Association between supplementation with vitamin A, iron and micronutrients with adequate psychomotor development in children from 9 to 36 months in Peru

Background: Worldwide, it is estimated that 52.9 million children < 5 years of age experience delayed psychomotor development, which is associated with multiple factors. Our primary objective is to evaluate whether there is an association between supplementation with Vitamin A, Iron, and Micronutrients and Adequate Psychomotor Development in children aged 9 – 36 months at the national level in Peru. Methods: The study was an observational, analytical, cross-sectional study based on the secondary analysis of the Demographic and Family Health Survey databases from 2018 to 2020. The independent variables include the consumption of Vitamin A, Iron, and Micronutrients. The dependent variables encompass Motor Development in children aged 9 – 18 months, Psychological Development in children aged 9 – 18 months, and Psychological Development in children aged 19 – 36 months. Results: The study included a total of 24 838 participants. In the adjusted regression model, the factors associated with adequate motor development between 9 and 18 months of age were: region of residence, overcrowding, and exclusive breastfeeding. For adequate cognitive development between 9 and 18 months of age, the associated factors were: vitamin A consumption, mother ’ s education, child sex, delivery complications, and complete vaccinations. Regarding adequate psychological development in children aged 19 – 36 months, the associated factors were: mother ’ s education, maternal employment, child sex, and birth weight. Conclusions: There was no association found between nutritional supplementation and adequate development, except for the relationship between Vitamin A consumption and adequate psychological development in children aged 9 – 18 months. Therefore, further research, such as cohort studies and clinical trials, is suggested to corroborate this association.


Introduction
Psychomotor development (PD) is a dynamic process in which individuals acquire motor, cognitive, linguistic, and social skills as they progress through the years. 1 In Latin America, screening tests such as the Psychomotor Development Assessment Scale are used for children aged 0-24 months, while the Psychomotor Development Test is utilized for children over 2 years of age. 2 Since 2015, Peru has conducted the Demographic and Family Health Survey (ENDES) annually at the national level to assess the psychomotor development in children under 5 years of age based on maternal reports. 3orldwide, it is estimated that 52.9 million children under 5 years of age experience delayed psychomotor development, with 95 % residing in low-and middle-income countries. 4Consequently, numerous researchers have sought to identify risk and protective factors influencing adequate psychomotor development.
For example, Young et al. observed a significant enhancement in motor and mental development among Indian children aged 6-18 months who received 12 months of home fortification with micronutrient powders (Cohen's d: Motor = 0.12, 95 % CI 0.03-0.22;Mental = 0.15, 95 % CI 0.06-0.25). 5Similarly, Sales et al. found that Brazilian children aged 0-35 months who received Vitamin A supplementation had a 67 % reduced risk of cognitive delay (adjusted PR = 0.33, 95 % CI 0.21-0.53). 6In addition, Angulo-Barroso et al. (2016) conducted a study on iron supplementation in 1196 infants during pregnancy and childhood.They concluded that iron supplementation from week 6 to month 9 of infancy, even without iron supplementation during gestation, resulted in improved gross motor development at 9 months of age (RR 0.64, 95 % CI 0.52-0.80). 7urthermore, several other crucial factors influence psychomotor development, including prematurity, breastfeeding, harmful habits during pregnancy, maternal or child violence, maternal mental health, socioeconomic factors, and the ongoing COVID-19 pandemic. 8n this context, the role of micronutrient, vitamin A, and iron supplementation in children's psychomotor development gains significance.However, there is a scarcity of studies evaluating the nutritional factors associated with good or poor psychomotor development.Hence, investigating this association at the national level using population data holds great relevance.Such research could not only raise awareness among prospective parents about the importance of maintaining proper supplementation for their children but also guide public health entities in investment, prioritization, and reporting on the benefits of such measures.

Study design
An observational, analytical, cross-sectional study was conducted based on the secondary analysis of the Demographic and Family Health Survey (ENDES) databases for the years 2018-2020.ENDES is a national population survey in Peru.The study population consisted of children of both sexes aged between 9 and 36 months who participated in ENDES between 2018 and 2020.
The dependent variables included Motor Development for children aged 9-18 months, Psychological Development for children aged 9-18 months, and Psychological Development for children aged 19-36 months.Adequate development was defined as meeting all ageappropriate milestones, while inadequate development was defined as not meeting at least one milestone.It is important to note that milestone criteria varied for different age groups (9-12 months, 13-18 months, 19-23 months, and 24-36 months).ENDES established milestones for motor development only between 9 and 18 months but recorded psychological development milestones for the entire age range from 9 to 36 months.ENDES did not record milestones for children under 9 months, so they were excluded from the study.
The independent variables included Vitamin A Supplementation, Iron Supplementation, and Micronutrient Supplementation.Sociodemographic control variables were also incorporated.
Inclusion criteria encompassed children aged 9-36 months with parents who voluntarily participated in ENDES.Records lacking essential data such as sex, age, or geographic location were excluded.Additionally, records without data on any of the supplementation types (Vitamin A, Iron, and Micronutrients), those without data on Psychomotor Development, records corresponding to children with disabilities affecting psychomotor development (such as Cerebral Palsy or Down Syndrome), and children with extreme or very extreme prematurity (gestational age <28 weeks) were also excluded.

Sample design
The ENDES survey employs a two-stage, probabilistic, balanced, stratified, and independent design for each department, both in urban and rural areas.Given the fixed population for each of the ENDES surveys conducted in 2018, 2019, and 2020, a power calculation was performed.In this calculation, psychomotor development (PD) was the outcome of interest, while supplementation with Vitamin A, Iron, and Micronutrients served as the exposure variables.
Based on previous research findings, Sales et al. 6 reported a 67 % lower risk of cognitive delay among individuals who received vitamin A (adjusted PR: 0.33; 95 % CI 0.21-0.53),Angulo-Barroso et al. 7 found a 36 % reduced risk of being in the lowest quartile of Developmental Psychomotor Milestones (DPM) in children who received iron compared to those who received a placebo (RR: 0.64; 95 % CI 0.52-0.80),and Masuda et al. 9 observed a lower risk of psychomotor retardation associated with the use of micronutrients compared to spirulina (OR: 2.55; 95 % CI 1. 26-5.14).
The total number of children under 5 years of age, combining data from the ENDES surveys conducted in 2018, 2019, and 2020, amounted to 31 400 children.Since the study analyzed data stratified into two groups: children aged 9-18 months (10 months) and those aged 19-36 months (18 months), the sample size for the first group was calculated as 5233 (31 400 × 10/60), and for the second group, it was calculated as 9420 (31 400 × 18/60).This calculation assumed a homogeneous distribution of children across each age in months.
Utilizing the Epidat 4.2 program for comparing proportions, a significance level of 0.05 was applied, followed by manual Bonferroni correction for three simultaneous exposures (0.05/3 = 0.017).Moreover, a correction for the two-stage structure of the original survey was considered, which involved dividing the population by the number of stages, in this case, 2. As a result, powers greater than 90 % were identified for each of the exposures within each population segment to be analyzed, as detailed in Table 1.

Statistical analysis
The databases required for this study were obtained from the Institute of Statistics website (http://iinei.inei.gob.pe/microdatos/) in dbf format for the necessary modules of the ENDES surveys conducted in 2018, 2019, and 2020.Subsequently, these files were exported to Stata 15.0 dat format for further analysis.The final database was processed and analyzed using the Stata statistical package.
Given the complex sampling design of the original study, all analyses were conducted using the 'Complex survey data' (svy) option.The strata defined by ENDES, the blocks, and dwellings served as conglomerates, while the expansion factors were applied as sample weights (pweights).Confidence intervals were set at 95 %, and statistical significance was determined at p values < 0.05.As all variables in the dataset were categorical, they were described in terms of absolute frequencies, relative frequencies (percentages), and weighted percentages, taking into account the sample weights.
Bivariate analysis was performed using the chi2 test corrected for clusters, using the Rao-Scott correction.Prevalence ratios (PRs) were obtained using Poisson regression (Generalized Linear Model, Poisson family, logarithmic linkage).Regressions were run in crude and adjusted form corrected for complex sampling using Taylor Linearization to estimate PRs.The variances were obtained in a robust way by conglomerates.The adjusted model (multivariate) included the exposure variables (vitamin A, iron, micronutrients), along with all variables that exhibited p < 0.05 values in the crude models (statistical criterion).Separate models were conducted for motor development at 9-18 months, psychological development at 9-18 months, and psychological development at 19-36 months.

Descriptive analysis
A total of 24 838 participants within the age range of 9-36 months were included in the analysis using data from the Demographic and Family Health Survey (ENDES) conducted between 2018 and 2020.Among these participants, 23 997 (approximately 0.97 %) had available data on iron supplementation, 23 514 (about 0.95 %) had data on vitamin A supplementation, and 23 765 (approximately 0.96 %) had data on micronutrient supplementation.
Table 2 provides a description of the characteristics of children aged 9-36 months.It's worth noting that the proportion of male participants exceeded that of females.Most children had birth weight and height within the normal range.Additionally, a significant portion of the population adhered to exclusive breastfeeding, attended Control of Growth and Development (CRED) sessions, and received complete vaccinations appropriate for their age.

Bivariate analysis
Examining the factors associated with adequate motor development in children aged 9-18 months reveals a complex interplay of environmental and physiological influences as region of residence, area of residence (urban-rural disparities), socioeconomic status (indicated by poverty level), overcrowding, exclusive breastfeeding and level of anemia emerge a significant effect for motor skill development (Table 3).
On the other hand, analyzing the factors linked to adequate psychological development in children aged 9-18 months reveals a multifaceted landscape of influences.Vitamin A supplementation stands out as a noteworthy factor, indicating the potential role of essential nutrients in supporting early cognitive development.Additionally, poverty level, overcrowding and education level of the mother may create stressors that influence a child's emotional well-being and cognitive development.Finally, the sex of the child, birth complications, control of growth and development and complete vaccinations have a significant effect for psychological development in early childhood (Table 3).
The factors associated with adequate psychological development in children aged 19-36 months sheds light on area of residence and poverty level, that emerges as a persistent factors, suggesting the enduring impact of socioeconomic disparities on early childhood development.Maternal education level and the maternal work status presents significance, raising questions about the balance between maternal employment and caregiving responsibilities.At last, gender differences (indicated by the sex of the child) and birth weight have a significant effect for psychological growth (Table 3).

Regression models
Crude and Adjusted models were developed for the exposure variables (Vitamin A, Iron, and Micronutrients) as well as for all variables that demonstrated statistical significance in the bivariate analysis.
The adjusted model will include the exposures variables and all variables that had an association with the outcome variable in the crude analysis with p values < 0.05, and that have not shown collinearity between them.Collinearity was previously evaluated using the variance inflation factor (VIF), and all selected variables had a value < 5, so none were excluded.
Table 4 shows the final model for adequate motor development from 9 to 18 months.It was found that those living in the Sierra Region had a 7 % lower probability of having adequate motor development (OR 0.93; 95 % CI 0.89-0.97)and living in overcrowded conditions had a 4 % lower probability (OR 0.96; 95 % CI 0.93-0.99).Children who received exclusive breastfeeding (EBF) also had a 3 % lower probability (OR 0.97; 95 % CI 0.95-0.99).
Finally, found that vitamin A supplementation varies according to the poverty level of the household; poor households had 4 % vitamin A supplementation, compared with a prevalence of 20 % supplementation for lower-poverty households. 12

Nutritional supplementation and psychomotor development
An association was only found between Vitamin A supplementation and adequate psychological development between 9 and 18 months of age.Concordantly, Casamayor et al. demonstrated an association between the consumption of micronutrients (iron, zinc, folic acid, vitamin A and C) and normal psychomotor development (92.86 % vs 57.14 % with some disorder). 13Likewise, Ali et al. demonstrated the association between antenatal or birth vitamin A supplementation and better school performance in the areas of reading, spelling, mathematics, and computing. 14No association was found between iron or micronutrient supplementation and adequate psychomotor development.Corimaya et al. concluded that the consumption of iron and/or vitamin C in children between 6 and 59 months of age had no direct association with adequate psychomotor development (iron: p = 0.938; vitamin C: p = 0.056). 15On the other hand, Rueda et al. suggest that nutritional supplementation with polyunsaturated fatty acids (DHA, AA, omega 3 and 6) and minerals (iron and zinc) provided benefits in cognitive development, preferably in infants and schoolchildren. 16

Other factors associated with adequate motor development
A reduced likelihood of adequate motor development in children residing in the Sierra region has been attributed, possibly due to prenatal stressors.Ticona-Rendón M's research revealed a higher incidence of intrauterine growth retardation in the Sierra, at 14.6 %, in contrast to the coastal region, where it stood at 8.1 %. 17 Zambrano et al. determined that insufficient opportunities for effective learning are more prevalent in rural and low-income areas.This can be attributed to factors such as the low educational attainment of parents, overcrowded living conditions, and limited income. 18urthermore, living in crowded environments has also been linked to a diminished likelihood of child development.In this regard, Alvarado Llatance's study uncovered a negative correlation between overcrowding and child development. 19dditionally, children exclusively breastfed exhibited a lower likelihood of achieving adequate motor development.Comparatively, Hye Jeong Choi et al. found that infants who received exclusive breastfeeding for up to 4 months demonstrated improved communication (OR = 4.12; CI: 1.11-15.28)and social interaction (OR = 6.04;CI: 1.05-34.66),and at 12 months, enhanced cognition (OR = 6.66;CI: 1.02-43.63),communication (OR = 3.93; CI: 1.07-14.40),and social interaction (OR = 8.17; CI: 1.59-42.05). 20However, Tintaya-Peña's study in Villa el Salvador, Peru, did not find any significant association between psychomotor development and exclusive breastfeeding (p = 0.90), breastfeeding within the first hour (p = 0.50), or maternal breastfeeding technique (p = 0.74). 21Finally, Michels et al. observed a trend indicating that introducing solid foods alongside breastfeeding at 4 months postpartum may potentially be associated with slightly faster achievement of standing (Acceleration Factor (AF): 0.93; 95 % CI: 0.87, 0.99) and walking milestones (AF: 0.93; 95 % CI: 0.88, 0.98) in term infants when compared with those exclusively breastfed. 22These nuanced findings underscore the importance of continued investigation into the complex interplay between infant feeding practices and developmental outcomes.

Other factors associated with adequate psychological development
A mother's higher level of education (secondary or higher) was associated with a higher likelihood of adequate psychological development for both age groups, namely 9-18 months and 19-36 months.This finding aligns with the research of Nima Chistama C. A, which also established a direct relationship between mothers with higher educational levels and satisfactory psychomotor development (p < 0.023). 23imilarly, Alvarado et al., in their study conducted in Peru, demonstrated that a greater degree of maternal education leads to improved psychomotor development (p < 0.01). 24emale gender was also associated with a higher likelihood of adequate psychological development in both age groups.Furthermore, Alvarado Llatance's nationwide study revealed that females exhibited superior child development in cognitive, communication, motor, and socio-emotional skills (OR: 2.35; p = 0.002). 19onversely, maternal employment for mothers of children aged 19-36 months was linked to a higher probability of achieving adequate psychological development.Similarly, Nima Chistama's research demonstrated that mothers engaged in employment had children with enhanced psychomotor development (p = 0.017), potentially due to improved economic resources or increased psychological stimulation. 23or children aged 9-18 months, a complete vaccination schedule was also associated with a greater likelihood of adequate psychological development.In line with this, Joe and Kumar's findings indicated that  25 Lastly, low birth weight was associated with a reduced probability of adequate psychological development in children aged 19-36 months.Correspondingly, Rodriguez et al. found that low birth weight (weight <2500 g) led to developmental delays in psychomotor skills. 21Similarly, Díaz-Granda, R. identified low birth weight (weight <2500 g) as a factor associated with psychomotor retardation (OR = 5.9; 95 % CI = 2.3-15.2;p = 0.000). 26

Conclusions
No significant association was found between adequate psychomotor development with nutritional supplementation, except between Vitamin A and adequate psychological development in children aged 9-18 months (PR: 1.06; 95 % CI 1.01-1.13).Adequate motor development in children from 9 to 18 months was negatively associated with living in the Sierra region, overcrowding, and receiving exclusive breastfeeding.Adequate psychological development in children from 9 to 18 months was positively associated with the mother's secondary educational level, female children, and having complete vaccinations.Adequate psychological development in children from 19 to 36 months was positively associated with secondary or higher educational level, working mother and female sex; instead, it was negatively associated with low birth weight.Further research is suggested, such as cohort studies and clinical trials, to assess with greater certainty whether there is an association between psychomotor development and nutritional supplementation.

Table 4
11 was shown that most children between 9 and 18 months old reached an adequate motor development, however, psychological development declined at an older age.In this context, Quezada et al. found that 91.3 % achieve adequate motor development between 9 and 12 months of age.10Likewise,Veliz and Yanqui demonstrated that, of 100 children from 1 to 2 years of age, 42 % had deficient development in the sensory/motor area, while 55 % had deficient development in the cognitive area.114.2.Nutritional supplement coverageVitamin A, Iron and Micronutrient supplementation doses can vary widely depending on several factors, including individual's age, gestational age and/or birth weight.In our country, the Ministry of Health recommends supplementation with Vitamin A for children between and 11 months at dose 100 000 UI once every 6 months and for children between 12 and 59 months at dose 200 000 UI once every 6 months.For Iron supplementation, the recommendation for children with low birth weight and/or preterm is 2 mg of elemental iron per kilogram per day from 2 months of age for 12 months.Children with adequate birth weight and/or born at term should receive 35-40 mg of elemental iron per week starting at 6 months of age for 6 months.Finally, for Micronutrients supplementation, all children should receive 1 sachet daily starting at 6 months of age and continuing for 12 months.In our study, a coverage of 17.22 % for Vitamin A, 47.34 % for Iron and 54.19 % for Micronutrients was evidenced; The lower coverage of Vitamin A in our country stands out.Coincidentally, Morasso et al.
shows the final model for adequate psychological development from 19 to 36 months.A secondary educational level (OR

Table 1
Statistical Analysis based on the ENDES 2018-2020 survey.
a Actual value divided by two, by two-stage sampling design.A. Chaponan-Lavalle et al.

Table 2
Sociodemographic characteristics and characteristics of the mothers and children between 9 and 36 months of age, with data on iron, vitamin A, or micronutrient supplementation, in the ENDES 2018-2020 surveys.

Psychological development for children from 24 to 36 months (
b Quintiles of wealth using the "Wealth Index".cIncludes prolonged labor, excessive bleeding, fever, seizures, and others.dComplete Vaccines up to 6 months: BCG, and three doses of vaccines for Polio, Pertussis, Tetanus and Diphtheria.e Complete Vaccines up to 12 months: BCG, three doses of vaccines for Polio, Pertussis, Tetanus and Diphtheria, plus one dose of Measles.A. Chaponan-Lavalle et al.

Table 3
Sociodemographic, mother, and individual characteristics of children between 9 and 36 months of age, according to Age-Appropriate Motor and Psychological Development, in the ENDES 2018-2020 surveys.

Table 3
(continued ) Appropriate Motor and Psychological Development: Meets motor development milestones for children 9-12 months and for children 13-18 months as appropriate.Meets psychological development milestones for children 19-23 months and for children 24-36 months as appropriate.Chi2 test with Rao-Scott correction by cluster sampling.Complete Immunizations as appropriate for children 9-12 months (BCG, and three doses of vaccines for Polio, Pertussis, Tetanus and Diphtheria), and for children 13-18 months (BCG, three doses of vaccines for Polio, Pertussis, Tetanus and Diphtheria, plus a dose of Measles).d Complete Vaccines for children over one year of age (BCG, three doses of vaccines for Polio, Pertussis, Tetanus and Diphtheria, plus one dose of Measles).fully vaccinated children at 12 months, in the 8 to 10-year-old age group, outperformed their peers who were either incompletely vaccinated or not vaccinated in math tests (OR: 1.87, 95 % CI: 1.48-2.35),writing (OR: 1.77, 95 % CI: 1.44-2.18),and reading (OR: 1.60, 95 % CI: 1.23-2.09).
CRED: Control of Growth and Development.a Quintiles of wealth using the "Wealth Index".b Includes prolonged labor, excessive bleeding, fever, seizures, and others.c