Inflammation and infections such as malaria affect micronutrient biomarker concentrations and hence estimates of nutritional status. It is unknown whether correction for C-reactive protein (CRP) and α1-acid glycoprotein (AGP) fully captures the modification in ferritin concentrations during a malaria infection, or whether environmental and sociodemographic factors modify this association. Cross-sectional data from eight surveys in children aged 6-59 months (Cameroon, Cote d'Ivoire, Kenya, Liberia, Malawi, Nigeria and Zambia; n 6653) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) project were pooled. Ferritin was adjusted using the BRINDA adjustment method, with values < 12 μg/l indicating iron deficiency. The association between current or recent malaria infection, detected by microscopy or rapid test kit, and inflammation-adjusted ferritin was estimated using pooled multivariable linear regression. Age, sex, malaria endemicity profile (defined by the Plasmodium falciparum infection prevalence) and malaria diagnostic methods were examined as effect modifiers. Unweighted pooled malaria prevalence was 26·0 % (95 % CI 25·0, 27·1) and unweighted pooled iron deficiency was 41·9 % (95 % CI 40·7, 43·1). Current or recent malaria infection was associated with a 44 % (95 % CI 39·0, 52·0; P < 0·001) increase in inflammation-adjusted ferritin after adjusting for age and study identifier. In children, ferritin increased less with malaria infection as age and malaria endemicity increased. Adjustment for malaria increased the prevalence of iron deficiency, but the effect was small. Additional information would help elucidate the underlying mechanisms of the role of endemicity and age in the association between malaria and ferritin.

OBJECTIVES: To examine US in-hospital exclusive breastfeeding (EBF) and the associations with Baby-Friendly designation and neighborhood sociodemographic factors. METHODS: Hospital data from the 2018 Maternity Practices in Infant Nutrition and Care survey were linked to hospital zip code tabulation area (ZCTA) sociodemographic data from the 2014-2018 American Community Survey (n = 2,024). The percentages of residents in the hospital ZCTA were dichotomized based on the relative mean percentage of the hospital's metropolitan area, which were exposure variables (high/low Black hospitals, high/low poverty hospitals, high/low educational attainment hospitals) along with Baby-Friendly designation. Using linear regression, we examined the associations and effect measure modification between Baby-Friendly designation and hospital sociodemographic factors with in-hospital EBF prevalence. RESULTS: US mean in-hospital EBF prevalence was 55.1%. Baby-Friendly designation was associated with 9.1% points higher in-hospital EBF prevalence compared to non-designated hospitals [95% confidence interval (CI): 7.0, 11.2]. High Black hospitals and high poverty hospitals were associated with lower EBF prevalence (difference= -3.3; 95% CI: -5.1, -1.4 and - 3.8; 95% CI: -5.7, -1.8). High educational attainment hospitals were associated with higher EBF prevalence (difference = 6.7; 95% CI: 4.1, 9.4). Baby-Friendly designation was associated with significant effect measure modification of the in-hospital EBF disparity attributed to neighborhood level poverty (4.0% points higher in high poverty/Baby-Friendly designated hospitals than high poverty/non-Baby-Friendly designated hospitals).

OBJECTIVES: To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between vitamin A deficiency (VAD) and infectious causes of death (CoD). STUDY DESIGN: In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hours of death were analyzed from 405 stillbirths and children under 5 years in Kenya and South Africa. Total liver vitamin A (VA) concentrations were quantified using ultra-performance liquid chromatography, and cutoffs of ≤0.1 μmol/g, >0.1 to <0.7 μmol/g, ≥0.7 to <1.0 μmol/g, and ≥1.0 μmol/g were used to define VAD, adequate VA status, high VA, and hypervitaminosis A, respectively. Causes of death (CoD) were determined by expert panel review. RESULTS: Among 366 liver samples with viable extraction, pooled prevalences of VAD, adequacy, high VA, and hypervitaminosis were 34.2%, 51.1%, 6.0%, and 8.7%, respectively. VAD was more common among neonates compared with stillbirths, infants, or children, and among those with low birthweight, underweight, or stunting (p<0.05). When adjusting for site, age, and sex, there was no significant association of VAD with increased infectious CoD (OR 1.9, 95%CI 0.9, 3.8, p=0.073). In stratified analyses, VA deficient boys, but not girls, had an increased risk of infectious CoD (OR 3.4, 95%CI 1.3, 10.3, p=0.013). CONCLUSIONS: Definitive post-mortem assessment of VA status identified both VAD and VA excess among children under 5 years of age in Kenya and South Africa. VAD in boys was associated with increased risk of infectious mortality. Our findings may inform a transition from universal VA supplementation to targeted strategies in certain countries.

Objective: The aim of this study is to examine in-hospital exclusive breastfeeding (EBF) and its association with sociodemographic factors, medical factors, breastfeeding intentions, and health care system breastfeeding support. Materials and Methods: We conducted a retrospective cross-sectional study using medical records from 2015 to 2019 of healthy term infants without breastfeeding contraindications at a public teaching hospital serving a racially and ethnically diverse patient population. Using multivariable regression analysis, we examined the associations between in-hospital EBF and sociodemographic factors, medical factors, breastfeeding intentions, and health care system breastfeeding support (in-hospital breastfeeding education and lactation support). Results: The prevalence of in-hospital EBF was 29.0%. The statistically significant findings from our fully adjusted regression analysis include that there was a higher prevalence of in-hospital EBF among adult mothers (prevalence ratio [PR]: range 1.78-1.96), married mothers (PR: 1.35, 95% confidence interval [CI]: 1.23-1.44), and mothers who were White (PR: 1.41, 95% CI: 1.20-1.66, compared with Black). Factors associated with a lower prevalence of in-hospital EBF were maternal diabetes (PR: 0.82, 95% CI: 0.70-0.95), pre-eclampsia/eclampsia (PR: 0.82, 95% CI: 0.71-0.95), cesarean delivery (PR: 0.84, 95% CI: 0.77-0.92), neonatal hypoglycemia (PR: 0.46, 95% CI: 0.36-0.59), and intention in the prenatal period to formula feed only (PR: 0.15, 95% CI: 0.10-0.22). In-hospital lactation support was associated with higher prevalence of in-hospital EBF (PR: 1.24, 95% CI: 1.16-1.33). Conclusions: Prioritizing lactation support for Black mothers, adolescent mothers, those intending in the prenatal period to formula feed only, and mother-infant dyads with certain medical factors could improve in-hospital EBF.

Despite decades of research and programmatic focus, | anaemia is a persistent global health problem and | can have negative health implications across the | lifecycle, including impaired child development and | work productivity and increased risk of adverse birth | outcomes, morbidity and mortality.1,2 | In The Lancet Haematology, the GBD 2021 Anaemia | Collaborators use 2021 data from the Global Burden | of Disease, Injuries and Risk Factors Study (GBD 2021) | to report that nearly one in four individuals worldwide | have anaemia, with notable differences by age, sex, | and geography.3 | The most common estimated causes | of anaemia were dietary iron deficiency, haemoglobinopathies and haemolytic anaemias, and other | neglected tropical diseases; iron deficiency alone | contributed up to 66% of the total anaemia burden. | These findings highlight the crucial role of nutrition in | reducing anaemia. Although iron deficiency has long been | considered a leading cause of anaemia, estimates vary | widely across reports and settings. GBD 2021 presents | the most comprehensive and current analysis of anaemia | burden and causes globally; however, some researchers | have questioned how micronutrient deficiencies, | including iron deficiency, are estimated in the GBD | analyses.4 | Rather than estimating iron deficiency using | valid inflammation-adjusted micronutrient biomarker | data from representative surveys, GBD 2021 used | complex statistical modelling.3 | In brief, spatiotemporal | Gaussian process regression models were used to estimate | the prevalence of anaemia and predictive covariates | were modelled using separate mixed-effects linear | regression to create an ensemble model. Iron deficiency | was modelled as a residual cause, which assumes that | the causal attribution not explained by other causes of | anaemia was due to iron deficiency. The comparability of | the GBD modelling approach to a biomarker approach for | estimating iron deficiency is unclear.

BACKGROUND: In-hospital exclusive breastfeeding (EBF) is associated with longer breastfeeding durations, yet only 64% of US newborns are EBF for 7 days. The Ten Steps to Successful Breastfeeding (Ten Steps) are a set of evidenced-based maternity practices shown to improve breastfeeding outcomes; these were updated in 2018. METHODS: Using hospital-level data from the 2018 Maternity Practices in Infant Nutrition and Care Survey (n = 2045 hospitals), we examined the prevalence of implementation of Ten Steps indicators (each step and total number of steps implemented). Using linear regression, we also examined the association between the steps and EBF prevalence adjusted for hospital characteristics and all other steps. Discharge support was not included in the models since it primarily occurs after hospital discharge. RESULTS: The most frequently implemented step was the provision of prenatal breastfeeding education (95.6%). Steps with low implementation included rooming-in (18.9%), facility policies supportive of breastfeeding (23.4%), and limited formula supplementation (28.2%). After adjusting for hospital characteristics and all other steps, limited formula supplementation (difference = 14.4: 95% confidence interval [CI]: 12.6, 16.1), prenatal breastfeeding education (difference = 7.0; 95% CI: 3.3, 10.8), responsive feeding (difference = 6.3; 95% CI: 3.7, 9.0), care right after birth (skin-to-skin; difference = 5.8; 95% CI: 4.2, 7.4), and rooming-in (difference = 2.4; 95% CI: 0.4, 4.6) were associated with higher in-hospital EBF prevalence. We found a dose-response relationship between the number of steps implemented and in-hospital EBF prevalence. CONCLUSION: Increased implementation of the updated Ten Steps may improve EBF and infant and maternal health outcomes.

Micronutrient deficiency is a common global health problem, and accurately assessing micronutrient biomarkers is crucial for planning and managing effective intervention programs. However, analyzing micronutrient data and applying appropriate cutoffs to define deficiencies can be challenging, particularly when considering the confounding effects of inflammation on certain micronutrient biomarkers. To address this challenge, we developed the Statistical Apparatus of Micronutrient Biomarker Analysis (SAMBA) R package, a new tool that increases ease and accessibility of population-based micronutrient biomarker analysis. The SAMBA package can analyze various micronutrient biomarkers to assess status of iron, vitamin A, zinc, and B vitamins, adjust for inflammation, account for complex survey design when appropriate, and produce reports of summary statistics and prevalence estimates of micronutrient deficiencies using recommended age- and sex-specific cutoffs. We have provided a step-by-step procedure for how to use the SAMBA R package, including how to customize it for broader use, and made both the package and user manual publicly available on GitHub. SAMBA was validated by comparing results from analyzing 24 datasets on non-pregnant women of reproductive age from 23 countries and 30 datasets on preschool-age children from 26 countries with those obtained by an independent analyst. SAMBA generated identical means, percentiles, and prevalence of micronutrient deficiencies to those calculated by the independent analyst. In conclusion, SAMBA simplifies and standardizes the process for deriving survey-weighted and inflammation-adjusted (when appropriate) estimates of the prevalence of micronutrient deficiencies, reducing the time from data cleaning to result generation. SAMBA is a valuable tool that facilitates the accurate and rapid analysis of population-based micronutrient biomarker data, which can inform public health research, programs, and policy across contexts.

Anemia is a major public health concern. Young children, menstruating adolescent girls and women, and pregnant women are among the most vulnerable. Anemia is the consequence of a wide range of causes, including biological, socioeconomic, and ecological risk factors. Primary causes include: iron deficiency; inherited red blood cell disorders; infections, such as soil-transmitted helminthiasis, schistosomiasis, and malaria; gynecological and obstetric conditions; and other chronic diseases that lead to blood loss, decreased erythropoiesis, or destruction of erythrocytes. The most vulnerable population groups in low- and middle-income countries are often at the greatest risk to suffer from several of these causes simultaneously as low socioeconomic status is linked with an increased risk of anemia through multiple pathways. Targeted and effective action is needed to prevent anemia. Understanding the causes and risk factors of anemia for different population subgroups within a country guides the design and implementation of effective strategies to prevent and treat anemia. A coordinated approach across various expert groups and programs could make the best use of existing data or could help to determine when newer and more relevant data may need to be collected, especially in countries with a high anemia burden and limited information on the etiology of anemia.

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.

BACKGROUND: It is unclear whether 25(OH)D concentrations in children and female adults may be influenced by inflammation and thus require adjustment when estimating the population prevalence of vitamin D deficiency. OBJECTIVES: We examined correlations between inflammation biomarkers, CRP or alpha-1-acid glycoprotein (AGP), and serum 25(OH)D concentrations among preschool children (PSC; 6-59 mo) and nonpregnant females of reproductive age (FRA; 15-49 y). METHODS: We analyzed cross-sectional data from 6 nationally representative nutrition surveys (Afghanistan, Cambodia, Pakistan, UK, USA, and Vietnam) conducted among PSC (n = 9880) and FRA (n = 14,749) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project. Rank correlations between CRP or AGP and 25(OH)D concentrations were examined while taking into account complex survey design effects. RESULTS: Among both PSC and FRA, correlations between inflammation and vitamin D biomarkers were weak and inconsistent across surveys. For PSC, correlation coefficients between CRP and 25(OH)D concentrations ranged from -0.04 to 0.08, and correlations between AGP and 25(OH)D ranged from 0.01 to 0.05. Correlation coefficients between CRP and 25(OH)D for FRA ranged from -0.11 to 0.14, and correlations between AGP and 25(OH)D concentrations ranged from -0.05 to 0.01. CONCLUSIONS: Based on the weak and inconsistent correlations between CRP or AGP and 25(OH)D, there is no rationale to adjust for these inflammation biomarkers when estimating population prevalence of vitamin D deficiency in PSC or FRA.

Background: Attributable fractions (AF) of anemia are often used to understand the multifactorial etiologies of anemia, despite challenges interpreting them in cross-sectional studies. We aimed to compare different statistical approaches for estimating AF for anemia due to inflammation, malaria, and micronutrient deficiencies including iron, vitamin A, vitamin B12, and folate.

BACKGROUND: In the presence of inflammation, the serum or plasma ferritin concentration ("ferritin" hereafter) transiently increases, confounding its interpretation as an iron status marker. The extent to which adiposity-related inflammation may influence ferritin interpretation is uncertain. OBJECTIVES: We describe relationships between weight status, inflammation, and ferritin among nonpregnant women of reproductive age (WRA; 15-49 years) and preschool-age children (PSC; 6-59 months) with normal weight to overweight or obesity (OWOB) in differing geographic settings. METHODS: Cross-sectional data were separately analyzed from 18 surveys (WRA) and 25 surveys (PSC) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project, excluding observations with underweight, wasting, pregnancy, or malaria. Relationships were assessed between BMI (in WRA) or BMI-for-age z-score (BAZ; in PSC), inflammatory biomarkers of C-reactive protein (CRP) and/or α-1-acid glycoprotein (AGP), ferritin by linear regression, and potential mediation by CRP and/or AGP in relationships between BMI or BAZ and ferritin with structural equation modeling. Regression and mediation models accounted for complex survey designs. Results were grouped by World Bank income classifications. RESULTS: In 5 of 6 surveys among WRA from upper-middle and high-income countries, ferritin was significantly positively associated with BMI, and this relationship was partially (or fully, in the United States) mediated by CRP and/or AGP. Mediation was present in 4 of 12 surveys for WRA in low- and lower-middle income countries. Among PSC, ferritin was positively associated with CRP and/or AGP in all surveys, but there were no significant CRP- or AGP-mediated relationships between ferritin and BAZ, except a negative relationship in the Philippines. CONCLUSIONS: Where having OWOB is common among WRA, measurements of inflammatory biomarkers and their uses in interpreting ferritin may improve iron status assessments. While these relationships were inconsistent among PSC, inflammation was common and should be measured to interpret iron status. Included Kenyan trial data are registered at clinicaltrials.gov as NCT01088958.

BACKGROUND: Standardized practices are needed in the analysis of inflammation biomarker values outside limits of detection (LOD) when used for inflammation correction of nutritional biomarkers. OBJECTIVE: We assessed the direction and extent to which serum C-reactive protein (CRP) and alpha-1-acid-glycoprotein (AGP) values outside LODs (<0.05 mg/L and >4.0 g/L, respectively) affect inflammation regression correction of serum ferritin and compared approaches to addressing such values when estimating inflammation-adjusted ferritin and iron deficiency (ID). METHODS: Examined 29 cross-sectional datasets from 7 countries with reproductive-age women (15-49y) (n = 12,944), preschool-age children (6-59m) (n = 18,208) and school-age children (6-14y) (n = 4,625). For each dataset, we compared 6 analytic approaches for addressing CRP <LOD: listwise deletion, single imputation (lower, middle, or upper bound; LOD/√2; random number), with multiple imputation (MI). For each approach, inflammation-adjusted ferritin and ID using BRINDA regression correction were estimated. We calculated deviance of each estimate from that given by MI within each dataset and performed fixed effects multivariate meta-regression with analytic approach as moderator to compare the reliability of each approach to MI. RESULTS: Across datasets, observations outside LOD ranged from 0.0 to 35.0% of CRP values and 0.0 to 2.5% of AGP values. Pooled deviance estimates for mean ferritin (µg/L) and ID (percentage points) were: listwise deletion -0.46 (95%CI: -0.76, -0.16) and 0.14 (-0.43, 0.72), lower bound 0.45 (0.14, 0.76) and -0.36 (-0.91, 0.20), middle bound -0.21 (-0.51, 0.09) and 0.22 (-0.34, 0.79), LOD/√(2) -0.26 (-0.57, 0.04) and 0.25 (-0.31, 0.81), upper bound -0.31 (-0.61, -0.01) and 0.30 (-0.27, 0.86), and random number -0.08 (-0.38, 0.22) and 0.11 (-0.46, 0.67). There was moderation by approach in the ferritin model (p<0.001). CONCLUSIONS: Findings demonstrate the need for standardized analyses of inflammation biomarker values outside LODs and suggest that random number single imputation may be a reliable and feasible alternative to MI for CRP <LOD.

In-hospital infant formula supplementation of breastfed infants reduces breastfeeding duration, yet little is known about common reasons for infant formula supplementation. We examined the three most common reasons for in-hospital infant formula supplementation of healthy, term, breastfed infants in the US reported by hospital staff. Hospital data were obtained from the 2018 Maternity Practices in Infant Nutrition and Care survey (n = 2045), which is completed by hospital staff. An open-ended question on the top three reasons for in-hospital infant formula supplementation was analyzed using thematic qualitative analysis and the frequencies for each reason were reported. The top three most common reasons for in-hospital infant formula supplementation reported by hospital staff included medical indications (70.0%); maternal request/preference/feelings (55.9%); lactation management-related issues (51.3%); physical but non-medically indicated reasons (36.1%); social influences (18.8%); perceived cultural/societal/demographic factors (8.2%) and medical staff/institutional practices (4.7%). These findings suggest that a variety of factors should be considered to address unnecessary infant formula supplementation. Lactation management support delivered in a timely and culturally sensitive manner and targeted to mother-infant dyads with potential medical and physical indications may reduce unnecessary in-hospital infant formula supplementation.

IMPORTANCE: Anemia, defined as low hemoglobin (Hb) concentration insufficient to meet an individual's physiological needs, is the most common blood condition worldwide. OBJECTIVE: To evaluate the current World Health Organization (WHO) Hb cutoffs for defining anemia among persons who are apparently healthy and to assess threshold validity with a biomarker of tissue iron deficiency and physiological indicator of erythropoiesis (soluble transferrin receptor [sTfR]) using multinational data. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, data were collected and evaluated from 30 household, population-based nutrition surveys of preschool children aged 6 to 59 months and nonpregnant women aged 15 to 49 years during 2005 to 2016 across 25 countries. Data analysis was performed from March 2020 to April 2021. EXPOSURE: Anemia defined according to WHO Hb cutoffs. MAIN OUTCOMES AND MEASURES: To define the healthy population, persons with iron deficiency (ferritin <12 ng/mL for children or <15 ng/mL for women), vitamin A deficiency (retinol-binding protein or retinol <20.1 μg/dL), inflammation (C-reactive protein >0.5 mg/dL or α-1-acid glycoprotein >1 g/L), or known malaria were excluded. Survey-specific, pooled Hb fifth percentile cutoffs were estimated. Among individuals with Hb and sTfR data, Hb-for-sTfR curve analysis was conducted to identify Hb inflection points that reflect tissue iron deficiency and increased erythropoiesis induced by anemia. RESULTS: A total of 79 950 individuals were included in the original surveys. The final healthy sample was 13 445 children (39.9% of the original sample of 33 699 children; 6750 boys [50.2%]; mean [SD] age 32.9 [16.0] months) and 25 880 women (56.0% of the original sample of 46 251 women; mean [SD] age, 31.0 [9.5] years). Survey-specific Hb fifth percentile among children ranged from 7.90 g/dL (95% CI, 7.54-8.26 g/dL in Pakistan) to 11.23 g/dL (95% CI, 11.14-11.33 g/dL in the US), and among women from 8.83 g/dL (95% CI, 7.77-9.88 g/dL in Gujarat, India) to 12.09 g/dL (95% CI, 12.00-12.17 g/dL in the US). Intersurvey variance around the Hb fifth percentile was low (3.5% for women and 3.6% for children). Pooled fifth percentile estimates were 9.65 g/dL (95% CI, 9.26-10.04 g/dL) for children and 10.81 g/dL (95% CI, 10.35-11.27 g/dL) for women. The Hb-for-sTfR curve demonstrated curvilinear associations with sTfR inflection points occurring at Hb of 9.61 g/dL (95% CI, 9.55-9.67 g/dL) among children and 11.01 g/dL (95% CI, 10.95-11.09 g/dL) among women. CONCLUSIONS AND RELEVANCE: Current WHO cutoffs to define anemia are higher than the pooled fifth percentile of Hb among persons who are outwardly healthy and from nearly all survey-specific estimates. The lower proposed Hb cutoffs are statistically significant but also reflect compensatory increased erythropoiesis. More studies based on clinical outcomes could further confirm the validity of these Hb cutoffs for anemia.

BACKGROUND: Anemia is a worldwide concern. Nutritional deficiencies and inflammation are considered main contributors, but zinc deficiency has only recently been associated with anemia. OBJECTIVES: In this study we assessed associations between zinc status and hemoglobin (Hb) concentrations and anemia in preschool children 6-59 mo old (PSC) and nonpregnant women of reproductive age 15-49 y old (WRA) in population-based nutrition surveys. METHODS: Cross-sectional data from 13 (PSC) and 12 (WRA) countries within the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were used. Multivariable linear models were constructed that included zinc status (plasma/serum zinc concentrations), Hb concentrations and anemia, iron status, age, sex, and inflammation (C-reactive protein and α-1-acid glycoprotein). Zinc was adjusted for inflammation in PSC according to the BRINDA algorithm. RESULTS: Data were available for 18,658 PSC and 22,633 WRA. Prevalence of anemia ranged from 7.5% to 73.7% and from 11.5% to 94.7% in PSC and WRA, respectively. Prevalence of zinc deficiency ranged from 9.2% to 78.4% in PSC and from 9.8% to 84.7% in WRA, with prevalence of zinc deficiency >20% in all countries except Azerbaijan (PSC), Ecuador (PSC), and the United Kingdom (WRA). Multivariable linear regression models showed that zinc concentrations were independently and positively associated with Hb concentrations in 7 of 13 countries for PSC and 5 of 12 countries for WRA. In the same models, ferritin concentration was also significantly associated with Hb among PSC and WRA in 9 and 10 countries, respectively. Zinc deficiency was significantly associated with anemia in PSC and WRA in 5 and 4 countries respectively. CONCLUSIONS: Zinc deficiency was prevalent in most countries and associations between zinc and Hb in roughly half of the countries examined suggesting that strategies to combat zinc deficiency may help reduce anemia prevalence. More research on mechanisms by which zinc deficiency is associated with anemia and the reasons for the heterogeneity among countries is warranted.

BACKGROUND: Accurate assessment of iron and vitamin A status is needed to inform public health decisions, but most population-level iron and vitamin A biomarkers are independently influenced by inflammation. OBJECTIVES: We aimed to assess the reproducibility of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) regression approach to adjust iron [ferritin, soluble transferrin receptor (sTfR)] and vitamin A [retinol-binding protein (RBP), retinol] biomarkers for inflammation (α-1-acid glycoprotein and C-reactive protein). METHODS: We conducted a sensitivity analysis comparing unadjusted and adjusted estimates of iron and vitamin A deficiency using the internal-survey regression approach from BRINDA phase 1 (16 surveys in children, 10 surveys in women) and 13 additional surveys for children and women (BRINDA phase 2). RESULTS: The relations between inflammation and iron or vitamin A biomarkers were statistically significant except for vitamin A biomarkers in women. Heterogeneity of the regression coefficients across surveys was high. Among children, internal-survey adjustments increased the estimated prevalence of depleted iron stores (ferritin <12 µg/L) by a median of 11 percentage points (pp) (24 pp and 9 pp in BRINDA phase 1 and phase 2, respectively), whereas estimates of iron-deficient erythropoiesis (sTfR >8.3 mg/L) decreased by a median of 15 pp (15 pp and 20 pp in BRINDA phase 1 and phase 2, respectively). Vitamin A deficiency (RBP <0.7 µmol/L or retinol <0.7 µmol/L) decreased by a median of 14 pp (18 pp and 8 pp in BRINDA phase 1 and phase 2, respectively) in children. Adjustment for inflammation in women resulted in smaller differences in estimated iron deficiency than in children. CONCLUSIONS: Our findings are consistent with previous BRINDA conclusions that not accounting for inflammation may result in an underestimation of iron deficiency and overestimation of vitamin A deficiency. Research is needed to understand the etiology of the heterogeneity in the regression coefficients before a meta-analyzed regression correction can be considered.

BACKGROUND: Rising prevalence of overweight/obesity (OWOB) alongside persistent micronutrient deficiencies suggests many women face concomitant OWOB and undernutrition. OBJECTIVES: We aimed to 1) describe the prevalence of the double burden of malnutrition (DBM) among nonpregnant women of reproductive age, defined as intraindividual OWOB and either ≥1 micronutrient deficiency [micronutrient deficiency index (MDI) > 0; DBM-MDI] or anemia (DBM-anemia); 2) test whether the components of the DBM were independent; and 3) identify factors associated with DBM-MDI and DBM-anemia. METHODS: With data from 17 national surveys spanning low- and middle-income countries (LMICs) and high-income countries from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project (n = 419 to n = 9029), we tested independence of over- and undernutrition using the Rao-Scott chi-square test and examined predictors of the DBM and its components using logistic regression for each survey. RESULTS: Median DBM-MDI was 21.9% (range: 1.6%-39.2%); median DBM-anemia was 8.6% (range: 1.0%-18.6%). OWOB and micronutrient deficiencies or anemia were independent in most surveys. Where associations existed, OWOB was negatively associated with micronutrient deficiencies and anemia in LMICs. In 1 high-income country, OWOB women were more likely to experience micronutrient deficiencies and anemia. Age was consistently positively associated with OWOB and the DBM, whereas the associations with other sociodemographic characteristics varied. Higher socioeconomic status tended to be positively associated with OWOB and the DBM in LMICs, whereas in higher-income countries the association was reversed. CONCLUSIONS: The independence of OWOB and micronutrient deficiencies or anemia within individuals suggests that these forms of over- and undernutrition may have unique etiologies. Decision-makers should still consider the prevalence, consequences, and etiology of the individual components of the DBM as programs move towards double-duty interventions aimed at addressing OWOB and undernutrition simultaneously.

BACKGROUND: The associations between anemia and household water source and sanitation remain unclear. OBJECTIVES: We aimed to assess the associations between anemia and household water source or sanitation in preschool children (PSC; age 6-59 mo) using population-based surveys from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. METHODS: We analyzed national and subnational data from 21 surveys, representing 19 countries (n = 35,963). Observations with hemoglobin (Hb) and ≥1 variable reflecting household water source or sanitation were included. Anemia was defined as an altitude-adjusted Hb concentration <110 g/L. Household water source and sanitation variables were dichotomized as "improved" or "unimproved." Poisson regressions with robust variance estimates were conducted for each survey, adjusting for child sex, age, household socioeconomic status, maternal education, and type of residence. RESULTS: Access to an improved water source and improved sanitation ranged from 29.9% (Burkina Faso) to 98.4% (Bangladesh, 2012), and from 0.2% (Kenya, 2007) to 97.4% (Philippines), respectively. Prevalence of anemia ranged from 20.1% (Nicaragua) to 83.5% (Bangladesh, 2010). Seven surveys showed negative associations between anemia and improved sanitation. Three surveys showed association between anemia and improved water, with mixed directions. Meta-analyses suggested a protective association between improved household sanitation and anemia [adjusted prevalence ratio (aPR) = 0.88; 95% CI: 0.79, 0.98], and no association between improved household water and anemia (aPR = 1.00; 95% CI: 0.91, 1.10). There was heterogeneity across surveys for sanitation (P < 0.01; I2 = 66.3%) and water (P < 0.01; I2 = 55.8%). CONCLUSIONS: Although improved household sanitation was associated with reduced anemia prevalence in PSC in some surveys, this association was not consistent. Access to an improved water source in general had no association with anemia across surveys. Additional research could help clarify the heterogeneity between these conditions across countries to inform anemia reduction programs.

BACKGROUND: Vitamin B-12 and folate deficiencies in women and children have important public health implications. However, the evidence is conflicting and limited on whether the influence of inflammation on biomarker concentrations may be sufficiently and consistently influenced by inflammation to require adjustment for interpreting concentrations or estimating population prevalence of deficiencies. OBJECTIVE: We examined correlations between concentrations of the inflammation biomarkers C-reactive protein (CRP) and alpha1-acid glycoprotein (AGP) and serum vitamin B-12 and serum and RBC folate among nonpregnant women of reproductive age (WRA; 15-49 yr) and preschool children (PSC; 6-59 mo). METHODS: We analyzed cross-sectional data from 16 nationally representative nutrition surveys conducted in WRA (n = 32,588) and PSC (n = 8,256) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project. Spearman correlations between CRP or AGP and vitamin B-12 or folate concentrations were examined, taking into account complex survey design effects. RESULTS: Correlations between inflammation and vitamin B-12 or folate were weak, with no clear pattern of association in either WRA or PSC. Correlation coefficients between CRP and vitamin B-12 for WRA and PSC ranged from -0.25 to 0.16, and correlations between AGP and vitamin B-12 ranged between -0.07 and 0.14. Similarly, correlations between CRP and serum folate ranged from -0.13 to 0.08, and correlations between AGP and serum folate between -0.21 and 0.02. Only 3 surveys measured RBC folate, and among them, correlations for WRA ranged from -0.07 to 0.08 for CRP and -0.04 for AGP (1 country). CONCLUSIONS: Based on the weak and inconsistent correlations between CRP or AGP and vitamin B-12 or folate biomarkers, there is no rationale to adjust for inflammation when estimating population prevalence of vitamin B-12 or folate deficiencies in WRA or PSC.

BACKGROUND: Valid measurement of hemoglobin is important for tracking and targeting interventions. This study compares hemoglobin distributions between surveys matched by country and time from The Demographic and Health Survey (DHS) Program and the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. METHODS: Four pairs of nationally representative surveys measuring hemoglobin using HemoCue(R) with capillary (DHS) or venous (BRINDA) blood were matched by country and time. Data included 17,719 children (6-59 months) and 21,594 non-pregnant women (15-49 y). Across paired surveys, we compared distributional statistics and anemia prevalence. RESULTS: Surveys from three of the four countries showed substantial differences in anemia estimates (9 to 31 percentage point differences) which were consistently lower in BRINDA compared to DHS (2 to 31 points for children, 1 to 16 points for women). CONCLUSION: We identify substantial differences in anemia estimates from surveys of similar populations. Further work is needed to identify the cause of these differences to improve the robustness of anemia estimates for comparing populations and tracking improvements over time.

We thank McSorley, Talwar, and McMillan for their comments on the series of publications on assessing iron status in settings of inflammation, from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Specifically, the authors highlight the lack of availability of α1-acid glycoprotein (AGP) in clinical settings as a measure of inflammation and suggest instead, to use C-reactive protein (CRP) and serum albumin, which are more routinely available. We acknowledge that assessment of the acute phase response is complicated and that many potential biomarkers of inflammation could be used depending on factors such as the stage of inflammation (e.g., acute compared with chronic), clinical compared with population use, and applicability in resource-limiting settings. The advantages and disadvantages of available biomarkers of inflammation have been recently reviewed, and there has been a call for field-friendly and cost-effective biomarkers that are standardized across laboratories (1, 2). In the datasets that were compiled for the BRINDA project, no surveys measured albumin, so we were unable to assess its relationship with the various biomarkers of nutrition. Serum albumin, which has a long half-life (∼20 d), is most commonly used to identify malnutrition in clinical settings; however, because albumin also acts as a negative acute phase protein, concentrations are lowered by infection, injury, or inflammation irrespective of nutritional status (3, 4). We concur with the authors that the utility of serum albumin or other inflammatory biomarkers, as a potential replacement of AGP as a measure of long-term inflammation, could be explored further.

The accurate estimation of vitamin A deficiency (VAD) is critical to informing programmatic and policy decisions that could have important public health implications. However, serum retinol and retinol binding protein (RBP) concentrations, two biomarkers often used to estimate VAD, are temporarily altered during the acute phase response, potentially overestimating the prevalence of VAD in populations with high levels of inflammation. In 22 nationally-representative surveys, we examined (1) the association between C-reactive protein (CRP) or alpha1-acid glycoprotein (AGP) and retinol or RBP, and (2) how different adjustment approaches for correcting for inflammation compare with one another. In preschool age children (PSC) and school age children (SAC), the association between inflammation and retinol and RBP was largely statistically significant; using the regression approach, adjustments for inflammation decreased the estimated prevalence of VAD compared to unadjusted VAD (range: -22.1 to -6.0 percentage points). In non-pregnant women of reproductive age (WRA), the association between inflammation and vitamin A biomarkers was inconsistent, precluding adjustments for inflammation. The burden of VAD can be overestimated if inflammation is not accounted for, and the regression approach provides a method for adjusting retinol and RBP for inflammation across the full range of concentrations in PSC and SAC.

BACKGROUND: Food fortification is one approach for addressing anemia, but information on program effectiveness is limited. OBJECTIVE: We evaluated the impact of Costa Rica's fortification program on anemia in women aged 15-45 y and children aged 1-7 y. DESIGN: Reduced iron, an ineffective fortificant, was replaced by ferrous fumarate in wheat flour in 2002, and ferrous bisglycinate was added to maize flour in 1999 and to liquid and powdered milk in 2001. We used a one-group pretest-posttest design and national survey data from 1996 (baseline; 910 women, 965 children) and 2008-2009 (endline; 863 women, 403 children) to assess changes in iron deficiency (children only) and anemia. Data were also available for sentinel sites (1 urban, 1 rural) for 1999-2000 (405 women, 404 children) and 2008-2009 (474 women, 195 children), including 24-h recall data in children. Monitoring of fortification levels was routine. RESULTS: Foods were fortified as mandated. Fortification provided about one-half the estimated average requirement for iron in children, mostly and equally through wheat flour and milk. Anemia was reduced in children and women in national and sentinel site comparisons. At the national level, anemia declined in children from 19.3% (95% CI: 16.8%, 21.8%) to 4.0% (95% CI: 2.1%, 5.9%) and in women from 18.4% (95% CI: 15.8%, 20.9%) to 10.2% (95% CI: 8.2%, 12.2%). In children, iron deficiency declined from 26.9% (95% CI: 21.1%, 32.7%) to 6.8% (95% CI: 4.2%, 9.3%), and iron deficiency anemia, which was 6.2% (95% CI: 3.0%, 9.3%) at baseline, could no longer be detected at the endline. CONCLUSIONS: A plausible impact pathway suggests that fortification improved iron status and reduced anemia. Although unlikely in the Costa Rican context, other explanations cannot be excluded in a pre/post comparison.