Intermittent iron supplementation for improving nutrition and development in children under 12 years of age

  • Review
  • Intervention

Authors


Abstract

Background

Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that half of the cases are due to iron deficiency. Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity and mortality. The provision of daily iron supplements is a widely used strategy for improving iron status in children but its effectiveness has been limited due to its side effects, which can include nausea, constipation or staining of the teeth. As a consequence, intermittent iron supplementation (one, two or three times a week on non-consecutive days) has been proposed as an effective and safer alternative to daily supplementation.

Objectives

To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children from birth to 12 years of age compared with a placebo, no intervention or daily supplementation.

Search methods

We searched the following databases on 24 May 2011: CENTRAL (2011, Issue 2), MEDLINE (1948 to May week 2, 2011), EMBASE (1980 to 2011 Week 20), CINAHL (1937 to current), POPLINE (all available years) and WHO International Clinical Trials Registry Platform (ICTRP). On 29 June 2011 we searched all available years in the following databases: SCIELO, LILACS, IBECS and IMBIOMED. We also contacted relevant organisations (on 3 July 2011) to identify ongoing and unpublished studies.

Selection criteria

Randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of 12 years at the time of intervention with no specific health problems. The intervention assessed was intermittent iron supplementation compared with a placebo, no intervention or daily supplementation.

Data collection and analysis

Two authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies.

Main results

We included 33 trials, involving 13,114 children (˜49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed.

Nineteen trials evaluated intermittent iron supplementation versus no intervention or a placebo and 21 studies evaluated intermittent versus daily iron supplementation. Some of these trials contributed data to both comparisons. Iron alone was provided in most of the trials.

Fifteen studies included children younger than 60 months; 11 trials included children 60 months and older, and seven studies included children in both age categories. One trial included exclusively females. Seven trials included only anaemic children; three studies assessed only non-anaemic children, and in the rest the baseline prevalence of anaemia ranged from 15% to 90%.

In comparison with receiving no intervention or a placebo, children receiving iron supplements intermittently have a lower risk of anaemia (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72, ten studies) and iron deficiency (RR 0.24, 95% CI 0.06 to 0.91, three studies) and have higher haemoglobin (mean difference (MD) 5.20 g/L, 95% CI 2.51 to 7.88, 19 studies) and ferritin concentrations (MD 14.17 µg/L, 95% CI 3.53 to 24.81, five studies).

Intermittent supplementation was as effective as daily supplementation in improving haemoglobin (MD –0.60 g/L, 95% CI –1.54 to 0.35, 19 studies) and ferritin concentrations (MD –4.19 µg/L, 95% CI –9.42 to 1.05, 10 studies), but increased the risk of anaemia in comparison with daily iron supplementation (RR 1.23, 95% CI 1.04 to1.47, six studies). Data on adherence were scarce and it tended to be higher among those children receiving intermittent supplementation, although this result was not statistically significant.

We did not identify any differential effect of the type of intermittent supplementation regimen (one, two or three times a week), the total weekly dose of elemental iron, the nutrient composition, whether recipients were male or female or the length of the intervention.

Authors' conclusions

Intermittent iron supplementation is efficacious to improve haemoglobin concentrations and reduce the risk of having anaemia or iron deficiency in children younger than 12 years of age when compared with a placebo or no intervention, but it is less effective than daily supplementation to prevent or control anaemia. Intermittent supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. Information on mortality, morbidity, developmental outcomes and side effects, however, is still lacking.

Résumé scientifique

Intermittent iron supplementation for improving nutrition and development in children under 12 years of age

Contexte

Environ 600 millions d'enfants d'âge préscolaire et scolaire dans le monde sont anémiques. On estime que la moitié des cas sont dus à une carence en fer. Les conséquences de l'anémie ferriprive dans l'enfance comprennent le retard de croissance, la moins bonne réussite scolaire, le développement moteur et cognitif déficient et l'augmentation de la morbidité et la mortalité. La supplémentation quotidienne en fer est une stratégie largement utilisée pour améliorer le statut du fer chez les enfants mais son efficacité a été limitée en raison de ses effets secondaires, tels que nausées, constipation ou taches sur les dents. En conséquence, la supplémentation en fer intermittente (une, deux ou trois fois par semaine, des jours non consécutifs) a été proposée comme alternative efficace et plus sûre à la supplémentation quotidienne.

Objectifs

Évaluer les effets de la supplémentation en fer intermittente, seule ou en combinaison avec d'autres vitamines et minéraux, sur les résultats nutritionnels et développementaux chez les enfants de la naissance à l'âge de 12 ans, comparativement à un placebo, à l'absence d'intervention ou à une supplémentation quotidienne.

Stratégie de recherche documentaire

Nous avons cherché dans les bases de données suivantes le 24 mai 2011 : CENTRAL (2011, numéro 2), MEDLINE (de 1948 à la 2ème semaine de mai 2011), EMBASE (de 1980 à la 20ème semaine de 2011), CINAHL (de 1937 à aujourd'hui), POPLINE (toutes les années disponibles) et le Système d'enregistrement international des essais cliniques de l'OMS (ICTRP). Le 29 Juin 2011, nous avons passé au crible toutes les années disponibles dans les bases de données suivantes : SCIELO, LILACS, IBECS et IMBIOMED. Nous avons également contacté des organisations pertinentes (le 3 Juillet 2011) pour identifier des études en cours ou non publiés.

Critères de sélection

Des essais randomisés et quasi-randomisés avec randomisation individuelle ou en grappes. Les participants étaient des enfants âgés de moins de 12 ans au moment de l'intervention, sans problèmes de santé spécifiques. L'intervention évaluée était une supplémentation en fer intermittente comparée à un placebo, à l'absence d'intervention ou à une supplémentation quotidienne.

Recueil et analyse des données

Deux auteurs ont évalué de manière indépendante l'éligibilité des études au regard des critères d'inclusion, extrait les données des études incluses et évalué le risque de biais des études incluses.

Résultats principaux

Nous avons inclus 33 essais, portant au total sur 13 114 enfants (~ 49 % de filles) de 20 pays d'Amérique latine, d'Afrique et d'Asie. La qualité méthodologique des essais était inégale.

Dix-neuf essais ont évalué la supplémentation intermittente en fer par rapport à l'absence d'intervention ou à un placebo et 21 études ont comparé les supplémentations en fer quotidienne versus intermittente. Certains de ces essais ont fourni des données pour les deux comparaisons. Dans la plupart des essais le fer était administré seul.

Quinze études incluaient des enfants de moins de 60 mois, 11 essais incluaient des enfants de 60 mois et plus, et sept études incluaient des enfants des deux tranches d'âge. Un essai ne comprenait que des filles. Sept essais incluaient seulement des enfants anémiques, trois études n'avaient évalué que des enfants non anémiques, et dans les autres études la prévalence de l'anémie au départ variait de 15 % à 90 %..

En comparaison avec l'absence d'intervention ou avec la réception d'un placebo, les enfants recevant des suppléments de fer par intermittence ont un moindre risque d'anémie (ratio de risque moyen (RR) 0,51 ; intervalle de confiance (IC) à 95 % 0,37 à 0,72 ; dix études) et de carence en fer (RR 0,24 ; IC à 95 % 0,06 à 0,91 ; trois études) et ont des taux plus élevés d'hémoglobine (différence moyenne (DM) 5,20 g/L ; IC à 95 % 2,51 à 7,88 ; 19 études) et de concentration de ferritine (DM 14,17 mg/L ; IC à 95 % 3,53 à 24,81 ; cinq études).

La supplémentation intermittente s'est montrée aussi efficace que la supplémentation quotidienne dans l'amélioration des concentrations d'hémoglobine (DM -0,60 g/L ; IC à 95 % -1,54 à 0,35 ; 19 études) et de ferritine (DM -4,19 mg/L ; IC à 95 % -9,42 à 1,05 ; 10 études), mais augmentait le risque d'anémie en comparaison avec la supplémentation en fer quotidienne (RR 1,23 ; IC à 95 % 1,04 à 1,47 ; six études). Les données sur l'observance du traitement étaient rares et elle avait tendance à être plus élevée chez les enfants recevant une supplémentation intermittente, bien que ce résultat n'était pas statistiquement significatif.

Nous n'avons pas relevé d'effet différentiel du type de régime de supplémentation intermittente (une, deux ou trois par semaine), de la dose hebdomadaire totale de fer élémentaire, de la composition en éléments nutritifs, du fait que les bénéficiaires étaient des garçons ou des filles, ou de la durée de l'intervention.

Conclusions des auteurs

La supplémentation en fer intermittente est efficace pour améliorer le taux d'hémoglobine et réduire le risque d'anémie ou de carence en fer chez les enfants âgés de moins de 12 ans en comparaison avec un placebo ou avec l'absence d'intervention, mais il est moins efficace que la supplémentation quotidienne pour prévenir ou contrôler l'anémie. La supplémentation intermittente peut être une intervention de santé publique viable dans des contextes où la supplémentation quotidienne a échoué ou n'a pas été mise en œuvre. On manque cependant encore d'informations sur la mortalité, la morbidité, les résultats développementaux et les effets secondaires.

摘要

間歇性補鐵以改善12歲以下孩童的營養與發展

背景

全世界約有60億的學齡前與學齡兒童貧血。估計有半數的原因是缺鐵。兒童時期缺鐵貧血的後果包含有生長遲緩、降低學業成就、運動與認知發展受損、還有增加的發病率與死亡率。每日鐵質的補充是改善兒童鐵質條件所廣泛使用的策略,但其有效性因為副作用而受限,副作用會造成噁心、便秘或牙齒染色。因此,提出間歇性補鐵一周1、2或3次於非連續天) 做為每日補充更為有效且安全的替代方案。 評估間歇性補鐵與安慰劑、無干介入或是每日補充比較,以單獨或是與其他微生素與礦物質結合方式,對出生到12歲兒童在營養與發展成果的效果。

目的

評估間歇性補鐵與安慰劑、無干介入或是每日補充比較,以單獨或是與其他微生素與礦物質結合方式,對出生到12歲兒童在營養與發展成果的效果。

搜尋策略

我們搜尋了下列數據庫到2011年5月24日為止: CENTRAL (2011年第2期), MEDLINE (1948年到2011年5月第2周)、EMBASE (1980 年到2011年第20周)、 CINAHL (1937年至今)、POPLINE (所有可得年份)以及WHO國際臨床試驗註冊平台(ICTRP)。至2011年6月29日止,我們搜尋了下列資料庫中所有可取得的年份: SCIELO、LILACS、IBECS與IMBIOMED。我們也與相關組織聯絡(於2011年7月3日)以找出進行中與未公開的研究。

選擇標準

隨機與準隨機試驗,不論是個人或群集隨機分派。參與者為12歲以下孩童,介入時無特定健康問題。評估介入為間歇性補鐵與安慰劑、無介入或是每日補充進行比較。

資料收集與分析

兩位作者獨立評估研究對比納入條件之合格性、由所包含研究中萃取資訊並評估所包含研究的偏誤風險。

主要結果

我們納入了33個試驗,涵蓋來自拉丁美洲、非洲與亞洲20個國家的13114名兒童(~49% 女性) 。試驗方法論品質是混合的。

19個試驗評值了間歇性補鐵對比無介入或是安慰劑,而有21個試驗評估間歇性對照每日補充鐵質。這些試驗中有某些在兩個比較中都有貢獻。單獨補鐵在大多數的試驗中提出 。

15個研究中包含60個月以下的孩童; 11個試驗包含60個月與以上的孩童,還有7個研究包含兩個年齡類別的孩童。一個試驗中僅有女性。7個試驗僅包含貧血孩童;3個研究僅評估非貧血孩童,且在其餘中,貧血基線普遍率範圍由15%到 90%。

與接受無介入與安慰劑者比較,接受間歇性補鐵的兒童貧血 (平均風險比 (RR) 0.51, 95% 信賴區間 (CI) 0.37到 0.72,10個研究)與缺鐵風險較低(RR 0.24, 95% CI 0.06到0.91,3個研究),並有較高的血紅素 (平均數差異(MD) 5.20 g/L, 95% CI 2.51 到 7.88,19個研究) 與鐵蛋白濃度(MD 14.17 µg/L, 95% CI 3.53 到24.81,5個研究)。

間歇性補鐵在改善血紅素 (MD –0.60 g/L, 95% CI –1.54到0.35,19個研究)與鐵蛋白濃度(MD –4.19 µg/L, 95% CI –9.42 到1.05,10個研究)上與每日補充一樣有效,但與每日補鐵相比增加了貧血的風險(RR 1.23, 95% CI 1.04到1.47,6個研究)。 缺少一致性相關數據,且其傾向於在接受間歇性補充的孩童身上風險較高,雖然此結果不具統計上的顯著性。

我們沒有找出任何間歇性補鐵治療方法(一周1、2或3次)、一週總計的鐵素劑量、營養成分類型的差異效果,不論接受者為男性或女性,又或是介入長度。

作者結論

與安慰劑或無介入相比,間歇性補鐵在改善血紅素濃度與降低貧血風險或是12歲以下兒童缺鐵上有效,但較每日補充在避免或控致貧血上效果差 。於每日補充失敗或是未曾執行處,週期性補充或許是可行的大眾健康介入。然而,死亡率、發病率、發展性成果與副作用相關資訊仍然缺乏。

Plain language summary

One, two or three times a week iron supplements for improving health and development among children under 12 years of age

Approximately 600 million preschool and school-age children are anaemic worldwide. It is estimated that half of these cases are due to a lack of iron. Iron deficiency anaemia during childhood may slow down growth, reduce motor and brain development, and increase illness and death. If anaemia is not treated promptly, these problems may persist later in life. Taking supplements containing iron (sometimes combined with folic acid and other vitamins and minerals) on a daily basis has shown to improve children's health but its use has been limited because supplements may produce side effects such as nausea, constipation or staining of the teeth. It has been suggested that giving iron one, two or three times a week (known as 'intermittent' supplementation) may reduce these side effects and be easier to remember, and thus encourage children to continue taking the iron supplements.

We analysed 33 trials involving 13,314 children (49% females) from 20 countries in Latin America, Africa and Asia, to assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children from birth to 12 years of age compared with a placebo, no intervention.or daily supplementation.

The studies were of mixed quality. Overall, the results of this review show that giving children supplements with iron alone or in combination with other vitamins and minerals one, two or three times a week approximately halves their risk of having anaemia in comparison with receiving no iron supplements or a placebo. Giving children supplements on a intermittent basis was as effective as daily supplementation for improving haemoglobin and ferritin concentrations, although, children receiving iron supplements intermittently were at higher risk of having anaemia.

We aimed to examine the effects of intermittent supplementation on illness, death, and school and physical performance, as well as on other side effects, but there was insufficient information to draw firm conclusions.

In summary, intermittent iron supplementation is efficacious to improve haemoglobin concentrations and reduce the risk of having anaemia or iron deficiency in children younger than 12 years of age when compared with a placebo or no intervention, but it is less effective than daily supplementation to prevent or control anaemia. Intermittent supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. Information on mortality, morbidity, developmental outcomes and side effects, however, is still lacking.

Résumé simplifié

La supplémentation en fer une, deux ou trois fois par semaine pour améliorer la santé et le développement des enfants de moins de 12 ans

Environ 600 millions d'enfants d'âge préscolaire et scolaire dans le monde sont anémiques. On estime que la moitié de ces cas sont dus à une carence en fer. L'anémie ferriprive durant l'enfance peut ralentir la croissance, réduire le développement moteur et cérébral, et augmenter les risques de maladie et de mort. Si l'anémie n'est pas traitée rapidement, ces problèmes peuvent persister plus tard dans la vie. Il a été montré que la prise de suppléments contenant du fer (parfois combiné avec de l'acide folique et d'autres vitamines et minéraux) sur une base quotidienne améliorait la santé des enfants, mais son utilisation a été limitée parce que les suppléments peuvent produire des effets secondaires tels que nausées, constipation ou taches sur les dents. Il a été suggéré que ne donner du fer qu'une, deux ou trois fois par semaine (ce qu'on appelle la supplémentation 'intermittente') pourrait réduire ces effets secondaires et être plus facile à ne pas oublier, et donc encourager les enfants à continuer à prendre les suppléments de fer

Nous avons analysé 33 essais impliquant 13 314 enfants (49 % de filles) de 20 pays d'Amérique latine, d'Afrique et d'Asie, afin d'évaluer les effets de la supplémentation en fer intermittente, seule ou en combinaison avec d'autres vitamines et minéraux, sur les résultats nutritionnels et développementaux chez les enfants de la naissance à l'âge de 12 ans, comparativement à un placebo, à l'absence d'intervention ou à la supplémentation quotidienne.

Les études étaient de qualité inégale. Globalement, les résultats de cette revue montrent que donner aux enfants des suppléments de fer, seul ou en combinaison avec d'autres vitamines et minéraux, une, deux ou trois fois par semaine diminue à peu près de moitié leur risque de souffrir d'anémie, en comparaison avec ne pas recevoir de suppléments de fer ou recevoir un placebo. Donner des suppléments aux enfants sur une base intermittente était aussi efficace que la supplémentation quotidienne pour améliorer le taux d'hémoglobine et de ferritine, mais toutefois les enfants recevant des suppléments de fer par intermittence avaient un risque plus élevé d'anémie.

Nous avons cherché à examiner les effets de la supplémentation intermittente sur la maladie, la mort, les performances physiques et scolaires, ainsi que sur d'autres effets secondaires, mais il n'y avait pas suffisamment d'informations pour tirer des conclusions solides.

En résumé, la supplémentation en fer intermittente est efficace pour améliorer le taux d'hémoglobine et réduire le risque d'anémie ou de carence en fer chez les enfants âgés de moins de 12 ans en comparaison avec un placebo ou avec l'absence d'intervention, mais il est moins efficace que la supplémentation quotidienne pour prévenir ou contrôler l'anémie. La supplémentation intermittente peut être une intervention de santé publique viable dans des contextes où la supplémentation quotidienne a échoué ou n'a pas été mise en œuvre. On manque cependant encore d'informations sur la mortalité, la morbidité, les résultats développementaux et les effets secondaires..

Notes de traduction

Traduit par: French Cochrane Centre 5th March, 2014
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

淺顯易懂的口語結論

一週1、2或3次補鐵以改善12歲以下孩童的健康與發展

全世界約有60億學齡前與學齡兒童有貧血問題。估計此情形半數是因為缺鐵。兒童時期缺鐵貧血會延緩生長、降低運動與腦部發展、並增加疾病與死亡。若未適當治療貧血,這些問題會持續到往後的人生。以每日基礎服用含鐵的補充 (有時與葉酸與及其他微生素與礦物質結合)顯示出能改善兒童健康,但它的使用因為可能產生噁心、便秘或牙齒染色這樣的副作用而受限制 。建議一週補鐵1、2或3次(稱為"間歇性"補充)可能可以降低這些副作用並易於記得,因此可鼓勵孩童繼續服用鐵質補充。

我們分析了33個試驗,涵蓋來自拉丁美洲、非洲與亞洲20個國家的13314名兒童(49%女性),與安慰劑、無介入或每日補充相比,想要評估間歇性補鐵、單獨或是與其他微生素與礦物質結合在12歲以下兒童營養與發展上的效果。

研究品質是混合。整體而言,此文獻回顧的研究結果顯示與無治療與安慰劑相比,單獨提供兒童鐵質補充或是與其他為生素與礦物質結合,一週1、2或3次,大約可減半他們產生貧血的風險。雖然接受間歇性補充的兒童貧血風險較高,但以間歇基礎提供兒童補充在改善血紅素與鐵蛋白濃度上與每日補充一樣有效。

我們的目標在於檢驗間歇性補血在疾病、死亡、以及學校與身體表現、還有其他副作用上的影響,但沒有充分的證據可得出確切的結論。

總之,與安慰劑或無介入比較,間歇性補鐵在改善血紅素濃度與降低12歲以下孩童貧血風險或缺鐵情形上有效,但較每日補充在預防或控制貧血的效果差。於每日補充失敗或是未曾執行處,間歇性補充或許是可行的大眾健康介入。然而,死亡率、發病率、發展性成果與副作用相關資訊仍然缺乏。

譯註

翻譯: East Asian Cochrane Alliance 5th March, 2014
翻譯補助: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Summary of findings(Explanation)

Summary of findings for the main comparison. Intermittent use of iron supplements versus placebo or no intervention in children younger than 12 years of age
Patient or population: children under 12 years of age
Settings: community settings
Intervention: intermittent supplementation with iron alone or with other nutrients
Comparison: placebo or no intervention
Outcomes Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Anaemia (haemoglobin below a cut-off defined by trialists, taking into account the age and altitude)

 

RR 0.51
(0.37–0.72)
1824
(10 studies)
⊕⊕⊕⊝
moderate 1
Haemoglobin (g/L) MD 5.20
(2.51–7.88)

3032

 (19 studies)

⊕⊕⊝⊝
low 2,3
Iron deficiency (using ferritin concentrations)

RR 0.24
(0.06–0.91)

 

431
(3 studies)
⊝⊝⊝⊝
very low 2,3,4
Iron status (ferritin (μg/L) MD 14.17
(3.53–24.81)
550
(5 studies)
⊕⊕⊝⊝
low 2,3
Iron deficiency anaemiaNot estimable0
(0 studies)
None of the trials reported on this outcome
All-cause mortalityNot estimable0
(0 studies)
None of the trials reported on this outcome

CI, confidence interval; RR, risk ratio; MD, mean difference.

*GRADE Working Group grades of evidence:
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We have moderate confidence in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect.

1There was high statistical heterogeneity. Given the large and consistent effect (RR 0.51; 95% CI 0.37–0.72) we have refrained from downgrading even though three of the nine studies are at high risk of bias.

2 High statistical heterogeneity but results were consistent.
3 Some studies lacked blinding and clear methods of allocation.

4 Wide confidence intervals.

Note: For cluster-randomised trials the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.

Summary of findings 2 Intermittent versus daily use of iron supplements in children younger than 12 years of age

Summary of findings 2. Intermittent versus daily use of iron supplements in children younger than 12 years of age
Patient or population: children under 12 years of age
Settings: community settings
Intervention: intermittent supplementation with iron alone or with other micronutrients
Comparison: daily supplementation with iron alone or with other micronutrients
Outcomes Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Anaemia (haemoglobin below a cut-off defined by trialists, taking into account the age and altitude) RR 1.23
(1.04–1.47)
980
(6 studies)

⊕⊕⊝⊝

low 1,2

Haemoglobin (g/L) MD –0.60
(–1.54-0.35)

2851

(19 studies)

⊕⊕⊝⊝

low 1,3

Iron deficiency (using ferritin concentrations)

RR 4.00
(1.23–13.05)

 

76
(1 study)
⊝⊝⊝⊝
very low 4
Iron status (ferritin (µg/L)

MD –4.19

(–9.42- 1.05)

 

902

(10 studies)

⊕⊕⊝⊝

low 1 3

Iron deficiency anaemiaNot estimable0
(0 studies)
None of the trials reported on this outcome
MortalityNot estimable0
(0 studies)
None of the trials reported on this outcome

CI, confidence interval; RR, risk ratio; MD, mean difference.

*GRADE Working Group grades of evidence:
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We have moderate confidence in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect.

1 Some studies lacked blinding and clear methods of allocation.

2 Wide confidence intervals.

3 High heterogeneity but results were mostly consistent.

4 Only one trial with unclear methods to generate the random sequence and conceal the allocation. Wide confidence intervals.

Note: For cluster-randomised trials the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.

Background

Description of the condition

Iron is an essential nutrient for all body tissues and is present in the brain of the developing fetus, where it is needed for proper formation of neural tissue (Iannoti 2006) and development of brain cells (Beard 2008). Iron deficiency, a common form of nutritional deficiency, results from long-term imbalance caused by an inadequate dietary iron intake; poor iron absorption or utilisation; increased iron requirements for growth during childhood, adolescence or pregnancy; or chronic blood losses (Moy 2006). In the later stages of iron depletion, the haemoglobin concentration decreases, resulting in a condition known as iron deficiency anaemia.

Anaemia is characterised by a reduction in the oxygen-carrying capacity of blood such that the body's needs can no longer be met. In addition to iron deficiency, other vitamin and mineral deficiencies (for example, folate, vitamin B12 and vitamin A), chronic inflammation, parasitic infections and inherited disorders of haemoglobin structure can result in all-cause anaemia (WHO 2001). Among females, anaemia is often exacerbated after beginning menstruation, especially if it occurs at an early age and the young females do not consume sufficient iron to offset menstrual losses (WHO 2001). Haemoglobin concentrations are used to diagnose anaemia, while serum ferritin, an iron storage protein, and serum transferrin, an iron transport protein, are commonly used as indicators of iron status in populations (WHO 2011a; WHO 2011b).  

Children, particularly those younger than five years, are vulnerable to iron deficiency anaemia because of their increased needs as a result of rapid growth. It is estimated that approximately 600 million preschool and school-aged children are anaemic worldwide, and it is calculated that at least half of the cases are due to iron deficiency (WHO/CDC 2008). In general, low-income countries have a higher prevalence of anaemia (WHO/CDC 2008). This association is also true in high-income countries where people of low socioeconomic status are especially susceptible to iron and other vitamin and mineral deficiencies (Cole 2010).

Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity from a variety of causes including diarrhoea and acute respiratory infections (WHO 2001). Specifically, iron deficiency can lead to deficits in memory and behavioural regulation as iron is required to make neurotransmitters such as dopamine, epinephrine and serotonin (Iannoti 2006; Moy 2006; Beard 2008), while impaired myelination contributes to deficits in motor function. Long-term effects of early iron deficiency include decreased work capacity and impaired cognitive and behavioural development (Lozoff 2000; Lozoff 2007). Some of these impairments are thought to be irreversible if they occur at an early age and the consequences may continue even after treatment, reinforcing the importance of prevention (Siddiqui 2004; Iannoti 2006; Lozoff 2007).

Description of the intervention

Mass fortification of food staples with iron; dietary diversification to increase iron intake, absorption and utilisation; and iron supplementation have been used to prevent or treat iron deficiency anaemia. Mass fortification of staple foods with iron is usually not aimed at meeting the needs of young children, with the exception of targeted complementary infant feeding programmes (WHO 2009a). Dietary diversification to improve iron status in populations at risk is also difficult because of limited food access among the most vulnerable populations, the limited quantity of food that children can consume, and the fact that the strategy requires multiple behavioural changes among children and their families. To date, there are few effective dietary diversification intervention programmes at scale (Davidsson 2003). Finally, iron supplementation, which is the provision of doses of iron alone or in combination with other micronutrients in the form of tablets, syrups or capsules, is the most widespread strategy for improving iron status in children worldwide.

The World Health Organization (WHO) recommends a supplemental provision of 2 mg of elemental iron per kilogram body weight per day for three months in children less than six years of age who were born at term. Children of school age and older should receive 30 mg of elemental iron and 250 μg (0.25 mg) of folic acid daily, particularly in populations where anaemia prevalence is greater than 40% (WHO 2001). Though the current recommendations include iron alone or with folic acid, it has been suggested that administration of additional vitamins and minerals may prevent or reverse anaemia derived from one or more nutritional deficiencies (Bhutta 2009). Daily iron supplementation has proven to be effective in increasing haemoglobin concentrations in children, especially in those who are anaemic (Gera 2007). In spite of this, in real world settings the long regimen duration, the low coverage rates and insufficient tablet distribution, and side effects associated with daily iron supplementation (for example, gastrointestinal discomfort, constipation and staining of teeth with drops or syrups) limit adherence, especially in young children (ACC/SCN 1991; Stoltzfus 2011). In older children these effects may partially be controlled with the use of slow-release iron tablets in which iron has similar bioavailability to regular iron compounds (for example, ferrous sulphate or ferrous fumarate) (Simmons 1993; Bothwell 2000), although their higher cost may be a limiting factor for wider use.

How the intervention might work

Oral iron supplementation on an intermittent basis (that is once, twice or three times a week on non-consecutive days) has been suggested as a more efficient preventive intervention in public health programmes than the more common daily iron supplementation scheme. The basis for this iron intermittent supplementation regimen is that the absorption is maximised by provision of iron in synchrony with the turnover of the mucosal cells (that is, intestinal cells are 'fresh' to take up iron) (Wright 1990; Berger 1997; Viteri 1997; Beaton 1999; Tavil 2003). In addition, other minerals such as zinc and copper may be more readily absorbed because they are not regularly competing with iron for absorption channels, leading to an improved micronutrient status (Baqui 2005). It has been reported that intermittent supplementation may be safer than daily supplementation because intestinal cells are less exposed to an iron-rich environment, which may cause cell damage (Casanueva 2003; Viteri 2005). Also, it has been suggested that additional iron may exacerbate malaria infection and so this reduced exposure to iron overall is particularly relevant in malaria settings as less iron is available for the parasite's growth (Ekvall 2000; NIH 2011). Though side effects may still occur with intermittent regimens, they are experienced less frequently and may be perceived as more acceptable as a result, increasing adherence to supplementation programmes (Thu 1999; Viteri 2005).

Despite the biological plausibility of this intervention to reduce anaemia, its success as a public health intervention will likely be determined by several factors such as the available resources; the existence of the appropriate policies and legislation; the production and supply of the supplements; the development of delivery systems; the development and implementation of external and internal quality control systems, and the development and implementation of strategies for information, education and communication for behaviour change among consumers. Figure 1 presents a generic logic model for micronutrient interventions that depicts the programme theory and the plausible relationships between inputs and expected changes in health and outcomes that can be adapted to the context of each setting (De-Regil 2011; WHO/CDC 2011).

Figure 1.

WHO/CDC logic model for micronutrients interventions in public health (with permission from WHO)

Why it is important to do this review

There are currently no international recommendations on intermittent iron supplementation regimens in children. It has been reported that the provision of an iron supplement once a week is comparable to daily supplementation in improving anaemia status (Siddiqui 2004). Other authors suggest that this effect may be enhanced when iron is given twice a week (Schultink 1995; Tavil 2003; Olsen 2006).

Weekly iron and folic acid supplementation has recently been recommended by the WHO to prevent anaemia in women of reproductive age (WHO 2009b). This intervention is currently implemented at scale in many countries around the world as part of public health programmes. It could potentially be targeted to other age groups, such as young children and school-aged children, since the supplement can be provided at home and in schools or other institutional settings. However, to date, there has been no systematic assessment of the safety and effectiveness of weekly or any other intermittent iron supplementation regimen among children to inform policy makers.

This review complements the findings of two related Cochrane systematic reviews exploring the effects of intermittent regimens among menstruating women (Fernández-Gaxiola 2011) and pregnant women (Peña-Rosas 2009).

Objectives

To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children less than 12 years of age compared with daily supplementation, a placebo or no supplementation.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised and quasi-randomised studies with randomisation at either an individual or cluster level. We defined quasi-randomised trials as trials which use systematic methods to allocate participants to treatment groups, such as alternation, assignment based on date of birth or case record number (Higgins 2011). We did not include cross-over trials nor other types of evidence (for example, cohort or case-control studies) in the meta-analysis but we have considered such evidence in the discussion where relevant.

Types of participants

Children under the age of 12 years at the time of the trials.

We did not include studies specifically targeting premature or low birth weight infants, or children with severe infectious diseases, such as HIV, as they may metabolise iron differently and have different health and disease indicators. These topics are subject to separate Cochrane reviews (Adetifa 2009; Mills 2009).

Types of interventions

Oral supplements of iron, alone or with other vitamins and minerals, given on an intermittent basis and compared with a placebo or no supplementation, or compared with the same supplements provided daily.

Oral iron supplementation refers to the delivery of iron compounds directly to the oral cavity, either as a tablet, capsule, dispersible tablet or liquid. For the purpose of this review, intermittent supplementation is defined as the provision of iron supplements one, two or three times a week on non-consecutive days.

We performed the following comparisons:

  1. any intermittent iron supplementation versus no supplementation or placebo (0 to < 12 years of age);

  2. any intermittent iron supplementation versus any daily iron supplementation (0 to < 12 years of age);

  3. any intermittent iron supplementation versus no supplementation or placebo (0 to 59 months of age);

  4. any intermittent iron supplementation versus any daily iron supplementation (0 to 59 months of age);

  5. any intermittent iron supplementation versus no supplementation or placebo (5 to < 12 years of age);

  6. any intermittent iron supplementation versus any daily iron supplementation (5 to < 12 years of age).

Any intermittent or daily supplementation with iron includes the provision of iron alone, iron plus folic acid or iron plus other vitamins and minerals.

We have included studies that examined interventions where iron supplementation was combined with co-interventions such as deworming, education or other approaches only if the co-interventions were the same in both the intervention and comparison groups. 

We excluded studies examining tube feeding, parenteral nutrition or supplementary food-based interventions such as mass fortification of staple or complementary foods, home fortification with micronutrient powders, lipid-based supplements or Foodlets tablets, or biofortification.

Types of outcome measures

Primary outcomes
  1. Anaemia (haemoglobin below a cut-off defined by trialists, taking into account the age and altitude)*

  2. Haemoglobin (g/L)*

  3. Iron deficiency (as measured by trialists by using indicators of iron status, such as ferritin or transferrin)*

  4. Iron status (ferritin in μg/L)*

  5. Iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency, diagnosed with an indicator of iron status selected by trialists)*

  6. All-cause mortality (number of deaths during the trial)*

* Outcomes that were included in the 'Summary of Findings' tables.

Secondary outcomes
  1. All-cause morbidity (number of children with at least one reported illness during the trial)

  2. Acute respiratory infection (as measured by trialists)

  3. Diarrhoea (as measured by trialists)

  4. Any other adverse side effects (as measured by trialists, such as stained teeth, headache, stomach ache, discomfort, constipation)

  5. Adherence (percentage of children who consumed more than 70% of the expected doses)

  6. Folate status (as measured by trialists)

  7. Mental development and motor skill development (children 0 to 59 months) (as assessed by trialists, including Bayley Mental Development Index (MDI), Bayley Psychomotor Development Index (PDI), Stanford-Binet Test, DENVER II Developmental Screening Test)

  8. School performance (children 60 months and older) (as measured by trialists)

  9. Physical capacity (children 60 months and older) (as measured by trialists)

  10. Height-for-age Z-scores and weight-for-age Z-scores

We planned to group the outcome time points as follows: immediately after the end of the intervention, one to six months after the end of intervention, and seven to 12 months after the end of the intervention. However, we limited our analyses to the end of the intervention as only two trials reported on continued follow-up after the end of the intervention. We have described this in Characteristics of included studies and plan to extract this information in future updates, if available.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases:

Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), part of The Cochrane Library (searched 24 May 2011);
MEDLINE,1948 to May week 2, 2011 (searched 24 May 2011);
EMBASE, 1980 to 2011 Week 20 (searched 24 May 2011);
CINAHL, 1937 to current (searched 24 May 2011);
ICTRP (searched 24 May 2011);
POPLINE (searched 24 May 2011);
SCIELO (searched 29 June 2011);
LILACS (searched 29 June 2011);
IBECS (searched 29 June 2011);
IMBIOMED (searched 29 June 2011).

The search strategies are in Appendix 1.

We did not apply any language restrictions. For those articles written in a language other than English, we extracted the information or commissioned their translation into English.

Searching other resources

For assistance in identifying ongoing or unpublished studies, we contacted authors and known experts to identify any additional or unpublished data. We also contacted the Departments of Nutrition for Health and Development and regional offices of the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), the nutrition section of the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI) and Sight and Life Foundation (3 July 2011).

We searched the International Clinical Trials Registry Platform (ICTRP) (searched 24 May 2011) for any ongoing or planned trials.

Data collection and analysis

Selection of studies

LMD screened all titles and abstracts for potential eligibility, while MEJ, TD and AS each assessed one-third of the abstracts. LMD contacted relevant institutions and searched for ongoing trials. All the authors independently assessed half of the full-text articles for inclusion according to the above mentioned criteria; each paper was therefore assessed by two review authors. We resolved any disagreement through discussion.

If studies were published only as abstracts, or the study reports contained little information on methods, we contacted the authors to obtain further details of study design and results.

Data extraction and management

For eligible studies, two authors independently extracted data using a form designed for this review. LMD extracted data from all the studies and the remaining authors each extracted a third. LMD entered data into the Review Manager 5 software (RevMan 2011). The same review author who extracted one-third of the data in duplicate carried out checks for accuracy. We resolved any discrepancies through discussion and documented each stage of the process.

We completed the data collection form electronically and recorded information as follows.

(1) Trial methods
  • Study design

  • Unit and method of allocation

  • Unit of analysis

  • Masking of participants and outcome assessors

  • Exclusion of participants after randomisation and proportion of losses at follow-up

  • Study power

(2) Participants
  • Location of the study

  • Sample size

  • Age

  • Sex

  • Socioeconomic status (as defined by trialists and where such information was available)

  • Baseline status of anaemia

  • Inclusion and exclusion criteria as described in the Criteria for considering studies for this review

(3) Intervention
  • Dose

  • Type of iron compound

  • Supplementation regimen

  • Duration of the intervention

  • Co-intervention

(4) Comparison group
  • Type of comparison (no intervention, placebo or daily supplementation with the same nutrients)

(5) Outcomes

We recorded both prespecified and non-prespecified outcomes, although we did not use the latter to underpin the conclusions of the review.

When information regarding any of the studies was unclear, we contacted authors of the original reports to provide further details. If there was insufficient information for us to be able to assess risk of bias, studies were put into the awaiting assessment section of the review until further information is published or made available to us.

Assessment of risk of bias in included studies

One author (LMD) assessed the risk of bias for all the included studies and the remaining authors each assessed one-third of the studies so that all the trials were assessed by two authors independently, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving a third assessor.

We reported this assessment in the 'Description of studies' and risk of bias tables. We explicitly mention when authors provided input on their trials.

(1) Sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence.

We assessed the method as:

  • low risk of bias (any truly random process, for example, random number table; computer random number generator);

  • high risk of bias (any non-random process, for example, odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We have described for each included study the method used to conceal the allocation sequence and have assessed whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes);

  • unclear risk of bias.   

(3) Blinding (checking for possible performance and detection bias)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. For interventions involving the provision of iron supplements it may be possible to blind children, clinical staff and outcome assessors to group allocation by providing placebo preparations.

We assessed blinding separately for different classes of outcomes and have noted where there has been an attempt at partial blinding.

We assessed the risk of performance bias associated with blinding as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

We assessed the risk of detection bias associated with blinding as:

  • low, high or unclear risk of bias for outcome assessors.

Whilst assessed separately, we combined the results into a single evaluation of risk of bias associated with blinding (Higgins 2011).

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total number of randomised participants), reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups. We assessed methods as:

  • low risk of bias (less than 20% of cases lost to follow-up and balanced in numbers across intervention groups);

  • high risk of bias (20% or more cases lost to follow-up or outcome data imbalanced in numbers across intervention groups);

  • unclear risk of bias .

(5) Selective reporting bias

We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other sources of bias

We have described for each included study any important concerns we have about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

  • high risk of other bias;

  • low risk of other bias;

  • unclear risk of other bias.

(7) Overall risk of bias

We summarised the risk of bias at two levels: within studies (across domains) and across studies.

For the first, we made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. Attrition, lack of blinding and losses to follow-up may be particular problems in studies looking at different regimens of iron supplementation and where children are followed up over time. We explored the impact of the level of bias by undertaking sensitivity analyses, see Sensitivity analysis below.

For the assessment across studies, the main findings of the review are set out in 'Summary of findings for the main comparison and Summary of findings 2 (SoF) prepared using GRADE profiler software (GRADEpro 2008). The primary outcomes for each comparison have been listed with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, the quality of the evidence has been assessed independently by two review authors using the GRADE approach (Balshem 2010), which involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias; this results in one out of  four levels of quality (high, moderate, low or very low). This assessment was limited only to the trials included in this review and as we did not consider there was a serious risk of indirectness or publication bias we did not downgrade in these domains.

Measures of treatment effect

Dichotomous data

For dichotomous data, we have presented results as average risk ratios (RR) with 95% confidence intervals (CI). 

Continuous data

We present the results as mean difference (MD) with 95% confidence intervals at the end of the intervention. If trials did not provide this information but reported the mean change, we included these data as suggested by Higgins 2011. There was no need to use the standardised mean difference to combine trials as these outcomes were measured with the same methods.

Unit of analysis issues

Cluster-randomised trials

We included cluster-randomised trials in the analyses along with individually-randomised trials. Cluster-randomised trials are labelled with a (C). We obtained the intra-cluster correlation coefficient (ICC) from Hall 2002 (C) (ICC 0.0698; average cluster size (ACS): 18.55; design effect (DE) 2.22), Desai 2004 (C) (ICC 0.069; ACS: 1.5; DE 1.035) and Roschnik 2004 (C) (ICC 0.1123; ACS: 33.82; DE 4.35). We calculated the ACS from the reports and imputed the ICC from Roschnik 2004 (C) to Roschnik 2003 (C) as the study designs were very similar (ACS: 29); and from Hall 2002 (C) to Liu 1995 (C) (ACS: 27.3), Sinisterra 1997 (C) (ACS: 199.5), Yang 2004 (C) (ACS: 32), Sen 2009 (C) (ACS: 60) and Arcanjo 2011 (C) (ACS: 17.7) and then calculated each trial's effective sample size. In the case of Yang 2004 (C), the number of classes was not clear so we assumed an average cluster size of 32 based on other reports (Okebe 2011). On the other hand, Awasthi 2005 (C) reported that the sample size was calculated including a design effect of 2.0. We used this value to calculate its effective sample size and also to conduct a sensitivity analysis to examine the potential effect of clustering on the CIs of the summary estimates. As the CIs did not change significantly (5% or more), we do not report the results of the sensitivity analysis. Desai 2004 (C) and Engstrom 2008 (C) were not adjusted as the trial authors reported that the analyses accounted for the effect of clustering.

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies), we included the directly relevant arms only. When we identified studies with various relevant arms, we combined the groups into a single pair-wise comparison (Higgins 2011) and included the disaggregated data in the corresponding subgroup category. When the control group was shared by two or more study arms, we divided the control group (events and total population) over the number of relevant subgroup categories to avoid double counting the participants. The details are described in the Characteristics of included studies tables.

Cross-over trials

We did not include cross-over trials.

Dealing with missing data

For included studies, we have noted levels of attrition in the Characteristics of included studies tables. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by carrying out sensitivity analysis (these same trials were assessed as being at high risk of bias, see Sensitivity analysis below).

We carried out analyses, as far as possible, on an intention-to-treat basis (ITT), that is, by attempting to include all participants randomised to each group in the analyses. If this was not possible, we performed an available case analysis in which data were analysed for every participant for whom the outcome was obtained.

Assessment of heterogeneity

We visually examined the forest plots from meta-analyses to look for any obvious heterogeneity among studies in terms of the size or direction of treatment effect. We used the I2 statistic, Tau2 and Chi2 test to quantify the level of heterogeneity among the trials in each analysis. If we identified moderate or substantial heterogeneity, we explored it by prespecified Subgroup analysis and investigation of heterogeneity. 

Assessment of reporting biases

Where we suspected reporting bias (see 'Selective reporting bias' above), we attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and the missing data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by a sensitivity analysis. 

We generated funnel plots (estimated differences in treatment effects against their standard error) only for haemoglobin in comparisons one and two, and ferritin in comparison two, as sufficient studies contributed data to these outcomes. Asymmetry could be due to publication bias but it can also be due to a real relationship between trial size and effect size, such as when larger trials have lower adherence and adherence is positively related to effect size.

Data synthesis

We carried out statistical analysis using the Review Manager 5 software (RevMan 2011). In this review we prespecified that we would use random-effects model analyses in view of anticipated heterogeneity in the interventions, populations and methods used in different trials.

Subgroup analysis and investigation of heterogeneity

Where data were available, we carried out the following subgroup analysis:

  1. by dose of elemental iron per week in the intermittent group: 25 mg or less; greater than 25 mg to 75 mg; greater than 75 mg;

  2. by duration of the supplementation: 0 to three months or less; more than three months;

  3. by type of compound: ferrous sulphate; ferrous fumarate; other;

  4. by anaemia status at baseline (haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 months or 5 to 11 years old, respectively, adjusted by altitude where appropriate): anaemic; non-anaemic; mixed or not reported;

  5. by intermittent supplementation regimen: one supplement a week; other intermittent regimen;

  6. by sex: males; females; mixed or not reported; and

  7. by micronutrient composition: iron alone; iron + folic acid; iron + other micronutrient; iron + multiple micronutrients.

We used the primary outcomes in subgroup analysis.

Pragmatically, we decided not to conduct subgroup analyses for those outcomes with three trials or fewer. We examined differences between subgroups by visual inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. We also used the Borenstein 2008 approach to formally investigate the differences between two or more subgroups. Analyses were conducted in Revman version 5.1.1 (RevMan 2011).

Sensitivity analysis

We carried out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear randomisation and allocation concealment, and either blinding or high or imbalanced losses to follow-up) from the analysis. We also examined the effect of different intra-cluster correlation coefficients imputed to cluster-randomised trials on the summary estimates of primary outcomes.

Results

Description of studies

Results of the search

The search strategy identified 7784 references for possible inclusion, 2453 of which were duplicate references. We assessed 81 published articles in full text, three unpublished reports, one review that contained published and unpublished data, and one abstract that has not been published in full. Nine studies were published in languages other than English: Chinese (Yang 2004 (C)), Farsi (Kargarnovin 2010), French (Nguyen 2002) and Spanish (Sinisterra 1997 (C); Rivera 1998; Sotelo-Cruz 2002; Evangelista-Salazar 2004; UNICEF 2006; Avila-Jimenez 2011). Figure 2 depicts the process for assessing and selecting the studies. We included 33 trials (42 references); excluded 40 (41 references); three trials are awaiting assessment (Husseini 1999; Reid 2001; Kargarnovin 2010), and we identified one ongoing study (Zeeba Zaka-ur-Rab 2010).

Figure 2.

Study flow diagram.

Included studies

We included 33 trials with 13,114 children; those studies which included more than two intervention arms may have been included in more than one comparison. All included trials contributed data to the review but some studies randomised participants to intervention arms that were not relevant to the comparisons we assessed. For these studies we did not include data from all groups in the analyses. We have indicated in the Characteristics of included studies tables if any randomised arms were not included.

Three of the trials had two arms providing different regimens of intermittent supplementation (Liu 1995 (C); Faqih 2006; Sen 2009 (C)). In these cases we combined the study arms for the overall comparison and included the disaggregated information in the subgroup analyses. Levels of supervision varied among trials but most of them were unsupervised. In addition, very few studies addressed the use of co-interventions such as health education to improve adherence or deworming prior to supplementation.

The sample size ranged between 60 and 1785 participants but overall tended to be small: 75% of the studies included fewer than 500 children. However, for cluster-randomised trials the analyses only included the estimated effective sample size, after adjusting the data to account for the clustering effect.

Settings

The studies included in the review were carried out over the last 16 years in low- and middle-income countries in Asia, Africa and Latin America: Bangladesh (Baqui 2003), Bolivia (Berger 1997; Aguayo 2000), Brazil (Da Silva 2008; Engstrom 2008 (C); Arcanjo 2011 (C)), China (Liu 1995 (C); Yang 2004 (C)), India (Awasthi 2005 (C); Sen 2009 (C)), Indonesia (Schultink 1995; Palupi 1997; Soemantri 1997), Iran (Khademloo 2009), Jordan (Faqih 2006), Kenya (Olsen 2000; Verhoef 2002; Desai 2004 (C)), Malawi (Young 2001; Roschnik 2003 (C)), Mali (Hall 2002 (C)), Mexico (Evangelista-Salazar 2004), Pakistan (Siddiqui 2004), Panama (Sinisterra 1997 (C)), Phillipines (Roschnik 2004 (C)), South Africa (Taylor 2001), Tanzania (Ekvall 2000), Thailand (Sungthong 2002), Turkey (Ermis 2002; Tavil 2003; Yurdakok 2004) and Vietnam (Thu 1999; Nguyen 2002).

Participants

Participant ages ranged from newborn to 19 years old. While we did not include studies specifically recruiting postmenarchal females, as these are the subject of a separate review (Fernández-Gaxiola 2011), three included studies recruited adolescents and separate data were not available for younger children (Olsen 2000; Taylor 2001; Hall 2002 (C)). Based on the age range reported in these studies, at least half of their participants fulfilled our inclusion criteria and thus we decided to retain them in the review. If the disaggregated data by age is made available to us, we will include it in future updates of the review.

In the analyses (comparisons three to six), we have set out our findings separately for studies recruiting children in these younger and older age groups. Fifteen studies included children from birth to 59 months of age only (Schultink 1995; Palupi 1997; Thu 1999; Ekvall 2000; Young 2001; Ermis 2002; Nguyen 2002; Verhoef 2002; Baqui 2003; Tavil 2003; Evangelista-Salazar 2004; Desai 2004 (C); Yurdakok 2004; Engstrom 2008 (C); Khademloo 2009) and 11 trials included only older children 60 months of age and older (Sinisterra 1997 (C); Soemantri 1997; Aguayo 2000; Taylor 2001; Sungthong 2002; Roschnik 2003 (C); Roschnik 2004 (C); Siddiqui 2004; Da Silva 2008; Sen 2009 (C); Arcanjo 2011 (C)). Seven studies included children in both age categories (Liu 1995 (C); Berger 1997; Olsen 2000; Hall 2002 (C); Yang 2004 (C); Awasthi 2005 (C); Faqih 2006). In those cases we took into account the reported average age in allocating the trial. For example, Faqih 2006 recruited children aged two to six years of age and was included in comparisons two and four (younger children), while Olsen 2000 assessed children aged four to 19 years and was included in comparisons one and five (older children).

On average, 49% of the participants were females, with a range from 37% (Tavil 2003) to 100% (Sen 2009 (C)). Seven trials included only anaemic children (Schultink 1995; Berger 1997; Verhoef 2002; Tavil 2003; Desai 2004 (C); Faqih 2006; Siddiqui 2004); three only non-anaemic (Aguayo 2000; Yang 2004 (C); Yurdakok 2004); and the rest of the trials had a baseline prevalence of anaemia ranging between 15% and 90%.

Participants socioeconomic status was not explicit in most of the studies although references to underprivileged populations were frequent.

Intermittent regimens, dose and type of iron compounds

Nine trials included arms where children were supplemented with iron twice a week (Liu 1995 (C); Schultink 1995; Olsen 2000; Verhoef 2002; Tavil 2003; Desai 2004 (C); Awasthi 2005 (C); Faqih 2006; Sen 2009 (C)) and in two studies children were provided with iron every other day (three times a week) (Ekvall 2000; Ermis 2002). The rest of the studies provided iron supplements once weekly.

The total weekly iron dose given to the children ranged from 7.5 to 200 mg of elemental iron per week. Evangelista-Salazar 2004 provided 7.5 mg; Nguyen 2002 gave 15 mg; two trials provided 20 mg elemental iron (Thu 1999; Baqui 2003); in two trials children received a total weekly dose of 25 mg elemental iron (Da Silva 2008; Engstrom 2008 (C)); three trials gave 30 mg (Palupi 1997; Ekvall 2000; Yang 2004 (C)); one trial (Awasthi 2005 (C)) supplemented participants with 40 mg per week and another trial with 50 mg of iron per week (Arcanjo 2011 (C)). In five trials children received 60 mg of elemental iron per week (Schultink 1995; Sinisterra 1997 (C); Young 2001; Sungthong 2002; Siddiqui 2004); in three trials children received in total a weekly dose of 65 mg (Taylor 2001; Hall 2002 (C); Roschnik 2003 (C)); in one study the dose was 108 mg (Roschnik 2004 (C)); in another study the dose was 120 mg (Olsen 2000); and in Sen 2009 (C) the total weekly dose was 200 mg of elemental iron.

Some studies reported the provision of 1 mg to 8 mg of elemental iron per kg per day (Liu 1995 (C); Berger 1997; Soemantri 1997; Aguayo 2000; Ermis 2002; Verhoef 2002; Tavil 2003; Desai 2004 (C); Yurdakok 2004; Faqih 2006). In these cases we calculated the weekly dose by using the median or average age reported in the trial and the corresponding weight according to the WHO growth charts, percentile 50.

In almost all the studies, ferrous sulphate was the source of supplemental iron. Other iron compounds tested were ferrous polymaltose (Olsen 2000); ferrous dextran (Sen 2009 (C)) and ferrous fumarate (Taylor 2001; Verhoef 2002).

Most of the studies supplemented only with iron; one study gave iron in combination with 30 mg of vitamin C (Evangelista-Salazar 2004) and five studies gave iron in combination with folic acid. In these trials the weekly dose of folic acid also varied: one trial gave 100 µg (0.1 mg) of folic acid per week (Taylor 2001; Awasthi 2005 (C)), in two the dose was 250 µg (0.25 mg) (Hall 2002 (C); Roschnik 2003 (C)), while in Sen 2009 (C) the dose was 500 µg (0.5 mg) folic acid per week . Four studies provided supplements containing multiple micronutrients (Thu 1999; Young 2001; Baqui 2003; Yang 2004 (C)).

Excluded studies

We excluded 40 trials (41 references) from the review. In 12 trials the evaluated population was out of the scope of this review (Beasley 2000; Kianfar 2000; Sharma 2000; Zavaleta 2000; Ahmed 2001; Februhartanty 2002; Shah 2002; Agarwal 2003; Shobha 2003; Jaleel 2004; Soekarjo 2004; Leenstra 2009). The second main reason for exclusion was that trials were not randomised (Rivera 1998; Jayatissa 1999; Perrin 2002; Sotelo-Cruz 2002; Jackson 2003; Kapur 2003; Kanal 2005; Lima 2006; UNICEF 2006; Vir 2008; Mwanakasale 2009; Azeredo 2010). We excluded eight trials because the supplements were provided as Foodlets a (a crushable tablet that may be mixed with foods) and this intervention is outside the scope of this review (Briars 2003; Hop 2005; López de Romaña 2005; Smuts 2005; Lechtig 2006; López de Romaña 2006; Wijaya-Erhardt 2007; Schümann 2009). Six trials were excluded because intermittent supplementation regimens were not compared with daily regimens or no treatment or placebo (Menendez 1997; Tee 1999; Tomashek 2001; Ahmed 2005; Risonar 2008; Avila-Jimenez 2011). We excluded Hafeez 1998 because the intermittent supplements were given on consecutive days and Lin 2001 because the nutrient tested was vitamin A. We have described these studies in the Characteristics of excluded studies tables.

Risk of bias in included studies

Overall, study methods were not well described in many of the included studies and this meant that assessing risk of bias was difficult (see Figure 3 and Figure 4). We attempted to contact the study authors for further clarifications and noted in the Characteristics of included studies when the information was provided by the authors.

Figure 3.

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

Figure 4.

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

Where we assessed methods of randomisation or allocation concealment as being at high risk of bias (or unclear), and trials were either not blinded or had high or imbalanced attrition rates, we assumed that they were at high risk of bias in the sensitivity analysis looking at the impact of study quality. Using these criteria, nine studies were assessed as being at low risk of bias (Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Hall 2002 (C); Sungthong 2002; Verhoef 2002; Desai 2004 (C); Arcanjo 2011 (C)). The remaining studies were either assessed as being at high risk of bias or the methods were unclear.

Allocation

In 20 of the included trials, it was unclear how the randomisation sequence had been generated. In six studies investigators used random number tables (Thu 1999; Aguayo 2000; Verhoef 2002; Roschnik 2004 (C); Faqih 2006; Arcanjo 2011 (C)); in a further six studies computer-generated randomisation sequences were used (Ekvall 2000; Olsen 2000; Hall 2002 (C); Sungthong 2002; Desai 2004 (C); Da Silva 2008), and in two studies the groups were assigned to the treatments by drawing lots (Sinisterra 1997 (C); Sen 2009 (C)).

Eleven of the included studies used methods of concealing group allocation that we judged were low risk of bias, for example, by providing coded supplements to treatment and control groups that appeared similar to participants and to those carrying out randomisation (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Nguyen 2002; Sungthong 2002; Verhoef 2002; Baqui 2003). In the remaining trials, methods were either not described or were unclear.

Eleven trials were randomised at cluster level (Liu 1995 (C); Sinisterra 1997 (C); Hall 2002 (C); Roschnik 2003 (C); Desai 2004 (C); Roschnik 2004 (C); Yang 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Sen 2009 (C); Arcanjo 2011 (C)) and in these cases it was judged that selection bias at individual level was unlikely (low risk of bias).

Blinding

In 14 trials, we considered that there was low risk of bias related to blinding (Schultink 1995; Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Nguyen 2002; Olsen 2000; Taylor 2001; Verhoef 2002; Sungthong 2002; Baqui 2003; Yang 2004 (C); Arcanjo 2011 (C)). In the remaining trials, blinding was either not attempted or not mentioned.

Incomplete outcome data

While we assessed that the majority of the included trials (20 out of 33) had acceptable levels of attrition (with loss to follow-up and missing data being less than 20% and balanced across groups), in the remaining trials the levels of attrition were high or not balanced across groups. In these studies high levels of attrition were likely to represent an important source of bias and thus results are difficult to interpret; this is the case particularly if we consider that reasons for attrition may have been related to outcomes (for example, when children with side effects or those who developed anaemia were excluded from the analysis). In one trial (Baqui 2003) the dropout rate was considerably higher in one of the intervention groups (those receiving multi-micronutrients lost 41% compared to a loss of 8% to 19% in other groups) and there were further missing data for some outcomes. High levels of loss to follow-up also occurred in the studies by Engstrom 2008 (C) (20.2% attrition); Faqih 2006 (53% attrition); Young 2001 (60% attrition); Schultink 1995 (75% attrition); Sen 2009 (C) (68% missing data for some outcomes); Roschnik 2003 (C) (41.2% attrition), and Taylor 2001 (36% attrition). In one study (Da Silva 2008), 16% of participants were lost to follow up and loss was not balanced across groups; the reasons given by the authors included children developing anaemia or side effects, with no clarity about the number of children lost in each group for these reasons. In four trials losses to follow-up were not clear as the denominators were not provided (Tavil 2003; Roschnik 2004 (C); Yang 2004 (C); Khademloo 2009).

Selective reporting

We were not able to fully assess outcome reporting bias as we only had access to published study reports. We assessed publication bias using funnel plots only for haemoglobin (in comparisons one and two) and for ferritin (comparison two), as more than 10 trials contributed data to those outcomes. We did not find clear asymmetry that may suggest publication bias (graphs not shown). In the analyses we have ordered studies by weight so that the effect of small studies is more apparent; we have drawn attention to any results where visual inspection of the forest plot seems to suggest a more pronounced treatment effect in small as compared with larger studies.

Other potential sources of bias

In a study (Awasthi 2005 (C)) some children received supervised intake of the supplement; it was not clear whether this varied depending on intervention group.

There was some baseline imbalance on outcomes or other potential confounders in terms of participant characteristics in some studies (Schultink 1995; Sinisterra 1997 (C); Taylor 2001; Siddiqui 2004; Faqih 2006; Arcanjo 2011 (C)).

A potentially important source of bias was the impact of unit of randomisation; several of the included trials did not randomise at the individual level but used classes, schools or clinics as clusters for randomisation. The impact of the cluster-design effect was not clearly taken into account in most of the cluster-randomised trials (Liu 1995 (C); Sinisterra 1997 (C); Hall 2002 (C); Roschnik 2003 (C); Roschnik 2004 (C); Yang 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Arcanjo 2011 (C)). In the Engstrom 2008 (C) trial, regression analysis was carried out to try to identify possible confounding factors but unit of analysis did not appear to be part of this analysis. We were able to obtain the ICCs for three trials (Desai 2004 (C); Roschnik 2003 (C) and Hall 2002 (C)) and we imputed the last two values to other trials to obtain their effective sample size. The summary estimates obtained from cluster trials did not differ significantly from those obtained from studies randomised at an individual level.

There are three trials awaiting assessment (Husseini 1999; Reid 2001; Kargarnovin 2010). Based on the sample size of Kargarnovin 2010 and the findings reported in the abstract, we do not consider that its temporary exclusion from the analysis will bias the results of this review. Similarly, we did not consider that the omission of the data from Reid 2001 was likely to introduce serious bias due to the small sample size. On the other hand, the effect of excluding Husseini 1999 is uncertain as the only information available is published in Beaton 1999 who obtained it by personal communication. At the end of the intervention haemoglobin concentrations were higher and anaemia prevalence was lower among those children receiving daily supplements in comparison to those children receiving intermittent supplements. As we do not have access to the primary information, it is difficult to assess the quality of the study and to adjust data by the effect of clustering, which limits any assessment of its impact on our summary estimate.

Effects of interventions

See: Summary of findings for the main comparison Intermittent use of iron supplements versus placebo or no intervention in children younger than 12 years of age; Summary of findings 2 Intermittent versus daily use of iron supplements in children younger than 12 years of age

We have included data from 33 trials; overall, these trials involved 13,114 children. This figure represents the number of children recruited to studies, in some studies we have not included data for all arms of the trials in the review comparisons. The analyses include only the estimated effective sample size, after adjusting the data to account for the clustering effect.

We have organised the summary of results by comparing supplementation regimens and by primary and secondary outcomes. Most of the included studies focused on haematological outcomes and few reported on any of the other outcomes pre-specified in the review protocol. See the Data and analyses section for detailed results on primary and secondary outcomes.

Comparison 1. Intermittent iron supplementation versus no supplementation or placebo (19 trials)

Nineteen trials evaluated this comparison (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Ermis 2002; Hall 2002 (C); Verhoef 2002; Sungthong 2002; Baqui 2003; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Yurdakok 2004; Yang 2004 (C); Sen 2009 (C); Arcanjo 2011 (C)). Seven of the trials met the prespecified criteria mentioned above for being at lower risk of bias (Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Hall 2002 (C); Verhoef 2002; Sungthong 2002). In sensitivity analyses these trials were retained in the analysis whilst trials at higher risk of bias were temporarily removed to examine whether this had any impact on the overall pattern of results.

Primary outcomes
Anaemia

Ten trials with 1824 children provided data on anaemia following the interventions (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Hall 2002 (C); Verhoef 2002; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Arcanjo 2011 (C)). Those receiving intermittent iron supplementation were significantly less likely to have anaemia at follow-up compared with children receiving no intervention (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72) (Analysis 1.1). There was variation among trials in terms of the size of the treatment effect (T2 = 0.18, I2 = 81% and Chi2 test for heterogeneity P < 0.00001). The large effect remained significant even after excluding the trials at higher risk of bias (RR 0.60; 95% CI 0.42 to 0.87).

Haemoglobin concentrations (g/L)

Nineteen studies with 3032 participants provided data on mean haemoglobin levels following the intervention (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Ermis 2002; Hall 2002 (C); Verhoef 2002; Sungthong 2002; Baqui 2003; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Yang 2004 (C); Yurdakok 2004; Sen 2009 (C); Arcanjo 2011 (C)). Those receiving intermittent iron supplements on average had higher haemoglobin (Hb) levels than those receiving no intervention or a placebo; the difference was statistically significant (mean difference (MD) 5.20, 95% CI 2.51 to 7.88) (Analysis 1.9). There were high levels of heterogeneity among trials (T2 = 32.45, I2 = 93% and Chi2 test for heterogeneity P < 0.00001). The effect remained significant after removing the trials at high risk of bias (RR 5.02, 95% CI 2.01 to 8.03).

Iron deficiency

Three trials with 431 children (Verhoef 2002; Evangelista-Salazar 2004; Yang 2004 (C)) reported on this outcome. Findings suggested that children receiving intermittent supplements were at lower risk of having iron deficiency at the end of the intervention as those receiving nothing or a placebo (RR 0.24, 95% CI 0.06 to 0.91) (Analysis 1.17). There were high levels of heterogeneity among trials (T2 = 1.01, I2 = 88% and Chi2 test for heterogeneity P < 0.0003).

Iron status measured by ferritin (μg/L)

Five trials with follow-up data for 550 participants (Ermis 2002; Sungthong 2002; Baqui 2003; Yang 2004 (C); Yurdakok 2004) reported higher mean levels of ferritin among those receiving intermittent supplements compared with those receiving no treatment (MD 14.17, 95% CI 3.53 to 24.81) (Analysis 1.18). Only one trial (Sungthong 2002) was assessed as being at lower risk of bias.

Iron deficiency anaemia

No trials reported on this outcome.

All-cause mortality

No trials reported on mortality.

Secondary outcomes
All-cause morbidity

Information on all-cause morbidity was reported in one trial (Palupi 1997), with data for 194 children. There was no evidence of differences between groups (Analysis 1.26).

Acute respiratory infection

No trials reported on this outcome.

Diarrhoea

No trials provided information on diarrhoea.

Any other adverse effects

One trial (Ermis 2002) reported no statistically significant difference in the total number of side effects reported by those children receiving supplements intermittently and those receiving no intervention or a placebo (Analysis 1.27). One trial (Aguayo 2000) reported on nausea and did not find differences between groups (Analysis 1.28).

Adherence

Baqui 2003 and Ekvall 2000 reported that children receiving intermittent iron supplements had similar levels of adherence to intermittent iron supplementation as those children receiving a placebo or no intervention (RR 1.04, 95% CI 0.98 to 1.09) (Analysis 1.29).

Folate status (as measured by trialists)

No trials reported on this outcome.

Mental development and motor skill development

Baqui 2003 reported on several measures of cognitive and physical development. There was no clear evidence of difference between groups for most of these outcomes (Analysis 1.30; Analysis 1.31; Analysis 1.32; Analysis 1.34).

School performance

One study (Sungthong 2002) examined intelligence quotient (IQ), language development and mathematics performance; there were no clear differences between those receiving intermittent iron and those on no supplementation (Analysis 1.35; Analysis 1.36; Analysis 1.37).

Physical capacity

One trial examined (Baqui 2003) the motor quality of children, which included seven items such as motor control and tone, and expressed the results in percentile scores. Authors found that children receiving intermittent supplementation had higher percentile scores although the clinical significance of this difference was not clear (MD 15.60, 95% CI 7.66 to 23.54) (Analysis 1.33).

Height-for-age and weight-for-age Z-scores

Three trials (Palupi 1997; Thu 1999; Aguayo 2000) reported results for weight-for-age and height-for-age Z-scores for school-aged children and did not find a statistically significant effect on these outcomes (Analysis 1.38; Analysis 1.39).

Comparison 2. Intermittent iron supplementation versus daily iron supplementation (21 trials)

Twenty-one trials evaluated this comparison (Liu 1995 (C);,Schultink 1995; Berger 1997; Sinisterra 1997 (C); Soemantri 1997; Thu 1999; Young 2001; Ermis 2002; Nguyen 2002; Sungthong 2002, Tavil 2003; Desai 2004 (C); Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Awasthi 2005 (C); Faqih 2006; Da Silva 2008; Engstrom 2008 (C); Khademloo 2009; Sen 2009 (C)) and all of them contributed data to the analysis. Three of these trials were assessed as being at lower risk of bias and, where they contributed data, they were retained in the analysis when we conducted sensitivity analyses (Thu 1999; Sungthong 2002; Desai 2004 (C)).

Primary outcomes
Anaemia

Six trials with 980 participants provided data on the number of children with anaemia following the interventions (Schultink 1995; Berger 1997; Sinisterra 1997 (C); Thu 1999; Awasthi 2005 (C); Engstrom 2008 (C)). Children receiving intermittent iron supplementation had a higher risk of being anaemic at the end of the study period compared to those receiving daily iron supplementation (RR 1.23, 95% CI 1.04 to 1.47) (Analysis 2.1). Only one trial was considered at low risk of bias (Thu 1999) and found similar results (RR 1.31, 95% CI 0.31 to 5.57).

Haemoglobin concentrations (g/L)

Nineteen trials with 2851 participants provided data on mean haemoglobin levels following the intervention (Liu 1995 (C); Schultink 1995; Berger 1997; Soemantri 1997; Thu 1999; Young 2001; Ermis 2002; Nguyen 2002; Sungthong 2002; Tavil 2003; Desai 2004 (C); Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Awasthi 2005 (C); Faqih 2006; Engstrom 2008 (C); Khademloo 2009; Sen 2009 (C)). The groups receiving intermittent iron supplements on average had 0.60 less grams of haemoglobin per litre than those receiving daily supplementation but the difference between groups was not statistically significant (95% CI -1.54 to 0.35) (Analysis 2.9). There were high levels of heterogeneity for this outcome (T2 = 2.26, I2 = 56%, and Chi2 test for heterogeneity P = 0.001). When only those trials at lower risk of bias (Sungthong 2002; Desai 2004 (C)) were retained in the analysis, the difference between groups remained statistically non-significant (MD -0.87, 95% CI -2.77 to 1.02) (data for sensitivity analysis not shown).

Iron deficiency

Only one trial (Yang 2004 (C)) reported on iron deficiency and found that at the end of the intervention the number of children with iron deficiency was higher among those who received iron supplements intermittently compared to daily (RR 4.00, 95% CI 1.23 to 13.05) (Analysis 2.17).

Iron status measured by ferritin (ng/L)

Ten trials with data for 902 participants (Liu 1995 (C); Schultink 1995; Ermis 2002; Sungthong 2002; Tavil 2003; Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Faqih 2006; Khademloo 2009) reported that ferritin values were not statistically different between those receiving iron intermittently and those receiving daily iron (MD -4.19, 95% CI -9.42 to 1.05) (Analysis 2.18). Only one trial was at low risk of bias (Sungthong 2002) and found no differences between these two interventions. There was high heterogeneity for this outcome with considerable variation in mean values between trials; in addition, one of the studies reported exceptionally low standard errors for mean ferritin values (from which we calculated SDs) (Siddiqui 2004). We carried out a sensitivity analysis temporarily excluding this study from the meta-analysis; removing this study did not change the interpretation of results (MD - 5.20, 95% CI -10.76 to 0.35).

Iron deficiency anaemia

No trials reported data on iron deficiency anaemia.

All-cause mortality

No trials reported mortality by any cause.

Secondary outcomes
All-cause morbidity

Information on all-cause morbidity was reported in two trials (Desai 2004 (C); Da Silva 2008), with data for 601 children. There was no evidence of a difference between groups (RR 0.96, 95% CI 83 to 1.12) (Analysis 2.27).

Acute respiratory infection

No trials reported on this outcome.

Diarrhoea

Two trials (Yurdakok 2004; Da Silva 2008) had data on diarrhoea and did not find differences between groups (Analysis 2.28).

Any other adverse effects

Four trials (Liu 1995 (C); Ermis 2002; Desai 2004 (C); Yurdakok 2004) reported side effects among 895 children. There was no evidence of differences between intermittent and daily iron supplementation (RR 0.60, 96% CI 0.19 to 1.87) (Analysis 2.29).

Adherence

Five trials involving 1130 participants reported on this outcome (Berger 1997; Desai 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Sen 2009 (C)). There was no statistically significant difference in adherence to the interventions between groups although it tended to be higher among those children receiving intermittent iron supplements (RR 1.23, 95% CI 0.98 to 1.54) (Analysis 2.30).

Folate status (as measured by trialists)

No trials reported on this outcome.

Mental development and motor skill development

No trials reported on this outcome.

School performance

One study (Sungthong 2002) examined IQ, Thai language development and mathematics performance; there were no clear differences between groups receiving intermittent iron versus no supplementation (Analysis 2.31; Analysis 2.32; Analysis 2.33).

Physical capacity

One trial that provided weekly and twice-a-week supplementation (Sen 2009 (C)) did not find statistically significant differences in the increment of steps climbed by children receiving either intermittent or daily supplementation (Analysis 2.26).

Height-for-age and weight-for-age Z-scores

Three trials reported results for height-for-age Z-scores for school-aged children and did not find an effect on this outcome (Analysis 2.34).

Subgroup comparisons

There was considerable variation among trials in terms of the populations examined and the way studies were conducted, which very likely resulted in the high statistical heterogeneity observed in some outcomes. For primary outcomes, we examined subgroups to look for possible differences between studies in terms of the duration of the intervention; children's anaemia status at baseline; higher and lower weekly doses of iron; type of iron compound provided; and supplementation regimen.

For most of the outcomes very few studies contributed data, so we limited the subgroup analysis to anaemia and haemoglobin and ferritin concentrations. In the analyses we have provided overall totals along with subtotals for subgroups, and the statistics for subgroup differences.

Intermittent iron dose per week (25 mg or less; greater than 25 mg to 75 mg; greater than 75 mg)

Most of the trials provided between 25 and 75 mg of iron per week. There was some within subgroup heterogeneity and no consistent and clear differences between subgroup categories (Analysis 1.10; Analysis 1.19; Analysis 2.2; Analysis 2.10; Analysis 2.19). It seemed that the effect of intermittent supplementation on anaemia was lost among those children receiving iron doses greater than 75 mg per week, although only two trials contributed to this subgroup (Analysis 1.2).

Duration of the intervention (0 to three months; more than three months)

An almost even number of trials provided iron supplements for three months or less, or for more than three months. There was no statistical evidence that the response of haematological outcomes to intermittent supplementation differed by duration of the intervention (Analysis 1.3; Analysis 1.11; Analysis 1.20; Analysis 2.3; Analysis 2.11; Analysis 2.20).

Type of compound (ferrous sulphate; ferrous fumarate; other)

Most of the trials provided iron in the form of ferrous sulphate, but when other compounds were given there was no clear statistical evidence that they produced different results on haematological outcomes from those observed with ferrous sulphate (Analysis 1.4; Analysis 2.4; Analysis 2.12; Analysis 2.21). In one case haemoglobin responded better to supplementation with fumarate, but only one study contributed to this subgroup category and findings should be cautiously interpreted (Analysis 1.21).

Anaemia status at baseline (anaemic; non-anaemic; mixed or not reported)

Intermittent supplementation appeared to be as efficacious in trials that included only anaemic children as in those studies that included populations with different degrees of anaemia (Analysis 1.5; Analysis 1.13; Analysis 1.22; Analysis 2.5; Analysis 2.13; Analysis 2.22). One study conducted in anaemic Bolivian children (Berger 1997) reported a very pronounced therapeutic effect on haematological outcomes and this trial contributed to the observed statistical heterogeneity; its results were consistent in terms of direction with the rest of the trials.

Intermittent regimen (one supplement a week; other intermittent regimen)

Most of the trials supplemented children on a weekly basis and in some cases only one study was included in each subgroup, which impeded the interpretation of the analyses (Analysis 1.6; Analysis 1.23). For the rest of the subgroup comparisons, there was no statistical evidence that the results of haematological outcomes differed when the supplements were given once, twice or three times a week (Analysis 1.14; Analysis 2.6; Analysis 2.14; Analysis 2.23).

Sex (males; females; mixed or not reported)

All but one trial included males and females, although it was possible to extract the results by sex only from Hall 2002 (C). There was no statistical evidence that in this population the positive effect of intermittent supplementation on haematological outcomes differed by sex (Analysis 1.7; Analysis 1.15; Analysis 1.24; Analysis 2.7; Analysis 2.15; Analysis 2.24).

Supplement's nutrient composition (iron alone; iron + folic acid; iron+other nutrient; iron + multiple micronutrients)

Most of the trials provided only iron. In the majority of the subgroup analyses there was no evidence that the provision of other nutrients in addition to iron altered the effects of intermittent supplementation on haematological outcomes (Analysis 1.16; Analysis 1.25; Analysis 2.8; Analysis 2.16; Analysis 2.25). However, it seemed that the effect of intermittent supplementation on anaemia was higher among those children receiving iron + vitamin C (Analysis 1.8), although this result should be interpreted cautiously as only one trial assessed the joint effect of these micronutrients.

Comparisons 3 to 6. Analysis by age group: children younger than 60 months versus 60 months and older

We have summarised the results of comparisons 3 to 6 in Table 1 and Table 2.

Table 1. Intermittent iron supplementation versus placebo or no intervention by age group
Outcome

Comparison 3

Children 0 to 59 months

Relative effect
(95% CI)

Number of trials and effective sample size

Comparison 5

Children 60 months and older

Relative effect
(95% CI

Number of trials and effective sample size

Anaemia

RR 0.43

(0.23 to 0.80)

4 trials, 658 children

RR 0.54,

(0.33 to 0.90)

6 trials, 1166 children

Haemoglobin (g/L)

MD 6.45

(2.36 to 10.55)

9 trials, 1254 children

MD 4.04

(0.30 to 7.78)

10 trials, 1778 children

4.04 [0.30, 7.78]

Iron deficiency (using ferritin concentrations)

RR 0.24

(0.06 to 0.91)

3 trials, 431 children

None of the trials reported

on this outcome

Ferritin (μg/L)

MD 13.15

(-2.28 to 28.59)

4 trials, 310 children

MD 16.60

(11.12 to 22.08)

1 trial, 240 children

Adherence

RR 1.04

(0.98 to 1.09)

2 trials, 289 children 

None of the trials reported

on this outcome

Table 2. Intermittent versus daily iron supplementation by age group
Outcome

Comparison 4

Children 0 to 59 months

Relative effect
(95% CI)

Number of trials and effective sample size

Comparison 6

Children 60 months and older

Relative effect
(95% CI)

Number of trials and effective sample size

Anaemia

RR 1.26

(1.05 to 1.51)

3 trials, 770 children

RR 0.95

(0.47 to 1.91)

2 trials, 145 children

Haemoglobin (g/L)

MD -0.75

(-1.80 to 0.29)

14 trials, 2270 children

 

MD -0.31

(-2.59 to 1.97)

5 trials, 581 children

Iron deficiency

RR 4.00

(1.23 to 13.05)

1 trial, 76 children

None of the trials reported

on this outcome

Ferritin (μg/L)

MD -3.10

(-6.59 to 0.39)

8 trials, 582 children

MD -11.57

(-38.75 to 15.61)

2 trials, 320 children

Adherence

RR 1.29

(1.15 to 1.45)

3 trials, 1185 children

RR 1.29

(0.44 to 3.75)

2 trials, 245 children

The visual examination of the confidence intervals suggests that the haematological effects produced by intermittent supplementation are similar between young (0 to 59 months) and older children (60 months and older), although the statistical power may be an issue in assessing the consistency among results.

Discussion

Summary of main results

Available data indicate that among children less than 12 years of age, intermittent supplementation with iron (alone or in combination with other nutrients) effectively increases haemoglobin and ferritin concentrations and reduces the prevalence of anaemia compared to placebo or no intervention. Overall, this positive response does not differ between once, biweekly or three times weekly supplementation; nor does it depend on child's sex or age or the duration of the intervention.

In comparison to daily iron supplementation, children receiving intermittent iron supplementation are more likely to develop anaemia but their haemoglobin and ferritin concentrations are similar.

Adherence tends to be higher in children receiving intermittent iron supplementation compared with those receiving daily iron supplements, although the results were not statistically significant.

Information on morbidity, mortality, adverse side effects, neurocognitive and motor outcomes is scarce and therefore no clear conclusions can be drawn.

Overall completeness and applicability of evidence

A total of 33 randomised trials were included in this review, with data for 13,114 children included in the analysis. Seventy-five per cent of the included trials had a sample size of less than 500 children and the trials often lacked blinding and a clear description of randomisation methods. The trials were published in a wide variety of journals (and the level of quality of the journals might vary) and were mostly written in English. The diversity of publications may also reflect the range of settings in which studies were carried out: Latin America, Africa and Asia.

No studies were conducted in high-income countries and it is uncertain whether the results would be similar in those settings. On the one hand, the prevalences of anaemia and iron deficiency are lower in high income countries and there is an inverse relationship between initial iron status and response to iron supplementation. On the other hand, intermittent supplementation for children in high income countries could, however, be successful because of potentially strong institutional infrastructure and high attendance rates at schools that could support sustained high coverage and use of this intervention.

We decided to include only randomised and quasi-randomised trials in this review. Whilst randomisation reduces the risk of bias, this approach also limited the inclusion of large scale pre-post trials with no comparison groups. Such studies are more likely to be affected by external circumstances, such as famines, and it is possible that the magnitude of the effect of intermittent iron supplementation might be different under programmatic conditions.

The baseline anaemia and iron deficiency status varied across studies; most were conducted in settings with a high prevalence of anaemia. The studies included in this review largely examined this intervention for prevention as a public health strategy and not treatment of anaemia and iron deficiency as part of clinical practice. However, seven of the 33 trials included only anaemic children and subgroup analysis suggested that weekly supplementation was efficacious compared with daily supplementation. The efficacy of the intermittent supplementation schemes on haematological outcomes also seemed similar across different age groups, with few inconsistencies.

There were insufficient studies to allow us to evaluate in detail all the outcomes of interest, and by subgroups. Particularly, there were insufficient trials and a lack of comparable measures to examine mortality, morbidity, cognitive and developmental outcomes.

In addition, there was a lack of data to meaningfully examine adherence and adverse effects specifically related to intensity and frequency of dosing. These last two are critical limitations considering that these are primary justifications for the use of weekly over daily supplementation.

Quality of the evidence

1. Quality of the evidence across within studies. Less than one third of the trials were assessed as having a low risk of bias after considering the methods for allocating the treatment, the blinding and the attrition rates, with many studies being at high risk of bias (see Risk of bias in included studies). In most of the included trials, the methods used to randomly assign participants and conceal allocation were not described. Blinding of participants, care providers and outcome assessors was not generally attempted, although in some studies technical staff carrying out laboratory investigations were reported to be unaware of group allocation. The lack of blinding may represent a potentially serious source of bias. Attrition was also a problem in many of these studies.

2. Quality of the evidence across studies. We used the GRADE methodology for this assessment and set out the results for primary outcomes in the Summary of findings for the main comparison and the Summary of findings 2. We considered that indirectness or publication bias was unlikely but the quality of the trials and inconsistency (or the lack of studies) were potentially important factors in the overall assessment of the evidence. When intermittent supplementation was compared with a placebo or no intervention, the overall quality of the available evidence was found to be moderate for anaemia, whereas for haemoglobin and ferritin concentrations it was low and very low for iron deficiency. When compared with daily supplementation, the quality of the available evidence with regard to anaemia, haemoglobin and ferritin concentrations was found to be low and for iron deficiency it was very low.

Potential biases in the review process

There were a number of potential biases in the review process. We attempted to be as inclusive as possible in the search strategy and found publications in different languages in journals from all the continents, although the literature identified was predominantly written in English. We were also able to obtain unpublished information.

We attempted to minimise bias in several ways: two review authors independently assessed eligibility for inclusion and two review authors checked data extraction, assessments of risk of bias and data entry. However, carrying out reviews is not an exact science and may require a number of subjective judgements; it is possible that a different review team may have reached different decisions regarding assessments of eligibility and risk of bias. We would encourage readers to examine the Characteristics of included studies tables to assist in the interpretation of results.

In addition to the individual assessments of the study risk of bias, we included 'Summary of findings' tables to assess the overall quality of the evidence for primary outcomes. We attempted to produce the tables using a transparent process with two review authors independently assessing the evidence for each outcome for each quality domain and discussing any disagreements.

Agreements and disagreements with other studies or reviews

To our knowledge, only one meta-analysis of randomised controlled trials has been conducted on the efficacy of intermittent iron supplementation in the control of iron deficiency anaemia (Beaton 1999). It includes the results of 22 trials completed before 1999 in different age groups. In some cases authors were able to obtain the full data sets but in the rest of the cases summary statistics were collected from abstracts, final reports or directly supplied by investigators. Of the included studies, four were carried out among preschool-aged children (age range five months to five years), 10 among school-aged children and adolescents (age range three years to 21 years) and eight among pregnant women. All of the preschool and school children or adolescent trials compared once or twice a week versus daily supplementation, and most included control groups. All the studies reported results for haemoglobin; two studies in preschool children and three in schoolchildren or adolescents also measured ferritin. All the studies that Beaton 1999 included involving preschool and school-aged children were also included in this review. 

The authors found that intermittent supplementation was efficacious compared to no treatment and that it increased haemoglobin and ferritin levels and reduced anaemia. In contrast to the present review, they found that daily supplementation was more efficacious than intermittent supplementation in improving haemoglobin and ferritin levels. The authors concluded that weekly supplementation should be considered for preschool and school-aged children only in situations where there is strong assurance of supervision and high adherence.

The larger number of trials included in this Cochrane review, conducted in different settings and with different levels of supervision, suggest that intermittent supplementation is an efficacious public health intervention in children younger than 12 years of age that may be implemented in a various contexts. It may be a viable approach to consider, particularly where daily supplementation has failed, is operationally complex or unfeasible or in settings where it has not been implemented yet.

The results of the present review are only applicable to children 12 years and younger. However, other systematic review assessing the benefits and safety of this intervention in menstruating women (Fernández-Gaxiola 2011) concur with our findings. From the programme implementation perspective, a recent narrative review reports that weekly iron and folic acid supplementation has been successfully implemented in Cambodia, Egypt, India, Laos, Philippines and Vietnam, reaching over half a million menstruating women (WHO 2009).

Authors' conclusions

Implications for practice

The findings from this review show that intermittent supplementation with iron (alone or in combination with other nutrients) is efficacious in improving haemoglobin concentrations and ferritin levels and reducing anaemia among children younger than 12 years of age in settings with moderate to high prevalence of anaemia. The effects of intermittent supplementation on haemoglobin and ferritin outcomes were similar to those achieved with daily supplementation although children receiving intermittent supplements were at higher risk of anaemia.

Most of the evidence in this review is derived from trials providing weekly doses between 25 and 75 mg of elemental iron, either alone, with folic acid or with other micronutrients. The positive effect of intermittent supplementation was observed in populations of males and females, with different anaemia backgrounds, and seemed not to be affected by the duration of the intervention, although a minimum of three months seems reasonable to trigger the haematological response and build some iron stores. Very few trials reported on the level of supervision or the use of a communication or education strategy to improve the use of supplements. An integrated approach with a strong behaviour change communication component that targets different audiences may be necessary to adequately support adherence and appropriate use for any supplementation regimen. Intermittent supplementation for children might be an option for countries with strong institutional infrastructures for delivery that facilitate wide and sustained coverage, for example, where school attendance is high; although it is clear that efforts should be made to also reach those children not covered by the school or health systems.

This review attempted to examine several of the primary justifications for choosing intermittent over daily supplementation, including improved adherence, reduced side effects and improved efficiency in absorption. Surprisingly, very few trials reported on these outcomes and they did not show that the children receiving supplements intermittently adhere better to the intervention or have fewer side effects that those receiving daily supplements. Clearly, more research is needed in this area. Other rationales for intermittent supplementation include diminished exposure to an iron-rich environment, which may exacerbate oxidative stress in the gut lumen and intestinal mucosal cells, as well as decreased competition with other minerals such as zinc and copper for absorption channels. Unfortunately, few trials reported on other indicators of vitamin and mineral status and therefore no conclusions can be drawn.

In summary, intermittent supplementation is efficacious at improving haemoglobin and ferritin concentrations and reducing anaemia prevalence, although children receiving daily supplements were less likely to present anaemia compared to those receiving intermittent supplements. These results suggest that in settings where daily supplementation is likely to be unsuccessful or not feasible, intermittent supplementation could be an effective public health strategy to improve iron status and reduce anaemia in children under 12 years of age.

Implications for research

Important research is needed at different levels before we can fully assess the effects and safety of intermittent iron supplementation regimens on anaemia, iron status and development in children less than 12 years of age. Future research should focus on the following.

  • Clinical research

  1. Examining the efficacy of intermittent iron regimens on neurocognitive and developmental outcomes and growth. In addition, attempts should be made to use comparable measures across studies, when possible.

  2. Reporting the side effects in greater detail to acknowledge not only the presence of a side effect but also its intensity and frequency.

  3. Expanding the evidence on the provision of multiple micronutrients on an intermittent basis and their effect on iron status and other indicators of vitamin and mineral status, such as retinol or zinc.

  4. Reporting comprehensively the effects of the intermittent supplementation on anaemia, haemoglobin concentrations or ferritin to better understand the clinical significance of haemoglobin changes.

  • Programme implementation

  1. Establishing the periodicity of this intervention over a year, taking into account both its biological and programmatic feasibility.

  2. Improving reporting of adherence and addressing the relevance of direct and continued supervision.

  3. Exploring the factors which may influence adherence (such as behaviour change communication (BCC)) and the types of support needed to improve adherence in supplementation interventions. BCC and supporting adherence may be important components of an effective supplementation programme but trials rarely provide detailed information about them. This limits the ability to understand the intensity of these activities needed to achieve the effects found in the trials.

  4. Examining the cost effectiveness of intermittent compared with daily supplementation, taking into account more than just the differential cost of pills.

Acknowledgements

We would like to thank the trial authors and organisations who contributed additional information for this review and Ms Xiaoting Huo for her help in translating Yang 2004 (C) into English. Thanks are due to Deidre Thomas from the US CDC Public Health Library and Information Center and Margaret Anderson from the Cochrane Developmental, Psychosocial and Learning Problems Group (CDPLPG) for their help in devising the search strategy. We would also like to thank the staff at the editorial office of the CDPLPG for their support in the preparation of this review.

As part of the prepublication editorial process the text has been commented on by three peers (an editor and two referees who are external to the editorial team) and one of CDPLPG's statistical editors. We are grateful for their feedback.

Data and analyses

Download statistical data

Comparison 1. Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
2 Anaemia (by dose of elemental iron in the intermittent group)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
2.1 25 mg or less/week2157Risk Ratio (M-H, Random, 95% CI)0.15 [0.06, 0.37]
2.2 Greater than 25 mg to 75 mg/week61256Risk Ratio (M-H, Random, 95% CI)0.54 [0.37, 0.80]
2.3 Greater than 75 mg/week2411Risk Ratio (M-H, Random, 95% CI)0.71 [0.48, 1.04]
3 Anaemia (by duration of the intervention)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
3.1 0 to three months51456Risk Ratio (M-H, Random, 95% CI)0.63 [0.49, 0.82]
3.2 More than three months5368Risk Ratio (M-H, Random, 95% CI)0.37 [0.14, 1.02]
4 Anaemia (by type of compound)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
4.1 Ferrous sulphate91517Risk Ratio (M-H, Random, 95% CI)0.47 [0.30, 0.75]
4.2 Ferrous fumarate1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]
4.3 Other00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Anaemia (by anaemia status at baseline)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
5.1 Anaemic2424Risk Ratio (M-H, Random, 95% CI)0.30 [0.07, 1.38]
5.2 Non-anaemic164Risk Ratio (M-H, Random, 95% CI)0.78 [0.27, 2.31]
5.3 Mixed/unknown71336Risk Ratio (M-H, Random, 95% CI)0.59 [0.41, 0.85]
6 Anaemia (by intermittent regimen)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
6.1 One supplement a week91517Risk Ratio (M-H, Random, 95% CI)0.47 [0.30, 0.75]
6.2 Other intermittent regimen1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]
7 Anaemia (by sex)101824Risk Ratio (M-H, Random, 95% CI)0.55 [0.41, 0.73]
7.1 Girls1248Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]
7.2 Boys1253Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]
7.3 Mixed/unknown91323Risk Ratio (M-H, Random, 95% CI)0.46 [0.30, 0.70]
8 Anaemia (by nutrient)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]
8.1 Iron alone61074Risk Ratio (M-H, Random, 95% CI)0.48 [0.31, 0.74]
8.2 Iron + folic acid2593Risk Ratio (M-H, Random, 95% CI)0.83 [0.66, 1.03]
8.3 iron + vitamin C150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]
8.4 Iron + multiple micronutrients1107Risk Ratio (M-H, Random, 95% CI)0.16 [0.06, 0.44]
9 Haemoglobin (ALL)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]
10 Haemoglobin (by by dose of elemental iron in the intermittent group)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]
10.1 25 mg or less/week3324Mean Difference (IV, Random, 95% CI)8.19 [-4.01, 20.38]
10.2 Greater than 25 mg to 75 mg/week122059Mean Difference (IV, Random, 95% CI)5.45 [2.31, 8.58]
10.3 Greater than 75 mg/week4649Mean Difference (IV, Random, 95% CI)1.84 [0.25, 3.44]
11 Haemoglobin (by duration of the intervention)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]
11.1 0 to three months71616Mean Difference (IV, Random, 95% CI)5.16 [2.82, 7.51]
11.2 More than three months121416Mean Difference (IV, Random, 95% CI)5.13 [0.90, 9.36]
12 Haemoglobin (by type of compound)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]
12.1 Ferrous sulphate142288Mean Difference (IV, Random, 95% CI)5.57 [2.21, 8.92]
12.2 Ferrous fumarate2432Mean Difference (IV, Random, 95% CI)7.03 [3.36, 10.71]
12.3 Other3312Mean Difference (IV, Random, 95% CI)2.03 [-0.26, 4.33]
13 Haemoglobin (by anaemia status at baseline)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]
13.1 Anaemic2422Mean Difference (IV, Random, 95% CI)13.17 [3.07, 23.26]
13.2 Non-anaemic164Mean Difference (IV, Random, 95% CI)2.0 [-2.46, 6.46]
13.3 Mixed/unknown162546Mean Difference (IV, Random, 95% CI)4.35 [1.88, 6.82]
14 Haemoglobin (by intermittent regimen)193032Mean Difference (IV, Random, 95% CI)5.15 [2.52, 7.79]
14.1 One supplement a week152256Mean Difference (IV, Random, 95% CI)5.61 [2.13, 9.09]
14.2 Other intermittent regimen5776Mean Difference (IV, Random, 95% CI)3.67 [1.05, 6.28]
15 Haemoglobin (by sex)193032Mean Difference (IV, Random, 95% CI)5.17 [2.56, 7.77]
15.1 Girls1248Mean Difference (IV, Random, 95% CI)4.0 [0.83, 7.17]
15.2 Boys1253Mean Difference (IV, Random, 95% CI)3.70 [0.58, 6.82]
15.3 Mixed/unknown182531Mean Difference (IV, Random, 95% CI)5.31 [2.40, 8.22]
16 Haemoglobin (by nutrient)193032Mean Difference (IV, Random, 95% CI)4.83 [2.25, 7.41]
16.1 Iron alone111699Mean Difference (IV, Random, 95% CI)4.41 [1.32, 7.50]
16.2 Iron + folic acid4756Mean Difference (IV, Random, 95% CI)3.36 [1.51, 5.21]
16.3 iron + zinc177Mean Difference (IV, Random, 95% CI)-1.60 [-8.09, 4.89]
16.4 Iron + vitamin C150Mean Difference (IV, Random, 95% CI)20.70 [17.51, 23.89]
16.5 Iron + multiple micronutrients4450Mean Difference (IV, Random, 95% CI)5.47 [0.32, 10.61]
17 Iron deficiency (ALL)3431Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.91]
18 Ferritin (ALL)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
19 Ferritin (by dose of elemental iron in the intermittent group)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
19.1 25 mg or less/week1148Mean Difference (IV, Random, 95% CI)4.60 [-0.89, 10.09]
19.2 Greater than 25 mg to 75 mg/week4402Mean Difference (IV, Random, 95% CI)17.77 [8.21, 27.34]
19.3 Greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
20 Ferritin (by duration of the supplementation)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
20.1 0 to three months135Mean Difference (IV, Random, 95% CI)15.80 [-1.23, 32.83]
20.2 More than three months4515Mean Difference (IV, Random, 95% CI)13.82 [1.84, 25.81]
21 Ferritin (by type of compound)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
21.1 Ferrous sulphate4476Mean Difference (IV, Random, 95% CI)16.28 [4.68, 27.87]
21.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
21.3 Other174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]
22 Ferritin (by anaemia status at baseline)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
22.1 Anaemic00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
22.2 Non-anaemic174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]
22.3 Mixed/unknown4476Mean Difference (IV, Random, 95% CI)16.28 [4.68, 27.87]
23 Ferritin (by supplementation regimen)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
23.1 One supplement a week4497Mean Difference (IV, Random, 95% CI)10.14 [1.74, 18.53]
23.2 Other intermittent regimen153Mean Difference (IV, Random, 95% CI)27.80 [22.88, 32.72]
24 Ferritin (by sex)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
24.1 Girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.3 Mixed/unknown5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]
25 Ferritin (by nutrient)5550Mean Difference (IV, Random, 95% CI)11.41 [2.71, 20.11]
25.1 Iron alone4379Mean Difference (IV, Random, 95% CI)16.25 [5.41, 27.09]
25.2 Iron + folic acid00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
25.3 Iron + zinc153Mean Difference (IV, Random, 95% CI)5.50 [-3.91, 14.91]
25.4 Iron + multiple micronutrients2118Mean Difference (IV, Random, 95% CI)3.80 [-4.96, 12.56]
26 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]
27 Any side effects (ALL)153Risk Ratio (M-H, Fixed, 95% CI)3.87 [0.19, 76.92]
28 Nausea164Risk Ratio (M-H, Random, 95% CI)2.82 [0.12, 66.82]
29 Adherence (ALL)2289Risk Ratio (M-H, Random, 95% CI)1.04 [0.98, 1.09]
30 Mental development scale (ALL)1172Mean Difference (IV, Random, 95% CI)2.0 [-2.40, 6.40]
31 Orientation engagement (ALL)1172Mean Difference (IV, Random, 95% CI)8.40 [-1.79, 18.59]
32 Emotional regulation (ALL)1172Mean Difference (IV, Random, 95% CI)-2.5 [-11.58, 6.58]
33 Motor quality (ALL)1172Mean Difference (IV, Random, 95% CI)15.60 [7.66, 23.54]
34 Psychomotor development index (ALL)1172Mean Difference (IV, Random, 95% CI)6.90 [1.35, 12.45]
35 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]
36 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]
37 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]
38 WAZ3366Std. Mean Difference (IV, Random, 95% CI)-0.03 [-0.33, 0.27]
39 HAZ3366Mean Difference (IV, Random, 95% CI)0.03 [-0.04, 0.10]
Analysis 1.1.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 1 Anaemia (ALL).

Analysis 1.2.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 2 Anaemia (by dose of elemental iron in the intermittent group).

Analysis 1.3.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 3 Anaemia (by duration of the intervention).

Analysis 1.4.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 4 Anaemia (by type of compound).

Analysis 1.5.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 5 Anaemia (by anaemia status at baseline).

Analysis 1.6.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 6 Anaemia (by intermittent regimen).

Analysis 1.7.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 7 Anaemia (by sex).

Analysis 1.8.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 8 Anaemia (by nutrient).

Analysis 1.9.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 9 Haemoglobin (ALL).

Analysis 1.10.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 10 Haemoglobin (by by dose of elemental iron in the intermittent group).

Analysis 1.11.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 11 Haemoglobin (by duration of the intervention).

Analysis 1.12.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 12 Haemoglobin (by type of compound).

Analysis 1.13.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 13 Haemoglobin (by anaemia status at baseline).

Analysis 1.14.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 14 Haemoglobin (by intermittent regimen).

Analysis 1.15.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 15 Haemoglobin (by sex).

Analysis 1.16.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 16 Haemoglobin (by nutrient).

Analysis 1.17.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 17 Iron deficiency (ALL).

Analysis 1.18.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 18 Ferritin (ALL).

Analysis 1.19.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 19 Ferritin (by dose of elemental iron in the intermittent group).

Analysis 1.20.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 20 Ferritin (by duration of the supplementation).

Analysis 1.21.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 21 Ferritin (by type of compound).

Analysis 1.22.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 22 Ferritin (by anaemia status at baseline).

Analysis 1.23.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 23 Ferritin (by supplementation regimen).

Analysis 1.24.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 24 Ferritin (by sex).

Analysis 1.25.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 25 Ferritin (by nutrient).

Analysis 1.26.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 26 All cause morbidity (ALL).

Analysis 1.27.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 27 Any side effects (ALL).

Analysis 1.28.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 28 Nausea.

Analysis 1.29.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 29 Adherence (ALL).

Analysis 1.30.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 30 Mental development scale (ALL).

Analysis 1.31.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 31 Orientation engagement (ALL).

Analysis 1.32.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 32 Emotional regulation (ALL).

Analysis 1.33.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 33 Motor quality (ALL).

Analysis 1.34.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 34 Psychomotor development index (ALL).

Analysis 1.35.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 35 IQ (ALL).

Analysis 1.36.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 36 Thai language (ALL).

Analysis 1.37.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 37 Mathematics (ALL).

Analysis 1.38.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 38 WAZ.

Analysis 1.39.

Comparison 1 Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years, Outcome 39 HAZ.

Comparison 2. Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
2 Anaemia (by dose of elemental iron in the intermittent group)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
2.1 25 mg or less/week2404Risk Ratio (M-H, Random, 95% CI)1.20 [0.98, 1.47]
2.2 Greater than 25 mg to 75 mg/week4576Risk Ratio (M-H, Random, 95% CI)1.34 [0.96, 1.88]
2.3 Intermittent group: greater than 75 mg/week00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Anaemia (by duration of the supplementation)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
3.1 0 to three months2172Risk Ratio (M-H, Random, 95% CI)1.24 [0.55, 2.77]
3.2 More than three months4808Risk Ratio (M-H, Random, 95% CI)1.23 [1.03, 1.47]
4 Anaemia (by type of compound)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
4.1 Ferrous sulphate6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
4.2 Ferrous fumarate00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Other00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Anaemia (by anaemia status at baseline)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
5.1 Anaemic2183Risk Ratio (M-H, Random, 95% CI)0.96 [0.50, 1.82]
5.2 Non-anaemic00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Mixed/unknown4797Risk Ratio (M-H, Random, 95% CI)1.26 [1.05, 1.51]
6 Anaemia (by supplementation regimen)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
6.1 One supplement a week4549Risk Ratio (M-H, Random, 95% CI)1.18 [0.97, 1.43]
6.2 Other intermittent regimen2431Risk Ratio (M-H, Random, 95% CI)1.49 [1.02, 2.19]
7 Anaemia (by sex)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
7.1 Girls00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.2 Boys00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.3 Mixed/unknown6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
8 Anaemia (by nutrient)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]
8.1 Iron alone4507Risk Ratio (M-H, Random, 95% CI)1.17 [0.97, 1.42]
8.2 Iron + folic acid1366Risk Ratio (M-H, Random, 95% CI)1.55 [1.02, 2.36]
8.3 Iron + multiple micronutrients1107Risk Ratio (M-H, Random, 95% CI)1.31 [0.31, 5.57]
9 Haemoglobin (ALL)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]
10 Haemoglobin (by dose of elemental iron in the intermittent group)182751Mean Difference (IV, Random, 95% CI)-0.62 [-1.60, 0.37]
10.1 25 mg or less/week3536Mean Difference (IV, Random, 95% CI)-2.42 [-4.18, -0.66]
10.2 Greater than 25 mg to 75 mg/week132078Mean Difference (IV, Random, 95% CI)-0.58 [-1.62, 0.45]
10.3 Greater than 75 mg/week2137Mean Difference (IV, Random, 95% CI)1.00 [-4.68, 6.68]
11 Haemoglobin (by duration of the supplementation)192842Mean Difference (IV, Random, 95% CI)-0.38 [-1.26, 0.50]
11.1 0 to three months111455Mean Difference (IV, Random, 95% CI)0.47 [-0.91, 1.84]
11.2 More than three months81387Mean Difference (IV, Random, 95% CI)-1.14 [-2.07, -0.22]
12 Haemoglobin (by type of compound)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]
12.1 Ferrous sulphate172733Mean Difference (IV, Random, 95% CI)-0.60 [-1.60, 0.40]
12.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
12.3 Other2118Mean Difference (IV, Random, 95% CI)-0.46 [-4.24, 3.32]
13 Haemoglobin (by anaemia status at baseline)192851Mean Difference (IV, Random, 95% CI)-0.61 [-1.54, 0.32]
13.1 Anaemic7957Mean Difference (IV, Random, 95% CI)-0.76 [-2.59, 1.07]
13.2 Non-anaemic3166Mean Difference (IV, Random, 95% CI)0.79 [-1.42, 2.99]
13.3 Mixed/unknown101728Mean Difference (IV, Random, 95% CI)-0.76 [-2.00, 0.48]
14 Haemoglobin (by supplementation regimen)192851Mean Difference (IV, Random, 95% CI)-0.70 [-1.70, 0.30]
14.1 One supplement a week141612Mean Difference (IV, Random, 95% CI)-0.25 [-1.57, 1.07]
14.2 Other intermittent regimen81239Mean Difference (IV, Random, 95% CI)-1.42 [-3.02, 0.19]
15 Haemoglobin (by sex)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]
15.1 Girls142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]
15.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
15.3 Mixed/unknown182809Mean Difference (IV, Random, 95% CI)-0.53 [-1.51, 0.46]
16 Haemoglobin (by nutrient)192851Mean Difference (IV, Random, 95% CI)-0.59 [-1.52, 0.35]
16.1 Iron alone152144Mean Difference (IV, Random, 95% CI)-0.51 [-1.61, 0.59]
16.2 Iron + folic acid2408Mean Difference (IV, Random, 95% CI)-2.26 [-4.30, -0.22]
16.3 Iron + multiple micronutrients3299Mean Difference (IV, Random, 95% CI)0.61 [-2.04, 3.26]
17 Iron deficiency (ALL)176Risk Ratio (M-H, Random, 95% CI)4.0 [1.23, 13.05]
18 Ferritin (ALL)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
19 Ferritin (by dose of elemental iron in the intermittent group)9802Mean Difference (IV, Random, 95% CI)-4.34 [-10.20, 1.53]
19.1 by dose of elemental iron in the intermittent group: 25 mg or less/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
19.2 by dose of elemental iron in the intermittent group: greater than 25 mg to 75 mg/week9802Mean Difference (IV, Random, 95% CI)-4.34 [-10.20, 1.53]
19.3 by dose of elemental iron in the intermittent group: greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
20 Ferritin (by duration of the supplementation)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
20.1 by duration of the supplementation: 0 to three months6442Mean Difference (IV, Random, 95% CI)-1.06 [-6.62, 4.51]
20.2 by duration of the supplementation: more than three months4460Mean Difference (IV, Random, 95% CI)-9.58 [-23.08, 3.93]
21 Ferritin (by type of compound)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
21.1 by type of compound: ferrous sulphate9826Mean Difference (IV, Random, 95% CI)-3.85 [-9.28, 1.59]
21.2 by type of compound: ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
21.3 by type of compound: other176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]
22 Ferritin (by anaemia status at baseline)10902Mean Difference (IV, Random, 95% CI)-4.93 [-9.98, 0.12]
22.1 by anaemia status at baseline: anaemic5285Mean Difference (IV, Random, 95% CI)-2.94 [-12.23, 6.34]
22.2 by anaemia status at baseline: non-anaemic3167Mean Difference (IV, Random, 95% CI)-2.67 [-5.89, 0.54]
22.3 by anaemia status at baseline: mixed/unknown3450Mean Difference (IV, Random, 95% CI)-9.42 [-23.19, 4.35]
23 Ferritin (by supplementation regimen)10902Mean Difference (IV, Random, 95% CI)-4.48 [-9.68, 0.71]
23.1 by supplementation regimen: one supplement a week7595Mean Difference (IV, Random, 95% CI)-7.34 [-16.12, 1.44]
23.2 by supplementation regimen: other intermittent regimen5307Mean Difference (IV, Random, 95% CI)-0.93 [-3.94, 2.08]
24 Ferritin (by sex)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
24.1 by sex: girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.2 by sex: boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.3 by sex: mixed/unknown10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
25 Ferritin (by nutrient)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]
25.1 By nutrient: iron alone9826Mean Difference (IV, Random, 95% CI)-3.85 [-9.28, 1.59]
25.2 By nutrient: iron + folic acid00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
25.3 By nutrient: iron + multiple micronutrients176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]
26 Increase in steps climbed (ALL)165Mean Difference (IV, Random, 95% CI)-5.0 [-13.34, 3.34]
27 All cause morbidity (ALL)2599Risk Ratio (M-H, Random, 95% CI)0.96 [0.83, 1.12]
28 Diarrhoea (ALL)2122Risk Ratio (M-H, Random, 95% CI)1.17 [0.60, 2.28]
29 Any side effects (ALL)4895Risk Ratio (M-H, Random, 95% CI)0.60 [0.19, 1.87]
30 Adherence (ALL)51130Risk Ratio (M-H, Random, 95% CI)1.23 [0.98, 1.54]
31 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]
32 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]
33 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]
34 HAZ3279Std. Mean Difference (IV, Random, 95% CI)-0.26 [-0.80, 0.28]
Analysis 2.1.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 1 Anaemia (ALL).

Analysis 2.2.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 2 Anaemia (by dose of elemental iron in the intermittent group).

Analysis 2.3.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 3 Anaemia (by duration of the supplementation).

Analysis 2.4.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 4 Anaemia (by type of compound).

Analysis 2.5.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 5 Anaemia (by anaemia status at baseline).

Analysis 2.6.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 6 Anaemia (by supplementation regimen).

Analysis 2.7.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 7 Anaemia (by sex).

Analysis 2.8.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 8 Anaemia (by nutrient).

Analysis 2.9.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 9 Haemoglobin (ALL).

Analysis 2.10.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 10 Haemoglobin (by dose of elemental iron in the intermittent group).

Analysis 2.11.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 11 Haemoglobin (by duration of the supplementation).

Analysis 2.12.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 12 Haemoglobin (by type of compound).

Analysis 2.13.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 13 Haemoglobin (by anaemia status at baseline).

Analysis 2.14.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 14 Haemoglobin (by supplementation regimen).

Analysis 2.15.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 15 Haemoglobin (by sex).

Analysis 2.16.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 16 Haemoglobin (by nutrient).

Analysis 2.17.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 17 Iron deficiency (ALL).

Analysis 2.18.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 18 Ferritin (ALL).

Analysis 2.19.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 19 Ferritin (by dose of elemental iron in the intermittent group).

Analysis 2.20.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 20 Ferritin (by duration of the supplementation).

Analysis 2.21.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 21 Ferritin (by type of compound).

Analysis 2.22.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 22 Ferritin (by anaemia status at baseline).

Analysis 2.23.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 23 Ferritin (by supplementation regimen).

Analysis 2.24.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 24 Ferritin (by sex).

Analysis 2.25.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 25 Ferritin (by nutrient).

Analysis 2.26.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 26 Increase in steps climbed (ALL).

Analysis 2.27.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 27 All cause morbidity (ALL).

Analysis 2.28.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 28 Diarrhoea (ALL).

Analysis 2.29.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 29 Any side effects (ALL).

Analysis 2.30.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 30 Adherence (ALL).

Analysis 2.31.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 31 IQ (ALL).

Analysis 2.32.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 32 Thai language (ALL).

Analysis 2.33.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 33 Mathematics (ALL).

Analysis 2.34.

Comparison 2 Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years, Outcome 34 HAZ.

Comparison 3. Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
2 Anaemia (by dose of elemental iron in the intermittent group)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
2.1 25 mg or less/week2157Risk Ratio (M-H, Random, 95% CI)0.15 [0.06, 0.37]
2.2 Greater than 25 mg to 75 mg/week2501Risk Ratio (M-H, Random, 95% CI)0.61 [0.51, 0.74]
2.3 Greater than 75 mg/week00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Anaemia (by duration of the supplementation)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
3.1 0 to three months3608Risk Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]
3.2 More than three months150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]
4 Anaemia (by type of compound)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
4.1 Ferrous sulphate3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]
4.2 Ferrous fumarate1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]
4.3 Other00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Anaemia (by anaemia status at baseline)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
5.1 Anaemic1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]
5.2 Non-anaemic00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Mixed/unknown3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]
6 Anaemia (by intermittent regimen)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
6.1 One supplement a week3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]
6.2 Other intermittent regimen1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]
7 Anaemia (by sex)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
7.1 Girls00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.2 Boys00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7.3 Mixed/unknown4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
8 Anaemia (by nutrient)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]
8.1 Iron alone2501Risk Ratio (M-H, Random, 95% CI)0.61 [0.51, 0.74]
8.2 Iron + folic acid00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.3 iron + vitamin C150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]
8.4 Iron + multiple micronutrients1107Risk Ratio (M-H, Random, 95% CI)0.16 [0.06, 0.44]
9 Haemoglobin (ALL)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
10 Haemoglobin (by dose of elemental iron in the intermittent group)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
10.1 25 mg or less/week3324Mean Difference (IV, Random, 95% CI)8.19 [-4.01, 20.38]
10.2 Greater than 25 mg to 75 mg/week6930Mean Difference (IV, Random, 95% CI)5.50 [2.64, 8.36]
10.3 Greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
11 Haemoglobin (by duration of the supplementation)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
11.1 0 to three months4643Mean Difference (IV, Random, 95% CI)6.64 [3.01, 10.27]
11.2 More than three months5611Mean Difference (IV, Random, 95% CI)6.16 [-1.55, 13.87]
12 Haemoglobin (by type of iron compound)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
12.1 Ferrous sulphate7873Mean Difference (IV, Random, 95% CI)6.54 [1.44, 11.63]
12.2 Ferrous fumarate1307Mean Difference (IV, Random, 95% CI)8.0 [5.00, 11.00]
12.3 Other174Mean Difference (IV, Random, 95% CI)4.06 [-1.32, 9.44]
13 Haemoglobin (by anaemia status at baseline)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
13.1 Anaemic1307Mean Difference (IV, Random, 95% CI)8.0 [5.00, 11.00]
13.2 Non-anaemic00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
13.3 Mixed/unknown8947Mean Difference (IV, Random, 95% CI)6.25 [1.60, 10.90]
14 Haemoglobin (by supplementation regimen)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
14.1 One supplement a week6699Mean Difference (IV, Random, 95% CI)7.35 [0.92, 13.77]
14.2 Other intermittent regimen3555Mean Difference (IV, Random, 95% CI)4.68 [1.28, 8.08]
15 Haemoglobin (by sex)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
15.1 Girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
15.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
15.3 Mixed/unknown91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]
16 Haemoglobin (by nutrient)91254Mean Difference (IV, Random, 95% CI)6.01 [2.13, 9.89]
16.1 Iron alone5744Mean Difference (IV, Random, 95% CI)3.81 [1.61, 6.01]
16.2 Iron + folic acid00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
16.3 Iron + multiple micronutrients5510Mean Difference (IV, Random, 95% CI)8.46 [0.60, 16.32]
17 Iron deficiency (ALL)3431Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.91]
18 Ferritin (ALL)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
19 Ferritin (by dose of iron in the intermittent group)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
19.1 25 mg or less/week1148Mean Difference (IV, Random, 95% CI)4.60 [-0.89, 10.09]
19.2 Greater than 25 mg to 75 mg/week3162Mean Difference (IV, Random, 95% CI)16.91 [0.99, 32.82]
19.3 Greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
20 Ferritin (by duration of the supplementation)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
20.1 0 to three months135Mean Difference (IV, Random, 95% CI)15.80 [-1.23, 32.83]
20.2 More than three months3275Mean Difference (IV, Random, 95% CI)12.34 [-6.19, 30.87]
21 Ferritin (by type of iron compound)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
21.1 Ferrous sulphate3236Mean Difference (IV, Random, 95% CI)16.12 [-1.81, 34.05]
21.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
21.3 Other174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]
22 Ferritin (by anaemia status at baseline)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
22.1 by anaemia status at baseline: anaemic00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
22.2 by anaemia status at baseline: non-anaemic174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]
22.3 by anaemia status at baseline: mixed/unknown3236Mean Difference (IV, Random, 95% CI)16.12 [-1.81, 34.05]
23 Ferritin (by supplementation regimen)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
23.1 One supplement a week3257Mean Difference (IV, Random, 95% CI)5.37 [0.39, 10.36]
23.2 Other intermittent regimen153Mean Difference (IV, Random, 95% CI)27.80 [22.88, 32.72]
24 Ferritin (by sex)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
24.1 Girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
24.3 Mixed/unknown4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]
25 Ferritin (by nutrient)4310Mean Difference (IV, Random, 95% CI)11.15 [-1.92, 24.22]
25.1 Iron alone3144Mean Difference (IV, Random, 95% CI)15.70 [-2.68, 34.08]
25.2 Iron + folic acid00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
25.3 Iron + multiple micronutrients2166Mean Difference (IV, Random, 95% CI)4.58 [-2.27, 11.43]
26 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]
27 Any side effects (ALL)153Risk Ratio (M-H, Random, 95% CI)3.87 [0.19, 76.92]
28 Adherence (ALL)2289Risk Ratio (M-H, Random, 95% CI)1.04 [0.98, 1.09]
29 Mental development scale (ALL)1172Mean Difference (IV, Random, 95% CI)2.0 [-2.40, 6.40]
30 Orientation engagement (ALL)1172Mean Difference (IV, Random, 95% CI)8.40 [-1.79, 18.59]
31 Emotional regulation (ALL)1172Mean Difference (IV, Random, 95% CI)-2.5 [-11.58, 6.58]
32 Motor quality (ALL)1172Mean Difference (IV, Random, 95% CI)15.60 [7.66, 23.54]
33 Psychomotor development index (ALL)1172Mean Difference (IV, Random, 95% CI)6.90 [1.35, 12.45]
34 HAZ2302Mean Difference (IV, Random, 95% CI)0.04 [-0.03, 0.11]
Analysis 3.1.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 1 Anaemia (ALL).

Analysis 3.2.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 2 Anaemia (by dose of elemental iron in the intermittent group).

Analysis 3.3.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 3 Anaemia (by duration of the supplementation).

Analysis 3.4.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 4 Anaemia (by type of compound).

Analysis 3.5.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 5 Anaemia (by anaemia status at baseline).

Analysis 3.6.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 6 Anaemia (by intermittent regimen).

Analysis 3.7.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 7 Anaemia (by sex).

Analysis 3.8.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 8 Anaemia (by nutrient).

Analysis 3.9.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 9 Haemoglobin (ALL).

Analysis 3.10.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 10 Haemoglobin (by dose of elemental iron in the intermittent group).

Analysis 3.11.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 11 Haemoglobin (by duration of the supplementation).

Analysis 3.12.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 12 Haemoglobin (by type of iron compound).

Analysis 3.13.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 13 Haemoglobin (by anaemia status at baseline).

Analysis 3.14.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 14 Haemoglobin (by supplementation regimen).

Analysis 3.15.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 15 Haemoglobin (by sex).

Analysis 3.16.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 16 Haemoglobin (by nutrient).

Analysis 3.17.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 17 Iron deficiency (ALL).

Analysis 3.18.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 18 Ferritin (ALL).

Analysis 3.19.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 19 Ferritin (by dose of iron in the intermittent group).

Analysis 3.20.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 20 Ferritin (by duration of the supplementation).

Analysis 3.21.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 21 Ferritin (by type of iron compound).

Analysis 3.22.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 22 Ferritin (by anaemia status at baseline).

Analysis 3.23.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 23 Ferritin (by supplementation regimen).

Analysis 3.24.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 24 Ferritin (by sex).

Analysis 3.25.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 25 Ferritin (by nutrient).

Analysis 3.26.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 26 All cause morbidity (ALL).

Analysis 3.27.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 27 Any side effects (ALL).

Analysis 3.28.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 28 Adherence (ALL).

Analysis 3.29.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 29 Mental development scale (ALL).

Analysis 3.30.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 30 Orientation engagement (ALL).

Analysis 3.31.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 31 Emotional regulation (ALL).

Analysis 3.32.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 32 Motor quality (ALL).

Analysis 3.33.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 33 Psychomotor development index (ALL).

Analysis 3.34.

Comparison 3 Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months, Outcome 34 HAZ.

Comparison 4. Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)3770Risk Ratio (M-H, Random, 95% CI)1.26 [1.05, 1.51]
2 Haemoglobin (ALL)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
3 Haemoglobin (by dose of elemental iron in the intermittent group)142438Mean Difference (IV, Random, 95% CI)-0.82 [-1.82, 0.18]
3.1 25 mg or less/week3536Mean Difference (IV, Random, 95% CI)-2.42 [-4.18, -0.66]
3.2 Greater than 25 mg to 75 mg/week111902Mean Difference (IV, Random, 95% CI)-0.45 [-1.59, 0.68]
3.3 Greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4 Haemoglobin (by duration of supplementation)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
4.1 0 to three months91309Mean Difference (IV, Random, 95% CI)-0.15 [-1.66, 1.36]
4.2 More than three months5961Mean Difference (IV, Random, 95% CI)-1.53 [-2.95, -0.11]
5 Haemoglobin (by type of compound)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
5.1 Ferrous sulphate132194Mean Difference (IV, Random, 95% CI)-0.85 [-1.91, 0.21]
5.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Other176Mean Difference (IV, Random, 95% CI)1.96 [-3.05, 6.97]
6 Haemoglobin (by anaemia status at baseline)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
6.1 Anaemic5834Mean Difference (IV, Random, 95% CI)-0.57 [-2.81, 1.68]
6.2 Non-anaemic2113Mean Difference (IV, Random, 95% CI)1.99 [-0.72, 4.70]
6.3 Mixed/unknown71323Mean Difference (IV, Random, 95% CI)-1.20 [-2.22, -0.19]
7 Haemoglobin (by supplementation regimen)142270Mean Difference (IV, Random, 95% CI)-0.72 [-1.71, 0.27]
7.1 One supplement a week91054Mean Difference (IV, Random, 95% CI)-0.23 [-1.67, 1.21]
7.2 Other intermittent regimen71216Mean Difference (IV, Random, 95% CI)-1.14 [-2.57, 0.29]
8 Haemoglobin (by sex)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
8.1 Girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
8.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
8.3 Mixed/unknown142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
9 Haemoglobin (by nutrient)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]
9.1 Iron alone101490Mean Difference (IV, Random, 95% CI)-0.80 [-2.05, 0.46]
9.2 Iron + folic acid1366Mean Difference (IV, Random, 95% CI)-2.40 [-4.94, 0.14]
9.3 Iron + multiple micronutrients3414Mean Difference (IV, Random, 95% CI)0.57 [-1.84, 2.98]
10 Iron deficiency (ALL)176Risk Ratio (M-H, Random, 95% CI)4.0 [1.23, 13.05]
11 Ferritin (ALL)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]
12 Ferritin (by dose of elemental iron in the intermittent subgroup)8582Mean Difference (IV, Random, 95% CI)-2.22 [-6.03, 1.59]
12.1 25 mg or less/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
12.2 Greater than 25 mg to 75 mg/week8582Mean Difference (IV, Random, 95% CI)-2.22 [-6.03, 1.59]
12.3 Greater than 75 mg/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
13 Ferritin (by duration of supplementation)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]
13.1 0 to three months5382Mean Difference (IV, Random, 95% CI)-3.02 [-7.91, 1.87]
13.2 More than three months3200Mean Difference (IV, Random, 95% CI)-1.63 [-5.88, 2.62]
14 Ferritin (by type of compound)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]
14.1 Ferrous sulphate7506Mean Difference (IV, Random, 95% CI)-2.69 [-6.42, 1.05]
14.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
14.3 Other176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]
15 Ferritin (by anaemia status at baseline)8582Mean Difference (IV, Random, 95% CI)-3.70 [-8.25, 0.86]
15.1 Anaemic4225Mean Difference (IV, Random, 95% CI)-4.47 [-15.45, 6.52]
15.2 Non-anaemic3167Mean Difference (IV, Random, 95% CI)-2.67 [-5.89, 0.54]
15.3 Mixed/unknown2190Mean Difference (IV, Random, 95% CI)-1.53 [-5.23, 2.17]
16 Ferritin (by supplementation regimen)8582Mean Difference (IV, Random, 95% CI)-3.27 [-7.87, 1.33]
16.1 One supplement a week5291Mean Difference (IV, Random, 95% CI)-6.21 [-12.98, 0.55]
16.2 Other intermittent regimen4291Mean Difference (IV, Random, 95% CI)-0.81 [-3.89, 2.27]
17 Ferritin (by sex)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.58, 0.39]
17.1 Girls00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
17.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
17.3 Mixed/unknown8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.58, 0.39]
18 Ferritin (by nutrient)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]
18.1 Iron alone7506Mean Difference (IV, Random, 95% CI)-2.69 [-6.42, 1.05]
18.2 Iron + folic acid00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
18.3 Iron + multiple micronutrients176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]
19 All cause morbidity (ALL)1522Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.16]
20 Diarrhoea (ALL)145Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 67.03]
21 Any side effects (ALL)4895Risk Ratio (M-H, Random, 95% CI)0.60 [0.19, 1.87]
22 Adherence (ALL)31185Risk Ratio (M-H, Random, 95% CI)1.29 [1.15, 1.45]
23 HAZ1109Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.52, 0.23]
24 WAZ1109Std. Mean Difference (IV, Random, 95% CI)-0.44 [-0.82, -0.06]
Analysis 4.1.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 1 Anaemia (ALL).

Analysis 4.2.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 2 Haemoglobin (ALL).

Analysis 4.3.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 3 Haemoglobin (by dose of elemental iron in the intermittent group).

Analysis 4.4.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 4 Haemoglobin (by duration of supplementation).

Analysis 4.5.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 5 Haemoglobin (by type of compound).

Analysis 4.6.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 6 Haemoglobin (by anaemia status at baseline).

Analysis 4.7.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 7 Haemoglobin (by supplementation regimen).

Analysis 4.8.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 8 Haemoglobin (by sex).

Analysis 4.9.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 9 Haemoglobin (by nutrient).

Analysis 4.10.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 10 Iron deficiency (ALL).

Analysis 4.11.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 11 Ferritin (ALL).

Analysis 4.12.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 12 Ferritin (by dose of elemental iron in the intermittent subgroup).

Analysis 4.13.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 13 Ferritin (by duration of supplementation).

Analysis 4.14.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 14 Ferritin (by type of compound).

Analysis 4.15.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 15 Ferritin (by anaemia status at baseline).

Analysis 4.16.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 16 Ferritin (by supplementation regimen).

Analysis 4.17.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 17 Ferritin (by sex).

Analysis 4.18.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 18 Ferritin (by nutrient).

Analysis 4.19.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 19 All cause morbidity (ALL).

Analysis 4.20.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 20 Diarrhoea (ALL).

Analysis 4.21.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 21 Any side effects (ALL).

Analysis 4.22.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 22 Adherence (ALL).

Analysis 4.23.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 23 HAZ.

Analysis 4.24.

Comparison 4 Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months, Outcome 24 WAZ.

Comparison 5. Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
2 Anaemia (by dose)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
2.1 25 mg or less/week00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Greater than 25 mg to 75 mg/week4755Risk Ratio (M-H, Random, 95% CI)0.47 [0.21, 1.02]
2.3 Greater than 75 mg/week2411Risk Ratio (M-H, Random, 95% CI)0.71 [0.48, 1.04]
3 Anaemia (by duration)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
3.1 0 to three months2848Risk Ratio (M-H, Random, 95% CI)0.77 [0.67, 0.89]
3.2 More than three months4318Risk Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.24]
4 Anaemia (by type of compound)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
4.1 Ferrous sulphate61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
4.2 Ferrous fumarate00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Other00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Anaemia (by anaemia status at baseline)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
5.1 Anaemic1117Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.27]
5.2 Non-anaemic164Risk Ratio (M-H, Random, 95% CI)0.78 [0.27, 2.31]
5.3 Mixed/unknown4985Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.98]
6 Anaemia (by intermittent regimen)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
6.1 One supplement a week61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
6.2 Other intermittent regimen00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Anaemia (by sex)61166Risk Ratio (M-H, Random, 95% CI)0.59 [0.40, 0.86]
7.1 Girls1248Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]
7.2 Boys1253Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]
7.3 Mixed/unknown5665Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.01]
8 Anaemia (by nutrient)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]
8.1 Iron alone4573Risk Ratio (M-H, Random, 95% CI)0.39 [0.17, 0.90]
8.2 Iron + folic acid2593Risk Ratio (M-H, Random, 95% CI)0.83 [0.66, 1.03]
8.3 Iron + multiple micronutrients00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
9 Haemoglobin (ALL)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
10 Haemoglobin (by dose of elemental iron in the intermittent group)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
10.1 25 mg or less/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
10.2 Greater than 25 mg to 75 mg/week61129Mean Difference (IV, Random, 95% CI)5.24 [-0.78, 11.26]
10.3 Group: greater than 75 mg/week4649Mean Difference (IV, Random, 95% CI)1.84 [0.25, 3.44]
11 Haemoglobin (by duration of the supplementation)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
11.1 0 to three months3973Mean Difference (IV, Random, 95% CI)3.13 [1.49, 4.77]
11.2 More than three months7805Mean Difference (IV, Random, 95% CI)4.38 [-1.20, 9.96]
12 Haemoglobin (by type of iron compound)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
12.1 Ferrous sulphate71415Mean Difference (IV, Random, 95% CI)4.59 [-0.30, 9.47]
12.2 Ferrous fumarate1125Mean Difference (IV, Random, 95% CI)3.4 [-4.09, 10.89]
12.3 Other2238Mean Difference (IV, Random, 95% CI)1.79 [-1.25, 4.84]
13 Haemoglobin (by anaemia status at baseline)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
13.1 Anaemic1115Mean Difference (IV, Random, 95% CI)18.30 [15.55, 21.05]
13.2 Non-anaemic164Mean Difference (IV, Random, 95% CI)2.0 [-2.46, 6.46]
13.3 Mixed/unknown81599Mean Difference (IV, Random, 95% CI)2.37 [1.17, 3.57]
14 Haemoglobin (by supplementation regimen)101868Mean Difference (IV, Random, 95% CI)4.04 [0.45, 7.62]
14.1 One supplement a week91647Mean Difference (IV, Random, 95% CI)4.43 [0.21, 8.65]
14.2 Other intermittent regimen2221Mean Difference (IV, Random, 95% CI)1.17 [-1.27, 3.61]
15 Haemoglobin (by sex)101778Mean Difference (IV, Random, 95% CI)4.03 [0.51, 7.55]
15.1 Girls1248Mean Difference (IV, Random, 95% CI)4.0 [0.83, 7.17]
15.2 Boys1253Mean Difference (IV, Random, 95% CI)3.70 [0.58, 6.82]
15.3 Mixed/unknown91277Mean Difference (IV, Random, 95% CI)4.05 [-0.37, 8.46]
16 Haemoglobin (by nutrient)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]
16.1 Iron alone61022Mean Difference (IV, Random, 95% CI)4.98 [-0.71, 10.68]
16.2 Iron + folic acid4756Mean Difference (IV, Random, 95% CI)2.91 [0.65, 5.16]
16.3 Iron + multiple micronutrients00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
17 Ferritin (ALL)1240Mean Difference (IV, Random, 95% CI)16.6 [11.12, 22.08]
18 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]
19 Any side effects (ALL)153Risk Ratio (M-H, Random, 95% CI)3.87 [0.19, 76.92]
20 Nausea164Risk Ratio (M-H, Random, 95% CI)2.82 [0.12, 66.82]
21 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]
22 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]
23 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]
24 Increase in steps climbed (ALL)160Mean Difference (IV, Random, 95% CI)8.0 [-0.72, 16.72]
25 WAZ164Std. Mean Difference (IV, Random, 95% CI)-0.24 [-0.74, 0.25]
26 HAZ164Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.69, 0.21]
Analysis 5.1.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 1 Anaemia (ALL).

Analysis 5.2.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 2 Anaemia (by dose).

Analysis 5.3.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 3 Anaemia (by duration).

Analysis 5.4.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 4 Anaemia (by type of compound).

Analysis 5.5.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 5 Anaemia (by anaemia status at baseline).

Analysis 5.6.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 6 Anaemia (by intermittent regimen).

Analysis 5.7.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 7 Anaemia (by sex).

Analysis 5.8.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 8 Anaemia (by nutrient).

Analysis 5.9.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 9 Haemoglobin (ALL).

Analysis 5.10.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 10 Haemoglobin (by dose of elemental iron in the intermittent group).

Analysis 5.11.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 11 Haemoglobin (by duration of the supplementation).

Analysis 5.12.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 12 Haemoglobin (by type of iron compound).

Analysis 5.13.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 13 Haemoglobin (by anaemia status at baseline).

Analysis 5.14.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 14 Haemoglobin (by supplementation regimen).

Analysis 5.15.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 15 Haemoglobin (by sex).

Analysis 5.16.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 16 Haemoglobin (by nutrient).

Analysis 5.17.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 17 Ferritin (ALL).

Analysis 5.18.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 18 All cause morbidity (ALL).

Analysis 5.19.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 19 Any side effects (ALL).

Analysis 5.20.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 20 Nausea.

Analysis 5.21.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 21 IQ (ALL).

Analysis 5.22.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 22 Thai language (ALL).

Analysis 5.23.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 23 Mathematics (ALL).

Analysis 5.24.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 24 Increase in steps climbed (ALL).

Analysis 5.25.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 25 WAZ.

Analysis 5.26.

Comparison 5 Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years, Outcome 26 HAZ.

Comparison 6. Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Anaemia (ALL)2145Risk Ratio (M-H, Random, 95% CI)0.95 [0.47, 1.91]
2 Haemoglobin (ALL)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
3 Haemoglobin (by dose of elemental iron)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
3.1 25 mg or less/week00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Greater than 25 mg to 75 mg/week3444Mean Difference (IV, Random, 95% CI)-1.10 [-3.01, 0.80]
3.3 Intermittent group: greater than 75 mg/week2137Mean Difference (IV, Random, 95% CI)1.00 [-4.68, 6.68]
4 Haemoglobin (by duration of the supplementation)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
4.1 0 to three months2155Mean Difference (IV, Random, 95% CI)0.32 [-6.54, 7.18]
4.2 More than three months3426Mean Difference (IV, Random, 95% CI)-0.64 [-2.12, 0.84]
5 Haemoglobin (by type of compound)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
5.1 Ferrous sulphate4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]
5.2 Ferrous fumarate00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Other142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]
6 Haemoglobin (by baseline prevalence of anaemia)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
6.1 Anaemic3271Mean Difference (IV, Random, 95% CI)0.37 [-3.44, 4.17]
6.2 Non-anaemic00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
6.3 Mixed/unknown2310Mean Difference (IV, Random, 95% CI)-1.22 [-3.08, 0.63]
7 Haemoglobin (by supplementation regimen)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
7.1 by supplementation regimen: one supplement a week5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
7.2 by supplementation regimen: other intermittent regimen00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
8 Haemoglobin (by sex)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
8.1 Girls142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]
8.2 Boys00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
8.3 Mixed/unknown4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]
9 Haemoglobin (by nutrient)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]
9.1 Iron alone4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]
9.2 Iron + folic acid142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]
9.3 By nutrient: iron + multiple micronutrients00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
10 Ferritin (ALL)2320Mean Difference (IV, Random, 95% CI)-11.57 [-38.75, 15.61]
11 All cause morbidity (ALL)177Risk Ratio (M-H, Random, 95% CI)0.92 [0.68, 1.24]
12 Diarrhoea (ALL)177Risk Ratio (M-H, Random, 95% CI)1.12 [0.56, 2.22]
13 Adherence (ALL)2245Risk Ratio (M-H, Random, 95% CI)1.29 [0.44, 3.75]
14 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]
15 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]
16 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]
17 Increase in steps climbed (ALL)165Mean Difference (IV, Random, 95% CI)-5.0 [-13.34, 3.34]
18 HAZ2170Std. Mean Difference (IV, Random, 95% CI)-0.32 [-1.26, 0.63]
19 WAZ2170Std. Mean Difference (IV, Random, 95% CI)0.09 [-0.21, 0.39]
20 WAZ2302Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.34, 0.41]
Analysis 6.1.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 1 Anaemia (ALL).

Analysis 6.2.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 2 Haemoglobin (ALL).

Analysis 6.3.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 3 Haemoglobin (by dose of elemental iron).

Analysis 6.4.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 4 Haemoglobin (by duration of the supplementation).

Analysis 6.5.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 5 Haemoglobin (by type of compound).

Analysis 6.6.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 6 Haemoglobin (by baseline prevalence of anaemia).

Analysis 6.7.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 7 Haemoglobin (by supplementation regimen).

Analysis 6.8.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 8 Haemoglobin (by sex).

Analysis 6.9.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 9 Haemoglobin (by nutrient).

Analysis 6.10.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 10 Ferritin (ALL).

Analysis 6.11.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 11 All cause morbidity (ALL).

Analysis 6.12.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 12 Diarrhoea (ALL).

Analysis 6.13.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 13 Adherence (ALL).

Analysis 6.14.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 14 IQ (ALL).

Analysis 6.15.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 15 Thai language (ALL).

Analysis 6.16.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 16 Mathematics (ALL).

Analysis 6.17.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 17 Increase in steps climbed (ALL).

Analysis 6.18.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 18 HAZ.

Analysis 6.19.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 19 WAZ.

Analysis 6.20.

Comparison 6 Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years, Outcome 20 WAZ.

Appendices

Appendix 1. Search strategies

CENTRAL

#1MeSH descriptor Iron, this term only
#2MeSH descriptor Iron, Dietary, this term only
#3MeSH descriptor Anemia, Iron-Deficiency, this term only
#4MeSH descriptor Folic Acid, this term only
#5MeSH descriptor Dietary Supplements, this term only
#6MeSH descriptor Trace Elements, this term only
#7iron*
#8folic* or folate* or folvite* or folacin* or pteroylglutamic*
#9diet* NEAR/3 supplement*
#10micro-nutrient* or micronutrient* or multi-nutrient* or multinutrient*
#11MeSH descriptor Ferric Compounds, this term only
#12MeSH descriptor Ferrous Compounds, this term only
#13ferrous* or ferric* or fe
#14MeSH descriptor Micronutrients, this term only
#15(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14)
#16MeSH descriptor Drug Administration Schedule, this term only
#17MeSH descriptor Dose-Response Relationship, Drug explode all trees
#18MeSH descriptor Time Factors, this term only
#19week* or biweek* or bi NEXT week* or intermittent* or alternat*
#20(#16 OR #17 OR #18 OR #19)
#21(#15 AND #20)
#22(iron NEAR/3 (dose* or dosage or administer* or administration or frequency))
#23(#21 OR #22)
#24 (baby or babies or newborn* or neonat* or toddler* or child* or preschool* or schoolchild* or boy* or girl* or pre-school* or teen* or adolescen* or preteen* or youth* or young person* or young people)
#25(#23 AND #24)

MEDLINE

1 Iron/ or Anemia, Iron-Deficiency/ or Iron, Dietary/
2 Folic Acid/
3 micronutrients/
4 Dietary Supplements/
5 iron$.tw.
6 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
7 Trace Elements/
8 (diet$ adj3 supplement$).tw.
9 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
10 Ferric Compounds/
11 Ferrous Compounds/
12 (ferrous$ or ferric$ or fe).tw.
13 or/1-12
14 Drug Administration Schedule/
15 Dose-Response Relationship, Drug/
16 Time Factors/
17 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
18 or/14-17
19 13 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
21 19 or 20
22 exp Infant/
23 exp Child/
24 Adolescent/
25 (baby or babies or newborn$ or neonat$ or toddler$ or child$ or preschool$ or schoolchild$ or boy$ or girl$ or pre-school$ or teen$ or adolescen$ or preteen$ or youth$ or young person$ or young people).tw.
26 or/22-25
27 randomized controlled trial.pt.
28 controlled clinical trial.pt.
29 randomi#ed.ab.
30 placebo$.ab.
31 drug therapy.fs.
32 randomly.ab.
33 trial.ab.
34 groups.ab.
35 or/27-34
36 exp animals/ not humans.sh.
37 35 not 36
38 21 and 26 and 37

EMBASE

1 iron/
2 iron intake/
3 iron deficiency anemia/
4 folic acid/
5 exp trace element/
6 diet supplementation/
7 iron$.tw.
8 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
9 (diet$ adj3 supplement$).tw.
10 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
11 ferric ion/
12 ferrous ion/
13 or/1-12
14 drug administration/
15 drug dose regimen/
16 time/
17 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
18 or/14-17
19 13 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
21 19 or 20
22 exp infant/
23 exp child/
24 adolescent/
25 (baby or babies or newborn$ or neonat$ or toddler$ or child$ or preschool$ or schoolchild$ or boy$ or girl$ or pre-school$ or teen$ or adolescen$ or preteen$ or youth$ or young person$ or young people).tw.
26 or/22-25
27 21 and 26
28 exp Clinical trial/
29 Randomization/
30 Single blind procedure/
31 Double blind procedure/
32 Crossover procedure/
33 Placebo/
34 Randomi#ed.tw.
35 RCT.tw.
36 (random$ adj3 (allocat$ or assign$)).tw.
37 randomly.ab.
38 groups.ab.
39 trial.ab.
40 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
41 Placebo$.tw.
42 prospective study/
43 (crossover or cross-over).tw.
44 prospective.tw.
45 or/28-44
46 27 and 45

CINAHL

S43 S24 and S42
S42 S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or
S35 or S36 or S37 or S38 or S39 or S40 or S41
S41 (MH "Evaluation Research") OR (MH "Summative Evaluation Research") OR
(MH "Program Evaluation")
S40 (MH "Treatment Outcomes")
S39 (MH "Comparative Studies")
S38 TI (evaluat* study or evaluat* research) or AB (evaluat* study or
evaluat* research) or TI (effectiv* study or effectiv* research) or AB
(effectiv* study or effectiv* research) OR TI (prospectiv* study or
prospectiv* research) or AB(prospectiv* study or prospectiv* research) or
TI (follow-up study or follow-up research) or AB (follow-up study or follow-up research)
S37 placebo*
S36 crossover* or "cross over*"
S35 (MH "Crossover Design")
S34 (tripl* N3 mask*) or (tripl* N3 blind*)
S33 (trebl* N3 mask*) or (trebl* N3 blind*)
S32 (doubl* N3 mask*) or (doubl* N3 blind*)
S31 (singl* N3 mask*) or (singl* N3 blind*)
S30 (clinic* N3 trial*) or (control* N3 trial*)
S29 (random* N3 allocat*) or (random* N3 assign*)
S28 randomis* or randomiz*
S27 (MH "Meta Analysis")
S26 (MH "Clinical Trials+")
S25 MH random assignment
S24 S19 and S23
S23 S20 or S21 or S22
S22 baby or babies or newborn* or neonat* or toddler* or child or preschool* or schoolchild* or boy* or girl* or pre-school* or teen* or adolescen* or preteen* or youth* or young person* or young people
S21 AG adolescent
S20 AG infant or child
S19 S17 or S18
S18 (iron N3 dose*) or (iron N3 dosage) or (iron N3 administer*) or (iron N3 administration) or (iron N3 frequency)
S17 S11 and S16
S16 S12 or S13 or S14 or S15
S15 (week* or biweek* or bi-week*or bi week* or intermittent* or alternat*)
S14 (MH "Time Factors")
S13 (MH "Dose-Response Relationship, Drug")
S12 (MH "Drug Administration Schedule")
S11 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10
S10 micro-nutrient* or micronutrient* or micro nutrient* multi-nutrient* or multinutrient* or multi nutrient*
S9 ferrous* or ferric* or "fe"
S8 diet* N3 supplement*
S7 folic* or folate* or folvite* or folacin* or pteroylglutamic*
S6 iron*
S5 (MH "Micronutrients")
S4 (MH "Trace Elements")
S3 (MH "Dietary Supplements")
S2 (MH "Folic Acid")
S1 (MH "Iron") OR (MH "Anemia, Iron Deficiency") OR (MH "Iron Compounds") OR (MH "Ferric Compounds") OR (MH "Ferrous Compounds")

POPLINE

(iron* /folic* / folate* /supplement*/micronutrient*/micro-nutrient*) & (week* /bi-week* / bi week* / biweek* / intermittent / alternat*)

ICTRP

Intervention: iron or folic or folate or micronutrient*
limited to Clinical trials in children

IMBIOMED

Intervention: suplementacion hierro

LILACS

Intervention: suplementacion hierro

IBECS

Intervention: suplementacion hierro

Scielo

Intervention: suplementacion hierro

Contributions of authors

All four review authors contributed to drafting the text of the review, commented on the drafts and approved the final version.

Declarations of interest

Luz Maria De-Regil - none known.
Maria Elena D Jefferds - none known.
Allison C Sylvetsky - none known.
Therese Dowswell - none known.

Disclaimer: Luz Maria De-Regil is a full-time staff member of the World Health Organization (WHO), Allison C Sylvetsky did a 6-week internship at WHO (summer 2010), and Therese Dowswell has received financial support from the WHO for her work on this review. Maria Elena Jefferds is a full-time staff member of the US Centers for Disease Control and Prevention. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the official position, decisions, policy or views of these Organisations.

Sources of support

Internal sources

  • Centers for Disease Control and Prevention (CDC), Division of Nutrition, Physical Activity, and Obesity, USA.

  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

External sources

  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

    Dr Therese Dowswell received partial financial support for her work on this review.

  • Government of Luxembourg, Luxembourg.

    WHO acknowledges the Government of Luxembourg for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrient interventions

Differences between protocol and review

We added a description of the methodology followed to produce the 'Summary of findings' tables in the 'Assessment of risk of bias in included studies' section.

We made the following changes to the outcomes section:

  • we modified the order of the primary outcomes so that the effects of the same indicator, presented either as a continuous or as a dichotomous variable, could be assessed together (for example, anaemia and haemoglobin concentrations);

  • since there are no official cut-offs for children younger than 6 months, we changed the definition of anaemia from "haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 months or 5 to 11 years old, respectively, adjusted by altitude where appropriate" to "haemoglobin below a cut-off defined by trialists, taking into account the age group and altitude";

  • for our secondary outcome 'all-cause morbidity', we replaced 'at least one event' with 'at least one reported illness' to make it clearer;

  • we renamed our secondary outcome 'folic acid status' as 'folate status' and replaced the units with 'as measured by trialists'. Folate may be measured in serum, plasma or red blood cells and the most frequently used units may vary.

  • as the duration of the trials was mostly short, we changed the definition of our secondary outcome 'growth impairment (stunting and wasting)' to 'height-for-age and weight-for-age Z-scores' and moved this to the end of our list of outcomes.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aguayo 2000

MethodsRandomised double-blind placebo-controlled trial. 2-arm design with individual randomisation.
Participants73 children (64 children followed up), both sexes (30 females (47%)), aged 6–11.9 years (9 years in average), from outskirts of La Paz, Bolivia (4000 m above sea level). Inclusion criterion: non-anaemic. Socioeconomic status not reported.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 37): children received weekly tablets containing iron. The iron dose was calculated to provide children with 3 mg of elemental iron per kg of body weight (approximately 85 mg of iron per week). The supplement consisted of two types of tablets containing either 20 mg or 36 mg of elemental iron (as ferrous sulphate). These tablets were used in combination to adjust the dose to the child’s weight;

Group 2 (n = 36): children received a placebo similar in colour and appearance to the iron supplement.

Length of the intervention: 18 weeks

OutcomesHaemoglobin, mean haemoglobin change, anaemia, anthropometric measurements (weight for age Z-score, height for age Z-score and mid-upper arm circumference), and side effects.
Notes

A teacher trained by the principal investigator was responsible for delivering the iron tablets in the classrooms. All children completed at least 17 doses. Pills were administered on Wednesday and students who were not in school on Wednesday were administered the supplements on Thursday.

Z-scores used the National Center for Health Statistics data as a reference.

Non-malaria area.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskChildren were randomly assigned to the treatment or the control group using a table with randomly assorted digits.
Allocation concealment (selection bias)Low riskA teacher trained by the principal investigator was responsible for the delivery of the iron tablets in the classrooms. The teacher was provided with a list of the names of the children and the number and kind of pills (colour coded) each child should take every week. Neither the teacher nor the assistant were aware of the composition of the tablets delivered to the children and tablets were similar in appearance.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Tablets were similar in appearance.

Participants:Children were not aware of the treatment.

Personnel: Neither the teacher nor his assistant were aware of the composition of the tablets delivered to the children

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskA complete set of data was obtained for 33 children in the treatment group (89.2 %) and for 31 children (86.1 %) in the control group
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskNo significant differences at baseline in the variables studied,and females/males ratio. No differences at baseline between those that completed the study and those who dropped out.

Arcanjo 2011 (C)

MethodsCluster-randomised, placebo-controlled double-blind trial. 2 arm design with randomisation at classroom level.
Participants106 preschool children, both sexes (56 females (52.8%), aged 5 years. The study was conducted in a public school located in the City of Sobral, in the northeast of Brazil between September and December 2009. Exclusion criteria: current supplement intake. Baseline prevalence of anaemia: 58.5%. Forty per cent of the families had an income <300 USD.
Interventions

Classrooms were allocated to one of the following groups:

Group 1 (3 classrooms, 52 children): children received once a week 50 mg of elemental iron (as ferrous sulphate heptahydrate) once a week;

Group 2 (3 classrooms, 54 children): children received once a week a placebo (on Wednesdays). The placebo contained 2 ml of natural colour additive, annatto, which is odourless and tasteless, providing a yellow–orange colour similar to that of the elemental iron used in the study.

Length of the intervention: 14 weeks.

OutcomesHaemoglobin, hematocrit and anaemia (Hb less than 115 g/L)
Notes

The supplements were administered on Wednesdays. The supplement was administered by a teacher using a plastic medical syringe with scale to squirt the composition into the child’s mouth. The syringes were prepared on an individual basis by medical staff.

We adjusted the results of this study to account for the effect of clustering in data; the estimated effective sample size was used in the analyses. 

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAn allocation code was generated with a table of random numbers for randomizations of schools and classes.
Allocation concealment (selection bias)Low riskThe study used a placebo. Since randomisation occurred at classroom level, it is unlikely a selection bias at individual level.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants: were not aware of different interventions.

Personnel: the teacher was not aware of the treatment nor involved in data collection.

Ouctome assessors: the staff involved in data collection was blinded with regard to the intervention and placebo groups.

Incomplete outcome data (attrition bias)
All outcomes
Low riskDuring the study, there were 2 (3.8%) dropouts in group 1, and 5 (9.2%) dropouts in group 2. Intention to treat analysis.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear risk

The data was not adjusted by the effect of clustering.

Anaemia prevalence at baseline was not balanced between groups: 48% in group 1 and 69% in group 2 (but similar concentrations of haemoglobin).

Awasthi 2005 (C)

MethodsCluster-randomised community effectiveness trial. 2 arm design with randomisation at subcentre level.
Participants803 children, both sexes (730 females (45.4%)), aged 3-6 years, living in sub centres of Shahpur Baxolia and Sipa Hidayatpur from Nindura Block, Barabanki district, North India. Exclusion criteria: those without written informed consent, or those likely to move within the next three months. Children identified as severely anaemic were given iron and folic acid in therapeutic doses under close supervision (but does not say they were excluded). Baseline prevalence of anaemia in children was 53.79 %. Socioeconomic status not reported.
Interventions

Sub centres were allocated to one of the following groups:

Group 1 (n = 403): children in Shahpur Baxolia sub centre received tablets containing 20 mg elemental iron (presumably in form of ferrous sulphate) iron and 100 μg (0.1 mg) folic acid twice a week, on fixed days (Wednesday and Saturday);

Group 2 (n = 400): children in Sipa Hidayatpur sub centre received one tablet daily.

Length of the intervention: one year.

OutcomesHaemoglobin, haemoglobin mean change, anaemia, and adherence.
Notes

Iron and folic acid was given to the children either by the Anganwadi worker, if they were registered and used the informal education services of the Integrated Child Health Development Services, or by the mother for non-registered children. Mothers could pick up monthly supplies for their children one day a month from an Anganwadi centre.

A monitoring in-charge was responsible for each intervention type. He visited each Anganwadi centre every 15 days to take an account of the IFA distributed to registered children. The monitor in-charge also visited 20 randomly selected houses of non-registered children and collected information about the IFA tablet intake, including the number of pills consumed.

Sample size was calculated taking into consideration a design effect of 2. We adjusted the results of this study to account for the effect of clustering in data; the estimated effective sample size was used in the analyses. 

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskFor this study all sub centres were listed alphabetically, serially numbered, and two were selected by random for assessment of the interventional strategies, one per sub-centre. It is unclear whether the allocation to the treatment was at random.
Allocation concealment (selection bias)Low riskSince the intervention was allocated at sub-centre level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported.

Personnel: Not reported.

Outcome assessors: Not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow up 8.34% at one year with no difference between groups (biweekly 8.1% versus daily 8.5%).
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh risk

Some children had directly observed intake and others were given the pills by the mother. About 1/3 of the children are registered to obtain services of the Anganwadi centre (under the ICDS services) and this had a differential effect on supplementation (favouring registered children).

Results did not account for the cluster effect.

Baqui 2003

MethodsRandomised, double-blinded community-based trial. 5-arm design with individual randomisation.
Participants799 Bangladeshi children, both sexes (406 females (50.8%)), enrolled at 5-6 months of age for a 6 month study (12 mo old when completed). Potential families were identified through ongoing health and demographic surveillance system. Participants were eligible if did not receive infant formula, were not severely malnourished (mid-upper arm circumference >110mm), not severely anaemic (haemoglobin >90 g/L), with no obvious neurologic disorders, physical disabilities, or chronic illnesses that might affect feeding, activity, and cognitive development. There were no differences in monthly income, household size or father's education across the arms. Approximately two-thirds of the children were mildly anaemic at recruitment.
Interventions

Infants were randomly allocated to one of the following groups:

Group 1 (n = 154): Infants received once a week multiple micronutrients in a dose that doubled the recommended dietary allowance (WHO standards) of thiamine, niacin, folic acid, pantothenic acid, iodine, copper, manganese, selenium, and vitamins C, D, E, B6 and B12. It contained 20 mg elemental iron (as ferrous sulphate), 20 mg elemental zinc (as zinc acetate), and 1 mg riboflavin.

Group 2 (n = 161): Infants received once a week 20 mg elemental iron and 1 mg riboflavin.

Group 3 (n = 161): Infants received once a week 20 mg of elemental zinc and 1 mg riboflavin.

Group 4 (n = 162): Infants received once a week 20 mg of elemental zinc, 20 mg elemental iron and 1 mg riboflavin.

Group 5 (n = 157): Infants received riboflavin (control).

For the purpose of this review, groups 1, 2 & 4 were merged and compared with group 5.

Length of the intervention: 6 months.

OutcomesFerritin, diarrhoea, ALRI, physical growth, mental, motor, behavioral development from 6 to 12 month (measured using Bayley II scales of infant development), adherence. Data on diarrhoea and ALRI was not combined as it is reported in incidence rate/(child-y)
Notes

Supplements were prepared as capsules, which were mixed with flavoured syrup and fed to infants by community health workers.

All supplements had similar taste and appearance and all groups also received 100,000 IU of vitamin A at the beginning of the study, in line with national policy in Bangladesh.

Trial with sub-studies with different sample sizes.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskParticipants were randomly allocated to the study groups. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskEach study infant received the assigned supplement in the same type of capsules and labelled in such a way that the various types of supplements could not be differentiated.
Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as doubled-blinded clinical trial. Each study infant received the assigned supplement in the same type of capsules and labelled in such a way that the various types of supplements could not be differentiated
Incomplete outcome data (attrition bias)
All outcomes
High risk

Drop out rate much higher (41%) in the MM group than in other groups (8-19%). Motor/Cognitive outcomes: 125 kids (36%) did not complete 12 mo-assessment, leaving 221 children in final sample. There were no differences among arms or major sociodemographic variables for dropouts. 16.3% did not undergo evaluation with HOME scale.

5% did not have haemoglobin data at 12 mo, 1.8% did not have anthropometric data at 12 mo but did for other measures.

Selective reporting (reporting bias)High riskTrial with sub studies with different sample sizes.
Other biasUnclear riskNo discussion of adjustment or exclusion for inflammation for iron status analysis.

Berger 1997

MethodsDouble-blind randomised controlled trial. 3-arm design with individual randomisation.
Participants176 children, both sexes (91 females (52%)), aged 3.3-8.3 years (69 months old in average), attending the schools administered by the non-governmental organization "Fe y Alegria" located in a socio-economically disadvantaged district of La Paz, Bolivia (altitude of 4000 m above sea level). Inclusion criterion: anaemia (haemoglobin concentration equal to or lower than 144 g/L). No additional exclusion criteria listed. Socioeconomic status not reported.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 59): children received every Tuesday 3-4 mg of iron per kg of body weight (approximately 60-80 mg per week);

Group 2 (n = 59): children received a daily dose of 3-4 mg of iron per kg of body weight, 5 days per week, Monday to Fri. Daily group received 5 times as much iron as weekly;

Group 3 (n = 58): children received a placebo, once a week, every Tuesday. Placebo consisted of same tablets without iron.

Supplements given to groups 1 and 2 consisted of two types of tablets containing either 20 mg or 36 mg of elemental iron in form of ferrous sulphate. These tablets were used in combination to adjust the dose to the child’s weight

Length of the intervention: 16 weeks

OutcomesHaemoglobin, change in haemoglobin, anaemia, zinc erythrocyte protoporphyrin, adherence.
Notes

Tablets were given to children at school, with clean, boiled water, at mid morning, by trained school assistants, under the supervision of a member of the research team. Same tablets were used for weekly, daily, and same tablets without iron were used for placebo.

Non malaria area.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomly assigned to one of three groups. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskMethod of concealment not described, but the study reported as double blind.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Described as double-blind trial. Same tablets were used for weekly, daily, and same tablets without iron were used for placebo.

Participants: children were not aware of the treatment

Personnel: personnel were not aware of the treatment

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly one person lost to follow-up in each group, 3 people total. Dropouts were due to migration of the family out of the area of study
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Da Silva 2008

MethodsRandomised controlled trial. 3-arm design with randomisation at individual level.
Participants135 children (114 followed up, 54 female (47%)), both sexes, aged 5 to 6.9 months, from Vicosa, the Southeast of Brazil. Children were identified from live birth forms and parents were interviewed; parents who were interested in participating were recruited (213 children were screened, 78 infants with anaemia were excluded and treated). Inclusion criteria: non-anaemic infants (Hb equal to or greater than 110 g/L), living in urban area; full term, singleton births; birth weight > 2500 g; mother aged > 19 years old; no neonatal abnormalities or chronic disease; no previous iron supplements; non-exclusive breastfeeding. Maternal years of education ranged between 4 and 11 years (mean approximately 8 years).
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 51): infants received 1 mg of elemental iron/kg/day (as liquid ferrous sulphate);

Group 2 (n = 42): infants received 2 mg of elemental iron/kg/day (as liquid ferrous sulphate);

Group 3 (n = 42): infants received 25 mg elemental iron once a week (as liquid ferrous sulphate).

Length of the intervention: 16 weeks

For the purpose of this review only groups 2 and 3 were compared as the overall dose of iron given to the children was similar between them.

OutcomesHeight, weight and change scores for height and weight (with Z-scores), morbidity (diarrhoea, fever, cough, nasal congestion, wheezing).
Notes

Supplements were provided free to all groups and participants were advised to take 1 hour before meals.

Z scores used the World Health Organization data as a reference.

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA computer-generated random number list (method communicated by the author).
Allocation concealment (selection bias)High riskOpen random allocation schedule. Children were enrolled to the study in a row; there was a list showing the sequence in which children would be allocated to the groups (method communicated by the author).
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported.

Personnel: Not reported.

Outcome assessors: Not reported.

Incomplete outcome data (attrition bias)
All outcomes
High risk

135 children were randomised. 114 completed the intervention (84%). Loss was not balanced across groups: 12/51 lost from group 1, 6/42 from group 2, 3/42 from group 3.

Reasons for loss included patient withdrawal (7) supplement intolerance (6) anaemia (2) and other reasons. It was not clear how many withdrew from each group for these reasons.

It was stated that analysis was based on an intention to treat principle, irrespective of adherence, but those lost to follow up did not appear to be included in the analysis, although denominators were not clear in the data tables.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Desai 2004 (C)

MethodsCluster-randomised trial. 2x2 factorial design in which housing compounds were the unit of randomisation.
Participants

1049 children, both sexes (519 females (49.5%)), aged 2-59 months (27 months in average), living in 14 villages in Asembo, Bondo district, Nyanza Province, western Kenya. Inclusion criteria: haemoglobin 50-109 g/L (anaemic); asexual parasite count <20,000/mm; no history of intake of iron, sulphadoxine-pyrimethamine or amodiaquine use, or blood transfusion within the last 2 weeks, no known sickle cell disease

Baseline prevalence of anaemia in children was 74%. Caretakers had a median of 6 or more years of education across all arms and 48.6% of households had a wealth score above the median.

Interventions

Compounds were allocated to one of the following groups at baseline:

Group 1 (n = 266): children received two doses of 3-6 mg/kg each, separated by 3-4 days (total dose per week: 6-12 mg/kg; approximately 36-72 mg of iron per week). Supervised;

Group 2 (n = 271): children received two doses of 3-6 mg/kg each, separated by 3-4 days (total dose per week: 6-12 mg/kg). Unsupervised;

Group 3 (n = 261): children received one daily dose of 3-6 mg/(kg per day). Supervised;

Group 4 (n = 251): children received one daily dose of 3-6 mg/(kg per day). Unsupervised

Target iron dose was ferrous sulphate syrup 40 g/L, 27.5% elemental iron. Iron doses were based on body weight (<5 kg: 1.25 mL/d, 5-10 kg: 2.5 mL/d, >10 kg: 5.0 mL/d). No folic acid was given.

Supervised arms (Groups 1 and 3) were used to assess the haematological response while unsupervised groups (2 and 4) provided data on adherence and side effects.

Length of the intervention: 6 weeks.

OutcomesHaemoglobin, haemoglobin mean change, hematological recovery, microcytosis, all-cause morbidity, clinical malaria, malaria parasitaemia, adherence.
Notes

All parents received the 6-week supply of oral iron and received identical instructions in the local language about use, expected side effects, safety and correct dose of iron supplementation.

To determine differences in the duration of any treatment effect on Hb levels, children were seen again at 12 wk (1 d)

The mean cluster size was 1.5 children per compound, and the reported design effect was 1.035. Standard errors were adjusted for clustering at the compound level.

Malaria-endemic area.

All arms were given single treatment dose of sulfadoxine-pyrimethamine (SP).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA computer-generated random number listing was used to sequentially assign eligible children to 1 of 4 treatment groups, using the housing compound as the randomisation unit.
Allocation concealment (selection bias)Low riskPlastic screw top bottles used, labelled with personal identifiers and dosing instructions. Since the intervention was allocated at compounds level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants:were aware of the treatment assigned.

Personnel: no blinding

Outcome assessors: no blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk8.9% (n = 93) and equally divided among the four arms.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskChildren lost to follow up had lower (P=0.01) haemoglobin concentrations at enrolment than those successfully followed for 6 wk, but were not different for other characteristics. None of the characteristics differed among the groups after excluding children lost to follow up. 6 children (4 compounds) excluded from analyses at 6 wk follow up due to missing haemoglobin values. No discussion on adjustment/exclusion for inflammation.

Ekvall 2000

MethodsRandomised trial. 2-arm design with individual randomisation.
Participants207 children, both sexes (sex distribution unknown), 5 months-3 years of age, living in Fukayosi village, Bagamoyo district of coastal Tanzania, from June to November 1995, during the seasonal peak of perennial malaria transmission. Exclusion criteria: migration plans, the presence of congenital malformations and Hb concentration, 50 g/L at baseline, requiring immediate treatment. Baseline prevalence of anaemia in children was 89% (Hb lower than 110 g/L). Socioeconomic status not reported.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 104): children received three times a week 1 mL of a micronutrient preparation containing 10 mg iron (as ferrous sulphate), 1500 IU vitamin A, 400 IU vitamin D, 5 IU vitamin E, 35 mg vitamin C, 0.5 mg vitamin B1, 0.6 mg vitamin B2, 8 mg niacin and 0.4 mg vitamin B6;

Group 2 (n = 103): children received three times a week 1 mL of a placebo (1 mg of promethazine hydrochloride).

Iron compound and weekly dose: 30 mg of elemental iron (as ferrous sulphate) per week.

Length of the intervention: 5 months.

OutcomesHaemoglobin, mean cell volume as an indicator of iron status, clinical malaria, fever, adherence.
Notes

All children were to receive a total of 56 doses over 5 months administered during home visits by six research assistants who were assigned 30–35 children each.

Malaria holoendemic area. For active case detection of clinical malaria episodes, all children were seen fortnightly by the research team at the village dispensary for axillary temperature measurement. Children with malaria received chloroquine syrup (25 mg/kg over three days), and additional treatment with sulphadoxine pyrimethamine (SP) was given if a child showed clinical signs of treatment failure.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe children were randomly allocated to the supplement group or the placebo group by a computer-generated number table.
Allocation concealment (selection bias)Low riskThe supplement and placebo had different colours to facilitate correct administration. However, neither the research assistants involved in the project nor the mothers of
the children knew the treatment code.
Blinding (performance bias and detection bias)
All outcomes
Low risk

The supplement and placebo had different colours to facilitate correct administration.

Participants: mothers did not know the treatment code

Personnel: research assistants did not know the treatment code

Ouctome assessors: not described

Incomplete outcome data (attrition bias)
All outcomes
Low risk6 children were lost to follow up in each group (6%).
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Engstrom 2008 (C)

MethodsCluster-randomised trial. 3 arm design in which health facilities were the unit of randomisation.
Participants

391 children, both sexes (184 females (47%)), 6 months old. Study carried out through primary healthcare units in Rio de Janeiro, Brazil. 15 health care centres (6 intervention, 9 control). Inclusion criteria: absence of iron supplementation in the month preceding recruitment and negative for sickle cell anaemia.

Baseline prevalence of anaemia (taken from the control group): 60.4%. Socioeconomic status:approximately 30% of the mothers worked outside the home; most families (> 90%) had access to radio and television, but < 20% had access to a car.

Interventions

Health facilities were allocated to one of the following groups:

Group 1 (n = 188): children received weekly supplementation with 25 mg of elemental iron (as oral ferrous sulphate) per week in syrup and education on anaemia and diet;

Group 2 (n = 188): children received daily supplements containing 12.5 mg elemental iron dailyand education on anaemia and diet;

Group 3 (n = 94): children received received no intervention and was recruited retrospectively.

Length of the intervention: 24 weeks.

For the purposes of this review we only compared groups 1 and 2.

OutcomesHaemoglobin, anaemia (Hb <110 g/L) and adherence.
Notes

Analyses were performed taking into account cluster sampling.

Non-malaria area.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskHealthcare units were randomly selected. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at health care unit level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Mothers were aware of supplements

Personnel: Clinic staff were aware of supplements

Outcome assessors: Unlikely

Control group identified retrospectively so they were not aware of trial during treatment phase.

Incomplete outcome data (attrition bias)
All outcomes
High risk38/188 (20.2%) were lost to follow up the daily group and 41/188 (21.8%) in the weekly group.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskBaseline characteristics were similar for most variables. Regression analysis was carried out to identify possible confounders and where possible confounders accounted for at least 10% of variation they were entered into the final model. However for anaemia no confounders were maintained in the final regression analysis.

Ermis 2002

MethodsRandomised placebo-controlled trial. 4-arm design with individual randomisation.
Participants113 infants, both sexes (56 females (50%)), 5-month old, receiving routine paediatric care at the Research hospital of Karaelmas University in Zonguldak, Turkey. Inclusion criteria: no gestational problems (hypertension, preeclampsia, infection), no congenital anomalies, no neonatal complications, no emergency caesarian delivery, no jaundice requiring phototherapy, no hospitalisation, no chronic illness, no iron therapy, no formula feeding. Must have been exclusively breasted, birthweight > 3.0 kg and gestational age of > 37 weeks. Exclusion: Hb < 95 g/L, serum ferritin <12 ng/mL, MCV < 74 fl or infection during iron supplementation. Children were eliminated from the study if compliance was lower than 75%. 58.6%-74. Baseline prevalence of anaemia not reported. One percent of the mothers of participants included in the study graduated from high school or university.
Interventions

Infants were allocated to one of the following groups:

Group 1 (n = 30): infants were given a supplement containing 1 mg iron/kg (as ferrous sulphate) daily;

Group 2 (n = 30): infants were given a supplement of 2 mg iron/kg (as ferrous sulphate) daily;

Group 3 (n = 30): infants were given a supplement of 2 mg iron/kg (as ferrous sulphate)) every other day (approximately 42 mg of iron per week);

Group 4 (n = 23): infants received a placebo.

Length of the intervention: 4 months.

Groups 1 and 2 were combined and compared with group 3.

OutcomesHaemoglobin, MCV, ferritin, side effects.
Notes

Supplements were given by mothers just before or just after breastfeeding and at least one hour before or after any other food intake.

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomised to the different groups. Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported.

Personnel: Not reported.

Outcome assessors: Not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo, three and one cases were eliminated because of low compliance(<75%), in group 1, 2 and 3, respectively. The causes of non-compliance were infection during iron usage, refusing iron droplets due to unpleasant taste, or mothers forgetting to use the iron drops.
Selective reporting (reporting bias)Unclear riskCases with less than 75% of adherence were excluded.
Other biasUnclear riskCases with less than 75% of adherence were excluded. It is unclear why the control group has 25% less participants.

Evangelista-Salazar 2004

MethodsRandomised controlled trial. 4-arm design with individual randomisation.
Participants100 newborns, both sexes (50 females), living in Urban areas in Colima, Mexico. Incluson criteria: healthy, term, single-born babies during their first year of life. Exclusion criteria: low birth weight, unknown date of last menses to calculate term pregnancy, twins, bleeding disorder or other medical conditions that may be associated with anaemia (i.e., malabsorption). Baseline prevalence of anaemia: unknown. Socioeconomic status not reported but children were born to parents that were receiving a salary.
Interventions

Neonates were randomly allocated at one of the following groups:

Group 1 (n = 25): infants were given weekly a supplement of 7.5 mg elemental iron (as ferrous sulphate), and 30 mg vitamin C;

Group 2 (n = 25): infants were given fortnightly a supplement of 7.5 mg elemental iron (as ferrous sulphate), and 30 mg vitamin C;

Group 3 (n = 25): infants were given monthly a supplement of 7.5 mg elemental iron (as ferrous sulphate) and 30 mg vitamin C;

Group 4 (n = 25): received no intervention.

Length of the intervention: 12 months. During the first 6 months children received 7.5 mg and after that the dose was double. We only included the first period of evaluation in our analysis.

For the purposes of this review we only compared groups 1 and 4.

OutcomesAnaemia, iron deficiency, haemoglobin, ferritin. Neurocognitive development (Brazelton score at birth, Bayley mental and motor assessment) and growth. The latter data were not extracted as no measures of dispersion are reported.
Notes

Trained personnel visited families to assess illness incidence and adherence.

Ferritin data for the group receiving intermittent supplementation was 201.2 ± 51.08 and 120.0 ± 56.63 ng/mL (or μg/L). Although the results are consistent in terms of direction, these concentrations are much higher than those observed in the rest of the trials included in this review. The corresponding author was contacted to verify this information and we decided not include this information while we await for the response.

Malaria-free area. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren randomly allocated to the study groups. Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Participants: unclear

Personnel: unclear

Outcome assessors: Not reported.

Trial reported as single blind but the use of placebos is not described, so it is not clear who was not aware of the intervention.

Incomplete outcome data (attrition bias)
All outcomes
Low riskApparently there were no losses to follow-up.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Faqih 2006

MethodsRandomised clinical effectiveness trial. 3-arm design with randomisation at individual level.
Participants134 children, both sexes (38.1% female at follow up), aged 2 to 6 years (in average 43 months), attending Prince Hashim Military Hospital of the Royal Medical Services in Zarqa, Jordan. This clinic is open to children from families affiliated with the army who are not medically insured and have generally low income. Inclusion criteria: Iron deficiency anaemia at baseline (Hb ≤ 105 g/L and mean corpuscular volume ≤ 75), born at full term with birthweight equal or higher than 2.5 kg and exhibited normal growth with no signs of thalassaemia, chronic illness, congential abnormalities, or chronic and repeated infections. Baseline prevalence of anaemia not reported. Socioeconomic status not reported.
Interventions

Children were allocated to one of the following groups:

Group 1 (n = 45): children received a daily dose of 5 mg elemental iron per kilogram of body weight;

Group 2 (n = 45): children received once a week 5 mg of elemental iron per kg of body weight on Fridays (approximately 45 mg of iron per week);

Group 3 (n = 44): children received 5 mg of elemental iron per kilogram of body weight twice a week, Friday and Monday (approximately 90 mg of iron per week).

Parents were instructed to give the ferrous sulphate supplement in 2 portions between 30 to 60 minutes before breakfast and dinner. Parents were advised to mix the supplement with water, orange juice or lemonade if the child refused the supplement.

Length of the intervention: three months.

All the groups were analysed in this review. Groups 2 and 3 were combined and only reported separately for the subgroup analysis by regimen.

OutcomesWeight, height, haemoglobin, mean corpuscular value, hematocrit, ferritin.
Notes

The dose was administered by either of the parents who were advised to mix the supplement with water, orange juice,or lemonade if the child refused to take the supplement on an empty stomach. Families also counselled on nutritional causes of IDA, consequences if not treated, iron rich foods, enhancers and inhibitors. Families also received home check up visits every two weeks.

In Jordan, malaria, hookworm, and schistosoma do not constitute a problem.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were allocated randomly to one of three groups according to a table of random digits.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported

Personnel: Not reported

Outcome assessors: Not reported

Incomplete outcome data (attrition bias)
All outcomes
High risk71 of 134 children (53%) did not complete the study. Children lost because 1) refused to take the iron, 2) parents did not administer iron for 3 months, 3) parents did not return to clinic for follow up visits. Final number of participants did not differ across groups.
Selective reporting (reporting bias)High riskOnly 34 children had ferritin values.
Other biasHigh riskVery large age range and small sample size for the outcomes, age is important for risk of anaemia and iron deficiency. Baseline haemoglobin higher in group 2 than in group 1.

Hall 2002 (C)

MethodsCluster-randomised trial. 2-arm design with randomisation at school level (60 schools, 30 per arm).
ParticipantsChildren (1201 randomised, 1113 followed up), both sexes (613 female (51%)), aged 6-19 years (mean of 11.4 years), attending rural informal community schools in the Kolondieba district of Mali. Approximately 20 randomly children (10 boys and 10 females) attending 2nd or 4th grade were selected from each school. Any child with severe anaemia (Hb ≤80 g/L) were excluded. Baseline prevalence of anaemia: approximately 55%. Socioeconomic status not reported.
Interventions

Schools were allocated to one of the following groups:

Group 1 (n = 551 at follow up, number randomised not clear): children received 65 mg elemental iron (as 200 mg of ferrous sulphate) and 250 μg (0.25 mg) of folic acid once a week;

Group 2 (n = 562 at follow up, number randomised not clear): No intervention.

Length of the intervention: 10 weeks

OutcomesAnaemia, haemoglobin. Results by sex are included in the corresponding subgroup analysis.
Notes

All children in every school were treated for parasitic infections at baseline using albendazole, and vitamin A to treat night blindness. Supplements were given by the teachers and 83% of children were given all 10 tablets and 91% received at least nine tablets.

Malaria is endemic in Mali, although the study was done in the dry season when transmission is less intense than in the wet season.

Authors provided the ICC (0.0698) and design effect (2.22) to adjust data by the effect of clustering; the estimated effective sample size was used in the analyses. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk60 schools were randomly assigned to either a treatment or a comparison group by using a computer-generated random number list (information communicated by the author).
Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at health care unit level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported

Personnel: Not reported

Outcome assessors: Not reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk1201 children at baseline, 1113 followed up at 14-16 weeks. (93% followed up). 88 children who did not provide second samples had similar Hb levels at baseline than as those children remaining in the study.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other bias.

Khademloo 2009

MethodsRandomised controlled trial. 2-arm design with individual randomisation
Participants100 Infants, both sexes (sex distribution not reported), aged 6-24 months referred to the public health care centre in Sari, Iran. Urban area. Inclusion and exclusion criteria were not adequately described. Baseline prevalence of anaemia not reported. Socioecomic status: although information on sex and mothers' educational level were collected this information was not reported.
Interventions

Children were allocated to one of the following groups:

Group 1 (n = 50): infants received fifteen drops containing elemental iron (as ferrous sulphate) given daily.

Group 2 (n = 50): infants received thirty drops of iron once a week.

Length of the intervention: 12 weeks

OutcomesFerritin, haemoglobin.
Notes

Trial not included in the subgroup analysis by dose

Malaria endemicity not reported.

The total dose of iron per week is unknown.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskBabies "randomly divided in two equal groups". Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported

Personnel: Not reported

Outcome assessors: Not reported.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described. Denominators not provided in the results tables.
Selective reporting (reporting bias)Unclear riskGroups were described as similar at baseline, but information on methods and results was scarce.
Other biasLow riskThe study appears to be free of other sources of bias.

Liu 1995 (C)

MethodsRandomised clinical trial. 3 arm design with randomisation at classroom level.
Participants246 healthy children, both sexes (131 females (57%)), aged 3 to 6 years, attending Kindergarten in Changxi, China, an autonomous region of China. Kindergarten has 9 large classrooms and two meals and two snacks are provided daily. Exclusion criteria were chronic infectious diseases, cardiopathies, or respiratory diseases, and intake during the previous month of supplements or drugs containing iron or specially prescribed iron-rich and absorption-promoting foods for the month prior to entering the study. Approximately 29 % of the children were anaemic at baseline. Socioeconomic status not reported.
Interventions

Classrooms were allocated to one of the following groups:

Group 1 (n = 89): children received 5-6 mg of elemental iron per kilogram (as ferrous sulphate) daily;

Group 2 (n = 74): children received 5-6 mg of elemental iron per kilogram (as ferrous sulphate) twice a week (approximately 170 -204 mg of iron per week);

Group 3 (n=83): children received 5-6 mg of elemental iron per kilogram (as ferrous sulphate) tablet once a week (approximately 75 -120 mg of iron per week);.

Iron tablets were administered by teachers under direct supervision 1 hour after breakfast, making sure that the child swallowed it.

Length of the intervention: 3 months

Group 2 and 3 were combined and compared with group 1; their individual results are presented in the subgroup analyses by regimen and by anaemia status.

OutcomesHaemoglobin and ferritin.
Notes

We adjusted the results of this study to account for the effect of clustering in data; the estimated effective sample size was used in the analyses. 

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomly allocated to the classroom according to their age and then classrooms were randomised to each of the three intervention groups. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskNot reported. Since randomisation occurred at classroom level, it is unlikely a selection bias at individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported

Personnel: Not reported

Outcome assessors: Results were tabulated, without knowledge of the children's supplementation regimen, by two nurses in charge of the clinic at the kindergarten with the assistance of a nonparticipating physician.

Incomplete outcome data (attrition bias)
All outcomes
Low risk238 children completed the study. 5 left the kindergarten during the study and 3 children from daily group discontinued supplementation due to persistent nausea.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh riskData not adjusted by the effect of clustering in data

Nguyen 2002

MethodsRandomised trial. 4 arm design with individual randomisation.
Participants280 children, both sexes (133 females (47.5%), aged 5 to 12 months, living in one of four communes in the rural district of Bac Ninh, Vietnam. Inclusion criteria: Hb< 70 g/L, no pathologies after a clinical examination and not receiving any iron supplements. Baseline prevalence of anaemia: ˜60%.Socioeconomic status: ˜95% dedicated to agriculture.
Interventions

Two communes were allocated to one of the following groups:

Group 1 (n = 70): children received a placebo (2.5 ml of syrup without iron) every day;

Group 2 (n = 70): children received a daily dose of 15 mg elemental iron (2.0 ± 0.3 mg iron/day/kg body weight) (as ferrous sulphate).

Participants from other two communes were randomly allocated to one of the following groups:

Group 3 (n = 70): children received a daily dose of 15 mg elemental iron (2.0 ± 0.3 mg iron/day/kg body weight) (as ferrous sulphate);

Group 4 (n = 70): children received a weekly dose of 15 mg elemental iron (as ferrous sulphate).

Length of the intervention: 3 months (groups 1 and 2) and 6 months (groups 3 and 4).

For the purposes of this review only groups 3 and 4 were compared.

OutcomesHaemoglobin, anthropometric measurements (height for age, weight, age and weight for height were Z-scores)
Notes

Article translated from French.

The supplements were administered between 8 and 10 am by local auxiliaries, under regular supervision of a member of the research team. 98% and 95% of the infants in group 3 and 4, respectively, received more than 90% of the expected total dose of iron.

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskOnly children from groups 3 and 4 were randomly allocated to either daily or weekly supplementation. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskNot described, but the trial included the provision of a placebo and multiple blinding.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants: the nature of the treatment was unknown to the family of the infant; all the infants received identical looking syrups (with or without iron).

Personnel: community auxiliaries were not aware of the treatments.

Outcome assessors: Neither the people in charge of measurements researcher nor the data analysts were aware of the treatments.

Incomplete outcome data (attrition bias)
All outcomes
Low risk10 children did not complete the study, 4 because parents refused to continue, 3 due to address change and 4 because of low compliance (consumed less than 80% of the doses).
Selective reporting (reporting bias)High riskResults on growth not reported.
Other biasLow riskThe study appears to be free of other sources of bias.

Olsen 2000

MethodsRandomised, placebo-controlled, double-blind study. 2-arm design with individual randomisation.
Participants231 children, both sexes (99 females (43%)), aged 4-15 years (8.6 years in average), living in Luo villages of Asino, Ohala, and Pith-Kodhiambo in Kisumu district of Nyanza Province in western Kenya. Participants had moderately low blood haemoglobin concentrations (80-130 g/L for children 4-14 years of age or non-pregnant female >14 years of age and 80-135 g/Lif male and >14 years of age). Exclusion criteria: severe anaemia (Hb <80 g/L) or pregnant. Baseline prevalence of anaemia: 47.5%. Socioeconomic status not reported
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 121): children received treatment twice weekly with a 60 mg of elemental iron (total of 120 mg of iron per week, as 200 mg of ferrous dextran);

Group 2 (n = 110): children received a placebo.

Length of the intervention: 12 months.

OutcomesHaemoglobin, serum ferritin (median and interquartile range, could not be extracted), reinfection rates and intensities of hookworm, Ascaris lumbricoides, Trichuris trichiura, and Schistosoma mansoni, compliance ("reasonable").
Notes

At baseline, any individual infected with any intestinal helminth. S. mansoni, and malaria were treated (only abstract says treated with malaria).

After baseline examination, each subject was given a container (labelled with the subject's name, study number and identification sticker) containing 50 tablets. At the end of each 4-month period, the number of tablets taken was registered, based on the number of remaining tablets. In order to encourage intake, field assistants visited every participant at least once a month. Tablet intake for the whole study period was 98.9% of the scheduled value, and 90.1% of the children each appeared to take between 80% and 120% of the scheduled number of tablets.

Iron supplementation had no effect on either reinfection rates or intensities in children. Multiple
logistic regression analyses controlling for baseline infection status confirmed the effect in adults of

Malaria endemic area.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSimple randomisation using a programme written in advance.
Allocation concealment (selection bias)Low riskThe tablets were coded by the manufacturer and sealed envelopes containing the codes were kept closed until the end of the study.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants: received identical pills and instructions

Personnel: envelopes revealing randomizations code not opened until analysis was complete.

Outcome assessors: envelopes revealing randomizations code not opened until analysis was complete.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOf 231 randomised, one became pregnant and 30 lost to follow up. Lost equally distributed across both arms.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskBaseline intensity of A. Lumbricoides infection was higher in the placebo group than in the iron group. HIV not assessed at baseline, but at 4 months, and assumed to reflect baseline status; it is unclear what treatment was available for participants.

Palupi 1997

MethodsDouble-masked, randomised controlled field trial. 3-arm design with individual randomisation.
Participants299 children, both sexes (sex distribution not reported), aged 2-5 years, who were registered at the West Javanese village of Setia Asih. Of 344 potential subjects, parental permission was obtained for 299 children. No further inclusion or exclusion criteria mentioned. Baseline prevalence of anaemia: 36.7%. Socioeconomic status not reported.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 98): children received 30 mg elemental iron (as ferrous sulphate) once per week and anthelminthic treatment;

Group 2 (n = 96): children received 30 mg elemental iron (as ferrous sulphate) once per week and placebo for anthelminthic treatment;

Group 3 (n = 98): children received placebos for both iron supplements and anti-helminthic treatment. The placebo syrup did not contain ferrous sulphate, but was similar in taste and appearance to the iron-containing syrup.

Length of the intervention: 9 weeks

For the purpose of this review only groups 2 and 3 were compared.

OutcomesHaemoglobin, haemoglobin mean change, anaemia, anthropometric measurements (Height-for-age Z-score, Weight-for-age Z-score, Weight-for-height Z-score change), helminthic infection.
Notes

The anthelminthic tablets as well as the placebos were ingested under supervision of the researcher one week before iron supplementation started. The supplements were given to the children by their mothers and intake was not supervised by health centre staff or the researchers, but compliance was controlled by checking the iron content in the stool.

Z-scores used the National Center for Health Statistics data as a reference.

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomly divided into three, equal-sized treatment groups. Method of sequence generation not described.
Allocation concealment (selection bias)Low riskMothers received a bottle with 100 mL glucose syrup. Although the concealment is not clearly described, this is a double-blind trial and its unlikely that there was a selection bias.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Reported as double-masked trial.

Participants: were not aware of the treatment

Personnel: all mothers received a bottle with 100 mL glucose syrup containing or not iron.

Outcome assessors: unclear but probably blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk289 (out of 299) children remained; 10 (3%) dropped out because they had either moved or had become ill.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Roschnik 2003 (C)

MethodsCluster-randomised trial. 2-arm design with randomisation at school level and stratified by sponsorship status.
Participants1,160 children (752 followed up), both sexes (371 females (49.5%)), aged 7–8 years and 12-14 y. The study included 40 primary schools in the Mangochi District, Malawi. Baseline prevalence of anaemia: around 54%. Socioeconomic status not reported.
Interventions

Schools were randomly allocated to one of the following treatments:

Group 1 (20 schools, n = 640): children received 65 mg of elemental iron (as 200 mg ferrous sulphate) and 250 μg (0.25 mg) of folic acid once a week.

Group 2 (20 schools, n = 640): children received no intervention.

Length of the intervention: 15 weeks

Outcomes

Haemoglobin concentration, bilharzia infection, school attendance, test scores

and drop-out rate and repetition rate (at the school level).  

Notes

Results were stratified by age (<10 y, 10-14 y and 15+). For the purposes of this review we only included those data from children <10 years of age (192 in the intervention group and 190 in the control group), until we can obtain the data for all children <12 years.

A famine occurred in the region at the time of the study.

Each study group included 10 sponsorship schools and 10 non-sponsorship schools, 10 coastal and 10 upland schools. All children in Coastal intervention and comparison schools, where the prevalence of bilharzia was over 50%, were dewormed with Praziquantel (600mg) just after the baseline survey.

A vitamin A capsule (200,000 IU) was given to all children in standard 2 and below

63% of children took 10 iron tablets or more.

Analysis originally not adjusted by the effect of clustering. The effective sample was calculated by imputing the ICC from Roschnik 2004 (C), which has a similar study design; the estimated effective sample size was used in the analyses. 

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk40 primary schools in the Mangochi District were randomly divided into the intervention (1st iron group) and comparison group (2nd iron group). Each group includes 10 sponsorship schools and 10 non-sponsorship schools. Method of sequence generation not specified.
Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at school level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: not reported.

Personnel: not reported

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
High risk1280 were randomised, 1160 had haemoglobin levels at baseline and 752 were followed up: 41.2% children lost to follow up
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskChildren attending sponsored schools responded better to the treatment.

Roschnik 2004 (C)

MethodsCluster-randomised trial. 2-arm design with randomisation at school level.
Participants1785 children (1510 followed up), both sexes (747 females (49.5%), aged 7–12 years. The study included 51 primary schools: 20 in Iloilo and 31 in Guimaras, Philippines. Baseline prevalence of anaemia: ˜15%. Socioeconomic status not reported.
Interventions

Schools were randomly allocated to one of the following treatments:

Group 1 (25 schools, unclear the number of children randomised): children received 108 mg of elemental iron (as 325 mg ferrous sulphate);

Group 2 (26 schools, unclear the number of children randomised): children received no intervention.

Length of the intervention: 10 weeks

OutcomesAnaemia, haemoglobin, haemoglobin change.
Notes

Supplementation started between 1 and 7 weeks after the baseline survey and the second survey took place between 5 and 18 weeks after the end of the iron supplementation.

The consumption of each tablet was recorded by the teachers. Side effects were not recorded. All 10 iron tablets were taken by 93.4% of children.

67% of children were infected with one or more intestinal worms.

Malaria endemicity not reported.

Authors provided the ICC (0.1123) and design effect (4.35) to adjust data by the effect of clustering; the estimated effective sample size was used in the analyses. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAll 51 schools were assigned to two groups using a random number table.
Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at school level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: not reported.

Personnel: not reported

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk15.4% of attrition. Losses presumably higher among the control group as two schools were dropped out because they were unable to collect the baseline measurements within the month allotted.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh risk

The second blood sample was withdrawn between 5 and 18 weeks after the end of the iron supplementation.

Fourteen of the 49 schools in the study had participated for about 2 months in the fortified rice programme: six in the intervention group and eight in the control group. The mean haemoglobin concentration of children in the 14 schools that had participated in the programme was slightly but significantly higher than that of children in the other 25 schools (126.4 g/L versus 125.0 g/L, P ¼ 0.031).

Analysis was not adjusted by the effect of clustering in data.

Schultink 1995

MethodsRandomised clinical trial. 2-arm design with individual randomisation.
Participants87 children, both sexes, aged 2-5 years, from Subdistrict Kelurahan Tenga of East Jakarta, Indonesia. The initial selection criterion was a haemoglobin concentration < 110 g/L. 96 children were invited to receive anthelmintic treatment before starting iron supplementation; only 87 accepted and were randomised.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 44): children were supplemented daily with 30 mg elemental iron (as ferrous sulphate dissolved in 5 mL syrup);

Group 2 (n = 43): children were supplemented twice a week with 30 mg elemental iron (as ferrous sulphate dissolved in 5 mL syrup) (total 60 mg of iron per week).

Length of the intervention: 8 weeks.

OutcomesHaemoglobin, ferritin, zinc protoporphyrin, mean changes of haematological variables (anaemia prevalence taken from Beaton 1999).
Notes

Parents and supervising health staff were instructed that each child should take 5 mL from the small bottle on Mondays and Fridays and 5 mL from the large bottle on the remaining days of the week using a standardized spoon for 8 wk. Bottles had similar appearance

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSubjects were assigned at random to two groups. Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants: were not aware of the treatment

Personnel: all mothers received two small bottles (each 80 mL) and two large bottles (each 170 mL), each containing a syrup of similar appearance

Outcome assessors: supervising staff were not aware of the bottle content.

Incomplete outcome data (attrition bias)
All outcomes
High riskA complete set of data was obtained for 33 subjects in the group supplemented twice weekly (group 1) (75%) and for 32 subjects in the group supplemented daily (group 2) (74.4%).
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh riskBaseline haemoglobin concentrations were different between groups.
The results include 25 children with Hb> 110 g/L and the initial description only mentions 16

Sen 2009 (C)

MethodsCluster-randomised controlled trial. 4-arm design with randomisation at school level.
Participants240 school age females, aged 9-13 years, attending four schools in Vadodara area of India. Females were excluded from the analysis if menstruation commenced. None of the Females were involved in athletic sports on a regular basis. Baseline prevalence of anaemia: 68.3%. Socioeconomic status not described in detail but participants were described as "underprivileged".
Interventions

Schools were allocated to one of the following groups:

Group 1 (n = 65): females received 100 mg elemental iron (as ferrous gluconate) and 500 μg (0.5 mg) folic acid folic acid oral once weekly;

Group 2 (n = 89): females received the same supplement twice weekly (200 mg of elemental iron per week);

Group 3 (n = 59): females received 100 mg elemental iron (as ferrous gluconate) daily;

Group 4 (n = 41): females received no supplement.

Length of the intervention: 1 year.

Groups 1 and 2 were combined and compared with groups 3 and 4 as appropriate.

OutcomesPhysical work capacity, haemoglobin change and adherence.
Notes

Malaria endemicity not reported.

Analyses in this review include the estimated effective sample size only, after adjusting the data to account for the clustering effect.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskOf 17 schools meeting the inclusion criteria, 4 schools were selected randomly using a random numbers table. Once the four schools were selected, the chit system (chits representing school 1, 2, 3, 4) was used. The order of placing a school in a category was: the first school that is picked up (from the four) goes to daily; the chit is then put back; the next chit picked up goes to twice weekly; the next to once weekly and the one left over, to control so that all schools have an equal probability of being allocated to any of the four groups (information communicated by the author).
Allocation concealment (selection bias)Low riskNot reported. Since allocation was at school level it is unlikely that there is selection bias at individual level.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants, personnel and outcome assessors: Each school received a different intervention, although it is unclear if the intervention was blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk4 schools. In these schools a random sample of 240 children was selected. 163 had pre and postintervention data for work capacity (68% followed up). Females who started their periods were excluded from the analysis. For cognitive tests results relate to a sub-sample of 161 females available pre and post-test.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh riskThe design effect was not taken into account in the analysis.

Siddiqui 2004

MethodsRandomised controlled trial with. 2-arm design with individual randomisation.
Participants60 children, both sexes (30 females (50%)), aged 5-10 years, attending a private school, blue collar workers, in Karachi Pakistan. Inclusion: anaemia (haemoglobin <110 g/L). Exclusion criteria: acute disease (diarrhoea, fever, cough, running nose) or history of chronic disease (joint pain, bleeding disorders). Socioeconomic status not described.
Interventions

Participants were allocated to one of the following groups:

Group 1 (n = 30): Children took supplements containing 60 mg of elemental iron (as 200 mg ferrous sulphate) once a week for 2 months (8 doses total);

Group 2 (n = 30): Children took 60 mg of elemental iron supplements (as 200 mg ferrous sulphate) daily for 56 days.

Length of the intervention: ˜ 2 months (weekly dosing was 8 weeks but daily dosing only 56 days).

OutcomesHaemoglobin, hematocrit, serum iron, total iron binding capacity, serum ferritin.
Notes

Both groups de-wormed prior to start of study (mebendazole).

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomly assigned to one of the groups. Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: not reported.

Personnel: not reported.

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskUnclear whether 60 participants reflected all anaemic children in the school or whether (and if so how) the 30 males and 30 females were selected out of all eligible students in the school. Age in weekly group significantly different than those in daily group. Did not assess or adjust/exclude iron status indicators for inflammation

Sinisterra 1997 (C)

MethodsCluster-randomised trial. 2-arm design with randomisation at school level (5 schools).
ParticipantsChildren (909 randomised, 842 followed up), both sexes (408 female (48%)), aged 6-13 years, attending rural schools in the district of Anton, Cocle, Panama. Exclusion criterion: severe anaemia (Hb ≤90 g/L) and clinical conditions that could affect iron status. Baseline prevalence of anaemia: approximately 42.4%. Socioeconomic status not explicitly reported.
Interventions

Schools received one of the following interventions:

Group 1 (n = 176 at follow up, number randomised not clear): children received daily 60 mg of elemental iron (as ferrous sulphate) and "nutricrema";

Group 2 (n = 210 at follow up, number randomised not clear): "nutricrema".

Group 3 (n = 225 at follow up, number randomised not clear): children received daily 60 mg of elemental iron (as ferrous sulphate) and "nutricrema" once a week;

Group 4 (composed by two schools n=195 at follow up, number randomised not clear): Milk plus a fortified cookie plus folic acid

Length of the intervention: 6 months

Only groups 1 and 3 were randomised and thus included in our analysis.

OutcomesAnaemia (Hg < 120 g/L), haemoglobin, attitudes, beliefs, growth.
Notes

Malaria endemicity not reported.

We adjusted the results of this study to account for the effect of clustering in data; the estimated effective sample size was used in the analyses. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGroups allocated by drawing of lots (communicated by the author).
Allocation concealment (selection bias)Low riskNot described. Since the intervention was allocated at school level, it is unlikely there was a selection bias at the individual level.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: Not reported

Personnel: Not reported

Outcom assessors: Not reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk7.3% of losses to follow up. Unclear whether they were balanced across groups.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasHigh riskThe prevalence of anaemia among those receiving weekly supplementation was 20 percentage points higher than those receiving daily supplementation (54.7% vs 34.7%).

Soemantri 1997

MethodsRandomised controlled trial. 2-arm design with individual randomisation.
Participants97 children, both sexes (sex distribution not reported), aged 7-11 years, attending the primary school Batang, in Indonesia. Inclusion criteria: anaemia (Hb below 120 g/L); not taking iron supplements during the last six months; no evidence of hepatosplenomegaly, haemoglobinopathy, acute or chronic disease, severe anaemia. Baseline prevalence of anaemia: 67.36%. Socioeconomic status not reported.
Interventions

Children were divided into 2 groups and randomly assigned

Group 1 (n = 52): children received daily 3 mg of iron per kilogram (as ferrous sulphate);

Group 2 (n = 45): children received once a week 3 mg of elemental iron per kilogram (as ferrous sulphate) (approximately 85 mg of iron per week).

Length of the intervention: 3 months.

OutcomesAnthropometric measurements (weight for age Z-score, height for age Z-score) and haemoglobin.
Notes

The solutions were given by the school teachers on school days with careful supervision.

All children with intestinal parasites were treated prior to supplementation.

Z-scores used the National Center for Health Statistics data as a reference.

Malaria endemicity not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomly assigned to the study groups. Method of sequence generation not described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
High risk

Participants: not reported.

Personnel: not reported.

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo children (3.8%) were excluded from the daily group because of gastrointestinal side effects.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasLow riskThe study appears to be free of other sources of bias.

Sungthong 2002

MethodsDouble-blind, randomised, placebo-controlled trial. 3-arm design with individual randomisation.
Participants

Of 50 government schools located outside the municipality, selected schools had to met the following criteria: 1) high prevalence of underweight according to school-records (no # or prevalence given to define "high"); 2) a least 150 students in school; 3) not >1 h away by car from research centre; 4) teachers willing to cooperate in study; 5) no previous iron supplementation programme implemented. Subsequently 2 schools selected.

397 school age children in grades 1-6 (9.7 years of age in average), both sexes (212 females (53%)) only those with written parental consent included. Excluded those with severe Iron deficiency anaemia (Hb equal or lower than 80 g/L and serum ferritin equal or lower than 20 μg/L) severe malnutrition weight-for-height <3rd percentile of Thai reference, chronic illness such as thalassaemia, haemolytic disease and physical handicaps. Participants assigned to group stratified by anaemia status. Baseline prevalence of anaemia:˜ 35%. This study took place in a socioeconomically disadvantaged community.

Interventions

Participants were allocated to one of the following groups:

Group1 (n = 134): each child received 2 bottles with tablets, the first was to be taken on Monday only while the second was to be taken for the remaining days of the week (60 mg of elemental iron (as ferrous sulphate) weekly;

Group 2 (n = 140): each child received 2 bottles with tablets, the first was to be taken on Monday only while the second was to be taken for the remaining days of the week. Both bottles had 60 mg of elemental iron (as ferrous sulphate) daily);

Group 3 (n = 123): Same procedure as groups 1 and 2 but children received placebo. The tablets were similar in colour, shape, size, and taste as the iron tablets.

Length of the intervention: 16 weeks

OutcomesHaemoglobin, serum ferritin, mean changes of both, height, weight.
NotesThis area is free from malaria
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskChildren were stratified by anaemic status to balance the proportion of anaemic and non anaemic children across the intervention groups. The children were then assigned by simple random allocation within each stratum using a computer random number generator.
Allocation concealment (selection bias)Low riskTablets placed in packages labelled only with participants' name, content not known to any of the project personnel. 2 supplement packages similar in appearance: On Mondays received one packages which contained iron for daily and weekly group, but placebo for control group. Rest of week consumed tablets from other package, which were iron for daily group and placebos for weekly and placebo control group.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants: neither parents nor participants knew the content of supplement packages.

Personnel: researchers did not know the content of supplement packages.

Outcome assessors: not reported but probably blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 6 of 397 enrolled lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.
Other biasUnclear riskBaseline prevalence of anaemia was different among study arms (39, 40 & 28%, for daily, weekly and placebo, respectively), but haemoglobin concentrations were not statistically different.

Tavil 2003

MethodsRandomised clinical trial. 2-arm design with randomisation at individual level.
Participants94 children aged 5 months to 6 years (median age was 18 months of age), both sexes (35 females (37.2%)), attending Dr Sami Ulus Children's Hospital in Ankara, Turkey, from December 1999 to December 2000. Inclusion criteria: iron deficiency anaemia (defined as haemoglobin (Hb) levels below 100 g/L, transferrin saturation levels below 12%, and ferritin levels below 12 ng/mL) and negative supplement intake during the past 3-4 weeks. Exclusion criteria: chronic, metabolic, and genetic diseases. Socioeconomic status not described.
Interventions

Participants were randomly allocated to one of the following groups:

Group 1 (n = 48): children received daily 6 mg/kg of elemental iron as ferrous sulphate;
Group 2 (n = 46): children received 6 mg/kg of elemental iron as ferrous sulphate 2 days a week (Tuesday and Friday) (120 mg of iron per week). .

Twenty-three healthy children whose age and gender distribution were compatible with the other groups were included in the study as the control group. This group was not included in the analyses.

Length of the intervention: 2 months

OutcomesHaemoglobin, hematocrit; red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, iron deficiency anaemia, serum iron, serum iron binding capacity, transferrin saturation, transferrin.
NotesMalaria endemicity not reported.
Risk of bias