A Practical Guide to Adjust Micronutrient Biomarkers for Inflammation Using the BRINDA Method.

The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) research group was formed over a decade ago to improve the interpretation of micronutrient biomarkers in settings with inflammation. The BRINDA inflammation adjustment method uses regression correction to adjust for the confounding effects of inflammation on select micronutrient biomarkers and has provided important insights to micronutrient research, policy, and programming. However, users may face challenges when applying the BRINDA inflammation adjustment methods to their own data due to varying guidance on the adjustment approach for different biomarkers and the need to develop statistical programming to conduct these analyses. This may result in lost opportunities to have results of micronutrient data readily available during critical decision-making periods. Our research objectives are to 1) provide an all-in-one summary of the BRINDA method in adjusting multiple micronutrient biomarkers for inflammation, 2) evaluate whether malaria as a binary variable should be included in the BRINDA inflammation adjustment method, and 3) present standardized and user-friendly BRINDA adjustment R package and SAS macro. This paper serves as a practical guidebook for the BRINDA inflammation adjustment approach and aids users to use the BRINDA R package and SAS to streamline their analyses.

Measuring the impact of malaria infection on indicators of iron and vitamin A status: a systematic literature review and meta-analysis.

Inflammation and infections such as malaria affect estimates of micronutrient status. Medline, Embase, Web of Science, Scopus and the Cochrane library were searched to identify studies reporting mean concentrations of ferritin, hepcidin, retinol or retinol binding protein in individuals with asymptomatic or clinical malaria and healthy controls. Study quality was assessed using the US National Institute of Health tool. Random effects meta-analyses were used to generate summary mean differences. In total, forty-four studies were included. Mean ferritin concentrations were elevated by: 28·2 µg/l (95 % CI 15·6, 40·9) in children with asymptomatic malaria; 28·5 µg/l (95 % CI 8·1, 48·8) in adults with asymptomatic malaria; and 366 µg/l (95 % CI 162, 570) in children with clinical malaria compared with individuals without malaria infection. Mean hepcidin concentrations were elevated by 1·52 nmol/l (95 % CI 0·92, 2·11) in children with asymptomatic malaria. Mean retinol concentrations were reduced by: 0·11 µmol/l (95 % CI -0·22, -0·01) in children with asymptomatic malaria; 0·43 µmol/l (95 % CI -0·71, -0·16) in children with clinical malaria and 0·73 µmol/l (95 % CI -1·11, -0·36) in adults with clinical malaria. Most of these results were stable in sensitivity analyses. In children with clinical malaria and pregnant women, difference in ferritin concentrations were greater in areas with higher transmission intensity. We conclude that biomarkers of iron and vitamin A status should be statistically adjusted for malaria and the severity of infection. Several studies analysing asymptomatic infections reported elevated ferritin concentrations without noticeable elevation of inflammation markers, indicating a need to adjust for malaria status in addition to inflammation adjustments.

An Integrated Infant and Young Child Feeding and Small-Quantity Lipid-based Nutrient Supplementation Program Is Associated with Improved Gross Motor and Communication Scores of Children 6-18 Months in the Democratic Republic of Congo.

OBJECTIVE: To evaluate the impact of an infant, young child feeding practices-small-quantity lipid nutrient supplements (SQ-LNS) intervention on child development scores in children aged 6-18 months in the Katanga Province, Democratic Republic of Congo (DRC). STUDY DESIGN: We analyzed data of 2595 children from 2 health zones in a quasi-experimental design with preimplementation and postimplementation surveys to evaluate program impact on child development scores. Standard care was received in the comparison health zone and the intervention health zone received standard care plus enhanced infant, young child feeding practices with a monthly supply of 28 SQ-LNS sachets for up to 1 year. Program exposure and communication and motor domains of the Ages and Stages questionnaire were collected to assess changes in child development scores. A quasi-intent-to-treat and adjusted difference-in-difference analyses were used to quantify impact of the enhanced compared with the standard package. RESULTS: In adjusted models contrasting endline with baseline, there was a greater relative increase in proportion of children with normal communication (difference-in-difference, +13.7% [95%CI, 7.9-19.6; P < .001] and gross motor scores, +7.4% [95% CI: 1.3-13.5; P < .001]) in the intervention vs comparison health zones. Further, in separate analyses among children of intervention health zone at endline, each additional SQ-LNS distribution was associated with +0.09 (95% CI, 0.03-0.16) z-score unit increase in gross motor scores (P < .01). CONCLUSIONS: The integrated infant, young child feeding practice-SQ-LNS intervention was positively associated with larger relative improvements in measures of child communication and motor development in the Katanga province of DRC.

An integrated infant and young child feeding and small-quantity lipid-based nutrient supplementation programme in the Democratic Republic of Congo is associated with improvements in breastfeeding and handwashing behaviours but not dietary diversity.

Integrating small-quantity lipid-based nutrient supplements (SQ-LNS) into infant and young child feeding (IYCF) programmes can increase consumption of essential nutrients among children in vulnerable populations; however, few studies have assessed the impact of integrated IYCF-SQ-LNS programmes on IYCF practices. A 2-year, enhanced IYCF intervention targeting pregnant women and infants (0-12 months) was implemented in a health zone in the Democratic Republic of Congo (DRC). The enhanced IYCF intervention included community- and facility-based counselling for mothers on handwashing, SQ-LNS, and IYCF practices, plus monthly SQ-LNS distributions for children 6-12 months; a control zone received the national IYCF programme (facility-based IYCF counselling with no SQ-LNS distributions). Cross-sectional preintervention and postintervention surveys (n = 650 and 638 in intervention and control areas at baseline; n = 654 and 653 in each area at endline, respectively) were conducted in mothers of children 6-18 months representative of both zones. Difference in differences (DiD) analyses used mixed linear regression models. There were significantly greater increases in the proportion of mothers in the intervention (vs. control) zone who reported: initiating breastfeeding within 1 hr of birth (Adj. DiD [95% CI]: +56.4% [49.3, 63.4], P < 0.001), waiting until 6 months to introduce water (+66.9% [60.6, 73.2], P < 0.001) and complementary foods (+56.4% [49.3, 63.4], P < 0.001), feeding the minimum meal frequency the previous day (+9.2% [2.7, 15.7], P = 0.005); feeding the child in a separate bowl (+9.7% [2.2, 17.2], P = 0.01); awareness of anaemia (+16.9% [10.4, 23.3], P < 0.001); owning soap (+14.9% [8.3, 21.5], P < 0.001); and washing hands after defecating and before cooking and feeding the child the previous day (+10.5% [5.8, 15.2], +12.5% [9.3, 15.6] and +15.0% [11.2, 18.8], respectively, P < 0.001 for all). The enhanced IYCF intervention in the DRC was associated with an improvement in several important IYCF practices but was not associated with a change in dietary diversity (minimum dietary diversity and minimum acceptable diet remained below 10% in both zones without significant differences between zones). The provision of fortified complementary foods, such as SQ-LNS, may be an important source of micronutrients and macronutrients for young children in areas with high rates of poverty and limited access to diverse foods. Future research should verify the potential of integrated IYCF-SQ-LNS to improve IYCF practices, and ultimately children's nutritional status.

Accounting for the influence of inflammation on retinol-binding protein in a population survey of Liberian preschool-age children.

Vitamin A deficiency (VAD) is an important contributor to child morbidity and mortality. The prevalence of VAD, measured by retinol-binding protein (RBP) or retinol, is overestimated in populations with a high prevalence of inflammation. We aimed to quantify and adjust for the effect of inflammation on VAD prevalence in a nationally representative survey of Liberian children 6 to 35 months of age. We compared five approaches to adjust RBP for inflammation and estimate VAD prevalence (defined as RBP < 0.7 µmol/L): (1) ignoring inflammation; (2) excluding individuals with inflammation (C-reactive protein (CRP) >5 mg/L or alpha1-acid glycoprotein (AGP) >1 g/)L; (3) multiplying each individual's RBP by an internal correction factor; (4) by an external correction factor; and (5) using regression (corrected RBP = exp(InRBP - ß1 (lnCRPobs -lnCRPref ) - ß2 (lnAGPobs -lnAGPref )). Corrected RBP was based on a regression model where reference lnCRP and lnAGP were set to the maximum of the lowest decile. The unadjusted prevalence of VAD was 24.7%. Children with elevated CRP and/or AGP had significantly lower RBP concentrations than their apparently healthy peers (geometric mean RBP 0.79 µmol/L (95% CI: 0.76, 0.82) vs. 0.95 µmol/L (95% CI: 0.92, 0.97), P < 0.001). Using approaches 2-5 resulted in a prevalence of VAD of 11.6%, 14.3%, 13.5% and 7.3%, respectively. Depending on the approach, the VAD prevalence is reduced 10-17 percentage points when inflammation is taken into account. Further quantification of the influence of inflammation on biomarkers of vitamin A status from other national surveys is needed to compare and recommend the preferred adjustment approach across populations.

Evaluating equity dimensions of infant and child vitamin A supplementation programmes using Demographic and Health Surveys from 49 countries.

OBJECTIVES: Vitamin A deficiency affects an estimated 29% of all children under 5 years of age in low/middle-income countries, contributing to child mortality and exacerbating severity of infections. Biannual vitamin A supplementation (VAS) for children aged 6-59 months can be a low-cost intervention to meet vitamin A needs. This study aimed to present a framework for evaluating the equity dimensions of national VAS programmes according to determinants known to affect child nutrition and assist programming by highlighting geographical variation in coverage. METHODS: We used open-source data from the Demographic and Health Survey for 49 countries to identify differences in VAS coverage between subpopulations characterised by various immediate, underlying and enabling determinants of vitamin A status and geographically. This included recent consumption of vitamin A-rich foods, access to health systems and services, administrative region of the country, place of residence (rural vs urban), socioeconomic position, caregiver educational attainment and caregiver empowerment. RESULTS: Children who did not recently consume vitamin A-rich foods and who had poorer access to health systems and services were less likely to receive VAS in most countries despite potentially having a greater vitamin A need. Differences in coverage were also observed when disaggregated by administrative regions (88% of countries) and urban versus rural residence (35% of countries). Differences in vitamin A coverage between subpopulations characterised by other determinants of vitamin A status varied considerably between countries. CONCLUSION: VAS programmes are unable to reach all eligible infants and children, and subpopulation differences in VAS coverage characterised by various determinants of vitamin A status suggest that VAS programmes may not be operating equitably in many countries.

Multi-micronutrient-fortified biscuits decreased the prevalence of anaemia and improved iron status, whereas weekly iron supplementation only improved iron status in Vietnamese school children.

In Vietnam, nutrition interventions do not target school children despite a high prevalence of micronutrient deficiencies. The present randomised, placebo-controlled study evaluated the impact of providing school children (n 403) with daily multiple micronutrient-fortified biscuits (FB) or a weekly Fe supplement (SUP) on anaemia and Fe deficiency. Micronutrient status was assessed by concentrations of Hb, and plasma ferritin (PF), transferrin receptor (TfR), Zn and retinol. After 6 months of intervention, children receiving FB or SUP had a significantly better Fe status when compared with the control children (C), indicated by higher PF (FB: geometric mean 36·9 (95% CI 28·0, 55·4) µg/l; SUP: geometric mean 46·0 (95% CI 33·0, 71·7) µg/l; C: geometric mean 34·4 (95% CI 15·2, 51·2) µg/l; P < 0·001) and lower TfR concentrations (FB: geometric mean 5·7 (95% CI 4·8, 6·52) mg/l; SUP: geometric mean 5·5 (95% CI 4·9, 6·2) mg/l; C: geometric mean 5·9 (95% CI 5·1, 7·1) mg/l; P = 0·007). Consequently, body Fe was higher in children receiving FB (mean 5·6 (sd 2·2) mg/kg body weight) and SUP (mean 6·1 (sd 2·5) mg/kg body weight) compared with the C group (mean 4·2 (sd 3·3) mg/kg body weight, P < 0·001). However, anaemia prevalence was significantly lower only in the FB group (1·0%) compared with the C group (10·4%, P = 0·006), with the SUP group being intermediate (7·4%). Children receiving FB had better weight-for-height Z-scores after the intervention than children receiving the SUP (P = 0·009). Vitamin A deficiency at baseline modified the intervention effect, with higher Hb concentrations in vitamin A-deficient children receiving FB but not in those receiving the SUP. This indicates that vitamin A deficiency is implicated in the high prevalence of anaemia in Vietnamese school children, and that interventions should take other deficiencies besides Fe into account to improve Hb concentrations. Provision of biscuits fortified with multiple micronutrients is effective in reducing anaemia prevalence in school children.

Folate Deficiency Is Spatially Dependent and Associated with Local Farming Systems among Women in Ethiopia.

Background: Folate is essential for the synthesis and integrity of DNA, normal cell formation, and body growth. Folate deficiency among women of reproductive age (WRA) increases the risk of poor birth outcomes including neural tube defect (NTD)-affected pregnancies. Folate status is largely dependent on dietary intakes. Objectives: We aimed to explore the spatial distribution of biomarkers of folate status and their association with farming systems among nonpregnant WRA in Ethiopia. Methods: Serum and RBC folate concentration data were derived from the Ethiopia National Micronutrient Survey of 2015. The spatial dependencies of folate concentration of WRA were investigated and its relation with the dominant local farming system was explored. Results: The median serum folate and RBC folate concentrations were 12.3 nmol/L and 567.3 nmol/L, respectively. The national prevalence of folate deficiency using homocysteine concentration as a metabolic indicator based on serum and RBC folate concentration was 11.6% and 5.7%, respectively. The majority of women (77.9%) had low RBC folate concentrations consistent with increased risk of NTD-affected pregnancies. Folate nutrition was spatially dependent at distances of ≤ 300 km. A marked variability in folate concentration was observed between farming systems: greater RBC folate concentration (median: 1036 nmol/L) was found among women from the Lake Tana fish-based system, whereas the lowest RBC folate concentration (median: 386.7 nmol/L) was observed in the highland sorghum chat mixed system. Conclusions: The majority (78%) of WRA in Ethiopia had low folate status potentially increasing the risk of NTD-affected pregnancies. These findings may help national and subnational nutrition intervention strategies to target the most affected areas in the country.

Re-Defining the Population-Specific Cut-Off Mark for Vitamin A Deficiency in Pre-School Children of Malawi.

Retinol Binding Protein (RBP) is responsible for the transport of serum retinol (SR) to target tissue in the body. Since RBP is relatively easy and cheap to measure, it is widely used in national Micronutrient Surveys (MNS) as a proxy for SR to determine vitamin A status. By regressing RBP concentration against SR concentration measured in a subset of the survey population, one can define a population-specific threshold concentration of RBP that indicates vitamin A deficiency (VAD). However, the relationship between RBP and SR concentrations is affected by various factors including inflammation. This study, therefore, aimed to re-define the population-specific cut-off for VAD by examining the influence of inflammation on RBP and SR, among pre-school children (PSC) from the 2015-16 Malawi MNS. The initial association between RBP and SR concentrations was poor, and this remained the case despite applying various methods to correct for inflammation. The World Health Organization (WHO) recommends the threshold of 0.7 µmol/L to define VAD for SR concentrations. Applying this threshold to the RBP concentrations gave a VAD prevalence of 24%, which reduced to 10% after inflammation adjustments following methods developed by the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA). Further research is required to identify why SR and RBP were poorly associated in this population. Future MNS will need to account for the effect of inflammation on RBP to measure the prevalence of VAD in Malawi.

Combined infant and young child feeding with small-quantity lipid-based nutrient supplementation is associated with a reduction in anemia but no changes in anthropometric status of young children from Katanga Province of the Democratic Republic of Congo: a quasi-experimental effectiveness study.

BACKGROUND: Small-quantity lipid-based nutrient supplements (SQ-LNS) are efficacious in controlled settings; data are scarce on the effectiveness utilizing health care delivery platforms. OBJECTIVE: We evaluated the impact of an infant young child feeding (IYCF)-SQ-LNS intervention on anemia and growth in children aged 6-18 mo in the Democratic Republic of Congo following a quasi-experimental effectiveness design. METHODS: An intervention health zone (HZ) received enhanced IYCF including improved counseling on IYCF during pregnancy until 12 mo after birth and daily use of SQ-LNS for infants 6-12 mo; the control HZ received the standard IYCF package. We analyzed data from 2995 children, collected in repeated cross-sectional surveys. We used adjusted difference-in-difference analyses to calculate changes in anemia, iron and vitamin A deficiencies, stunting, wasting, and underweight. RESULTS: Of mothers, 70.5% received SQ-LNS at least once in the intervention HZ, with 99.6% of their children consuming SQ-LNS at least once. The mean number of batches of SQ-LNS (28 sachets per batch, 6 batches total) received was 2.3 ± 0.8 (i.e., 64.4 ± 22.4 d of SQ-LNS). The enhanced program was associated with an 11.0% point (95% CI: -18.1, -3.8; P < 0.01) adjusted relative reduction in anemia prevalence and a mean +0.26-g/dL (95% CI: 0.04, 0.48; P = 0.02) increase in hemoglobin but no effect on anthropometry or iron or vitamin A deficiencies. At endline in the intervention HZ, children aged 8-13 mo who received ≥3 monthly SQ-LNS batch distributions had higher anthropometry z scores [length-for-age z score (LAZ): +0.40, P = 0.04; weight-for-age z score (WAZ): +0.37, P = 0.04] and hemoglobin (+0.65 g/dL, P = 0.007) and a lower adjusted prevalence difference of stunting (-16.7%, P = 0.03) compared with those who received none. CONCLUSIONS: The enhanced IYCF-SQ-LNS intervention using the existing health care delivery platform was associated with a reduction in prevalence of anemia and improvement in mean hemoglobin. At endline among the subpopulation receiving ≥3 mo of SQ-LNS, their LAZ, WAZ, and hemoglobin improved. Future research could explore contextual tools to maximize coverage and intake adherence in programs using SQ-LNS.