Interaction between vitamin A supplementation and chronic malnutrition on child development

Interação entre suplementação de vitamina A e desnutrição crônica no desenvolvimento infantil

Luciano Lima Correia Hermano Alexandre Lima Rocha Jocileide Sales Campos Anamaria Cavalcante e Silva Dirlene Mafalda Ildefonso da Silveira Márcia Maria Tavares Machado Alvaro Jorge Madeiro Leite Antonio José Ledo Alves da Cunha About the authors

Abstract

200 million pre-school age children are not developing properly. Delays in child development are associated with multiple factors. This study aims to analyze if vitamin A supplementation is associated with improved development and how this effect could be mediated by nutritional status. Population-based study surveyed a representative sample of 8000 households, 1232 children 0-35 months, in the state of Ceará, Brazil. The variables analysed included child developmental status, nutritional determinants and confounding factors. The main effects and interactions were evaluated using Cox regressive models. Vitamin A supplementation showed protective effect to delay in cognitive and motor development modified by interaction with nutritional status. While well-nourished supplemented children presented a 67% lower risk of cognitive delay (adjusted PRR = 0·33 [0·21–0·53]), stunted children had no benefit from supplementation (adjusted PRR = 0·97 [0·39–2·40]). Vitamin A supplementation has a protective effect on child development, but not in stunted children. This suggests that supplementation is effective in promoting child development, especially if associated to a joint effort to improve the nutritional status of children, given the importance of this mediator.

Key words
Vitamin A; Malnutrition; Child development; Nutrition policy

Resumo

Duzentos milhões de crianças em idade pré-escolar não estão se desenvolvendo adequadamente. Os atrasos no desenvolvimento estão associados a múltiplos fatores. Este estudo pretende analisar se a suplementação de vitamina A está associada a melhor desenvolvimento e a forma como esse efeito pode ser mediado pelo estado nutricional. Estudo de base populacional com amostra de 8.000 famílias, 1.232 crianças 0-35 meses, no estado do Ceará, Brasil. As variáveis analisadas incluíram desenvolvimento, determinantes nutricionais e fatores de confusão. Os efeitos e as interações foram avaliados utilizando modelos regressivos de Cox. A suplementação de vitamina A foi protetora para atraso no desenvolvimento cognitivo e motor modificado pela interação com o estado nutricional. Crianças suplementadas bem nutridas apresentaram um risco 67% menor de atraso cognitivo (PRR ajustado = 0 33 [0 21-0 53]), já as crianças desnutridas não se beneficiaram (PRR ajustado = 0 97 [0 39-2 40]). A suplementação tem um efeito protetor sobre o desenvolvimento, mas não em crianças desnutridas. Isso sugere que a suplementação é eficaz na promoção do desenvolvimento, especialmente se associada a um esforço para melhorar o estado nutricional infantil, dada a importância desse mediador.

Palavras-chave
Vitamina A; Desnutrição; Desenvolvimento infantil; Política de nutrição

Introduction

It is estimated that, worldwide, over 200 million pre-school age children are not developing properly11 Walker SP, Wachs TD, Grantham-McGregor S, Black MM, Nelson CA, Huffman SL, Baker-Henningham H, Chang SM, Hamadani JD, Lozoff B, Gardner JM, Powell CA, Rahman A, Richter L. Inequality in early childhood: risk and protective factors for early child development. Lancet 2011; 378(9799):1325-1338.. Although there are few population estimates of child developmental delay, it is believed that the vast majority of cases occur in developing countries22 Bornstein MH, Britto PR, Nonoyama-Tarumi Y, Ota Y, Petrovic O, Putnick DL. Child development in developing countries: Introduction and methods. Child Dev 2012; 83(1):16-31.,33 Yousafzai AK, Rasheed MA, Rizvi A, Armstrong R, Bhutta ZA. Effect of integrated responsive stimulation and nutrition interventions in the Lady Health Worker programme in Pakistan on child development, growth, and health outcomes: a cluster-randomised factorial effectiveness trial. Lancet 2014; 384(9950):1282-1293.. In low- and middle-income countries 36.8% of children aged from 3 to 4 years performed poorly in development tests44 McCoy DC, Peet ED, Ezzati M, Danaei G, Black MM, Sudfeld CR, Fawzi W, Fink G. Early Childhood Developmental Status in Low- and Middle-Income Countries: National, Regional, and Global Prevalence Estimates Using Predictive Modeling. PLoS Med 2016; 13(6):e1002034..

Children who do not reach their full development do not achieve adequate learning, behavior, and mental and physical wellbeing; display poorer performance at school; and earn lower wages as adults. This perpetuates a cycle of poverty and continuously impaired human development55 Alderman H. The economic cost of a poor start to life. J Dev Orig Health Dis 2010; 1(01):19-25.,66 Heckman JJ. Skill formation and the economics of investing in disadvantaged children. Science. 2006; 312(5782):1900-1902..

Delays in child development are associated with nutritional, socioeconomic and family environment related factors, such as maternal depression77 Wachs TD, Black MM, Engle PL. Maternal depression: a global threat to children's health, development, and behavior and to human rights. Child Development Perspectives 2009; 3(1):51-59., maternal work88 Moreira RS, Magalhaes LC, Dourado JS, Lemos SM, Alves CR. Factors influencing the motor development of prematurely born school-aged children in Brazil. Res Dev Disabil 2014; 35(9):1941-1951., exposure to violence, and others11 Walker SP, Wachs TD, Grantham-McGregor S, Black MM, Nelson CA, Huffman SL, Baker-Henningham H, Chang SM, Hamadani JD, Lozoff B, Gardner JM, Powell CA, Rahman A, Richter L. Inequality in early childhood: risk and protective factors for early child development. Lancet 2011; 378(9799):1325-1338.. Of the recognized contributing factors, child undernutrition and micronutrient deficiency99 Walker SP, Wachs TD, Meeks Gardner J, Lozoff B, Wasserman GA, Pollitt E, Carter JA; International Child Development Steering Group. Child development: risk factors for adverse outcomes in developing countries. Lancet 2007; 369(9556):145-157. are often cited as the most important, and the specific deleterious effect of malnutrition on child development has broad scientific confirmation1010 Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B ; International Child Development Steering Group. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369(9555):60-70.

11 Bateson P, Barker D, Clutton-Brock T, Deb D, D'udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE. Developmental plasticity and human health. Nature 2004; 430(6998):419-421.

12 Levitsky DA, Strupp BJ. Malnutrition and the brain: changing concepts, changing concerns. J Nutr 1995; 125(8):2212S.
-1313 Pollitt E, Leibel RL, Greenfield D. Brief fasting, stress, and cognition in children. Am J Clin Nutr 1981; 34(8):1526-1533.. The effect of micro-nutrients, such as folic acid, iron, iodine, and vitamin A have been investigated in several studies1414 Lima AA, Anstead GM, Zhang Q, Figueiredo IL, Soares AM, Mota RM, Lima NL, Guerrant RL, Oriá RB. Effects of glutamine alone or in combination with zinc and vitamin A on growth, intestinal barrier function, stress and satiety-related hormones in Brazilian shantytown children. Clinics (Sao Paulo) 2014; 69(4):225-233., with clear relationships directly observed for iron1515 Sachdev H, Gera T, Nestel P. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutr 2005; 8(02):117-132. and iodine deficiency1616 Qian M, Wang D, Watkins WE, Gebski V, Yan YQ, Li M, Chen ZP. The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China. Asia Pac J Clin Nutr 2005; 14(1):32-42..

Regarding vitamin A, few studies so far have yielded conclusive results. Supplementation at birth has tended to show a small positive effect on child development at three years of age1717 Humphrey JH, Agoestina T, Juliana A, Septiana S, Widjaja H, Cerreto MC, Wu LS, Ichord RN, Katz J, West Junior KP. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr 1998; 68(1):109-117.; however this effect was not statistically significant, and when vitamin A was administered to very low birth weight babies, no effect was observed1818 Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, Leclerq SC, Tielsch JM. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA 2010; 304(24):2716-2723.. In animal models, it was found that the use of megadoses of vitamin A can lead to brain damage1919 Oliveira MR, Moreira JCF. Acute and chronic vitamin A supplementation at therapeutic doses induces oxidative stress in submitochondrial particles isolated from cerebral cortex and cerebellum of adult rats. Toxicol Lett 2007; 173(3):145-150.,2020 Oliveira MR, Silvestrin RB, Souza TM, Moreira JCF. Oxidative stress in the hippocampus, anxiety-like behavior and decreased locomotory and exploratory activity of adult rats: effects of sub acute vitamin A supplementation at therapeutic doses. Neurotoxicology 2007; 28(6):1191-1199., injury to motor functions2121 Oliveira MR, Bittencourt Pasquali MA, Silvestrin RB, Souza TM, Moreira JCF. Vitamin A supplementation induces a prooxidative state in the striatum and impairs locomotory and exploratory activity of adult rats. Brain Res 2007; 1169:112-119., and modulation of immunity2222 Rocha H, Silva A, Correia L, Campos J, Machado M, Leite A, Cunha AJ. Effects of Vitamin A supplementation on child morbidity: A twenty-year time series analysis in the northeastern region of Brazil. Matern Child Health J 2015; 19(7):1652-1656. (effects associated with increased oxidative stress1919 Oliveira MR, Moreira JCF. Acute and chronic vitamin A supplementation at therapeutic doses induces oxidative stress in submitochondrial particles isolated from cerebral cortex and cerebellum of adult rats. Toxicol Lett 2007; 173(3):145-150.

20 Oliveira MR, Silvestrin RB, Souza TM, Moreira JCF. Oxidative stress in the hippocampus, anxiety-like behavior and decreased locomotory and exploratory activity of adult rats: effects of sub acute vitamin A supplementation at therapeutic doses. Neurotoxicology 2007; 28(6):1191-1199.
-2121 Oliveira MR, Bittencourt Pasquali MA, Silvestrin RB, Souza TM, Moreira JCF. Vitamin A supplementation induces a prooxidative state in the striatum and impairs locomotory and exploratory activity of adult rats. Brain Res 2007; 1169:112-119.,2323 Pasquali MA, Schnorr CE, Feistauer LBH, Gelain DP, Moreira JCF. Vitamin A supplementation to pregnant and breastfeeding female rats induces oxidative stress in the neonatal lung. Reprod Toxicol 2010; 30(3):452-456.,2424 Oliveira MR, Oliveira MWS, Behr GA, Moreira JCF. Vitamin A supplementation at clinical doses induces a dysfunction in the redox and bioenergetics states, but did change neither caspases activities nor TNF-α levels in the frontal cortex of adult Wistar rats. J Psychiatr Res 2009; 43(8):754-762.). In other studies, vitamin A supplementation has reduced morbidity and mortality in populations with a high prevalence of malnutrition2222 Rocha H, Silva A, Correia L, Campos J, Machado M, Leite A, Cunha AJ. Effects of Vitamin A supplementation on child morbidity: A twenty-year time series analysis in the northeastern region of Brazil. Matern Child Health J 2015; 19(7):1652-1656.,2525 Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015; 385(9975):1268-1271..

Therefore, this study aims first, to analyze if vitamin A megadose supplementation is associated with improved child development, and second, to consider how this possible effect could be mediated by nutritional factors at a population level in the impoverished Ceará, in the northeastern region of Brazil. Ceará hosts the world’s largest population living under semi-arid climatic conditions.

Methods

Study type and population

This population-based cross-sectional study surveyed a representative sample of households in the state of Ceará, Northeast Brazil, collecting socioeconomic, health, and nutritional data on families, women at reproductive age, and pre-school aged children aged 0-35 months, in 2007.

Study site

Ceará is one of the poorest states in Brazil, with its whole 145 000 km2 territory situated within the vast semi-arid northeastern region of Brazil, and a population of 8·5 million. The main industries are commerce and tourism in the capital, Fortaleza (2·3 million inhabitants) and subsistence agriculture in the countryside, an area with recurrent periods of drought.

Study sample

We used cluster sampling with stratification between the capital Fortaleza and the rural municipalities. The sample size was calculated as 8000 households (after multiplication by a correction factor equal to two, covering the design effect of cluster sampling, plus a 10% increase to compensate for losses). These households were estimated to comprise about 35 000 people, with 11 000 women aged 12-49 years, and 1500 children under 3 years old. To ensure accurate representation of the study population, we selected municipalities and households randomly, following a process of multistage sampling. In each rural municipality ten geographical areas were randomly selected, allowing representation of even the most remote areas. More details about the sampling methodology can be found elsewhere2626 Correia LL, Silva AC, Campos JS, Andrade FMO, Silveira DMI, Machado MMT, Rocha HAL, Cunha AJLA. Metodologia das Pesquisas Populacionais de Saúde Materno-Infantil: uma série transversal realizada no Estado do Ceará de 1987 a 2007. Revista Brasileira de Saúde Materno Infantil 2014; 14(4):353-362..

Study variables

The variables analysed included child developmental status (the study’s focus), potential nutritional determinants, and confounding factors. The main variables of interest are described below:

Child development: To detect suspected cases of cognitive and motor development delay in children, we used a simplified scale for developmental surveillance of children 0 to 3 years of age. This scale was developed by the Brazilian Ministry of Health for use by primary care health professionals as a screening instrument2727 Melo Figueiras AC, Puccini RF, Silva EMK, Pedromônico MRM. Avaliação das práticas e conhecimentos de profissionais da atenção primária à saúde sobre vigilância do desenvolvimento infantil Evaluation of practices and knowledge among primary health care professionals in relation. Cad Saude Publica 2003; 19(6):1691-1699.. Children were evaluated as either achieving or not achieving selected cognitive and motor milestones by certain ages (Table 1). The upper limit of each age group evaluated was determined by the presence of just a residual number of children who had not yet reached the milestone (cases above 3 standard deviations of the mean in a distribution curve). Using this method, we found prevalence rates similar to expected in the literature44 McCoy DC, Peet ED, Ezzati M, Danaei G, Black MM, Sudfeld CR, Fawzi W, Fink G. Early Childhood Developmental Status in Low- and Middle-Income Countries: National, Regional, and Global Prevalence Estimates Using Predictive Modeling. PLoS Med 2016; 13(6):e1002034..

Table 1
Parameters of child development (CD) and age groups evaluated.

Vitamin A supplementation: Information on vitamin A supplementation was provided by the mother, with a recall period of 12 months prior to the interview. The child was considered to be supplemented with vitamin A if he/she received at least one dose of 100 000 units during the period. In Brazil, children from 0 to 5 years receive vitamin A supplementation annually, both during vaccination campaigns and as a part of routine primary care services.

Nutritional Status: To assess children’s nutritional status, three anthropometric indicators were used: weight-for-age (W/A), height-for-age (H/A) and weight-for-height (W/H). These were compared with the standards of the US National Center for Health Statistics, according to WHO recommendations. Deficits found were classified as follows: undernutrition, W/A < −2 Standard Deviation (SD); stunting, H/A < −2 SD; and wasting, W/H < −2 SD.

Food insecurity: This outcome was measured from the question that assessed food availability in the family, both in quantitative and qualitative terms.

Birth weight: Information was obtained from the child’s health chart, and, when this was unavailable, from the mothers.

Breastfeeding: This was recorded as a binary variable, differentiating between children who were breastfed for any length of time and children who never received breast milk.

Child weighing: Whether there was any record of the child’s weight plotted on a growth chart in the previous 3 months.

The variables considered as potential confounding factors were: child age and sex, family characteristics (including per capita monthly income, urban or rural home location, participation in cash transfer programs, level of schooling of the head of the family, and whether the father was living at home), availability of tap water and toilet facilities at home, and maternal features (level of education and nutritional status).

Data collection

Information was collected from September 2007 to February 2008 using three questionnaires on households, mothers, and children, administered by 25 interviewers/evaluators with graduate level qualifications. The child development assessment was conducted by the evaluators, who were properly trained in the application of the simplified child development scale, as developed by the Ministry of Health. Weight of mothers and their children were measured using portable electronic scales, Tanita® type, with a capacity of 150 kg and 0·1 kg calibration. Height was measured with a portable scale with a range of 30–110 cm, with a precision of 1 mm. Children < 24 months were measured horizontally and those 24–35 months in a standing position.

Data processing and analysis

Data were entered twice using EpiInfo 2000 (WHO/CDC), and analysed using Statistical Package for the Social Sciences 17·0 (Chicago, IL, USA), with the Anthro program (Centers for Disease Control and Prevention, Atlanta, GA, USA) used to analyse the anthropometric data.

Analysis included three main steps:

1: Describe and identify the main nutritional effects on child development. The initial analysis involved tabulating the frequency distributions of all selected variables. The prevalence rate ratio (PRR) was estimated, equivalent to the ratio of cumulative incidence in cohort studies. To analyse the impact of nutritional status on cognitive and motor development of children, models were constructed using Cox Hazard Regression with punctual time and robust variance in single and multiple approaches. Assuming a constant period of risk, the Cox model can be adapted to estimate PR in cross-sectional studies, and in these studies this measure seems to produce better estimates of risk than the Odds Ratio2828 Barros AJ, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC medical research methodology 2003; 3:21..

2: Identify possible interactions between nutritional effects, regardless of significant association. To test possible interactions between the factors, tests of maximum likelihood ratios by stratified analysis were first used. To access the interaction between the multiplicative main effect and other determinants, multiple Cox regression models were constructed with factorial analysis, in which the tested determinant, the main effect, and the multiplicative interaction term were present. We have presented data only on significant interactions (p < 0·10).

3: Subgroup analysis for interacting factors. When effect modification was identified we performed analyses of subgroups according to the variable modifier. The variables with p < 0·10 in the simple analysis models were evaluated as potential confounders via hierarchised multivariate stratified analysis, and also with Cox regression. The association of independent variables was expressed as a prevalence rate with 95% confidence intervals.

Ethical

All surveys were approved by the ethics committee of the institutions involved, the Brazilian Ministry of Health, the Ceará State Secretariat of Health and the Federal University of Ceará. All participants signed an informed consent form before entering the study.

Results

In 7890 households surveyed, a total of 1232 children in the age range 0-35 months were found. Of these children, 446 (36·2%) in the 18–35-month age group had their cognitive development evaluated. We found that 104 (22·2%) of them were suspected of a delay in the ability to speak (because they still could not speak three words, or could not articulate a simple sentence). Regarding motor development, 294 children (23·9%) aged 12 to 23 months were evaluated, with 46 (15·6%) presenting suspected motor delay (they were not able to stand up or could not walk a few steps without support). As a whole, 6·8% of children presented both forms of delay, 23.4% one form or the other, and 69·7% presented no delay.

(Table 2 shows the adjusted effects of selected nutritional factors on child development. Supplementation with vitamin A showed a strong protective effect: it was inversely associated with the three forms of delay studied. Children supplemented showed 53% lower probability of cognitive delay (p < 0·001), 48% lower probability of motor delay (p = 0·023) and 44% lower probability of combined cognitive–motor delay (p = 0·002), compared with children not supplemented. Chronic malnutrition was strongly associated with motor development, as stunted children presented 2·2 times greater risk of delay (p = 0·013) in comparison with children who were not stunted. Regarding cognitive delay, chronic malnutrition showed significant association in the bivariate analysis, and but this significance was not maintained in the adjusted analysis (p = 0·090). Breastfeeding was strongly associated with successful motor development: children who never received breast milk had a 2·9 times higher occurrence of delays in motor development compared with children who had been breastfed (p < 0·001).

Table 2
Adjusted effects of selected nutritional factors on the delay in child's cognitive, motor and cognitive-motor development. State of Ceará, Northeastern Brazil, 2007.

Food security, although significantly associated with cognitive delay in the bivariate analysis, did not remain significant in the adjusted analysis.

Other nutritional factors analysed (such as birth weight, growth monitoring and acute malnutrition) showed no association with cognitive or motor development, both in crude and adjusted analysis (Table 2).

Because of the magnitude and consistency of the association between vitamin A supplementation and reduced likelihood of delay in child development, the identification of possible effect modifiers of this association using regressive models with multiplicative interaction terms was performed. A strong statistically significant interaction between chronic malnutrition and vitamin A supplementation was found, yielding values of p < 0·015 for cognitive delay, p < 0·020 for motor delay, and < p 0·017 for cognitive-motor delay. Through analysis of the prevalence rate in each group of interaction possible using stratified analysis for cross-categories of these determinants, it was observed that the relationship between Vitamin A megadose supplementation and chronic malnutrition was antagonistic and determinant for all three forms of developmental delay (motor, cognitive, motor and cognitive), with the highest numerical relevance to cognitive delay. In this category, the difference between observed and expected prevalence rate was almost seven-fold. The expected prevalence rate for cognitive and motor delays were 6·7 and 1·6 times larger than those observed, respectively (Table 3 and (Table 4).

Table 3
Stratified analysis of the interaction between chronic malnutrition and vitamin A supplementation and its effects on child cognitive, motor, and cognitive-motor development. State of Ceará, Northeastern Brazil, 2007.
Table 4
Interaction analysis between stunting and vitamin A supplementation for children's cognitive, motor, and cognitive-motor development delay, expressed in prevalence rate/ratio of adjusted prevalence.

It is apparent in (Table 5 that non-stunted children benefited significantly from supplementation with vitamin A, showing a reduction of 67% in the risk of cognitive delay (adjusted PRR = 0·33; 95% CI 0·21–0·53; p < 0·001). However, children who were chronically malnourished showed no significant benefit from supplementation with vitamin A (adjusted PRR = 0·97; 95% CI 0·39–2·40; p = 0·956). A similar result was observed regarding motor development in non-stunted children, with supplementation of vitamin A reducing the risk of motor delay by 70% (adjusted PRR = 0·30; 95% CI 0·15–0·62; p = 0·001). Vitamin A supplementation of stunted children was not associated with an increase nor decrease in the risk of motor delay (adjusted PRR = 1·64; 95% CI 0·35–7·69; p = 0·525).

Table 5
Adjusted prevalence rate ratio of cognitive and motor development delay in children supplemented and not supplemented with vitamin A, according to nutritional status. State of Ceará, 2007.

The effects of interaction between chronic malnutrition and vitamin A supplementation have also been observed in relation to combined cognitive-motor development, with well-nourished children benefiting from protection, while chronically malnourished children showed no significant beneficial effect.

Finally, that the association between vitamin A supplementation and delay in child development remained highly statistically significant in the adjusted analysis, even after splitting of the database into ‘malnourished’ and ‘not malnourished’ children, with no confounding factors being identified.

Discussion

This study presents two main findings. First, suggests that supplementation with vitamin A has a protective effect against child developmental delay on a large scale. Second, suggest that this effect is selective, benefiting only those children who do not have chronic malnutrition. These findings are of great importance to public health. If confirmed, they may be formative in redirecting the strategy of nutritional programs worldwide, screening all children supplementation for malnutrition, for example2525 Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015; 385(9975):1268-1271..

This is possibly the first study to suggest a positive association between vitamin A supplementation and child development at the population level, as a comprehensive search of available literature revealed only two studies that evaluated the effects of vitamin A on child development. The first study, a trial carried out in Indonesia, assessed the effect of vitamin A supplemented at birth on child development, and found a small beneficial effect at the age of 3 years1717 Humphrey JH, Agoestina T, Juliana A, Septiana S, Widjaja H, Cerreto MC, Wu LS, Ichord RN, Katz J, West Junior KP. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr 1998; 68(1):109-117.. The second, conducted in the United States, studied the effects of neonatal vitamin A supplementation on very low birth weight babies, and found no positive effects2929 Ambalavanan N, Tyson JE, Kennedy KA, Hansen NI, Vohr BR, Wright LL, Carlo WA; National Institute of Child Health and Human Development Neonatal Research Network. Vitamin A Supplementation for Extremely Low Birth Weight Infants: Outcome at 18 to 22 Months. Pediatrics 2005; 115(3):e249-e254..

The positive effect of vitamin A supplementation found here proved to be of considerable benefit, but excluded a large group of very vulnerable children: the chronically malnourished. Supporting this result, laboratory studies in animal models have consistently shown that supplementation with megadose supplements of vitamin A may cause brain, mitochondrial, pulmonary, and muscular damage, resulting in functional impairment. This effect is due to the increased oxidative stress that occurs because of reduction in the organic capacity for decreasing free radicals1919 Oliveira MR, Moreira JCF. Acute and chronic vitamin A supplementation at therapeutic doses induces oxidative stress in submitochondrial particles isolated from cerebral cortex and cerebellum of adult rats. Toxicol Lett 2007; 173(3):145-150.

20 Oliveira MR, Silvestrin RB, Souza TM, Moreira JCF. Oxidative stress in the hippocampus, anxiety-like behavior and decreased locomotory and exploratory activity of adult rats: effects of sub acute vitamin A supplementation at therapeutic doses. Neurotoxicology 2007; 28(6):1191-1199.
-2121 Oliveira MR, Bittencourt Pasquali MA, Silvestrin RB, Souza TM, Moreira JCF. Vitamin A supplementation induces a prooxidative state in the striatum and impairs locomotory and exploratory activity of adult rats. Brain Res 2007; 1169:112-119.,2323 Pasquali MA, Schnorr CE, Feistauer LBH, Gelain DP, Moreira JCF. Vitamin A supplementation to pregnant and breastfeeding female rats induces oxidative stress in the neonatal lung. Reprod Toxicol 2010; 30(3):452-456.,2424 Oliveira MR, Oliveira MWS, Behr GA, Moreira JCF. Vitamin A supplementation at clinical doses induces a dysfunction in the redox and bioenergetics states, but did change neither caspases activities nor TNF-α levels in the frontal cortex of adult Wistar rats. J Psychiatr Res 2009; 43(8):754-762.. Chronic malnutrition (which involves repeated periods of insufficient calorific intake) also generates a state of oxidative stress, as has been demonstrated in laboratory animals3030 Sodhi C, Rana S, Mehta S, Vaiphei K, Attri S, Thakur S, Mehta S. Study of oxidative stress in isoniazid-induced hepatic injury in young rats with and without protein-energy malnutrition. J Biochem Toxicol 1996; 11(3):139-146.. In children, the effect of oxidative stress mediated by fasting is also seen as a factor contributing to developmental retardation1010 Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B ; International Child Development Steering Group. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369(9555):60-70.

11 Bateson P, Barker D, Clutton-Brock T, Deb D, D'udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE. Developmental plasticity and human health. Nature 2004; 430(6998):419-421.

12 Levitsky DA, Strupp BJ. Malnutrition and the brain: changing concepts, changing concerns. J Nutr 1995; 125(8):2212S.
-1313 Pollitt E, Leibel RL, Greenfield D. Brief fasting, stress, and cognition in children. Am J Clin Nutr 1981; 34(8):1526-1533.. This phenomenon is known as the nutritional stress hypothesis3131 Nowicki S, Searcy W, Peters S. Brain development, song learning and mate choice in birds: a review and experimental test of the" nutritional stress hypothesis". J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2002; 188(11-12):1003-1014.. Vitamin A also has an important role in the modulation of immunity. Mice with vitamin A deficiency present defects in the activity of their immune cells, in addition to various effects on their immunoglobulins3232 Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008; 8(9):685-698.. Also, stunted children have a higher risk of infections, that may also lead to developmental impairment3333 Berkman DS, Lescano AG, Gilman RH, Lopez SL, Black MM. Effects of stunting, diarrhoeal disease, and parasitic infection during infancy on cognition in late childhood: a follow-up study. Lancet 2002; 359(9306):564-571..

Vitamin A supplementation programs have been achieved on a global scale in the last 20 years, but instead of being a clearly defined beneficial intervention in health promotion, questions have been raised regarding the validity of the intervention. In 2013, the importance of vitamin A in reducing infant mortality was brought under additional scrutiny by the findings of the DEVTA study3434 Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; 381(9876):1469-1477.. Carried out in India, this was the largest cluster-randomized trial ever done regarding vitamin A supplementation programs. It found a non-significant mortality rate reduction of 4%, (95% CI 0·89–1·03, p = 0·22), with no specific causes of mortality averted. Other evaluations of the effectiveness of supplementation have found contradictory results, depending largely on the presence of confounding conditions2222 Rocha H, Silva A, Correia L, Campos J, Machado M, Leite A, Cunha AJ. Effects of Vitamin A supplementation on child morbidity: A twenty-year time series analysis in the northeastern region of Brazil. Matern Child Health J 2015; 19(7):1652-1656.,2525 Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015; 385(9975):1268-1271.. This can be attributed to the immunity modulator effect, or to subgroup effects of vitamin A (known as non-specific effects)3535 Benn CS, Aaby P, Arts RJ, Jensen KJ, Netea MG, Fisker AB. An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality. Int J Epidemiol 2015; 44(3):906-918..

This study is one of the few initiatives to measure delay in child development as an epidemiological outcome. Although outcomes measured in the field are less accurate than outcomes measured in a clinical environment, this inaccuracy is offset with additional value in being comprehensive, as well as representative of real-world conditions.

The high prevalence (30·3%) of suspected cognitive–motor delay in children aged 12 to 35 months observed in this study are consistent with those found in a study in the wealthy southern region of Brazil, where 34% of children aged up to 12 months were suspected of developmental delay according to the Denver II screening test3636 Halpern R, Victora CG, Barros FC, Horta BL, Giugliani ERJ. Fatores de risco para suspeita de atraso no desenvolvimento neuropsicomotor aos 12 meses de vida. Jornal de Pediatria 2000; 76(6):421-428.. Although overestimation is possible in our method to access development, this would suggest that the screening test used in this study is highly sensitive, and suitable for community screening of children with suspected delays (to be referred to higher level of care for diagnostic confirmation).

Chronic malnutrition presents serious repercussions for health and productivity99 Walker SP, Wachs TD, Meeks Gardner J, Lozoff B, Wasserman GA, Pollitt E, Carter JA; International Child Development Steering Group. Child development: risk factors for adverse outcomes in developing countries. Lancet 2007; 369(9556):145-157.. In northeastern Brazil, chronic malnutrition is highly prevalent, affecting 12% of children under 3 years of age (a rate three times higher than is registered for acute malnutrition)3737 Correia LL, Campos JS, Andrade FMdO, Machado MMT, Lindsay AC, Leite AJ, Rocha HA, Cunha AJ. Prevalence and determinants of child undernutrition and stunting in semiarid region of Brazil. Rev Saude Publica 2014; 48(1):19-28.. A similar situation can be found in many other countries of the developing world, where rates of stunting range from 10 to 20%11 Walker SP, Wachs TD, Grantham-McGregor S, Black MM, Nelson CA, Huffman SL, Baker-Henningham H, Chang SM, Hamadani JD, Lozoff B, Gardner JM, Powell CA, Rahman A, Richter L. Inequality in early childhood: risk and protective factors for early child development. Lancet 2011; 378(9799):1325-1338.. Thus, considering the high prevalence of child chronic malnutrition, any indication that it is responsible for new deleterious effects to child health is of great concern.

Limitations

The fact that only about 30% of children have their cognitive and motor development evaluated reduced the statistical power of the sample and decreased the number of variables that could be included in the regression model. Cross-sectional studies do not allow to evaluate causality directly, and the factors found are only possible determinants. A simplification of the evaluation of the motor and cognitive development of children was necessary, but this is consistent with findings in other similar places.

Conclusions

Vitamin A supplementation undoubtedly has potential to benefit children’s health. Nevertheless, the non-specific effects of supplementation (with different effects in subgroups as well as a possible effect of modulating the immune system though oxidative effects) must be considered. If the findings of this study are confirmed by longitudinal cohorts or community trials the suggested intervention would be to provide stunted children with more than vitamin A supplements, as this alone could present an increased risk to their development. The fact that stunting is an easily identified condition favours the implementation of interventions aimed at this group of children. In this study, we found a protective effect of vitamin A on child development, but only in well-nourished children. This suggests that supplementation is worthwhile and should be continued, in a joint effort to improve the nutritional status of children.

Key messages

The vitamin A supplementation has an overall positive effect on child development.

The vitamin A supplementation has a non-specific effect on child development in stunted children.

The non-specific effects of supplementation with vitamin A should be considered.

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History

  • Received
    17 May 2017
  • Accepted
    17 Nov 2017
  • Reviewed
    19 Nov 2017
ABRASCO - Associação Brasileira de Saúde Coletiva Rio de Janeiro - RJ - Brazil
E-mail: revscol@fiocruz.br