Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia

  • Review
  • Intervention

Authors

  • Bo Wang,

    1. Chinese Academy of Medical Sciences, Health Science Popularization Research Center, Beijing, Beijing, China
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  • Siyan Zhan,

    1. School of Public Health, Peking University, Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics, Beijing, China
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  • Ting Gong,

    1. School of Public Health, Peking University, Department of Epidemiology and Biostatistics, Beijing, Beijing, China
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  • Liming Lee

    Corresponding author
    1. School of Public Health, Peking University, Department of Epidemiology and Biostatistics, Beijing, Beijing, China
    • Liming Lee, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 36 Xueyuan Road, Haidian District, Beijing, Beijing, 100191, China. lmlee@vip.163.com.

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Abstract

Background

Iron deficiency and iron deficiency anaemia (IDA) are common in young children. It has been suggested that the lack of iron may have deleterious effects on children's psychomotor development and cognitive function. To evaluate the benefits of iron therapy on psychomotor development and cognitive function in children with IDA, a Cochrane review was carried out in 2001. This is an update of that review.

Objectives

To determine the effects of iron therapy on psychomotor development and cognitive function in iron deficient anaemic children less than three years of age.

Search methods

We searched the following databases in April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP). We also searched the reference lists of review articles and reports, and ran citation searches in the Science Citation Index for relevant studies identified by the primary search. We also contacted key authors.

Selection criteria

Studies were included if children less than three years of age with evidence of IDA were randomly allocated to iron or iron plus vitamin C versus a placebo or vitamin C alone, and assessment of developmental status or cognitive function was carried out using standardised tests by observers blind to treatment allocation.

Data collection and analysis

Two review authors independently screened titles and abstracts retrieved from the searches and assessed full-text copies of all potentially relevant studies against the inclusion criteria. The same review authors independently extracted data and assessed the risk of bias of the eligible studies. Data were analysed separately depending on whether assessments were performed within one month of beginning iron therapy or after one month.

Main results

We identified one eligible study in the update search that had not been included in the original review. In total, we included eight trials.

Six trials, including 225 children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function within 30 days of commencement of therapy. We could pool data from five trials. The pooled difference in pre- to post-treatment change in Bayley Scale Psychomotor Development Index (PDI) between iron and placebo groups was -1.25 (95% confidence interval (CI) -4.56 to 2.06, P value = 0.65; I2 = 33% for heterogeneity, random-effects meta-analysis; low quality evidence) and in Bayley Scale Mental Development Index (MDI) was 1.04 (95% CI -1.30 to 3.39, P value = 0.79; I2 = 31% for heterogeneity, random-effects meta-analysis; low quality evidence).

Two studies, including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function more than 30 days after commencement of therapy. One of the studies reported the mean number of skills gained after two months of iron therapy using the Denver Developmental Screening Test. The intervention group gained 0.8 (95% CI -0.18 to 1.78, P value = 0.11, moderate quality of evidence) more skills on average than the control group. The other study reported that the difference in pre- to post-treatment change in Bayley Scale PDI between iron-treated and placebo groups after four months was 18.40 (95% CI 10.16 to 26.64, P value < 0.0001; moderate quality evidence) and in Bayley Scale MDI was 18.80 (95% CI 10.17 to 27.43, P value < 0.0001; moderate quality evidence).

Authors' conclusions

There is no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development or cognitive function within 30 days after commencement of therapy. The effect of longer-term treatment remains unclear. There is an urgent need for further large randomised controlled trials with long-term follow-up.

摘要

背景

以鐵劑治療 (Iron therapy) 改進3歲以下缺鐵性貧血 (iron deficiency anaemia) 兒童的精神運動 (psychomotor) 發展和認知功能

鐵缺乏和缺鐵性貧血常見於年幼兒童。鐵缺乏可能對兒童的精神運動發展和認知功能產生重要影響。

目標

研究鐵劑治療對3歲以下鐵缺乏兒童精神運動發展和認知功能的療效

搜尋策略

搜尋以下資料庫:COCHRANE LIBRARY (2000 ISSUE 4) MEDLINE (1966August 2000) EMBASE (1980August 2000) Latin American Database (LILACS) PsycLIT Journal articles (1974August 2000) PsycLIT Chapters and Books (1987August 2000) 挑出的試驗文獻和重要文章都被仔細研讀。在Science Citation Index內檢索之前挑選出的試驗所引用的文獻。有聯繫主要作者。

選擇標準

符合以下條件的試驗會被納入:三歲以下有缺鐵性貧血的兒童,被隨機分配至鐵治療或鐵和維生素治療,對照安慰劑組或只有維生素C治療。發展狀態或認知功能的評估由不知兒童接受何種治療的觀察者以標準化的檢驗評估。

資料收集與分析

閱讀由電子資料庫找出的研究摘要和題目,以決定這些研究是否符合納入標準。由電子資料庫或其他方式得到之可能符合納入標準的文獻全文,由兩位獨立審閱者評估。若對是否適合納入有不同意見,則經由討論取得共識。依受試者是否在開始鐵劑治療一個月內或之後有鐵評估將資料分開分析。

主要結論

5個總共包含180位有缺鐵性貧血兒童的試驗,檢視鐵劑治療對治療5至11天後的精神運動發展之療效。四個試驗的資料可以合併。合併後的資料顯示鐵劑治療組和安慰劑組治療前後的貝萊量表精神運動發展指標 (Bayley Scale PDI) 差異為 −3.2 (95% 信賴區間 (CI) −7.24, 0.85) ,而貝萊量表心智發展指標 (Bayley Scale MDI) 差異為0.55 (95% CI −2.84, 1.75) 。2個共隨機分配160位缺鐵性貧血兒童的試驗,檢視鐵劑治療進行30天以後對精神運動發展指標的影響。Aukett及其他人得到鐵劑治療兩個月後用丹佛檢驗 (Denver test) 得到的平均技能得分。介入組比安慰劑組的技能得分平均高出 0.8 (95% CI −0.18, 1.78) 。Idjrandinata及其他人得到鐵劑治療和安慰劑兩組,在治療4個月後,治療前後貝萊量表精神運動發展指標差別為18.40 (95% CI 10.16, 26.64) 且貝萊量表心智發展指標差別為18.80 (95% CI 10.19, 27.41) 。

作者結論

沒有決定性證據證明鐵劑治療5 – 11天就可對缺鐵性貧血年輕兒童的精神運動發展有療效。長期療效仍不清楚但資料將與臨床顯著益處相容。急需進一步有長期追蹤的隨機對照試驗。

翻譯人

共識仍待確認。

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

本次結論為並沒有明顯證據證明治療缺鐵性貧血年幼病童能增進他們的發展。年幼兒童缺鐵可能會影響體智能發展,因此缺鐵性貧血兒童應該接受治療。長久以來一直建議缺鐵性貧血兒童應該接受治療,因年幼兒童缺鐵可能會影響體智能發展。但這裡的證據並不認為口服鐵或注射鐵,於接受治療的6 – 11天內會改進兒童發展。兩個進行治療兩個月以上的試驗中,一個於發展有顯著益處但另一個則沒有。撰稿者不確定鐵劑治療是否有益於鐵缺乏的貧血兒童之發展。

Résumé scientifique

Thérapie ferrique pour améliorer le développement psychomoteur et la fonction cognitive des enfants de moins de trois ans présentant une anémie ferriprive

Contexte

La déficience en fer et l'anémie ferriprive sont courantes chez les jeunes enfants. On pense que le manque de fer pourrait avoir des effets délétères sur le développement psychomoteur et la fonction cognitive des enfants. Pour évaluer les bénéfices de la thérapie ferrique sur le développement psychomoteur et la fonction cognitive des enfants présentant une anémie ferriprive, une revue Cochrane a été réalisée en 2001. Ce document est une mise à jour de cette revue.

Objectifs

Déterminer les effets de la thérapie ferrique sur le développement psychomoteur et la fonction cognitive des enfants de moins de trois ans présentant une anémie ferriprive.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données suivantes en avril 2013 : le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov et World Health Organization International Clinical Trials Registry Platform (ICTRP). Nous avons également effectué des recherches dans les bibliographies des articles et les rapports, et réalisé des recherches de citations dans le Science Citation Index pour les études pertinentes identifiées lors de la recherche principale. Nous avons également contacté les principaux auteurs.

Critères de sélection

Les études étaient incluses si les enfants de moins de trois ans avec une anémie ferriprive évidente se voyaient attribuer de manière aléatoire du fer ou du fer plus de la vitamine C par rapport à un placebo ou de la vitamine C seule ; l'évaluation du statut de développement ou de la fonction cognitive a été réalisée à l'aide de tests standards par des observateurs ne connaissant pas l'attribution des traitements.

Recueil et analyse des données

Deux auteurs ont indépendamment examiné les titres et les résumés issus des recherches et évalué les copies intégrales de toutes les études potentiellement pertinentes en fonction des critères d'inclusion. Les mêmes auteurs ont indépendamment extrait des données et évalué les risques de biais des études éligibles. Nous avons analysé les données séparément si les évaluations étaient réalisées sous un mois après le début de la thérapie ferrique ou après un mois.

Résultats principaux

Nous avons identifié une étude éligible dans la recherche de la mise à jour qui n'avait pas été incluse dans la revue d'origine. Au total, nous avons inclus huit essais.

Six essais, totalisant 225 enfants avec une anémie ferriprive, étudiaient les effets de la thérapie ferrique sur les mesures du développement psychomoteur et de la fonction cognitive 30 jours après le début du traitement. Nous avons pu regrouper les données de cinq essais. La différence regroupée du changement pré- et post- traitement pour l'indice de développement psychomoteur (IDP) de l'échelle de Bayley entre les groupes avec fer et placebo était de -1,25 (intervalle de confiance (IC) à 95 % -4,56 à 2,06, valeur P = 0,65 ; I2 = 33% pour l'hétérogénéité, méta-analyse à effets aléatoires ; données de mauvaise qualité) et pour l'indice de développement moteur (IDM) de l'échelle de Bayley, elle était de 1,04 (IC à 95 % -1,30 à 3,39, valeur P = 0,79 ; I2 = 31% pour l'hétérogénéité, méta-analyse à effets aléatoires ; données de mauvaise qualité).

Deux essais, totalisant 160 enfants avec une anémie ferriprive, étudiaient les effets de la thérapie ferrique sur les mesures du développement psychomoteur et de la fonction cognitive plus de 30 jours après le début du traitement. Une étude indiquait le nombre moyen de compétences acquises après deux mois de thérapie ferrique à l'aide du test de dépistage de Denver. Le groupe avec intervention a gagné 0,8 (IC à 95 % -0,18 à 1,78, valeur P = 0,11, qualité modérée des données) compétences en plus en moyenne par rapport au groupe témoin. L'autre étude indiquait que la différence concernant le changement pré- à post- traitement pour l'IDP de l'échelle de Bailey entre le groupe traité avec du fer et le groupe sous placebo après quatre mois était de 18,40 (IC à 95 % 10,16 à 26,64, valeur P < 0,0001 ; données de qualité modérée) et pour l'IDM de l'échelle de Bayley, elle était de 18,80 ( IC à 95 % 10,17 à 27,43, valeur P < 0,0001 ; données de qualité modérée).

Conclusions des auteurs

Il n'existe aucune donnée convaincante permettant d'affirmer que la thérapie ferrique chez les jeunes enfants avec une anémie ferriprive a un effet sur le développement psychomoteur ou sur la fonction cognitive sous 30 jours après le début du traitement. L'effet du traitement à plus long terme reste incertain. Il est urgent de réaliser d'autres essais contrôlés randomisés à grande échelle avec un suivi à long terme.

Plain language summary

Iron therapy for improving physical and intellectual development in children under the age of three who are anaemic due to a lack of iron

It has been suggested that a lack of iron in young children negatively affects their physical and intellectual development and therefore those who are anaemic should be treated. To assess the effects of iron therapy on psychomotor development and cognitive function in very young iron deficient anaemic children, we searched eight electronic databases in April 2013 for relevant studies. We looked for studies where children less than three years of age with iron deficiency anaemia were randomly assigned either to receive iron or iron plus vitamin C versus a placebo ('dummy pill') or vitamin C alone, and their developmental status or cognitive function was independently assessed by someone who did not know if they had received any iron. To make sure we had not missed any studies, we also searched reference lists, ran citation searches and contacted key experts in this area.

Two review authors independently read through all the titles and abstracts retrieved from the searches to see if the studies were relevant. Where necessary, we looked at the full-text version of the paper to check if it matched the inclusion criteria for our review. The same review authors independently extracted data from the studies for analysis and assessed the risk of bias in each of the studies. We analysed the data separately depending on whether assessments were performed within one month of beginning iron therapy or after one month.

We found eight studies to include in the review. Six studies (involving 225 children) looked at the effects of iron therapy within 30 days of starting it and we were able to combine the results of five of them. Iron therapy did not appear to improve scores on either the Bayley Scale Psychomotor Development Index (PDI) or the Bayley Scale Mental Development Index (MDI). Two studies (160 children) considered the effects of iron therapy more than 30 days after starting it. One study found no benefit of iron therapy on the acquistion of skills as measured by the Denver Developmental Screening Test. The other study, however, found that scores on the Bayley scales PDI and MDI were significantly higher for the group receiving iron therapy.

This review concludes that there is no convincing evidence that iron given by mouth or by injection will improve physical or intellectual development in young children who are anaemic because of a lack of iron within one month after start of treatment. It is unclear whether longer-term treatment is beneficial for physical and intellectual development in these children. Large randomised controlled trials with long-term follow-up are needed in the future.

Résumé simplifié

Thérapie ferrique pour améliorer le développement physique et intellectuel des enfants de moins de trois ans qui sont anémiés en raison d'un manque de fer

On pense qu'un manque de fer chez les jeunes enfants affecte de manière négative leur développement physique et intellectuel et par conséquent, ceux qui sont anémiés devraient être traités. Pour évaluer les effets d'une thérapie ferrique sur le développement psychomoteur et la fonction cognitive des très jeunes enfants anémiés en fer, nous avons effectué des recherches dans huit bases de données électroniques en avril 2013 pour trouver les études pertinentes. Nous avons recherché les études dans lesquelles des enfants de moins de trois ans avec une anémie ferriprive étaient assignés de manière aléatoire pour recevoir du fer ou du fer plus de la vitamine C par rapport à un placebo ('pilule factice') ou de la vitamine C seule, et dans lesquelles leur statut de développement ou leur fonction cognitive était évalué indépendamment par une personne qui ne savait pas s'ils avaient reçu du fer. Pour être certain de n'avoir oublié aucune étude, nous avons également effectué des recherches dans les bibliographies, réalisé des recherches de citations et contacté les experts principaux dans ce domaine.

Deux auteurs ont indépendamment parcouru tous les titres et les résumés provenant des recherches pour voir si les études étaient pertinentes. Lorsque cela était nécessaire, nous avons recherché la version intégrale du document pour vérifier qu'il correspondait aux critères d'inclusion de notre revue. Les mêmes auteurs ont indépendamment extrait les données des études pour analyse et évalué le risque de biais de chacune des études. Nous avons analysé les données séparément si les évaluations étaient réalisées sous un mois après le début de la thérapie ferrique ou après un mois.

Nous avons identifié huit études à inclure dans la revue. Six études (totalisant 225 enfants) évaluaient les effets de la thérapie ferrique après 30 jours de traitement et nous avons pu combiner les résultats pour cinq d'entre elles. La thérapie ferrique ne semblait pas améliorer les scores de l'indice de développement psychomoteur (IDP) de l'échelle de Bayley ou de l'indice de développement mental (IDM) de l'échelle de Bayley. Deux études (160 enfants) considéraient les effets de la thérapie ferrique plus de 30 jours après le début du traitement. Une étude n'a démontré aucun bénéfice de la thérapie ferrique sur l'acquisition des compétences telles que mesurées dans le test de dépistage de Denver. L'autre étude a toutefois démontré que les scores IDP et IDM sur les échelles de Bayley étaient bien plus élevés pour le groupe qui avait reçu une thérapie ferrique.

Cette revue conclut qu'il n'y a pas de données convaincantes permettant d'affirmer que le fer administré par voie orale ou par injection améliorera le développement physique ou intellectuel des jeunes enfants qui présentent une anémie ferriprive sous un mois après le début du traitement. On ne sait pas si un traitement à plus long terme est bénéfique pour le développement physique et intellectuel de ces enfants. Des essais contrôlés randomisés plus vastes avec un suivi à long terme devront être réalisés.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laienverständliche Zusammenfassung

Eisentherapie zur Verbesserung körperlicher und intellektueller Entwicklung bei Kindern unter drei Jahren, die aufgrund von Eisenmangel anämisch sind

Es wurde vermutet, dass sich ein Eisenmangel bei jungen Kindern negativ auf ihre körperliche und intellektuelle Entwicklung auswirkt. Dementsprechend sollten diejenigen, die anämisch sind, behandelt werden. Zur Erhebung der Wirksamkeit von Eisentherapie auf die psychomotorische Entwicklung und kognitiven Funktionen bei sehr jungen, aufgrund von Eisendefiziten anämischen Kindern, durchsuchten wir im April 2013 acht elektronische Datenbanken nach relevanten Studien. Wir suchten nach Studien, in denen Kinder, unter drei Jahre und mit Eisenmangelanämie, zufällig zugeteilt entweder Eisen oder Eisen plus Vitamin C oder ein Placebo (Scheinmedikament) oder Vitamin C allein erhalten und in denen der Entwicklungsstatus oder die kognitiven Fähigkeiten unabhängig durch jemanden, der nicht wusste ob das Kind Eisen erhalten hatte oder nicht, erhoben wurden. Um sicherzugehen, dass wir keine Studien übersehen hatten, durchsuchten wir außerdem Literaturverzeichnisse, suchten nach Referenzen und kontaktierten Schlüsselexperten in diesem Bereich.

Zwei Review Autoren lasen unabhängig voneinander alle Titel und Abstracts der Suchergebnisse, um herauszufinden welche Studien relevant sind. Wenn nötig, betrachteten wir die Volltextversionen der Publikationen, um zu überprüfen ob sie den Einschlusskriterien entsprachen. Die gleichen Review Autoren extrahierten unabhängig voneinander die Daten der Studien zur Analyse und bewerteten das Risiko für Bias in den einzelnen Studien. Wir analysierten die Daten getrennt, abhängig davon, ob die Erhebung innerhalb des ersten Monats oder nach dem ersten Monat nach Beginn der Eisentherapie durchgeführt wurde.

Wir fanden acht Studien, die wir in unser Review einschlossen. Sechs Studien (225 Kinder umfassend) betrachteten die Wirkung von Eisentherapie innerhalb von 30 Tagen nach Beginn der Einnahme und wir waren in der Lage die Ergebnisse von fünf davon zu kombinieren. Eisentherapie schien die Werte weder auf der Skala des Bayley "Psychomotor Development Index" (PDI) noch auf der Skala des Bayley "Mental Deveopment Index" (MDI) zu verbessern. Zwei Studien (160 Kinder) untersuchten die Wirkung der Eisentherapie mehr als 30 Tage nach Beginn der Einnahme. Eine Studie fand keinen Nutzen der Eisentherapie auf das Erlernen von Fähigkeiten, gemessen durch den Denver-Developmental-Screening-Test (DDST). Die andere Studie fand jedoch, dass die Werte auf der Skala des Baylay PDI und MDI signifikant höher waren für die Gruppe, die Eisentherapie erhalten hatte.

Dieser Review schlussfolgert, dass keine überzeugende Evidenz vorliegt, dass Eisen (entweder durch den Mund oder durch Injektionen verabreicht) die körperliche und intellektuelle Entwicklung von jungen Kindern verbessert, die aufgrund eines Eisenmangels anämisch sind, wenn der Zeitraum innerhalb des ersten Monats nach Beginn der Therapie betrachtet wird. Es bleibt unklar, ob Langzeitbehandlungen einen Nutzen für die körperliche und intellektuelle Entwicklung dieser Kindern bringt. Zukünftig werden große randomisierte kontrollierte Studien mit einer langen Nachbeobachtungsdauer benötigt.

Anmerkungen zur Übersetzung

I. Nolle, freigegeben durch Cochrane Deutschland.

Streszczenie prostym językiem

Leczenie żelazem w celu poprawy rozwoju fizycznego i intelektualnego u dzieci w wieku poniżej trzech lat, z anemią spowodowaną brakiem żelaza

Sugeruje się, że niedobór żelaza u małych dzieci, ma negatywny wpływ na ich rozwój fizyczny i intelektualny, z tego powodu dzieci cierpiące na anemię powinno się odpowiednio leczyć. Aby ocenić wpływ leczenia żelazem na rozwój psychomotoryczny i czynności poznawcze u bardzo małych dzieci z niedokrwistością, z niedoborem żelaza, aby znaleźć odpowiednie badania przeszukaliśmy w kwietniu 2013 roku osiem elektronicznych baz danych. Poszukiwaliśmy badań, w których dzieci poniżej trzech lat, cierpiące na niedokrwistość z niedoboru żelaza, były losowo przydzielane do grupy otrzymującej albo żelazo, albo żelazo wraz z witaminą C, w porównaniu z placebo ("tabletki obojętne") lub witaminą C samodzielnie, a ich rozwój lub czynności poznawcze były niezależnie oceniane przez osobę, która nie wiedziała czy otrzymywały żelazo. Aby upewnić się, że wszystkie możliwe badania zostały odnalezione, przeszukano także piśmiennictwo publikacji, prowadzono wyszukiwanie na podstawie cytowań, a także skontaktowaliśmy się z ekspertami w tej dziedzinie.

Dwaj autorzy niezależnie analizowali wszystkie odnalezione tytuły i streszczenia, w celu wyłonienia odpowiednich badań. Gdy było to konieczne, analizie poddawano pełne teksty artykułów, by sprawdzić, czy spełniają kryteria włączenia do przeglądu. Ci sami autorzy niezależnie zgromadzili dane z włączonych do analizy badań i oceniali ryzyko błędu w poszczególnych badaniach. Przeanalizowano dane oddzielnie w zależności od tego, czy oceny zostały przeprowadzone w ciągu jednego miesiąca od rozpoczęcia leczenia żelazem lub po upływie jednego miesiąca.

Znaleźliśmy osiem badań spełniających kryteria włączenia. Sześć badań (z udziałem 225 dzieci) oceniało wpływ leczenia żelazem w ciągu 30 dni i dla pięciu z nich możliwe było połączenie wyników. Nie wydaje się, by leczenie żelazem skutkowało poprawą wyników wskaźnika rozwoju psychoruchowego skali Bayleya (PDI) czy poprawą wskaźnika rozwoju umysłowego skali Bayleya (MDI). W dwóch badaniach (160 dzieci) analizowano skutki leczenia żelazem przez okres powyżej 30 dni po rozpoczęciu interwencji. W jednym z badań nie wykazano żadnych korzyści z leczenia żelazem w odniesieniu do nabywania umiejętności mierzonych skalą Denver. Jednakże, w innym badaniu, wykazano, że wyniki w obu skalach Bayleya: PDI i MDI były istotnie wyższe w grupie otrzymującej żelazo.

Wyniki niniejszego przeglądu, ​​nie przedstawiają przekonujących danych naukowych, które potwierdzałyby, że żelazo podawane doustnie lub przez zastrzyk poprawia rozwój fizyczny i intelektualny u małych dzieci, które cierpią na anemię wywołaną brakiem żelaza w ciągu jednego miesiąca po rozpoczęciu leczenia. Nie jest jasne, czy interwencja długoterminowa jest korzystna dla rozwoju fizycznego i intelektualnego u tych dzieci. Niezbędne są duże badania z randomizacją, z długoterminowym okresem obserwacji, przeprowadzone w przyszłości.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Zając Redakcja: Magdalena Koperny

Summary of findings(Explanation)

Summary of findings for the main comparison. Iron therapy compared with placebo for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia
  1. 1 The funnel plot indicated small study effects. Number of children was less than 400.

    2 Number of children was less than 400.

Iron therapy compared with placebo for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia

Patient or population: children less than 3 years of age with iron deficiency anaemia

Settings: communities or hospitals

Intervention: iron therapy

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
PlaceboIron therapy

Bayley Scale PDI

within 30 days of commencement of therapy

The mean change in pre- to post-treatment test scores ranged across control groups from 0.2 to 11The mean change in pre- to post-treatment test scores in the intervention groups was 1.25 lower (95% CI -4.56 to 2.06)-

162

(5 studies)

++OO
low1
-

Bayley Scale MDI

within 30 days of commencement of therapy

The mean change in pre- to post -treatment test scores ranged across control groups from 4.1 to 13.58The mean change in pre- to post-treatment test scores in the intervention groups was 1.04 higher (95% CI -1.30 to 3.39)-

164

(5 studies)

++OO
low1
-

Bayley Scale PDI

more than 30 days of commencement of therapy

The mean change in pre- to post-treatment test scores in the control group was 5.1The mean change in pre- to post-treatment test scores in the intervention group was 18.4 higher (95% CI 10.16 to 26.64)-

47

(1 study)

+++O2

moderate

-

Bayley Scale MDI

more than 30 days of commencement of therapy

The mean change in pre- to post-treatment test scores in the control group was 0.5The mean change in pre- to post-treatment test scores in the intervention group was 18.8 higher (95% CI 10.17 to 27.43)-

47

(1 study)

+++O2

moderate

-

Denver Developmental Screening Test

more than 30 days of commencement of therapy

The mean change in pre- to post-treatment test scores in the control group was 3.2The mean change in pre- to post-treatment test scores in the intervention group was 0.8 higher (95% CI -0.18 to 1.78)-

97

(1 study)

+++O2

moderate

-
CI: confidence interval; MDI: Mental Development Index; PDI: Psychomotor Development Index.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Iron is important in the production of haemoglobin (Hb) and myoglobin and as co-factor in the metabolism of some neurotransmitters including dopamine. In addition, it has been suggested that iron is required for the myelin production in the developing brain (Larkin 1990). Animal studies, mainly in rats, have suggested that severe iron deficiency can lead to a deficit of brain iron, that iron deficiency may be associated with alterations in motor activity and behaviour and that these deficits may persist (Dallman 1975; Felt 1996). In the clinical literature, children with severe iron deficiency are often described as irritable and apathetic with a poor appetite. Most, but not all, of the large number of observational studies that have examined the association between iron deficiency anaemia (IDA) and psychomotor development have found lower scores on tests of psychomotor development in young children with IDA (Lansdown 1995).

The reported prevalence of IDA in toddlers varies in different populations, depending in part on the case definition used, with estimates ranging from around 10% in Western societies to around 50% in less developed societies (De Maeyer 1985). IDA is generally defined as an Hb level of less than 110 g/L (with a microcytic, hypochromic picture after the exclusion of haemoglobinopathies). Children may also be classified as iron deficient without anaemia on the basis of decreased serum ferritin (< 10 μg/L), raised erythrocyte protoporphyrin (> 2.5 μg/g Hb), a decreased mean corpuscular volume (MCV) (< 72 fL) or some combination of these since earlier stages of iron deficiency may lead to decreased Hb synthesis before the appearance of frank anaemia. The choice of a particular cut-off point is essentially arbitrary as there is no clear evidence to determine at which level iron deficiency begins to have significant deleterious effects (Logan 1997).

Description of the intervention

Iron therapy can be administered to children less than three years of age with IDA orally (ferrous sulphate, ferrous fumarate, sodium iron ethylenediaminetetra-acetate and ferrous gluconate), intravenously (iron dextran, iron sucrose and ferric carboxymaltose) or intramuscularly (iron dextran) (Goddard 2011).

How the intervention might work

A number of possible mechanisms have been suggested for a postulated effect of iron deficiency on children's psychomotor development (Lozoff 1986; Roncagliolo 1998; Walter 1994). Lack of iron might interfere with the metabolism of neurotransmitters, which either might affect psychomotor function directly or might affect scores on tests of psychomotor function indirectly through effects on behaviour. Iron is important in the synthesis of Hb and myoglobin, and deficiency might adversely affect oxygen transport or storage, which might have effects on either the central nervous system or motor function. Finally, lack of iron at a critical stage of development of the nervous system might lead to interference with myelination. Iron therapy acts by replenishing the iron stores in the body. Since iron is essential to neurotransmitters, Hb and myelination, iron therapy may improve psychomotor development and cognitive function in iron deficient anaemic children.

The timing of any therapeutic response to iron therapy will depend on what mechanisms underlie the relationship between iron and psychomotor function. Many early studies were designed to look for rapid effects of iron, partly because clinicians treating children and adults with severe IDA often reported dramatic improvements in mood soon after beginning treatment (Lee 1993). Such rapid effects (i.e. within days of beginning treatment) would be consistent with the effects of iron being attributable to direct effects on the central nervous system, perhaps as a result of effects on metabolism of neurotransmitters. However, although children with IDA show raised levels of Hb soon after commencing treatment with iron, the full effect on Hb synthesis develops over weeks (Lee 1993). If an effect of iron on psychomotor function were mediated via effects of iron deficiency on oxygen transport or storage, then it might be expected that the therapeutic effects of iron would take some weeks to manifest in changes in scores on tests of psychomotor function. If this latter mechanism were involved, the inclusion of results of assessments of outcome carried out before sufficient time has elapsed would introduce bias. For this reason, in this review, studies were analysed separately depending on how long after institution of treatment the outcomes were measured (with an arbitrary cut-off 30 days after beginning of treatment).

Why it is important to do this review

If lack of iron is associated with adverse effects on children's psychomotor development and these effects could be reversed by administration of iron, there would be a strong argument for either population supplementation with iron or screening of young children for IDA. It is widely acknowledged that the age period from birth to three years old is critical for psychomotor development and cognitive development, thus children under the age of three years would be the most sensitive population for this review. Consequently, we considered only children under the age of three years in this review. Safety outcomes are important to a Cochrane review. However, the purpose of this review is to assess the effect of iron therapy specifically on psychomotor development and cognitive development. The assessment of harm of iron therapy is beyond the scope of this review.

This is an update of a Cochrane review originally published in 2001 (Martin 2001). The original review concluded that there is no convincing evidence that iron therapy of iron deficient anaemic children under three years of age improves psychomotor development or cognitive function within 30 days of beginning treatment, and the effect of longer-term treatment remains unclear.

Objectives

To assess the effect of iron therapy given to children less than three years of age with IDA on psychomotor development and cognitive function.

Methods

Criteria for considering studies for this review

Types of studies

  1. Random allocation of participants to treatment and placebo arms.

  2. Assessment of psychomotor development or cognitive function by assessors blind to treatment allocation.

Types of participants

Children up to three years of age with evidence of IDA based on Hb level, Hb plus ferritin or other author-defined evidence of IDA.

Types of interventions

Iron (oral, intramuscular or intravenous) versus placebo or iron plus vitamin C versus placebo and vitamin C.

Types of outcome measures

Primary outcomes
  • Psychomotor development

  • Cognitive development

We had no secondary outcomes.

We accepted only standardised measures. Safety outcomes measures addressing adverse effects of iron therapy were ineligible. Outcome data were analysed separately depending on whether the testing was performed within 30 days of entry to the study or more than 30 days after entry to the study.

Search methods for identification of studies

We ran the searches for the original review in 2007 (Appendix 1). When we updated the searches in April 2013, we corrected a syntax error in the original MEDLINE and EMBASE searches, and added search terms for intramuscular injections and alternative forms of iron (Appendix 2). We ran the revised searches for all years and deduplicated against the records found in 2007 using EndNote. We applied no language limits.

Electronic searches

We searched the following databases.

  • Cochrane Central Register of Controlled Trials (CENTRAL), 2013, Issue 3, last searched 23 April 2013.

  • Ovid MEDLINE, 1948 to April week 2 2013, last searched 22 April 2013.

  • EMBASE (Ovid), 1980 to 2013 week 16, last searched 22 April 2013.

  • CINAHL (EBSCOhost), 1937 to current, last searched 23 April 2013.

  • PsycINFO (Ovid), 1806 to April week 3 2013, last searched 23 April 2013.

  • PaycINFO (EBSCOhost), 1837 to current, last searched 2 February 2011.

  • BIOSIS (Web of Knowledge), 1969 to 3 February 2011, last searched 3 February 2011.

  • LILACS, last searched 23 April 2013.

  • ClinicalTrials.gov, last searched 23 April 2013.

  • WHO International Clinical Trials Registry Platform (ICTRP), last searched 23 April 2013.

Searching other resources

We scrutinised the references of identified trials and important review articles for possible trials missed by the electronic searches. In addition, we performed forward citation searches on trials from the primary search within the Science Citation Index (24 April 2013). Finally, we contacted a number of key authors requesting other trials.

Data collection and analysis

Selection of studies

Two review authors (BW and TG) independently read titles and abstracts of studies identified on searches of electronic databases to determine whether they might meet the inclusion criteria, and then assessed full-text copies of those possibly eligible articles. We resolved differences of opinion about suitability for inclusion by discussion. A third review author (SZ) made provision for arbitration.

Data extraction and management

Data including year of publication, randomisation procedures, allocation concealment, blinding, setting, characteristics of participants and interventions, outcomes as well as main results, were extracted independently by two review authors (BW and TG), using a pilot-tested data extraction form. We resolved any disagreements by discussion. Where data were not available in the published trial reports, study authors were asked to supply missing information. One review author (BW) entered data for meta-analysis into Review Manager (RevMan) software (RevMan 2011) and a second review author (TG) checked the entries.

Assessment of risk of bias in included studies

Two review authors (BW and TG) independently assessed the risk of bias in each included study following the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). We resolved any disagreements through consultation with a third review author (SZ). In order for a trial to be included in the review, we required blind assessment of outcome. We assessed risk of bias based on the following six domains with ratings of 'Yes' (low risk of bias); 'No' (high risk of bias) and 'Unclear' (uncertain risk of bias):

Sequence generation

Description: the method used to generate the allocation sequence was described in sufficient detail so as to enable an assessment to be made as to whether it should have produced comparable groups.

Review authors' judgement: was the allocation concealment sequence adequately generated?

Allocation concealment

Description: the method used to conceal allocation sequence was described in sufficient detail to assess whether intervention schedules could have been foreseen in advance of, or during, recruitment.

Review authors' judgement: was allocation adequately concealed?

Blinding of participants and personnel

Description: any measures used to blind participants and personnel were described in sufficient detail so as to assess possible knowledge of which intervention a given participant might have received.

Review authors' judgement: was participants and personnel knowledge of the allocated intervention adequately prevented during the study?

Blinding of outcome assessment

Description: any measures used to blind outcome assessor were described in sufficient detail so as to assess possible knowledge of which intervention a given participant might have received.

Review authors' judgment: was outcome assessor knowledge of the allocated intervention adequately prevented during the study?

Incomplete outcome data

Description: data on attrition were reported as well the numbers involved (compared with total randomised), and reasons for attrition were reported or obtained from investigators.

Review authors' judgement: were incomplete data dealt with adequately by the study authors?

Selective outcome reporting

Description: attempts were made to assess the possibility of selective outcome reporting by investigators, to include comparing published results to outcomes detailed in the study protocol or published methods, considering whether primary outcomes were stated a priori and considering whether or not commonly used outcomes reported in similar studies were reported.

Review authors' judgement: were reports of the study free of suggestion of selective outcome reporting?

Measures of treatment effect

As eligible measures of psychomotor development or cognitive function are continuous variables, we calculated mean difference (MD) with 95% confidence interval (CI). We used change values in pre- to post-test scores on tests of psychomotor development or cognitive function to undertake meta-analyses.

Unit of analysis issues

The unit of analysis was individual children under the age of three with IDA. We identified no cluster-randomised trials, cross-over trials or studies with multiple treatment groups for inclusion in this review. See Table 1 for other methods to be used in future updates of the review.

Table 1. Methods to be used in future updates, where applicable

Unit of analysis issues

 

Cluster-randomised trials

Effect estimates and their standard errors from correct analyses of cluster-randomized trials will be meta-analysed using the generic inverse-variance method in RevMan (RevMan 2011). For cluster-randomised trials analysed by incorrect statistical methods (not taking the clustering into account), we plan to adjust their sample sizes using the methods, described in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), using an estimate of the intracluster correlation coefficient (ICC) derived from the trial or other sources. If we use ICC from other sources, sensitivity analyses will be conducted to investigate the effect of variation in the ICC.

Cross-over trials

For cross-over trials, we will extract and analyse data from the first period only.

Studies with multiple treatment groups

For factorial studies, we will include all comparisons that differ only in the presence or absence of iron. For other studies, multiple eligible intervention groups will be combined.

Assessment of reporting biases

 

Funnel plots can investigate the relationship between effect size and standard error. Asymmetry may be attributable to publication bias, but might also reflect true heterogeneity. If we find such a relationship between trial size and effect size, we will examine clinical variation (such as intensity of intervention, underlying risk) of the studies. In current version of this review, no such analysis was undertaken due to the small number of included studies.

Data synthesis

 

If a high level of heterogeneity is detected (I2 ≥ 75%), we will combine studies by narrative summary rather than in a meta-analysis, and explore the sources of heterogeneity by conducting predefined subgroup analyses.

Subgroup analysis and investigation of heterogeneity

 

If significant heterogeneity is identified within a meta-analysis and there is a sufficient number of included studies (> 10), 3 possible sources will be investigated separately:

  • baseline haemoglobin level, i.e. ≤ 90 g/L versus >90 g/L

  • intervention dose, i.e. ≤ 10 mg/day versus > 10 mg/day

  • duration of iron therapy, i.e. ≤ 10 days versus >10 days

Dealing with missing data

We used available-case analysis. We sought unclear or missing information by contacting the authors of the individual trials. The standard deviations (SD) for change values in pre- to post -test scores were not reported in most eligible studies; however, it was possible to impute SDs for these differences according to the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Where appropriate data were available, we checked the plausibility of these estimates by calculating the implied correlation between pre- and post-treatment test scores. See Table 2 for methods used to impute SDs for change values (where P values were treated as if resulting from paired or unpaired t-tests as appropriate).

Table 2. Methods used to impute standard deviations for changes values
  1. MDI: Mental Development Index; PDI: Psychomotor Development Index; SD: standard deviation.

    1 P values resulted from paired t-tests (for within group changes). The SD for the change MDI in the intervention group (10.94) was used for the SDs of the change in PDI in both groups and the change MDI in the control group in the analyses, which were impossible to be imputed.

    2 P values resulted from paired t-tests (for within group changes). The SD for the change PDI in the intervention group (21.22) and for the change in MDI (15.14) were used for the SDs of the change in PDI and MDI in the control group, respectively, which were impossible to be imputed.

    3 P values derived from a repeated measures analysis of variance were treated as if resulting from unpaired t-tests (for the between group differences in changes).

    4 Here the SDs for the change in MDI were imputed from the reported power of the study to detect differences of specified sizes in MDI given the observed SDs of the changes (although not giving the values of these SDs), rather than from P values. The SDs for the change MDI were used for the SDs of the change in PDI in the analyses, which were impossible to be imputed.

    5 P values derived from a repeated measures analysis of variance were treated as if resulting from unpaired t-tests (for the between group differences in changes).

    6 P values were derived from a repeated measures analysis of variance. For PDI, P values were treated as if resulting from unpaired t-tests (for the between group differences in changes). For MDI, P values were treated as if resulting from paired t-tests (for within group changes). The SD for the change MDI in the intervention group (25.09) was used for the SDs of the change in MDI in the control group, which was impossible to be imputed. However, the estimated SDs for change in MDI would imply correlations between pre- and post-test scores substantially in excess of -1, which is impossible. It was, therefore, decided instead to estimate SDs from these reported scores and standard errors, following methods described by Follmann (Follmann 1992), assuming a correlation of 0 between pre- and post-treatment test scores. This provided an estimate of the SD for the change in MDI of 15.26 for the control group and 14.90 for the intervention group and of the SD for the change in PDI of 14.21 for the intervention group and 14.58 for the control group.

StudyGroupOutcome measureP valueImputationImputed SDsImplied correlationPlausibility of imputation
Driva 1985 1InterventionPDI> 0.05Impossible10.940.69Plausible
MDI< 0.01Possible10.940.78Plausible
ControlPDI> 0.05Impossible10.940.82Plausible
MDI> 0.05Impossible10.940.79Plausible
Honig 1978 2InterventionPDI0.10Possible21.22-0.26Plausible
MDI0.01Possible15.14-0.27Plausible
ControlPDI> 0.05Impossible21.220.20Plausible
MDI> 0.05Impossible15.140.57Plausible
Kimmons [pers comm] 3InterventionPDI0.36Possible9.730.79Plausible
MDI0.27Possible3.900.97Plausible
ControlPDI0.36Possible9.730.79Plausible
MDI0.27Possible3.900.97Plausible
Lozoff 1982 4InterventionPDI-Impossible7.40.92Plausible
MDI-possible7.40.93Plausible
ControlPDI-Impossible7.40.94Plausible
MDI-possible7.40.998Plausible
Lozoff 1987 5InterventionPDI> 0.80Impossible---
MDI> 0.69Impossible---
ControlPDI> 0.80Impossible---
MDI> 0.69Impossible---
Idjradinata 1993 6InterventionPDI< 0.001Possible17.91-0.59Plausible
MDI< 0.001Possible25.09-1.84Implausible
ControlPDI< 0.001Possible17.91-0.51Plausible
MDI-Impossible25.09-1.70Implausible

Assessment of heterogeneity

We evaluated heterogeneity using the Chi2 test, with significance set at P value = 0.10. We measured the quantity of heterogeneity by the I2 statistic. It shows the percentage of the variability in effect estimates that is due to heterogeneity rather than to chance. I2 values of 50% or greater denoted significant heterogeneity. Values over 75% indicated a high level of heterogeneity (Higgins 2003).

Assessment of reporting biases

We assessed selective reporting of outcomes. See the 'Risk of bias' tables in the Characteristics of included studies tables for the judgements on the risk of selective reporting for each study. We drew funnel plots to investigate any relationships between effect size and study precision (Higgins 2011). No statistical tests were used to detect publication bias. See Table 1 for other methods to be used in future updates of the review.

Data synthesis

In this review, data from assessments carried out within 30 days of commencement of treatment were analysed separately from data from assessments carried out later. Data were combined using random-effects methods. Sensitivity analyses were conducted in which fixed-effect methods were used (see Sensitivity analysis). We adopted the inverse variance (IV) method for synthesis both in fixed-effect models and random-effects models, as all eligible outcome measures were continuous data. We used RevMan 5 software (RevMan 2011) to undertake heterogeneity test and meta-analysis. See Table 1 for other methods to be used in future updates of the review.

Subgroup analysis and investigation of heterogeneity

As only eight studies were included in this review, no subgroup analyses were performed for investigation of heterogeneity. See Table 1 for other methods to be used in future updates of the review.

Sensitivity analysis

Meta-analyses were repeated using fixed-effect methods. Only two studies reported SDs for changes in pre- to post-test scores (Aukett 1986; Walter 1989). As the SDs for the other five trials had to be imputed, we decided to conduct a sensitivity analysis in which post-intervention outcome measures were pooled in a meta-analysis. Five studies (Driva 1985; Honig 1978; Idjradinata 1993; Kimmons [pers comm]; Lozoff 1982) reported post-test Mental Development Index (MDI) and Psychomotor Development Index (PDI) scores on the Bayley Scales, of which four (Driva 1985; Honig 1978; Idjradinata 1993; Lozoff 1982) reported the SDs for these scores. For the study by Kimmons [pers comm], we decided to use the population SDs (15 points) for the Bayley scale in the sensitivity analysis (Bayley 1993).

Results

Description of studies

Results of the search

Figure 1 shows the selection of eligible studies. In total, we retrieved 7211 records from electronic databases and other sources. We removed 1007 records as duplicates, and 6194 records did not meet the inclusion criteria. Finally, 10 records (eight studies) were included in this systematic review.

Figure 1.

Selection of eligible studies: a flow diagram

Included studies

Although no new eligible study published after 2001 was identified, one study published in 1985 was determined as eligible and missed by the initial review (Driva 1985), and then included in this update. In total, eight trials (Aukett 1986; Driva 1985; Honig 1978; Idjradinata 1993; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989) were included with data from two studies reported in two papers each (Honig 1978; Walter 1989). The Characteristics of included studies tables provides details of each study.

Publication year

These studies were published between 1978 and 1993.

Location of studies

The trials were conducted in the USA (Honig 1978), Costa Rica (Lozoff 1987), Chile (Walter 1989), Indonesia (Idjradinata 1993), Greece (Driva 1985), Guatemala (Lozoff 1982) and the UK (Aukett 1986; Kimmons [pers comm]).

Participants

Included studies were relatively small, with 385 (range 24 to 110) iron-deficient children randomised. In three studies (Honig 1978; Idjradinata 1993; Kimmons [pers comm]), children were recruited from paediatric clinics; in four (Aukett 1986; Lozoff 1982; Lozoff 1987; Walter 1989), community samples were recruited, and in one study (Driva 1985), children were recruited from an orphanage. All the children in included studies were less than 26 months old.

Interventions

The iron was given in oral form in four trials (Aukett 1986; Idjradinata 1993; Lozoff 1982; Walter 1989), intramuscularly in three (Driva 1985; Honig 1978; Kimmons [pers comm]), and both intramuscularly and orally in one (Lozoff 1987). Iron was compared to placebo in seven studies (Driva 1985; Honig 1978; Idjradinata 1993; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989), and iron plus vitamin C was compared to vitamin C alone in one study (Aukett 1986).

Outcome measures

All studies other than Aukett 1986, which used the Denver Developmental Screening Test, assessed development using the Bayley Scales of Infant Development administered by trained personnel. The Bayley Scale consists of two, age-standardised subscales, MDI and PDI. The Denver Developmental Screening Test is a screening test for a limited numbers of psychomotor skills. All carried out pre-treatment assessments. Outcome assessments were carried out between five and 11 days after commencement of therapy in six studies (Driva 1985; Honig 1978; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989), and after two (Aukett 1986), and four months (Idjradinata 1993), in the others.

Excluded studies

We excluded eight studies (see Characteristics of excluded studies tables). We excluded five studies due to lack of a placebo control (Deinard 1986; Linos 1990; Lozoff 1996; Oski 1983; Walter 1983), and the other three due to ineligible participants (Lozoff 2003; Moffatt 1994; Stoltzfus 2001).

Risk of bias in included studies

In general, the trials included in this review were at unclear risk of bias. The 'Risk of bias' tables in the Characteristics of included studies tables give acomprehensive description of the risk of bias for each study. Figure 2 provides review authors' judgements about each risk of bias item presented as percentages across all included studies. Figure 3 provides review authors' judgements about each risk of bias item for each included study.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Random sequence generation

We judged two studies to be 'low risk of bias' (Idjradinata 1993; Kimmons [pers comm]), and the other six studies to be 'unclear' as information about generation of random sequence was not reported (Aukett 1986; Driva 1985; Honig 1978; Lozoff 1982; Lozoff 1987; Walter 1989).

Allocation concealment

We judged five studies to be 'low risk of bias' (Aukett 1986; Honig 1978; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987), while the remaining three trials were 'unclear' due to insufficient reporting (Driva 1985; Idjradinata 1993; Walter 1989).

Blinding of participants and personnel

The risk of bias for blinding of participants and personnel was judged 'low risk of bias' in six studies (Aukett 1986; Honig 1978; Idjradinata 1993; Lozoff 1982; Lozoff 1987; Walter 1989), and 'unclear' in two studies as not enough information on blinding of personnel was provided (Driva 1985; Kimmons [pers comm]). Although the trials gave no information on blinding of participants, this was unlikely to cause bias as children under the age of three might not fully comprehend the treatment or the trial itself.

Blinding of outcome assessment

Blinding of outcome assessment was an inclusion criterion for the review and was reported in all included studies.

Incomplete outcome data

Four trials reported complete follow-up (Driva 1985; Honig 1978; Lozoff 1987; Walter 1989). For the other four trials, the attrition rate ranged from 0% to 20% in the intervention group (11.1% in Aukett 1986, 4.0% in Idjradinata 1993, 19.0% in Kimmons [pers comm], 20.0% for PDI and 0% for MDI in Lozoff 1982) and 0% to 19.0% in the control group (12.5% in Aukett 1986, 8.0% in Idjradinata 1993, 19.0% in Kimmons [pers comm], 9.2% for MDI and 0% for PDI in Lozoff 1982). None of the studies reported important differences in follow-up between intervention and control groups.

Selective outcome reporting

All the included studies were free of suggestion of selective outcome reporting.

Effects of interventions

See: Summary of findings for the main comparison Iron therapy compared with placebo for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia

Short-term effects of iron therapy

We included six trials (Driva 1985; Honig 1978; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989) reported in eight papers (Driva 1985; Honig 1978; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989), which examined the effects of iron therapy on measures of psychomotor development within 30 days of commencement of therapy. The trials involveed 225 children with IDA. As described above, data from one study could not be included in the meta-analysis (Lozoff 1987). All studies included measures of development before and between 5 to 11 days after commencement of therapy and used the Bayley Scales of Infant Development in the assessment of outcome.

The pooled difference in pre-post treatment change in the Bayley Scale PDI between iron-treated and placebo groups was -1.25 (95% CI -4.56 to 2.06, P value = 0.65; I2 = 33% for heterogeneity, random-effects meta-analysis, Figure 4) and in the Bayley Scale MDI was 1.04 (95% CI -1.30 to 3.39, P value = 0.79; I2 = 31% for heterogeneity, random-effects meta-analysis, Figure 5). Funnel plots for both outcomes indicated small study effects (Figure 6; Figure 7). The quality of evidence for both outcomes was low (Summary of findings for the main comparison).

Figure 4.

Forest plot of comparison: 1 iron treatment versus placebo in children with iron deficiency anaemia (IDA), outcome: 1.1 Tests of psychomotor development performed 5 to 30 days after study entry: change in Bayley Scale Psychomotor Development Index (PDI)

Figure 5.

Forest plot of comparison: 1 iron treatment versus placebo in children with iron deficiency anaemia (IDA), outcome: 1.2 Tests of mental development performed 5 to 30 days after study entry: change in Bayley Scale Mental Development Index (MDI)

Figure 6.

Funnel plot of comparison: 1 iron treatment versus placebo in children with iron deficiency anaemia (IDA), outcome: 1.1 Tests of psychomotor development performed 5 to 30 days after study entry: change in Bayley Scale Psychomotor Development Index (PDI)

Figure 7.

Funnel plot of comparison: 1 iron treatment versus placebo in children with iron deficiency anaemia (IDA), outcome: 1.2 Tests of mental development performed 5 to 30 days after study entry: change in Bayley Scale Mental Development Index (MDI)

Sensitivity analysis showed compatible results between fixed-effect methods and random-effects methods. We pooled data from four trials reporting the post-treatment difference between iron-treated and placebo groups. The pooled difference in the post-treatment Bayley Scale PDI was -1.62 (95% CI -9.79 to 6.55, P value = 0.70; I2 = 51% for heterogeneity, random-effects meta-analysis) and in the Bayley Scale MDI was -0.01 (95% CI -9.17 to 9.15, P value = 0.97; I2 = 62% for heterogeneity, random-effects meta-analysis).

The trial that was excluded from the meta-analysis (Lozoff 1987), included 19 children randomised to receive intramuscular iron, 16 oral iron and 17 oral placebo. The authors compared both groups receiving iron with those only receiving placebo, and found that neither intramuscular iron nor oral iron treatments differed from placebo treatment in effects on Bayley Scale scores.

Long-term effects of iron therapy

Two studies (Aukett 1986; Idjradinata 1993), including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development more than 30 days after commencement of therapy. The use of very different outcome measures precluded the combination of results from these two studies: the Bayley Scale assesses developmental skills across a wide range of different aspects of development, while the Denver Developmental Screening Test was devised as a screening test for developmental problems rather than as an assessment tool for psychomotor development and only tests for a limited number of psychomotor skills. Therefore, we reported the results of these two studies separately.

Aukett 1986 assessed changes in children's development by administering 24 items taken from the Denver Developmental Screening Test at the beginning of the study and after two months of iron or placebo treatment. The results were reported as the mean number of skills gained over the period. On average, the intervention group gained 0.8 (95% CI -0.18 to 1.78, P value = 0.11) more skills than the control group. The quality of evidence for this outcomes was moderate (Summary of findings for the main comparison).

Idjradinata 1993 assessed the children's development using the Bayley Scales at the beginning of the study and after four months of iron or placebo treatment. The difference in pre- to post-treatment change in Bayley Scale PDI between iron-treated and placebo-treated groups was 18.40 (95% CI 10.16 to 26.64, P value < 0.0001) and in Bayley Scale MDI was 18.80 (95% CI 10.17 to 27.43, P value < 0.0001). The post-treatment difference between iron-treated and placebo-treated groups in Bayley Scale PDI was 14.50 (95% CI 8.82 to 20.18, P value < 0.00001) and in Bayley Scale MDI was 15.20 (95% CI 8.96 to 21.44, P value < 0.00001). The quality of evidence in both outcomes was moderate (Summary of findings for the main comparison).

Discussion

Summary of main results

The results of the studies included in this review provide no convincing evidence that administration of iron improves children's scores on tests of psychomotor development within six to 11 days of receiving intramuscular or commencing oral iron supplements (Summary of findings for the main comparison). The relatively small numbers of children included in these studies means, however, that the CIs around the effects of treatment are wide and the results could be compatible with moderate positive or adverse effects of short-term iron therapy. Five other possible explanations have been advanced to explain this finding (AHRQ 2006; Sachdev 2004). First, prevention of neurodevelopmental consequences of IDA may require acting to prevent iron deficiency rather than detection and treatment of existing iron deficiency. Second, the duration of iron treatment may have been too short to correct the iron deficiency; all six trials that examined the effects of iron therapy within 30 days of commencement of therapy intervened for less than 11 days. Third, structural brain changes caused by iron deficiency or IDA may be irreversible in younger children below three years of age. Fourth, it is also arguable that changes in Bayley Scale scores, the outcome measures employed in these studies, may well be an insensitive measure of real changes, particularly of attributes such as attention or mood. Fifth, prevention of neurodevelopmental consequences may require screening and early treatment of multiple nutritional deficiencies, rather than IDA alone.

On the basis of the data included here, the effects of longer periods of iron therapy on psychomotor development in children with IDA remain unclear (Summary of findings for the main comparison). The larger of the two included studies (Aukett 1986), unfortunately employed a test designed to be used as a screening tool on a single occasion as the outcome measure, not a tool for the assessment of psychomotor development or for changes in psychomotor development. This measure may well be an insensitive instrument for the detection of changes in psychomotor development. Accepting these limitations, the data from this study did not suggest a substantial beneficial effect on psychomotor development of two months of iron therapy for children with IDA. On the contrary, Idjradinata 1993 reported extremely large effects, greater than one population SD of the tests, of four months of iron therapy in these children. Given the high prevalence of IDA in most populations, if an effect of this magnitude on children's psychomotor development could be achieved by the treatment of IDA, this intervention would have an enormous impact. However, given the inconsistency in the results of these two trials and the small numbers of children studied, the data should be interpreted with caution.

Overall, the evidence that lack of iron affects the psychomotor development of young children with IDA is unclear. Given the high prevalence of iron deficiency, there is an urgent need for large-scale randomised controlled trials of iron therapy in young children with IDA.

Overall completeness and applicability of evidence

This review aimed to determine the effects of iron therapy on psychomotor development and cognitive function in children with IDA less than three years of age, but data were only available for children aged less than 26 months of age, and failed to include those aged 26 to 36 months. In terms of administration routes of iron therapy, only oral and intramuscular routes were addressed and the effects of iron therapy by the intravenous route were not investigated in this review. This means that the results of this review cannot be directly extrapolated to children aged 26 to 36 months or to iron therapy administrated intravenously.

Quality of the evidence

For changes in Bayley Scale PDI and MDI within 30 days of commencement of therapy, 162 children from five studies and 164 children from five studies were included, respectively. Neither serious methodological limitations of nor statistical heterogeneity across studies were found. The quality of the evidence for both outcomes was low due to possible publication bias and imprecision of results.

For changes in Bayley Scale PDI and MDI more than 30 days of commencement of therapy, one study with 46 children was included (Idjradinata 1993). No serious methodological limitations of the study existed. The quality of evidence for both outcomes was moderate due to imprecision of results.

For changes in Denver Developmental Screening Test, more than 30 days after commencement of therapy, only one study with 97 children was included (Aukett 1986). No serious methodological limitations of the study were identified and the quality of evidence was moderate due to imprecision of results.

Potential biases in the review process

Three limitations merit consideration. First, a comprehensive search strategy was developed and a large body of the published literature was scrutinised. However, we did not handsearch key journals and grey literature websites for this update. A potential publication bias should be taken into account in those outcomes for which no funnel plots were used. Second, one eligible study was not included in the meta-analysis due to unavailable data (Lozoff 1987). However, the finding of this study that there was no evidence of effects of iron therapy on psychomotor development or cognitive function within seven days of commencement of therapy was consistent with the meta-analysis. Third, SDs for changes in pre- to post-test scores were imputed in five studies. Sensitivity analysis using post-treatment measures, however, demonstrated the robustness of the results. All review authors had no conflicts of interest in the review process.

Agreements and disagreements with other studies or reviews

The findings of this updated review do not differ from those of the original review, which was first published 2001. One systematic review of randomised controlled trials evaluated the effect of iron supplementation on mental and motor development in children (less than 18 years old, including both anaemic and non-anaemic) (Sachdev 2004). It found that there was no convincing evidence (Bayley Scale MDI, MD 0.95, 95% CI -0.56 to 2.46) that iron treatment had an effect on mental development in children below 27 months of age or on motor development. This has provided support to the result of our review to some degree. Another recently published systematic review of randomised controlled trials assessed the effect of iron supplementation in non-anaemic children less than three years of age on mental development (Szajewska 2010). It found limited available evidence suggesting a possible positive effect on the Bayley Scale PDI (MD 4.21, 95% CI 2.31 to 6.12) and no effect on the MDI (MD 1.66, 95% CI -0.14 to 3.47). It is proposed that the inconsistency between Szajewska 2010 and our review is caused by different types of participants (iron deficient anaemic versus non-anaemic) or different precisions of results, or both.

Authors' conclusions

Implications for practice

Most clinicians seeing a child with IDA would elect either to treat with elemental iron or to attempt to improve the child's intake of dietary iron. However, clinicians cannot be sure if treatment of IDA to remedy the anaemia will result in positive changes to psychomotor development and cognitive function.

Implications for research

There is an urgent need for large randomised controlled trials of iron therapy in young children less than three years old with IDA with long-term follow-up, and Bayley Scales of Infant Development should be used to assess development both at and more than one month after commencement of iron therapy. Meanwhile, appropriate methodologies in design and implementation should be used and clearly reported in these studies, including adequate allocation sequence generation; allocation concealment; and blinding of participants, personnel and outcome assessors.

Acknowledgements

The review authors gratefully acknowledge the important assistance provided by Margaret Anderson and Joanne Abbott in the development of the search strategy. The review authors also thank Geraldine Macdonald, Laura MacDonald and Jane Dennis for co-ordination and editorial feedback in the update of this review. We also acknowledge the authors of the original review who have not been involved in the update: Susanna Martins, Stewart Logan and Ruth Gilbert.

Data and analyses

Download statistical data

Comparison 1. Iron treatment versus placebo in children with iron deficiency anaemia
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Tests of psychomotor development performed 5-30 days after study entry: change in Bayley Scale Psychomotor Development Index (PDI)5162Mean Difference (IV, Random, 95% CI)-1.25 [-4.56, 2.06]
2 Tests of mental development performed 5-30 days after study entry: change in Bayley Scale Mental Development Index (MDI)5164Mean Difference (IV, Random, 95% CI)1.04 [-1.30, 3.39]
3 Tests of psychomotor development performed 5-30 days after study entry: post treatment Bayley Scale PDI4123Mean Difference (IV, Random, 95% CI)-1.62 [-9.79, 6.55]
4 Tests of mental development performed 5-30 days after study entry: post treatment Bayley Scale MDI4125Mean Difference (IV, Random, 95% CI)-0.01 [-9.17, 9.15]
5 Tests of psychomotor development performed more than 30 days after study entry: change in Bayley Scale PDI147Mean Difference (IV, Random, 95% CI)18.4 [10.16, 26.64]
6 Tests of mental development performed more than 30 days after study entry: change in Bayley Scale MDI147Mean Difference (IV, Random, 95% CI)18.8 [10.17, 27.43]
7 Tests of psychomotor development and mental development performed more than 30 days after study entry: change in Denver Developmental Screening Test scores197Mean Difference (IV, Random, 95% CI)0.80 [-0.18, 1.78]
8 Tests of psychomotor development performed more than 30 days after study entry: post treatment Bayley Scale PDI147Mean Difference (IV, Random, 95% CI)14.5 [8.82, 20.18]
9 Tests of mental development performed more than 30 days after study entry: post treatment Bayley Scale MDI147Mean Difference (IV, Random, 95% CI)15.20 [8.96, 21.44]
Analysis 1.1.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 1 Tests of psychomotor development performed 5-30 days after study entry: change in Bayley Scale Psychomotor Development Index (PDI).

Analysis 1.2.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 2 Tests of mental development performed 5-30 days after study entry: change in Bayley Scale Mental Development Index (MDI).

Analysis 1.3.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 3 Tests of psychomotor development performed 5-30 days after study entry: post treatment Bayley Scale PDI.

Analysis 1.4.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 4 Tests of mental development performed 5-30 days after study entry: post treatment Bayley Scale MDI.

Analysis 1.5.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 5 Tests of psychomotor development performed more than 30 days after study entry: change in Bayley Scale PDI.

Analysis 1.6.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 6 Tests of mental development performed more than 30 days after study entry: change in Bayley Scale MDI.

Analysis 1.7.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 7 Tests of psychomotor development and mental development performed more than 30 days after study entry: change in Denver Developmental Screening Test scores.

Analysis 1.8.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 8 Tests of psychomotor development performed more than 30 days after study entry: post treatment Bayley Scale PDI.

Analysis 1.9.

Comparison 1 Iron treatment versus placebo in children with iron deficiency anaemia, Outcome 9 Tests of mental development performed more than 30 days after study entry: post treatment Bayley Scale MDI.

Appendices

Appendix 1. Search strategies 2007

MEDLINE 1966 to present

1 Anemia, Iron-Deficiency/ (3474)

2 an#emi$.tw. (18,875)

3 (iron adj3 deficien$).tw. (10,598)

4 or/1-3 (28,559)

5 child, preschool/ or infant/ (770,144)

6 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or girl$ or boy$ or child$).tw. (884,110)

7 or/5-6 (1,248,065)

8 Dietary Supplements/ (12,350)

9 (iron adj3 (supplement$ or therap$)).tw. (4485)

10 iron.tw. (76,623)

11 Iron/ (56,146)

12 or/8-11 (106,526)

13 4 and 7 and 12 (3243)

14 randomized controlled trial.pt. (233,672)

15 controlled clinical trial.pt. (74,707)

16 randomized controlled trials.sh. (48,151)

17 random allocation.sh. (57,661)

18 double blind method.sh. (90,848)

19 single blind method.sh. (10,848)

20 or/14-19 (396,309)

21 (animals not humans).sh. (3,077,794)

22 20 not 21 (372,349)

23 clinical trial.pt. (434,900)

24 exp Clinical Trials/ (190,060)

25 (clin$ adj25 trial$).ti,ab. (128,925)

26 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. (90,129)

27 placebos.sh. (26,065)

28 placebo$.ti,ab. (101,593)

29 random$.ti,ab. (368,011)

30 research design.sh. (47,102)

31 or/23-30 (839,228)

32 31 not 21 (779,398)

33 32 not 22 (424,737)

34 comparative study.sh. (0)

35 exp Evaluation Studies/ (592,383)

36 follow up studies.sh. (336,398)

37 prospective studies.sh. (219,516)

38 (control$ or prospectiv$ or volunteer$).ti,ab. (1,763,635)

39 or/34-38 (2,548,511)

40 39 not 21 (2,032,351)

41 40 not (22 or 33) (1,545,989)

42 22 or 33 or 41 (2,343,075)

43 13 and 42 (1092)

CENTRAL May 2007

#1 MeSH descriptor: [Anemia, Iron-Deficiency] explode all trees
#2 an?emi* OR iron near/3 deficien*
#3 #1 or #2
#4 MeSH descriptor: [Infant] explode all trees
#5 child preschool near "MESH check words"
#6 (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)
#7 #4 or #5 or #6
#8 MeSH descriptor: [Dietary Supplements] this term only
#9 iron near/3 supplement*
#10 iron near/3 therap*
#11 iron
#12 MeSH descriptor: [Iron] this term only
#13 #8 or #9 or #10 or #11 or #12
#14 #3 and #7 and #13

CINAHL - Cumulative Index to Nursing & Allied Health Literature, 1982 to May week 1 2007

1 Anemia, Iron Deficiency/ (757)

2 an#emi$.tw. (495)

3 (iron adj3 deficien$).tw. (617)

4 or/1-3 (1435)

5 child, preschool/ or infant/ (60,016)

6 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or girl$ or boy$ or child$).tw. (104,587)

7 or/5-6 (127,455)

8 Dietary Supplements/ (1104)

9 (iron adj3 (supplement$ or therap$)).tw. (384)

10 iron.tw. (2066)

11 IRON/ (1184)

12 or/8-11 (3511)

13 4 and 7 and 12 (370)

14 randomi$.mp. [mp=title, subject heading word, abstract, instrumentation] (26,401)

15 clin$.mp. [mp=title, subject heading word, abstract, instrumentation] (208,923)

16 trial$.mp. [mp=title, subject heading word, abstract, instrumentation] (54,940)

17 (clin$ adj3 trial$).mp. [mp=title, subject heading word, abstract, instrumentation] (39,249)

18 singl$.mp. [mp=title, subject heading word, abstract, instrumentation] (21,294)

19 doubl$.mp. [mp=title, subject heading word, abstract, instrumentation] (13,887)

20 tripl$.mp. [mp=title, subject heading word, abstract, instrumentation] (1185)

21 trebl$.mp. [mp=title, subject heading word, abstract, instrumentation] (17)

22 mask$.mp. [mp=title, subject heading word, abstract, instrumentation] (2220)

23 blind$.mp. [mp=title, subject heading word, abstract, instrumentation] (16,974)

24 (18 or 19 or 20 or 21) and (22 or 23) (12,672)

25 crossover.mp. [mp=title, subject heading word, abstract, instrumentation] (3869)

26 random$.mp. [mp=title, subject heading word, abstract, instrumentation] (56,592)

27 allocate$.mp. [mp=title, subject heading word, abstract, instrumentation] (2289)

28 assign$.mp. [mp=title, subject heading word, abstract, instrumentation] (22,677)

29 (random$ adj3 (allocate$ or assign$)).mp. (18,139)

30 Random Assignment/ (15,190)

31 exp Clinical Trials/ (43,840)

32 exp Meta Analysis/ (5259)

33  29 or 25 or 24 or 17 or 14 or 30 or 31 or 32 (65,563)

34 13 and 33 (98)

EMBASE 1980 to 2007 week 19

1 Iron Deficiency Anemia/ (4788)

2 an#emi$.tw. (13,101)

3 (iron adj3 deficien$).tw. (7522)

4 or/1-3 (21,031)

5 Preschool Child/ (95,548)

6 Infant/ (157,383)

7 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or girl$ or boy$ or child$).tw. (599,782)

8 or/5-7 (670,044)

9 diet supplementation/ (25,066)

10 (iron adj3 (supplement$ or therap$)).tw. (3667)

11 iron.tw. (62,538)

12 Iron/ (39,708)

13 or/9-12 (99,486)

14 4 and 8 and 13 (2244)

15 clin$.tw. (1,319,956)

16 trial$.tw. (294,775)

17 (clin$ adj3 trial$).tw. (103,306)

18 singl$.tw. (548,489)

19 doubl$.tw. (231,554)

20 trebl$.tw. (214)

21 tripl$.tw. (35,994)

22 blind$.tw. (123,512)

23 mask$.tw. (27,831)

24 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. (85,120)

25 randomi$.tw. (187,558)

26 random$.tw. (335,411)

27 allocat$.tw. (29,580)

28 assign$.tw. (94,268)

29 (random$ adj3 (allocat$ or assign$)).tw. (45,687)

30 crossover.tw. (24,127)

31 30 or 29 or 25 or 24 or 17 (328,908)

32 exp Randomized Controlled Trial/ (118,046)

33 exp Double Blind Procedure/ (63,899)

34 exp Crossover Procedure/ (18,621)

35 exp Single Blind Procedure/ (6576)

36 exp RANDOMIZATION/ (22,296)

37 32 or 33 or 34 or 35 or 36 or 31 (372,982)

38 14 and 37 (291)

LILACS (MAY 2007)

 ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Palavras] and ((anemi$ OR anaemi$ OR (iron deficien$)) AND (baby or babies or infant$ or preschool$ or toddler$ or girl$ or boy$ or child$)) [Palavras] and ((iron supplement$) OR (iron therap$) OR iron) [Palavras]

PsycINFO

#17 (((baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)) and ((( an?emi* )or( iron near3 deficien* )) or ("Anemia-" in MJ,MN)) and (("Dietary-Supplements" in MJ,MN) or ("Iron-" in MJ,MN) or (iron) or (( iron near 3 supplement* )or( iron near3 therap* )))) and ((random* or trial*) or ("Clinical-Trials" in MJ,MN))(11 records)

#16 ((random* or trial*) or ("Clinical-Trials" in MJ,MN)) and ((((baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)) and ((( an?emi* )or( iron near3 deficien* )) or ("Anemia-" in MJ,MN)) and (("Dietary-Supplements" in MJ,MN) or ("Iron-" in MJ,MN) or (iron) or (( iron near 3 supplement* )or( iron near3 therap* )))) and (( develop* )or( behavio?r* )))(8 records)

#15 (random* or trial*) or ("Clinical-Trials" in MJ,MN)(122,212 records)

#14 random* or trial*(122,212 records)

#13 "Clinical-Trials" in MJ,MN(1436 records)

#12 (((baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)) and ((( an?emi* )or( iron near3 deficien* )) or ("Anemia-" in MJ,MN)) and (("Dietary-Supplements" in MJ,MN) or ("Iron-" in MJ,MN) or (iron) or (( iron near 3 supplement* )or( iron near3 therap* )))) and (( develop* )or( behavio?r* ))(90 records)

#11 ( develop* )or( behavio?r* )(1,077,624 records)

#10 ((baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)) and ((( an?emi* )or( iron near3 deficien* )) or ("Anemia-" in MJ,MN)) and (("Dietary-Supplements" in MJ,MN) or ("Iron-" in MJ,MN) or (iron) or (( iron near 3 supplement* )or( iron near3 therap* )))(107 records)

#9 ("Dietary-Supplements" in MJ,MN) or ("Iron-" in MJ,MN) or (iron) or (( iron near 3 supplement* )or( iron near3 therap* ))(1266 records)

#8 "Iron-" in MJ,MN(238 records)

#7 iron(946 records)

#6 ( iron near 3 supplement* )or( iron near3 therap* )(21 records)

#5 "Dietary-Supplements" in MJ,MN(334 records)

#4 (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)(483,212 records)

#3 (( an?emi* )or( iron near3 deficien* )) or ("Anemia-" in MJ,MN)(1124 records)

#2 ( an?emi* )or( iron near3 deficien* )(1124 records)

#1 "Anemia-" in MJ,MN(251 records)

BIOSIS

#1 TS=(an*emi*) OR TS=(iron defien*)

#2 TS=(baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)

#3 TS=(iron supplement*) OR TS=(iron therap*) OR TS=(iron)

#4 #3 AND #2 AND #1

#5 TS=(random* or trial*)

#6 #5 AND #4

CENTRAL

#1 Anemia, Iron-Deficiency/

#2 an*emi*

#3 (iron near/3 deficien*).

#4 #1 or #2 or #3

#5 child, preschool/ or infant/

#6 (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)

#7 #5 or #6

#8 Dietary Supplements/

#9 (iron near/3 supplement*)

#10 (iron near/3 therap*)

#11 iron

#12 Iron/

#13 #8 or #9 or #10 or #11 or #12

#14 4 and 7 and 13

Appendix 2. Search strategies April 2013

CENTRAL

2011, Issue 1 searched 3 February 2011
2013, Issue 3 searched 23 April 2013

#1 MeSH descriptor: [Anemia, Iron-Deficiency] explode all trees
#2 (anemi* or anaemi*) or iron near/3 deficien*
#3 #1 or #2
#4 MeSH descriptor: [Infant] explode all trees
#5 child preschool near "MESH check words"
#6 (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)
#7 #4 or #5 or #6
#8 MeSH descriptor: [Dietary Supplements] this term only
#9 MeSH descriptor: [Micronutrients] this term only
#10 MeSH descriptor: [Trace Elements] this term only
#11 MeSH descriptor: [Food, Fortified] this term only
#12 MeSH descriptor: [Injections, Intramuscular] this term only
#13 (inject* or intramuscular* or intra next muscular*)
#14 iron near/3 supplement*
#15 iron near/3 therap*
#16 iron or "Fe" or ferrous* or ferric*
#17 MeSH descriptor: [Iron] this term only
#18 MeSH descriptor: [Iron Compounds] this term only
#19 MeSH descriptor: [Ferrous Compounds] this term only
#20 MeSH descriptor: [Ferrous Compounds] this term only
#21 MeSH descriptor: [Iron, Dietary] this term only
#22 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21
#23 #3 and #7 and #22

Ovid MEDLINE (R)

1948 to January week 3 2011, searched 2 February 2011
1948 to April week 2 2013, searched 22 April 2013

1 Anemia, Iron-Deficiency/
2 (anaemi$ or anemi$).tw.
3 (iron adj3 deficien$).tw.
4 or/1-3
5 infant/
6 child, preschool/
7 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or girl$ or boy$ or child$).tw.
8 or/5-7
9 Food, Fortified/
10 Dietary Supplements/
11 Micronutrients/
12 Trace elements/
13 Injections, Intramuscular/
14 (inject$ or intramuscular$ or intra-muscular$).tw.
15 Iron/
16 Iron, dietary/
17 exp iron compounds/ or ferric compounds/ or ferrous compounds/
18 (iron or Fe or ferrous$ or ferric$).mp.
19 or/9-18
20 4 and 8 and 19
21 randomized controlled trial.pt.
22 controlled clinical trial.pt.
23 randomi#ed.ab.
24 placebo$.ab.
25 drug therapy.fs.
26 randomly.ab.
27 trial.ab.
28 groups.ab.
29 or/21-28
30 exp animals/ not humans.sh.
31 29 not 30
32 20 and 31
33 limit 32 to ed=20070501-20110202
34 32 not 33

EMBASE (Ovid)
1980 to 2011 week 4, searched 2 February 2011
1980 to 2013 week 16, searched 22 April 2013

1 iron deficiency anemia/
2 (anaemi$ or anemi$).tw.
3 (iron adj3 deficien$).tw.
4 or/1-3
5 infant/
6 preschool child/
7 toddler/
8 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or girl$ or boy$ or child$).tw.
9 or/5-8
10 iron/
11 iron intake/
12 iron derivative/ or ferric ion/ or ferrous ion/
13 (iron or Fe or ferrous$ or ferric$).mp.
14 exp trace element/
15 diet supplementation/
16 intramuscular drug administration/
17 (inject$ or intramuscular$ or intra-muscular$).tw.
18 or/10-17
19 Clinical trial/
20 Randomized controlled trial/
21 Randomization/
22 Single blind procedure/
23 Double blind procedure/
24 Crossover procedure/
25 Placebo/
26 Randomi#ed.tw.
27 RCT.tw.
28 (random$ adj3 (allocat$ or assign$)).tw.
29 randomly.ab.
30 groups.ab.
31 trial.ab.
32 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
33 Placebo$.tw.
34 Prospective study/
35 (crossover or cross-over).tw.
36 prospective.tw.
37 or/19-36
38 4 and 9 and 18 and 37

BIOSIS

1969 to 3 February 2011, searched 3 February 2011
BIOSIS was not available to the editorial base or author team in 2013 so the search was not updated

#9 #7 NOT #8
#8 #7
#7 #6 AND #5 AND #4 AND #3
#6 TS=(random* or trial* )
#5 #2 OR #1
#4 TS=(iron or ferric* or ferrous* or Fe)
#3 TS=(baby or babies or infant* or preschool* or pre-school* or toddler* or child*)
#2 TS=(anemi* or anaemi*)
#1 TS=(iron deficien*)

CINAHL (EBSCOhost)

1937 to current, searched 2 February 2011
1937 to current, searched 23 April 2013

S40 S37 NOT S39
S39 S37 and S38
S38 PY 2007-2011
S37 S4 and S8 and S22 and S36
S36 S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35
S35 "cross over*"
S34 crossover*
S33 (MH "Crossover Design")
S32 (tripl* N3 mask*) or (tripl* N3 blind*)
S31 (trebl* N3 mask*) or (trebl* N3 blind*)
S30 (doubl* N3 mask*) or (doubl* N3 blind*)
S29 (singl* N3 mask*) or (singl* N3 blind*)
S28 (clinic* N3 trial*) or (control* N3 trial*)
Database - CINAHL Plus 113390 Edit S28
S27 (random* N3 allocat* ) or (random* N3 assign*)
S26 randomis* or randomiz*
S25 (MH "Meta Analysis")
S24 (MH "Clinical Trials+")
S23 MH random assignment
S22 S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21
S21 TI (inject* or intramuscular* or intra-muscular*)
S20 (MH "Injections, Intramuscular")
S19 (MH "Dietary Supplements") Search modes - Boolean/Phrase Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL Plus 6735 Edit S19
S18 (MH "Food, Fortified")
S17 (MH "Dietary Supplementation")
S16 "Fe"
S15 ferrous*
S14 ferric*
S13 (MH "Ferrous Compounds") OR (MH "Ferric Compounds")
S12 iron*
S11 (MH "Micronutrients")
S10 (MH "Trace Elements")
S9 (MH "Iron") OR (MH "Iron Compounds")
S8 S5 or S6 or S7
S7 TI (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*) or AB (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)
S6 (MH "Child, Preschool")
S5 (MH "Infant")
S4 S1 or S2 or S3
S3 TI (iron N3 deficien*) or AB (iron N3 deficien*)
S2 AB (anaemi* or anemi*) OR TI (anaemi* or anemi*)
S1 (MH "Anemia, Iron Deficiency")

PsycINFO (EBSCOhost)

1837 to current, searched 2 February 2011

S33 S30 NOT S31
S32 S30 and S31
S31 PY 2007-2011
S30 S4 and S8 and S15 and S29
S29 S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28
S28 (evaluation N3 stud* or evaluation N3 research*)
S27 (effectiveness N3 stud* or effectiveness N3 research*)
S26 DE "Placebo" or DE "Evaluation" or DE "Program Evaluation" OR DE "Educational Program Evaluation" OR DE "Mental Health Program Evaluation"
S25 (DE "Random Sampling" or DE "Clinical Trials") or (DE "Experiment Controls")
S24 "cross over*"
S23 crossover*
S22 (tripl* N3 mask*) or (tripl* N3 blind*)
S21 (trebl* N3 mask*) or (trebl* N3 blind*)
S20 (doubl* N3 mask*) or (doubl* N3 blind*)
S19 (singl* N3 mask*) or (singl* N3 blind*)
S18 (clinic* N3 trial*) or (control* N3 trial*)
S17 (random* N3 allocat* ) or (random* N3 assign*)
S16 randomis* or randomiz*
S15 S9 or S10 or S11 or S12 or S13 or S14
S14 TI (inject* or intramuscul or intra-muscul*) OR AB(inject* or intramuscul or intra-muscul*)
S13 DE "Injections" OR DE "Intramuscular Injections"
S12 TI ( ferrous* or ferric* or Fe) or AB( ferrous* or ferric* or Fe)
S11 TI (iron*) or AB (iron*)
S10 DE "Dietary Supplements"
S9 DE "Iron"
S8 S5 or S6 or S7
S7 (ZG "infancy (2-23 mo)") or (ZG "neonatal (birth-1 mo)")
S6 (ZG "preschool age (2-5 yrs)")
S5 TI(baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*) or AB (baby or babies or infant* or preschool* or pre-school* or toddler* or girl* or boy* or child*)
S4 S1 or S2 or S3
S3 TI (iron N3 deficien*) or AB (iron N3 deficien*)
S2 TI (anem* or anaemi*) or AB (anem* or anaemi*)
S1 DE "Anemia"

PsycINFO (Ovid)

1806 to April week 3 2013, searched 23 April 2013

1 anemia/
2 (anem$ or anaemi$).tw.
3 (iron adj3 deficien$).tw.
4 1 or 2 or 3
5 (baby or babies or infant$ or preschool$ or pre-school$ or toddler$ or boy$ or girl$ or child$).tw.
6 (childhood birth 12 yrs or infancy 2 23 mo or neonatal birth 1 mo or preschool age 2 5 yrs).ag.
7 5 or 6
8 Dietary Supplements/
9 iron$.tw.
10 (ferrous$ or ferric$ or Fe).tw.
11 Intramuscular Injections/ or Injections/
12 (inject* or intramuscul$ or intra-muscul$).tw.
13 iron/
14 or/8-13
15 clinical trials/
16 (randomis$ or randomiz$).tw.
17 (random$ adj3 (allocat$ or assign$)).tw.
18 ((clinic$ or control$) adj trial$).tw.
19 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
20 (crossover$ or "cross over$").tw.
21 random sampling/
22 Experiment Controls/
23 Placebo/
24 placebo$.tw.
25 exp program evaluation/
26 treatment effectiveness evaluation/
27 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw.
28 or/15-27
29 4 and 7 and 14 and 28

LILACS (VHL interface)

Searched 3 February 2011 and 23 April 2013

anemi$ or anaemi$ [Words] or "ANEMIA, iron-deficiency" [Subject descriptor] [Words] AND (iron

[Subject descriptor] or iron or ferrous or ferric) [Words] AND child$ or baby or babies or infant$ or

pre-school or preschool [Words]

ClinicalTrials.gov

Searched 3 February 2011 and 23 April 2013

anemia AND iron AND children

WHO ICTRP

All years searched 23 April 2013

CONDITION=anemia OR anaemia AND Intervention=iron* AND Trials in Children is selected

What's new

DateEventDescription
30 January 2013New citation required but conclusions have not changedNew study included.
24 October 2012New search has been performedUpdated search. 'Risk of bias' tables and a 'Summary of findings' table added.

History

Protocol first published: Issue 1, 1999
Review first published: Issue 2, 2001

DateEventDescription
13 September 2010AmendedConverted to new review format.
26 February 2001New citation required and conclusions have changedSubstantive amendment

Contributions of authors

All four review authors were involved in the planning and processing of this substantial update. BW and TG selected the trials for inclusion, extracted the data and performed the analyses, while SZ was the referee review author. LL and SZ provided critical input for the statistical analysis and the interpretation of data. All of the review authors took part in the discussion of the results and contributed to the drafting of the final version.

Declarations of interest

Bo Wang - none known.
Si-Yan Zhan - none known.
Ting Gong - none known.
Liming Lee - none known.

Sources of support

Internal sources

  • Peking University Health Science Center, China.

    Allowance

  • Chinese Academy of Medical Sciences, China.

    Salary

External sources

  • Ministry of Education, China.

    Research fund

Differences between protocol and review

We added 'Risk of bias' tables and a 'Summary of findings' table.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aukett 1986

MethodsRCT. Allocation by investigators not connected with study. Investigators, parents and assessors blind to allocation
Participants110 children aged 17-19 months with IDA (Hb 8-11 g/dL). Community sample
InterventionsFerrous sulphate 24 mg and vitamin C 10 g or vitamin C 10 mg as identical appearing placebo. Compliance checked twice weekly
OutcomesDenver Developmental Screening Tests before and 8-9 weeks after commencement of treatment. Also measured weight change and measures of iron status
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Low riskQuote (from report): "Allocation was double blind using consecutively numbered bottles"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low risk6/54 missing from intervention group; 7/56 missing from control group. Characteristics of these 2 groups were similar to each other and to the group who reattended
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Driva 1985

MethodsRCT. No details of allocation process available. Nursery nurse and assessors blind to allocation
Participants40 infants with IDA (Hb < 11.0 g/dL and all suffering from iron deficiency) aged 3-25 months recruited from an orphanage in Greece
InterventionsIM injection of iron 50 mg in the intervention group
OutcomesBayley Scales of infant Development administered pre and 10 days post commencement of intervention
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Unclear riskComment: no sufficient information provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Quote (from the report): "Neither the tester nor the nursery nurse knew the type of therapeutic intervention"

Comment: Insufficient information on blinding of investigators

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from the report): "Neither the tester nor the nursery nurse knew the type of therapeutic intervention"
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome measures are available for all children. Complete follow-up in both intervention group and control group
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Honig 1978

MethodsRCT. No details of allocation process available. Investigators, parents and assessors blind to allocation
Participants24 infants with IDA (Hb < 10.5 g/dL and at least 2 abnormal measures of iron
status), aged 9-26 months, recruited from paediatric clinic in New York
InterventionsIron dextran complex at a dose calculated to raise Hb to 12 g/dL. Placebo of IM sterile saline
OutcomesBayley Scales of infant Development and Bayley Infant Behaviour Record administered pre and 5-8 days post commencement of intervention. However, only some subscales of the Behaviour Record were reported
NotesAuthors provided unpublished details of allocation concealment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Low riskComment: Authors provided unpublished details of adequate allocation concealment
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from the report): "Neither the examiner nor the nurse was informed as to which group any infant belonged until Bayley protocols had been scored"
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome measures are available for all children. Complete follow-up in both intervention group and control group
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Idjradinata 1993

MethodsRCT. Allocation sequence derived from table of random
numbers, no details provided of who carried this out. Infants grouped by iron status class and randomised separately. Investigators, parents and assessors blind to allocation
ParticipantsChildren aged 12-18 months: 50 with IDA (Hb ≤ 10.5 g/dL, transferrin saturation < 10% and serum ferritin < 12 mg/dL) recruited from a paediatric clinic in Indonesia. 29 non-anaemic, iron deficient and 47 iron sufficient infants also randomised to treatment or control
InterventionsFerrous sulphate 3 mg/kg body weight by mouth for 4 months or placebo syrup of same appearance and flavour. Compliance checked weekly
OutcomesBayley Scales of Infant Development administered pre and 4 months post commencement of intervention. Measures of weight, length and Hb status
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote (from report): "Random assignment of the infants to either the iron treatment or placebo intervention was done with a table of random numbers"
Allocation concealment (selection bias)Unclear riskComment: no sufficient information provided
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low risk1/25 missing from intervention group; 2/25 missing from control group. Missing outcome data balanced in numbers across groups
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Kimmons [pers comm]

MethodsAllocation sequence generated by random number table prepared by pharmacy and intervention performed by research nurse who was not further involved in study. Assessors blind to allocation
Participants42 children aged 6-24 months with Hb < 10.6 g/dL and MCV < 73 fL were randomised. Children recruited from general paediatric outpatients
InterventionsIron dextran complex calculated to raise Hb to 12 g/dL or dot of India ink at covered injection site
OutcomesBayley Scales of Infant Development and Bayley Infant Behaviour Record
administered pre and 1 week post commencement of intervention
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote (from the report): "Allocation sequence generated by random number table prepared by pharmacy"
Allocation concealment (selection bias)Low riskQuote (from the report): "Allocation by nurse not connected with study"
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: no sufficient information provided
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low risk4/21 missing from either of both groups. Missing outcome data balanced in numbers across groups
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Lozoff 1982

MethodsRCT. Allocation by investigators not involved in other
aspects of the study. Investigators, parents and assessors blind to allocation
Participants28 children aged 6-24 months with IDA (Hb < 10.5 g/dL and at least 2 abnormal measures of iron status) and 40 children without IDA (Hb > 12 g/dL) randomised. Volunteers invited to have iron screening from a community in Guatemala
InterventionsFerrous ascorbate 5 mg/kg body weight orally twice daily for 7 days or identical
placebo prepared by pharmacy and administered by researcher blind to allocation
OutcomesBayley Scales of Infant Development administered pre and 6-8 days post
commencement of intervention
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Low riskQuote (from the report): "Both anaemic and nonanaemic infants were randomly assigned to oral iron or placebo treatment groups by investigators who did not participate in screening , testing"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low risk0/15 (MDI) or 3/15 (PDI) missing from intervention group; 0/13 (PDI) or 1/13 (MDI) missing from control group. Missing outcome data almost balanced in numbers across groups
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Lozoff 1987

MethodsRCT. Allocation by investigators not involved in other
aspects of the study. Investigators, parents and assessors blind to allocation
Participants

52 children with IDA (Hb ≤ 10.5 g/dL and at least 2 abnormal measures of iron status)

45 children with Hb > 10.5 to < 12 g/dL and 2 abnormal measures of iron status

21 children with Hb > 12 g/dL and 2 abnormal measures of iron status

38 children with Hb > 12 g/dL and only serum ferritin < 12 μg/dL

35 children with Hb > 12 g/dL and normal measures of iron status

Those with Hb < 12 g/dL were randomised to IM iron followed by placebo, IM placebo followed by oral iron or IM placebo followed by oral placebo. The remaining children were randomised to IM placebo followed by either oral iron or oral placebo

InterventionsIM iron (Imferon) calculated to raise Hb to 12.5 g/dL or IM placebo then ferrous
sulphate 5 mg/kg or similar placebo given twice daily by investigators for 7 days
OutcomesBayley Scales of Infant Development administered pre and 7 days post
commencement of intervention
NotesOutcome assessments performed on all children at 1 week but data not easily interpretable (see analysis section). The authors report no significant differences between intervention and control groups on MDI or PDI scores
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Low riskQuote (from correspondence): "Allocation by investigators not involved in other aspects of the study"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up in both intervention group and control group
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Walter 1989

  1. a

    Hb: haemoglobin; IDA: iron deficiency anaemia; IM: intramuscular; MCV: mean corpuscular volume; MDI: Mental Development Index; PDI: Psychomotor Development Index; RCT: randomised controlled trial.

MethodsRCT. Method of allocation unclear. Children within each
iron-status group were randomly assigned to intervention and control. Investigators, parents and assessors blind to allocation
Participants39 anaemic (Hb < 11.0 g/dL) children aged 12 months allocated to iron (n = 24) or placebo (n = 15). Children recruited from within community-based RCT of iron supplementation
InterventionsFerrous sulphate 15 mg 3 times daily for 10 days or placebo
OutcomesBayley Scales of Infant Development administered pre and 11 days post commencement of intervention
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: no sufficient information provided
Allocation concealment (selection bias)Unclear riskComment: no sufficient information provided
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote (from correspondence): "Investigators, parents and assessors were blind to allocation"
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome assessments available on all children. Complete follow-up in both intervention and control group
Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Deinard 1986No non-treated controls
Linos 1990No non-treated controls
Lozoff 1996No non-treated controls
Lozoff 2003Children were free of iron-deficient anaemia
Moffatt 1994Some children were free of iron-deficient anaemia
Oski 1983No non-treated controls
Stoltzfus 2001Some children were free of iron-deficient anaemia
Walter 1983No non-treated controls