children longer term by compromising nutritional status early in life calls for special attention to enable appropriate management of clinical and nutritional consequences.

Complementary and alternative metrics for tracking population-level trends in child linear growth

Stunting prevalence is commonly used to track population-level child nutritional status. However, other metrics derived from anthropometric datasets may be used as alternatives to stunting or provide complementary perspectives on the status of linear growth faltering in low- and middle-income countries (LMICs). Data from 156 Demographic and Health Surveys in 63 LMICs (years 2000 to 2020) were used to generate 2 types of linear growth metrics: (i) measures of location of height distributions (including stunting) for under-5 years (<5y) and 2 to 5 years (2-5y); (ii) model-derived metrics including predicted mean height-for-age z-score (HAZ) at 0, 2, and 5 years; interval slopes of HAZ, height-for-age difference (HAD), and growth delay (GD) from 1 month to 2 years (1mo-2y) and 2-5y; and the SITAR intensity parameter (SITAR-IP) for <5y. Using Spearman's rank correlation coefficient (r), metrics were considered alternatives to stunting if very strongly correlated with stunting (|r|≥0.95) and at least as strongly correlated as stunting with selected population indicators (under 5y mortality, gross domestic product, maternal education). Metrics were considered complementary if less strongly correlated with stunting (|r|<0.95) yet correlated with population indicators. We identified 6 of 15 candidate metrics (stunting 2-5y, mean HAZ <5y and 2-5y, p25 HAZ <5y and 2-5y, predicted HAZ at 2y) as potential alternatives to stunting and 6 as complementary metrics (SITAR-IP, predicted HAZ at 5y, HAZ slope 1m-2y, HAD slope 1m-2y, GD slopes 1m-2y and 2-5y). Three metrics (HAZ slope 2-5y, HAD slope 2-5y years and predicted HAZ at birth) had weak correlations with population indicators (|r| ≤ 0.43). In conclusion, several linear growth metrics could serve as alternatives to stunting prevalence and others may be complementary to stunting in tracking global progress in child health and nutrition. Further research is needed to explore the real-world utility of these alternative and complementary metrics.

Characteristics and health service utilization of children most at risk for prolonged temporary tube feeding.

This study aimed to describe children at risk of prolonged temporary tube feeding and evaluate associations between tube feeding duration and child and health service variables. A prospective medical hospital records audit was conducted between November 1, 2018, and November 30, 2019. Children at risk of prolonged temporary tube feeding were identified as having a tube feeding duration of >5 days. Information was collected on patient characteristics (eg, age) and service delivery provision (eg, tube exit plans). Data were collected from the pretube decision-making phase until tube removal (if applicable) or until 4 months after tube insertion. Descriptively, 211 at-risk children (median, 3.7 years; interquartile range [IQR], 0.4-7.7) differed from 283 not-at-risk children (median age, 0.9 years; IQR, 0.4-1.8) in terms of age, geographical location of residence, and tube exit planning. Medical diagnoses of neoplasms, congenital abnormalities, perinatal problems, and digestive system diseases in the at-risk group were individually associated with longer than average tube feeding duration, as were the primary reasons for tube feeding of nonorganic growth faltering and inadequate oral intake related to neoplasms. Yet, variables independently associated with greater odds of lengthier tube feeding durations were consultations with a dietitian, speech pathologist, or interdisciplinary feeding team. Children at risk of prolonged temporary tube feeding access interdisciplinary management because of their complexity. Identified descriptive differences between at-risk and not-at-risk children may be useful when selecting patients for tube exit planning and developing tube feeding management education programs for health professionals.

Assessment of aflatoxin exposure, growth faltering and the gut microbiome among children in rural Guatemala: protocol for an observational prospective cohort and bioreactor simulations

IntroductionAflatoxin B1 (AFB1) is a carcinogen produced by Aspergillus flavus and Aspergillus parasiticus which grow on maize. Given the high prevalence of child stunting (ie, impaired growth) and other nutritional...

Essential Fatty Acid Deficiency Associates with Growth Faltering and Environmental Enteric Dysfunction in Children.

Environmental enteric dysfunction (EED) is characterized by intestinal inflammation, malabsorption and growth-faltering in children with heightened exposure to gut pathogens. The aim of this study was to characterize serum non-esterified fatty acids (NEFA), in association with childhood undernutrition and EED, as potential biomarkers to predict growth outcomes. The study comprised a cohort of undernourished rural Pakistani infants (n = 365) and age-matched controls followed prospectively up to 24 months of age. Serum NEFA were quantified at ages 3-6 and 9 months and correlated with growth outcomes, serum bile acids and EED histopathological biomarkers. Serum NEFA correlated with linear growth-faltering and systemic and gut biomarkers of EED. Undernourished children exhibited essential fatty acid deficiency (EFAD), with low levels of linoleic acid and total n-6 polyunsaturated fatty acids, compensated by increased levels of oleic acid and increased elongase and desaturase activities. EFAD correlated with reduced anthropometric Z scores at 3-6 and 9 months of age. Serum NEFA also correlated with elevated BA and liver dysfunction. Essential fatty acid depletion and altered NEFA metabolism were highly prevalent and associated with acute and chronic growth-faltering in EED. The finding suggests that targeting early interventions to correct EFAD and promote FA absorption in children with EED may facilitate childhood growth in high-risk settings.

Catch-Up Growth in Infants and Young Children With Faltering Growth: Expert Opinion to Guide General Clinicians.

Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease-related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing FG. An invited international group of experts in pediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age infants and children up to the age of 2 years in low-, middle-, and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how FG should be defined in different young child populations at risk, how FG should be assessed and managed, and the role of catch-up growth after a period of FG. We also suggested areas where further research is needed to answer remaining questions on this important issue.

Metagenomic Sequencing Identified Specific Bacteriophage Signature Discriminating between Healthy and Diarrheal Neonatal Piglets

Neonatal diarrhea is one of the most severe diseases in human beings and pigs, leading to high mortality and growth faltering. Gut microbiome-related studies mostly focus on the relationship between bacteria and neonatal diarrhea onset, and no research study has investigated the role of the gut virome in neonatal diarrhea. Here, using metagenomic sequencing, we characterized the fecal viral community of diarrheal and healthy neonatal piglets. We found that the viral community of diarrheal piglets showed higher individual heterogeneity and elevated abundance of Myoviridae. By predicting the bacterial host of the identified viral genomes, phages infecting Proteobacteria, especially E. coli, were the dominant taxa in neonatal diarrheal piglets. Consistent with this, the antibiotic resistance gene of E. coli origin was also enriched in neonatal diarrheal piglets. Finally, we established a random forest model to accurately discriminate between neonatal diarrheal piglets and healthy controls and identified genus E. coli- and genus listeria-infecting bacteriophages, including psa and C5 viruses, as key biomarkers. In conclusion, we provide the first glance of viral community and function characteristics in diarrheal and healthy neonatal piglets. These findings expand our understanding of the relationship among phages, bacteria and diarrhea, and may facilitate the development of therapeutics for the prevention and treatment of neonatal diarrhea.

Effect of pregnancy versus postpartum maternal isoniazid preventive therapy on infant growth in HIV-exposed uninfected infants: a post-hoc analysis of the TB APPRISE trial

Isoniazid preventive therapy (IPT) initiation during pregnancy was associated with increased incidence of adverse pregnancy outcomes in the TB APPRISE trial. Effects of in utero IPT exposure on infant growth are unknown. This post-hoc analysis used data from the TB APPRISE trial, a multicentre, double-blind, placebo-controlled trial, which randomised women to 28-week IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT) in eight countries with high tuberculosis prevalence. Participants were enrolled between August 2014 and April 2016. Based on modified intent-to-treat analyses, we analysed only live-born babies who had at least one follow-up after birth and compared time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum in overall and sex-stratified multivariable Cox proportional hazards regression. Factors adjusted in the final models include sex of infant, mother's baseline BMI, age in years, ART regimen, viral load, CD4 count, education, and household food insecurity. Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in pregnancy-IPT had a 1.47-fold higher risk of becoming underweight by 12 weeks (aHR 1.47 [95% CI: 1.06, 2.03]) than infants in the postpartum-IPT; increased risk persisted to 48 weeks postpartum (aHR 1.34 [95% CI: 1.01, 1.78]). Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of low birth weight (LBW) (aRR 2.04 [95% CI: 1.16, 3.68), preterm birth (aRR 1.81 [95% CI: 1.04, 3.21]) and becoming underweight by 12 weeks (aHR 2.02 [95% CI: 1.29, 3.18]) and 48 weeks (aHR 1.82 [95% CI: 1.23, 2.69]). Maternal IPT timing did not influence growth in female infants. Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, particularly male infants. These data add to prior TB APPRISE data, suggesting that IPT during pregnancy impacts infant growth, which could inform management, and warrants further examination of mechanisms. The TB APPRISE study Supported by the National Institutes of Health (NIH) (award numbers, UM1AI068632 [IMPAACT LOC], UM1AI068616 [IMPAACT SDMC], and UM1AI106716 [IMPAACT LC]) through the National Institute of Allergy and Infectious Diseases, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract number, HHSN275201800001I) and the National Institute of Mental Health.

Learning from health system actor and caregiver experiences in Ghana and Nepal to strengthen growth monitoring and promotion.

Globally, growth monitoring and promotion (GMP) of infants and young children is a fundamental component of routine preventive child health care; however, programs have experienced varying degrees of quality and success with enduring challenges. The objective of this study was to describe implementation of GMP (growth monitoring, growth promotion, data use, and implementation challenges) in two countries, Ghana and Nepal, to identify key actions to strengthen GMP programs. We conducted semi-structured key informant interviews with national and sub-national government officials (n = 24), health workers and volunteers (n = 40), and caregivers (n = 34). We conducted direct structured observations at health facilities (n = 10) and outreach clinics (n = 10) to complement information from interviews. We coded and analyzed interview notes for themes related to GMP implementation. Health workers in Ghana (e.g., community health nurses) and Nepal (e.g., auxiliary nurse midwives) had the knowledge and skills to assess and analyze growth based on weight measurement. However, health workers in Ghana centered growth promotion on the growth trend (weight-for-age over time), whereas health workers in Nepal based growth promotion on measurement from one point in time to determine whether a child was underweight. Overlapping challenges included health worker time and workload. Both countries tracked growth-monitoring data systematically; however, there was variation in growth monitoring data use. This study shows that GMP programs may not always focus on the growth trend for early detection of growth faltering and preventive actions. Several factors contribute to this deviation from the intended goal of GMP. To overcome them, countries need to invest in both service delivery (e.g., decision-making algorithm) and demand generation efforts (e.g., integrate with responsive care and early learning).

Early-Life Slow Enteral Feeding Progression Pattern Is Associated with Longitudinal Head-Size Growth Faltering and Neurodevelopmental Impairment Outcomes in Extremely Preterm Infants

To determine whether feeding progression patterns in the first eight postnatal weeks, depicted by clustering analysis of daily enteral feeding volume, are associated with longitudinal head-circumference (HC) growth and neurodevelopmental outcomes in extremely preterm (EP) infants. 200 infants who were admitted at gestational ages 23-27 weeks between 2011 and 2018; survived to discharge; and underwent longitudinal HC growth measurements at birth, term-equivalent age (TEA), corrected age (CA) 6-month, 12-month, and 24-month; and neurodevelopmental assessment using the Bayley Scales of Infant Development at CA 24 months were included for analysis. kmlShape analysis identified two distinct enteral feeding progression patterns: fast progression in 131 (66%) infants and slow progression in 69 (34%) infants. Compared to the fast progression group, the slow progression group showed significantly lower daily enteral volumes after day 13, was older in postnatal age reaching full feeding, had a higher rate of Delta z scores of HC (zHC) < -1 (p < 0.001) between birth and TEA, and displayed lower longitudinal zHC from TEA to CA 24 months. The slow progression group also showed higher rates of microcephaly [42% vs. 16%, p < 0.001; adjusted odd ratio (aOR): 3.269, p = 0.001] and neurodevelopmental impairment (NDI) (38% vs. 19%, p = 0.007; aOR: 2.095, p = 0.035) at CA 24 months. For NDI, the model including feeding progression patterns showed a lower Akaike information criterion score and a better goodness of fit than the model that did not include feeding patterns. Characterizing feeding progression pattern may help identify EP infants at high-risk of head-size growth faltering and NDI at early childhood.