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Intermittent iron supplementation for reducing anaemia and its associated impairments in menstruating women

  1. Ana C Fernández-Gaxiola1,
  2. Luz Maria De-Regil2,*

Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

Published Online: 7 DEC 2011

Assessed as up-to-date: 4 NOV 2011

DOI: 10.1002/14651858.CD009218.pub2


How to Cite

Fernández-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia and its associated impairments in menstruating women. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD009218. DOI: 10.1002/14651858.CD009218.pub2.

Author Information

  1. 1

    Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico

  2. 2

    Micronutrient Initiative, Ottawa, ON, Canada

*Luz Maria De-Regil, Micronutrient Initiative, 180 Elgin Street, Suite 1000, Ottawa, ON, K2P 2K3, Canada. lderegil@micronutrient.org.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 7 DEC 2011

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Characteristics of included studies [ordered by study ID]
Agarwal 2003 (C)

MethodsCluster-randomised trial. 3 arm design with randomisation at class section level.


Participants2088 girls, aged 10-17 years, attending one of four Government Senior Secondary Schools. All these schools cater to the middle socioeconomic group population in North-East Delhi, India.

Baseline prevalence of anaemia: ˜48%.


Interventions60 class sections were allocated to one of the following groups:

Group 1 (n = 691): participants did not receive any tablets for the first 100 days and haemoglobin was estimated at 115 ± 5 days. They were thereafter given tablets containing 100 mg of elemental iron and 500 μg (0.5 mg) of folic acid with advice to take 1 tablet daily for 100 days; distributed weekly as in group 2.

Group 2 (n = 702): participants received one iron folic acid tablet daily for 100 days; blister packs provided once a week.

Group 3 (n = 695): participants received the weekly tablet until group 1 completed the study (230 days).

Tablets were distributed weekly in blister pack and provided 100 mg of elemental iron and 500 μg (0.5 mg) of folic acid each.

Length of the intervention: 100 days (we did not consider the second period in which group 1 and 3 received supplementation)


OutcomesAnaemia (Hb<120 g/L), haemoglobin, ferritin.


NotesIntervention supervised. Compliance was monitored verbally on weekly visits when 7 tablets in a blister pack were distributed. The used blisters were collected each week; results not reported.

Sexual maturity rating was done using Tanner’s criteria. The time of menarche and regularity of menstrual periods was noted.

Malaria endemicity not reported.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe randomisation was done at the class section level for 60 class sections. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskNot mentioned. Since randomisation was performed at class section level it is unlikely a selection bias at individual level.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: not described;

Personnel: not described;

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskSeven girls in the daily administered group during the second week of intervention complained of gastric side effects and requested not to continue in the study and were excluded.

Selective reporting (reporting bias)High riskGirls with haemoglobin <70 g/L (0.3%) were eliminated from the analysis.

Plasma ferritin and C-reactive proteins (CRP) were estimated in every tenth girl of the study groups; it is unclear how each girl was selected for these analyses. Data not available for the second measurement.

Other biasLow riskThe study appears to be free of other bias.

Ahmed 2001

MethodsRandomised, double-blind, placebo-controlled experimental trial. 2x2 factorial design with randomisation at individual level.


Participants480 postmenarchal, nonpregnant teenagers aged 14–19 years who worked in garment factories in Dhaka City, Bangladesh. Inclusion criteria: haemoglobin concentration between 80 and 120 g/L (anaemic). Exclusion criteria: Hemoglobin below 80 g/L and those with clinical manifestations of chronic or infectious disease. The study population was highly transitional with a high rate of migration.

Baseline prevalence of anaemia: ˜90%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 120): participants received a placebo.

Group 2 (n = 120): participants received vitamin A only (2.42 mg retinol as retinyl palmitate).
Group 3 (n = 120): participants received 120 mg elemental of iron (as ferrous sulphate), 3500 μg (3.5 mg) of folic acid, and a placebo for vitamin A).

Group 4 (n = 120): participants received 120 mg of elemental iron (as ferrous sulphate), 3500 μg (3.5 mg) of folic acid, and 2.42 mg retinol as retinyl palmitate).

All the groups received weekly supplementation.

Length of the intervention: 12 weeks.

For the purpose of this review groups 3 and 4 were combined and only presented separately for the subgroup analysis by nutrient. The combined group was compared with group 1.


OutcomesAnaemia, haemoglobin, iron deficiency, ferritin,serum iron, TIBC, Transferrin saturation (%), vitamin A, adherence (75% of the doses).


NotesMalaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubjects were randomly allocated to one of the study groups. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskAn independent person coded the preparations and the code was not broken until all data data had been entered into the computer.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants: were not aware of the treatment;

Personnel: were not aware of the treatment;

Outcome assessors: were not aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
High risk289 out of 480 (60%) participants completed the study and the losses were imbalanced among groups: 41%, 44%, 38% and 35%, for groups 1, 2, 3 & 4, respectively.

Subjects were lost to follow-up for the following reasons: 75% left their job or moved to another factory, 3% became pregnant, 5% refused to give a second blood sample, 12% were absent on the day of blood collection, and 5% did not take the supplements for the full 12-wk supplementation period.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasUnclear riskThere was some variability in the administration of the supplements, depending on the factory management. In some factories, supplements were given before lunch and in some they were given after lunch. Many subjects came to work after having eaten little or no breakfast and ate only a small lunch.

Angeles-Agdeppa 1997

MethodsRandomised, double-blind, placebo-controlled trial. 3 arm trial with randomisation at individual level.


Participants363 girls, aged 14-18 years, enrolled in a governmental senior high school in East Jakarta, Indonesia. Inclusion criterion: presence of regular menstruation.

Baseline prevalence of anaemia: 21%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 92): participants received 60 mg of elemental iron, 250 μg (0.25 mg) of folic acid, 750 µg of retinol, and 60 mg of vitamin C on every school day of the week (Monday-Friday).

Group 2 (n = 92): participants received 60 mg of elemental iron + 500 µg (0.5 mg) of folic acid + 6000 µg of vitamin A (as retinol) + 60 mg of vitamin C only on Friday (Muslim prayer day) and placebos during the rest of the week.

Group 3 (n = 92): participants received 120 mg of elemental iron + 500 µg (0.5 mg) of folic acid + 6000 µg of vitamin A (as retinol) + 60 mg of vitamin C only on Friday (Muslim prayer day) and placebos during the rest of the week.

Group 4 (n = 92): participants received a placebo on every school day.

Length of the intervention: 12 weeks.

For the purpose of the review groups 2 and 3 were combined and only split up for the subgroup analysis by dose.


OutcomesAnaemia, iron deficiency, prevalence of low retinol, haemoglobin, ferritin, retinol, diarrhoea, adverse side effects (nausea, vomiting, sleepiness), positive side effects (increased appetite).


NotesAll participants were dewormed at the start of the study with a single 500-mg dose of mebendazole because 34% of a sub sample of 104 participants were found to be infested with Trichuris trichiura.

Intervention supervised during the first 8 weeks, and during weeks 9-12 the supplements were provided on a take-home basis after the girls had received careful instruction on tablet intake (because the last 4 weeks of supplementation fell in the Muslim fasting month). Compliance was monitored by retrieving plastic bags in which the tablets were provided and remaining tablets were count.

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubjects were randomly selected and then randomly assigned to one of the study groups. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskNot mentioned, but trial had a double masked placebo design.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants: were not aware of the treatment;

Personnel: were not aware of the treatment;

Outcome assessors: not described but likely did not know the treatments.

Supplements and placebos had the same red colour and shape, and were not distinguishable by sight.

Incomplete outcome data (attrition bias)
All outcomes
High risk75% of the participants completed the study and the losses were imbalanced among study groups: 30%, 24%, 30%, 19% for groups 1, 2, 3 & 4, respectively.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasUnclear riskIntervention supervised during the first 8 weeks, and during weeks 9-12 the supplements were provided on a take-home basis after the girls had received careful instruction on tablet intake (because the last 4 weeks of supplementation fell in the Muslim fasting month).

Beasley 2000

MethodsSingle-blind randomised controlled trial. 2 arm design with randomisation at individual level.


Participants234 females, aged 12-18 years, living in the rural area of Muheza District in the villages of Misongeni, Ubembe and Kilometa Saba, Tanzania. Girls were excluded if haemoglobin concentration lower than 70 g/L.

Baseline prevalence of anaemia (Hb lower than 110g/L): 27%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 50): women were given 120 mg of elemental iron (as 200 mg of ferrous sulphate) per week.

Group 2 (n = 57): women were given a control treatment - cyanocobalamin (vitamin B12) (2 x 50 μg)

Both groups were treated for infection with Albendazol before the intervention.

Length of the intervention: 16 weeks, where supplementation was given at intervals of "at least once a week"


OutcomesAnaemia, serum ferritin, haemoglobin (and mean change of both), weight and prevalence and intensity (parasites/200 wbc) of infection with P. falciparum.


NotesMalaria is holo-endemic in the study area.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation took place before anthelmintic treatment. Groups were matched for intensity of infection with hookworm and S. haematobium. Method of sequence generation not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: unclear, a control was used but it is unclear whether pills had the same appearance;

Personnel: aware of the treatment;

Outcome assessors: did not know the treatment group..

Incomplete outcome data (attrition bias)
All outcomes
High riskOf the girls included in the study, 119 (51% of those recruited) received 12 doses of iron or control treatment and completed all follow-up measures. It is unclear why children dropped out of the study or failed to receive all 12 doses of treatment

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasUnclear riskControl was vitamin B12, which could have potentially improved anaemia status. However macrocytosis was observed in only 8% of blood films taken at baseline.

Dos Santos 1999

MethodsRandomised blinded trial. 2 arm design with randomisation at individual level.


Participants193 women, aged 15-45 years, living in a low-income community in the city of Recife, Pernambuco, Brazil. Inclusion criteria: mild to moderate anaemia (Haemoglobin between 75 g/L and 119 g/L), non pregnant and with "regular" menstruation. Exclusion criteria: use of iron supplements during the last thirty days, haematological and renal diseases.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 96): women were given daily 60 mg of elemental iron (as ferrous sulphate).

Group 2 (n = 97): women were given once a week 60 mg of elemental iron (as ferrous sulphate).

Length of the intervention: 12 weeks.


OutcomesHaemoglobin, MCV, adherence (optima), weight


NotesArticle translated into English from Portuguese.

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskWomen were randomly allocated to the treatments by drawing of lots.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatments;

Personnel: staff in charge of haematological measurements did not know the study hypothesis, objectives and treatments received by the participants;

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
High risk150 out of 187 (80.2%) participants completed the study but the losses were imbalanced among groups: 26.0% and18.5%, for groups 1 & 2, respectively.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThere is no evidence of other bias.

Februhartanty 2002

MethodsSingle-blind community experimental study. 3 arm design with randomisation at individual level.


Participants100 post menarchal female adolescent students (˜14-15 years old) were chosen from two different junior high schools in Kupang, East Nusa Tenggara, in the eastern part of Indonesia. Both schools were public and located in relatively similar urban areas. The other 50 students were recruited at random from a different junior high school and allocated to the menstruation group.

Baseline prevalence of anaemia: 58%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 50): girls received a tablet containing 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) of folic acid every Wednesday.

Group 2 (n = 50): girls received a placebo tablet every Wednesday.

Group 3 (n = 50): girls were given an iron tablet each day for four consecutive days (during menstruation).

For the purpose of this review only groups 1 and 2 were compared.

Length of the intervention: 16 weeks.


OutcomesHaemoglobin, ferritin.


NotesFor subjects attending morning classes, tablets were taken in the morning. For subjects attending afternoon classes, tablets were taken in the afternoon. To control parasitic infestation, all subjects were given a single dose of 500 mg of mebendazole three days before supplementation.

Due to unfavourable environmental conditions in the study area during late November 1998, the 16th week tablets for the placebo and weekly groups were taken in the 17th week. The second blood collection was delayed around five days.

Malaria area.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskParticipants were allocated randomly only to placebo or weekly groups. Method of sequence generation not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants: were not aware of the treatments;

Personnel: not described;

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe final data set consisted of 48 subjects in each of the study groups (4% dropout per group). Common reasons for dropping out were refusal to undergo blood collection, absent from class on the day of blood collection, and transfer to another school.

Selective reporting (reporting bias)Unclear riskAfter excluding extreme values (serum ferritin changes of more than 50 μg/L), a complete data set of serum ferritin levels covered 34 subjects in the placebo group and 31 subjects in the weekly group.

Other biasHigh riskHigher prevalence of anaemia in the weekly group.

Gilgen 2001

MethodsRandomised, double-blind trial. 4 arm design with randomisation at individual level.


Participants553 non-pregnant and non-breastfeeding tea pluckers (39.6 years of age in average) in north-east Bangladesh.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 139): participants received weekly supplement containing 200 mg of elemental iron (as ferrous fumarate) and 200 μg (0.2 mg) of folic acid.

Group 2 (n = 143): participants received anthelmintic treatment on two occasions, at the beginning of the trial and 12 weeks later (using a single dose of albendazole 400 mg).

Group 3 (n = 130): participants received weekly supplement containing 200 mg of elemental iron (as ferrous fumarate) and 200 μg (0.2 mg) of folic acid + single dose of albendazole 400 mg on two occasions.

Group 4 (n = 141): participants received placebos for both iron supplementation (weekly) and antihelminthic treatment (beginning and 12 weeks later).

Length of the intervention: 24 weeks.

For the purpose of this review only groups 1 and 4 were compared.


OutcomesHaemoglobin, ferritin, labour productivity, helminth infections, adverse side effects (giddiness, dizziness, nausea, bouts of vomiting, diarrhoea and stomach pains), positive side effects (well being, feeling stronger and more energetic, feeling relief from stomach pains, anorexia, diarrhoea).


NotesData on work productivity could not be extracted as it does not include standard deviations. There were no significant differences in the number of days plucked on pruned, unpruned and young tea bushes between the study groups.

Of 139 women in the iron-supplemented group, 87 (62.2%) reported an improvement in well-being after the 24 weeks of iron supplementation. Nearly half (46.6%) felt stronger and more energetic and 15.2% felt relief from stomach pains, anorexia and diarrhoea. In the placebo group, 51.1% felt better after the trial with 38.9% feeling stronger and more energetic and 6.4% feeling relief from stomach pains, anorexia and diarrhoea.

No screening for malaria parasites was performed as malaria is not known to be endemic in the study region.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSubjects were randomly assigned to one of the study groups. The random number generator in SPSS (Version 7.5) was used to create four groups of equal size and the process was repeated until there was no statistically significant difference between the randomised groups in mean age, years of plucking experience, productivity of the previous plucking season, haemoglobin and ferritin values and prevalence and egg counts of Ascaris, Trichuris and hookworms.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
Low riskStudy described as double-blind.

Participants: were not aware of the treatments;

Personnel: were not aware of the treatments;

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot mentioned.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThere is no evidence of other bias.

Gonzalez-Rosendo 2002

MethodsRandomised clinical trial. 3 arm design with randomisation at individual level.


Participants637 female adolescents, aged 12-18 years, attending 15 public schools in Morelos, Mexico.

Baseline prevalence of anaemia: 28%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 169): girls received 60 mg of elemental iron (as ferrous sulphate) on week days (Monday to Friday).

Group 2 (n = 172): girls received 60 mg of elemental iron (as ferrous sulphate) once a week (Monday).

Group 3 (n = 170): girls received no treatment. These group was composed of non anaemic women only .

Length of the intervention: 16 weeks.

For the purpose of this review only group 1 and 2 were compared.


OutcomesAnaemia, haemoglobin, hematocrit, adherence, weight, height, circumference of waist and hip.


NotesArticle translated from Spanish into English.

Prior to the study, adolescents with parasitaemia were treated with 400 mg of albendazol.

Teachers administered the supplements and supervised the adherence to the intervention.

In average, the group receiving weekly iron supplementation consumed 81% of the total doses while women in the daily group consumed 56%.

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to either the weekly or the daily group by using a computer-generated random sequence.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatments;

Personnel: were aware of the treatments;

Outcome assessors: were aware of the treatments.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described, apparently there were no losses to follow up.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThere is no evidence of other bias.

Hall 2002 (C)

MethodsCluster randomised trial. 2 arm design with randomisation at school level (60 schools, 30 per arm).


Participants552 girls, aged 6-19 years of age (mean age 11.4 y), attending rural informal community schools in the Kolondieba district of Mali, Africa. Approximately 20 randomly selected children (10 boys and 10 girls) in each school. Any child with severe anaemia (Hb=80 g/L or lower) was excluded.

Baseline prevalence of anaemia: approximately 55%


InterventionsSchools were allocated to one of the following groups:

Group 1 (n = 271) at follow up, number randomised not clear): children received 65 mg elemental iron (as 200 mg of ferrous sulphate) and 250 μg (0.25 mg) of folic acid once a week.

Group 2 (n = 281) at follow up, number randomised not clear): no treatment.

Length of the intervention: 10 weeks.


OutcomesAnaemia, haemoglobin. Only the results for girls are included in this review.


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

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

The study also includes data for boys but were not included in this review.

For the analyses we only included the estimated effective sample size. Authors provided the ICC (0.0698) and design effect (2.22) to adjust data by the effect of clustering. The analyses include only the estimated effective sample size.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk60 schools were randomly assigned to either a treatment or a comparison group by using a computer-generated random number list (information communicated by the author).

Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at school level, it is unlikely there was a selection bias at the individual level.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: not reported;

Personnel: not reported;

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low risk93% children followed up.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Jayatissa 1999 (C)

MethodsDouble-blinded, placebo controlled clinical trial. 3 arm design with randomisation at class level.


Participants690 adolescents, aged 10-17 years (mean age 11.4 y), attending schools in the district of Colombo, Sri Lanka. Subjects were excluded if they had chronic infectious diseases or cardiopathies, if they had taken supplements or medications containing iron during the previous month, or if they had a haemoglobin level less than 100 g/L with a blood picture showing any other kind of anaemia.

Baseline prevalence of anaemia: 21.1%


InterventionsClasses were allocated to one of the following groups:

Group 1 (n = 243): participants received a daily dose of 60 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) of folic acid in a combined tablet (iron/folate) and 100 mg of vitamin C five days per week, Monday through Friday.

Group 2 (n = 230): participants received the same dose of iron/folate and vitamin C, but only once a week on Monday, and they were given a placebo replacement for the iron/folate and vitamin C during the other four days.

Group 3 (n = 217): participants received a placebo replacement for iron/folate and
vitamin C five days per week, Monday through Friday.

Length of the intervention: 8 weeks.


OutcomesAnaemia, haemoglobin, ferritin (only in a subsample), adverse side effects (side effects reported included constipation, sleepiness, abdominal pain, rash, and nausea).


NotesFerritin measurements were obtained from only one school; we did not include this information.

Malaria endemicity not reported.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskIt is stated that treatments were randomly allocated by classes. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at class level, it is unlikely there was a selection bias at the individual level.

Blinding (performance bias and detection bias)
All outcomes
Low riskSupplements and placebos had the same colour and shape and were not distinguishable by sight.

Participants: girls were not aware of differences among
the treatment regimes;

Personnel: teachers were not aware of differences among the treatment regimes;

Outcome assessors: interviewers were not aware of differences among the treatment regimes.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe dropout rate was 4.5%.The reasons for dropping out were
side effects (16 girls, 52%), leaving school (10 girls, 32%), or doctor’s advice not to take the tablet with other treatment (5 girls, 16%).

Selective reporting (reporting bias)Unclear riskFerritin samples were taken from a randomly selected subsample

Other biasLow riskThe study appears to be free of other bias.

Kianfar 2000

MethodsRandomised controlled trial. 2x4 arm design with randomisation at individual level.


Participants523 female adolescents selected from among students of grades 1-3 attending four high schools in urban areas of Zahedan and Rasht, Iran (average age 16.1 years of age).  Inclusion criterion: written consent secured from subject's families.  No exclusion criteria listed.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 92): adolescents were given a daily tablet containing 50 mg of elemental iron (as 150 mg ferrous sulphate) at least one hour after dinner and before sleeping to be taken with water on Wednesdays.

Group 2 (n = 112): adolescents were given twice weekly 50 mg of elemental iron (as 150 mg ferrous sulphate) tablet at least one hour after dinner and before sleeping to be taken with water on Wednesdays and Saturday.

Group 3 (n = 171): adolescents were given once a week a tablet containing 50 mg of elemental iron (as 150 mg ferrous sulphate) at least one hour after dinner and before sleeping to be taken with water on Wednesdays.

Group 4 (n = 148): adolescents received no intervention.

Length of the intervention: 3 months.

For the purpose of this review we combined groups 2 and 3 and present their individual results only in the subgroup analysis by scheme.


OutcomesHaemoglobin, serum ferritin, serum transferrin, anaemia, iron deficiency (ferritin <12ng/mL), side effects and adherence.

Data reported only by anaemia status; we combined the groups to include the trial's information.


NotesAdherence ranged between 70 and 90%. No differences in the incidence of side effects between supplementation regimens.

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubjects stratified by anaemia status were randomly allocated to the groups. Method of sequence generation not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: only staff did not know the treatment group;

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low risk88/92 (95.6%), 108/112 (96.4%), 168/171 (98.2%), 145/148 (97.9%) of the participants finished the study in groups 1, 2, 3 and 4, respectively.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Leenstra 2009

MethodsRandomised controlled trial. 2x2 factorial design with randomisation at individual level.


Participants279 non-pregnant school girls aged 12-18 years, with mild-to-moderate anaemia (Hb < 70 g/L but > 120 g/L) attending one of 10 schools in the City of Kisumu in Nyanza Province, western Kenya. Exclusion criteria: severe anaemia (hb < 70 g/L), signs of xerophthalmia, pregnancy or disease requiring hospitalisation.

Baseline prevalence of anaemia:˜30% and iron deficiency ˜40%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 68): participants received once weekly oral iron 120 mg (2 ferrous sulphate tablets 200 mg) and 25,000 IU (8.3 mg) of retinol (vitamin A) in gelatin capsule.

Group 2 (n = 70): participants received once weekly iron (as group 1) and vitamin A placebo.

Group 3 (n = 70): participants received once weekly vitamin A with iron placebo.

Group 4 (n = 71): participants received placebo only (no iron nor vitamin A).

Length of the intervention: 5 months.

For the purpose of this review only groups 2 and 4 were compared.


OutcomesHaemoglobin (estimated from graph 1 in the paper), malaria, parasitaemia, morbidity, side effects


NotesThe intervention was supervised except during school holiday.

Approximately 26% of 15-19 year old girls are affected by HIV.

Girls receiving iron were more likely to report constipation or dark stools than girls receiving iron placebo (Rate ratio 2.2 (1.1, 4.4) and 6.4 (1.0, 41.5), respectively). There was no difference between groups regarding the occurrence of potential side effects as nausea, vomiting or diarrhoea (data not shown).

Malaria transmission in this urban area is largely uncharacterized, but is perennial with highest transmission during peak rainfall from April–July and October–December.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskBalanced block randomisation (block size 12). Method of sequence generation not described.

Allocation concealment (selection bias)Low riskThis was a placebo controlled trial and individual packs were left for girls in the study schools. Active and placebo supplements were manufactured by Laboratory and Allied Limited (Nairobi, Kenya) and the key was only revealed after completion of the study.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants: were not aware of the treatment;

Personnel: were not aware of the treatment;

Outcome assessors: were not aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low risk249 out of 279 participants completed the study (89%). Loss to follow up appeared balanced across groups and reasons were explained. Analyses were done on an intention to treat basis.

Selective reporting (reporting bias)Unclear riskData on several outcomes were described as non significant but were not shown (side effects including vomiting and diarrhoea).

Other biasUnclear riskGroups appeared similar at baseline. Most of the results for the four randomised groups are presented in graphs which are difficult to interpret (and have not been included in our data and analysis tables). Data on several outcomes were described as non significant but were not shown (side effects including vomiting and diarrhoea). Placebo figures are not reported.

Mozaffari 2010 (C)

MethodsCluster community-based randomised supplementation trial. 2 arm design with randomisation at school level


Participants200 high school girls, aged 14-16 years, from Yazd City in central Iran. Exclusion criteria: students who had hepatic or neural diseases or received or donated blood within the previous 2 weeks.

Baseline anaemia prevalence: ˜13%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 100): girls received 30 mg of elemental iron (as ferrous sulphate) on the first working day of each week.

Group 2 (n = 100): girls received no intervention.

Length of the intervention: 16 weeks.

For the purpose of this review both groups were analysed.


OutcomesHeight, weight, anaemia, iron deficiency, haemoglobin, RBC, MCV, MCH, MCHC, ferritin values, side effects.


NotesSupplements were distributed by the school health officer among the participants each week under supervision of the school master.

Compliance and side effects were assessed by asking the supplemented students about consuming and any possible adverse reactions.

"The good organization and supervision of the trial with lack of side effects yielded a compliance rate of 96% that can justify the desirable achieved results". Data not shown.

Malaria endemicity not reported.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy described as a community-based randomised trial. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskNot mentioned. Since this is a cluster trial, it is unlikely a selection bias at individual level.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: were aware of the treatment;

Outcome assessors: were aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFour girls from the iron supplemented group and three girls from the non supplemented group dropped out on grounds of travel, illness, or some personal reasons.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Muro 1999 (C)

MethodsCluster community-based randomised controlled trial. 3 arm design with randomisation at school level.


Participants237 adolescent girls, aged 14-17 year, attending one of 5 schools in Dar-es-Salaam, Tanzania. Exclusion criterion: girls suffering from infection with fever at the time of the interview.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 78): girls received 65 mg of elemental iron plus 250 μg (0.25 mg) of folic acid once a week and communication sessions.

Group 2 (n = 39): girls received 65 mg of elemental iron and 250 μg (0.25 mg) of folic acid once a week.

Group 3 (n = 120): girls received no intervention.

Length of the intervention: 8 weeks.

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


OutcomesAnaemia, side effects and compliance (only for those who took the supplements).


NotesFull compliance was measured during the third week by positive iron stool tests was 60-100% and declined to 40-87 at the 5th week. Self reported compliance tended to be higher.

Supplements were distributed by the school teacher and a supplementation record book was provided to each class leader for the weekly collection of information about ingestion of the tablet, eventual side effects, illness, and absenteeism throughout the whole supplementation period. Increased appetite, stomach irritation, increase in activity and less sleepiness were the reported side effects.

Malaria area.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskMethod of sequence generation not described. Each group should have contained a similar number of girls. However, this goal was not reached, because after the schools had been randomly assigned to the three groups, the parents of the girls in school 4, who were assigned to receive iron supplementation without communication, did not approve of their daughters receiving iron tablets. The girls from this school were added to the non-intervention group.

Allocation concealment (selection bias)High riskSee above.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: were aware of the treatment;

Outcome assessors: were aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low risk100% of the participants finished the treatment.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Nguyen 2008

MethodsRandomised double-blind control trial. 4 arm design with randomisation at the individual level.


Participants459 healthy women, aged 15 to 49 years, recruited from Concepción, Chiquirichapa, in the western highlands of Guatemala. Exclusion criteria: pregnancy, lactation (having had a child within the last 3 months), consumption of folic acid supplements, chronic diseases that interfere with folic acid metabolism, and severe anaemia


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 114): participants received weekly a supplement containing 5000 µg (5 mg) of folic acid, 120 mg of iron, 30 mg of zinc, and 16.8 µg of vitamin B12.

Group 2 (n = 115): Weekly supplement containing 2800 µg (2.8 mg) of folic acid, 120 mg of iron, and 16.8 µg of vitamin B12.

Group 3 (n = 114): participants received daily supplement containing 400 µg (0.4 mg) of folic acid, 60 mg of iron, 15 mg of zinc, and 2.4 µg of vitamin B12.

Group 4 (n = 116): participants received daily supplement containing 200 µg (0.2 mg) of folic acid, 60 mg of iron, and 2.4 µg of vitamin B12.

The weekly dose groups received 6 placebos and 1 active pill on the 3rd day of the week. Daily records were kept to track the participants’ health.

Length of the intervention: 12 weeks

For the purposes of this review, we combined groups 1 and 2 and compared them with the also combined groups 3 and 4.


OutcomesDepression status, body mass index, serum and RBC folate, adverse side effects (gastric complaint, head ache, nausea).


NotesCompliance was assessed by trained field workers from the community that visited each women 7 days a week to deliver and observe the ingestion of the supplements for the entire 12 week duration of the supplementation. All women received 7 pills per week.

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated random numbers were used to assigned women to one of the treatment groups.

Allocation concealment (selection bias)Low riskThe code allocation was kept secure at Emory University and was only revealed after completion of the trial.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants: were not aware of the treatment;

Personnel: were not aware of the treatment;

Outcome assessors: were not aware of the treatment.

All supplements were identical in appearance and taste and were coded with lot numbers at the factory, corresponding to 1 of 4 treatment arms.

Incomplete outcome data (attrition bias)
All outcomes
High riskOf the 459 women randomised to one of the treatment groups, 369 completed the 12-weeks study protocol:

Group 1: 8 women withdraw from the study. Reasons:1 new pregnancy, 1 prevented by husband, 3 hospitalizations, 2 gastric complaints, 1 headache, nausea.

Group 2: 7 women withdraw from the study. Reasons: 1 moved, 1 hospitalisation, 1 inconvenience by daily visits, 2 gastric complaints, 2 headache, nausea.

Group 3: 17 women withdraw from the study. Reasons: 3 new pregnancies, 2 moved, 3 prevented by husband, 2 hospitalizations, 6 gastric complaints, 1 don't like the visits.

Group 4: 5 women withdraw from the study. Reasons: 2 new pregnancies, 1 moved, 1 inconvenienced by daily visits, 1 gastric complaint.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Riuvard 2006

MethodsRandomised controlled trial. 2 arm design with randomisation at individual level.


Participants24 women, aged 18 to 30 years. Inclusion criteria: iron deficiency (ferritin <15ug/L) and haemoglobin above 100 g/L.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 13): women received 50 mg of iron as ferrous chloride daily.

Group 2 (n = 11): women received 50 mg of iron as ferrous chloride twice weekly.

Length of the intervention: 3 months


OutcomesHaemoglobin, serum ferritin, serum soluble transferrin receptor/TfR, serum Iron, plasma transferrin, oxidative stress.


NotesOn day 10 (D10) and on day 90 (D90) of Fe supplementation, blood samples were obtained, and women received orally about 5 mg of 57Fe, and blood was sampled at different times over 24 h. The 57Fe absorption was evaluated by calculating the areas under the curves (AUC).

Malaria free area.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSubjects were randomly assigned to one of the study groups with the aid of a randomisation table.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: were aware of the treatment;

Outcome assessors: were aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 participants withdrew from the study, 2 from group 1 and 1 from group 2.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias

Roschnik 2003 (C)

MethodsCluster-randomised trial. 2 arm design with randomisation at school level (40 schools) and stratified by sponsorship status.


Participants1160 boys and girls randomised, 752 followed-up. 371 girls attending standard 2 grade (˜7–8 years of age) and standard 6 grade (˜12-15 years of age). The study included 40 primary schools in the Mangochi District, Malawi.

Baseline prevalence of anaemia: around 54%.


InterventionsGirls were randomly allocated to one of the following treatments:

Group 1 (n = 184 at follow up): participants received 65 mg of elemental iron (as 200 mg ferrous sulphate) and 250 μg (0.25 mg) of folic acid once a week.

Group 2 (n = 187 at follow up): participants received no intervention.

Length of the intervention: 15 weeks


OutcomesHaemoglobin concentration, bilharzia infection, school attendance, test scores

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


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

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

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

63% of children took 10 iron tablets or more.

Malaria endemicity not reported.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk40 primary schools in the Mangochi District were randomly divided into the intervention (1st iron group) and comparison group (2nd iron group). Each group includes 10 sponsorship schools and 10 non-sponsorship schools. Method of sequence generation not specified.

Allocation concealment (selection bias)Low riskNot reported. Since the intervention was allocated at school level, it is unlikely there was a selection bias at the individual level.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: not reported;

Personnel: not reported;

Outcome assessors: not reported.

Incomplete outcome data (attrition bias)
All outcomes
High risk1280 were randomised, 1160 had haemoglobin levels at baseline and 752 were followed up: 41.2% children lost to follow up

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasUnclear riskChildren attending sponsored schools responded better to the treatment.

Shah 2002

MethodsRandomised controlled trial. 3 arm design with individual randomisation.


Participants209 girls, aged 11 to 18 years, enrolled in the Government Girl School of the Dharan Municipality, an urban foothill town in Nepal. No specific inclusion or exclusion criteria were listed although it is mentioned that some criteria did exist.

Baseline prevalence of anaemia: 48%.


InterventionsParticipants were allocated to one of the following groups:

Group 1 (n = 67): participants received 70 mg of elemental iron (as 350 mg of ferrous sulphate) and 1500 μg (1.5 mg) of folic acid on a fixed day once a week.

Group 2 (n = 70): participants received daily supplementation with tablets containing 70 mg of elemental iron (as 350 mg of ferrous sulphate) and 1500 μg (1.5 mg) of folic acid once a day for 90 to 100 days (˜14 weeks).

Group 3 (n = 72): participants received no treatment during the study period.

Length of the intervention: 90 to 100 days (˜14 weeks).


OutcomesAnaemia (defined as hematocrit 36%), mean hematocrit, and net change in haematocrit and adherence that was the only outcome included in this review.


NotesDaily supplements were given to the parents on a weekly basis, and they were asked to maintain a record of its consumption. Weekly supplements intake was supervised by a study investigator.

"Drop-outs because of poor compliance were almost double in the daily supplementation group as compared with the weekly group, and persistent adverse effects were also limited to the daily supplementation group. However, because there were fewer subjects, the impact of a daily vs weekly schedule on the adverse effects of iron therapy could not be confidently demonstrated". (data not shown).

Malaria endemicity not reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubjects were randomly assigned to 1 of the 3 groups. Method of sequence generation not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: were aware of the treatment;

Outcome assessors: were aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOf the 209 girls who met the inclusion criteria, 181 completed the study (87%); losses were balanced among groups. Severe adverse effects, noncompliance to treatment, and non availability for final hematocrit measurement were listed as reasons for losses. Numbers of subjects who left for each reason was not documented.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasHigh riskSubjects in the daily regimen group were not explicitly supervised while those in the weekly group were not supervised.

Shobha 2003

MethodsRandomised controlled trial. 3x2 arm design with individual randomisation.


Participants244 females aged 13 to 15 years old, attending Andhra Pradesh Social Welfare Residential School, located in Ranga Reddy district, India. Based on their initial haemoglobin levels, subjects were then classified as normal (higher than120 g/L), mild (100-119.9 g/L), moderate (80-99.9 g/L) or severely (80 g/L) anaemic as per the WHO standard. Baseline prevalence of anaemia: 83%.


InterventionsAdolescents were allocated to one of the following groups:

Group 1 (n = 102): participants received 60 mg of iron and 500 μg (0.5 mg) of folic acid daily.

Group 2 (n = 101): participants received 60 mg of iron and 500 μg (0.5 mg) of folic acid twice a week, every Wednesday and Saturday.

Length of the intervention: 84 days.


OutcomesHaemoglobin (stratified by anaemia status), attendance, morbidity, adherence and side effects.

For the purpose of this review all girls in group 1 were pooled independently of the degree of anaemia and the same for group 2.


NotesThe subjects were dewormed with a single dose of 400 mg albendazole one week prior to supplementation.

Supplementation was carried out under the strict supervision of the investigator and the supplement was administered around 4.00 p.m., three hours after lunch and three hours before dinner.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubjects were stratified by grade of anaemia (mild, moderate or severe) and randomly divided into the study groups. Method of sequence generation not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: not mentioned;

Personnel: not mentioned;

Outcome assessors: not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot mentioned.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Soekarjo 2004 (C)

MethodsCluster effectiveness school-based supplementation trial. 4 arm design with randomisation at class level.


Participants1460 postmenarchal adolescents aged 12-15 years, attending one of 24 rural or urban schools selected from two districts (Bangkalan and Sampang) on the island of Madura, representing both main school types in Indonesia.


Interventions15 Intervention schools, all children received supplements (n=2,990) and according to their grade students were divided into three groups:

Group 1 (n = 489): students received 10 000 IU of vitamin A;

Group 2 (n = 516): students took once weekly 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) of folic acid.

Group 3 (n = 533): students received weekly doses of 10,000 IU vitamin A, 60 mg elemental iron, 250 μg (0.25 mg) folic acid.

Group 4: (9 schools; n = 923): children did not receive the intervention.

Length of the intervention: 3 months.

Given that it is unclear how nine schools were allocated to receive no intervention and that the three intervention groups were allocated at random to each intervention, we only compared groups 1 and 3.


OutcomesHaemoglobin concentration (stratified subsequently by sex, pubertal status and anaemia status), compliance, side effects. Only data data for pubescent girls was included.


NotesThis study also includes data for boys but were not used for this review.

Children took 9 tablets under supervision of trained field workers (1-2 field workers per ˜50 students) while 5 tablets were distributed at school to be taken at home during Ramadan and school holidays with instructions to be taken once a week on a fixed day.

All pupils aware of the supplements they were taking and were told iron would improve health and prevent/cure anaemia.

Self-reported compliance and side effects were recorded at the end of the intervention from a random sub sample of girls taking supplements (n=413; 13.8%). Almost all respondents (90–97%) claimed to have taken at least half the tablets distributed under supervision. Without supervision, however, this proportion dropped to 50–70%. 41% of the girls taking supplements reported gastrointestinal side effects.

Malaria endemicity not reported.

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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAdolescents from 15 schools were randomly selected to receive
weekly supplements, while adolescents in the other nine
schools served as controls. In each of the schools receiving supplements, each of the three grades was randomly allocated to
receive one of the three supplementation regime. Method of sequence generation not mentioned.

Allocation concealment (selection bias)Low riskNot mentioned. Since this is a cluster trial, it is unlikely a selection bias at individual level.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants: were aware of the treatment;

Personnel: were aware of the treatment;

Outcome assessors: were aware of the treatment.

Incomplete outcome data (attrition bias)
All outcomes
Low risk4810 out of 5116 participants completed the study (96%). Losses were mainly caused by absenteeism on several consecutive days during the end-line data collection. There was no difference in dropout rate between the four groups.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

Zavaleta 2000

MethodsDouble blind placebo-controlled trial. 3 arm design with randomisation at individual level.


Participants312 adolescent girls, 12-18 years old, attending a public secondary school in Villa El Salvador, a peri-urban shanty town in Lima, Peru.  Inclusion criteria: Living in community for at least 6 months, healthy, nulliparous, menstruating regularly in the last three months, haemoglobin lower than 80 g/L.  Exclusion criterion:  Multi-vitamin/mineral supplement intake in the last 6 months.


InterventionsParticipants were allocated to one of the following groups.

Group 1 (n = 98 ): girls were given a tablet containing 60 mg of elemental iron as ferrous sulphate 2 days of the week and a placebo the other 3 days of the week, from Monday through Friday.

Group 2 (n = 101): girls were given a tablet containing 60 mg of elemental iron as ferrous sulphate 5 days of the week, from Monday through Friday. 

Group 3 (n = 97): girls were given a placebo 5 days of the week, from Monday through Friday.  

All tablets had the same brick colour and shape. 

Length of the intervention: 17 weeks.


OutcomesAnaemia, haemoglobin, serum ferritin, free erythrocyte protoporphyrin. Continuous data not used because we do not have standard deviations (final Hhb concentrations for daily, intermittent and control groups were 123.7 g/L, 120 g/L & 110.4 g/L, respectively).


NotesSupplements were administered daily at school, between meals, together with a sweetened flavoured drink without ascorbic acid, and under close supervision of a field worker.

Girls took 94% of the expected dose of 85 pills, and the median consumption was 80 tablets in the three groups. Few girls in the three groups reported side effects (e.g., gastrointestinal problems or headache) during the intervention, and there was no significant difference in the frequency of side effects reported by any group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskParticipants were assigned at random to the treatments. Method of sequence generation not described.

Allocation concealment (selection bias)Low riskAll tablets had the same brick colour and shape and were distributed in coded blister packages.

Blinding (performance bias and detection bias)
All outcomes
Low riskTablets all looked similar and were administered in coded packages.

Participants: were not aware of the treatment;

Personnel: were not aware of the treatment;

Outcome assessors: not described.

Incomplete outcome data (attrition bias)
All outcomes
Low riskA total of 312 girls started the study and 16 dropped out (5.1%). Of these 16, 8 moved to another school, 2 disliked the tablets, 4 complained of side effects and withdrew, and 2 were absent at the time of final evaluation.

Selective reporting (reporting bias)Unclear riskThere is insufficient information to permit judgement.

Other biasLow riskThe study appears to be free of other bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ahmed 2005Randomised double-blind clinical trial conducted in Bangladesh. Anaemic (haemoglobin less than 120 g/L) girls (n = 197) aged 14-18 yrs from rural schools in Dhaka District were entered into a randomised double-blind trial and received twice-weekly supplements of iron and folic acid or multiple micronutrients (15 micronutrients, including iron and folic acid for 12 wk. In conclusion, twice-weekly multiple micronutrients supplementation for 12 wk significantly improved the status of the micronutrients assessed but was not more efficacious than was supplementation with iron and folic acid alone in improving the hematologic status of anaemic adolescent girls.

The study was excluded because the authors did not compare intermittent iron supplementation vs daily supplementation or placebo and hence it is out of the scope of this review.

Ahmed 2010Randomised double-blind trial conducted in Bangladesh. Anaemic adolescent girls (n = 324) aged 11-17 y attending rural schools were given once- or twice-weekly multiple micronutrient supplements or twice-weekly iron-folic acid supplements, containing 60 mg elemental iron/dose in both supplements, for 52 wk. Both once- and twice-weekly multiple micronutrient supplements significantly improved riboflavin, vitamin A, and vitamin C status compared with iron-folic acid supplements. Overall, once-weekly multiple micronutrient supplements was less efficacious than twice-weekly multiple micronutrient supplements in improving iron, riboflavin, red blood cell folate, and vitamin A levels. Micronutrient supplementation beyond 26 wk was likely important in sustaining improved micronutrient status.

The study was excluded because the authors did not compare intermittent iron supplementation vs daily supplementation or placebo and hence it is out of the scope of this review.

Beaton 1999A report based on the analysis of 22 completed trials of iron supplementation. The major objective of the analyses was to determine, to the extent possible, the situations in which the apparent efficacy of intermittent supplementation was maximized.

The report was excluded because it is a review.

Berger 2005Community-based trial in all 19 communes of the Thanh Mien district in the Hai Duong province in Hanoi, Vietnam. Women were informed by the social marketing campaign about the benefits of taking preventive iron-folic acid supplementation before and during pregnancy, combined with improved diets. Women recruited were married, nulliparous and planning to have a child. They were allocated to 2 treatments according to their pregnancy status at baseline: daily supplements containing 60 mg of elemental iron + 250 μg (0.25 mg) of folic acid) to pregnant women or weekly intervention to non-pregnant women.

The study was excluded because it is not randomised and does not have a control group.

Bruner 1996Double-blind, placebo-controlled clinical trial that assessed the effects of iron supplementation on cognitive function in adolescent girls (n = 716) with non-anaemic iron deficiency. Girls who enrolled at four high schools in Baltimore, United States of America were screened for non-anaemic iron deficiency (serum ferritin 12 μg/L or less with normal haemoglobin). 98 (13.7%) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial. Participants were randomly assigned oral ferrous sulphate (650 mg twice daily) or placebo for 8 weeks. The effect of iron treatment was assessed by questionnaires and haematological and cognitive tests, which were done before treatment started and repeated after the intervention. Authors used four tests of attention and memory to measure cognitive functioning. Intention-to-treat and per-protocol analyses were done. Of the 81 enrolled girls with non-anaemic iron deficiency, 78 (96%) completed the study (39 in each group). Five girls (three control, two treatment) developed anaemia during the intervention and were excluded from the analyses. Thus, 73 girls were included in the per-protocol analysis. Ethnic distribution, mean age, serum ferritin concentrations, haemoglobin concentrations, and cognitive test scores of the groups did not differ significantly at baseline. Post-intervention haematological measures of iron status were significantly improved in the treatment group (serum ferritin 27.3 vs 12.1 μg/L, p<0.001). Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group (p<0.02). In this urban population of non-anaemic iron-deficient adolescent girls, iron supplementation improved verbal learning and memory

The study was excluded because the authors did not compare intermittent iron supplementation versus daily supplementation or placebo and hence is out of the scope of this review.

Casey 2009Distribution of weekly iron and folic acid supplementation and deworming were integrated with routine health services and made available to 52,000 women. Demographic data and blood and stool samples were collected in baseline, and three and 12-month post-implementation surveys using a population-based, stratified multi-stage cluster sampling design.Authors concluded that a free, universal weekly iron and folic acid supplementation program with regular deworming was associated with reduced prevalence and severity of anaemia, iron deficiency and hookworm infection when made available to Vietnamese women over a 12-month period.
The study was excluded because it is not randomised and does not have a control group.

Cook 1995Study designed to examined the inhibition in absorption from iron taken on the previous day by measuring iron absorption from 50 mg radiolabeled ferrous sulphate in 23 female volunteer subjects divided into two groups. In the first group, a labelled ferrous sulphate supplement was given with water, and in the second group it was given with a rice-based meal. In both groups, absorption was measured in a randomised fashion twice in each subject, once with daily and once with weekly supplementation.
Those tested for daily supplementation were given an iron supplement daily for 6 d before testing whereas those tested for weekly supplementation were given no iron for 6 d before testing. When the labelled iron supplement was given with water only, absorption averaged 8.5% with daily and 9.8% with weekly administration compared with 2.3% and 2.6%, respectively, when given with food. The 13% lower absorption observed with daily administration in both groups was not statistically significant (P > 0.20). These results indicate that there is no significant absorptive advantage in giving iron less often than once daily.

The study was excluded because it is not a controlled trial.

Crape 2005A social marketing programme promoting weekly iron-folic acid supplementation improved haemoglobin levels in women of reproductive age in Cambodia. Supplementation was increasingly effective among women of higher socioeconomic status.

The study was excluded because it is not randomised and does not have a control group.

Deshmukh 2008Effectiveness trial of a weekly iron supplementation regimen through the government health system among urban-slum, rural, and tribal girls of Nashik district, India. Participnats were adolescent girls 14-18 years old were given supplements containing 100 mg iron and 500 μg (0.5 mg) of folic acid and were trained for three hours every day for three days. In conclusion, the overall prevalence of anaemia came down significantly to 54.3% from 65.3%.

The study was excluded because it is not randomised and does not have a control group hence is out of the scope of this review.

Dwividi 2006Review of programmes in India of weekly iron supplementation to control anaemia in adolescent girls. Programmes target two different groups: girls in school and out of school girls, implemented in 13 states with varying coverage. The objective of the review were to summarize and analyse the status/characteristics of the various adolescent anaemia programmes in India, summarize and analyse the results of the impact assessments that have already been conducted, and to estimate and analyse the costs of the programmes. From results, it is evident that weekly iron/folic acid supplementation in adolescents girls lead to a marked decrease in the prevalence of anaemia. In some cases, a large long-term impact (70%, 2 years) was reported. Reasons for small but significant decrease in the prevalence of anaemia include low compliance and a possible multi-causality of anaemia as deficiency in other vitamins and minerals or genetic causes. It could also be that a larger reduction in anaemia prevalence may be achieved only after prolonged supplementation. Supplementation programs should continue until other sources of iron intake become available, be it from natural dietary sources and/or from fortified foods.

Programmes targeting out-of-school girls can be successful as the interventions targeting these girls also resulted in significant decreases in anaemia prevalence. Success factors include: ensuring compliance, counselling not only the beneficiaries but the community, ensuring continuous tablet supply and regular monitoring, among others. It is clear that if well conceived, the supplementation component of an overall package of services for the adolescent girl costs very little.

The reference was excluded because it is a review.

Horjus 2005Pre-post study to assess the program effectiveness of two school-based weekly iron-folic acid supplementation regimens: 5 months vs. 8 months. In both groups participant girls received 60 mg of elemental iron and 400 µg (0.4 mg) of folic acid. All girls received a single dose of mebendazol at the beginning of the study and at six months. In conclusion, school based weekly supplementation is a feasible and effective intervention to prevent seasonal drops in haemoglobin concentration and increases in anaemia prevalence.

The study was excluded because it is not randomised and the comparisons do not fit into the scope of this review.

Jackson 2003Randomised trial to ascertain whether, short term supplementation with iron, assigning 608 girls with mild to moderate anaemia from high schools to three treatment groups. Supplementation included 60 mg of iron per week, 3500 μg (3.5 mg) of folic acid per week, iron + folic acid (same dose), and a control group. In conclusion, 8 weeks of supplements given on a weekly basis were well tolerated causing few symptoms and was effective in reducing anaemia by 30-40%.

The study was excluded because the control group was not randomised as it was conformed by non anaemic classmates (with normal haemoglobin values).

López de Romaña 2006Cluster trial conducted in Peru among women and adolescent girls of childbearing age and children under 5 years of age to assess the impact of the campaign on the growth of children and on anaemia among children and among women and adolescent girls of childbearing age. Weekly multimicronutrient supplementation was provided for 8 weeks in communities with high prevalence of stunting and control households were selected from communities with a lower prevalence of stunting. There were no significant effects of weekly multimicronutrient supplementation on anaemia or growth

The study was excluded because it is not randomised.

Pasricha 2009Multi-stage cluster sampling study. A program of weekly iron and folic acid supplementation and deworming every 4 months for all women of reproductive age living in Yen Bai province, Vietnam was implemented by active distribution through the existing primary health structure. Women received ferrous sulphate and folic acid tablets. After 3 months, anaemia prevalence fell to 58/221 (26.2%), and the mean haemoglobin change was +3.5 g/L (95% confidence interval, 0.9, 6.6).

The study was excluded because it is not randomised and does not have a control group, hence the study is out of the scope of this review.

Perrin 2002It is a commentary paper on Shah 2002.

Siddiqui 2004Study to compare improvement in haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin and ferritin levels in children aged 5-10 years of age and women of reproductive age (15-45 years of age) supplemented with daily oral and once weekly with single and double dose of ferrous sulphate.Twenty children received 200 mg ferrous sulphate daily and 20 received the same dose once weekly for two months. Ten women received 300 mg ferrous sulphate daily, 10 received the same dose once weekly while 10 received 600 mg of ferrous sulphate once weekly for one month. All parameters improved significantly in children who received 200 mg ferrous sulphate daily and weekly. Similarly, the parameters improved significantly in women who received 300 mg of ferrous sulphate daily and 600 mg of ferrous sulphate weekly. In conclusion, weekly supplementation of iron is far better in controlling iron deficiency anaemia due to cost effectiveness and better compliance.

The study was excluded because it is not randomised and does not have a control group, hence the study is out of the scope of this review.

Taylor 2001Randomized control trial with 428 primary school students stratified into 6 groups by age, sex and intervention with the objective of measure the effect of different anthelmintic treatments and iron supplementation regimens provided twice at 6-monthly intervals for 1 year. Half the students received iron supplementation (ferrous fumarate 200 mg weekly for 10 weeks). Students received 2 anthelmintic regimens, either (i) albendazole 400 mg plus praziquantel 40 mg/kg or (ii) albendazole 400 mg on 3 consecutive days plus praziquantel 40 mg/kg or (iii) placebo. Twelve months after treatment there was a significant increase in haemoglobin levels (P = 0.02) among pupils receiving triple-dose albendazole, praziquantel and ferrous fumarate; students receiving no anthelmintic treatment showed a significant decrease as did pupils who received triple-dose albendazole and praziquantel but no iron.

The study was excluded because postmenarchal girls were excluded from the study due to risk of pregnancy and treatments were no secure during pregnancy.

Tee 1999Study that investigated whether long-term, weekly iron and folic acid supplements administered at school would improve haemoglobin and ferritin concentrations in adolescent girls, including those with mild-to-moderate anaemia and haemoglobin concentrations indicating borderline anaemia. 266 girls with haemoglobin concentrations of 80–119.9 g/L (group A) and 358 girls with haemoglobin concentrations of 120–130 g/L (group B) who were otherwise healthy. Two hundred sixty-six girls in group A and 268 girls in group B were randomly assigned to receive either 60 or 120 mg elemental iron plus 3500 μg (3.5 mg) folic acid weekly for 22 wk. Ninety of the girls in group B were randomly assigned to receive only 5000 μg (5 mg) folic acid weekly. Authors concluded that long-term, weekly iron-folic acid supplementation was found to be a practical, safe, effective, and inexpensive method for improving iron nutrition in adolescent schoolgirls.

Study was excluded because girls in both arms were given iron on a weekly basis. Group C did not receive supplements but was not followed up.

Vir 2008Study performed in school and non-school girls aged 11 to 18 years that aimed to assess the effectiveness of weekly iron-folic acid supplementation in reducing the prevalence of anaemia in adolescent girls. The project provided weekly iron-folic acid tablets, family life education, and deworming tablets every 6 months to 150,700 adolescent school girls and non-schoolgirls of a total district population of 3,647,834. Groups were not evaluated simultaneously. In 4 years, the overall prevalence of anaemia was reduced from 73.3% to 25.4%. Hemoglobin levels and anaemia prevalence were influenced significantly at 6 months. No difference in the impact on haemoglobin or anaemia prevalence was observed between supervised and unsupervised girls.

The study was excluded because it was not randomised and does not have a control group.

Viteri 1999Randomised double-blind trial involving 239 healthy, menstruating women, older than 18 years of age (some anaemic and some iron deficient) from the University of California, Berkely community, United States of America. Exclusion criteria: blood donation during the previous 6 months, pregnancy, pregnancy terminated during the previous year, lactating, meno-metrorrhagia, having a chronic condition interfering with normal iron metabolism, currently taking or having taken therapeutic iron during the last 6 months, and predicted impossibility to comply with the experimental protocol. Group 1 received daily 60 mg of elemental iron + 250 µg (0.25 mg) folic acid for 3 months and 250 µg (0.25 mg) folic acid weekly for 4 months. Group 2 received daily daily 60 mg of elemental iron + 250 µg (0.25 mg) folic acid for 3 months and 60 mg of elemental iron + 250 µg (0.25 mg) folic acid weekly (same dose) for 4 months. Group 3 received daily 250 µg (0.25 mg) folic acid for 3 months and weekly 250 µg (0.25 mg) folic acid (same dose) for 4 months.

The study was excluded because intervention groups do not match the comparisons in this review.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Olsen 2000

MethodsRandomised placebo-controlled, double-blind trial. Simple randomisation was used.

Participants181 adults from the villages of Nyanza province, Kenya (an area endemic of hookworm). Exclusion criteria: pregnant women and persons with severe anaemia

InterventionsParticipants (both anaemic and non anaemic) were allocated to one of the following intervention groups:

1) Group 1 (n = 91): Twice-weekly green film-coated ferrous dextran (200 mg corresponding to 60 mg of elemental iron)

2) Group 2 (n = 90): Identical-looking placebo tablet

After baseline examination each person received 1 container labelled with name, study number and identification sticker containing 50 tablets, which were more than the 31-35 tablets necessary for a 4-month period. At the end of each 4-month period, the number of tablets taken was registered. Compliance was assessed by visiting each participant at least once a month.

Length of the intervention:12 months

For the purpose of this review both groups will be analysed

OutcomesAnaemia, iron deficiency, iron deficiency anaemia, haemoglobin, ferritin, intestinal infections

NotesStudy is awaiting classification because data can not be extracted from the results provided as they all include "adults" and are not divided by sex. We attempted to contact the authors to obtain the disaggregated data.

Sharma 2000

MethodsRandomised experimental trial. 3-arm study design

Participants270 adolescent girls of poor communities of urban areas of Delhi and rural parts of Bharatpur. Inclusion criterion: Haemoglobin levels of >12 g/dL

InterventionsParticipants were allocated to one of the following groups:

1) Group 1 (n = 83): girls received one tablet with 100 mg elemental iron plus 500 μg (0.5 mg) folic acid once weekly;

2) Group 2 (n = 95): girls received one tablet with 100 mg elemental iron, 500 μg (0.5 mg) folic acid and 25 mg vitamin C once weekly;

3) Group 3 (n = 37): girls received one tablet of iron-folic acid (100 mg elemental iron + 500 μg (0.5 mg) folic acid) daily. Only from the rural region.

4) Group 4 (n = 55): urban control group (unclear if received no intervention or a placebo).

Length of the intervention: 6 months

For the purpose of this review groups 1 and 3 were combined and only divided for the subgroup analysis by composition.

OutcomesAnthropopmetric measures, anaemia, and change in haemoglobin.

NotesIn the school the tablets were distributed weekly to the subjects by a research worker immediately after lunch time so that it was not taken on an empty stomach. The intake of the tablets by the subjects was assured by a helper. In the rural area, two field workers were responsible for the distribution and ensuring intake of tablets by the subjects only after brunch.

Malaria endemicity not reported.

Student awaiting assessment until receiving more information about the study design and groups as it is unclear the number of people leaving in rural/urban areas and there is a clear imbalance between study arms.

We attempted to contact the authors to obtain further information on this trial.

 
Characteristics of ongoing studies [ordered by study ID]
Brabin 2010

Trial name or titleLong-term Iron Supplements and Malaria Risk in Early Pregnancy: a Randomized Controlled Trial (PALUFER)

MethodsRandomised, double-blind controlled trial with randomisation at individual level.

ParticipantsFemales 15 to 24 years of age. Inclusion Criteria: never given birth, resident within the Demographic Surveillance System (DSS) area, willing to adhere to the study requirements (including weekly observed drug intake), provision of written informed consent (if non emancipated minor by guardian/parent with minor's assent). Exclusion criteria: no menses for >3 months and/or palpable uterus or positive pregnancy test if history unclear, concurrent enrolment in another study, intention to move out of the study area for more than 2 months within the next 18 months, any significant illness at the time of screening that requires hospitalisation, including clinical signs of severe anaemia (conjunctival or mucosal pallor, tachycardia, respiratory distress)

history or presence of major clinical disease likely to influence pregnancy outcome (sickle cell disease, diabetes mellitus, severe renal or heart disease, open tuberculosis, epilepsy).

InterventionsWomen will be randomly allocated to one of the following groups before pregnancy:

1) Group 1: women will receive 2800mg folic acid once a week.

2) Group 2: women will receive 60mg Iron and 2800mg folic acid once a week

OutcomesPregnant cohort, maternal outcomes: prevalence of iron deficiency and anaemia at first antenatal visit (13-16 weeks gestation), prevalence of peripheral parasitaemia at first antenatal clinic visit; birth outcomes: birth size, gestational age, incidence of adverse pregnancy outcomes, prevalence of placental malaria. Non pregnant cohort: incidence of gastrointestinal adverse events, incidence of clinical malaria, prevalence of iron deficiency after at least 18 months supplementation, adherence to supplementation, acceptability of weekly supplementation.

Starting dateApril 2011, currently recruiting participants.

Contact informationSabine GIES, PhD sgies@itg.be

NotesClinicalTrials.gov identifier: NCT01210040

Sponsors and collaborators: Liverpool School of Tropical MedicineInstitute of Tropical Medicine, BelgiumUniversity of ManchesterInstitut de Recherche en Sciences de la Sante-Direction Regionale de l'OuestCentre MurazNational Institutes of Health (NIH)Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Ramakrishan 2011

Trial name or titleImpact of Pre-Pregnancy Micronutrient Supplementation on Maternal and Child Health Outcomes

MethodsRandomised, double-blind controlled trial with randomisation at commune level (16 communes in 4 districts in Vietnam).

ParticipantsApproximately 5500 women will be provided pre-pregnancy supplementation. Aproximately 1900 of them are expected to become pregnant to yield a final sample of  ˜1650 mother-infant pairs. The study is taking place in Thai Nguyen, Viet Nam.

Inclusion criteria: Women 18-35 years of age living in 1 of 10 villages surrounding a Commune Health Centerlocated in one of 16 pre-selected communes.  Participants must intend to live in area for 24 months following recruitment, be married, have fewer than 2 children, plan to have children in the next year, provide informed consent. Exclusion criteria: being currently pregnant, regular consumption of IFA or MM supplements in the past 2 months, be diagnosed with severe anaemia (Hb < 7g/L), have a history of high risk pregnancy, have chronic hematological diseases, have hereditary defects of red blood cell or haemoglobin.

InterventionsWomen will be randomly allocated to one of the following groups before pregnancy:

1) Group 1: women will receive 2800mg folic acid once a week.

2) Group 2: women will receive 60mg Iron and 2800mg folic acid

3) Group 3: women will receive a multiple micronutrient supplement containing iron, folic acid, vitamin D, vitamin A, vitamin E, vitamin C, thiamine, riboflavin, niacin, B6, B12, zinc, copper, selenium, iodine once a week.

OutcomesMaternal outcomes: post-partum iron store and anaemia. Birth outcomes: birth size, gestational age. Infant iron status: cord blood iron status, anaemia and iron store at 3 months.

Starting dateWomen recruitment started on September 2011

Contact informationUsha Ramakrishnan, Principal Investigator

Emory University, Atlanta, GA

Email: uramakr@sph.emory.edu

 

Phuong Hong Nguyen, Co-Principal Investigator

Thainguyen University of Medicine and Pharmacy (TUMP), Vietnam

Email: P.H.Nguyen@cgiar.org

 

Alyssa Lowe, Research Project Coordinator

Emory University, Atlanta, GA

Email: alowe3@emory.edu

NotesProject supported by the Micronutrient Initiative.

 
Comparison 1. Intermittent iron supplementation vs. no supplementation/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (All)102996Risk Ratio (M-H, Random, 95% CI)0.73 [0.56, 0.95]

 2 Anaemia (by supplement composition)102996Risk Ratio (M-H, Random, 95% CI)0.72 [0.57, 0.91]

    2.1 Iron alone
2292Risk Ratio (M-H, Random, 95% CI)0.45 [0.09, 2.13]

    2.2 Iron and folic acid
71732Risk Ratio (M-H, Random, 95% CI)0.82 [0.64, 1.04]

    2.3 Iron and other micronutrients
3972Risk Ratio (M-H, Random, 95% CI)0.52 [0.25, 1.07]

 3 Anaemia (by anaemic status at baseline)102996Risk Ratio (M-H, Random, 95% CI)0.73 [0.56, 0.95]

    3.1 Anaemic
1222Risk Ratio (M-H, Random, 95% CI)0.39 [0.30, 0.52]

   3.2 Non anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Mixed/Unknown
92774Risk Ratio (M-H, Random, 95% CI)0.84 [0.70, 1.01]

 4 Anaemia (by iron deficiency status at baseline)102996Risk Ratio (M-H, Random, 95% CI)0.73 [0.56, 0.95]

   4.1 Iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.2 Not iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Mixed/unknown
102996Risk Ratio (M-H, Random, 95% CI)0.73 [0.56, 0.95]

 5 Anaemia (by iron dose per week in the intermittent group)102996Risk Ratio (M-H, Random, 95% CI)0.72 [0.55, 0.93]

    5.1 60 mg of iron or less per week
51855Risk Ratio (M-H, Random, 95% CI)0.68 [0.43, 1.10]

    5.2 More than 60 mg of iron per week
61141Risk Ratio (M-H, Random, 95% CI)0.73 [0.51, 1.03]

 6 Anaemia (by duration of the intervention)102996Risk Ratio (M-H, Random, 95% CI)0.73 [0.56, 0.95]

    6.1 3 months or less
62176Risk Ratio (M-H, Random, 95% CI)0.67 [0.44, 1.00]

    6.2 More than 3 months
4820Risk Ratio (M-H, Random, 95% CI)0.88 [0.69, 1.13]

 7 Anaemia (by malaria endemicity)103088Risk Ratio (M-H, Random, 95% CI)0.74 [0.56, 0.96]

    7.1 No malaria/Unknown
82798Risk Ratio (M-H, Random, 95% CI)0.69 [0.49, 0.96]

    7.2 Malaria
2290Risk Ratio (M-H, Random, 95% CI)0.86 [0.56, 1.30]

 8 Haemoglobin in g/L (All)132599Mean Difference (IV, Random, 95% CI)4.58 [2.56, 6.59]

 9 Haemoglobin in g/L (by supplement composition)132599Mean Difference (IV, Random, 95% CI)4.94 [3.01, 6.87]

    9.1 Iron alone
4606Mean Difference (IV, Random, 95% CI)6.13 [1.90, 10.36]

    9.2 Iron and folic acid
81671Mean Difference (IV, Random, 95% CI)3.56 [1.11, 6.01]

    9.3 Iron and other micronutrients
2322Mean Difference (IV, Random, 95% CI)7.94 [2.37, 13.52]

 10 Haemoglobin in g/L (by anaemic status at baseline)132599Mean Difference (IV, Random, 95% CI)4.58 [2.56, 6.59]

    10.1 Anaemic
2352Mean Difference (IV, Random, 95% CI)8.64 [3.90, 13.38]

   10.2 Non anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    10.3 Mixed/unknown
112247Mean Difference (IV, Random, 95% CI)3.91 [1.99, 5.83]

 11 Haemoglobin in g/L (by iron deficiency status at baseline)122438Mean Difference (IV, Random, 95% CI)5.00 [2.98, 7.01]

   11.1 Iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   11.2 Not iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Mixed/Unknown iron deficient
122438Mean Difference (IV, Random, 95% CI)5.00 [2.98, 7.01]

 12 Haemoglobin in g/L (by iron dose per week in the intermittent group)132599Mean Difference (IV, Random, 95% CI)4.68 [2.75, 6.61]

    12.1 60 mg of iron or less per week
6971Mean Difference (IV, Random, 95% CI)5.21 [2.06, 8.36]

    12.2 More than 60 mg of iron per week
81628Mean Difference (IV, Random, 95% CI)4.28 [1.64, 6.93]

 13 Haemoglobin in g/L (by duration of the intervention)132599Mean Difference (IV, Random, 95% CI)4.58 [2.56, 6.59]

    13.1 3 months or less
51100Mean Difference (IV, Random, 95% CI)5.37 [2.32, 8.41]

    13.2 More than 3 months
81499Mean Difference (IV, Random, 95% CI)3.95 [1.28, 6.63]

 14 Haemoglobin in g/L (by malaria endemicity)132599Mean Difference (IV, Random, 95% CI)4.58 [2.56, 6.59]

    14.1 No malaria/Unknown
102102Mean Difference (IV, Random, 95% CI)4.94 [2.51, 7.36]

    14.2 Malaria
3497Mean Difference (IV, Random, 95% CI)3.04 [0.52, 5.56]

 15 Iron deficiency (All)3624Risk Ratio (M-H, Random, 95% CI)0.50 [0.24, 1.04]

 16 Ferritin in µg/L (All)6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

 17 Ferritin in µg/L (by supplement composition)6980Mean Difference (IV, Random, 95% CI)7.88 [5.11, 10.66]

    17.1 Iron alone
2204Mean Difference (IV, Random, 95% CI)7.80 [1.38, 14.23]

    17.2 Iron and folic acid
3455Mean Difference (IV, Random, 95% CI)5.87 [3.23, 8.52]

    17.3 Iron and other micronutrients
2321Mean Difference (IV, Random, 95% CI)11.05 [2.94, 19.17]

 18 Ferritin in µg/L (by anaemic status at baseline)6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

    18.1 Anaemic
1222Mean Difference (IV, Random, 95% CI)6.70 [4.08, 9.32]

   18.2 Non anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    18.3 Mixed/Unknown anaemic
5758Mean Difference (IV, Random, 95% CI)9.15 [4.36, 13.95]

 19 Ferritin in µg/L (by iron deficiency status at baseline)6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

   19.1 Iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   19.2 Not iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    19.3 Mixed/Unknown iron deficient
6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

 20 Ferritin in µg/L (by iron dose per week in the intermittent group)6980Mean Difference (IV, Random, 95% CI)8.74 [5.50, 11.97]

    20.1 60 mg of iron or less per week
3269Mean Difference (IV, Random, 95% CI)12.37 [7.06, 17.69]

    20.2 More than 60 mg of iron per week
4711Mean Difference (IV, Random, 95% CI)7.40 [3.62, 11.18]

 21 Ferritin in µg/L (by duration of the intervention)6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

    21.1 3 months or less
2431Mean Difference (IV, Random, 95% CI)10.69 [2.10, 19.27]

    21.2 More than 3 months
4549Mean Difference (IV, Random, 95% CI)6.31 [2.82, 9.81]

 22 Ferritin in µg/L (by malaria endemicity)6980Mean Difference (IV, Random, 95% CI)8.32 [4.97, 11.66]

    22.1 No malaria/Unknown
4808Mean Difference (IV, Random, 95% CI)8.95 [4.48, 13.41]

    22.2 Malaria
2172Mean Difference (IV, Random, 95% CI)6.79 [0.48, 13.10]

 23 Iron deficiency anaemia (All)197Risk Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.16]

 24 All cause morbidity (All)1119Risk Ratio (M-H, Random, 95% CI)1.12 [0.82, 1.52]

 25 Diarrhoea1209Risk Ratio (M-H, Random, 95% CI)0.28 [0.05, 1.49]

 26 Any adverse side effects3630Risk Ratio (M-H, Random, 95% CI)1.98 [0.31, 12.72]

 27 Adherence3556Risk Ratio (M-H, Random, 95% CI)0.99 [0.96, 1.01]

 28 Prevalence of malaria parasitaemia1119Odds Ratio (M-H, Fixed, 95% CI)1.41 [0.68, 2.94]

 29 Any malaria parasitaemia (Incidence rate; per 1000 person months)1249Odds Ratio (M-H, Random, 95% CI)1.61 [0.93, 2.79]

 30 High density malaria parasitaemia (parasites 200/wbc)1119Mean Difference (IV, Fixed, 95% CI)12.0 [6.06, 17.94]

 31 Clinical malaria1249Odds Ratio (M-H, Random, 95% CI)1.93 [0.69, 5.39]

 
Comparison 2. Intermittent iron supplementation vs. daily iron supplementation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (All)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

 2 Anaemia (by supplement composition)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

    2.1 Composition: iron alone
3690Risk Ratio (M-H, Random, 95% CI)1.39 [0.97, 1.99]

    2.2 Composition: iron and folic acid
2604Risk Ratio (M-H, Random, 95% CI)1.23 [0.98, 1.53]

    2.3 Composition: iron and other micronutrients
1198Risk Ratio (M-H, Random, 95% CI)0.86 [0.30, 2.46]

 3 Anaemia (by anaemic status at baseline)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

    3.1 Anaemic
1150Risk Ratio (M-H, Random, 95% CI)1.18 [0.62, 2.24]

   3.2 Non anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Mixed/Unknown anaemic
51342Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.53]

 4 Anaemia (by iron deficiency at baseline)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

   4.1 Iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.2 Not iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Mixed/Unknown iron deficient
61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

 5 Anaemia (by iron dose per week in the intermittent group)61492Risk Ratio (M-H, Random, 95% CI)1.25 [1.04, 1.51]

    5.1 Dose of 60 mg of iron or less per week
4614Risk Ratio (M-H, Random, 95% CI)1.23 [0.82, 1.85]

    5.2 Dose of more than 60 mg of iron per week
3878Risk Ratio (M-H, Random, 95% CI)1.26 [1.02, 1.55]

 6 Anaemia (by duration of the intervention)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

    6.1 During 3 months or less
3511Risk Ratio (M-H, Random, 95% CI)1.10 [0.68, 1.77]

    6.2 During more than 3 months
3981Risk Ratio (M-H, Random, 95% CI)1.29 [1.05, 1.57]

 7 Anaemia (by malaria endemicity)61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

    7.1 No malaria/Unknown
61492Risk Ratio (M-H, Random, 95% CI)1.26 [1.04, 1.51]

   7.2 Malaria
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 8 Haemoglobin g/L (All)81676Mean Difference (IV, Random, 95% CI)-0.15 [-2.20, 1.91]

 9 Haemoglobin g/L (by supplement composition)81676Mean Difference (IV, Random, 95% CI)-0.15 [-2.20, 1.91]

    9.1 Composition: iron alone
4671Mean Difference (IV, Random, 95% CI)0.31 [-1.15, 1.78]

    9.2 Composition: iron and folic acid
3807Mean Difference (IV, Random, 95% CI)-0.99 [-6.10, 4.13]

    9.3 Composition: iron and other micronutrients
1198Mean Difference (IV, Random, 95% CI)0.30 [-2.02, 2.62]

 10 Haemoglobin g/L (by anaemic status at baseline)81676Mean Difference (IV, Random, 95% CI)-0.15 [-2.20, 1.91]

    10.1 Anaemic
2353Mean Difference (IV, Random, 95% CI)2.77 [1.37, 4.17]

   10.2 Non anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    10.3 MIxed/Unknown anaemic
61323Mean Difference (IV, Random, 95% CI)-1.14 [-3.15, 0.87]

 11 Haemoglobin in g/L (by iron deficiency at baseline)81676Mean Difference (IV, Random, 95% CI)-0.15 [-2.20, 1.91]

    11.1 Iron deficient
121Mean Difference (IV, Random, 95% CI)-1.0 [-7.94, 5.94]

   11.2 Not iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Mixed/Unknown iron deficient
71655Mean Difference (IV, Random, 95% CI)-0.09 [-2.26, 2.07]

 12 Haemoglobin in g/L (by iron dose per week in the intermittent group)81676Mean Difference (IV, Random, 95% CI)-0.31 [-2.25, 1.63]

    12.1 Dose of 60 mg of iron or less per week
6843Mean Difference (IV, Random, 95% CI)1.14 [-0.34, 2.62]

    12.2 Dose of more than 60 mg of iron per week
3833Mean Difference (IV, Random, 95% CI)-2.41 [-5.24, 0.42]

 13 Haemoglobin in g/L (by duration of the intervention)81676Mean Difference (IV, Random, 95% CI)-0.15 [-2.20, 1.91]

    13.1 During 3 months or less
6939Mean Difference (IV, Random, 95% CI)1.21 [-0.15, 2.57]

    13.2 During more than 3 months
2737Mean Difference (IV, Random, 95% CI)-3.00 [-6.92, 0.92]

 14 Haemoglobin in g/L (by malaria endemicity)92085Mean Difference (IV, Random, 95% CI)-0.20 [-2.02, 1.63]

    14.1 No malaria/Unknown
92085Mean Difference (IV, Random, 95% CI)-0.20 [-2.02, 1.63]

   14.2 Malaria
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 15 Iron deficiency (All)1198Risk Ratio (M-H, Random, 95% CI)4.30 [0.56, 33.20]

 16 Ferritin in µg/L (All)3657Mean Difference (IV, Random, 95% CI)-11.32 [-22.61, -0.02]

 17 Diarrhoea1198Risk Ratio (M-H, Random, 95% CI)2.41 [0.12, 49.43]

 18 Any side effects4823Risk Ratio (M-H, Random, 95% CI)0.36 [0.10, 1.31]

 19 Depression1369Risk Ratio (M-H, Random, 95% CI)0.82 [0.63, 1.07]

 20 Adherence4507Risk Ratio (M-H, Random, 95% CI)1.04 [0.99, 1.09]

 21 Hospitalization (non prespecified outcome)1259Odds Ratio (M-H, Fixed, 95% CI)2.05 [0.37, 11.38]

 22 Oxidative stress -FRAP (non prespecified outcome)121Mean Difference (IV, Fixed, 95% CI)-75.0 [-183.91, 33.91]

 
Summary of findings for the main comparison. Intermittent use of iron supplements versus placebo/no intervention in menstruating women

Patient or population: menstruating women
Settings: community settings
Intervention: intermittent supplementation with iron alone or with other nutrients
Comparison: placebo or no intervention


OutcomesRelative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Anaemia (as defined by trialists)RR 0.73
(0.56 to 0.95)
2996
(10 studies)
⊕⊕⊝⊝
low1,2

Haemoglobin (g/L)MD 4.58
(2.56 to 6.59)
2599
(13 studies)
⊕⊕⊝⊝
low1,2

Iron deficiency (as defined by trialists)RR 0.50
(0.24 to1.04)
624
(3 studies)
⊕⊝⊝⊝
low1,3

Iron status (ferritin in μg/L)MD 8.32
(4.97 to 11.66)
980
(6 studies)
⊕⊕⊝⊝
low1,3

Iron deficiency anaemia (anaemia and one indicator of iron deficiency) RR 0.07
(0 to 1.16)
193
(1 study)
very low1,3,4

All-cause morbidityRR 1.12
(0.82 to 1.52)
119
(1 study)
very low1,4

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

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


1 In several trials, the method of allocation concealment was not clear and there was lack of blinding.
2 There was high heterogeneity and some inconsistency in the direction on the effect.
3 Wide confidence intervals.

4 Only one study reported on this outcome.

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

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

Patient or population: menstruating women
Settings: community settings
Intervention: intermittent supplementation with iron alone or with other micronutrients
Comparison: daily supplementation with iron alone or with other micronutrients


OutcomesRelative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Anaemia (as defined by trialists)RR 1.26
(1.04 to 1.51)
1492
(6 studies)
⊕⊕⊕⊝
moderate1

Haemoglobin (g/L)MD –0.15
(–2.20 to 1.91)
1676
(8 studies)
⊕⊕⊕⊝
low1,2

Iron deficiency (as defined by trialists)RR 4.30
(0.56 to 33.20)
198
(1 study)
very low3

Iron status (ferritin in μg/L)MD –11.32
(–22.61 to –0.02)
657
(3 studies)
⊕⊕⊝⊝
low1,2

Iron deficiency anaemia (anaemia and one indicator of iron deficiency) Not estimable0
(0 studies)

All-cause morbidityNot estimable0
(0 studies)

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

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


1 In several trials, the method of allocation concealment was not clear and there was lack of blinding.
2 There was high statistical heterogeneity but consistency in the direction on the effect.
3 Only one study with ˜25 losses to follow up reported on this outcome; wide confidence intervals.

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