Mandatory fortification of rice in the public distribution system in India: An ethics perspective.

In response to the continuing high prevalence of anaemia recorded in the National Family Health Survey-5, the Indian government launched a policy for mandatory iron fortification of the rice provided through public nutrition programmes in India. This was done even though a rigorous evidence analysis had already concluded that rice fortification was not effective in preventing anaemia or iron deficiency at the population level. Fortification also poses a potential risk of iron toxicity over time, but there is no stated time period for the policy's implementation. The risk is particularly high in segments of the population who already have a high habitual iron intake, and who could be exposed to simultaneous fortification in different staples and food commodities along with the ongoing weekly Iron and Folic Acid tablets supplementation programme. Finally, this fortification policy also requires significant additional funding and resources to implement. It is crucial to examine such mandatory health actions, and to weigh the benefits and risks of harm, using the principles of public health ethics.

Haemoglobin diagnostic cut-offs for anaemia in Indian women of reproductive age.

BACKGROUND: The persistent high prevalence of anaemia among Indian women of reproductive age (WRA) despite aggressive long-term iron supplementation could be related to over-diagnosis from an inappropriately high haemoglobin (Hb) diagnostic cut-off. To develop an appropriate cut-off for Indian WRA, we hypothesized that during iron-folic acid (IFA) supplementation to a mixed (anaemic/non-anaemic) WRA population, the positive slope of the Hb-plasma ferritin (PF) response in anaemic women would inflect into a plateau (zero-response) as a non-anaemic status is reached. The 2.5th percentile of the Hb distribution at this inflection point will be the diagnostic Hb cut-off for iron-responsive anaemia. METHOD: A hierarchical mixed effects model, with a polynomial mean and variance model to account for intraclass correlation due to repeated measures, was used to estimate the response curve of Hb to PF, or body iron stores, in anaemic and non-anaemic WRA (without inflammation), who were receiving a 90-day IFA supplementation. RESULTS: The Hb response curve at low PF values showed a steep increase, which inflected into a plateau at a PF of 10.1 µg/L and attained a steady state at a PF of 20.6 µg/L. The Hb distribution at the inflection was a normal probability distribution, with a mean of 12.3 g/dL. The 2.5th percentile value of this distribution, or the putative diagnostic Hb cut-off for anaemia, was 10.8 g/dL (~11 g/dL). CONCLUSION: The derived Hb cut-off is lower than the current adult values of 12 g/dL and could partly explain the persistently high prevalence of anaemia.

A proposed method for defining the required fortification level of micronutrients in foods: An example using iron.

In 2006, the WHO published a framework for calculating the desired level of fortification of any micronutrient in any staple food vehicle, to reduce micronutrient malnutrition. This framework set the target median nutrient intake, of the population consuming the fortified food, at the 97.5th percentile of their nutrient requirement distribution; the Probability of Inadequacy (PIA) of the nutrient would then be 2.5%. We argue here that the targeted median nutrient intake should be at Estimated Average Requirement (50th percentile), since the intake distribution will then overlap the requirement distribution in a population that is in homeostasis, resulting in a PIA of 50%. It is also important to recognize that setting the target PIA at 2.5% may put a sizable proportion at risk of adverse consequences associated with exceeding the tolerable upper limit (TUL) of intake. This is a critical departure from the WHO framework. For a population with different age- and sex-groups, the pragmatic way to fix the fortification level for a staple food vehicle is by achieving a target PIA of 50% in the most deprived age- or sex-group of that population, subject to the condition that only a very small proportion of intakes exceed the TUL. The methods described here will aid precision in public health nutrition, to pragmatically determine the precise fortification level of a nutrient in a food vehicle, while balancing risks of inadequacy and excess intake.

Association of Vitamin A Status With Under-Five Mortality in India.

OBJECTIVE: To re-estimate the survival benefit from Vitamin A supplementation (VAS) in India using meta-analysis and to correlate mortality and vitamin A deficiency (VAD) in children aged 6 month to 5 year. METHODS: Pooled risk ratio (fixed effects model) for mortality reduction with VAS was calculated from available Indian studies. Computed mortality rates in 6 months to 5 years children in Indian states were regressed on VAD prevalence estimates of the states. RESULTS: There was no reduction in risk of all-cause mortality with VAS (RR=0.96; 95% CI: 0.89, 1.03). When regressing mortality on VAD in high or low VAD prevalence states, the regression coefficients were discordant. CONCLUSION: No survival benefit was observed for VAS in India from the available literature. The targeting of VAS programs should be given serious consideration.

Perspective: When the cure might become the malady: the layering of multiple interventions with mandatory micronutrient fortification of foods in India.

When public health programs with single nutrients are perceived to have a poor impact on the target health outcome, the policy response can be to supply more, by layering additional mandatory programs upon the extant programs. However, we argue for extreme caution, because nutrients (like medicines) are beneficial in the right dose, but potentially harmful when ingested in excess. Unnecessary motivations for the reactionary layering of multiple intervention programs emerge from incorrect measurements of the risk of nutrient inadequacy in the population, or incorrect biomarker cutoffs to evaluate the extent of nutrient deficiencies. The financial and social costs of additional layered programs are not trivial when traded off with other vital programs in a resource-poor economy, and when public health ethical dilemmas of autonomy, equity, and stigma are not addressed. An example of this conundrum in India is the perception of stagnancy in the response of the prevalence of anemia to the ongoing pharmacological iron supplementation program. The reaction has been a policy proposal to further increase iron intake through mandatory iron fortification of the rice provided in supplementary feeding programs like the Integrated Child Development Services and the School Mid-Day Meal. This is in addition to the ongoing pharmacological iron supplementation as well as other voluntary iron fortifications, such as those of salt and manufactured food products. However, before supplying more, it is vital to consider why the existing program is apparently not working, along with consideration of the potential for excess intake and related harms. This is relevant globally, particularly for countries contemplating multiple interventions to address micronutrient deficiencies. Supplying more by layering multiple nutrient interventions, instead of doing it right, without thoughtful considerations of social, biological, and ethics frameworks could be counterproductive. The cure, then, might well become the malady.

Prevalence of Iron Deficiency and its Sociodemographic Patterning in Indian Children and Adolescents: Findings from the Comprehensive National Nutrition Survey 2016-18.

BACKGROUND: Anemia control programs in India focus mainly on the measurement of hemoglobin in response to iron-folic acid supplementation. However, representative national estimates of iron deficiency (ID) are not available. OBJECTIVES: The objective of the present study was to evaluate ID prevalence among children and adolescents (1-19 y) using nationally representative data and to examine the sociodemographic patterning of ID. METHODS: Cross-sectional data from the Comprehensive National Nutrition Survey in children (1-4 y: n = 9635; 5-9 y: n = 11,938) and adolescents (10-19 y; n = 11,507) on serum ferritin (SF) and other biomarkers were analyzed to determine inflammation-adjusted ID prevalence [SF (µg/L): <12 in 1-4 y and <15 in 5-19 y] and its relation to sociodemographic indicators. Multiple-regression analyses were conducted to identify the exposure associations of iron status. In addition, the relation between SF and hemoglobin was assessed as an indicator of iron utilization in different wealth quintiles. RESULTS: ID prevalence was higher in 1- to 4-y-old children (31.9%; 95% CI: 31.0%, 32.8%) and adolescent girls (30.4%; 95% CI: 29.3%, 31.5%) but lower in adolescent boys and 5- to 9-y-old children (11%-15%). In all age groups, ID prevalence was higher in urban than in rural participants (1-4 y: 41% compared with 29%) and in those from richer quintiles (1-4 y: 44% in richest compared with 22% in poorest), despite adjustment for relevant confounders. SF significantly interacted with the wealth index, with declining trends in the strength of association between hemoglobin and SF from the richest to the poorest groups suggesting impaired iron utilization for hemoglobin synthesis in poorer wealth quintiles. CONCLUSIONS: ID prevalence was indicative of moderate (in preschool children and adolescent girls) or mild (in 5- to 9-y-old children and adolescent boys) public health problem with significant variation by state and age. Focusing on increasing iron intake alone, without addressing the multiple environmental constraints related to poverty, may not result in intended benefits.

HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

PURPOSE: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. EXPERIMENTAL DESIGN: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. RESULTS: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. CONCLUSIONS: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.

Vitamin A deficiency among children younger than 5 y in India: an analysis of national data sets to reflect on the need for vitamin A supplementation.

BACKGROUND: Biochemical vitamin A deficiency (VAD) is believed to be a serious public health problem (low serum retinol prevalence >20%) in Indian children, justifying universal high-dose vitamin A supplementation (VAS). OBJECTIVE: To evaluate in Indian children younger than 5 y the risk of biochemical VAD from the Comprehensive National Nutrition Survey, as well as dietary vitamin A inadequacy and excess over the tolerable upper limit of intake (TUL) from national and subnational surveys, factoring in fortification and VAS. METHODS: Child serum retinol data, corrected for inflammation, were examined to evaluate national- and state-level prevalence of VAD. Simultaneously, dietary intakes from the National Sample Survey Office and the National Nutrition Monitoring Bureau were examined for risk of dietary vitamin A deficiency against its average requirement (AR) derived for Indian children. Theoretical estimates of risk reduction with oil and milk vitamin A fortification were evaluated along with the risk of exceeding the TUL, as well as when combined with intake from VAS. RESULTS: The national prevalence of biochemical VAD measured in 9563 children was 15.7% (95% CI: 15.2%, 16.3%), and only 3 states had prevalence significantly >20%. The AR of vitamin A was 198 and 191 µg/d for boys and girls; the risk of dietary inadequacy was ∼70%, which reduced to 25% with oil and milk fortification. Then, the risk of exceeding the TUL was 2% and 1% in 1- to 3-y-old and 4- to 5-y-old children, respectively, but when the VAS dose was added to this intake in a cumulative 6-mo framework, the risk of exceeding the TUL rose to 30% and 8%, respectively. CONCLUSION: The national prevalence of VAD risk is below 20% in Indian children. Because there is risk of excess intake with food fortification and VAS, serious consideration should be given to a targeted approach in place of the universal VAS program in India.

Thiamine-responsive acute severe pulmonary hypertension in exclusively breastfeeding infants: a prospective observational study.

OBJECTIVES: Severe pulmonary hypertension (PH) causing right heart failure can occur due to thiamine deficiency in exclusively breastfeeding infants. This study describes the clinical profile and management of thiamine-responsive acute pulmonary hypertension. METHODS: A prospective observational study of infants presenting with severe PH without any other significant heart or lung disease. History of symptoms, clinical examination, echocardiography and basic investigations were performed. Dietary patterns of mothers were recorded. Thiamine was administered and serial echocardiography was performed. RESULTS: A total of 250 infants had severe PH and 231 infants responded to thiamine. The mean age was 3.2±1.2 months. Fast breathing, poor feeding, vomiting and aphonia were the main symptoms. Tachypnoea, tachycardia and hepatomegaly were found on examination. Echocardiogram revealed grossly dilated right heart with severe PH. Intravenous thiamine was administered to all the babies based on clinical suspicion. Clinical improvement with complete resolution of PH was noticed within 24-48 hours. Babies were followed up to a maximum of 60 months with no recurrence of PH. All the mothers consumed polished rice and followed postpartum food restriction. CONCLUSION: Thiamine deficiency is still prevalent in selected parts of India. It can cause life-threatening PH in exclusively breastfeeding infants of mothers who are on a restricted diet predominantly consisting of polished rice. It can contribute to infant mortality. Thiamine administration based on clinical suspicion leads to remarkable recovery. High degree of awareness and thiamine supplementation in relevant geographical areas is required to tackle this fatal disease.

Demographic and Risk-Factor Differences between Users and Non-Users of Unscheduled Healthcare among Pediatric Outpatients with Persistent Asthma.

This study assesses differences between users and non-users of unscheduled healthcare for persistent childhood asthma, with regard to select demographic and risk factors. The objectives are to provide important healthcare utilization information and a foundation for future research on self-management effectiveness (SME), informed by a recently developed "holistic framework" for measuring SME in childhood asthma. An 18-month retrospective chart review was conducted on 59 pediatric outpatients with persistent asthma-mild, moderate, or severe, to obtain data on various demographic and risk factors, and healthcare use for each child. The study examined five types of "unscheduled" healthcare use. Users had non-zero encounters (at least one) in any of the five types; non-users had zero encounters (not even one) in all five types. Differences between users and non-users were assessed using contingency table and logistic regression analysis. There were 25 users and 34 non-users of unscheduled healthcare. Each severity category contained users and non-users. The only statistically significant finding was that the mild persistent category had fewer users than severe persistent (p < 0.05). There were no significant differences between users and non-users for any other demographic or risk factor examined. After adjusting for asthma severity, there were no other significant differences between users and non-users of unscheduled healthcare. This is a crucial finding which suggests that something else is driving unscheduled healthcare use in these children, given there were users and non-users in each asthma severity category. These results provide impetus for future research on the role of other aspects of the "holistic framework" in explaining differences in uses of unscheduled healthcare in persistent childhood asthma.

Daily Iron Requirements in Healthy Indian Children and Adolescents.

OBJECTIVE: This study aimed to define the estimated average requirement and the recommended dietary allowance of iron for Indian children and adolescents. Methods: The Estimated average requirement was derived for children aged 1-17y, from the mean bioavailability-adjusted daily physiological iron requirement, which in turn was estimated using a factorial method. This consisted of mean daily iron losses from the body and additional iron required for tissue growth and storage, while also defining the variance of each factor to derive the Recommended dietary allowance. RESULTS: Results: The estimated average requirement of iron for children ranged from 5.6 to 11.0 mg/d in children aged 1-9y. For adolescents aged 10-17y, these ranged from 10.8 to 18.4 mg/d and 15.4 to 18.5 mg/d for adolescent boys and girls, respectively. CONCLUSIONS: New estimates of estimated average requirement for iron in Indian children are presented, and same may be used to inform iron supplementation and food fortification policies.

Dietary Iron Intake and Anemia Are Weakly Associated, Limiting Effective Iron Fortification Strategies in India.

BACKGROUND: Anemia prevalence in India remains high despite preventive iron supplementation programs. Consequently, concurrent national policies of iron fortification of staple foods have been initiated. OBJECTIVES: This study evaluated the relation between dietary iron intake and anemia (hemoglobin <12 g/dL) in women of reproductive age (WRA; 15-49 y) with respect to iron fortification in India. METHODS: Data from 2 national surveys were used. Data on hemoglobin in WRA were sourced from the National Family Health Survey-4, whereas dietary intakes were sourced from the National Sample Survey. Adjusted odds for anemia with increasing iron intake were estimated, along with the effect of modulating nutrients such as vitamins B-12 and C, from statistically matched household data from the 2 surveys. The risks of inadequate (less than the Estimated Average Requirement for WRA) and excess (more than the tolerable upper limit for WRA) intakes of iron were estimated by the probability approach. RESULTS: The relation between iron intake and the odds of anemia was weak (OR: 0.992; 95% CI: 0.991, 0.994); increasing iron intake by 10 mg/d reduced the odds of anemia by 8%. Phytate and vitamin B-12 and C intakes modified this relation by reducing the odds by 1.5% when vitamin B-12 and C intakes were set at 2 µg/d and 40 mg/d, respectively. The additional intake of 10 mg/d of fortified iron reduced the risk of dietary iron inadequacy from 24-94% to 9-39% across states, with no risk of excess iron intake. Approximately doubling this additional iron intake reduced the risk of inadequacy to 2-12%, but the risk of excess intake reached 22%. CONCLUSIONS: Providing fortified iron alone may not result in substantial anemia reduction among WRA in India and could have variable benefits and risks across states. Geographically nuanced dietary strategies that include limited fortification and the intake of other beneficial nutrients should be carefully considered.

Revisiting Dietary Iron Requirement and Deficiency in Indian Women: Implications for Food Iron Fortification and Supplementation.

Anemia in Indian women continues to be highly prevalent, and is thought to be due to low dietary iron content. The high risk of dietary iron deficiency is based on the Indian Council of Medical Research recommendation of 21 mg/d, but there is a need for a secure and transparent determination of the Estimated Average Requirement (EAR) of iron in this population. In nonpregnant, nonlactating women of reproductive age (WRA), the EAR of iron was determined to be 15 mg/d. Applying this value to daily iron intakes among WRA in nationally representative Indian state-based data showed that the median risk of dietary iron deficiency was lower than previously thought (65%; IQR: 48-78%), with considerable heterogeneity between states (range: 25-93%). However, in a validation, this risk matched the risk of iron deficiency as defined by blood biomarkers in a recently completed survey. When the risk of dietary iron deficiency was modelled for an increase in iron intake through food fortification of a single dietary staple, that provided 10 mg/d, the median risk reduced substantially (from 65% to 20%), and it virtually disappeared when supplementary iron intakes through the national iron supplementation program were considered. The risk of exceeding the tolerable upper level (TUL) of intake of iron remains low in the population when receiving fortification of 10 mg/d, but is much higher if they consume greater amounts of iron through supplements (range: 0-54%). This newly and transparently defined Indian EAR of iron should be used to evaluate, with precision, the benefits and risks of iron fortification and supplementation policies.