Development of specific growth charts for children with Fanconi anemia.

Patients with Fanconi anemia (FA) are often perceived to have poor growth when general population growth curves are utilized. We hypothesize that FA patients have unique growth and aimed to create FA-specific growth charts. Height and weight data from ages 0 to 20 years were extracted from medical records of patients treated at the Fanconi Anemia Comprehensive Care Clinic at the University of Minnesota. Height, weight, and BMI growth curves were generated and fitted to reference percentiles using the Lambda-Mu-Sigma method. FA-specific percentiles were compared to WHO standards for ages 0-2 and CDC references for ages 2-20. In FA males, the 50th height- and weight-for-age percentiles overlap with the 3rd reference percentile. In FA females, only the 50th height-for-age percentile overlaps with the 3rd reference percentile. For weight, FA females show progressive growth failure between 6 and 24 months followed by stabilization around the 50th percentile. The FA BMI-for-age percentiles show similar patterns to the weight-for-age percentiles but have different timing of onset of adiposity rebound and broader variability in females. Growth in FA patients follows a different trajectory than available normative curves. FA-specific growth charts may be useful to better guide accurate growth expectations, evaluations, and treatment.

Trends in Micronutrient Interventions, Anemia, and Iron Deficiency among Women and Children in Guatemala, 2009-2019.

Background: Food fortification and micronutrient supplementation are public health strategies to improve micronutrient status in Guatemala; their population effectiveness has not been evaluated in recent years. Objective: We evaluated trends in food fortification, micronutrient supplementation, anemia, and iron deficiency among nonpregnant women aged 15-49 y [women of reproductive age (WRA)] and children 6-59 aged mo [preschool age children (PSC)]. Method: Nationally representative serial cross-sectional surveys were used to assess changes in hemoglobin, anemia, ferritin, iron deficiency, iron deficiency anemia, and self-reported consumption of fortifiable foods and micronutrient supplements during 2008/2009, 2013, 2015, 2016, 2017/2018, and 2018/2019. Predictors of hemoglobin and ferritin were assessed using generalized linear mixed models adjusted for survey year as random effects, and the consumption of fortifiable foods, supplements, and other potential confounders were fixed effects. Results: Multiple micronutrient powder consumption among PSC during the previous 3 mo was 53.3% (95% CI: 49.4, 57.2) in 2013 and 33.6% (28.8, 38.4) in 2018/2019. Anemia among PSC was 11.3% (8.0, 14.5) in 2008/2009 and 6.1% (3.6, 8.6) in 2018/2019. Anemia among WRA was 10.7% (7.2, 14.2) in 2008/2009 and 3.9% (2.7, 5.2) in 2018/2019. Iron deficiency among PSC was 15.5% (12.1, 19.0) in 2008/2009 and 10.9% (7.4, 14.5) in 2016 (lowest), but 17.1 (13.3, 21.0) in 2017/2018 (highest). Iron deficiency among WRA was 14.9% (11.6, 18.2) in 2008/2009, 13.8% (11.8, 15.8) in 2013 (lowest), and 18.9% (16.3, 21.6) in 2017/2018 (highest). Wheat flour/bread consumption was positively associated with hemoglobin among PSC, and sugar consumption was positively associated with hemoglobin among WRA. The reported consumption of fortifiable foods was not associated with ferritin among PSC or WRA. Conclusions: Guatemala has implemented multiple food fortification strategies, and anemia has declined. Increases in iron deficiency in 2017-2019 warrant further attention. Secular trends toward poverty alleviation, education, and development might be responsible for changes not explained by the micronutrient interventions evaluated.

Comparison of Current World Health Organization Guidelines with Physiologically Based Serum Ferritin Thresholds for Iron Deficiency in Healthy Young Children and Nonpregnant Women Using Data from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Current WHO serum ferritin (SF) thresholds for iron deficiency (ID) in children (<12 µg/L) and women (<15 µg/L) are derived from expert opinion based on radiometric assays in use decades ago. Using a contemporary immunoturbidimetry assay, higher thresholds (children, <20 µg/L; women, <25 µg/L) were identified from physiologically based analyses. OBJECTIVE: We examined relationships of SF measured using an immunoradiometric assay from the era of expert opinion with 2 independently measured indicators of ID, hemoglobin (Hb) and erythrocyte zinc protoporphyrin (eZnPP), using data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). The SF at which circulating Hb begins to decrease and eZnPP begins to increase provides a physiological basis for identifying the onset of iron-deficient erythropoiesis. METHODS: We analyzed NHANES III cross-sectional data from 2616 apparently healthy children, aged 12-59 mo, and 4639 apparently healthy nonpregnant women, aged 15-49 y. We used restricted cubic spline regression models to determine SF thresholds for ID. RESULTS: SF thresholds identified by Hb and eZnPP did not differ significantly in children, 21.2 µg/L (95% confidence interval: 18.5, 26.5) and 18.7 µg/L (17.9, 19.7), and, in women, were similar although significantly different, 24.8 µg/L (23.4, 26.9) and 22.5 µg/L (21.7, 23.3). CONCLUSIONS: These NHANES results suggest that physiologically based SF thresholds are higher than the thresholds from expert opinion established during the same era. SF thresholds found using physiological indicators detect the onset of iron-deficient erythropoiesis, whereas the WHO thresholds identify a later, more severe stage of ID.

Physiologically based serum ferritin thresholds for iron deficiency in women of reproductive age who are blood donors.

Our objective is to develop a physiologically based method to determine serum ferritin thresholds for iron deficiency in healthy individuals. The current World Health Organization threshold of <15 µg/L for iron deficiency in women is based on expert opinion. We examined the relationship between serum ferritin and 2 independently measured indicators of iron-deficient erythropoiesis, soluble transferrin receptor (sTfR) and hemoglobin, in baseline data from 286 women, 20 to 49 years, who were first-time or reactivated donors in the Retrovirus Epidemiology Donor Study-II Donor Iron Status Evaluation (REDS-RISE) study. At lower serum ferritin concentrations, median sTfR increased as hemoglobin decreased. Using restricted cubic spline regression analysis to determine thresholds for iron-deficient erythropoiesis, the thresholds identified by sTfR (serum ferritin < 25.4 µg/L) and hemoglobin (serum ferritin < 25.3 µg/L) did not differ significantly. The thresholds found in the REDS-RISE study do not differ from those identified by sTfR (serum ferritin < 25.5 µg/L) and hemoglobin (serum ferritin < 26.6 µg/L) in a previous study of 5442 women, 20 to 49 years, in the US National Health and Nutrition Examination Survey 2003 to 2018 (P = .98 and 0.83, respectively). Although international comparisons are needed, these results with US data provide additional evidence for the potential usefulness of a physiologically based method to identify serum ferritin thresholds for iron deficiency.

Limits of Detection in Acute-Phase Protein Biomarkers Affect Inflammation Correction of Serum Ferritin for Quantifying Iron Status among School-Age and Preschool-Age Children and Reproductive-Age Women.

BACKGROUND: Standardized practices are needed in the analysis of inflammation biomarker values outside limits of detection (LODs) when used for inflammation correction of nutritional biomarkers. OBJECTIVE: We assessed the direction and extent to which serum C-reactive protein (CRP) and α-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: We examined 29 cross-sectional datasets from 7 countries with reproductive-age women (age 15-49 y) (n = 12,944), preschool-age children (age 6-59 mo) (n = 18,208), and school-age children (age 6-14 y) (n = 4625). For each dataset, we compared 6 analytic approaches for addressing CRP

A Qualitative Analysis of Program Fidelity and Perspectives of Educators and Parents after Two Years of the Girls' Iron-Folate Tablet Supplementation (GIFTS) Program in Ghanaian Secondary Schools.

BACKGROUND: To address the burden of anemia in adolescent girls in Ghana, the Girls' Iron-Folate Tablet Supplementation (GIFTS) program was established in 2017. An evaluation found that although iron and folic acid (IFA) supplementation reached nearly all adolescent girls in schools during year 1, most girls received fewer than the minimum effective number of tablets over the school year. Barrier analyses highlighted schools as drivers of adherence, though information was incomplete on the reasons for the disparities among schools. Information was also lacking on the implementation of health and nutrition education. OBJECTIVES: At the start of year 3 of an integrated adolescent anemia prevention program with IFA supplementation, the present study sought to illuminate differences in program fidelity among schools and across time and potential factors that drive such differences. METHODS: After stratifying by school level, size, geographic location, and intake adherence during year 1, 16 schools were purposively selected. For each school, semistructured key informant interviews were conducted with 1 coordinator at the district level, 3 educators at the school level, and 1 parent leader. Following thematic analysis methods, recorded and transcribed interviews were coded and organized into deductive and inductive themes. RESULTS: Limited training, challenges during distribution of IFA, lack of incentives, and inconsistent health and nutrition education diminished program fidelity. Strong supply chain, widespread awareness promotion, improved acceptability, and intrinsically motivated educators improved program fidelity. After 2 y of implementation, schools had made program adaptations, and widespread changes in attitudes and beliefs about the IFA tablets had improved their acceptability. However, limitations remained related to supply chain, program ownership, communication between health and education sectors, training, motivation, and resources. CONCLUSIONS: The fidelity of Ghana's GIFTS program is strengthened by its supply chain, acceptability, and motivated stakeholders; however, training, curricula, clear communication, and incentives could improve it.

Physiologically based serum ferritin thresholds for iron deficiency in children and non-pregnant women: a US National Health and Nutrition Examination Surveys (NHANES) serial cross-sectional study.

BACKGROUND: Serum ferritin concentrations are the most widely used indicator for iron deficiency. WHO determined that insufficient data are available to revise the serum ferritin thresholds of less than 12 µg/L for children and less than 15 µg/L for women, which were developed on the basis of expert opinion, to define iron deficiency. We aimed to derive new physiologically based serum ferritin concentration thresholds for iron deficiency in healthy young children and non-pregnant women using data from the US National Health and Nutrition Examination Survey (NHANES). METHODS: In this serial cross-sectional study, we examined the relationship of serum ferritin with two independent indicators of iron-deficient erythropoiesis, haemoglobin and soluble transferrin receptor (sTfR), in children (12-59 months) and non-pregnant women (15-49 years) using cross-sectional NHANES data from 2003-06, 2007-10, and 2015-18. NHANES is a US national stratified multistage probability sample that includes a household interview followed by a standardised physical examination in a mobile examination centre. We excluded individuals with missing serum ferritin, sTfR, haemoglobin, or white blood cell counts measurements; non-pregnant women with missing C-reactive protein (CRP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) data were also excluded. In addition, individuals with infection (white blood cell counts >10·0×109/L) and non-pregnant women with possible liver disease (ALT >70 IU/L or AST >70 IU/L) and inflammation (CRP >5·0 mg/L) were excluded. We examined distributions of haemoglobin and sTfR with serum ferritin and used restricted cubic spline regression models to determine serum ferritin thresholds for iron-deficient erythropoiesis. FINDINGS: 5964 children and 10 462 non-pregnant women had physical examinations and were screened for inclusion in the study, of whom 2569 (43·1%) children and 7498 (71·7%) non-pregnant women were included. At lower serum ferritin concentrations, median haemoglobin concentration decreased as sTfR concentration increased, with each varying in a curvilinear manner. Using restricted cubic spline plateau points to determine the onset of iron-deficient erythropoiesis, the serum ferritin thresholds identified by haemoglobin and sTfR concentrations were not different. For children, the haemoglobin identified serum ferritin threshold was 19·9 µg/L (95% CI 18·8-22·6) and the sTfR identified serum ferritin threshold was 20·0 µg/L (19·4-20·9; p=0·89). For women the haemoglobin identified serum ferritin threshold was 25·2 µg/L (24·2-26·2) and the sTfR identified serum ferritin threshold was 24·0 µg/L (23·3-24·6; p=0·05). INTERPRETATION: The association between two independent indicators of iron-deficient erythropoiesis, haemoglobin and sTfR, identified serum ferritin concentration thresholds of about 20 µg/L for children and 25 µg/L for non-pregnant women, providing physiological evidence of potential new thresholds for consideration when determining the prevalence and distribution of iron deficiency in populations. In healthy children and non-pregnant women, physiologically based thresholds for iron deficiency might be more clinically and epidemiologically relevant than those based on expert opinion. Validation of this physiologically based approach in non-US populations might help the international harmonisation of serum ferritin thresholds for iron deficiency. FUNDING: None.

A School-Based Weekly Iron and Folic Acid Supplementation Program Effectively Reduces Anemia in a Prospective Cohort of Ghanaian Adolescent Girls.

BACKGROUND: School-based iron and folic acid (IFA) supplementation is recommended for adolescent girls in countries with high burdens of anemia. OBJECTIVES: We aimed to evaluate the context-specific effectiveness of a school-based, integrated anemia control program with IFA supplementation in Ghana. METHODS: Using data from a pre-post, longitudinal program evaluation, we evaluated the effectiveness of school-based weekly IFA supplementation in reducing the burden of anemia and increasing hemoglobin concentrations (Hb; primary outcomes) in 2 regions of Ghana. Generalized linear mixed effects models with schools (clusters) as random effects were used to quantify the change in the anemia prevalence and the mean Hb associated with cumulative IFA tablet consumption over 1 school year (30-36 weeks), controlling for participant-level potential confounders. A cut point for minimum effective cumulative IFA consumption that is reflective of adequate Hb was derived following logistic regression. This cut point was verified by a restricted cubic spline model of IFA consumption and Hb. RESULTS: The analytical sample included 60 schools and 1387 girls ages 10-19 years. The prevalence of anemia declined during 1 school year of the intervention, from 25.1% to 19.6% (P = 0.001). Students consumed a mean of 16.4 IFA tablets (range, 0-36). IFA consumption was positively associated with Hb and negatively associated with anemia. Each additional IFA tablet consumed over the school year was associated with a 5% (95% CI, 1-10%) reduction in the adjusted odds of anemia at follow-up, though the relationship is nonlinear. The cut point for minimum effective consumption was 26.7 tablets over a 30-36-week school year, with tablets provided weekly. CONCLUSIONS: School-based weekly IFA supplementation is effective in improving Hb and reducing the anemia prevalence among schoolgirls in Ghana, though most participants consumed fewer than the minimum effective number of IFA tablets. Increasing intake adherence may further improve anemia outcomes in this population.

Initial engagement and persistence of health risk behaviors through adolescence: longitudinal findings from urban South Africa.

BACKGROUND: Little is known about longitudinal patterns of adolescent health risk behavior initial engagement and persistence in low- and middle-income countries. METHODS: Birth to Twenty Plus is a longitudinal birth cohort in Soweto-Johannesburg, South Africa. We used reports from Black African participants on cigarette smoking, alcohol, cannabis, illicit drug, and sexual activity initial engagement and adolescent pregnancy collected over 7 study visits between ages 11 and 18 y. We fit Kaplan-Meier curves to estimate behavior engagement or adolescent pregnancy, examined current behavior at age 18 y by age of first engagement, and performed a clustering analysis to identify patterns of initial engagement and their sociodemographic predictors. RESULTS: By age 13 y, cumulative incidence of smoking and alcohol engagement were each > 21%, while the cumulative incidence of other behaviors and adolescent pregnancy were < 5%. By age 18 y (15 y for cannabis), smoking, alcohol, and sexual activity engagement estimates were each > 65%, cannabis and illicit drug engagement were each > 16%; adolescent pregnancy was 31%. Rates of engagement were higher among males. Current risk behavior activity at age 18 y was generally unrelated to age of initial engagement. We identified three clusters reflecting low, moderate, and high-risk patterns of initial risk behavior engagement. One-third of males and 17% of females were assigned to the high-risk cluster. Sociodemographic factors were not associated with cluster membership. CONCLUSIONS: Among urban dwelling Black South Africans, risk behavior engagement across adolescence was common and clustered into distinct patterns of initial engagement which were unrelated to the sociodemographic factors assessed. Patterns of initial risk behavior engagement may inform the timing of primary and secondary public health interventions and support integrated prevention efforts that consider multiple behaviors simultaneously.

Barriers to and Facilitators of Iron and Folic Acid Supplementation within a School-Based Integrated Nutrition and Health Promotion Program among Ghanaian Adolescent Girls.

BACKGROUND: Anemia is a moderate public health problem among adolescent girls in Ghana. OBJECTIVES: We aimed to evaluate the barriers to and facilitators of program fidelity to a school-based anemia reduction program with weekly iron and folic acid (IFA) supplementation. METHODS: Authors analyzed directly observed weekly IFA consumption data collected longitudinally and cross-sectional data from a representative survey of 60 secondary schools and 1387 adolescent girls in the Northern and Volta regions of Ghana after 1 school year (2017-2018) of the intervention (30-36 wk). A bottleneck analysis was used to characterize the levels of IFA coverage and used adjusted generalized linear mixed-effects models to quantify the school and student drivers of IFA intake adherence. RESULTS: Of girls, 90% had ever consumed the tablet, whereas 56% had consumed ≥15 weekly tablets (mean: 16.4, range: 0-36), indicating average intake adherence was about half of the available tablets. Among ever consumers, 88% of girls liked the tablet, and 27% reported undesirable changes (primarily heavy menstrual flow). School-level factors represented 75% of the variance in IFA consumption over the school year. Total IFA tablets consumed was associated with the ability to make up missed IFA distributions (+1.4 tablets; 95% CI: +0.8, +2.0 tablets), junior compared with senior secondary school (+5.8; 95% CI: +0.1, +11.5), educators' participating in a program-related training (+7.6; 95% CI: +2.9, 12.2), and educator perceptions that implementation was difficult (-6.9; 95% CI: -12.1, -1.7) and was an excessive time burden (-4.4; 95% CI: -8.4, -0.4). CONCLUSIONS: Although the program reached Ghanaian schoolgirls, school-level factors were barriers to adherence. Modifications such as expanded training, formalized make-up IFA distributions, sensitization (awareness promotion), and additional support to senior high schools may improve adherence. Spreading the responsibility for IFA distribution to other teachers and streamlining monitoring may reduce the burden at the school level. Strengthening the health education component and improving knowledge of IFA among students may also be beneficial.

Reexamination of hemoglobin adjustments to define anemia: altitude and smoking.

The correct interpretation of hemoglobin (Hb) to identify anemia requires adjusting for altitude and smoking. Current adjustments were derived using data collected before 1985, from low-income preschool-aged children (PSC) in the United States and indigenous men in Peru for altitude, and from White women of reproductive age (WRA) in the United States for smoking. Given the oldness and limited representativeness of these data, we reexamined associations between Hb and altitude and/or smoking using 13 population-based surveys and 1 cohort study each conducted after 2000. All WHO regions except South-East Asia were represented. The dataset included 68,193 observations among PSC (6-59 months) and nonpregnant WRA (15-49 years) with data on Hb and altitude (-28 to 4000 m), and 19,826 observations among WRA with data on Hb and smoking (status or daily cigarette quantity). Generalized linear models were used to assess the robustness of associations under varying conditions, including controlling for inflammation-corrected iron and vitamin A deficiency. Our study confirms that Hb should be adjusted for altitude and/or smoking; these adjustments are additive. However, recommendations for Hb adjustment likely need updating. Notably, current recommendations may underadjust Hb for light smokers and for those residing at lower altitudes and overadjust Hb for those residing at higher altitudes.

Four years after implementation of a national micronutrient powder program in Kyrgyzstan, prevalence of iron deficiency and iron deficiency anemia is lower, but prevalence of vitamin A deficiency is higher.

BACKGROUND/OBJECTIVES: In 2009, the Ministry of Health of Kyrgyzstan launched a national Infant and Young Child Nutrition (IYCN) program which included point-of-use fortification of foods with micronutrient powders (MNP) containing iron, vitamin A, and other micronutrients. Caretakers of children aged 6-23 months were given 30 sachets of MNP every 2 months. Micronutrient surveys were conducted in 2009 and 2013. The objective of the study was to compare the prevalence of anemia and deficiencies of iron and vitamin A among children aged 6-29 months prior to the MNP program (2009) with those after full implementation (2013). SUBJECTS/METHODS: Cross-sectional national surveys were conducted in 2009 (n = 666) and 2013 (n = 2150). Capillary blood samples were collected to measure hemoglobin, iron (ferritin and soluble transferrin receptor [sTfR]) and vitamin A (retinol binding protein [RBP]) status, and inflammation status (C-reactive protein [CRP] and α-1-acid glycoprotein [AGP]). Ferritin, sTfR, and RBP were adjusted for inflammation; hemoglobin was adjusted for altitude. RESULTS: The prevalence of anemia was non-significantly lower in 2013 compared to 2009 (32.7% vs. 39.0%, p = 0.076). Prevalence of inflammation-adjusted iron deficiency (54.8% vs. 74.2%, p<0.001) and iron deficiency anemia (IDA, 25.5% vs. 35.1%, p = 0.003) were lower and the prevalence of inflammation-adjusted vitamin A deficiency was higher (4.3% vs. 2.0%, p = 0.013) in 2013 compared to 2009. CONCLUSIONS: Four years after the initiation of a national Infant and Young Child Nutrition program including the introduction of point-of-use fortification with MNP, the prevalence of iron deficiency and IDA is lower, but the prevalence of vitamin A deficiency is higher.

Adjusting total body iron for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.

Background: Total body iron (TBI) that is calculated from ferritin and soluble transferrin receptor (sTfR) allows for the evaluation of the full range of iron status from deficiency to excess. However, both ferritin and sTfR are affected by inflammation and malaria, which may require a statistical adjustment. TBI has been used to assess iron status in the United States, but its use worldwide and in settings with inflammation has been limited.Objective: We examine whether inflammation-adjusted ferritin and sTfR concentrations affect TBI values and the prevalence of low TBI (<0 mg/kg) in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y).Design: Cross-sectional data for PSC (8 surveys; n = 8413) and WRA (4 surveys; n = 4258) from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined. TBI and the prevalence of low TBI were compared following 3 adjustment approaches for ferritin and sTfR: 1) the exclusion of individuals with inflammation (C-reactive protein concentration >5 mg/L or α-1-acid glycoprotein concentration >1 g/L), 2) the application of arithmetic correction factors, and 3) the use of regression correction.Results: Regardless of the method that was used to adjust ferritin and sTfR for inflammation, the adjusted mean TBI decreased in both PSC and WRA compared with unadjusted values. Subsequently, inflammation-adjusted TBI increased the prevalence of low TBI by a median of 4-14 percentage points (pps) in PSC and 1-3 pps in WRA compared with unadjusted TBI. The regression approach resulted in a greater median increase than was achieved with the exclusion or correction-factor approaches, and accounting for malaria in addition to inflammation did not have an added effect on the prevalence estimates.Conclusion: The prevalence of low TBI is underestimated if it is not adjusted by inflammation, particularly in children living in areas with a high prevalence of inflammation.

In utero exposure to cigarette smoking, environmental tobacco smoke and reproductive hormones in US girls approaching puberty.

BACKGROUND/AIMS: Evidence is unclear whether prenatal smoking affects age at menarche and pubertal development, and its impact upon hormones has not been well studied. We aim to identify potential pathways through which prenatal smoking and environmental tobacco smoke (ETS) affect reproductive hormones in girls approaching puberty. METHODS: We examined the association between prenatal smoking, current ETS and luteinizing hormone (LH) and inhibin B (InB) in 6- to 11-year-old girls in the 3rd National Health and Nutrition Examination Survey, 1988-1994. Parents/guardians completed interviewer-assisted questionnaires on health and demographics at the time of physical examination. Residual blood samples were analyzed for reproductive hormones in 2008. RESULTS: Of 660 girls, 19 and 39% were exposed to prenatal smoke and current ETS, respectively. Accounting for multiple pathways in structural equation models, prenatally exposed girls had significantly lower LH (ß = -0.205 log-mIU/ml, p < 0.0001) and InB (ß = -0.162, log-pg/ml, p < 0.0001). Prenatal smoking also influenced LH positively and InB negatively indirectly through BMI-for-age. ETS was positively associated with LH, but not with InB. CONCLUSION: Exposure to maternal smoking may disrupt reproductive development manifesting in altered hormone levels near puberty.