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Base de datos Cochrane de Revisiones Sistemáticas Revisión - Intervención

Administración intermitente de suplementos de hierro para la reducción de la anemia y las deficiencias asociadas en mujeres adolescentes y adultas que menstrúan

Declaraciones de intereses de los autores

Versión publicada: 31 enero 2019 Historial de versiones

https://doi.org/10.1002/14651858.CD009218.pub3
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Resumen

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Antecedentes

La anemia es una enfermedad en que la cantidad de eritrocitos es insuficiente para satisfacer las necesidades fisiológicas. Está causada por muchos trastornos, especialmente la deficiencia de hierro. Tradicionalmente, la administración diaria de suplementos de hierro ha sido una práctica generalizada para la prevención y el tratamiento de la anemia. Sin embargo, el uso a largo plazo ha sido limitado, ya que se ha asociado con efectos secundarios adversos como náuseas, estreñimiento y manchas en los dientes. Se ha indicado que la administración intermitente de suplementos de hierro es una opción efectiva y más segura a la administración diaria para la prevención y la reducción de la anemia a nivel poblacional, sobre todo en áreas de alta prevalencia de la enfermedad.

Objetivos

Evaluar los efectos de la administración intermitente de suplementos de hierro por vía oral, solo o en combinación con otros nutrientes, sobre la anemia y las deficiencias asociadas en mujeres que menstrúan, en comparación con ninguna intervención, placebo o la administración diaria.

Métodos de búsqueda

En febrero de 2018, se buscó en CENTRAL, MEDLINE, Embase, otras nueve bases de datos y dos registros de ensayos. En marzo de 2018, también se buscó en LILACS, IBECS e IMBIOMED. También se examinaron las listas de referencias y se estableció contacto con autores y expertos conocidos para identificar estudios adicionales.

Criterios de selección

Ensayos controlados aleatorizados (ECA) y cuasialeatorizados con asignación al azar individual o grupal. Las participantes eran mujeres que menstruaban, es decir mujeres que ya han tenido la menarquia y antes de la menopausia, que no estaban embarazadas ni lactaban, y que no presentaban una afección conocida que impidiera la presencia de los períodos menstruales. La intervención fue el uso de suplementos de hierro administrados de forma intermitente (una, dos o tres veces a la semana en días no consecutivos) en comparación con ninguna intervención, placebo o los mismos suplementos diariamente.

Obtención y análisis de los datos

Los dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los estudios en relación con los criterios de inclusión, extrajeron los datos de los estudios incluidos, verificaron la exactitud de la introducción de los datos, evaluaron el riesgo de sesgo de los estudios incluidos y calificaron la certeza de la evidencia con los criterios GRADE.

Resultados principales

Se incluyeron 25 estudios con 10 996 mujeres. No se describieron los métodos de estudio en muchos de los estudios incluidos, por lo que fue difícil evaluar el riesgo de sesgo. Las limitaciones principales de los estudios fueron la falta de cegamiento y el desgaste alto. Los estudios fueron financiados principalmente por organizaciones internacionales, universidades y ministerios de salud nacionales. Cerca de un tercio de los estudios incluidos no indicó una fuente de financiamiento.

Aunque la calidad de los estudios fue variable, los resultados mostraron de forma consistente que la administración intermitente de suplementos de hierro (solos o con otras vitaminas y minerales), en comparación con ninguna intervención o un placebo, redujo el riesgo de presentar anemia (riesgo relativo [RR] 0,65; intervalo de confianza [IC] del 95%: 0,49 a 0.87; 11 estudios, 3135 participantes; evidencia de calidad baja), y mejoró la concentración de hemoglobina (diferencia de medias [DM] 5,19 g/l; IC del 95%: 3,07 a 7,32; 15 estudios, 2886 participantes; evidencia de calidad moderada), y ferritina (DM 7,46 μg/l; IC del 95%: 5,02 a 9,90; siete estudios, 1067 participantes; evidencia de calidad baja). Los regímenes intermitentes también pueden reducir el riesgo de presentar deficiencia de hierro (RR 0,50; IC del 95%: 0,24 a 1,04; tres estudios, 624 participantes; evidencia de calidad baja), pero la evidencia no fue concluyente con respecto a la anemia ferropénica (RR 0,07; IC del 95%: 0,00 a 1,16; un estudio, 97 participantes; evidencia de calidad muy baja) ni la morbilidad por todas las causas (RR 1,12; IC del 95%: 0,82 a 1,52; un estudio, 119 participantes; evidencia de calidad muy baja). Fue menos probable que las pacientes del grupo control presentaran efectos secundarios en comparación con las que recibieron los suplementos de hierro de forma intermitente (RR 1,98; IC del 95%: 0,31 a 12,72; tres estudios, 630 participantes; evidencia de calidad moderada).

En comparación con la administración diaria de suplementos, los resultados mostraron que la administración intermitente (sola o con otras vitaminas y minerales) produjo efectos similares a la administración diaria (solo o con otras vitaminas y minerales) en la anemia (RR 1,09; IC del 95%: 0,93 a 1,29; ocho estudios, 1749 participantes; evidencia de calidad moderada). La administración intermitente puede producir concentraciones de hemoglobina similares (DM 0,43 g/l; IC del 95%: ‐1,44 a 2,31; diez estudios, 2127 participantes; evidencia de calidad baja) pero concentraciones de ferritina más bajas en promedio (DM ‐6,07 μg/l; IC del 95%: ‐10,66 a ‐1,48; cuatro estudios, 988 participantes; evidencia de calidad baja) en comparación con la administración diaria. En comparación con los regímenes diarios, los regímenes intermitentes también pueden reducir el riesgo de tener una deficiencia de hierro (RR 4,30; IC del 95%: 0,56 a 33,20; un estudio, 198 participantes; evidencia de calidad muy baja). Las mujeres que recibieron suplementos de hierro de forma intermitente tuvieron menos probabilidades de presentar efectos secundarios adversos que las que recibieron suplementos de hierro diariamente (RR 0,41; IC del 95%: 0,21 a 0,82; seis estudios, 1166 participantes; evidencia de calidad moderada). Ningún estudio informó sobre el efecto de los regímenes intermitentes versus diarios en la anemia ferropénica y la morbilidad por todas las causas.

Es escasa la información sobre los resultados de la enfermedad, la adherencia, la productividad económica y el desempeño laboral, y la evidencia acerca de los efectos de la administración intermitente de suplementos es incierta.

En general, el hecho de si los suplementos se administraron una vez o dos veces por semana, por menos o más de tres meses, si contenían menos o más de 60 mg de hierro elemental por semana, o si se administraron a poblaciones con diferentes grados de anemia al inicio no pareció afectar los resultados. Además, no hubo diferencias en la respuesta en las áreas donde el paludismo es frecuente, aunque en estos ámbitos se realizaron muy pocos ensayos.

Conclusiones de los autores

La administración intermitente de suplementos de hierro puede reducir la anemia y mejorar las reservas de hierro en mujeres que menstrúan con distintos antecedentes de anemia y paludismo. En comparación con la administración diaria de suplementos, la administración intermitente es menos efectiva para prevenir o controlar la anemia. Se necesita más información sobre la morbilidad (incluidos los resultados del paludismo), los efectos secundarios, el desempeño laboral, la productividad económica, la depresión y la adherencia a la intervención. La calidad de esta base de la evidencia varió de muy baja a moderada, lo que sugiere la falta de certeza acerca de estos efectos.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Suplementos de hierro una, dos o tres veces por semana para la prevención de la anemia y sus consecuencias en mujeres que menstrúan

¿Cuál es el problema?

En todo el mundo, aproximadamente una de cada tres mujeres no embarazadas en edad fértil presenta anemia, es decir, tienen menos glóbulos rojos o menos hemoglobina (una sustancia roja que se combina con el oxígeno y lo transporta por el organismo) de la normal en cada glóbulo rojo. Aunque existen varias causas de anemia, con frecuencia es resultado de la deficiencia de hierro sostenida. La práctica generalizada para la prevención o el tratamiento de la anemia en mujeres ha sido la administración diaria de suplementos de hierro (a veces combinado con ácido fólico y otras vitaminas y minerales) durante tres meses. Sin embargo, esta práctica se asocia a menudo con efectos secundarios como náuseas o estreñimiento. La administración intermitente de suplementos (que es el consumo de suplementos una, dos o tres veces a la semana en días no consecutivos) se ha propuesto como una opción eficaz y más segura a la administración diaria de suplementos.

¿Por qué es esto importante?

Las mujeres con anemia pueden sentirse con menos energía para la actividad física y tornarse más propensas a las infecciones. La mayoría de las mujeres en todo el mundo comienzan el embarazo con anemia, lo que aumenta el riesgo de recién nacidos de bajo peso al nacer y otras complicaciones durante el parto.

Algunos científicos creen que la administración de hierro varias veces por semana (en lugar de todos los días) mejora el estado de las pacientes con anemia y los niveles de hemoglobina sin tantos efectos secundarios. Si las pacientes presentan menos efectos secundarios, es más probable que tomen los suplementos de hierro de modo más regular y por períodos más prolongados.

¿Qué evidencia se encontró?

Se revisó la evidencia hasta febrero de 2018. Se incluyeron 25 ensayos controlados aleatorizados (un tipo de experimento en que los participantes se asignan al azar a uno o más grupos de tratamiento) con 10 996 mujeres. Se incluyeron los estudios que examinaron la administración intermitente de suplementos de hierro versus ninguna intervención, placebo (comprimido inactivo) o los mismos suplementos administrados diariamente. La mayoría de los estudios se realizaron en ámbitos escolares y financiados sobre todo por organizaciones internacionales, universidades y ministerios de salud nacionales. Cerca de un tercio de los estudios incluidos no indicó una fuente de financiamiento.

Los resultados muestran que fue menos probable que las pacientes con administración intermitente de suplementos con hierro solo, o en combinación con ácido fólico u otros nutrientes, presentaran anemia o deficiencia de hierro en comparación con las pacientes a las que no se les indicó ningún suplemento de hierro o se les indicó un placebo. Además, también presentaron una mayor concentración de hemoglobina y ferritina (una proteína que transporta el hierro), pero informaron más efectos secundarios.

Asimismo, los resultados indican que la administración intermitente de suplementos tuvo la misma efectividad que la administración diaria en la reducción de la prevalencia de la anemia y en el aumento de la concentración de hemoglobina, con menos efectos secundarios. Es posible que también haya reducido el riesgo de tener una deficiencia de hierro, pero no tuvo efectos en el aumento de las concentraciones de ferritina más que la dosis diaria.

Se encontró escasa evidencia sobre el efecto de la administración intermitente de suplementos en comparación con placebo o la administración diaria sobre la anemia ferropénica, la morbilidad por todas las causas, los resultados de la enfermedad, la adherencia, la productividad económica y el desempeño laboral.

¿Qué significa esto?

La administración intermitente de suplementos de hierro en mujeres que menstrúan puede ser una intervención efectiva para disminuir la anemia y mejorar la concentración de hemoglobina en comparación con ningún tratamiento, placebo o la administración diaria. La administración intermitente de suplementos se puede asociar con menos efectos secundarios en comparación con la administración diaria. Los resultados no se vieron afectados por ninguna de las siguientes condiciones: administración una o dos veces por semana de los suplementos, duración de menos o más de tres meses, contenido de menos o más de 60 mg de hierro elemental por semana, administración a poblaciones con diferentes grados de anemia al inicio (punto de partida para las comparaciones). La calidad general de la base de la evidencia fue baja.

Authors' conclusions

Implications for practice

Intermittent supplementation with iron alone or in combination with other micronutrients may reduce anaemia and may improve iron stores among menstruating women in populations with different anaemia and malaria backgrounds. Women receiving supplements intermittently can probably reduce their anaemia and may achieve similar haemoglobin concentrations at the end of the intervention than women receiving supplements daily. With the current evidence, there is no indication that this intervention has detrimental effects on women's health and other indicators of nutritional status. Good supervision and adherence is fundamental for the intervention to succeed. Intermittent iron supplementation is a feasible intervention for reaching other populations in a variety of settings, outside antenatal‐care (ANC) visits, immunisation programmes, and health programmes for adolescents and women of reproductive age.

Most studies provided 60 mg of elemental iron or more on a weekly basis, and the effect on the haematological status may not be affected by the duration of the intervention. The provision of micronutrients other than iron may not alter the haematological response. Iron and folic acid supplementation, therefore, have the possibility of impacting not only menstruating women, but also of benefiting those women who become pregnant and their babies, and improving their nutritional status and impacting other indicators of micronutrients status and health.

The evidence on the efficacy and effectiveness of this intervention is uncertain due to the low quality of the evidence base. The true effect may be substantially different from the estimate of the effect.

Implications for research

This review has highlighted the need for further research in this area, particularly on:

  1. side effects and adherence to the intervention;

  2. patient‐important outcomes and adverse effects;

  3. the effects of the provision of multiple micronutrients on an intermittent basis and their effect on iron status and other indicators of micronutrients status and health;

  4. the periodicity of intermittent iron supplementation to maintain an adequate iron status throughout the reproductive years;

  5. the effective and safe dose of folic acid that should be used along with iron to supplement women intermittently;

  6. the effects of intermittent iron supplementation regimens on work performance and productivity outcomes;

  7. economic analyses; and

  8. the effects of intermittent iron supplementation regimens on malaria outcomes.

Lack of methodological rigor in some RCTs included in this review has resulted in low‐quality evidence in the review. Improving the quality of primary studies is needed.

Summary of findings

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Summary of findings 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women

Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women

Patient or population: adolescent and adult menstruating women
Setting: community settings
Intervention: intermittent iron supplementation (alone or with any other micronutrients)
Comparison: no supplementation or placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants (studies)

Quality of the evidence
(GRADE)

Comments

Risk with no supplementation or placebo

Risk with intermittent iron supplementation (alone or with any other micronutrients)

Anaemia (haemoglobin concentration below a cut‐off defined by the trialists, adjusted by altitude and smoking as appropriate)
Follow‐up: range 2 months to 6 months

Study population

RR 0.65
(0.49 to 0.87)

3135 (11 studies)

⊕⊕⊝⊝
Lowa

Includes seven cluster‐randomised trials b

39 per 100

25 per 100
(19 to 34)

Haemoglobin (g/L)
Follow‐up: range 2 months to 6 months

The mean haemoglobin g/L in the control groups ranged from −0.24 to 133.20

The mean haemoglobin g/L in the intervention groups was5.19 higher (3.07 higher to 7.32 higher)

‐

2886 (15 studies)

⊕⊕⊕⊝
Moderatec

Includes five cluster‐randomised trials b

Iron deficiency (as defined by trialists by using indicators of iron status such as ferritin or transferrin)
Follow‐up: range 3 months to 4 months

Study population

RR 0.50
(0.24 to 1.04)

624 (3 studies)

⊕⊕⊝⊝
Lowd

Includes one cluster‐randomised trial b

49 per 100

25 per 100
(12 to 51)

Ferritin (µg/L)
Follow‐up: range 3 months to 6 months

The mean ferritin µg/L in the control groups ranged from −5.31 to 41

The mean ferritin μg/L in the intervention groups was7.46 higher (5.02 higher to 9.90 higher)

‐

1067 (7 studies)

⊕⊕⊝⊝
Lowe

Includes one cluster‐randomised trial b

Iron deficiency anaemia (as defined by the presence of anaemia plus iron deficiency diagnosed with an indicator of iron status selected by the trialists)
Follow‐up: 4 months

Study population

RR 0.07
(0.00 to 1.16)

97 (1 study)

⊕⊕⊝⊝
Lowf

The included trial is a cluster‐randomised trial b

7 per 100

1 per 100
(0 to 8)

All‐cause morbidity (the most frequent event associated with the intervention, independent of the cause, as defined by the trialists)

Follow‐up: 4 months

Study population

RR 1.12
(0.82 to 1.52)

119 (1 study)

⊕⊕⊝⊝
Lowg

‐

55 per 100

61 per 100
(45 to 83)

Any adverse side effects

13 per 100

26 per 100

(4 to 100)

RR 1.98

(0.31 to 12.72)

630

(3 studies)

⊕⊕⊕⊝
Moderateh

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

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 are moderately confident 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 effect.

aDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) and one level due to inconsistency (high heterogeneity) (I2 = 83%).
bFor cluster‐randomised trials (C), the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.
cDowngraded one level due to inconsistency (high heterogeneity) (I2 = 85%).
dDowngraded one level due to imprecision (wide CI) and one level due to inconsistency (high heterogeneity) (I2 = 89%).
eDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) and one level due to imprecision (wide CI) (I2 = 48%).
fDowngraded one level due to lack of blinding and one level due to imprecision (wide CI and not enough information to detect a precise estimate of the effect ‐ only one study reported on this outcome) (I2 = not estimable).
gDowngraded one level due to study attrition and one level due to imprecision (not enough information to detect a precise estimate of the effect ‐ only one study reported on this outcome) (I2 = not estimable).
hDowngraded one level due to inconsistency (high heterogeneity) (l2 = 91%)

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Summary of findings 2. Intermittent iron supplementation versus daily iron supplementation in menstruating women

Intermittent iron supplementation versus daily iron supplementation in menstruating women

Patient or population: adolescent and adult menstruating women
Setting: community settings
Intervention: intermittent iron supplementation alone or with any other micronutrients
Comparison: daily iron supplementation alone or with any other micronutrients

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants (studies)

Quality of the evidence
(GRADE)

Comments

Risk with daily iron supplementation

Risk with intermittent iron supplementation

Anaemia (haemoglobin concentration below a cut‐off defined by the trialists, adjusted by altitude and smoking as appropriate)
Follow‐up: range 2 months to 4 months

Study population

RR 1.09
(0.93 to 1.29)

1749 (8 studies)

⊕⊕⊕⊝
Moderatea

Includes two cluster‐randomised trials* b

23 per 100

25 per 100
(22 to 30)

Haemoglobin (g/L)
Follow‐up: range 2 months to 1 year

The mean haemoglobin g/L in the control groups ranged from 7.40 g/L to 132.00 g/L

The mean haemoglobin g/L in the intervention groups was 0.43 g/L higher (1.44 lower to 2.31 higher)

‐

2127 (10 studies)

⊕⊕⊝⊝
Lowc

Includes two cluster‐randomised trials* b

Iron deficiency (as defined by the trialists using indicators of iron status such as ferritin or transferrin)
Follow‐up: mean 3 months

Study population

RR 4.30
(0.56 to 33.20)

198 (1 study)

⊕⊝⊝⊝
Very lowd

‐

2 per 100

7 per 100
(1 to 52)

Ferritin (µg/L)
Follow‐up: range 2 months to 1 year

The mean ferritin µg/L in the control groups ranged from 16.70 µg/L to 62.00 µg/L

The mean ferritin µg/L in the intervention groups was 6.07 µg/L lower (10.66 lower to 1.48 lower)

‐

988
(4 studies)

⊕⊕⊝⊝
Lowe

Includes one cluster‐randomised trial b

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

Not estimable

‐

(0 studies)

‐

‐

All‐cause morbidity (the most frequent event associated with the intervention, independent of the cause, as defined by the trialists)

Not estimable

‐

(0 studies)

‐

‐

Any adverse side effects

29 per 100

2 per 100

(6 to 24)

RR 0.41

(0.21 to 0.82)

1166

(6 studies)

⊕⊕⊕⊝
Lowf

Includes one cluster‐randomised trial b

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

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 are moderately confident 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 effect.

aDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) (I2 = 12%).
bFor cluster‐randomised studies (C), the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.
cDowngraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 78%).
dDowngraded two levels due to imprecision (only one study with 25 losses to follow‐up reported data on this outcome; wide CI) and one level for study limitations (concerns about attrition) (l2 = not estimable).
eDowngraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 91%).
f Downgraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 82%).

Background

Description of the condition

Anaemia is a condition in which the oxygen‐carrying capacity of the blood is insufficient to meet the physiologic needs of body tissues. The global prevalence of this condition in non‐pregnant women of reproductive age is estimated to be 29.0% (WHO 2015), and it is more frequent in low‐ and middle‐income countries or among women who belong to a low socioeconomic stratum (Soekarjo 2001; Bodnar 2002; Bentley 2003). Anaemia has multiple direct causes that very often coexist: it can result from parasitic infections (Kumar 2007; Anah 2008); inflammatory disorders (Yip 1988); inherited disorders of haemoglobin structure; oxidative stress (i.e. imbalance between free radicals and antioxidants) and vitamin and mineral deficiencies such as that of vitamins A and B12, and folate (Herbert 1987; Hercberg 1992; Jimenez 2010), and especially iron, which is responsible for at least half of the cases of anaemia (WHO 2001).

Iron deficiency results from long‐term imbalance caused by inadequate dietary iron intake, poor iron absorption or utilisation, increased iron requirements, or chronic blood loss (Alleyne 2008). Individual iron requirements vary considerably throughout the human life cycle (Lynch 2007), and both physiological (for example, pregnancy or early postpartum) or pathological (for example, HIV infection) conditions affect iron requirements (WHO 2001). Postmenarchal women are at higher risk of developing iron deficiency because of menstrual losses, and if they do not have an adequate iron intake, this condition can progress to anaemia (known as iron deficiency anaemia or IDA).

Iron deficiency is one of the most prevalent forms of malnutrition globally. It is estimated that 50% of anaemia is attributable to iron deficiency worldwide (WHO 2001). Iron deficiency, even in the absence of anaemia, may either cause disability directly or be a risk factor for it (Stoltzfus 2003). For example, it causes impaired muscle function and impaired resistance to infections in all age groups (Beard 2005), and it is associated with reduced physical capacity and work performance in adolescents and adults (Beard 2001; WHO 2001; Clark 2008). Most women throughout the world enter pregnancy with less than desirable iron reserves, which reduce their reproductive performance (Viteri 2005). In addition to iron deficiency, women are frequently deficient in other vitamins and minerals that play important roles in the body (Ramakrishnan 2002; Kontic‐Vucinic 2006; Ahmed 2008). An adequate folate intake during the periconceptional period, for example, is crucial to reducing the risk of having a baby with neural tube defects (NTDs) (De‐Regil 2015); vitamin B12 and folate deficiencies are major causes of anaemia (Green 2017), while vitamin A regulates many critical functions, including vision, integrity of epithelial tissue (i.e. membranous tissue covering internal organs and other internal surfaces of the body), the expression of several hundred genes, and its deficiency also contributes to nutritional anaemia (WHO 2011a). Although these deficiencies may not translate into a comparable prevalence of anaemia, supplementation of these nutrients in women may improve their health throughout life, as there is some indication that these deficiencies are of public health concern in certain countries (McLean 2008).

Anaemia in women of reproductive age is diagnosed when the haemoglobin concentration in the blood is below 120 g/L, a cut‐off that varies with residential elevation above sea level (altitude) and smoking (WHO 2011b). Iron deficiency anaemia is diagnosed by the combined presence of anaemia and iron deficiency, measured by ferritin (< 15 μg/L) or any other indicator of iron status such as serum transferrin receptors or zinc protoporphyrin (WHO 2011c).

Description of the intervention

Daily iron plus folic acid supplementation remains the standard approach for the prevention and treatment of anaemia among menstruating women, since dietary changes alone usually cannot correct this condition, as the iron content in the diet is relatively constant and difficult to increase (DeMaeyer 1989). The recommended daily, supplemental dosage for non‐pregnant women of reproductive age living in countries where anaemia is highly prevalent (i.e. above 40%) is 60 mg of elemental iron and 400 µg of folic acid for three months (WHO 2001). The use of folic acid prior to pregnancy aims to improve folate status, and this dose has been shown to be effective for preventing NTDs in women who become pregnant (WHO 2001). Despite its proven efficacy, the main problem with the daily regimen is lack of compliance, due to side effects such as diarrhoea, constipation, dark stools, metallic taste, teeth staining, and nausea (Yip 1994).

Intermittent oral iron supplementation (i.e. one, two or three times a week on non‐consecutive days) has been suggested as an effective alternative to daily iron supplementation to prevent anaemia at the population level. The efficacy of intermittent iron supplementation for the prevention of anaemia and iron deficiency has been studied over the last 15 years in children, adolescents and pregnant and non‐pregnant women of reproductive age. A review of 22 trials performed in all of these groups concluded that both daily and once‐weekly iron supplementation were efficacious under favourable conditions in reducing anaemia (Beaton 1999). Subsequent trials in menstruating women have confirmed these findings (Crape 2005; Khan 2005; Paulino 2005), although some study authors have suggested that the weekly intake of supplemental iron may be insufficient to meet women's needs and have proposed the use of iron supplements twice a week (Kianfar 2000; Olsen 2000). Recent trials have used a variety of intermittent iron supplementation schemes such as: a double dose, once‐ and twice‐a‐week scheme, which reduced iron deficiency efficiently (Ahmed 2012); and a once‐a‐week scheme, with and without other micronutrients, which improved iron status (Bansal 2016) and haemoglobin concentration significantly (Kätelhut 1996).

The international recommendation for weekly supplementation for non‐pregnant women of reproductive age is that supplements should contain 60 mg of elemental iron in the form of ferrous sulphate and 2800 µg (2.8 mg) of folic acid (WHO 2011d). Although evidence for the effective dose of folic acid for intermittent supplementation is very limited, the current recommendation is based on the rationale of providing seven times the recommended daily dose to prevent NTDs, and experimental evidence that high weekly doses can improve red blood cell folate concentrations to levels that have been associated with a reduced risk of NTDs (Martinez‐de Villareal 2001; Martinez‐de Villareal 2002; Norsworthy 2004; Nguyen 2008). However, some countries have chosen to give a higher dose in their programmes. India, for example, provides 100 mg of elemental iron (Vir 2008) under supervised and unsupervised conditions, decreasing the prevalence of anaemia from 73.3% to 25.4%. The provision of vitamins and minerals other than iron and folic acid on an intermittent basis may also help to supplement women's diets and therefore improve health and development throughout the life cycle (Allen 2009a; Allen 2009b; Dalmiya 2009).

How the intervention might work

Intestinal cells turn over every five to six days in humans. Hence, providing iron on an intermittent basis would expose this nutrient to new mucosal cells (made up of epithelial tissue) only, improving absorption efficiency (Viteri 1995), and reducing oxidative stress and side effects (Viteri 2005). It may also reduce absorption blockage due to high iron levels in the gut lumen (i.e. inside space of the gut) and in the enterocyte (i.e. intestinal cell) (Anderson 2005; Oates 2007). Intermittent regimens may be perceived as more tolerable, ergo increasing adherence to supplementation (Casanueva 2006). In order to improve the success of this intervention, the World Health Organization (WHO) encourages the integration of intermittent iron supplementation programmes with other public health measures, including deworming to prevent hookworm infections, improved bioavailable dietary iron intake, and interventions to control other prevalent causes of anaemia, particularly malaria, other infections, and vitamin A deficiency (WHO 2011d).

The endemicity of malaria in a given region is an important consideration when providing iron supplements at the population level. Malaria, which is responsible for more than a million deaths per year (Gajida 2010), causes anaemia through several mechanisms. Provision of iron in malaria‐endemic areas, particularly to children, has been a long‐standing controversy due to concerns that iron therapy may exacerbate infections, particularly malaria (Oppenheimer 2001; Okabe 2011). Although the mechanisms by which additional iron can benefit the parasite are far from clear (Prentice 2007), intermittent supplementation might be an effective option to prevent anaemia and improve malaria treatment in malaria‐endemic areas since less iron is available for the parasite.

Why it is important to do this review

Improving iron and folate nutrition of adolescent and adult menstruating women may contribute to adequate mental and physical performance and reproductive health, which may, in turn, significantly enhance maternal and infant health outcomes. Intermittent supplementation is proposed as a viable approach for improving iron and folate status in populations, especially in areas where anaemia is highly prevalent, and where mass fortification of staple foods with iron and folic acid is not available and not likely to be available in the near future.

After the publication of the first version of this review (Fernández‐Gaxiola 2011a), WHO published guidelines on intermittent iron supplementation (WHO 2011d), and WHO Member States committed to the World Health Assembly to halve anaemia in pregnant and non‐pregnant women of reproductive age by 2025 (WHO 2014). To date, weekly iron supplementation has been implemented in more than 10 countries in Asia and Africa, but there is still a need for the literature to be systematically reviewed so there is updated evidence on the efficacy, effectiveness, and safety of this intervention, to inform a possible scale‐up as part of public health programmes.

This is an update of the previous review (Fernández‐Gaxiola 2011a), which was to inform the WHO guideline on intermittent supplementation in menstruating women (WHO 2011d). The evidence will complement the findings of other Cochrane Reviews exploring the effects of intermittent regimens among pregnant women (Peña‐Rosas 2015), the effects of intermittent iron supplementation in children under 12 years of age (De‐Regil 2011), and the effect of oral iron supplementation on preventing and treating anaemia among children in malaria‐endemic areas (Okabe 2011).

Objectives

To assess the effects of intermittent oral iron supplementation, alone or in combination with other nutrients, on anaemia and its associated impairments among menstruating women, compared with no intervention, a placebo, or daily supplementation.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs with randomisation at either the individual or cluster level. Quasi‐RCTs are trials that use systematic methods to allocate participants to treatment groups such as alternation or assignment based on date of birth or case record number (Reeves 2011).

Types of participants

Menstruating women; that is, women beyond menarche and prior to menopause who are not pregnant or lactating or have any condition that impedes the presence of menstrual periods, regardless of their baseline iron status or anaemia status, ethnicity, country of residence, or level of endurance.

We did not include studies targeting women with conditions affecting iron metabolism such as intestinal malabsorption conditions, ongoing excessive blood loss (including ongoing blood donations), inflammatory bowel disease, cancer, chronic congestive cardiac failure, chronic renal failure, chronic liver failure, or chronic infectious disease.

Types of interventions

Interventions involving an intermittent dosage of oral iron, either alone or with other vitamins and minerals, versus no intervention or placebo or the same supplements provided on a daily basis.

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. intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo; and

  2. intermittent iron supplementation versus daily iron supplementation.

We included studies that combined iron supplementation with other cointerventions, such as education or deworming, but only if the other cointerventions 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 foodlet (i.e. food‐like) tablets, or biofortification.

Types of outcome measures

Primary outcomes

  1. Anaemia (haemoglobin concentration below a cut‐off defined by the trialists, adjusted by altitude and smoking, as appropriate)*

  2. Haemoglobin (g/L)*

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

  4. Ferritin (µg/L)*

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

  6. All‐cause morbidity (the most frequent event associated with the intervention, independent of the cause, as defined by the trialists)*

* Outcomes included in the 'Summary of findings' tables.

Secondary outcomes

  1. Diarrhoea (number of women with at least three liquid stools in one day)

  2. Respiratory infections (as defined by the trialists)

  3. Any adverse side effects (e.g. nausea, vomiting, constipation, gastrointestinal discomfort, as defined by the trialists)

  4. Work performance and economic productivity (as defined by the trialists)

  5. School performance and cognitive function (for adolescents) (as defined by the trialists)

  6. Depression (as defined by trialists)

  7. Adherence (percentage of participants who consumed 70% or more of the prescribed dosage throughout the trial)

We considered the following outcomes in malaria settings only.

  1. Malaria incidence (as defined by the trialists)

  2. Malaria severity (as defined by the trialists)

All outcomes were evaluated at the end of the intervention or at the time point closest to the end.

Search methods for identification of studies

We analysed the indexing terms in the MEDLINE records for the included studies in the first version of this review using Yale MeSH Analyser (Grossetta Nardini 2017), and concluded that a number of indexing terms used in the previous strategy were redundant. We revised the search strategy for this update by removing these terms, which increased the precision of the search (Appendix 1). Search strategies for the previous version of this review are in Appendix 2. We limited our searches to studies published from 1980 onwards since the first trials on this intervention were published after this year. We did not apply any language restrictions. For those articles written in a language other than English, we commissioned their translation into English, to assess them for eligibility according to the prespecified selection criteria (Criteria for considering studies for this review).

Electronic searches

For this update, we searched the electronic databases and trials registers listed below up to February 2018, apart from Scientific Electronic Library Online (SciELO), IBECS and IMBIOMED, which we searched in March 2018.

  1. Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1) in the Cochrane Library, which contains the Developmental, Psychosocial and Learning Problems Specialised Register (searched 20 February 2018).

  2. MEDLINE Ovid (1946 to February week 2 2018).

  3. MEDLINE In‐Process & Other Non‐Indexed Citations Ovid (searched 20 February 2018).

  4. MEDLINE Epub Ahead of Print Ovid (searched 20 February 2018).

  5. Embase Ovid (1974 to week 8 2018).

  6. CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1937 to 21 February 2018).

  7. Science Citation Index Web of Science (SCI; 1970 to 20 February 2018).

  8. Conference Proceedings Citation Index ‐ Science Web of Science (CPCI‐S; 1990 to 20 February 2018).

  9. Cochrane Databse of Systematic Reviews (CDSR; 2017, Issue 12), in the Cochrane Library (searched 20 February 2018).

  10. Database of Abstracts of Reviews of Effectiveness (DARE; 2015, Issue 2), in the Cochrane Library (final issue of DARE searched 13 January 2017).

  11. POPLINE (www.popline.org; searched 22 February 2018).

  12. SciELO (www.scielo.org/php/index.php?lang=es; searched 8 March 2018).

  13. LILACS (Latin American and Caribbean Health Science Information database; lilacs.bvsalud.org/en; searched 20 February 2018).

  14. IBECS (ibecs.isciii.es; searched 5 March 2018).

  15. IMBIOMED (www.imbiomed.com.mx/1/1/catalogo.html; searched 10 March 2018).

  16. ClinicalTrials.gov (clinicaltrials.gov; searched 22 February 2018).

  17. WHO International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch; searched 22 February 2018).

See Differences between protocol and review for changes to the search methods used in this update.

Searching other resources

We contacted authors and known experts in the field for additional or unpublished data in order to identify any ongoing or unpublished studies. We also contacted the Departments of Nutrition for Health and Development, regional offices of the WHO, the nutrition section of the US Centers for Disease Control and Prevention (CDC), United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI), Helen Keller International (HKI), and the Sight and Life Foundation. In addition, we screened the reference lists of previously published reviews in order to identify other possible studies. One review author (LD‐R) searched these additional sources.

Data collection and analysis

We summarised the methods that we had planned to use, as per our published protocol (Fernández‐Gaxiola 2011b), but did not in Table 1. We may use these methods in future updates of this review.

Open in table viewer
Table 1. Unused methods

Method

Approach

Reason for non‐use

Measures of treatment effects

Continuous data

We had planned to use the SMD to combine trials that measured the same outcome but used different methods.

There was no need to use the SMD to combine trials as outcomes were measured with the same methods.

Sensitivity analysis

We had planned to conduct a sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with unclear or high risk of bias for sequence generation and allocation concealment, and either high levels of attrition or no blinding) from the analyses and comparing the effect.

It was not possible to conduct this analysis because only two studies were considered at low risk of bias according to our predefined criteria (Hall 2002 (C) and Nguyen 2008).

We had planned to conduct a sensitivity analysis to explore the effect of missing data.

We were not able to conduct this analysis given that 13 out of 25 studies had attrition, and 22 out of 25 studies had unclear risk of reporting bias.

SMD: standardised mean difference

Selection of studies

Using Covidence systematic review software (Covidence 2017), both reviewers (AF‐G; LD‐R) independently screened titles and abstracts of all records yielded by the searches against the selection criteria (Criteria for considering studies for this review), discarding those that were clearly irrelevant. Next, they both obtained the full‐text reports of all relevant or potentially relevant studies that seemed to meet the inclusion criteria, and assessed them for eligibility. There were a few disagreements, due to oversights of either one of the review authors, which they resolved through discussion.

We recorded the decisions of our selection process in a PRISMA diagram (Moher 2009).

Data extraction and management

Both review authors (AF‐G; LD‐R) independently extracted data from eligible studies using Covidence (Covidence 2017) and a form designed to collect other detailed data for this review. AF‐G entered the data into Review Manager 5 (RevMan 5) (Review Manager 2014), and LD‐R carried out checks for accuracy. We resolved any discrepancies through discussion. If the information regarding any of the studies was unclear, we attempted to contact the authors of the original reports, to ask them to provide further details.

We completed the data collection form electronically and recorded information (as set out below) on: study design; setting and participants (inclusion and exclusion criteria); study methods and assessment of risk of bias (see Assessment of risk of bias in included studies); intervention (for example, compound, dose, regimen, duration of intervention); outcomes (with details of how and when measured); and results.

  1. Trial methods:

    1. method of allocation and unit of randomisation;

    2. masking of participants and outcomes; and

    3. exclusion of participants after randomisation and proportion of losses at follow‐up.

  2. Participants:

    1. country of origin;

    2. sample size;

    3. age;

    4. sex;

    5. socioeconomic status; and

    6. inclusion and exclusion criteria, as described under Criteria for considering studies for this review.

  3. Intervention:

    1. type;

    2. dose;

    3. frequency;

    4. duration and length of time in follow‐up; and

    5. cointervention.

  4. Control:

    1. control, placebo, or daily supplementation.

  5. Outcomes:

    1. primary and secondary outcomes, as outlined under Types of outcome measures.

Assessment of risk of bias in included studies

Each reviewer independently assessed the risk of bias in each included study using a simple contingency form that followed the domain‐based evaluation (sequence generation; allocation concealment; blinding; incomplete outcome data; selective reporting bias; other sources of bias), described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) and set out in Appendix 3. If there was insufficient information to assess the risk of bias, we rated the domain at 'unclear risk of bias', until further information was published or made available to us. If there was sufficient information, we categorised the domain as being either at 'low risk of bias' or 'high risk of bias' accordingly. We resolved any disagreements by discussion.

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 Interventions (Higgins 2011a). With reference to the domains listed above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We considered a study to be at low risk of bias overall if it was assessed at low risk of bias for both sequence generation and allocation concealment and either blinding or incomplete outcome data.

For the second, we assessed the quality of the evidence for each individual outcome using the GRADE approach (Balshem 2010; Schünemann 2011); see 'Summary of findings' tables (beneath Data synthesis) below.

We reported the results of our assessment in the 'Risk of bias in included studies' section, in the 'Risk of bias' tables (beneath the Characteristics of included studies tables), in summary of findings Table 1 and summary of findings Table 2, and graphically.

Measures of treatment effect

Dichotomous data

We presented dichotomous outcome data as average risk ratios (RRs) with 95% confidence intervals (CIs).

Continuous data

We presented continuous outcome data as mean differences (MD) with 95% CIs, measured at the end of the intervention. If studies did not provide this information but reported the mean change, we included these data as suggested in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

See also Table 1 and Fernández‐Gaxiola 2011b.

Unit of analysis issues

Cluster‐randomised studies

We included cluster‐randomised studies in the analyses with individually‐randomised studies; cluster‐randomised studies are labelled with a (C). We estimated effective sample sizes for each one of them in order to perform correct analyses according to Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

We obtained the intra‐cluster correlation coefficients (ICC) from Hall 2002 (C) (ICC = 0.0698; average cluster size (ACS) = 18.55; design effect (DE) = 2.22) and Roschnik 2003 (C) (ICC = 0.1123; ACS = 29.0, DE = 4.35), which we imputed to all cluster studies except Roschnik 2003 (C). We then calculated the ACS from the reports and estimated each study's effective sample size. Based on other reports (Okabe 2011), we assumed an average cluster size of 32 for classes, when the average cluster size or number of clusters and individuals were not clear (Agarwal 2003 (C); Soekarjo 2004 (C)). In summary, we used the following information to account for the effect clustering in the data: Jayatissa 1999 (C) (ACS = 25.6; DE = 2.71); Muro 1999 (C) (ACS = 43.1; DE = 3.94); Agarwal 2003 (C) (ACS = 32; DE = 3.16); Soekarjo 2004 (C) (ACS = 32; DE = 3.16); Mozaffari 2010 (C) (ACS = 25; DE = 2.68).

Additionally, we conducted sensitivity analyses to examine the potential effect of clustering on the CI of the summary estimates, by removing cluster‐RCTs from the analyses and comparing the effects (Sensitivity analysis).

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 2011a), 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

As specified in our protocol (Fernández‐Gaxiola 2011b), we did not include cross‐over trials.

Dealing with missing data

For included studies, we noted the levels of attrition and reported it in the 'Risk of bias' tables (beneath the Characteristics of included studies tables).

We carried out analyses, as far as possible, on an intention‐to‐treat (ITT) basis; 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 we analysed the data for each and every participant for whom the outcome was obtained.

Assessment of heterogeneity

We assessed methodological heterogeneity by examining the risk of bias of the studies, and clinical heterogeneity by examining the similarity between the types of participants, interventions and outcomes. For statistical heterogeneity, we examined the forest plots from meta‐analyses to look for heterogeneity among studies, and used the I2 statistic, Tau2 and Chi2 tests as heterogeneity statistics to quantify the level of heterogeneity among the studies included in each analysis. When we identified moderate or substantial heterogeneity (I2 greater than approximately 30%), we explored it by conducting prespecified subgroup analyses (see Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

When we suspected reporting bias (see 'Selective reporting bias' under Assessment of risk of bias in included studies), we attempted to contact the study authors to ask them to provide missing outcome data. We investigated reporting biases (such as possible publication bias) using funnel plots, assessing asymmetry visually.

Data synthesis

We carried out statistical analyses using RevMan 5 (Review Manager 2014). We used random‐effects meta‐analyses due to possible heterogeneity in the interventions, populations and methods used in different trials. We used Mantel‐Haenszel weighting for dichotomous outcomes and inverse variance for continuous outcomes, to adjust the effect measure according to the extent of its variation both between and within studies.

'Summary of findings' table

We presented the main findings of the review in 'Summary of findings' tables, which we prepared using GRADE profiler software (GRADEpro 2015). We created two 'Summary of findings' tables for both main comparisons: 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo (summary of findings Table 1); and 2. intermittent iron supplementation versus daily iron supplementation (summary of findings Table 2). We included the following primary outcomes at the end of the intervention or at the time point closest to the end in these tables: anaemia (haemoglobin concentration below a cut‐off defined by trialists); haemoglobin (g/L); iron deficiency (as defined by trialists by using indicators of iron status such as ferritin or transferrin); ferritin (µg/L); iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency diagnosed with an indicator of iron status selected by trialists); all‐cause morbidity (the most frequent event associated with the intervention independent of the cause, as defined by the trialists) (see Primary outcomes). We also listed estimates of relative effects along with the number of participants and studies contributing data for each outcome.

Both review authors independently assessed the quality of the evidence for each individual outcome using the GRADE approach (Balshem 2010; Schünemann 2011), which involves consideration of within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates, and risk of publication bias. The results were expressed as one of four levels of quality (high, moderate, low, or very low).

Subgroup analysis and investigation of heterogeneity

When data were available and it was appropriate, we carried out the following subgroup analyses on three primary outcomes (anaemia, haemoglobin, and ferritin concentrations), to look for possible differences between studies (note, we pragmatically decided not to conduct subgroup analyses on those outcomes with three trials or fewer).

  1. Composition: iron alone; iron + folic acid; iron + multiple micronutrients

  2. Anaemia status at baseline (haemoglobin < 120 g/L, adjusted by altitude and smoking, as appropriate): anaemic; non‐anaemic; mixed/unknown

  3. Iron status at baseline (as defined by the trialists): iron deficient; not iron deficient; mixed/unknown

  4. Dose of elemental iron per week in the intermittent group: 60 mg of iron or less; more than 60 mg of iron

  5. Duration of supplementation: three months or less; more than three months

  6. Malaria status of the area at the time of the trial (as reported by trialists): yes; no/unknown

We examined differences between subgroups by visual inspection of the subgroups’ CI, with non‐overlapping CI suggesting a statistically significant difference in treatment effect between subgroups. We also used the Borenstein 2008 approach to formally investigate differences between two or more subgroup categories.

Sensitivity analysis

We conducted sensitivity analyses ad hoc to examine the potential effect of clustering on the CI of the summary estimates, by removing cluster‐RCTs from the analyses and comparing the effects (see Appendix 4). We conducted an additional sensitivity analysis ad hoc with two studies (Hall 2002 (C); Roschnik 2003 (C)), in which approximately half of the participants were young females (< 12 years of age) to see their effect on the analyses (see Effects of interventions).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

Results of the search

The search strategy for the first publication of this review identified 9484 records for possible inclusion, 2706 of which were duplicates. We assessed 52 full‐text reports and: included 21 studies (from 25 reports); excluded 20 studies (from 24 reports); identified two studies (from three reports) as awaiting classification; and identified two ongoing studies (see Fernández‐Gaxiola 2011a).

The updated search identified 7532 records through database searches and 296 additional records through searching other sources. Having removed duplicates, we screened 5098 records on the basis of title and abstract, and removed 5074 clearly ineligible records. We retrieved 24 full‐text reports, which we assessed against the inclusion criteria (Criteria for considering studies for this review). We excluded 18 reports (related to: eight newly excluded studies (12 reports), two previously excluded studies (two reports), and one previously ongoing study (four reports)) from the review, and included four new studies (from four reports). We also identified two studies (from three reports) as awaiting classification (of which, one study (two reports) was previously ongoing), and one new ongoing study (from one report).

Altogether this review excluded 28 studies (from 38 reports), included 25 studies (from 29 reports), has four studies (from six reports) awaiting classification, and one ongoing study (from one report).

Figure 1 depicts the process for assessing and selecting the studies.

Figure 1
Study flow diagram.

Study flow diagram.

Included studies

We included 25 studies, involving 10,996 participants, all of which met the pre‐established inclusion criteria (Criteria for considering studies for this review). All studies were published between 1997 and 2018. Most studies focused on the prevention of anaemia and iron deficiency by improving iron status indicators (Primary outcomes); few studies reported data on the prespecified secondary outcomes (Secondary outcomes). See the Characteristics of included studies tables for more detail.

Settings

Studies were conducted in 15 different countries, most of them low‐ and middle‐income countries: Bangladesh, Brazil, France, Guatemala, India, Indonesia, Iran, Kenya, Malawi, Mali, Mexico, Nepal, Pakistan, Peru, Sri Lanka and Tanzania. One study was conducted in Europe (Riuvard 2006), four in Latin America (Dos Santos 1999; Zavaleta 2000; Gonzalez‐Rosendo 2002; Nguyen 2008), five in Africa (Muro 1999 (C); Beasley 2000; Hall 2002 (C); Roschnik 2003 (C); Leenstra 2009), and 15 in Asia (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Kianfar 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Shah 2002; Agarwal 2003 (C); Shobha 2003; Soekarjo 2004 (C); Mozaffari 2010 (C); Joshi 2013; Gupta 2014; Rezaeian 2014; Jalambo 2018).

Most studies were conducted in school settings; however, five studies implemented the intervention in rural and urban communities, health centres, and villages (Dos Santos 1999; Beasley 2000; Gilgen 2001; Nguyen 2008; Joshi 2013), and one study was conducted among garment factory workers (Ahmed 2001). Five studies explicitly mentioned that they were conducted in areas with some degree of malaria endemicity (Muro 1999 (C); Beasley 2000; Februhartanty 2002; Hall 2002 (C); Leenstra 2009).

Participants

Participants' ages ranged from six (Hall 2002 (C) to 49 (Nguyen 2008) years of age. While we did not include studies specifically recruiting premenarchal girls ‐ as these are the subject of a separate review (De‐Regil 2011) ‐ two studies recruited young females and separate data were not available for postmenarchal girls only (Hall 2002 (C); Roschnik 2003 (C)). Based on the age range reported in these studies, we assumed that at least half of the participants fulfilled our inclusion criteria and thus we decided to retain them in the review. If the disaggregated data are made available to us, we will include them in future updates of the review.

Most studies involved a mix of anaemic and non‐anaemic women, with the exception of six studies that included women with mild‐to‐moderate anaemia (Dos Santos 1999; Ahmed 2001; Shobha 2003; Leenstra 2009; Joshi 2013; Gupta 2014), one of which, Shobha 2003, included only severely anaemic women (i.e. women with haemoglobin concentrations ≤ 8 g/dL). The remaining studies excluded these severely anaemic women and gave them treatment or referred them to health care (or both). Only two studies specifically included iron‐deficient women (i.e. women with serum ferritin concentrations ≤ 15 mcg/L) (Riuvard 2006; Jalambo 2018).

Samples size varied among included studies, ranging from 24 in Riuvard 2006 to 2461 in Soekarjo 2004 (C); however, for cluster‐randomised studies, the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.

Interventions (intermittent regimens, supplement composition and iron dose)
Intermittent regimens

Most studies provided intermittent iron supplementation once a week and compared it to control (i.e. no intervention), placebo, daily iron supplementation or other nutrients or dosages also given intermittently once a week. Five studies provided supplements twice a week compared with: once weekly supplementation (Kianfar 2000; Gupta 2014); daily supplementation (Shobha 2003; Riuvard 2006); or control (Rezaeian 2014). One study provided iron supplements three days a week and compared this with daily supplementation and placebo (Zavaleta 2000).

Duration of the intervention

Duration of the intervention varied greatly among studies. In 13 studies, women were supplemented for three months or less (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Muro 1999 (C); Kianfar 2000; Ahmed 2001; Hall 2002 (C); Shobha 2003; Soekarjo 2004 (C); Riuvard 2006; Nguyen 2008; Joshi 2013; Jalambo 2018). The duration of the intervention was: three and a half months in three studies (Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C)); four months in six studies (Beasley 2000; Zavaleta 2000; Februhartanty 2002; Gonzalez‐Rosendo 2002; Mozaffari 2010 (C); Rezaeian 2014); five months in one study (Leenstra 2009); and six months in one study (Gilgen 2001). The maximum duration of supplementation was one year (Gupta 2014).

Supplements composition

In 11 studies, women were supplemented with iron only (Dos Santos 1999; Beasley 2000; Kianfar 2000; Zavaleta 2000; Gonzalez‐Rosendo 2002; Shobha 2003; Riuvard 2006; Leenstra 2009; Mozaffari 2010 (C); Rezaeian 2014; Jalambo 2018). In the remaining studies, women received iron plus folic acid supplements in 10 studies (Jayatissa 1999 (C); Muro 1999 (C); Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C); Gupta 2014; Joshi 2013), iron plus multiple micronutrients supplements in two studies (Angeles‐Agdeppa 1997; Nguyen 2008), and iron plus folic acid and iron plus multiple nutrients in one (Ahmed 2001) and iron plus folic acid or vitamin A or iron plus folic acid plus vitamin A in another (Soekarjo 2004 (C)).

Most studies supplemented iron with ferrous sulphate, with the exception of three studies that used ferrous fumarate (Gilgen 2001; Joshi 2013; Jalambo 2018) and one study that used ferrous chloride (Riuvard 2006). Six studies did not specify the form of iron used for supplementing women (Angeles‐Agdeppa 1997; Muro 1999 (C); Agarwal 2003 (C); Shobha 2003; Nguyen 2008; Mozaffari 2010 (C)). All studies used supplements as tablets or caplets.

Iron dose

The 25 studies tested several supplemental doses of iron in the intermittent group but none of the studies exceeded 120 mg of elemental iron per week. See below.

  1. 10 mg of elemental iron (one study: Rezaeian 2014)

  2. 30 mg of elemental iron (one study: Mozaffari 2010 (C))

  3. 50 mg of elemental iron (two studies: Kianfar 2000; Riuvard 2006)

  4. 60 mg of elemental iron (seven studies: Dos Santos 1999; Jayatissa 1999 (C); Zavaleta 2000; Februhartanty 2002; Gonzalez‐Rosendo 2002; Shobha 2003; Soekarjo 2004 (C))

  5. 65 mg of elemental iron (five studies: Muro 1999 (C); Hall 2002 (C); Roschnik 2003 (C); Jalambo 2018)

  6. 66 mg of elemental iron (one study: Gilgen 2001)

  7. 70 mg of elemental iron (one study: Shah 2002)

  8. 100 mg of elemental iron (three studies: Agarwal 2003 (C); Joshi 2013; Gupta 2014)

  9. 120 mg of elemental iron (three studies: Beasley 2000; Ahmed 2001; Leenstra 2009)

Angeles‐Agdeppa 1997 and Nguyen 2008 examined the effects of two different doses of elemental iron: 60 mg and 120 mg of elemental iron per week.

Funding sources

Five studies were partially funded (Soekarjo 2004 (C)) or fully funded by international organisations (Jayatissa 1999 (C); Gilgen 2001; Hall 2002 (C); Agarwal 2003 (C)). Four studies were partially funded by government organisations; two by the Department for International Development in the UK (Beasley 2000; Ahmed 2001) and two by the Ministry of Health within the country (Kianfar 2000; Soekarjo 2004 (C)). Four studies were funded by universities and institutes (Kianfar 2000; Shah 2002; Mozaffari 2010 (C); Rezaeian 2014), and four were partially funded by a pharmaceutical company, as they provided the supplements used (Angeles‐Agdeppa 1997; Ahmed 2001; Riuvard 2006; Leenstra 2009). Two studies were partially funded by a technical collaboration (an agreement whereby a developed country agrees to provide technical assistance to a developing country) (Angeles‐Agdeppa 1997; Februhartanty 2002) and two were partially funded by a foundation (Beasley 2000; Leenstra 2009). Only two studies declared no funding source was used to implement their study (Shobha 2003; Jalambo 2018). Seven studies did not provide a funding source (Dos Santos 1999; Muro 1999 (C); Zavaleta 2000; Gonzalez‐Rosendo 2002; Roschnik 2003 (C); Nguyen 2008; Joshi 2013).

Excluded studies

We excluded 28 studies: 13 studies were not RCTs (Cook 1995; Jackson 2003; Siddiqui 2003; Berger 2005; Crape 2005; Horjus 2005; López de Romaña 2006; Deshmukh 2008; Vir 2008; Casey 2009; Pasricha 2009; Joseph 2013; Shah 2016); two were reviews (Beaton 1999; Dwividi 2006); one was a commentary on another study (Perrin 2002); nine compared interventions outside the scope of this review (Bruner 1996; Kätelhut 1996; Tee 1999; Viteri 1999; Ahmed 2005; Ahmed 2010; Ahmed 2012; Moretti 2015; Bansal 2016); two used a different population (Ramakrishnan 2012; Sen 2012); and one excluded postmenarchal girls because the anthelmintic drug given along with the iron supplementation was not safe in cases of pregnancy (Taylor 2001).

See the Characteristics of excluded studies tables for a detailed description of the studies and the reasons for their exclusion.

Studies awaiting classification

Four studies are awaiting classification (Olsen 2000; Sharma 2000; Brabin 2014; Malhotra 2013); two of these four RCTs are from Africa (Olsen 2000; Brabin 2014) and the other two are from India (Sharma 2000; Malhotra 2013). Olsen 2000 compared the efficacy of twice‐weekly iron supplementation versus placebo. Brabin 2014 compared the efficacy of once‐weekly iron‐folate supplementation versus folate (control). Sharma 2000 compared the efficacy of once‐weekly versus daily iron and folic acid supplementation plus the effect of added ascorbic acid on the efficacy of iron‐folate supplementation. Malhotra 2013 compared the efficacy of twice‐weekly iron‐folate supplementation versus control versus twice‐weekly iron‐folate supplementation plus the effect of nutrition education versus nutrition education only on haematological status.

The dosages of elemental iron used in the studies were: 60 mg in Olsen 2000 and Malhotra 2013, 100 mg in Sharma 2000, and unclear for Brabin 2014.

We were unable to extract data for our outcomes from Olsen 2000 as the data were not disaggregated by sex, or from Sharma 2000 as the data were categorised by percentages. Malhotra 2013 was only available as an abstract and did not provide data for our comparisons. The Brabin 2014 report included only the qualitative part of the RCT and was missing the quantitative part for our meta‐analysis. In addition, the participants in Brabin 2014 were young women enrolled prior to their first pregnancy, and more information is needed to clarify the study's eligibility for inclusion in the review.

Ongoing studies

We found one ongoing study from India (CTRI/2017/11/010453). This study is comparing the efficacy of once‐a‐week versus daily iron supplementation at controlling anaemia in adolescent school girls aged 12 to 16 years with anaemia. The trial will provide 60 mg of elemental iron for three months. Recruitment has been completed and some results have been already published. See Characteristics of ongoing studies table.

Risk of bias in included studies

Overall, many included studies did not describe study methods completely, which made it difficult to assess risk of bias. We contacted some study authors for support and are still awaiting a reply at the time of publication of this review. With the exception of two studies (Hall 2002 (C); Nguyen 2008), we considered all of the studies included in this update to be at high risk of bias (or of low quality).

See the 'Risk of bias' tables (under the Characteristics of included studies tables) for an assessment of the risk of bias of each included trial, and Figure 2 and Figure 3 for an overall graphical summary of the risk of bias of all included trials. In the 'Summary of findings' tables, we presented the overall quality of the evidence for each primary outcome, by comparison (summary of findings Table 1; summary of findings Table 2).

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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

Allocation

Sequence generation

Nine studies adequately randomised the participants to the intervention group (Dos Santos 1999; Gilgen 2001; Gonzalez‐Rosendo 2002; Hall 2002 (C); Riuvard 2006; Nguyen 2008; Joshi 2013; Gupta 2014; Rezaeian 2014). Of these nine studies, four used a random number generator (Gilgen 2001; Gonzalez‐Rosendo 2002; Hall 2002 (C); Nguyen 2008), one used drawing of lots (Dos Santos 1999), one used a randomisation table (Riuvard 2006), one used a generated block (Joshi 2013), one used a lottery method (Gupta 2014), and another used a simple draw (Rezaeian 2014).

Sixteen studies did not state the method used to generate the random sequence clearly, so we rated these at unclear risk of bias (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Muro 1999 (C); Beasley 2000; Kianfar 2000; Zavaleta 2000; Ahmed 2001; Februhartanty 2002; Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C); Shobha 2003; Soekarjo 2004 (C); Leenstra 2009; Mozaffari 2010 (C); Jalambo 2018).

Allocation concealment

Ten studies reported adequate allocation concealment (Jayatissa 1999 (C); Zavaleta 2000; Ahmed 2001; Hall 2002 (C); Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Nguyen 2008; Leenstra 2009; Mozaffari 2010 (C)). Of these 10 studies, three kept the code secure until all data were entered into the computer (Ahmed 2001) or until after study completion (Nguyen 2008; Leenstra 2009), and seven were randomised at cluster level and we considered that the risk of selection bias at the individual level was unlikely (Jayatissa 1999 (C); Zavaleta 2000; Hall 2002 (C); Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Mozaffari 2010 (C)).

In 15 studies, the method used to conceal the allocation was unclear or not mentioned (Angeles‐Agdeppa 1997; Dos Santos 1999; Muro 1999 (C); Beasley 2000; Kianfar 2000; Gilgen 2001; Februhartanty 2002; Gonzalez‐Rosendo 2002; Shah 2002; Shobha 2003; Riuvard 2006; Joshi 2013; Gupta 2014; Rezaeian 2014; Jalambo 2018).

Blinding

We rated 13 studies at low risk of performance and detection bias (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Beasley 2000; Kianfar 2000; Zavaleta 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Roschnik 2003 (C); Leenstra 2009; Nguyen 2008; Rezaeian 2014). Of these 13 studies, nine were described as being single or double blinded (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Beasley 2000; Zavaleta 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Nguyen 2008), and of these nine, five specified that the placebos were of identical appearance (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Zavaleta 2000; Nguyen 2008; Gilgen 2001). Four studies did not mention or describe blinding in the study, so we rated them at unclear risk of performance and detection bias (Hall 2002 (C); Agarwal 2003 (C); Joshi 2013; Jalambo 2018). We rated eight studies at high risk of performance and detection bias because participants, personnel and outcome assessors seemed to be aware of the treatments (Muro 1999 (C); Gonzalez‐Rosendo 2002; Shah 2002; Shobha 2003; Soekarjo 2004 (C); Riuvard 2006; Mozaffari 2010 (C); Gupta 2014).

Incomplete outcome data

Loss to follow‐up varied greatly among studies, from 1% in Agarwal 2003 (C) to 41% in Roschnik 2003 (C). We rated six studies, which lost more than 20% of randomised participants or had imbalanced losses between study groups (or both), at high risk of attrition bias (Angeles‐Agdeppa 1997; Dos Santos 1999; Beasley 2000; Ahmed 2001; Roschnik 2003 (C); Nguyen 2008). We judged a further seven studies, which did not mention attrition making it difficult to judge whether the lack of data were due to no losses to follow‐up or to incomplete reporting, at unclear risk of attrition bias (Gilgen 2001; Gonzalez‐Rosendo 2002; Shobha 2003; Joshi 2013; Gupta 2014; Rezaeian 2014; Jalambo 2018). We considered the remaining 12 studies to be at low risk of attrition bias (Jayatissa 1999 (C); Muro 1999 (C); Kianfar 2000; Zavaleta 2000; Februhartanty 2002; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Soekarjo 2004 (C); Riuvard 2006; Leenstra 2009; Mozaffari 2010 (C)).

Selective reporting

Although it was difficult to assess reporting bias, because we did not have access to study protocols, we did not find a clear indication of reporting or publication bias by assessing funnel plot asymmetry visually.

Of the 25 included studies, we rated 22 at unclear risk of reporting bias. We rated one study at low risk of reporting bias because there was apparently no selective reporting (Jalambo 2018). We considered two studies to be at high risk of reporting bias (Agarwal 2003 (C); Joshi 2013). In Agarwal 2003 (C), data for plasma ferritin concentrations were estimated only in some girls and it was unclear how the selection was made. In Joshi 2013, there was missing information on compliance at the individual level that was recorded through home visits and postintervention interviews.

Other potential sources of bias

We rated 14 studies, which appeared to be free of other sources of bias, at low risk of other bias (Dos Santos 1999; Jayatissa 1999 (C); Muro 1999 (C); Kianfar 2000; Zavaleta 2000; Gilgen 2001; Agarwal 2003 (C); Soekarjo 2004 (C); Riuvard 2006; Nguyen 2008; Mozaffari 2010 (C); Joshi 2013; Rezaeian 2014; Jalambo 2018).

We rated eight studies at unclear risk of other sources of bias (Angeles‐Agdeppa 1997; Beasley 2000; Ahmed 2001; Gonzalez‐Rosendo 2002; Hall 2002 (C); Roschnik 2003 (C); Shobha 2003; Leenstra 2009). In Angeles‐Agdeppa 1997, the intervention was unsupervised during the four‐week period, as the supplements were provided on a take‐home basis. In Beasley 2000, the control group was given vitamin B12, which could have potentially impacted anaemia status. Ahmed 2001 had some variability in the administration of the supplements depending on the factory (i.e. supplements were given before versus after lunch, with an empty stomach versus having eaten little). In Roschnik 2003 (C), the results were affected by a famine in Malawi at the time of the trial. In Angeles‐Agdeppa 1997, Gonzalez‐Rosendo 2002, Hall 2002 (C) and Shobha 2003, the distribution of anaemia was not shown. In Leenstra 2009, most of the results for the four randomised groups were presented in graphs that were difficult to interpret (and consequently have not been included in our Data and analyses tables), and data on several outcomes were described as non‐significant but were not shown (side effects, including vomiting and diarrhoea).

We rated three studies at high risk of other sources of bias (Februhartanty 2002; Shah 2002; Gupta 2014). In Februhartanty 2002, there was a higher prevalence of anaemia in the group that received supplements weekly. In Shah 2002, the daily group were not explicitly supervised while those in the weekly group were supervised. Finally, Gupta 2014 had missing information on side effects that were recorded by the intervention group.

Effects of interventions

See: Summary of findings 1 Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women; Summary of findings 2 Intermittent iron supplementation versus daily iron supplementation in menstruating women

The summary of results is organised by comparisons. In the analyses, we have provided overall totals along with subtotals for subgroups and the statistics for subgroup differences. See the Data and analyses section for detailed results on primary and secondary outcomes.

Intermittent supplementation of iron (alone or plus any other micronutrients) versus no supplementation or placebo

Eighteen studies involving 8988 women examined intermittent iron supplementation versus no supplementation or placebo (Angeles‐Agdeppa 1997; Muro 1999 (C); Jayatissa 1999 (C); Beasley 2000; Kianfar 2000; Zavaleta 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Leenstra 2009; Mozaffari 2010 (C); Rezaeian 2014; Jalambo 2018). Nine of these studies met the prespecified criteria mentioned above (see Assessment of risk of bias in included studies) for being at lower risk of bias.

Primary outcomes
Anaemia

Eleven studies reported data on this outcome (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Muro 1999 (C); Zavaleta 2000; Ahmed 2001; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Mozaffari 2010 (C)). We pooled these studies in a meta‐analysis and found evidence that women receiving intermittent supplementation were less likely to have anaemia at the end of the intervention than those women who received no intervention or placebo (RR 0.65, 95% CI 0.49 to 0.87; 3135 participants; Analysis 1.1). However, treatment effect sizes varied between studies (T2= 0.16; Chi2= 58.75 (P < 0.001); I2= 83%).

We conducted a subgroup analysis and found no evidence to suggest that the composition of the supplement (iron only, iron plus folic acid, or iron plus any other micronutrients) affected anaemia (Analysis 1.2). However, we did find evidence that mixed/unknown anaemic women in the intervention group were less likely to have anaemia than anaemic women in the intervention group (RR 0.71, 95% CI 0.55 to 0.93; 2913 participants; Analysis 1.3; Test for subgroup differences: Chi2 = 9.38 (P = 0.002); l2= 89.3%). All studies reported iron status as mixed/unknown at baseline so we were not able to conduct subgroup analysis (Analysis 1.4). In further subgroup analyses, we found no evidence to suggest that dose of elemental iron per week in the intervention group (Analysis 1.5), duration of supplementation (Analysis 1.6), or malaria endemicity at the time when the study was conducted (Analysis 1.7) affected anaemia. There was a high level of heterogeneity between the studies in these analyses (between 79% and 84%). We rated the quality of this evidence as low.

Haemoglobin

Fifteen studies examined haemoglobin concentrations (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Beasley 2000; Kianfar 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Roschnik 2003 (C); Agarwal 2003 (C); Soekarjo 2004 (C); Leenstra 2009; Mozaffari 2010 (C); Rezaeian 2014; Jalambo 2018). We pooled these studies in a meta‐analysis and found evidence that women receiving iron supplements intermittently had 5.19 more grams of haemoglobin per litre (95% CI 3.07 to 7.32; 2886 participants; Analysis 1.8), than those who received no intervention or a placebo. Again, treatment effect sizes varied between studies (T2 = 14.01; Chi2 = 87.02 (P < 0.001); I2 = 84%).

We conducted subgroup analyses and found no evidence to suggest that the composition of the supplement (iron only, iron plus folic acid, or iron plus any other micronutrients) (Analysis 1.9), or anaemia status at baseline (anaemic status before the supplementation) (Analysis 1.10) affected haemoglobin. Not enough studies contributed data for the analysis on women's iron status at baseline (iron deficiency before the supplementation) so that most women had a mixed/unknown iron status (Analysis 1.11). In further subgroup analyses, we found no evidence to suggest that dose of elemental iron per week in the intervention group (Analysis 1.12), duration of supplementation (Analysis 1.13), or malaria endemicity at the time when the study was conducted (Analysis 1.14) affected haemoglobin. There was a high level of heterogeneity between the studies in these analyses (around 85%). We rated the quality of this evidence as moderate.

Iron deficiency

Three studies reported data on iron deficiency (Angeles‐Agdeppa 1997; Ahmed 2001; Mozaffari 2010 (C)). We pooled these studies in a meta‐analysis and found no evidence that iron deficiency differed between the groups (RR 0.50, 95% CI 0.24 to 1.04; 624 participants; Analysis 1.15). The heterogeneity was high but the directions of the results were consistent (T2 = 0.36, Chi2 = 17.52 (P < 0.001); I2 = 89%) . We rated the quality of this evidence as low.

Ferritin

Seven studies examined ferritin concentrations (Angeles‐Agdeppa 1997; Beasley 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Mozaffari 2010 (C); Jalambo 2018). We pooled these studies in a meta‐analysis and found evidence in favour of the intervention group (MD 7.46 μg/L, 95% CI 5.02 to 9.90; 1067 participants, Analysis 1.16). The heterogeneity was moderate (T2 = 4.10; Chi2 = 10.94 (P = 0.09); I2 = 45%). We rated the quality of this evidence as low.

We conducted subgroup analyses and found no evidence to suggest that the composition of the supplement (iron only, iron plus folic acid, or iron plus any other micronutrients) (Analysis 1.17) or anaemic status at baseline (Analysis 1.18) affected ferritin. Not enough studies contributed data for the analysis on women's iron status at baseline (iron deficiency before the supplementation) so that most women had a mixed/unknown iron status (Analysis 1.19). In further subgroup analyses, we found no evidence to suggest that dose of elemental iron per week in the intervention group (Analysis 1.20), duration of supplementation (Analysis 1.21), or malaria endemicity at the time when the study was conducted (Analysis 1.22) affected ferritin.

Iron deficiency anaemia

A single study reported data on this outcome (Mozaffari 2010 (C)). It found no difference in iron deficiency anaemia between those women who received iron supplements intermittently and those women who did not receive iron (RR 0.07, 95% CI 0.00 to 1.16; 97 participants; see the illustrative forest plot in Analysis 1.23). We rated the quality of this evidence as low.

All‐cause morbidity

A single study reported data on this outcome (Beasley 2000). It found no difference in all‐cause morbidity between those women who received iron supplements intermittently and those who women did not receive iron (RR 1.12, 95% 0.82 to 1.52; 119 participants; see the illustrative forest plot in Analysis 1.24). We rated the quality of this evidence as low.

Secondary outcomes
Diarrhoea

A single study reported data on diarrhoea (Angeles‐Agdeppa 1997). It found no evidence that diarrhoea differed between the groups (RR 0.28, 95% CI 0.05 to 1.49; 209 participants; see the illustrative forest plot in Analysis 1.25).

Any adverse side effects

Three studies examined any adverse side effects (Angeles‐Agdeppa 1997; Gilgen 2001; Leenstra 2009). We pooled these studies in a meta‐analysis and found no evidence that adverse side effects differed between the groups (RR 1.98, 95% CI 0.31 to 12.72; 630 participants; Analysis 1.26).

Adherence

Two studies examined adherence (Zavaleta 2000; Ahmed 2001). We pooled these studies in a meta‐analysis and found no evidence that women receiving iron supplements intermittently adhered to the intervention better than those women who did not receive iron (RR 0.99, 95% CI 0.96 to 1.02; 417 participants; Analysis 1.27).

Malaria outcomes

Two studies reported data on malaria outcomes (Beasley 2000; Leenstra 2009). We pooled these studies in a meta‐analysis and found no evidence that the prevalence (Analysis 1.28) and incidence Analysis 1.29) of parasitaemia, prevalence of high‐density parasitaemia (Analysis 1.30), and clinical malaria (Analysis 1.31) differed between those women who received iron supplements intermittently and those women who did not receive iron.

No studies reported on our other prespecified secondary outcomes: respiratory infections; school performance and cognitive function; or depression.

Sensitivity analyses

We conducted sensitivity analyses by reanalysing the data for anaemia, haemoglobin, iron deficiency and ferritin with cluster‐RCTs excluded (Jayatissa 1999 (C); Muro 1999 (C); Hall 2002 (C); Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Mozaffari 2010 (C), and found no significant differences in the results. See Appendix 4.

In two studies (Hall 2002 (C); Roschnik 2003 (C)), approximately half of the participants (276 participants and 376 participants, respectively) were young females (< 12 years of age). We conducted a sensitivity analysis ad hoc and found that excluding these studies changed the estimate for anaemia from RR 0.65 (95% CI 0.49 to 0.87) to RR 0.58 (95% CI 0.40 to 0.86; results not shown), and haemoglobin from MD 5.19 g/L (95% CI 3.07 to 7.32) to MD 5.67 g/L (95% CI 3.37 to 7.97; results not shown). As the interpretation of our results did not change, we decided to retain these trials in our analyses and thus minimise the risk of publication bias.

Intermittent iron supplementation versus daily iron supplementation

We included 13 studies involving 6213 women in this comparison (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Kianfar 2000; Zavaleta 2000; Gonzalez‐Rosendo 2002; Shah 2002; Agarwal 2003 (C); Shobha 2003; Riuvard 2006; Nguyen 2008; Joshi 2013; Gupta 2014). We considered only two of these studies to be at higher risk of bias overall (Shah 2002 and Gupta 2014) and six of these to be at lower risk of bias overall (Jayatissa 1999 (C); Kianfar 2000; Zavaleta 2000; Gonzalez‐Rosendo 2002; Soekarjo 2004 (C); Nguyen 2008.

Primary outcomes
Anaemia

Eight studies reported data on this outcome (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Zavaleta 2000; Gonzalez‐Rosendo 2002; Shah 2002; Agarwal 2003 (C); Joshi 2013). We pooled these studies in a meta‐analysis and found evidence that women receiving iron supplements daily were as likely to have reduced anaemia at the end of the intervention as those women receiving iron supplements intermittently (RR 1.09, 95% CI 0.93 to 1.29; 1749 participants; Analysis 2.1). The heterogeneity was low (T2 = 0.01; Chi2 = 7.93 (P = 0.34); I2= 12%). We rated the quality of this evidence as moderate.

We conducted subgroup analyses and found no evidence to suggest that the composition of the supplement affected anaemia (Analysis 2.2). We found inconclusive results that anaemia status at baseline (anaemia status before the supplementation) affected anaemia (Analysis 2.3), and no studies reported data for the analysis exploring the effects of iron status at baseline (Analysis 2.4). Almost an even number of studies provided 60 mg of elemental iron or less per week (four studies) or more than 60 mg of elemental iron per week (five studies), and we found no evidence to suggest that the dose in the intervention group affected anaemia (Analysis 2.5). In further subgroup analyses, we found no evidence to suggest that the duration of the intervention (Analysis 2.6) or the malaria endemicity at the time when the study was conducted (Analysis 2.7) affected anaemia.

Haemoglobin

Ten studies reported data on this outcome (Angeles‐Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Kianfar 2000; Gonzalez‐Rosendo 2002; Agarwal 2003 (C); Shobha 2003; Riuvard 2006; Joshi 2013; Gupta 2014). We pooled these studies in a meta‐analysis and found no evidence that mean haemoglobin concentrations differed between women receiving intermittent iron supplementation and women receiving daily iron supplementation (MD 0.43, 95% CI −1.44 to 2.31; 2127 participants; Analysis 2.8). The level of heterogeneity was high (T2 = 6.45; Chi2 = 40.60 (P < 0.001); I2 = 78%). We rated the quality of the evidence as low.

We conducted subgroup analyses and found no evidence that the composition of the supplement (iron only, iron plus folic acid, or iron plus other micronutrients) affected haemoglobin (Analysis 2.9). However, we did find evidence that anaemic women had a stronger response to intermittent supplementation than women with mixed/unknown anaemia status (MD 0.43, 95% CI ‐1.44 to 2.31; 804 participants; Analysis 2.10), but only four studies contributed to this analysis so the results should be interpreted with caution. Not enough studies contributed data for the analysis on women's iron status at baseline (iron deficiency before the supplementation) so that most women had a mixed/unknown iron status (Analysis 2.11). Almost an even number of studies provided 60 mg of elemental iron or less per week (six studies) and more than 60 mg of iron per week (five studies); there was no statistical difference between the groups. In Angeles‐Agdeppa 1997, women who received 60 mg or less intermittently showed higher haemoglobin concentrations than women who received higher doses (Analysis 2.12). We found no evidence of any subgroup differences by duration of the intervention (Analysis 2.13) or malaria endemicity at the time when the study was conducted (Analysis 2.14). There was substantial heterogeneity between the studies in these analyses (between 76% and 80%).

Iron deficiency

Only a single study reported data on this outcome (Angeles‐Agdeppa 1997). It found no evidence that iron deficiency differed between the groups (RR 4.30, 95% CI 0.56 to 33.20; 198 participants; see the illustrative forest plot in Analysis 2.15). We rated the quality of this evidence as very low.

Ferritin

Four studies reported data on this outcome (Angeles‐Agdeppa 1997; Agarwal 2003 (C); Riuvard 2006; Gupta 2014). We pooled these studies in a meta‐analysis and found evidence that women receiving iron supplements daily had higher concentrations of ferritin at the end of the intervention than those women receiving iron supplements intermittently (MD −6.07 μg/L, 95% CI −10.66 to −1.48; 988 participants; Analysis 2.16). The heterogeneity was high (T2 = 15.55; Chi2 = 33.80 (P < 0.001); I2= 91%). We rated the quality of this evidence as very low.

We found statistical differences in all subgroup analyses: daily supplementation was more effective than intermittent supplementation at increasing ferritin concentrations in women regardless of the composition of the supplement (Analysis 2.21), anaemia (Analysis 2.18) or iron status at baseline (Analysis 2.19), dose of elemental iron (Analysis 2.20), duration of supplementation (Analysis 2.17), or malaria endemicity at the time when the study was conducted (Analysis 2.22). However, it should be noted that most subgroups had only one study or included all four studies in the same subgroup, or had no studies, and that there was substantial heterogeneity between studies in these analyses (between 74.4% and 91%). Therefore, results were inconclusive and should be interpreted with caution.

None of the included studies reported data on the other prespecified primary outcomes: iron‐deficiency anaemia and all‐cause morbidity.

Secondary outcomes
Diarrhoea

Only a single study reported data on this outcome (Angeles‐Agdeppa 1997). It found no evidence that diarrhoea differed between the groups (RR 2.41, 95% CI 0.12 to 49.43; 198 participants; see the illustrative forest plot in Analysis 2.23).

Any adverse side effects

Six studies reported data on this outcome (Angeles‐Agdeppa 1997; Jayatissa 1999 (C); Shobha 2003; Nguyen 2008; Joshi 2013; Gupta 2014). We pooled these studies in a meta‐analysis and found evidence that women receiving iron supplements intermittently were less likely to have any adverse side effects than those women receiving iron supplements daily (RR 0.41, 95% CI 0.21 to 0.82; 1166 participants; Analysis 2.24).

Depression

Only a single study reported data on this outcome (Nguyen 2008). It found no evidence that depression differed between the groups (RR 0.82, 95% CI 0.63 to 1.07; 369 participants; see the illustrative forest plot in Analysis 2.25).

Adherence

Four studies reported data on this outcome (Dos Santos 1999; Gonzalez‐Rosendo 2002; Shah 2002; Riuvard 2006). We pooled these studies in a meta‐analysis and found no evidence that adherence to intermittent supplementation differed from that for daily supplementation (RR 1.04, 95% CI 0.99 to 1.09; 507 participants; Analysis 2.26).

None of the included studies reported data on the other prespecified secondary outcomes: respiratory infections; work performance and economic productivity; school performance and cognitive function; and malaria incidence and severity.

Sensitivity analyses

We conducted sensitivity analyses to examine the potential effect of clustering on the CI of the summary estimates, by removing cluster‐RCTs from the analysis and comparing the effect for anaemia, haemoglobin, and ferritin. We found no significant differences in the results. See Appendix 4.

Discussion

Summary of main results

Available data indicate that, among menstruating women, intermittent oral supplementation with iron (alone or plus any other nutrients) increases haemoglobin and ferritin concentrations and reduces the prevalence of anaemia compared to no supplementation or placebo. Overall, this positive response does not differ when providing iron supplementation weekly or twice weekly; nor does it differ with the duration of the intervention, dose used, or malaria endemicity. As the quality of the evidence was, on average, low, the confidence in the effect estimate is limited and the true effect may be substantially different from the estimate of the effect.

Compared with daily supplementation, findings suggest that intermittent supplementation has a similar effect in reducing the prevalence of anaemia and increasing haemoglobin concentrations at the end of the intervention. However, information from a fewer number of trials shows that women receiving intermittent supplementation are more likely to have lower ferritin concentrations and fewer side effects at the end of the intervention. As the quality of the evidence was also, on average, low, the confidence in the effect estimate is limited and the true effect may be substantially different from the estimate of the effect.

Information on morbidity (including malaria outcomes), work performance and economic productivity, depression, and adherence to the intervention was scarce, but, thus far, there is no evidence that intermittent supplementation has any effect on these outcomes, either when compared with a placebo, no intervention, or with daily iron supplementation. There were no data for the subgroup analysis of the effect of iron status at baseline on anaemia for intermittent iron supplementation compared to placebo or no intervention; and, for the other outcomes, there was only one trial.

Overall completeness and applicability of evidence

This review included a total of 25 RCTs involving 10,996 women; most of them were conducted in low‐ and middle‐income countries in Latin America, Africa, and Asia where anaemia is a public health problem. The overall quality of the evidence was, on average, low, and the main limitation of the studies was the lack of blinding and high attrition.

Intermittent iron supplementation regimens have been proposed as an efficacious and efficient approach to the prevention and control of anaemia and at least 100 studies on intermittent iron supplementation regimens in different age groups have been published during the last 15 years. Although the real effect of an intervention is context‐specific, the results of this review showed that weekly or twice weekly iron supplementation regimens are effective in reducing the prevalence of anaemia and improving haemoglobin and ferritin concentrations in menstruating women in comparison with no supplementation or placebo. There was insufficient information to assess with certainty the effect of this intervention on other health and nutrition outcomes.

The results suggest that the provision of supplements once a week with 60 mg to 120 mg of iron is enough to produce a positive haematological response in populations with different degrees of anaemia. The efficacy of this intervention to treat anaemia was similar to the efficacy of daily supplementation. Furthermore, in all of the studies in which anaemia was an inclusion criterion, there was a higher increase in haemoglobin concentrations among women who received supplements intermittently. This finding was true even in different settings and with different levels of supervision. Folic acid merits a special mention, as its consumption did not have a differential effect on anaemia and haemoglobin concentrations; however, its use during the periconceptional period has been proven to reduce the risk of having babies with NTDs, an outcome that was outside the scope of this review (De‐Regil 2015).

According to our review, daily supplementation was more effective at increasing ferritin concentrations, compared with the provision of supplements once or twice a week. This may have implications for the use of intermittent iron supplementation regimens in populations with a high prevalence of iron deficiency where increasing ferritin concentrations are needed.

Although improved adherence and fewer side effects have been proposed as an advantage of intermittent supplementation over daily supplementation, there is no evidence that in relatively well‐controlled environments and for short periods of supplementation, women adhere better to intermittent regimens. However, there was no difference when women were compared with those receiving a placebo either. Clearly, there are gaps on how the duration, frequency and intensity of side effects affect short‐ and long‐term adherence to supplementation.

One study (459 participants) reported on the incidence of hospitalisation (Nguyen 2008) and one study (24 participants) reported on oxidative stress post‐supplementation (expressed as the Ferric Reducing Ability of the Plasma or FRAP) (Riuvard 2006). These studies found no evidence that the effects of intermittent supplementation on these indicators were different from that produced by daily supplementation. None of the other included studies reported data on these outcomes.

Quality of the evidence

We found the overall quality of the available evidence ranged between moderate to low in comparison 1 and comparison 2, both primarily due to substantial heterogeneity, risk of bias, and methodological inconsistency. Most outcomes with very low quality evidence have only one included study.

Study limitations/risk of bias in included studies

With the exception of two studies (Hall 2002 (C); Nguyen 2008), we considered all of the studies included in this update to be at high risk of bias (see Risk of bias in included studies; Figure 2; Figure 3). Most studies did not describe the methods used to randomly assign participants and conceal allocation. Generally, blinding of participants, care providers and outcome assessors was not attempted, although some studies reported that technical staff carrying out laboratory investigations were unaware of group allocation. This lack of blinding could represent a potentially serious source of bias. Inconsistency was also a problem in many of these studies.

Inconsistency

We considered that clinical inconsistency was unlikely for our outcomes. Variability in participants characteristics, interventions, and outcomes across the included studies was likely to be low (Ryan 2016). However, methodological inconsistency was a potentially important factor in the overall assessment of evidence for our outcomes. We found differences between studies in terms of methodological factors, specifically blinding and allocation concealment, that may have led to differences in the observed intervention effects (Higgins 2011a). We found substantial heterogeneity in some outcomes, especially anaemia and haemoglobin, that could be partly explained by subgroup analyses. Although this does not necessarily mean that the true intervention effect varies, results should be interpreted with some caution.

Imprecision

Imprecision due to small sample sizes or few events in the included studies was unlikely. However, we considered imprecision in continuous outcomes (i.e. haemoglobin and ferritin measurements) an important factor in the overall assessment of the evidence. There was a lot of variation in the effects of the intervention among participants for continuous outcomes, as results showed wide CIs around the effect estimate (Ryan 2016).

Indirectness

We considered that indirectness was unlikely. We found no indirectness regarding population, interventions, or outcomes assessed across studies. The study populations paralleled those of clinical and public health interest under real conditions. The evidence summarised in the review comes from studies addressing the main review questions, especially for our primary outcomes; and our secondary outcomes were almost not addressed.

Publication bias

We considered that publication bias was unlikely. Data used in the analyses came from representative samples from the studies that have been conducted. Overall, included studies had large sample sizes and numbers of events (i.e. more than 300) (Ryan 2016). However, some subgroup analyses had small sample sizes.

Potential biases in the review process

We attempted to minimise bias in several ways. We tried to be as inclusive as possible to avoid potential bias in the search strategy and found publications in different languages in journals from all continents, although the literature identified was predominantly written in English. We were also able to obtain some unpublished information. Both review authors independently assessed the eligibility of studies for inclusion, participated in data extraction, and conducted the 'Risk of bias' assessments. One review author entered the data into a form design for the review and the other checked the data for accuracy. 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.

Several studies had selection bias, with both unclear random sequence generation and unclear concealment of the allocation sequence, which could have introduced bias at the group level in terms of differences between the baseline characteristics of the groups that were compared. When the intervention was allocated at class level or studies were cluster (C) RCTs, such as Jayatissa 1999 (C) and Agarwal 2003 (C), we assumed that bias at the individual level was unlikely. We also assumed a low risk of bias when tablets had the same colour and shape, or were manufactured by the same laboratory, although some studies did not describe the method to conceal the allocation, such as Zavaleta 2000 and Leenstra 2009.

Agreements and disagreements with other studies or reviews

To our knowledge, only one meta‐analysis of RCTs has been conducted previously on the efficacy of intermittent iron supplementation in the control of iron deficiency anaemia (Beaton 1999). That review included the results of 22 studies completed before 1999 in different age groups. Of the included studies, nine were carried out among adolescents and compared once or twice a week versus daily supplementation; most of them also assessed a control group that did not receive iron. All studies reported results for haemoglobin and three also measured ferritin. The Beaton 1999 review did not include adult non‐pregnant women, and the review authors pooled the results from school‐aged children and adolescents.

Like us, the authors of Beaton 1999 concluded that intermittent supplementation increased haemoglobin and ferritin levels and reduced anaemia when compared with no intervention or a placebo. However, findings from Beaton 1999 and Fernández‐Gaxiola 2011a suggested that intermittent supplementation was less efficacious than daily supplementation in reducing anaemia (RR 1.44, 95% CI 1.33 to 1.56; and RR 1.26: 95% CI 1.04 to 1.52, respectively), but there were no statistical differences in haemoglobin concentrations between regimens. The authors of Beaton 1999 concluded that weekly supplementation should be considered for school‐aged children and adolescents only in situations where there is strong assurance of supervision and high adherence.

A more recent unpublished review included 12 studies evaluating the effects of weekly iron and folic acid supplementation among non‐pregnant women of reproductive age (Margetts 2007). The results suggested that the consumption of supplements containing 60 mg of elemental iron with folic acid for at least 12 weeks, with or without deworming treatment, increased iron status, as judged by increased haemoglobin and, in some studies, serum ferritin levels. The effect of weekly supplementation on haemoglobin concentration was similar to that reported for daily supplementation, except in subsets of women who were severely anaemic at baseline where daily supplementation was more effective. 

Overall, the findings of these reviews agree with the findings of this Cochrane Review. The 25 studies included in our review, conducted in different age groups, contexts and with different levels of supervision, show that intermittent supplementation may be an effective public health intervention. In contexts where daily supplementation has failed, has not been implemented or there is a strong need to increase coverage in at‐risk populations and economic resources are limited, the feasibility of delivering intermittent supplementation could make this intervention a viable alternative to consider.

The results of the present review are only applicable to menstruating women. However, another systematic review assessing the benefits and safety of this intervention in preschool‐aged and school‐aged children concurs with our findings (De‐Regil 2011). 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, the Philippines, and Vietnam, reaching over half a million menstruating women (WHO‐WPRO 2011).

Study flow diagram.

Figuras y tablas -
Figure 1

Study flow diagram.

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

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Figure 2

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

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

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Figure 3

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

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 1: Anaemia (All)

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Analysis 1.1

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 1: Anaemia (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 2: Anaemia (by supplement composition)

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Analysis 1.2

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 2: Anaemia (by supplement composition)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 3: Anaemia (by anaemia status at baseline)

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Analysis 1.3

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 3: Anaemia (by anaemia status at baseline)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 4: Anaemia (by iron status at baseline): Mixed/Unknown

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Analysis 1.4

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 4: Anaemia (by iron status at baseline): Mixed/Unknown

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 5: Anaemia (dose of elemental iron per week in the intermittent group)

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Analysis 1.5

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 5: Anaemia (dose of elemental iron per week in the intermittent group)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 6: Anaemia (by duration of supplementation)

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Analysis 1.6

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 6: Anaemia (by duration of supplementation)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 7: Anaemia (by malaria endemicity)

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Analysis 1.7

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 7: Anaemia (by malaria endemicity)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 8: Haemoglobin in g/L (All)

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Analysis 1.8

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 8: Haemoglobin in g/L (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 9: Haemoglobin in g/L (by supplement composition)

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Analysis 1.9

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 9: Haemoglobin in g/L (by supplement composition)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 10: Haemoglobin in g/L (by anaemia status at baseline)

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Analysis 1.10

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 10: Haemoglobin in g/L (by anaemia status at baseline)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 11: Haemoglobin in g/L (by iron status at baseline)

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Analysis 1.11

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 11: Haemoglobin in g/L (by iron status at baseline)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 12: Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group)

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Analysis 1.12

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 12: Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 13: Haemoglobin in g/L (by duration of supplementation)

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Analysis 1.13

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 13: Haemoglobin in g/L (by duration of supplementation)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 14: Haemoglobin in g/L (by malaria endemicity)

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Analysis 1.14

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 14: Haemoglobin in g/L (by malaria endemicity)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 15: Iron deficiency (All)

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Analysis 1.15

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 15: Iron deficiency (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 16: Ferritin in µg/L (All)

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Analysis 1.16

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 16: Ferritin in µg/L (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 17: Ferritin in µg/L (by supplement composition)

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Analysis 1.17

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 17: Ferritin in µg/L (by supplement composition)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 18: Ferritin in µg/L (by anaemia status at baseline)

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Analysis 1.18

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 18: Ferritin in µg/L (by anaemia status at baseline)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 19: Ferritin in µg/L (by iron status at baseline)

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Analysis 1.19

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 19: Ferritin in µg/L (by iron status at baseline)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 20: Ferritin in µg/L (by dose of elemental iron per week in the intermittent group)

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Analysis 1.20

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 20: Ferritin in µg/L (by dose of elemental iron per week in the intermittent group)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 21: Ferritin in µg/L (by duration of supplementation)

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Analysis 1.21

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 21: Ferritin in µg/L (by duration of supplementation)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 22: Ferritin in µg/L (by malaria endemicity)

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Analysis 1.22

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 22: Ferritin in µg/L (by malaria endemicity)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 23: Iron deficiency anaemia (All)

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Analysis 1.23

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 23: Iron deficiency anaemia (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 24: All cause morbidity (All)

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Analysis 1.24

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 24: All cause morbidity (All)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 25: Diarrhoea

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Analysis 1.25

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 25: Diarrhoea

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 26: Any adverse side effects

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Analysis 1.26

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 26: Any adverse side effects

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 27: Adherence

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Analysis 1.27

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 27: Adherence

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 28: Prevalence of malaria parasitaemia

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Analysis 1.28

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 28: Prevalence of malaria parasitaemia

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 29: Any malaria parasitaemia (Incidence rate; per 1000 person months)

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Analysis 1.29

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 29: Any malaria parasitaemia (Incidence rate; per 1000 person months)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 30: High density malaria parasitaemia (parasites 200/wbc)

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Analysis 1.30

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 30: High density malaria parasitaemia (parasites 200/wbc)

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Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 31: Clinical malaria

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Analysis 1.31

Comparison 1: Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo, Outcome 31: Clinical malaria

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 1: Anaemia (All)

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Analysis 2.1

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 1: Anaemia (All)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 2: Anaemia (by supplement composition)

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Analysis 2.2

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 2: Anaemia (by supplement composition)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 3: Anaemia (by anaemia status at baseline)

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Analysis 2.3

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 3: Anaemia (by anaemia status at baseline)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 4: Anaemia (by iron status at baseline): Mixed/Unknown

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Analysis 2.4

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 4: Anaemia (by iron status at baseline): Mixed/Unknown

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 5: Anaemia (by dose of elemental iron per week in the intermittent group)

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Analysis 2.5

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 5: Anaemia (by dose of elemental iron per week in the intermittent group)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 6: Anaemia (by duration of supplementation)

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Analysis 2.6

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 6: Anaemia (by duration of supplementation)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 7: Anaemia (by malaria endemicity)

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Analysis 2.7

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 7: Anaemia (by malaria endemicity)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 8: Haemoglobin in g/L (All)

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Analysis 2.8

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 8: Haemoglobin in g/L (All)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 9: Haemoglobin in g/L (by supplement composition)

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Analysis 2.9

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 9: Haemoglobin in g/L (by supplement composition)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 10: Haemoglobin in g/L (by anaemia status at baseline)

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Analysis 2.10

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 10: Haemoglobin in g/L (by anaemia status at baseline)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 11: Haemoglobin in g/L (by iron status at baseline)

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Analysis 2.11

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 11: Haemoglobin in g/L (by iron status at baseline)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 12: Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group)

Figuras y tablas -
Analysis 2.12

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 12: Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 13: Haemoglobin in g/L (by duration of supplementation)

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Analysis 2.13

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 13: Haemoglobin in g/L (by duration of supplementation)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 14: Haemoglobin in g/L (by malaria endemicity)

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Analysis 2.14

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 14: Haemoglobin in g/L (by malaria endemicity)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 15: Iron deficiency (All)

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Analysis 2.15

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 15: Iron deficiency (All)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 16: Ferritin in µg/L (All)

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Analysis 2.16

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 16: Ferritin in µg/L (All)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 17: Ferritin in µg/L (by duration of supplementation)

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Analysis 2.17

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 17: Ferritin in µg/L (by duration of supplementation)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 18: Ferritin in µg/L (by anaemia status at baseline)

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Analysis 2.18

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 18: Ferritin in µg/L (by anaemia status at baseline)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 19: Ferritin in µg/L (by iron status at baseline)

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Analysis 2.19

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 19: Ferritin in µg/L (by iron status at baseline)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 20: Ferritin in µg/L (by dose of elemental iron per week in the intermittent group)

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Analysis 2.20

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 20: Ferritin in µg/L (by dose of elemental iron per week in the intermittent group)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 21: Ferritin in µg/L (by supplement composition)

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Analysis 2.21

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 21: Ferritin in µg/L (by supplement composition)

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 22: Ferritin in µg/L (by malaria endemicity): No malaria/Unknown

Figuras y tablas -
Analysis 2.22

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 22: Ferritin in µg/L (by malaria endemicity): No malaria/Unknown

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 23: Diarrhoea

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Analysis 2.23

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 23: Diarrhoea

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 24: Any adverse side effects

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Analysis 2.24

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 24: Any adverse side effects

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 25: Depression

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Analysis 2.25

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 25: Depression

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Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 26: Adherence

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Analysis 2.26

Comparison 2: Intermittent iron supplementation versus daily iron supplementation, Outcome 26: Adherence

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Summary of findings 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women

Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women

Patient or population: adolescent and adult menstruating women
Setting: community settings
Intervention: intermittent iron supplementation (alone or with any other micronutrients)
Comparison: no supplementation or placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants (studies)

Quality of the evidence
(GRADE)

Comments

Risk with no supplementation or placebo

Risk with intermittent iron supplementation (alone or with any other micronutrients)

Anaemia (haemoglobin concentration below a cut‐off defined by the trialists, adjusted by altitude and smoking as appropriate)
Follow‐up: range 2 months to 6 months

Study population

RR 0.65
(0.49 to 0.87)

3135 (11 studies)

⊕⊕⊝⊝
Lowa

Includes seven cluster‐randomised trials b

39 per 100

25 per 100
(19 to 34)

Haemoglobin (g/L)
Follow‐up: range 2 months to 6 months

The mean haemoglobin g/L in the control groups ranged from −0.24 to 133.20

The mean haemoglobin g/L in the intervention groups was5.19 higher (3.07 higher to 7.32 higher)

‐

2886 (15 studies)

⊕⊕⊕⊝
Moderatec

Includes five cluster‐randomised trials b

Iron deficiency (as defined by trialists by using indicators of iron status such as ferritin or transferrin)
Follow‐up: range 3 months to 4 months

Study population

RR 0.50
(0.24 to 1.04)

624 (3 studies)

⊕⊕⊝⊝
Lowd

Includes one cluster‐randomised trial b

49 per 100

25 per 100
(12 to 51)

Ferritin (µg/L)
Follow‐up: range 3 months to 6 months

The mean ferritin µg/L in the control groups ranged from −5.31 to 41

The mean ferritin μg/L in the intervention groups was7.46 higher (5.02 higher to 9.90 higher)

‐

1067 (7 studies)

⊕⊕⊝⊝
Lowe

Includes one cluster‐randomised trial b

Iron deficiency anaemia (as defined by the presence of anaemia plus iron deficiency diagnosed with an indicator of iron status selected by the trialists)
Follow‐up: 4 months

Study population

RR 0.07
(0.00 to 1.16)

97 (1 study)

⊕⊕⊝⊝
Lowf

The included trial is a cluster‐randomised trial b

7 per 100

1 per 100
(0 to 8)

All‐cause morbidity (the most frequent event associated with the intervention, independent of the cause, as defined by the trialists)

Follow‐up: 4 months

Study population

RR 1.12
(0.82 to 1.52)

119 (1 study)

⊕⊕⊝⊝
Lowg

‐

55 per 100

61 per 100
(45 to 83)

Any adverse side effects

13 per 100

26 per 100

(4 to 100)

RR 1.98

(0.31 to 12.72)

630

(3 studies)

⊕⊕⊕⊝
Moderateh

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

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 are moderately confident 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 effect.

aDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) and one level due to inconsistency (high heterogeneity) (I2 = 83%).
bFor cluster‐randomised trials (C), the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.
cDowngraded one level due to inconsistency (high heterogeneity) (I2 = 85%).
dDowngraded one level due to imprecision (wide CI) and one level due to inconsistency (high heterogeneity) (I2 = 89%).
eDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) and one level due to imprecision (wide CI) (I2 = 48%).
fDowngraded one level due to lack of blinding and one level due to imprecision (wide CI and not enough information to detect a precise estimate of the effect ‐ only one study reported on this outcome) (I2 = not estimable).
gDowngraded one level due to study attrition and one level due to imprecision (not enough information to detect a precise estimate of the effect ‐ only one study reported on this outcome) (I2 = not estimable).
hDowngraded one level due to inconsistency (high heterogeneity) (l2 = 91%)

Figuras y tablas -
Summary of findings 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo in menstruating women
Ir a la tabla de la revisión
Summary of findings 2. Intermittent iron supplementation versus daily iron supplementation in menstruating women

Intermittent iron supplementation versus daily iron supplementation in menstruating women

Patient or population: adolescent and adult menstruating women
Setting: community settings
Intervention: intermittent iron supplementation alone or with any other micronutrients
Comparison: daily iron supplementation alone or with any other micronutrients

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants (studies)

Quality of the evidence
(GRADE)

Comments

Risk with daily iron supplementation

Risk with intermittent iron supplementation

Anaemia (haemoglobin concentration below a cut‐off defined by the trialists, adjusted by altitude and smoking as appropriate)
Follow‐up: range 2 months to 4 months

Study population

RR 1.09
(0.93 to 1.29)

1749 (8 studies)

⊕⊕⊕⊝
Moderatea

Includes two cluster‐randomised trials* b

23 per 100

25 per 100
(22 to 30)

Haemoglobin (g/L)
Follow‐up: range 2 months to 1 year

The mean haemoglobin g/L in the control groups ranged from 7.40 g/L to 132.00 g/L

The mean haemoglobin g/L in the intervention groups was 0.43 g/L higher (1.44 lower to 2.31 higher)

‐

2127 (10 studies)

⊕⊕⊝⊝
Lowc

Includes two cluster‐randomised trials* b

Iron deficiency (as defined by the trialists using indicators of iron status such as ferritin or transferrin)
Follow‐up: mean 3 months

Study population

RR 4.30
(0.56 to 33.20)

198 (1 study)

⊕⊝⊝⊝
Very lowd

‐

2 per 100

7 per 100
(1 to 52)

Ferritin (µg/L)
Follow‐up: range 2 months to 1 year

The mean ferritin µg/L in the control groups ranged from 16.70 µg/L to 62.00 µg/L

The mean ferritin µg/L in the intervention groups was 6.07 µg/L lower (10.66 lower to 1.48 lower)

‐

988
(4 studies)

⊕⊕⊝⊝
Lowe

Includes one cluster‐randomised trial b

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

Not estimable

‐

(0 studies)

‐

‐

All‐cause morbidity (the most frequent event associated with the intervention, independent of the cause, as defined by the trialists)

Not estimable

‐

(0 studies)

‐

‐

Any adverse side effects

29 per 100

2 per 100

(6 to 24)

RR 0.41

(0.21 to 0.82)

1166

(6 studies)

⊕⊕⊕⊝
Lowf

Includes one cluster‐randomised trial b

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

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 are moderately confident 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 effect.

aDowngraded one level due to study limitations (in several trials the method of allocation concealment was not clear and there was a lack of blinding) (I2 = 12%).
bFor cluster‐randomised studies (C), the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.
cDowngraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 78%).
dDowngraded two levels due to imprecision (only one study with 25 losses to follow‐up reported data on this outcome; wide CI) and one level for study limitations (concerns about attrition) (l2 = not estimable).
eDowngraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 91%).
f Downgraded two levels due to inconsistency (in the direction of the effect and the CI of some of the included studies cross the line of no effect, and high heterogeneity) (I2 = 82%).

Figuras y tablas -
Summary of findings 2. Intermittent iron supplementation versus daily iron supplementation in menstruating women
Ir a la tabla de la revisión
Table 1. Unused methods

Method

Approach

Reason for non‐use

Measures of treatment effects

Continuous data

We had planned to use the SMD to combine trials that measured the same outcome but used different methods.

There was no need to use the SMD to combine trials as outcomes were measured with the same methods.

Sensitivity analysis

We had planned to conduct a sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with unclear or high risk of bias for sequence generation and allocation concealment, and either high levels of attrition or no blinding) from the analyses and comparing the effect.

It was not possible to conduct this analysis because only two studies were considered at low risk of bias according to our predefined criteria (Hall 2002 (C) and Nguyen 2008).

We had planned to conduct a sensitivity analysis to explore the effect of missing data.

We were not able to conduct this analysis given that 13 out of 25 studies had attrition, and 22 out of 25 studies had unclear risk of reporting bias.

SMD: standardised mean difference
Figuras y tablas -
Table 1. Unused methods
Ir a la tabla de la revisión
Comparison 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Anaemia (All) Show forest plot

11

3135

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.49, 0.87]

1.2 Anaemia (by supplement composition) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.2.1 Iron alone

2

292

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.09, 2.13]

1.2.2 Iron plus folic acid

8

1871

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.52, 0.97]

1.2.3 Iron plus multiple micronutrients

3

972

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.25, 1.07]

1.3 Anaemia (by anaemia status at baseline) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.3.1 Anaemic

1

222

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.30, 0.52]

1.3.2 Mixed/Unknown

10

2913

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.55, 0.93]

1.4 Anaemia (by iron status at baseline): Mixed/Unknown Show forest plot

11

3135

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.49, 0.87]

1.5 Anaemia (dose of elemental iron per week in the intermittent group) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.5.1 60 mg of iron or less per week

5

1855

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.43, 1.10]

1.5.2 More than 60 mg of iron per week

7

1280

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.42, 0.91]

1.6 Anaemia (by duration of supplementation) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.6.1 3 months or less

6

2176

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.44, 1.00]

1.6.2 More than 3 months

5

959

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.34, 1.04]

1.7 Anaemia (by malaria endemicity) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.7.1 No malaria/Unknown

9

2937

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.41, 0.86]

1.7.2 Malaria

2

290

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.56, 1.30]

1.8 Haemoglobin in g/L (All) Show forest plot

15

2886

Mean Difference (IV, Random, 95% CI)

5.19 [3.07, 7.32]

1.9 Haemoglobin in g/L (by supplement composition) Show forest plot

15

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.9.1 Iron alone

6

893

Mean Difference (IV, Random, 95% CI)

7.16 [3.40, 10.92]

1.9.2 Iron plus folic acid

8

1671

Mean Difference (IV, Random, 95% CI)

3.56 [1.11, 6.01]

1.9.3 Iron plus multiple micronutrients

2

322

Mean Difference (IV, Random, 95% CI)

7.94 [2.37, 13.52]

1.10 Haemoglobin in g/L (by anaemia status at baseline) Show forest plot

15

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.10.1 Anaemic

3

439

Mean Difference (IV, Random, 95% CI)

7.21 [3.05, 11.37]

1.10.2 Mixed/Unknown

12

2447

Mean Difference (IV, Random, 95% CI)

4.71 [2.30, 7.13]

1.11 Haemoglobin in g/L (by iron status at baseline) Show forest plot

14

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.11.1 Iron deficient

1

87

Mean Difference (IV, Random, 95% CI)

4.80 [1.42, 8.18]

1.11.2 Mixed/Unknown

14

2725

Mean Difference (IV, Random, 95% CI)

5.59 [3.47, 7.72]

1.12 Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group) Show forest plot

15

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.12.1 60 mg of iron or less per week

6

971

Mean Difference (IV, Random, 95% CI)

5.21 [2.06, 8.36]

1.12.2 More than 60 mg of iron per week

10

1915

Mean Difference (IV, Random, 95% CI)

5.24 [2.43, 8.04]

1.13 Haemoglobin in g/L (by duration of supplementation) Show forest plot

15

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.13.1 3 months or less

7

1387

Mean Difference (IV, Random, 95% CI)

6.37 [3.37, 9.37]

1.13.2 More than 3 months

8

1499

Mean Difference (IV, Random, 95% CI)

3.95 [1.28, 6.63]

1.14 Haemoglobin in g/L (by malaria endemicity) Show forest plot

15

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.14.1 No malaria/Unknown

12

2389

Mean Difference (IV, Random, 95% CI)

5.63 [3.18, 8.09]

1.14.2 Malaria

3

497

Mean Difference (IV, Random, 95% CI)

3.04 [0.52, 5.56]

1.15 Iron deficiency (All) Show forest plot

3

624

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.24, 1.04]

1.16 Ferritin in µg/L (All) Show forest plot

7

1067

Mean Difference (IV, Random, 95% CI)

7.46 [5.02, 9.90]

1.17 Ferritin in µg/L (by supplement composition) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.17.1 Iron alone

3

291

Mean Difference (IV, Random, 95% CI)

6.01 [3.89, 8.13]

1.17.2 Iron plus folic acid

3

455

Mean Difference (IV, Random, 95% CI)

5.87 [3.23, 8.52]

1.17.3 Iron plus multiple micronutrients

2

321

Mean Difference (IV, Random, 95% CI)

11.05 [2.94, 19.17]

1.18 Ferritin in µg/L (by anaemia status at baseline) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.18.1 Anaemic

2

309

Mean Difference (IV, Random, 95% CI)

6.17 [4.47, 7.88]

1.18.2 Mixed/Unknown

5

758

Mean Difference (IV, Random, 95% CI)

9.15 [4.36, 13.95]

1.19 Ferritin in µg/L (by iron status at baseline) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.19.1 Iron deficient

1

87

Mean Difference (IV, Random, 95% CI)

5.79 [3.55, 8.03]

1.19.2 Mixed/Unknown

6

980

Mean Difference (IV, Random, 95% CI)

8.32 [4.97, 11.66]

1.20 Ferritin in µg/L (by dose of elemental iron per week in the intermittent group) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.20.1 60 mg of iron or less per week

3

269

Mean Difference (IV, Random, 95% CI)

12.37 [7.06, 17.69]

1.20.2 More than 60 mg of iron per week

5

798

Mean Difference (IV, Random, 95% CI)

6.60 [4.30, 8.91]

1.21 Ferritin in µg/L (by duration of supplementation) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.21.1 3 months or less

3

518

Mean Difference (IV, Random, 95% CI)

8.32 [4.38, 12.26]

1.21.2 More than 3 months

4

549

Mean Difference (IV, Random, 95% CI)

6.31 [2.82, 9.81]

1.22 Ferritin in µg/L (by malaria endemicity) Show forest plot

7

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.22.1 No malaria/Unknown

5

895

Mean Difference (IV, Random, 95% CI)

7.74 [4.79, 10.69]

1.22.2 Malaria

2

172

Mean Difference (IV, Random, 95% CI)

6.79 [0.48, 13.10]

1.23 Iron deficiency anaemia (All) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.24 All cause morbidity (All) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.25 Diarrhoea Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.26 Any adverse side effects Show forest plot

3

630

Risk Ratio (M‐H, Random, 95% CI)

1.98 [0.31, 12.72]

1.27 Adherence Show forest plot

2

417

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.96, 1.02]

1.28 Prevalence of malaria parasitaemia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.29 Any malaria parasitaemia (Incidence rate; per 1000 person months) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.30 High density malaria parasitaemia (parasites 200/wbc) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

1.31 Clinical malaria Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 1. Intermittent iron supplementation (alone or with any other micronutrients) versus no supplementation or placebo
Ir a la tabla de la revisión
Comparison 2. Intermittent iron supplementation versus daily iron supplementation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Anaemia (All) Show forest plot

8

1749

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.93, 1.29]

2.2 Anaemia (by supplement composition) Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.2.1 Iron alone

3

690

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.97, 1.99]

2.2.2 Iron plus folic acid

4

861

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.81, 1.30]

2.2.3 Iron plus multiple micronutrients

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.30, 2.46]

2.3 Anaemia (by anaemia status at baseline) Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.3.1 Anaemic

2

270

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.76, 1.16]

2.3.2 Mixed/Unknown

6

1479

Risk Ratio (M‐H, Random, 95% CI)

1.22 [1.01, 1.47]

2.4 Anaemia (by iron status at baseline): Mixed/Unknown Show forest plot

7

1629

Risk Ratio (M‐H, Random, 95% CI)

1.21 [1.01, 1.45]

2.5 Anaemia (by dose of elemental iron per week in the intermittent group) Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.5.1 60 mg of iron or less per week

4

614

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.82, 1.85]

2.5.2 More than 60 mg of iron per week

5

1135

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.85, 1.35]

2.6 Anaemia (by duration of supplementation) Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.6.1 3 months or less

4

631

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.77, 1.16]

2.6.2 More than 3 months

4

1118

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.99, 1.54]

2.7 Anaemia (by malaria endemicity) Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.7.1 No malaria/Unknown

7

1629

Risk Ratio (M‐H, Random, 95% CI)

1.21 [1.01, 1.45]

2.7.2 Malaria

1

120

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.73, 1.14]

2.8 Haemoglobin in g/L (All) Show forest plot

10

2127

Mean Difference (IV, Random, 95% CI)

0.43 [‐1.44, 2.31]

2.9 Haemoglobin in g/L (by supplement composition) Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.9.1 Iron alone

4

671

Mean Difference (IV, Random, 95% CI)

0.31 [‐1.15, 1.78]

2.9.2 Iron plus folic acid

4

1138

Mean Difference (IV, Random, 95% CI)

0.39 [‐4.18, 4.96]

2.9.3 Iron plus multiple micronutrients

2

318

Mean Difference (IV, Random, 95% CI)

0.84 [‐1.08, 2.76]

2.10 Haemoglobin in g/L (by anaemia status at baseline) Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.10.1 Anaemic

4

804

Mean Difference (IV, Random, 95% CI)

2.82 [1.56, 4.09]

2.10.2 MIxed/Unknown

6

1323

Mean Difference (IV, Random, 95% CI)

‐1.14 [‐3.15, 0.87]

2.11 Haemoglobin in g/L (by iron status at baseline) Show forest plot

9

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.11.1 Iron deficient

1

21

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐7.94, 5.94]

2.11.2 Mixed/Unknown

8

1986

Mean Difference (IV, Random, 95% CI)

0.36 [‐1.77, 2.49]

2.12 Haemoglobin in g/L (by dose of elemental iron per week in the intermittent group) Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.12.1 60 mg of iron or less per week

6

843

Mean Difference (IV, Random, 95% CI)

1.14 [‐0.34, 2.62]

2.12.2 More than 60 mg of iron per week

5

1284

Mean Difference (IV, Random, 95% CI)

‐0.34 [‐3.44, 2.76]

2.13 Haemoglobin in g/L (by duration of supplementation) Show forest plot

10

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.13.1 3 months or less

7

1059

Mean Difference (IV, Random, 95% CI)

1.36 [0.19, 2.53]

2.13.2 More than 3 months

3

1068

Mean Difference (IV, Random, 95% CI)

‐0.72 [‐5.41, 3.98]

2.14 Haemoglobin in g/L (by malaria endemicity) Show forest plot

11

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.14.1 No malaria/Unknown

10

2416

Mean Difference (IV, Random, 95% CI)

0.17 [‐1.65, 1.98]

2.14.2 Malaria

1

120

Mean Difference (IV, Random, 95% CI)

2.00 [‐1.40, 5.40]

2.15 Iron deficiency (All) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.16 Ferritin in µg/L (All) Show forest plot

4

988

Mean Difference (IV, Random, 95% CI)

‐6.07 [‐10.66, ‐1.48]

2.17 Ferritin in µg/L (by duration of supplementation) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.17.1 3 months or less

2

219

Mean Difference (IV, Random, 95% CI)

‐17.42 [‐23.44, ‐11.41]

2.17.2 More than 3 months

2

769

Mean Difference (IV, Random, 95% CI)

‐1.05 [‐3.59, 1.48]

2.18 Ferritin in µg/L (by anaemia status at baseline) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.18.1 Anaemic

1

331

Mean Difference (IV, Random, 95% CI)

0.10 [‐0.73, 0.93]

2.18.2 Mixed/Unknown

3

657

Mean Difference (IV, Random, 95% CI)

‐11.32 [‐22.61, ‐0.02]

2.19 Ferritin in µg/L (by iron status at baseline) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.19.1 Iron deficient

1

21

Mean Difference (IV, Random, 95% CI)

‐14.80 [‐22.99, ‐6.61]

2.19.2 Mixed/Unknown

3

967

Mean Difference (IV, Random, 95% CI)

‐3.80 [‐8.08, 0.47]

2.20 Ferritin in µg/L (by dose of elemental iron per week in the intermittent group) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.20.1 60 mg or iron or less per week

2

123

Mean Difference (IV, Random, 95% CI)

‐16.29 [‐23.09, ‐9.48]

2.20.2 More than 60 mg of iron per week

3

865

Mean Difference (IV, Random, 95% CI)

‐2.08 [‐5.44, 1.29]

2.21 Ferritin in µg/L (by supplement composition) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.21.1 Iron alone

1

21

Mean Difference (IV, Random, 95% CI)

‐14.80 [‐22.99, ‐6.61]

2.21.2 Iron plus folic acid

2

769

Mean Difference (IV, Random, 95% CI)

‐1.05 [‐3.59, 1.48]

2.21.3 Iron plus multiple micronutrients

1

198

Mean Difference (IV, Random, 95% CI)

‐18.50 [‐27.37, ‐9.63]

2.22 Ferritin in µg/L (by malaria endemicity): No malaria/Unknown Show forest plot

4

988

Mean Difference (IV, Random, 95% CI)

‐8.27 [‐16.21, ‐0.32]

2.23 Diarrhoea Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.24 Any adverse side effects Show forest plot

6

1166

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.21, 0.82]

2.25 Depression Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.26 Adherence Show forest plot

4

507

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.99, 1.09]
Figuras y tablas -
Comparison 2. Intermittent iron supplementation versus daily iron supplementation
Ir a la tabla de la revisión