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Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials |
Sachdev H P, Gera T, Nestel P |
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CRD summary This review concluded that iron supplementation has a modest effect on mental development, in particular for intelligence quotient scores in children 7 years or older, and in those who are initially anaemic or iron-deficient anaemic. Limitations in the review process, along with wide variation amongst the studies, mean that the reliability of the authors' conclusions is unclear.
Authors' objectives To evaluate the effect of iron supplementation on mental and motor development in children.
Searching MEDLINE (from 1966 to 2003), the Cochrane Controlled Trials Register, EMBASE, IBIDS and HeathSTAR were searched for potentially relevant studies; the search terms were not reported. The reference lists of relevant papers, along with those in handsearched reviews, were screened for further studies. In addition, bibliographies of books, personal files, conference proceedings or abstracts were consulted, and experts were contacted for additional or ongoing trials. Authors were contacted for information where necessary. Published and unpublished data were included in the review.
Study selection Study designs of evaluations included in the reviewRandomised placebo-controlled trials were eligible for inclusion in the review, except where iron supplementation was administered parenterally (in which case the trials did not have to be placebo-controlled).
Specific interventions included in the reviewStudies of iron supplementation administered via an oral or parenteral route, or as dietary fortification, were eligible for inclusion. Other studies containing additional micronutrients were included when the only difference between the study groups was iron supplementation. The majority of the studies were of orally administered supplements. The mean duration of the interventions ranged from 1 week to 15 months, although more than half of the studies included interventions of 4 months' duration or longer. A variety of doses was reported.
Participants included in the reviewThere were no specified inclusion criteria for the participants. The majority of the studies involved infants and toddlers, although 5 studies were conducted with older children (8 years or older).
Outcomes assessed in the reviewThe primary outcomes of interest were mental and motor development. Studies were included if they measured one or more of psychomotor development, cognition, mental development, intelligence quotient (IQ) and school performance. More than half of the studies (younger children) used the Bayley indices for mental and psychomotor development. Other specific outcome measures included motor and language development scores, discrimination learning, oddity learning, Peabody Picture Vocabulary Tests, cognition, visual recall, mazes, clerical tasks and the Denver Development Screening Test.
How were decisions on the relevance of primary studies made?Titles, abstracts and full texts of potentially relevant studies were screened in order to select those for inclusion in the review. The authors did not state how many reviewers performed the selection.
Assessment of study quality Studies were assessed for methodological quality using established checklists. The criteria used included method of randomisation, concealment of allocation (adequate, unclear, inadequate, or not used), blinding (double-blind, single-blind, no blinding, or unclear) and attrition (percentage lost to follow-up). The authors did not state how the papers were assessed for quality, or how many reviewers performed the quality assessment.
Data extraction One reviewer abstracted the data. Changes between study groups were recorded using sample size, mean changes in development score and standard deviations. Some manipulation of the data was carried out: e.g. the dividing of the control group (whilst retaining the values for mean and standard deviation) in studies of two or more intervention groups with different administration regimens. The standard deviations were calculated from actual data, back-calculated from other studies, or assuming correlations of 0.5 and 0 (independent).
For missing data, assumptions about the sample size, mean change in development score and age of the participants were made.
Methods of synthesis How were the studies combined?The studies were grouped and analysed in terms of mental or intelligence scores and motor development outcomes. Pooled estimates of the weighted mean difference (WMD) for changes in outcomes between study groups were derived from fixed-effect models; random-effects models were used when significant statistical heterogeneity was found. The standardised mean difference (SMD) was used where scoring methods were different between the studies. Funnel plots were used to evaluate publication bias, and this was tested using the Egger and Begg methods.
How were differences between studies investigated?Heterogeneity was explored using the chi-squared test. Variables were further analysed in a meta-regression using predetermined stratification. Items used in the latter were methodological quality, age of participants, route of intervention administration, duration, baseline haemoglobin (Hb) concentration in the intervention group, and iron status of the study population.
Results of the review Seventeen randomised controlled trials, of which 16 were published and one was unpublished, were included in the review (n=3,646).
There was no summary of methodological quality, although the method of randomisation was not mentioned and allocation concealment was unclear in the majority of the studies. Full details of the study scores were given in the paper.
Mental development.
The pooled estimate (SMD, random-effects model) from 15 studies (2,827 children) using a variety of scoring methods showed a significant effect of 0.30 (95% CI: 0.15, 0.46, P<0.001). There was significant heterogeneity amongst the studies (P<0.001). The sensitivity analysis confirmed this result and also suggested more favourable results from oral supplementation given for 1 month or more in children aged 5 years or older, with a lower baseline Hb and iron status. Lower baseline Hb levels and initial iron-deficient anaemia were significant predictors of a positive effect of iron supplementation in the meta-regression. There was no evidence of publication bias (Egger, P=0.694; Begg, P=0.453).
In individual mental development tests using the Bayley index, 8 studies of children aged 27 months or younger (899 children) showed a non significant pooled estimate (WMD) of 0.95 (95% CI: -0.56, 2.46, P=0.217). There was significant heterogeneity amongst the studies (P=0.016). Iron-deficient anaemia was shown to be a statistically significant predictor of a favourable response when all other variables were controlled in the meta-regression (WMD 2.76, 95% CI: 0.26, 5.25, P=0.03).
In children aged 8 years or older, 4 trials (1,666 children) showed a significant improvement in IQ score (SMD 0.41, 95% CI: 0.20, 0.62, P<0.001). There was some heterogeneity amongst the studies (P=0.07). In 2 trials, the effect of iron supplementation on individual components of the total cognition score showed a statistically significant result for mazes only (P<0.001). There were no significant effects on linguistic and mathematical skills.
Motor development.
Pooled data from 10 trials (1,246 children) showed no significant effect on motor development (SMD 0.09, 95% CI: -0.08, 0.26, P=0.28). There was significant heterogeneity amongst the studies (P=0.028). Sensitivity and meta-regression analyses showed that methodological quality, route and duration of the intervention, baseline Hb and iron status were not significant predictors of the SMD. There was no evidence of publication bias (Begg, P=0.921; Egger, P=0.826).
No benefits were observed in terms of psychomotor development and Bayley Psychomotor Development Index scores.
Authors' conclusions Iron supplementation has a modest effect on mental development in children. This is especially evident for IQ scores in those children aged 7 years or older, and in those who are initially anaemic or iron-deficient anaemic.
CRD commentary The review addressed a clear research question and the inclusion criteria were specific, except for those relating to the participants. The search strategy was comprehensive, but (except for MEDLINE) failed to specify the dates for the various searches. Unpublished material was considered in the analysis, along with a thorough exploration of publication bias. It was unclear whether language restrictions were applied; this information would have been relevant given the variety of countries from which the studies were drawn. The quality assessment was based on established criteria, but no summary was offered as to how study quality influenced the authors' conclusions. Bias could not be ruled out in the review process, given that it was unclear how the studies were selected and assessed for quality and that only one reviewer carried out the data extraction.
Substantial heterogeneity was evident amongst the studies and this was explored in further analyses. Although it is questionable whether the quantitative synthesis of the results was appropriate, the authors usefully reported those results arising from the use of a random-effects model. Many assumptions were made in the review and, although the results were supported by sensitivity testing, the authors' conclusions should be considered in this context. A number of valid points were raised in the study of public health interventions, such as those relating to potentially confounding factors and ambiguities in terminology. The authors' conclusions reflect the limited evidence presented, but the extent to which these are reliable (given the limitations highlighted) is not clear.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors stated that suitably designed trials are needed to evaluate the preventive role of iron supplementation in younger children.
Funding United States Agency for International Development, grant number HRN-A-00-98-00027-00.
Bibliographic details Sachdev H P, Gera T, Nestel P. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutrition 2005; 8(2): 117-132 Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Anemia, Iron-Deficiency /complications /drug therapy; Child; Child Development /drug effects; Child, Preschool; Cognition /drug effects; Dietary Supplements; Female; Humans; Infant; Infant, Newborn; Iron /administration & Male; Psychomotor Performance /drug effects; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; dosage /therapeutic use AccessionNumber 12005000037 Date bibliographic record published 31/10/2006 Date abstract record published 31/10/2006 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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