Long Term Effect of Early Iron Supplementation and Psychosocial Stimulation on Growth and Development of Iron-deficient Anaemic Infants
Condition: Anaemia
Study type: Interventional

Summary: 
      1. Burden: Anaemia is a public health problem in our country. Fifty one percent young
           children aged 6 to 59 months are suffering from anaemia in Bangladesh (BDHS-2011) and
           the main cause of this problem is iron deficiency. Research findings show that Iron
           deficiency leads to delayed development and even reduce working capacity. All these
           impact negatively on quality of life and loss of national gross domestic product (GDP).

        2. Knowledge gap: Little is known about long-term effects of early life iron deficiency
           anemia on development and behaviour of children after correction with iron supplements.
           There is also scarcity of information if early life psychosocial stimulation added to
           iron supplementation to these anemic children have long term benefits compared to
           non-stimulated anaemic children or non-anaemic children

        3. Relevance:

           The aim was to conduct a follow up study to examine whether the IDA children, who
           recovered from iron deficiency and received additional more intense psychosocial
           intervention catch up to their optimum development in later life at school age, similar
           like non-anaemic peers.

        4. Hypothesis (if any):

             1. The benefit of early iron supplementation in addition to Psychosocial stimulation
                on growth and development of IDA infants appears in later life.

             2. Addition of early psychosocial stimulation in treated IDA children help them catch
                up to their non-anemic peers in development over time.

        5. Study Objective(s)

             1. To determine the long term effect of early psychosocial stimulation provided at the
                age of 6-24 months in addition to iron treatment in IDA children on their growth
                (height, weight and Head Circumference), IQ, executive function, school
                achievement, fine motor, memory and behaviour

             2. To compare the growth and development of IDA infants with non-anemic infants after
                7 years of an intervention with iron supplementation and psychosocial stimulation.

        6. Methods:

      Sample: All children who participated in the iron and stimulation study at the age of 6 to 24
      months (n=424).

      Identification of sample: Using the addresses and by tracking through available mobile phone
      numbers.

      Measurements

      In the current follow-up, at the age of around 8-9 years all the available children will be
      measured for:

        -  WASI: The Wechsler Abbreviated Scale of Intelligence - Second Edition (WASI-II)

        -  School achievement

        -  Number Stroop

        -  SDQ (strength and difficulties):The Strengths and Difficulties Questionnaire (SDQ)

        -  Memory test of NEPSY (neuropsychological test)

        -  Digit span forward and backward

        -  Middle childhood HOME

        -  Fine motor skills using the Purdue peg board or Movement Assessment Battery Children- 2
           (age -band 2 for 7-10 years)

        -  SES Anthropometric measurement: Children's height, weight and head circumference
    

Detailed description: 
      Millions of young children in developing countries have developmental deficits due to some
      preventable factors like poor nutrition, lack of a stimulating environment, and poverty.
      Although Bangladesh is doing well in achieving MDGs, still poor nutrition, poverty and poor
      parental education are prevalent. These mutually exclusive factors have an implication not
      only for the individuals' future but also for national income and development.

      Usually, iron deficiency in the neonatal period and early childhood is considered a key to
      the development of disturbances in cognitive development. There is increasing evidence that
      iron deficiency anemia detrimentally affects children's development. Many cross sectional
      studies have shown that iron deficiency is associated with poor psycho motor development and
      behavioral deficits in young children, and poor cognition and school achievement in
      school-aged children. However, anemia is associated with many adverse social and economic
      family circumstances which may adversely affect children's development.

      Nutrition along with early child development interventions can have additive or synergistic
      effects on child development, and in some cases, nutritional outcomes. Meta analysis, studies
      conducted in low, middle and high income countries in randomized controlled trials among
      primary school aged children (5-12 years) showed that concurrent iron supplementation
      improved global cognitive scores and growth and reduced risk of anemia and iron deficiency
      among anemic children by 50% and 75% respectively. According to the Lancet reviews on child
      development iron deficiency anemia during early childhood, when brain growth spurt occurs is
      one of the identified risk factor for later development. Similarly early psycho social
      stimulation acts as a protective factor in optimizing later development. Studies in Indonesia
      and Canada both found benefits from iron treatment to infants' motor development but not to
      mental development. It has been suggested that the poor level of mental development found in
      IDA infants may be irreversible in some circumstances. One systematic review and meta
      analysis revealed that daily iron supplementation in 2 to 5 years children increases
      hemoglobin and ferretin but has limited evidence in cognitive development and physical
      growth..

      Anemia is a public health problem in Bangladesh where 51% of young children aged 6 to 59
      months are suffering and the main cause of this problem is iron deficiency. A study conducted
      in Bangladesh found a non significant benefit to motor development from iron alone however
      the power of the study was extremely limited and the group receiving iron and zinc benefited
      in motor development. We also conducted a cluster randomized controlled trial in 2007-2008 on
      6-24 months old iron deficient anemic (IDA) and non- anemic non-iron deficient (NANI)
      children with iron supplementation to IDA children for 6 months and weekly psycho social
      stimulation to all children in the stimulation clusters for 9 months in Bangladesh. The
      result showed that although the intervened IDA group recovered from their iron deficient
      status after 9 months, hey had significantly lower psycho motor development index (PDI) and
      responsiveness to the examiner compared to NANI group. Random-effects multilevel regressions
      of the developmental scores showed that psycho social stimulation improved children's mental
      development Index (MDI) in both the group. Interaction between iron status and stimulation
      showed a suggestive trend indicating that children with IDA and NANI responded differently to
      stimulation, i.e. the IDA group improved less than the NANI group. During that time we
      predicted that benefit of Iron supplementation and psycho social stimulation on children may
      appear in later life with application of more sensitive measurement tools for intelligence.
      The present study provides us a unique opportunity to examine long term effect of early iron
      supplementation and psycho social stimulation on growth and development of iron deficient
      anemic children.

      Hypothesis:

      3. The benefit of early iron supplementation in addition to Psycho social stimulation on
      growth and development of IDA infants appears in later life.

      4. Addition of early psycho social stimulation in treated IDA children help them catch up to
      their non-anemic peers in development over time.

      Study Objective(s)

        1. To determine the long term effect of early psycho social stimulation provided at the age
           of 6-24 months in addition to iron treatment in IDA children on their growth (height,
           weight and Head Circumference), IQ, executive function, school achievement, fine motor
           and behavior

        2. To compare the growth and development of IDA infants with non-anemic infants after 7
           years of an intervention with iron supplementation and psycho social stimulation.

      Study Setting Location: 30 villages of Monohardi Upazilla under Narsingdi district. Study
      design: Follow-up of a cluster randomized controlled trial. In the original study
      randomization was done at village level for psycho social stimulation. Two hundred and twelve
      children (106 anemic and 106 non anemic) aged 6-12 months in the "stimulation-villages (S)"
      received age specific psycho social stimulation and 212 children of "non-stimulation villages
      (NS: 106 anemic and 106 non anemic) were enrolled as controls. Mild and moderately anemic (Hb
      80.0-109 g/L) and iron deficient (ferritin <12 μg/L) children of all the assigned villages
      (both S and NS) received ferrous-sulphate (Fe2SO4) syrup. Children were considered non-anemic
      if they had Hb>110 g/L and ferritin levels ≥12 μg/L. For all groups parental education were
      less than X grade.

      Sample: All children who participated in the original study at the age of 6 to 24 months and
      can be located will be enrolled.

      IDA group: All the children who were identified as IDA during early childhood (6-24 months)
      based on Hb level between 80-110 g/L and sTfR levels ≥ 5.0 mg/L.

      Non-anemic group: All the children who were identified as NANI during early childhood based
      on Hb >110g/L and sTfR <5.0 mg/L) living in the same rural areas. .

      Identification of sample: the study will try to track the children through their addresses
      and available mobile phone numbers that are registered during their enrollment. The study
      will also contact the local staff who worked as the play leaders and health workers and had
      close contact with the families to help us locate the children.

      Randomization: In the original study the villages with at least 12 children (6 IDA and 6
      NANI) aged 6-24 months were selected and randomly assigned to either psycho social
      stimulation or non-stimulation groups.

      Intervention In the original study all anemic children in early childhood received 30 mg
      ferrous sulfate daily based on recommendations from both the WHO and IOM reports for 6
      months. The psycho social intervention lasted for 9 months and included play demonstrations
      at home by a play leader (PL) who was trained to visit homes and teach the mothers about
      child development and care practices. The study showed the mothers how to play with children
      using toys in a way to promote good child development.

      Plan of work: After taking written consent, the identified mothers and children will be
      interviewed for home based measurements (SES, HOME & SDQ) by team of two members - one
      trained testers (graduates in psychology or social science) and one health worker (high
      school graduate). The mother will be invited to come along with their children to the test
      centers (centrally located in the village) for developmental and anthropocentric assessments.
      The same tester will conduct the psychological assessments of the children while the health
      worker will assist in bringing and testing them. The testers and health workers will be
      unaware about the intervention group (blinded). Four teams will start assessments at the same
      time in 4 villages and rotate to the next after completing one. it is assumed that the
      testers will complete assessment of 10-12 children in one village in approximately two and
      half days.

      Measurements

      In the current follow-up, at the age of around 8-9 years all the available children will be
      measured for:

      • WASI: The Wechsler Abbreviated Scale of Intelligence - Second Edition (WASI-II), a revision
      of the WASI, provides a brief, reliable measure of cognitive ability for use in clinical,
      educational and research settings. It consists of four sub tests: Vocabulary, Block Design,
      Similarities and Matrix Reasoning. Scores of these sub tests lead to calculate performance IQ
      (PIQ), verbal IQ (VIQ) as well as a full scale IQ (FSIQ). The average reliability
      coefficients of the WASI subtest range from .87 to .92 for the overall children's sample
      (Guilford1954 and Nunnally 1978). WASI has been used by this group in Bangladesh previously
      and was culturally adapted before use. The adapted and translated version has been assessed
      for face validity before use and showed meaningful correlation with nutritional and
      socio-economic variables (Ali- personal communication).

      Previous study conducted by us showed that cognitive testing of pictures, piloted the
      original test on 35 children in Gaibandha and 20 children in Dhaka, and re-ranked the items
      according to difficulty. The test retest reliability of the adapted tool ranged from 0.77 to
      0.86 for different subscales.

        -  School achievement: Children's school achievement will be measured using a locally
           developed test based on the 'wide range achievement test (WRAT) that measures
           mathematics, reading, writing and comprehension abilities. In addition their grade
           level, number of grades repeated, attendance in school, age of enrolment at primary
           school, age of leaving school, preschool attendance etc. will also be measured. This
           test has been used by a member of our group in a previous intervention study in rural
           Bangladesh and was sensitive to changes in serum iodine. This adapted version of school
           achievement test showed good face validity before testing. It also showed high
           concurrent validity (r=0.71) with Wechsler Intelligence Scale for Children (WISC-IV) at
           10 years and moderately high predictive validity (r=0.54) of Wechsler Preschool and
           Primary Scale of Intelligence (WPPSI) used at 5 years in our recently completed cohort
           study in Bangladesh (Tofail -personal communication). It also showed meaningful
           correlation with socio-economic variables, parental education and children's nutritional
           status.

        -  Number Stroop: The number Stroop measures executive function of the children. It is a
           psychological test for mental (selective attention) vitality and flexibility. It has
           been used in Bangladesh in another study in Gaibandha where it picked up intervention
           effects (Ali- personal communication). We also used a modified word and color stroop
           test in Matlab that showed reasonable concurrent validity (r> 0.45) with other cognitive
           measures and socio-demographic variables .We will conduct a pilot test for number stroop
           in this study to assess face validity and test -retest reliability before using.

        -  Strength and difficulties questionnaire (SDQ): will be used to identify behavioral and
           emotional problems of the children based on mother's report. It is a widely and
           internationally used brief behavioral screening instrument assessing child positive and
           negative attributes across 5 sub-scales: 1) Emotional Symptoms, 2) Conduct Problems, 3)
           Hyperactivity-Inattention, 4) Peer Problems, 5) Pro social Behavior. The SDQ has been
           extensively researched with various populations and has been translated into over 40
           languages. Reliability was generally satisfactory when assessed by internal consistency:
           (mean Cronbach α: 0.73), cross-informant correlation (mean: 0.34), or retest stability
           after 4 to 6 months (mean: 0.62) . Our team used it in several studies in Bangladesh and
           showed meaningful correlation of the sub-scales with socio-economic variables. We used
           the parent's report of SDQ and it showed good face validity and a conceptually
           meaningful pattern of cross-scale correlations and the acceptable internal reliability
           estimates found for each subscale. At five years of age it picked up intervention effect
           of prenatal supplementation in our recent analysis.

        -  Memory sub tests of NEuro PSYchological (NEPSY) Assessment: is a comprehensive
           instrument designed to assess neuro psychological development and provide insights
           regarding academic, social, and behavioral difficulties in preschool and school-age
           children. We will use only the memory test of NEPSY. We have used this memory test in
           one of our recent rural study on school children. Although it has been used in
           Bangladesh earlier but we will pilot it on current population to modify and adapt it
           accordingly.

        -  Digit span: Digit span forward and backward will be used to measure memory and executive
           function of the children. It has been used as a part of Wechsler Intelligence Scale for
           Children (WISC-IV) on 10 years old children and currently being used in one study on
           rural population. It showed good face validity and test retest reliability after 7 days.
           We will also pilot it on our current study area on non-study children to modify and
           adapt it accordingly before use.

        -  HOME: the middle childhood version of home observation for measurement of environment
           will be used to assess quality of home stimulation. Overall inter-observer reliability
           for the middle childhood -HOME reported to be satisfactory. Percentage agreement for
           specific items in the EC-HOME ranged from 79-100% while Cohen's kappa values ranged from
           0.45 to 1. Intraclass correlation for subscale scores were in the interval of 0.79 to
           0.94. The intraclass correlation for the total scale was 0.92. It has been used in
           several studies of Bangladesh and showed moderately high concurrent validity with IQ
           measures (r> 0.5).

        -  Fine motor skills using the Purdue peg board or Movement Assessment Battery for
           Children- 2 (age -band 2 for 7-10 years): it was prefered to conduct MABC-2, but we will
           make decision after piloting both the tests. Correlations between MABC-2 test components
           ranged between 0.25 and 0.36 (indicating little overlap between subtests). Correlation
           scores range from 0.73 to 0.84 for component scores and are equal to 0.80 for total test
           score. The study conducted earlier by us MABC in Bangladesh in younger children and
           MABC-2 in 8-year old children. This time a pilot study will be done on our current study
           area on non-study children to modify and adapt it accordingly before use.

        -  Socio economic status (SES) will be measured using a standard questionnaire.
           Anthropometric measurement: Children's height, weight and had circumference will be
           measured using standard measures.All these measures were culturally adapted in
           Bangladesh and have been used previously by our group. All the instruments are ready to
           use but will be pre-tested in the community before using.

      Reliabilities Inter-observer reliabilities will be assessed on all measurements before the
      study begins and during the study on 10% of all the measurements.

      Sample Size In the original study the sample size was calculated as 212 children in each of
      the IDA and NANI group considering 5% level of significance, 80% power, an improvement of 0.5
      SD in children's development, an ICC of 0.01, design effect of 1.5 and 25% drop outs. In the
      follow-up we will assess all the available children of those groups. In the original study
      the analysis showed that there was no effect of clustering. Therefore we do not need to
      account for the design effect and the sample size without design effect will be 64 in each
      group. Considering a drop out of 10%, we need to enrol 70 children in each group and we
      believe it is possible to track that many children in those villages to have sufficient power
      to conduct the study.

      Data Analysis After coding, the data will be entered in to a personal computer using SPSS
      11.5 software. We will the check for normality of the data. Log transformation will be done
      if any data is positively skewed. The characteristics of the tested and lost groups will be
      compared using 'student t test' or ANOVA for continuous variables and χ2 for categorical
      variables. Pearson's bivariate correlation will be conducted to explore associations between
      the age of the child and each developmental measure.

      The sociodemographic characteristics and growth measures at baseline will be compared between
      the IDA and NANI groups as well as between the stimulated and unstimulated groups by using
      random effects ANOVA.

      Finally, it will be fitted random-effects multilevel regression model to the intelligence
      scores and nutritional outcome scores by using intention-to-treat analyses. We will
      investigate the effects of the IDA/NANI groups and stimulated/ unstimulated groups and their
      interaction. In each regression analysis, the outcome will be final developmental score, and
      we will adjust for the relevant initial score, along with the selected covariates that are
      identified as con-founders.

      Data Safety Monitoring Plan (DSMP) Study questionnaires will be recorded on paper forms,
      which will be kept in a secure facility under the responsibility of the Principal
      Investigator of this study. All questionnaires and data forms will be reviewed for
      inconsistencies and missing data points. Edited data will be entered in a personal computer
      using SPSS.

      Ethical Assurance for Protection of Human rights

      Approval of the Research and Ethical Review Committees of icddr,b will be collected.

      Written informed consent of one of the parents will be obtained after thorough explanation of
      the purpose of the study, requirements of participation, study procedures, and the risks and
      benefits to the child. Another person will be acting as witness at the time of consent
      signing.

      Measures will be taken to ensure strict confidentiality of the information obtained.
    

Intervention name(s): psycho social stimulation
Intervention type(s): Other
Intervention description(s): The psychosocial intervention lasted for 9 months and included play demonstrations at home by a play leader (PL) who was trained to visit homes and teach the mothers about child development and care practices. They also showed the mothers how to play with children using toys in a way to promote good child development. In the original study all anemic children in early childhood received 30 mg ferrous sulphate daily based on recommendations from both the WHO (2003) and IOM reports (2001) for 6 months.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)