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Intermittent oral iron supplementation during pregnancy

  1. Juan Pablo Peña-Rosas1,*,
  2. Luz Maria De-Regil1,
  3. Therese Dowswell2,
  4. Fernando E Viteri3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 11 JUL 2012

Assessed as up-to-date: 12 JUN 2012

DOI: 10.1002/14651858.CD009997


How to Cite

Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Intermittent oral iron supplementation during pregnancy. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD009997. DOI: 10.1002/14651858.CD009997.

Author Information

  1. 1

    World Health Organization, Evidence and Programme Guidance, Department of Nutrition for Health and Development, Geneva, Switzerland

  2. 2

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

  3. 3

    Children's Hospital and Oakland Research Institute, Oakland, CA, USA

*Juan Pablo Peña-Rosas, Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva, 1211, Switzerland. penarosasj@who.int.

Publication History

  1. Publication Status: New
  2. Published Online: 11 JUL 2012

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Characteristics of included studies [ordered by study ID]
Bhatla 2009

MethodsRCT, 3-arm trial with individual randomisation.


Participants109 pregnant non-anaemic women between 14 and 18 wks (49% vegetarian) with no prior intake of iron supplements in the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences in New Delhi, India were invited to participate in the study.

Exclusion criteria were: Hb < 110 g/L, packed cell volume (PCV) < 30; cigarette smoking; pre-existing hypertension or diabetes; history of chronic illness, e.g. liver or renal disease, tuberculosis, heart disease, malaria; history of bleeding disorders, bleeding piles, chronic peptic ulcer; thalassaemia or other haemoglobinopathies; intake of drugs such as antiepileptics, NSAIDs, antithyroid medication, vitamins, antioxidants; multiple pregnancy; and prior history of blood transfusion.


InterventionsParticipants were randomly allocated into 1 of three different groups: group 1 (n = 37) received the standard Government of India supply of Irofol®  tablets containing 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid (Nestor Pharmaceuticals Ltd., Faridabad, Haryana, India) to be taken once daily; group 2 (n = 36) received the standard Government of India supply of Irofol® tablets containing 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid and were instructed to take two tablets on any one day of the week; one before lunch and the other before dinner (total 200 mg elemental iron and 1000 μg (1 mg) folic acid per week) with no tablets taken during the rest of the week; and group 3 (n = 36) received Ferium® tablets iron (III)-hydroxide poly maltose complex tablets daily containing Iron (III) Hydroxide Polymaltose containing 100 mg elemental iron and 350 μg (0.35 mg) folic acid  to be taken one tablet daily (Emcure Pharmaceuticals Ltd., Pune).

All groups received health education regarding the importance of diet in pregnancy, iron-rich foods and appropriate dietary practices and were instructed to take the tablets 30 min before meals and not with tea, coffee or milk. All women were also advised to take calcium supplements after meals.

Setting and health worker cadre: the intervention was performed by obstetricians and hematologists at the All India Institute of Medical Sciences in New Delhi, India.


OutcomesMaternal: miscarriage, intrauterine demise, Hb, haematocrit, MCV and MCHC, thiobarbituric acid reactive substances (TBARS) and glutathione levels at baseline (14-16 wks) and at 30-34 wks, compliance, side effects, nausea, vomiting, diarrhoea, constipation, metallic taste, epigastric discomfort, premature birth, hypertension during pregnancy, pre­eclampsia, C-section.

Infant: birthweight, low birthweight (LBW), placental weight, 1 min Apgar score and incidence of meconium.


NotesMean gestation at which supplementation was started was 16.1 1.3 wks and mean duration of iron supplementation before final sampling was 17.9 1.4 wks.

Overall 22.2% of women were non-compliant: 12 (40%) women in the IFA daily (group 1) and four (13.3%) women in the IFA weekly (group 2) did not comply with the prescribed schedule (P = 0.016).

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: non-anaemic.

Dose of iron per week in intermittent group:high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in the whole country at altitudes below 2000 m, with overall 40–50% of cases due to Plasmodium falciparum and the remainder due to Plasmodium vivax.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers.

Allocation concealment (selection bias)High riskIt was not clear whether staff carrying out recruitment were aware of allocation at the point of randomisation.

Blinding (performance bias and detection bias)
All outcomes
High riskOpen to participants and care providers.

The “technician who performed the blood tests was not aware of the group to which the patient was allocated”.

It is not clear whether outcome assessment for other outcomes was blinded

Incomplete outcome data (attrition bias)
All outcomes
High risk109 women were enrolled, 90 were included in the analysis (rate of attrition 17%). Loss to follow-up and post randomisation exclusions were not balanced across groups and women were excluded for reasons likely to introduce bias. Five women were excluded (4 in the daily iron group and 1 in the weekly iron group) because they could not tolerate the supplementation and were given alternative treatment. 2 women were lost to follow-up because of adverse foetal outcome (1 miscarriage and 1 intrauterine death).

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

Other biasHigh riskThere was some baseline imbalance between groups,  e.g. in the daily iron sulphate group the supplementation was started earlier.

Bouzari 2011

MethodsRCT with 3 arms. individual randomisation. Six health centres were selected from 40 centres affiliated to the Babol University of Medical Sciences.


Participants150 healthy non-anaemic pregnant women with 16th wk of gestation attending 6 health centres affiliated to Babol University of Medical Sciences, northern Iran.

Exclusion criteria: women with Hb less than 11g/dL. with chronic haematological conditions (e.g. thalassaemia) or with multiple pregnancy.


InterventionsParticipants were randomly assigned to one of three groups: group 1 (n = 50) received 50 mg iron (presumably 50 mg elemental iron as ferrous sulphate); group 2 received 50 mg ferrous sulphate three times per week; group 3 received 100 mg (two 50 mg tablets) of ferrous sulphate weekly.

Setting and health worker cadre: it was not clear how the intervention was delivered; the setting was antenatal clinics so iron was probably provided by obstetricians or midwives.


OutcomesHb, serum ferritin and serum at the beginning (week 16) and the end of treatment (week 28).


NotesGestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: non-anaemic.

Dose of iron per week in intermittent group:high weekly dose of iron in the three times weekly (more than 120 mg elemental iron per week) (group 2) and lower weekly dose of iron in the once weekly (120 mg elemental iron or less per week) (group 3) .

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days (group 2) and provision of iron once a week on non-consecutive days (group 3).

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due to Plasmodium vivax and Plasmodium falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part
of Sistan-Baluchestan.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described but it was stated that women were "divided into three equal groups".

Allocation concealment (selection bias)Unclear riskMethod not described. The abstract states that women were "simply randomised".

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding was not mentioned.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk150 women were randomised. 8 women were excluded after randomisation (7 of these women were in the three times weekly group).

Selective reporting (reporting bias)Unclear riskAssessment was from a brief trial report and we did not have access to the study protocol.

Other biasUnclear riskThe methods were not well described. It was stated that the three randomised groups "were matched in terms of age, numbers of pregnant, income and education". This may mean that background characteristics in the three randomised groups were similar, but this was not clear.

Casanueva 2003a

MethodsRCT 2-arm trial with individual randomisation.


Participants120 singleton pregnant women attending the Instituto Nacional de Perinatologia in Mexico City, Mexico with Hb concentrations higher than 115 g/L at 20 wks of gestation (equivalent to 105 g/L at sea level).


InterventionsParticipants were randomly assigned to 1 of 2 groups, group 1: 1 tablet containing 60 mg of elemental iron (as ferrous sulphate), 200 μg (0.2 mg) folic acid and 1 μg vitamin B12 given daily, and group 2: 2 tablets (total 120 mg of elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid, and 2 μg vitamin B12) to be taken once weekly. The groups received either daily supplementation or weekly supplementation at no cost. Supplement tablets were identical in content and were to be ingested from the 20th week of pregnancy until delivery.

The 60 women in the daily group were supplied monthly with 30-31 tablets and were instructed to ingest 1 tablet daily. The women in the weekly group were supplied monthly with 8-10 tablets and were instructed to consume 2 tablets once each week. If the scheduled day was missed, they were instructed to take the tablets the next day and not to wait until the following week before ingesting them.

Both groups were told that the tablets were to be ingested with water at least 1 h after a meal and preferably before going to bed at night to decrease gastrointestinal side effects.

Setting and health worker cadre: the intervention was performed by obstetricians at the Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes (INPerIER), a teaching and research centre in Mexico City, Mexico.


OutcomesMaternal: Hb and serum ferritin concentrations every 4 wks from wks 20 until 36, side effects, compliance, birthweight, gestational age at birth, anaemia, iron deficiency, haemoconcentration (defined as Hb level was > 145 g/L, which considers an adjustment by altitude of Mexico city by the addition of 10 g/L , making it equivalent to sea level value of 135 g Hb/L.

Infant: weight.


NotesNon-compliance with allocated intervention (stopped/started) reported as adherence 50th percentile (i.e. positive outcome) was 93% in the weekly regimen and 90% in the daily regimen.

Gestational age at start of supplementation: late gestational age (supplementation started at 20 weeks of gestation or later);

Anaemic status at start of supplementation: non-anaemic.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due almost exclusively to Plasmodium vivax exists throughout the year in some rural areas. There is moderate risk in some localities in the states of Chiapas and Oaxaca; very low-risk localities are also found in the states of Chihuahua, Durango, Nayarit, Quintana Roo and Sinaloa.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation by drawing lots without replacement; there was a 50% probability of being placed in either group.

Allocation concealment (selection bias)Unclear riskThere is insufficient information to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
High riskInadequate: participant, care provider not blinded (number of pills for each group different). Outcome assessor described as blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk120 women were randomised, only 4 were lost to follow-up (all in the daily group). Reasons for loss were explained and did not appear to relate to supplementation.

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

Other biasLow riskGroup appeared similar in terms of baseline characteristics.

Chew 1996a

MethodsRCT 2-arm trial.


Participants256 clinically healthy pregnant women from low socioeconomic status attending one antenatal care clinic in Guatemala City, Guatemala and Hb > 80 g/L were recruited. City of Guatemala is at 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb.


InterventionsParticipants were randomly assigned to one of two groups: group 1: daily supervised intake of 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid; group 2: weekly supervised intake of 180 mg of elemental iron (as ferrous sulphate) and 3500 μg (3.5 mg) of folic acid in 1 intake once a week.
Supplementation started at different gestational age for each participant. Average gestational age at start was 20.5 wks until 38th wk.

Setting and health worker cadre: the intervention was performed by physicians and researchers at 1 antenatal care clinic in Guatemala City, Guatemala.


OutcomesMaternal: Hb concentration at baseline and at term (38th week of gestation); side effects and total iron intake.
Infant: birthweight.


NotesSupervised.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due predominantly to Plasmodium vivax exists throughout the year below 1500 m. There is moderate risk in the departments of Escuintla and Izabal, and low risk in Alta Verapaz, Baja Verapaz, Chiquimala, Petén, Suchitepéquez and Zacapa.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy computerised random numbers.

Allocation concealment (selection bias)Low riskAuthors used sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant, care provider and outcome assessor not blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up.

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

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

Chew 1996b

MethodsRCT, 2-arm trial.


Participants120 clinically healthy pregnant women attending 1 antenatal care clinic in Guatemala City, Guatemala with Hb > 80 g/L were recruited. Women were from low SES. City of Guatemala is 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb.


InterventionsParticipants from low SES were randomly assigned to 1 of 2 groups: group 3: daily unsupervised intake of 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid; or group 4: weekly unsupervised intake of 180 mg of elemental iron (as ferrous sulphate) and 3500 μg (3.5 mg) of folic acid in 1 intake once a week.
Supplementation started at an average of 20.5 wks of gestation until 38th wk.

Setting and health worker cadre: the intervention was performed by physicians and researchers at 1 antenatal care clinic in Guatemala City, Guatemala.


OutcomesMaternal: Hb concentration at baseline and at term (38th week of gestation); side effects and total iron intake.
Infant: birthweight.


NotesUnsupervised.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due predominantly to Plasmodium vivax exists throughout the year below 1500 m. There is moderate risk in the departments of Escuintla and Izabal, and low risk in Alta Verapaz, Baja Verapaz, Chiquimala, Petén, Suchitepéquez and Zacapa.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random numbers.

Allocation concealment (selection bias)Low riskSealed envelopes were used.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and provider not blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up.

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

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

Ekstrom 2002 (C)

MethodsCluster-randomised trial. 50 antenatal clinics randomised.


Participants209 apparently healthy women attending antenatal care clinics in rural areas of Mymemsingh thana, Bangladesh, with fundal height of 14-22 cm (18-24 wks of gestation), who had not used iron supplements prior to the study. Exclusion criteria: women with Hb concentrations < 80 g/L.


InterventionsEach clinic was randomly assigned to 1 of 2 interventions: 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid given in 1 tablet daily, or 120 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid once a week (given in 2 tablets 1 day of the week). Supplementation continued until 6 wks postpartum.
Supplementation started at baseline for 12 wks.

Setting and health worker cadre: the intervention was performed by lay health workers and health centre staff at rural community antenatal centres run by an NGO among primarily illiterate women of lower socioeconomic status in Bengladesh.


OutcomesMaternal: Hb concentration at baseline and after 12 wks of supplementation. Compliance, side effects, serum ferritin and serum transferrin receptors at 6 wks postpartum.


NotesUnsupervised.
Cluster randomisation used among 52 antenatal clinics: n = 25 to daily supplementation and n = 25 to weekly supplementation. 2 antenatal care units ceased operation during the trial period.

Compliance was 104% and 68% for weekly and daily groups respectively. The compliance above 100% for the weekly means that more tablets that were indicated to be taken were ingested in the period of time.

Cluster design effect was not taken into account in the analysis.

Gestational age at start of supplementation:early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in the whole country excluding Dhaka city, with highest risk in Chittagong Division, the districts of Mymensingh, Netrakona and Sherpur in Dhaka Division, and Kurigram district in Rajshahi Division.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCluster by random list numbers.

Allocation concealment (selection bias)High riskNot used.

Blinding (performance bias and detection bias)
All outcomes
High riskNeither participant nor provider blinded. Outcome assessor unclear.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up. 209 women in 50 centres randomised. 140 followed up, therefore attrition 33%. Attrition was not balanced across groups with women in the weekly arm being more likely to have incomplete data and 2 from this group were withdrawn with anaemia (versus 0 in daily group).

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

Other biasLow riskResults adjusted by initial Hb measurements as well as by clustering effect within subjects.

Goonewardene 2001

MethodsRCT, 3-arm trial with individual randomisation.


Participants92 pregnant women from 14-24 wks of gestation attending the university antenatal clinic, in Galle, Sri Lanka.


InterventionsParticipants were randomly assigned to one of three regimens: group 1 (n = 26) received a tablet containing 100 mg of elemental iron (as ferrous fumarate) 500 μg (0.5 mg) folic acid, 10 mg vitamin B12, 100 mg vitamin C, 10 mg vitamin B6 and 50 mg niacinamide once a week; group 2 (n = 35) received the same tablet but three times a week; and group 3 (n = 31) received the same supplement in a daily fashion. All groups received 100 mg mebendazole twice daily for 3 days before they were randomly allocated to the groups.

Women were advised to take the supplement with water at 11:00 a.m. (approximately one hour before lunch).

Setting and health worker cadre: the intervention was performed by obstetricians at a prenatal clinic in Galle, Sri Lanka.


OutcomesHb, serum ferritin, hematocrit at entry and at 34-36 wks gestation, before the onset of labour.


NotesUnsupervised.
Compliance was described as "good" in all three groups and no serious side effects were reported.

Gestational age at start of supplementation:mixed

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation. However 88/92 participants were anaemic at baseline.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (100 mg elemental iron in once weekly group) and high for the thrice weekly group that received 300 mg elemental iron).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous fumarate.

Intermittent regimen: provision of iron once a week on non-consecutive days and the other group provision of iron by three times on non-consecutive days or other intermittent regimens.

Malaria setting: study carried out in malaria risk locations. As of 2011: limited malaria risk – Plasmodium vivax (88%), Plasmodium falciparum (12%) – exists throughout the year, except in the districts of Colombo, Galle,
Gampaha, Kalutara, Matara and Nuwara Eliya.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as randomly assigned but method of sequence generation is unclear.

Allocation concealment (selection bias)Unclear riskNot reported.

Blinding (performance bias and detection bias)
All outcomes
High riskNot attempted.

Incomplete outcome data (attrition bias)
All outcomes
Low risk88 out of 92 provided blood sample for the analysis.

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

Other biasLow riskNo baseline imbalance apparent but baseline data were only provided for those women available to follow-up. There were not significant differences in income, educational level, age and parity.

Grover 1998

MethodsRCT, 2-arm trial with individual randomisation.


Participants200 pregnant women with gestation 16-24 weeks attending for care in rural health centre in Gazipur village in East Delhi, India from Jan-Dec 1994 with Hb 70 g/L or more and no tuberculosis, chronic diseases, "toxaemia", bleeding piles.

Participants: 9.2% > 30 years, nearly 60% were illiterate and 23.4% primigravid. Baseline Hb in the daily iron group was 96 g/L and in the intermittent group 97 g/L.

200 women randomised but data available for 120.


InterventionsFrom recruitment (16-24 weeks) until delivery (not clear).

Participants were randomly assigned to 1 of 2 groups: group 1: women received 100 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid on alternate days: (data available for 56 women); group 2: women received 100 mg of elemental iron daily (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid (data available for 64 women). It is not clear how the doses were supplied.

Setting and health worker cadre: the intervention was performed by physicians and medical social workers at a weekly, rural antenatal health centre run by the Department of Preventative and Social Medicine of the University College of Medical Sciences in New Delhi, India.


OutcomesBirthweight at 48-72 hours, side effects and compliance.


NotesMalarial status of the study area not stated.

Setting prevalence of anaemia, haemoglobinopathies, and hookworm not mentioned.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron by three times on non-consecutive days or other intermittent regimens.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in the whole country at altitudes below 2000 m, with overall 40–50% of cases due to Plasmodium falciparum and the remainder due to Plasmodium vivax. There is no transmission in parts of the states of Himachal Pradesh, Jammu and Kashmir, and Sikkim.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk“assigned to the two different groups randomly.”

Allocation concealment (selection bias)Unclear riskThere is insufficient information to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
High riskNot attempted, different treatment regimens no placebo.

Incomplete outcome data (attrition bias)
All outcomes
High risk“200 pregnant women were enrolled for the study out of which only 120 could complete the course of therapy”. It was not clear why women were lost to follow-up or did not complete the course of therapy, nor was it clear whether the loss from the 2 groups was at the same level or for the same reasons. This level of attrition (40%) means this study is at high risk of bias.

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

Other biasUnclear riskNo baseline imbalance apparent but baseline data were only provided for those women available to follow-up.

Liu 1996

MethodsRCT. 3-arm trial with additional non-random control group.


Participants395 healthy, anaemic and non-anaemic, pregnant women attending prenatal care at 2 outpatient clinics at Changji Hospital and Shihezi Maternal and Child Health Station in Xianjiang, China. Women with Hb < 80 g/L were excluded. Maternal age was 25.15 ± 2.28 years.


InterventionsParticipants were randomly assigned to one of 3 groups: group 1: 60 mg elemental iron as ferrous sulphate and 250 μg (0.25 mg) of folic acid daily; group 2: 120 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily; group 3: 120 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid once weekly. A control group that received no iron was composed of women who did not want to participate in the study and did not receive any iron supplements. Since the allocation of the control group was not randomised, we included this study in our comparisons of the effects of intermittent versus daily iron supplementation.

Setting and health worker cadre: the intervention was performed by physicians and researchers in 2 outpatient clinics of the department of Obstetrics in Changji Hospital and Shihezi Maternal and Child Health Station in Xianjiang, China.


OutcomesMaternal: Hb concentration at 3, 5, 8 months and at term; serum ferritin concentrations at 3 months and at term in a subgroup; side effects.
Weight at entry and at term (not used in the review).


NotesUnsupervised.
Iron supplementation is not mandatory for women in China, if they have a Hb concentration > 80 g/L.

Compliance for group 1 (daily 60 mg Fe), group 2 (daily 120 mg Fe) and group 3 (weekly 120 mg Fe) were 77%, 75% and 86% respectively.

Gestational age at start of supplementation: unspecified gestational age or mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk, including Plasmodium falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskMethod unclear. Non-supplemented group was self-selected.

Allocation concealment (selection bias)Low riskSealed closed envelopes were used.

Blinding (performance bias and detection bias)
All outcomes
High riskNeither participant nor provider blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% lost to follow-up but there were missing data for some outcomes (only two arms of this trial included in the analyses).

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

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

Mukhopadhyay 2004

MethodsRCT 2-arm trial.


Participants111 apparently healthy pregnant women with less than 20 wks and no prior intake of iron supplements during this pregnancy with Hb equal or higher than 100 g/L and singleton pregnancy in New Delhi, India. Women who were taking anti-epileptics or anti-thyroid medications, had history of menorrhagia, bleeding disorders, chronic peptic ulcers, bleeding piles, thalassaemia or other haemoglobinopathies, or history of haemorrhage in present or past pregnancies were excluded.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received 2 tablets of 100 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid each (total 200 mg elemental iron and 1000 μg (1 mg) folic acid), to be taken only once a week, 1 tablet before lunch and another tablet before dinner; group 2 received 1 tablet of 100 mg elemental iron and 500 μg (0.5 mg) folic acid daily. Women were advised to take the supplements 30 minutes before the meals and not with tea, coffee or milk. Also, women were advised to take calcium supplements after meals (500 mg elemental calcium twice daily). Iron supplementation started between 14 and 20 wks until delivery. Deworming, if required, was carried out with Mebendazole 100 mg twice a day for 3 days in the second trimester.

Setting and health worker cadre: the intervention was performed by physicians and lay health workers at the All India Institute of Medical Sciences in New Delhi, India.


OutcomesMaternal: Hb, serum ferritin concentrations at baseline and at 32-34 wks, prevalence of anaemia, compliance to treatment, presence of intestinal parasites.
Infant: birthweight.


NotesUnsupervised.
Compliance measured by pill count and interview. compliance was 85% in group 1 (intermittent) and 40% in group 2 (daily).

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: non-anaemic.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in the whole country at altitudes below 2000 m, with overall 40–50% of cases due to Plasmodium falciparum and the remainder due to Plasmodium vivax. There is no transmission in parts of the states of Himachal Pradesh, Jammu and Kashmir, and Sikkim.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers. Block randomisation (block size = 10).

Allocation concealment (selection bias)High riskThere is insufficient information to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
High riskOpen to participants and care providers. It was not clear if all outcomes were assessed blinded but stated that the technician "carrying out the laboratory analysis was not aware of the group". 

Incomplete outcome data (attrition bias)
All outcomes
High riskNumber randomised: 111 women. Only 80 were available to follow up (40 in each group) (20% attrition) and reasons for loss to follow-up were not balanced across groups. 7 women in the daily supplementation group compared with 2 in the intermittent group were not included in the analysis because the "complained of gastrointestinal intolerance and changed to a different iron preparation".  There was no intention-to-treat analysis. More than 20% excluded.

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

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

Mumtaz 2000

MethodsDouble blinded RCT, 2-arm trial with individual randomisation.


Participants191 anaemic pregnant women between the ages of 17-35 years of age, and uneventful obstetric history attending the Maternity wing of the Federal Government Services Hospital in Islamabad and the Maternal & Child Health Clinic at the Christian Mission Hospital in Taxila, Pakistan.


InterventionsParticipants were randomly assigned to 1 of 2 interventions: group 1 received 40 mg elemental iron (as 200 mg of ferrous sulphate) with 1000 μg (1 mg) of folic acid once daily; and group 2 received 40 mg elemental iron (as 200 mg of ferrous sulphate) with 1000 μg (1 mg) of folic acid on 2 days of the week and placebo the rest of the days.

Setting and health worker cadre: the intervention was performed by physicians at the Maternity Wing of the Federal Government Services Hospital, an urban, tertiary care hospital in Islamabad, and the Maternal & Child Health Clinic of the Christian Mission Hospital, a peri-urban mission hospital in Taxila, Pakistan.


OutcomesOutcomes measured included Hb concentration and serum ferritin at baseline and during the 3 following consecutive visits as well as compliance and weight. Change in Hb Z-scores after supplementation was the main outcome variable, in women recruited at different gestational ages and duration of intervention varied. Data were not reported on outcomes prespecified in this review.


NotesData from this study have not been included in the analyses.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron twice a week on non-consecutive days.

Malaria setting: malaria risk throughout the country including urban areas.As of 2011: malaria risk – Plasmodium vivax and Plasmodium falciparum – exists throughout the year in the whole country below 2000 m.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number generator.

Allocation concealment (selection bias)Low riskNot described clearly but women were provided with placebo.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants, care providers and outcome assessors blinded.

Incomplete outcome data (attrition bias)
All outcomes
High risk191 women recruited and 160 followed up for 4 wks but there was further drop out at subsequent visits with 55% completing 4 scheduled follow-up visits.

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

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

Pita Martin 1999

MethodsRCT 3-arm trial.


Participants203 healthy pregnant women with normal blood pressure at first visit, attending antenatal care clinic at Diego Paroissien Hospital in the Province of Buenos Aires, Argentina were included in the study, but in this review only 41 women who were randomised and completed the study were included in the analysis.


InterventionsParticipants were assigned to 1 of 3 groups: group 1 received 60 mg of elemental iron (as ferrous fumarate) daily; group 2 received 60 mg elemental iron (as ferrous fumarate) every three days; and group 3 received no treatment. Supplementation started at 8-28 wks until 34-37 wks of gestation.

Setting and health worker cadre: the intervention was performed by physicians at the Diego Paroissien Hospital in the Matanza Provincia of Buenos Aires, Argentina.


OutcomesMaternal: Hb, haematocrit, erythroporphyrin, serum ferritin concentration at baseline and at 34-37 wks gestation, premature birth.
Infant: birthweight.


NotesUnsupervised.
Women from control group (group 3) were not assigned randomly. These women were recruited but due to delays in the acquisition of the iron tablets and the progression of their pregnancies without supplementation they were left as controls in the study.
This study is used only for comparison between intermittent and daily iron supplementation (group 2 vs group 1).
Compliance not reported.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous fumarate. Iron compound with equivalent or lower relative (to ferrous sulphate) bioavailability.

Intermittent regimen: every three days. Provision of iron twice a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due exclusively to Plasmodium vivax is very low and is confined to rural areas along the borders with Plurinational State of Bolivia (lowlands of Salta province) and with Paraguay (lowlands of Chacoand Misiones provinces).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskInadequate - quasi-randomised. Uneven group size.

Allocation concealment (selection bias)High riskNot used.

Blinding (performance bias and detection bias)
All outcomes
High riskInadequate - neither participant nor provider blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskInadequate. More than 20% lost to follow-up. 203 randomised but analysis was for only 88 women who completed the trial (57% attrition). It was not clear how many women were randomised to each group, at follow-up the size of the control group was much larger than the intervention groups: control n = 47, daily group n = 29 and intermittent group n = 12.

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

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

Quintero 2004

MethodsRCT, 2-arm trial with individual randomisation.


Participants107 healthy pregnant women with 6-20 wks of gestation who had not received iron supplements during the current pregnancy attending 19 health units in the State of Morelos, Mexico.


InterventionsParticipants were randomly assigned by block pairs (anaemic and not anaemic) to receive either 120 mg of elemental iron (as ferrous sulphate) in a single dose daily or once weekly for 10 weeks.

Setting and health worker cadre: the intervention was performed by physicians at primary health care clinics in Morelos, Mexico.


OutcomesHb concentration, prevalence of anaemia and nutrient consumption at baseline and after 10 wks of supplementation were measured. Data on none of the prespecified outcomes of this review were available. Gestational ages at recruitment and follow-up were very variable among the participants and results are therefore difficult to interpret.


NotesData from this study have not been included in the analyses.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation:mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due almost exclusively to Plasmodium vivax exists throughout the year in some rural areas. There is moderate risk in some localities in the states of Chiapas and Oaxaca; very low-risk localities are also found in the states of Chihuahua, Durango, Nayarit, Quintana Roo and Sinaloa.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy computer-generated random numbers.

Allocation concealment (selection bias)High riskNot used.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants, care providers not blinded. Outcome assessors unclear.

Incomplete outcome data (attrition bias)
All outcomes
High risk107 women recruited and complete data available for 77 women.

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

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

Ridwan 1996 (C)

MethodsCluster-randomised trial.


Participants176 pregnant women with 8-24 wks of gestation attending antenatal care at 6 health centres in West Java, Indonesia.


InterventionsHealth centres were randomised to 1 of 2 interventions: weekly regimen, where women received 120 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid; or daily regimen where women received 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily until week 28-32 of gestation.
Supplementation started at 8-24 wks until 28-32 wks of gestation.

Setting and health worker cadre: the intervention was performed by midwives at rural health centres in Tangeran, West Java, Indonesia.


OutcomesMaternal: Hb concentration, serum ferritin, weight at baseline and at 28-32 wks of gestation; compliance to treatment and prevalence of parasitic infections.


NotesUnsupervised but frequent contact with participants.
Randomisation was made by health centres.
Compliance measured by stool tests was 54.3% in the daily group and 62.2% in the weekly group.
Adjustment by intra class correlation coefficient to show effective sample size taking into account cluster randomisation and unit of analysis.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation.

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in all areas of the five eastern provinces of East Nusa Tenggara, Maluku, North Maluku, Papua and West Papua. In other parts of the country, there is malaria risk in some districts, except in Jakarta Municipality and in big cities.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlock randomised using randomised numbers table.

Allocation concealment (selection bias)High riskNot used.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and care provider not blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up. 176 women randomised, full data for 139. Dropouts were described as similar to those remaining to follow up and reasons for attrition were balanced across groups.

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

Other biasHigh riskSome differences at baseline; women in the weekly group had significantly lower Hb, and serum ferritin levels (NS).

Robinson 1998

MethodsRCT. 3 arms.


Participants680 pregnant women served by 11 health centres from 5 sub-districts on or near the western end of the island of Seram in the Province of Maluku, Indonesia.


InterventionsParticipants were assigned to 1 of 2 interventions: group 1 received 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily by a traditional birth attendant; group 2 received 120 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid once a week by the traditional home visiting birth attendants. A control group was formed by participants receiving traditional iron supplements (60 mg elemental iron) with folic acid from health centres, self administered without incentive.

Setting and health worker cadre: the intervention was performed by traditional birth attendants in villages greater than 10 km from a health centre in Maluku, Indonesia.


OutcomesMaternal: Hb concentration at baseline and after 12 and 20 wks of supplementation; serum ferritin at baseline and after 12 wks of supplementation; compliance.


NotesDaily group and control unsupervised. Weekly group supervised.
Each group was further assigned alternatively by registration number to receive 500 mg of mebendazole or a placebo at the second trimester of pregnancy.
Only groups 1 and 2 are used in this analysis. Compliance was 69.6%, 96.2% and 46.9% for groups 1, 2 and control respectively. The study area is endemic to malaria.

Gestational age at start of supplementation: unspecified gestational age or mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group:low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in all areas of the five eastern provinces of East Nusa Tenggara, Maluku, North Maluku, Papua and West Papua. In other parts of the country, there is malaria risk in some districts, except in Jakarta Municipality and in big cities.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised, by alternating numbers.

Allocation concealment (selection bias)Unclear riskUnclear.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and provider not blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up and missing data for some outcomes. "Women with missing or bizarre data were not included in the analysis. In addition, women who did not carry their pregnancy the whole study period... were not included."

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

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

Singh 2011

MethodsRCT; 2-arms


Participants100 apparently healthy women with a singleton pregnancy between 18-22 wks gestation attending routine antenatal care at the Department of Obstrtrics and Gynaecology of the Medical University, Lucknow in Uttar Pradesh, India. Women with less than 90 g/L or more than 110 g/L Hb and any chronic systemic disorder or with high risk pregnancy were excluded


InterventionsParticipants were randomly assigned to one of two groups: group 1 (n = 50) received one table daily containing 100 mg elemental iron, 1500 μg (1.5 mg) folic acid and 15 μg vitamin B12; group 2 (n = 50) received two tablets to be taken once a week containing a total of 200 mg elemental iron, 1500 μg (1.5 mg) folic acid and 15 μg vitamin B12). All participants were de-wormed using a single dose tablet containing 400 mg of albendazole. The intervention lasted 14 weeks.


OutcomesHb, packed cell volume (PCV) after 4, 8 and 14 wks of the intervention, side effects, serum iron, total iron binding capacity, serum ferritin at 14 weeks after supplementation


NotesParticipants in the weekly group received supervised intake on the tablets. Participants in the iron daily group reported every week to show the empty blister before getting the iron for the next week in an effort to improve compliance.

Gestational age at start of supplementation: unspecified gestational age or mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: non-anaemic at start of supplementation.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: unknown. non described.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk exists throughout the year in the whole country at altitudes below 2000 m, with overall 40–50% of cases due to Plasmodium falciparum and the remainder due to Plasmodium vivax.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as randomised but method not described.

Allocation concealment (selection bias)Unclear riskNot mentioned.

Blinding (performance bias and detection bias)
All outcomes
High riskAs patients had to report the blisters weekly to the care providers top receive the next week dose, and those participants in the weekly group received supervised intake, it is implied that this was an open trial.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 11%. Data for 89/100 were included in the trial. There were 5 losses in the daily group and 6 in the weekly iron supplemented group.

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

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

Winichagoon 2003 (C)

MethodsCluster-randomised trial.


Participants484 apparently healthy pregnant women with 13-17 wks of gestation who had not received iron supplements before enrolling in the study, and who had a Hb concentration > 80 g/L attending antenatal care clinics at the district hospital and 7 health centres from 54 villages in the Province of Khon-Kaen in northeast Thailand.


InterventionsThe villages were grouped according to size and then randomised in 4 clusters to 1 of 3 interventions: group 1 received a daily regimen providing 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily; group 2 received 120 mg of elemental iron (as ferrous sulphate) with 3500 μg (3.5 mg) of folic acid once a week; and group 3 received 180 mg of elemental iron (as ferrous sulphate) with 3500 μg (3.5 mg) of folic acid once a week.
Supplementation started at 15 +/- 2 wks until delivery.

Setting and health worker cadre: the intervention was performed by lay health workers in rural villages in Ubolrat district of Khon-Kaen Province in Thailand.


OutcomesMaternal: Hb concentration, serum ferritin, free erythrocyte protoporphyrin at baseline and at 35 +/- 2 wks of gestation, and 4-6 months postpartum; haematocrit prior to delivery; weight at baseline and at 35 wks of gestation; compliance, Hb type, and hookworm prevalence.
Infant: birthweight, Hb concentration and serum ferritin at 4-6 months.


NotesUnsupervised.
Compliance not reported.
Values adjusted to reflect effective sample size for cluster randomisation.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: (group 2) low weekly dose of iron in the weekly group (120 mg elemental iron or less per week) and (group 3) high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations.As of 2011: malaria risk exists throughout the year in rural, especially forested and hilly, areas of the whole country, mainly towards the international
borders, including the southernmost provinces. There is no risk in cities (e.g. Bangkok, Chiang
Mai city, Pattaya), Samui island and Phuket island. However, there is a risk in some other areas and islands.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskCluster-randomisation but method unclear.

Allocation concealment (selection bias)High riskNot used.

Blinding (performance bias and detection bias)
All outcomes
High riskOpen.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 20% lost to follow-up. "... the analysis of data was performed only on women who ingested more than 75% of the iron tablets provided and whose haemoglobin never fell < 80 g/L". 484 women randomised, 379 completed study (22% attrition). 11 excluded from the weekly group for poor compliance or because they received other supplements. Reasons for attrition across groups were not balanced.

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

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

Yekta 2011

MethodsRCT 3-arms with individual randomisation.


Participants210 pregnant women with 17–20 weeks' gestation and singleton pregnancies, no known disease, and Hb levels higher than 110 g/L attending local public health care centres at seven prenatal health care clinics between September 2007 and February 2009 in the urban regions of Urmia city North West Iran.


InterventionsParticipants were randomly assigned to one of three groups: group 1 (n = 70) received two iron supplementation tablets once weekly providing 100 mg elemental iron per week (as ferrous sulphate); group 2 (n = 70) received one tablet twice weekly providing 100 mg elemental iron per week (as ferrous sulphate); and group 3 (n = 70) received one tablet daily containing 50 mg elemental iron per day (as ferrous sulphate). No additional micronutrients were supplied.

Setting and health worker cadre: the intervention was performed by an assigned health care provider in local public healthcare centres at seven prenatal health care clinics between September 2007 and February 2009 in the urban regions of Urmia city North West Iran.


OutcomesHb and serum ferritin levels were measured at 20, 28, and 38 weeks; anaemia and haemoconcentration were calculated. Pregnancy and birth outcomes (pregnancy termination, method of delivery, birthweight, stillbirth) were reported. Adherence and side effects were also recorded.


NotesGestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: non anaemic

Dose of iron per week in intermittent group: low weekly dose of iron in both intermittent regimens (100 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: group 1 received provision of iron once a week on non-consecutive days; group 2 received one tablet twice weekly providing 100 mg elemental iron per week.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due to Plasmodium vivax and Plasmodium falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part
of Sistan-Baluchestan.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe assignment to the groups is described as random but the method of randomisation used is not described.

Allocation concealment (selection bias)Unclear riskThere is insufficient information in the article to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
High riskIt seems from the description that the participants, care providers and outcome assessor were not blinded to the interventions. It is described in the paper that some women decided to change to daily regimens based on the recommendations of their private physicians.

Incomplete outcome data (attrition bias)
All outcomes
Low risk201 women completed the study out of 210 randomised (less than 5% lost to follow-up). The exclusions were mostly in the group 1 that had 8 losses (11%), compared to 1 participant in group 2 (1/70 = 1%) and none in the daily regimen.

Selective reporting (reporting bias)Low riskThere does not seem to be selective reporting in this trial.

Other biasHigh riskParticipants were similar in age, body weight, parity, and height at baseline. Women in the weekly group had significantly lower Hb at baseline.

Young 2000

MethodsRCT 2-arm trial.


Participants413 healthy non-severely anaemic pregnant women attending antenatal care at Ekwendeni Hospital or its mobile clinics in northern Malawi with less than 30 wks of gestation at their first visit, stratified by initial Hb concentration before randomisation.
Supplementation starting time variable (22.2 +/- 4.8 wks) and ending time variable (32.2 +/- 4.4 wks of gestation).


InterventionsParticipants were randomly assigned within each anaemia grade category to 1 of 2 interventions: group 1 received 120 mg of elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid once a week; group 2 received 60 mg of elemental iron (as ferrous sulphate) with 250 μg (0.25 mg) of folic acid daily.

Setting and health worker cadre: the intervention was performed by midwives and public health workers at rural, weekly antenatal clinics and monthly mobile maternal and child health clinics in northern Malawi.


OutcomesMaternal: Hb concentration at baseline and after 8 wks of supplementation; compliance, presence of side effects, and prevalence of anaemia.


NotesUnsupervised.
Average gestational age at start was 22.2 +/- 4.8 wk and 32.2 +/- 4.4 wk at the end of study.
Compliance estimated by self reporting was 76% and 60% in the weekly and daily groups respectively.

Gestational age at start of supplementation: mixed gestational ages at the start of supplementation;

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk locations. As of 2011: malaria risk due predominantly to Plasmodium falciparum exists throughout the year in the whole country.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate by computer- generated random number table.

Allocation concealment (selection bias)Unclear riskThere is insufficient information to permit judgement.

Blinding (performance bias and detection bias)
All outcomes
High riskNeither participant nor provider blinded. Outcome assessor unclear.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 47% lost to follow-up.Stated that dropouts had similar baseline characteristics as those remaining for follow-up.

Selective reporting (reporting bias)High riskCompliance estimated by self-reporting was 76% and 60% in the weekly and daily groups respectively.

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

Yu 1998

MethodsQuasi-randomised trial.


Participants51 healthy pregnant women with 18-22 wks of gestation who had not taken supplements or medication in the previous 6 months attending public health centre in Ulsan, South Korea.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received 160 mg of elemental iron (as ferrous sulphate) in 1 intake once a week; group 2 received 80 mg of elemental iron (as ferrous sulphate) daily. Women with low Hb were assigned by the trialists to daily regimen. Supplementation started at 20.1 wks and 20.2 wks of gestation for groups 1 and 2 respectively.

Setting and health worker cadre: the intervention was performed by physicians at a public health centre in Ulsan, Korea.


OutcomesMaternal: Hb concentration, serum ferritin, red blood cell count, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, serum iron, total iron binding capacity, transferrin saturation at baseline and after intervention; zinc status before and after intervention, weight gain, nutrient intake before and after intervention.
Infant: birthweight.


NotesUnsupervised.
No compliance reported for all the groups. Analysis reported on high compliers only.

Gestational age at start of supplementation: late gestational age (supplementation started at 20 weeks of gestation or later);

Anaemic status at start of supplementation: unspecified/mixed anaemia status at start of supplementation.

Dose of iron per week in intermittent group: high weekly dose of iron in the weekly group (more than 120 mg elemental iron per week).

Iron release formulation: normal release iron supplement/not specified;

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: limited malaria risk due exclusively to Plasmodium vivax exists mainly in the northern areas of Gangwon-do and Gyeonggi-do Provinces and Incheon City (towards the Demilitarized Zone or DMZ).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised.

Allocation concealment (selection bias)High risk"The study subjects were divided to two groups randomly but the subjects whose Hb level was very low were allocated to the daily group ethically because the effect of weekly supplementation was not yet established as safety". It was not stated how many women this involved or whether these women were included in the analysis.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and care provider not blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskMore than 54% lost to follow-up. The number randomised was not clear. 14 were lost from the daily group for various reasons including wanting to change supplementation or low compliance. 10 were included in the analysis in the daily group and 13 in the weekly group.

Selective reporting (reporting bias)High riskNo compliance reported for all the groups. Analysis reported on high compliers only.

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

Zamani 2008

MethodsDescribed as a “field-based randomised trial”. 2 study arms. Individual randomisation.


Participants152 healthy, non-anaemic pregnant women aged 18-38 years, 15-16 weeks’ gestation (gestation estimated by menstrual dates and ultrasound) attending two clinics for prenatal care in Isfahan, Iran. ("In Iran, it is mandatory to prescribe iron (one tablet containing 45 mg elemental iron (as ferrous sulphate) per day) and folic acid supplements to pregnant women after the 15th- 18th week of gestation".)

Exclusion criteria: current anaemia (Hb < 110 g/L), past history of anaemia, thalassaemia, or other blood disorders, history of previous obstetric problems (haemorrhage, pregnancy-induced hypertension, diabetes) or any other chronic systemic disorder.


InterventionsParticipants were assigned to 1 of 2 groups: group 1 (experimental group) received two tablets of 45 mg elemental iron (as ferrous sulphate) taken on a single day each week. “Women in the trial group were instructed to choose any day of the week and to take 2 tablets of 45 mg elemental iron (as ferrous sulphate) each on the same day every week, one in the morning and one before dinner” i.e. 90 mg of “elemental iron (as ferrous sulphate) one day per week in two takes”. (Supplied as 8 tablets every 4 weeks) for 16 weeks (from recruitment at 16-18 weeks); group 2 (control group) were to take one tablet containing 45 mg elemental iron (as ferrous sulphate) daily for 16 weeks (from recruitment at 16-18 weeks). Supplied as 28 tablets every four weeks.

Women were followed up 4 weekly until 16 weeks of supplementation.

It was not clear whether or not women received additional nutritional supplements, but according to local protocol women in both groups probably received folate supplements but the length and dose of supplements were not mentioned.

Setting and health worker cadre: the intervention was performed by obstetricians at a prenatal clinic in Isfahan, Iran.


OutcomesCompliance and side effects recorded by women on diary card. Compliance was also assessed through interview.

Hb  concentration (g/L) before and after intervention (with breakdown of results at various baseline Hb levels)

Serum ferritin  (g/L) before  and after intervention.

In the introduction it was stated that gestation at delivery and mode of delivery were noted but results were not reported for these outcomes


NotesMalarial status of the study area: not mentioned.

Setting re anaemia, haemoglobinopathies, hookworm prevalence: not mentioned. 

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy).

Anaemic status at start of supplementation: non-anaemic.

Dose of iron per week in intermittent group: low weekly dose of iron in the weekly group (120 mg elemental iron or less per week).

Iron release formulation: normal release iron supplement/not specified.

Iron compound: ferrous sulphate.

Intermittent regimen: provision of iron once a week on non-consecutive days.

Malaria setting: study carried out in malaria risk free parts of countries that has malaria risk in other parts. As of 2011: malaria risk due to Plasmodium vivax and Plasmodium falciparum exists from March to November inclusive in rural areas of the provinces of Hormozgan and Kerman (tropical part) and the southern part
of Sistan-Baluchestan.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated numbers.

Allocation concealment (selection bias)Unclear riskDescribed the use of coded vials but these would contain different numbers of tablets. Not clear whether those carrying out recruitment distributed tablets.

Blinding (performance bias and detection bias)
All outcomes
High riskWomen would be aware that they were taking tablets every day vs 1 day each week.

Not clear whether blinding would be convincing to staff. It was stated that the tablets were provided in identical coded vials. “The investigators were blind to allocation of the treatment group ... at initial recruitment. Laboratory technicians were not aware of the group..”. However, the vials would feel different: one contained 8 and one 28 tablets. Not clear whether there was an attempt to blind outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes
High risk152 women recruited, 76 in each group, 30 women were lost to follow-up - 20% attrition, but loss was not balanced across groups: 7 were lost from the daily supplementation group and 23 from the intermittent group.

Selective reporting (reporting bias)Unclear riskIt was stated that gestation at delivery and mode of delivery were noted but results were not reported for these outcomes

Other biasUnclear riskBaseline information was only provided for those women completing the study and loss to follow-up was not balanced across groups - although it was stated in the text that the baseline characteristics of women that dropped out were similar to those that completed the study.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aaseth 200167 non-anaemic pregnant women attending prenatal care clinics in Kingsvinger Hospital, in Kingsvinger, Norway were allocated to a regimen of either 100 mg elemental iron daily or 15 mg elemental iron daily. Both groups received iron at different doses to be taken daily.

The types of interventions do not allow for comparisons within the scope of this review.

Abel 2000Community-based study in Vellore district, India using a pre-post experimental design measuring the impact of an iron supplementation program, helminthic treatment and education intervention in the prevalence of anaemia in the different trimesters of pregnancy. The same pregnant women were not followed.

Adhikari 2009320 pregnant women attending the Tribhuvan University Teaching Hospital, Nepal for antenatal care were randomised to one of four groups: group 1: 60 mg elemental iron daily (as ferrous sulphate); group 2: 60 mg elemental iron daily (as ferrous sulphate) with a count of unused pills at antenatal appointments; group 3: 60 mg elemental iron daily (as ferrous sulphate) with education (direct counselling and colour brochure) on iron and anaemia; group 4: 60 mg elemental iron daily (as ferrous sulphate) with pill count and education (direct counselling and colour brochure) on iron and anaemia. In this randomised trial the aim of the intervention was to increase compliance and all four intervention groups received daily iron supplements.

The types of interventions do not allow for comparisons within the scope of this review.

Afifi 1978260 pregnant women from Cairo, Egypt (formerly part of United Arab Republic) were randomly allocated to one of two groups: group 1 received 130 mg elemental iron daily (a slow release ferrous sulphate preparation, Plexafer-F®) and 360 μg (0.36 mg) folic acid; group 2 received iron (as ferrous sulphate, no dose reported) in addition to 5000 μg (5 mg) folic acid. Both groups received daily iron supplementation in different preparations.

The types of interventions do not allow for comparisons within the scope of this review.

Ahn 2006209 pregnant women between 18 and 45 years of age, attending outpatient obstetric clinics at North York General Hospital and the Hospital for Sick Children in Toronto, Canada were randomly assigned to receive multiple micronutrient supplements containing 60 mg of elemental iron (as ferrous fumarate) (Materna®) or another supplement (PregVit®) to be taken twice daily with the morning dose containing 35 mg of elemental iron (as ferrous fumarate) and the evening dose containing 300 mg calcium, and other vitamins and minerals. Both groups received daily iron in different doses as well as other vitamins and minerals.

The types of interventions do not allow for comparisons within the scope of this review.

Angeles-Agdeppa 2003744 apparently healthy pregnant (with less than 20 wks) and non-pregnant women of reproductive age (15-49 years) from the municipalities of Calasiao, Binmaley and Santa Barbara, Philippines who were pregnant or most likely to become pregnant within the 12-month duration of the study, and who volunteered to participate in the study were provided two preparations of iron+folic acid supplements. Women with severe anaemia or history of malaria were excluded. Non-pregnant women were prescribed four capsules monthly each containing 60 mg of elemental iron and 3500 μg (3.5 mg) folic acid to be taken once weekly before bedtime (to be purchased by the women in local drugstores). Pregnant women received free of cost four capsules monthly each containing 120 mg of elemental iron and 3500 μg (3.5 mg) of folic acid to be taken once a week before bedtime until delivery and for 3 months thereafter. Pregnant women seen at the health centres with 20 wks or more of gestation were advised to take their usual daily dose of iron+folic acid tablets containing 60 mg of elemental iron and 500 μg (0.5 mg) of folic acid. Women were followed for 12 months. Hb, haematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), serum ferritin, transferrin receptors, prevalence of iron deficiency and anaemia, compliance were assessed at baseline, 4.5, 9 and 12 months. There was not randomisation and the control group was not appropriate for comparisons.

Babior 198515 healthy pregnant women 22-32 years old, in the first trimester of pregnancy from Boston, Massachusetts, USA were randomly assigned to three different multiple micronutrient preparations to assess absorption of iron.

Barton 199497 healthy women attending prenatal care at National Maternity Hospital, Dublin, Ireland with singleton pregnancy, during their first trimester of pregnancy, and with haemoglobin equal or higher than 140 g/L were randomly assigned to one of two groups: group 1: received one tablet containing 60 mg elemental iron and 500 μg (0.5 mg) of folic acid and to be taken by mouth twice daily (total 120 mg elemental iron daily and 1000 μg (1 mg) folic acid); group 2: placebo tablets also to be taken by mouth twice daily. Supplementation started at 12 wks until delivery. No postpartum supplementation.

The types of interventions do not allow for comparisons within the scope of this review.

Batu 1976133 women attending an antenatal clinic for the fist time in Yangoon (also known as Rangoon), Myanmar (Burma). Women with severe anaemia were excluded. Women were randomly assigned to one of four groups starting at 22-25 wks: group 1: one tablet containing 60 mg of elemental iron (as ferrous sulphate), and one placebo tablet twice daily; group 2: one tablet containing 60 mg of elemental iron (as ferrous sulphate), and one tablet containing 500 μg (0.5 mg) of folic acid twice daily; group 3: two placebo tablets twice daily; group 4: one placebo tablet and one tablet containing 500 μg (0.5 mg) of folic acid twice daily. Administration of the treatments was carefully supervised. Supplementation started at 22-25 wks until term.

The types of interventions do not allow for comparisons within the scope of this review.

Bencaiova 2007260 women with singleton pregnancy in Zurich, Germany, were randomised at 21-24 wks of gestation to receive either intravenous iron group (further divided into two doses of 200 mg iron saccharate or three doses of 200 mg iron) or 80 mg elemental iron (as ferrous sulphate) daily. Both groups received iron in different routes of administration. No comparisons allowed within the scope of this review.

Berger 2003864 apparently healthy married pregnant and non-pregnant nulliparous women of reproductive age planning to have a child soon from 19 rural communes of the Thanh Mien district in Hai Duong province, Vietnam were invited to participate and assigned to one of the following interventions according to their pregnancy status at baseline: women who were pregnant received free of charge UNICEF tablets containing 60 mg of elemental iron and 250 μg (0.25 mg) of folic acid to be taken daily and women who were non-pregnant were prescribed pink packs of tablets containing 60 mg of elemental iron and 3500 μg (3.5 mg) of folic acid that they could buy at their village from the Women's Union, to be taken once weekly. If these women became pregnant, women received red packs of tablets containing 120 mg of elemental iron and 3500 μg (3.5 mg) of folic acid free of charge to be taken once weekly. After delivery women were given tablets containing 60 mg of elemental iron and 500 μg (0.5 mg) of folic acid free of charge for 3 months to be taken weekly. Hb concentration, serum ferritin, and serum ferritin receptors, prevalence of anaemia and iron deficiency and compliance were measured at baseline, at 4.5, 9 and 12 months. This is not a randomised study and no comparisons can be made for the aims of this review.

Bergsjo 1987Planned study registered at the Oxford Database of Perinatal Trials. Author contacted and informed the project was not completed.

Blot 1980203 pregnant women attending prenatal care clinics during their 6th month visit were randomly allocated to either 105 mg of elemental iron with 500 mg of ascorbic acid or a placebo. Both groups received iron. No comparisons allowed within the scope of this review.

Brown 1972109 pregnant women attending prenatal care clinics in Manchester, England were randomly allocated to one of three groups: group A: one tablet daily given in 'reminder packs', group B: one tablet daily given in loose forms, or group C two tablets daily given in loose form. Tablets contained 50 mg of elemental iron (as slow release ferrous sulphate) and 400 μg (0.4 mg) of folic acid. All groups received iron daily.

The types of interventions do not allow for comparisons within the scope of this review.

Burslem 1968472 pregnant women attending the booking clinic in Manchester, England were alternatively allocated to two forms of iron: group 1 received 105 mg elemental iron (as a slow release ferrous sulphate preparation) and a tablet containing 5000 μg (5 mg) folic acid; group 2 received 3 tablets of combined conventional 60 mg elemental iron (as ferrous sulphate) and one tablet containing 5000 μg (5 mg) folic acid for a total of 180 mg elemental iron daily. Both groups received daily iron supplementation in different preparations.

The types of interventions do not allow for comparisons within the scope of this review.

Buss 198118 pregnant women were randomly assigned to receive either a tablet containing 80 mg of elemental iron with a new mucous membrane vaccine (Tardyferon®) or a tablet containing 80 mg elemental iron with 350 μg (0.35 mg) folic acid (Tardyferon-Fol®) for a period of 3 months. All women received daily iron.

The types of interventions do not allow for comparisons within the scope of this review.

Butler 1968200 women before 20th week of gestation and Hb above 100 g/L attending antenatal clinic in Cardiff, United Kingdom were studied. Women were randomly allocated to three groups: group 1 received 122 mg of elemental iron (as ferrous sulphate) daily; group 2: received 122 mg of elemental iron (as ferrous sulphate) plus 3400 μg (3.4 mg) of folic acid daily; group 3: no treatment. A group 4 was formed as some participamts (n = 38) from group 3 received iron supplements for treatment of anaemia in the course of the intervention. Women were supplemented from week 20 to week 40 of gestation.

The types of interventions do not allow for comparisons within the scope of this review.

Buytaert 198345 non-anaemic women with singleton pregnancy and no major illnesses attending the University Hospital Obstetric and Gynaecologic Clinic in Antwerp, Belgium. Women were randomly assigned to one of two groups: group 1 received 105 mg of elemental iron (as sustained released ferrous sulphate) daily; group 2 received no iron supplement. Supplementation started at 14-16th week of gestation and continued until delivery.

The types of interventions do not allow for comparisons within the scope of this review.

Cantlie 197127 non-anaemic pregnant women 17-35 years of age from 4 participating obstetricians' private practice clinics from Montreal, Canada in their 1-5th month of pregnancy with Hb 12 g/dL or higher in first trimester and 11 g/dL or higher in second trimester. Women were randomly assigned to two groups: group 1 received 39 mg elemental iron to be taken twice daily with meals (total daily 78 mg elemental iron); group 2 who received no iron tablets. Both groups received one tablet of multiple micronutrients supplement daily containing: copper citrate 2 mg, magnesium stearate 6 mg, manganese carbonate 0.3 mg, vitamin A 1000 IU, vitamin D 500 IU, bone flour 130 mg, vitamin B1 1 mg, vitamin B2 1 mg, brewer yeast concentrate 50 mg, niacinamide 5 mg, vitamin C 25 mg, sodium iodide 0.2 mg and folate 0.049 μg (naturally occurring). Duration of supplementation unclear.

The types of interventions do not allow for comparisons within the scope of this review.

Carrasco 1962Two liquid preparations were used in this study: one with D-sorbitol and the other without. Both preparations contained vitamin B12, vitamin B6, ferric pyrophosphate and folic acid.

Chan 20091164 women with singleton pregnancies, a gestational age of 16 weeks or less and able to understand English or Chinese attending first antenatal booking visit at single regional hospital in Hong Kong, China between April 2005 and March 2007 were randomly assigned to receive 60 mg elemental iron daily (as ferrous sulphate) or daily placebo indistinguishable in appearance from the active treatment. Main maternal outcomes are development of gestational diabetes at 28 or 36 weeks, Hb (g/dL, serum transferrin (g/L), serum ferritin (pmol/L), compliance, glucose level, mode of delivery. Neonatal outcomes: gestational age at delivery, preterm delivery, birthweight, Apgar score at 1 and 5 minutes, arterial blood pH, Hb of cord blood (g/dl), ferritin of cord blood (pmol/L), jaundice, birth trauma, infection, congenital abnormality or metabolic disorder.

The types of interventions do not allow for comparisons within the scope of this review.

Chanarin 1965190 pregnant women attending antenatal clinic in St Mary's Hospital in London, England were invited to participate in the study and 189 accepted and were randomly assigned to one of three groups: group 1 received 3 tablets containing 100 mg of ferrous fumarate to be taken daily (total 300 mg ferrous fumarate daily); group 2 received 3 tablets containing 100 mg of ferrous fumarate with 10 μg (0.01 mg) folic acid (total 300 mg ferrous fumarate and 30 μg (0.03 mg) folic acid daily, or placebo (containing lactose). The outcomes measured include full blood count at 20th, 30th, 35th and 39th week of gestation and 6th day after delivery. The paper does not report standard deviations in the variables measured and no data can be extracted.

The types of interventions do not allow for comparisons within the scope of this review.

Chanarin 1971251 women attending antenatal clinic at a London hospital, United Kingdom before 20th week of gestation. Women were allocated by sequence to one of five groups: group 1: oral dose of 30 mg of elemental iron daily (as ferrous fumarate); group 2: oral dose of 60 mg of elemental iron (as ferrous fumarate) daily; group 3: oral dose of 120 mg of elemental iron (as ferrous fumarate) daily; group 4: placebo; group 5: 1 g of iron (Imferon, 4 x 250 mg) intravenously before week 20, and thereafter oral 60 mg of elemental iron (as ferrous fumarate) daily. Supplementation started at 20th week until 37th week.

The types of interventions do not allow for comparisons within the scope of this review.

Charoenlarp 1988325 pregnant women with Hb (AA) and 232 pregnant women with Hb (AE) attending midwife centres in 80 villages in the Ubon Province, Thailand. Chronic illness, complicated pregnancy, severe anaemia (Hb <80 g/L), haemoglobinopathies Hb (EE) and (EF), and unwillingness to cooperate were reason for exclusion. Individuals with Hb (AA) have normal haemoglobin genes. Women were divided into two groups according to Hb (AA) and Hb (AE) and studied separately. Women from each group were randomly assigned to one of the following interventions: group 1: placebo, supervised; group 2, 120 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) folic acid daily supervised; group 3, 240 mg of elemental iron (as ferrous sulphate) daily supervised; group 4: 240 mg of elemental iron (as ferrous sulphate) daily supervised; group 5: 120 mg elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid, motivated but unsupervised; and group 6: 240 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised. For the Hb (AE) group, women were randomly assigned to one of the following groups: group 7: placebo, supervised; group 8: 240 mg elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, supervised; group 9: 240 mg of elemental iron (as ferrous sulphate) daily, supervised; group 10: 120 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised, and group 11: 240 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised. Starting and ending time of supplementation not stated.

The types of interventions do not allow for comparisons within the scope of this review.

Chawla 199581 pregnant women with 20 +/- wks of gestation from Ludhiana City, India were divided to one of three groups: group 1 received 60 mg of elemental iron (as ferrous sulphate) and 500 ug of folic acid daily; group 2, 60 mg of elemental iron (as ferrous sulphate) and 2,000,000 IU of vitamin A, or group 3, who did not receive any supplements. Supplementation was for a period of 15 wks. Outcomes measured included haemoglobin, red blood cell count, total iron binding capacity, transferrin saturation, serum iron, serum vitamin A at baseline and at 36 +/- 2 wks of gestation. Poor methodological quality. None of the outcomes pre-specified in our protocol were recorded due to the varied time of final measurements.

The types of interventions do not allow for comparisons within the scope of this review.

Chisholm 1966360 non-anaemic women attending antenatal clinic in Oxford, United Kingdom before 28th week of gestation, who had not taken iron supplements in the preceding 8 wks and with Hb >= 102 g/L or a normal serum iron reading were randomly assigned to 6 groups as follows:group 1: 900 mg elemental iron (as ferrous gluconate) alone daily; group 2: 900 mg elemental iron (as ferrous gluconate) and 500 μg (0.5 mg) folic acid daily; group 3: 900 mg elemental iron (as ferrous gluconate) and 5000 ug (5 mg) folic acid daily; group 4: placebo; group 5: 500 μg (0.5 mg) folic acid daily; group 6: 5000 μg (5 mg) of folic acid daily. Iron and folic acid placebos were used. Supplementation started at 28th week until 40th week

The types of interventions do not allow for comparisons within the scope of this review.

Christian 2003Cluster-randomised trial. 4998 married pregnant women living in the south eastern plains district of Sarlahi, Nepal. Women were randomly assigned to one of five groups: group 1 received 1000 μg retinol equivalents vitamin A (control) daily; group 2 received 1000 μg retinol equivalents vitamin A and 400 μg (0.4 mg) folic acid daily; group 3 received 1000 μg retinol equivalents vitamin A, 400 ug (0.4 mg) folic acid and 60 mg elemental iron (as ferrous fumarate) daily; group 4 received 1000 μg retinol equivalents vitamin A, 400 μg (0.4 mg) folic acid, 60 mg of elemental iron (as ferrous fumarate) and 30 mg of zinc sulphate daily; and group 5 received 1000 μg retinol equivalents vitamin A, 400 μg (0.4 mg) folic acid, 60 mg elemental iron (as ferrous fumarate), 30 mg of zinc, 10 μg vitamin D, 10 mg vitamin E, 1.6 mg thiamine, 1.8 mg riboflavin, 20 mg niacin, 2.2 mg vitamin B6, 2.6 μg vitamin B12, 100 mg vitamin C, 65 μg vitamin K, 2 mg cooper, and 100 mg magnesium daily. Supplementation started at recruitment and continued until 3 month post-partum in the case of live births of 5 wks or more after a miscarriage or stillbirth. All participating women were offered deworming treatment (albendazole 400 mg single dose) in the second and third trimester.

The types of interventions do not allow for comparisons within the scope of this review.

Coelho 2000100 pregnant women with 20-34 wks of gestation attending the antenatal clinic at The Bandra Holy Family Hospital, Bandra, Mumbai India were randomly assigned to one of two groups: group 1 received 30 mg elemental iron + other essential vitamins and minerals daily; groups 2 received 116 mg elemental iron, folic acid, zinc and vitamin C daily. Outcomes included Hb concentration, maternal weight gain, infant birth weight and maternal compliance and side effects Both groups received iron supplementation. Both groups received daily iron supplementation.

The types of interventions do not allow for comparisons within the scope of this review.

Cogswell 2003275 non-anaemic, low-income pregnant women at < 20 wks of gestation with ferritin levels above 20 ug/L enrolled at the Cuyahoga County, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, USA were randomly assigned to one of two groups: group 1 received 1 gelatin capsule containing 30 mg of elemental iron (as ferrous sulphate) daily; group 2 received 1 placebo soft gelatin capsule daily for 119 days. Supplementation started at an average of 11 wks of gestation until delivery.

The types of interventions do not allow for comparisons within the scope of this review.

Cogswell 2006Randomised controlled trial.  Pregnant women 20 years or older who live in one of the study counties (Laoting, Mancheng, Fengrun, Xianghe, Yuanshi) in China., and who can follow instructions and can swallow pills were randomly assigned to receive a daily supplement containing 30 mg elemental iron and 400 μg (0.4 mg) folic acid; group 2 received a daily supplement containing 30 mg elemental iron, 400 μg (0.4 mg) folic acid and other vitamins and minerals (UNICEF formulation) and group 3 received a daily supplement containing 400 μg (0.4 mg) folic acid. Outcomes measured were mortality, morbidity, and complications during pregnancy, labour, and delivery.

The types of interventions do not allow for comparisons within the scope of this review.

Cook 1990200 women were randomly assigned to receive 50 mg iron daily given either as Gastric Delivery System (GDS) or conventional ferrous sulphate. Gastrointestinal side effects were evaluated. The participants were non-pregnant women.

Corrigan 1936In this quasi-randomised trial, 200 pregnant women voluntarily attending prenatal care clinic in at Boston City Hospital, Boston, USA between 3 and 7 months gestation were assigned a number according to the order they presented. Participants in an alternate fashion received either oral coated tablets containing 200 mg (0.2 g) of ferrous sulphate 3 times daily (those with odd numbers assigned) or a placebo of similar appearance containing only lactose (those with even number assigned). Women received daily iron or placebo.

The types of interventions do not allow for comparisons within the scope of this review.

Dawson 198742 healthy women with less than 16 wks of pregnancy were randomly assigned to receive either a daily multiple micronutrient supplement containing 65 mg of elemental iron or one daily multiple micronutrient supplement with no iron, calcium, zinc and copper and pantothenic acid. Both groups received different multivitamin/multi mineral supplement formulations.

The types of interventions do not allow for comparisons within the scope of this review.

De Benaze 1989191 non-anaemic pregnant women 12-18 wks of gestation attending an hospital antenatal clinic, Paris, France. Supplementation started at 12-18 wks until delivery. Women were randomly allocated to one of 2 groups: group 1: daily intake of 45 mg of elemental iron (as ferrous betainate hydrochloride) (15 mg elemental iron per tablet) and group 2: placebo tablet.

The types of interventions do not allow for comparisons within the scope of this review.

Dijkhuizen 2004170 pregnant women with less than 20 wk gestation from 13 adjacent villages in a rural area in Bogor District, West Java, Indonesia were randomly assigned to receive daily supplementation with B-carotene (4.5 mg), zinc (30 mg), both, or placebo containing 30 mg elemental iron and 400 μg (0.4 mg) folic acid. Both groups received daily iron and folic acid.

The types of interventions do not allow for comparisons within the scope of this review.

Dommisse 1983146 pregnant women with less than 20 wks of gestation were randomly allocated to receive either a multivitamin tablet twice a day or a multivitamin tablet in conjunction with a standard ferrous sulphate tablet twice a day providing a total of 120 mg of elemental iron daily. Both groups received a multivitamin supplement. No data can be extracted from the published article.

Edgar 1956179 pregnant women with Hb levels below 105 g/L and more than 16 wks of gestation volunteered for this study and were divided into four supplementation groups according to the stage of pregnancy: 16th week, 20th week, 24th week, and non-supplemented controls. 37% of these women were lost to follow-up and were excluded from the final analysis. Data are presented without standard deviation. No data can be extracted from the publication for this review.

Ekstrom 1996176 pregnant women attending Ilula Lutheran Health Center's antenatal service in Iringa region, Tanzania with 21-26 wks of gestational age and Hb > 80 g/L were randomly assigned to receive 120 mg elemental iron (as ferrous sulphate in conventional form) daily or 50 mg elemental iron as gastric delivery system (GDS) daily. Both groups received daily iron supplementation in different preparations.

The types of interventions do not allow for comparisons within the scope of this review.

Eskeland 199790 healthy non-anaemic pregnant women with singleton pregnancy of less than 13 wks, attending an inner city maternity centre in Bergen, Norway. Women were randomly allocated to one of the following: group 1: three tablets containing 1.2 mg heme iron from porcine blood and 9 mg of elemental iron (as ferrous fumarate) (Hemofer®) and one placebo tablet (total 27 mg elemental iron a day); group 2: one tablet containing 27 mg elemental iron (as iron fumarate) with 100 mg vitamin C (Collet®) and three placebo tablets; or group 3: four placebo tablets. Supplementation started at 20th week until 38-40th week.

Women received daily iron supplementation or placebo.

The types of interventions do not allow for comparisons within the scope of this review.

Fenton 1977154 pregnant women with less than 14 wks of gestation, and who had not received or were receiving treatment for a blood disorder were divided into 2 groups according to the day in which they attended the clinic in Cardiff: group 1 received 60 mg of elemental iron (as ferrous sulphate) daily and group 2 received placebo. Hb concentration, mean corpuscular volume (MCV), serum ferritin, serum iron and total iron binding capacity were measured at 10-14 wk and at term.

The types of interventions do not allow for comparisons within the scope of this review.

Fleming 1974146 consecutive pregnant women attending a public antenatal clinic in Western Australia before the 20th week of gestation who had not received iron supplements and were willing to participate were randomly assigned in sequences of 50 to one of the 5 interventions groups: group 1 received placebo; group 2 received 60 mg of elemental iron (as ferrous sulphate); group 3 received 500 μg (0.5 mg) of folic acid; group 4 received 60 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid; and group 5 received 60 mg of elemental iron (as ferrous sulphate) and 5000 μg (5 mg) of folic acid. Supplementation with iron was from 20th week of gestation until delivery. All women had received 50 mg of ascorbic acid daily from the first visit until week 20th. More than 20% of the women were lost to follow-up. No data can be extracted from the publication for this review.

Fleming 1986200 apparently healthy primigravidae Hausa women living in Zaria, Nigeria and planning to deliver in Zaria, with less than 24 wks of gestation, who had not taken any antimalarial treatment or iron supplements in current pregnancy were randomly assigned to one of five groups: group 1: received no active treatment; group 2: received chloroquine 600 mg base once, followed by proguanil 100 mg per day; group 3 received in addition to chloroquine and proguanil, 60 mg elemental iron daily; group 4 received in addition to chloroquine and proguanil, 1000 μg (1 mg) of folic acid daily, and group 5: in addition to chloroquine and proguanil received 60 mg of elemental iron and 1000 μg (1 mg) of folic acid daily. Eighty-nine out of 200 women delivered in the hospital and no other complete clear data can be extracted for the outcomes of interest in this review.

Fletcher 1971643 pregnant women attending antenatal clinic in London were randomly assigned to one of two groups: group 1 received 200 mg of ferrous sulphate daily; group 2 received 200 mg of ferrous sulphate with 5000 μg (5 mg) of folic acid daily. Both groups received iron. No comparisons allowed within the scope of this review.

Foulkes 1982568 apparently healthy pregnant women with less than 20 wks of pregnancy and no prior iron supplementation were allocated alternatively to receive 100 mg of elemental iron and 350 μg (0.35 mg) folic acid daily or no treatment. Ferritin and Hb concentrations were measured at baseline and at 28 and 36 wks of gestation and 2 days postpartum. Mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) were measured at 2 days postpartum. Only means and median are presented. No standard deviation is shown and for ferritin concentrations no ln-transformed data are presented. No data were extractable from the paper and subsequent communication with author.

Freire 1989412 non-black pregnant women with 26 ± 2 wks of gestation, who had not received iron supplements in the previous 6 months, from low SES using the prenatal unit of Quito's public obstetric hospital, Ecuador were randomly assigned to receive two tablets containing 78 mg of elemental iron (as ferrous sulphate) daily or placebo during a period of 2 months. Overall loss to follow-up rate was 41.7%. Hb, PCV, red cell indices, serum ferritin, total iron binding capacity, serum folate, serum vitamin B12 at baseline and after 2 months. Prevalence of iron deficiency was estimated by response to therapy. No prespecified outcomes from this review are presented in the paper. No further data were available.

Gomber 200240 apparently healthy women with singleton pregnancy in their second trimester (between 16-24 wks of gestation), living in urban slums, from low socio-economic status attending Guru Teg Bahadur Hospital, Delhi, India were randomly assigned to receive one tablet containing 100 mg of elemental iron as ferrous sulphate with 500 μg (0.5 mg) folic acid daily or once a week. Weekly intake was supervised. Duration of supplementation was 100 days. Hb and haematocrit concentrations at baseline, at 4 wks, 8 wks and 14 wks of supplementation, serum ferritin concentration, at baseline, at 14 wks of supplementation and at delivery.
No prespecified outcomes in this review are reported. Serum ferritin values is reported as log transformed values but no standard deviations are presented.

Gopalan 2004900 pregnant women of poor socio-economic status females attending government antenatal care clinics were grouped in three groups: group 1 (n = 300) received routine antenatal care; group 2 (n = 300) received 100 mg of elemental iron and 500 μg (0.5 mg) folic acid daily from the 20th week of gestation and group 3 (n = 300) received 100 mg of elemental iron and 500 μg (0.5 mg) folic acid daily from the 20th week of gestation and additionally 900 mg of alpha linolenic acid from the 22nd week of gestation. Outcomes assessed included birth weight, low birth weigh, premature delivery. The study is not reported as randomised and is excluded in the first screening for eligibility.  

Gringras 198240 pregnant women attending antenatal care clinic were given a tablet containing 47 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid daily or a tablet containing 100 mg of elemental iron (as ferrous glycine sulphate) daily. Both groups received iron. No comparisons allowed within the scope of this review.

Groner 198640 pregnant women attending antenatal care at the Adolescent Pregnancy Clinic and Obstetrics Clinics at the John Hopkins and Sinai Hospital in Baltimore, Maryland, USA at or before 16 wks of pregnancy with haematocrit equal or above 31% were randomly assigned to one of two groups: group 1 (n = 16) received 60 mg of elemental iron (as ferrous fumarate) and prenatal vitamins daily; or group 2 (n = 9) received only the prenatal vitamins with no iron. Two women objected to the randomisation and 13 dropped out of the study. Both groups received multiple micronutrients. Supplementation lasted a month. Psychometric tests (arithmetic, total digit span, digit symbol, vocabulary and others) were performed and hematologic status was measured at baseline and after a month. Hematologic outcomes cannot be extracted from the paper. None of the other outcomes were sought.

Guldholt 1991192 pregnant women were consecutively randomised to receive one of two treatments: group 1: received a daily vitamin-mineral tablet containing 15 mg of elemental iron or group 2: received a daily vitamin-mineral tablet containing 100 mg of elemental iron. Both groups received iron in different doses. No comparisons allowed within the scope of this review.

Hampel 197465 untreated and 54 treated pregnant women in West Berlin, Germany were assessed during pregnancy for Hb concentrations, iron an folate levels, total iron binding capacity, and red cell count. No data are presented for outcomes prespecified in the review. Women were of different gestational age. No outcomes can be extracted from the paper.

Han 2011153 anaemic pregnant women, with 80 g/L or more but less than 110 g/L in China were randomly allocated to one of three groups: group 1 (n = 51) received placebo, group 2 (n = 51) was supplemented daily with 60 mg elemental iron (as ferrous sulphate), and group I3 (n = 51) was supplemented daily with 60 mg elemental iron (as NaFeEDTA). The intervention lasted 2 months. There is not an intermittent iron supplementation group. The comparisons in this trial are outside the scope of this review.

Hankin 1963174 primigravidae or secundigravidae at their first visit at the antenatal Clinic of Queen Elizabeth Hospital in Woodville, Australia with ability to write and speak English. Women were divided into a supplemented group receiving a daily dose of 100 mg of elemental iron (as ferrous gluconate) or a control group that was unsupplemented. Supplementation started during 2nd trimester and ending time is unclear

Hartman-Craven 2009In this cross-over study two types of multivitamin supplements were compared: 18 healthy pregnant women 24- 32 weeks' gestation attending a Toronto hospital were recruited and received two different supplements in a random order and followed up over 8 hours. Both preparations contained iron and folic acid (although in different doses). the aim of the study was to see whether absorption was improved with a powdered preparation.

Harvey 200713 healthy non-anaemic pregnant women aged 18-40 years and < 14 wks of gestation with singleton pregnancy recruited through local medical practitioners and the Maternity Department of the Norfolk and Norwich University Hospital, England, United Kingdom.Women were randomly assigned to one of two groups: group 1 received 100 mg elemental iron (as ferrous gluconate) daily after food and group 2 received a placebo. Supplementation started at 16th week of gestation until delivery.

Hawkins 1987No report available of the study results.

Hemminki 19912994 pregnant women less than 16 wks' gestation attending 15 communal maternity centres and 12 centres in five neighbouring communities in Tampere, Finland. Women were randomly assigned to one of two groups: group 1 (routine) were recommended to take 100 mg elemental iron alone (iron compounds and dosage varied as per midwife recommendation) daily after the 16th week gestation; or group 2 (selective) who received no iron supplements unless required.

Hermsdorf 1986120 unselected pregnant women were given 114 mg of elemental iron daily from week 15 until delivery, or not treatment. Only an abstract with insufficient data available.

Hoa 2005202 apparently healthy pregnant women 20-32 years of age attending health clinics from 12 communes in Dong HungDistrict, Thai Binh Province, Vietnam with 14-18 wks of gestation who agreed to participate in the study were selected to participate. Women were assigned through block randomly assigned to one of 4 interventions: group 1 (n = 44) received 400 mL fortified milk with iron (ferrous fumarate), vitamin C and folic acid daily; group 2 (n = 41) received 400 mL of milk fortified with vitamin C and folic acid but no iron daily; group 3 (n = 40) received one tablet containing 60 mg of elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid daily and group 4 (n = 43) received one placebo tablet daily. This study looked at daily supplementation regimens.

Holly 1955207 pregnant women less than 26 wks of gestation and Hb > 100 g/L attending antenatal care clinic in Nebraska, USA. Women were randomly assigned to one of 3 groups: group 1 received 1 g of an iron salt daily; group 2 received 0.8-1.2 g of ferrous sulphate and 60-90 mg of cobalt chloride daily, and group 3 received no treatment. Supplementation started at various times before 26th week of gestation until delivery.

Hood 196075 pregnant women 32-34 wks of gestation attending a hospital maternity clinic in Oklahoma, USA. Women were randomly divided into three groups: group 1: no treatment; group 2 : 220 mg elemental iron (as ferrous sulphate) daily; and group 3: 55 mg elemental iron (as sustained release ferrous sulphate) daily. Supplementation started at 32-34 week of gestation until delivery

Horgan 196642 apparently healthy pregnant women attending two antenatal care clinics in London, England were assigned to one of three interventions: group 1 received 200 mg ferrous sulphate with 5000 μg (5 mg) of folic acid three times a day; group 2 received 350 mg of ferrous aminoate with 50 μg (0.05 mg) folic acid three times a day; and group 3 received 200 mg of ferrous sulphate with 500 μg (0.5 mg) folic acid once a day. Intervention period was 3 wks. All groups received daily iron and folic acid. No comparisons allowed within the scope of this review.

Hosokawa 198984 anaemic women seeking antenatal care in the Department of Obstetrics and Gynaecology of the Fukui School of Medicine Hospital, Japan were randomly assigned to receive 100 mg of elemental iron (as ferrous sulphate) daily after the evening meal, or the same dose + vitamin C for 4 wks. Both groups received daily iron. No comparisons allowed within the scope of this review.

Iyengar 1970800 pregnant women with less than 24 wks of gestation and Hb > 85 g/L in India were assigned by rotation to one of four groups: group 1 received placebo tablets; group 2 received 30 mg of elemental iron as ferrous fumarate in a single tablet daily; group 3 received 30 mg of elemental iron (as ferrous fumarate) with 500 μg (0.5 mg) folic acid in a single tablet; and group 4 received in addition to iron and folic acid, 2 μg of vitamin B12 in a single tablet. Loss to follow up was 65%. None of the pre-specified outcomes in the protocol was reported and no data were extractable from the paper.

Kaestel 20052100 pregnant women (22 +/- 7 wk gestation at entry) attending antenatal clinics in Bissau, Guinea-Bissau or who were identified by The Bandim Health project were randomly assigned to receive daily multi micronutrient tablet containing one Recommended Dietary Allowance (RDA) of 15 micronutrients, or daily multi micronutrients containing two times the RDA except for iron that was maintained at one RDA or a conventional prenatal daily iron (60 mg elemental iron) and 400 μg (0.4 mg) folic acid supplement. All groups receive iron and folic acid daily. No comparisons allowed within the scope of this review.

Kann 198836 healthy non-anaemic pregnant women in second or third trimesters of gestation were randomly assigned to receive one of four prenatal commercial multivitamin/multi mineral preparations daily: Stuartnatal 1+1; Stuart Prenatal; Materna; and Natalins Rx. All participants received multiple micronutrients. No comparisons allowed within the scope of this review.

Kerr 1958430 women with 24-25 wks of singleton pregnancy and Hb equal or above 104 g/L attending antenatal clinic in Edinburgh, Scotland, United Kingdom. Women were randomly allocated to one of 4 groups: group 1: 35 mg of elemental iron (as ferrous sulphate) three times a day; group 2: 35 mg of elemental iron (as ferrous gluconate) three times a day; group 3: 35 mg of elemental iron (as ferrous gluconate) with 25 mg of ascorbic acid, three times a day; group 4: placebo. Supplementation started at 24-25th week of gestation until term.

Khambalia 2009In this randomised trial carried out in Bangladesh childless, non-pregnant married women under 40 were randomised to receive food supplements (sprinkles) containing either iron and folic acid or folic acid alone. 272 women were randomised and were followed up for nine months. If women became pregnant they were withdrawn from the study and ALL pregnant women received both iron and folic acid. The study was excluded as it focused on a non-pregnant population.

Kuizon 1979679 pregnant women attending for antenatal care in public health clinics in Manila, Philippines were randomised to four groups. Group 1 received placebo only. Group 2 received 325 mg ferrous sulphate oral tablets (1 or 3 tablets daily). Group 3 100 mg ascorbic acid (1 or 3 tablets) and Group 4 received iron plus ascorbic acid (one or three tablets). Anaemic and non anaemic women were included and received different doses. All supplements were daily.

Kumar 2005220 pregnant women with a singleton pregnancy and Hb between 80-110 g/L at 16-24 wk gestation from New Delhi, India were randomly allocated to receive daily oral iron therapy of 100 mg elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) folic acid or 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4-6 wks. This trial compares the effects of daily oral iron with two injections of high dose parenteral iron. No comparisons allowed within the scope of this review.

Lee 2005154 apparently healthy pregnant women seeking prenatal care in Gwangju, South Korea during first trimester of pregnancy who did not receive other supplements or medications throughout pregnancy and who were willing to participate were recruited. Women were randomly allocated to one of 5 groups: group 1 received 30 mg elemental iron (as ferrous sulphate) and 175 μg (0.17 mg) folic acid daily from first trimester until delivery; group 2 received 60 mg of elemental iron (as ferrous sulphate) with 350 μg (0.35 mg) folic acid from first trimester until delivery; group 3 received 30 mg elemental iron (as ferrous sulphate) and 175 μg (0.17 mg) folic acid from 20th week of gestation until delivery; group 4 received 60 mg elemental iron (as ferrous sulphate) and 350 μg (0.35 mg) folic acid from 20th week of gestation until delivery; or control group with no supplement.

Madan 1999109 apparently healthy pregnant women with 16-24 wks of gestation who had not received iron supplements were randomly assigned to one of three groups: group 1 received 60 mg of elemental iron + 500 μg (0.5 mg) folic acid once daily; group 2 received 120 mg of elemental iron + 500 μg (0.5 mg) folic acid once daily; group 3 received 120 mg of elemental iron twice daily + 500 μg (0.5 mg) folic acid. Duration of supplementation was 12-14 wks. All participants received iron and folic acid daily. No comparisons allowed within the scope of this review.

Makrides 2003430 non-anaemic pregnant women attending antenatal clinics in Adelaide, Australia. Exclusion criteria: diagnosis of thalassaemia, history of drug or alcohol abuse and history of vitamin and mineral preparations containing iron prior to enrolment in study. Women were randomly assigned to receive one tablet containing 20 mg of elemental iron daily between meals from week 20 until delivery or a placebo tablet.

Mbaye 20061035 pregnant women attending mother and child health clinics near the town of Farafenni, Gambia were randomised to receive either folic acid (500-1500 μg/day) together with oral iron (47 mg of ferrous sulphate per tablet) or oral iron alone (60 mg of ferrous sulphate per tablet) daily for 14 days. All women received treatment with three tablets of SP (25 mg of pyrimethamine and 500 mg of sulfadoxine). Both groups received iron daily. No comparisons allowed within the scope of this review.

McKenna 2002102 healthy pregnant women attending antenatal clinics at the Royal Jubilee Maternity Hospital in Belfast, Ireland with a singleton pregnancy and haemoglobin > 104 g/L and known gestational age of less than 20 wks who were non-compliers with routine prescription of 200 mg of ferrous sulphate daily, were randomly assigned to receive 2 sachets of 24 mL each of Spatone® water containing 10 mg of elemental iron or placebo. Participants were instructed to take the two sachets daily half an hour before breakfast diluting it in orange juice. Primary outcomes were compliance and side effects. Duration of intervention was from week 22 to week 28 of gestation.

Meier 2003144 non-iron deficient adolescents 15-18 years old in their first pregnancy and adult women attending prenatal care at Marshfield Clinic, Wisconsin, USA. Women were randomly assigned to receive once daily 60 mg of elemental iron (as ferrous sulphate) 1000 μg (1 mg) folic acid daily or a placebo and 1000 μg (1 mg) folic acid daily.

Menendez 1994550 multi gravidae pregnant women were recruited with less than 34 wks of gestation attending antenatal care clinics in 18 villages near the town of Farafenni, in North Bank Division, Gambia where malaria is endemic with high transmission during 4-5 months a year. Women were allocated randomly by compound of residence to receive 60 mg of elemental iron (as ferrous sulphate) daily and a weekly tablet of 5000 μg (5 mg) of folic acid or placebo daily and a weekly tablet of 5000 μg (5 mg) of folic acid. The women received no antimalarial chemoprophylaxis. Supplementation started at 23-24 wks until delivery.

Menon 1962273 healthy pregnant women with 16-24 wks of gestation and Hb concentrations at or above 105 g/L attending antenatal care clinics were divided in order in which they were registered in three groups: group 1 was given 5 g of ferrous sulphate daily; group 2 received 5000 μg (5 mg) of folic acid daily; and group 3 received 5 g of ferrous sulphate and 5000 μg (5 mg) of folic acid daily. All participants were given 3 multivitamin tablets daily containing vitamin A, vitamin B, C and D. The study was not randomised.

Milman 1991248 women attending Birth Clinic in Copenhagen, Denmark within 9-18 wks of gestation and normal pregnancy. Women were randomly assigned to receive 66 mg of elemental iron (as ferrous fumarate) daily (n = 121) or placebo (n = 127) until delivery. Supplementation started at 8-9th week until delivery

Milman 2005427 healthy Danish pregnant women living in the north eastern part of Copenhagen County, Denmark were randomly allocated to receive iron (as ferrous fumarate) in daily doses of 20 mg (n = 105), 40 mg (n = 108), 60 mg (n = 106), and 80 mg (n = 108) from 18 wks of gestation. Hemoglobin (Hb), serum ferritin, and serum soluble transferrin receptor concentrations were measured at 18 wks (inclusion), 32 wks, and 39 wks of gestation and 8 wks postpartum. All women received iron daily. No comparisons allowed within the scope of this review.

Morgan 1961356 pregnant women attending two different antenatal care clinics at the King Edward Memorial Hospital for Women in Subiaco, Australia received according to the clinic they visited, either no treatment or 100 mg of elemental iron as ferrous gluconate daily. No systematic allocation was used in this open trial.

Morrison 1977105 pregnant women attending the University Unit, Mater Misericordiae Mothers' Hospital, South Brisbane, Australia, with normal height, weight and nutrition for the Australian population and with no previous adverse medical, surgical or obstetrical history were allotted by random selection to one of four types of supplements: group 1 received 50 mg of elemental iron as dried ferrous sulphate daily; group 2 received 80 mg elemental iron as dried ferrous sulphate with 300 μg (0.3 mg) folic acid daily; group 3 received 105 mg elemental iron as ferrous sulphate and group 4 received 105 mg of elemental iron (as ferrous sulphate) with 300 μg (0.3 mg) folic acid. All groups received iron daily. No comparisons allowed within the scope of this review.

Muslimatu 2001143 women 17-35 year swith 16-20 wk gestastional age, parity <6 and haemoglobin 80-140 g/L recruited from nine villages in the Leuwiliang subdistrict, Bogor district, West Java, Indonesia, were randomly assigned to one of two groups: group 1 received weekly supplements containing 120 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid;  group 2 received weekly supplements containing 120 mg elemental iron (as ferrous sulphate); 500 μg (0.5 mg) folic acid  and 4800 retinol equivalents (RE) of vitamin A.  A group of 123 pregnant women from other four villages participating in the ongoing national government daily iron plus folic acid supplementation program, were reported as control although they were not randomly assigned to the daily intervention. This daily supplementation programme consists of providing women with 90-120 mg elemental iron plus folic acid tablets daily throughout pregnancy distributed through medical services.  Only the women in the weekly regimens were randomly assigned.

The type of study and interventions do not allow for comparisons within the scope of this review.

Nguyen 2008167 pregnant women with less than 20 wks of gestation who called either Motherisk General Information line or the Motherisk Nausea and Vomiting of Pregnancy (NVP) Helpline (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were randomly assigned to one of two groups: group 1 were provided, PregVit®  (a small-size, containing 35 mg elemental iron as ferrous fumarate and multivitamins; or group 2 who received Orifer F®  (high iron content, small size) containing 60 mg elemental iron (as ferrous sulphate) and multivitamins. Follow-up interviews documented pill intake and adverse events. Participants from both groups received iron in different amounts and compounds.

Nogueira 200274 low-income pregnant adolescents ranging from 13-18 years of age attending antenatal care at the Evangelina Rosa Maternity Hospital in Teresina, Piaui State, Brazil were distributed into five groups: group 1 received 120 mg elemental iron as ferrous sulphate and 250 ug of folic acid daily; group 2 received 80 mg elemental iron as ferrous sulphate and 250 μg (0.25 mg) folic acid daily; group 3 received 120 mg of elemental iron, with 5 mg of zinc sulphate and 250 μg (0.25 mg) folic acid daily; and group 4 received 80 mg of elemental iron as ferrous sulphate, with 5 mg of zinc sulphate and 250 μg (0.25 mg) folic acid daily. All groups received iron and two groups received zinc in addition to iron and folic acid daily. No comparisons allowed within the scope of this review.

Ogunbode 198480 apparently healthy non-anaemic pregnant women attending University College Hospital and Inalende Maternity Hospital in Ibadan, Nigeria during the first and second trimesters of pregnancy were randomly allocated to one of two groups: group 1 (n = 39) received one tablet Ferrograd Folic 500 Plus® daily, a sustained-released formulation containing ferrous sulphate and folic acid (composition is not available); or group 2 (n = 41) received a capsule containing 200 mg ferrous sulphate and 5000 μg (5 mg) of folic acid daily. All patients were also provided 25 mg weekly of pyrimethamine throughout pregnancy as an anti-malarial agent. Patients who became anaemic during pregnancy were excluded of the study and analysis. Outcomes measured included reticulocyte count, haematocrit, anaemia, side effects. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.

Ogunbode 1992315 apparently healthy pregnant women attending four prenatal care clinics in 4 geographical areas of Nigeria with mild to moderate anaemia (as defined by haematocrit between 26%-34%) and 18-28 wks of gestation, single pregnancies, no complications and who consented to participate in the study were randomly allocated to one of two groups: group 1 (n = 159) received one daily capsule of a multiple micronutrient supplement Chemiron® containing 300 mg of ferrous fumarate, 5000 ug (5 mg) folic acid, 10 μg vitamin B12, 25 mg of vitamin C, 0.3 mg magnesium sulphate and 0.3 mg of zinc sulphate; group 2 (n = 156) received a capsule containing 200 mg ferrous sulphate and 5000 μg (5 mg) of folic acid. All patients were also provided 600 mg of cloroquine to be taken under supervision and 25 mg weekly of pyrimethamine throughout pregnancy. Patients who became anaemic during pregnancy were excluded of the study and analysis. Outcomes measured included blood Hb, anaemia, haematocrit, serum ferritin levels, side effects. A second published study followed these same women and their infants. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.

Ortega-Soler 199841 healthy pregnant women, attending prenatal care clinics at Hospital Diego Paroissien in La Matanza, Province of Buenos Aires, Argentina with serum ferritin below 50 mg/mL. Women were assigned to one of two groups: group 1 received 100 mg of elemental iron daily (as ferric maltosate), and group 2 received no treatment. Supplementation started at 21 +/- 7 wks of gestation until birth. Maternal outcomes measured included: Hb, erythrocyte protoporphyrin, serum ferritin at baseline and term, dietary intake. The iron intake was unsupervised and compliance was not reported. The trial is not randomised nor quasi randomised so it does not fill the inclusion criteria for this review.

Osrin 20051200 healthy pregnant women with a singleton pregnancy and less than 20 wk gestation attending an antenatal clinic at Janakpur zonal hospital in Nepal, were randomly assigned to receive routine 60 mg elemental iron and 400 μg (0.4 mg) folic acid supplements daily or a multiple micronutrient supplement containing 15 vitamins and minerals including 30 mg elemental iron and 400 μg (0.4 mg) folic acid daily. Both groups received iron and folic acid daily. No comparisons allowed within the scope of this review.

Paintin 1966180 primigravidae women with less than 20 wk gestation and Hb > 100 g/L attending antenatal clinic in Aberdeen Maternity Hospital, Scotland, United Kingdom.Women were randomly assigned to one of three groups: group 1 received 3 tablets containing 4 mg elemental iron each (total 12 mg daily); group 2 received 3 tablets containing 35 mg elemental iron (total 105 mg elemental iron daily) and group 3 received placebo. Intervention was from week 20 to week 36 of gestation.

Payne 1968200 pregnant women attending antenatal clinics in Glasgow, Scotland with less than 20 wk gestation, whose antenatal care was undertaken wholly by the hospital antenatal clinic and who subsequently had a normal delivery, were randomly allocated to receive 200 mg of ferrous sulphate daily or 200 mg of ferrous sulphate with 1700 μg (1.7 mg) folic acid daily throughout pregnancy. Both groups received daily iron. No comparisons allowed within the scope of this review.

Pena-Rosas 2003116 pregnant women of 10-30 wk of gestational age attended antenatal care clinics in Trujillo, Venezuela were randomly allocated to receive a 120 mg oral dose of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid weekly (n = 52) or 60 mg elemental iron and 250 μg (0.25 mg) folic acid and a placebo twice weekly (n = 44). Hb, hematocrit, serum ferritin and transferrin saturation were estimated at baseline and at 36-39 wk of gestation. All groups received iron and folic acid in two intermittent regimens with no control group. No comparisons allowed within the scope of this review.

Picha 1975In a randomised double-blind study the new effervescent iron tablet Loesferron® was tested in 57 postpartum women. The participants were not pregnant women.

Preziosi 1997197 healthy pregnant women 17-40 years of age, with 28 +/- 3 wks of gestation attending antenatal care clinic in a Mother-Child Health Center in Niamey, Niger. Women were randomly assigned to one of two groups: group 1 received 100 mg of elemental iron (as ferrous betainate) daily; group 2 received placebo. Supplementation was from 28 +/- 3 wks of gestation until delivery.

Pritchard 1958172 pregnant women in the second trimester of pregnancy attending a hospital antenatal care clinic in Dallas, Texas, USA. Women were randomly assigned to one of three interventions: group 1 received 1000 mg of iron intramuscularly as iron-dextran; group 2 received 112 mg of elemental iron (as ferrous gluconate) daily in 3 tablets; group 3 received placebo tablets. Supplementation started during 2nd trimester until delivery.

Puolakka 198032 healthy non-anaemic pregnant women attending antenatal care at maternity centres of Oulu University Central Hospital, Finland with uncomplicated pregnancy of less than 16 wks, and no earlier haematological problems.Women were randomly assigned to one of two groups: group 1 received 200 mg of elemental iron (as ferrous sulphate) daily; group 2 received no treatment. Supplementation started at 16th week of gestation until one month postpartum.

Ramakrishnan 2003873 pregnant women living near Cuernavaca, Morelos, Mexico with less than 13 wks of gestation who did not use micronutrient supplements were randomly assigned to receive a daily multiple micronutrient supplement or a daily iron-only supplement. Both supplements contained 60 mg of elemental iron (as ferrous sulphate). Supplement intake was supervised by trained workers from registration until delivery by home visits 6 days a week. No comparison allowed within the scope of this review.

Rayado 1997394 healthy non-anaemic adult pregnant women with 24-32 wks of gestation and singleton pregnancy from Fuentalabra, Spain were randomly assigned to one of two groups: group 1 received 40 mg of elemental iron (as iron mannitol albumin) daily; and group 2 received 40 mg elemental iron (as iron protein succinylate) daily. Both groups received iron daily. No comparisons allowed within the scope of this review.

Reddaiah 1989110 pregnant women attending the antenatal clinic at Comprehensive Rura Health Services Project Hospital, Ballabgarh, India, with 16-24 wks of gestation were randomly assigned to one of three groups: group 1 received 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid daily; group 2 received 120 mg elemental iron (as ferrous sulphate) with 500 μg (0.5 mg) of folic acid daily; and group 3 received 240 mg elemental iron (as ferrous sulphate) and 0.5 mg of folic acid daily. All groups received iron daily. No comparisons allowed within the scope of this review.

Romslo 198352 healthy pregnant women attending outpatient Women's clinic at Haukeland Hospital, Bergen, Norway. Women were randomly assigned to one of two groups: group 1 received 200 mg of elemental iron (as ferrous sulphate) daily; group 2 received placebo. Supplementation started at 10 wks of gestation.

Roztocil 199484 non-anaemic pregnant women at Mazarik University Brno in Czech Republic were treated from 20-24 wks with one capsule of Actiferrin Compositum®, and from 36 wks to delivery with 2 capsules. The group was compared with 57 non-anaemic pregnant women who received no supplements. The supplement contained 34.5 mg of elemental iron (as ferrous sulphate), 500 μg (0.5 mg) of folic acid, and 0.3 mg of cyanocobalamin. No comparisons allowed within the scope of this review.

Rybo 1971117 pregnant women between 20-29 wks of gestation were alternatively assigned during three consecutive two wks periods to receive daily tablets containing 200 mg of elemental iron (as ferrous sulphate), 200 mg of elemental iron (as a sustained released iron) or placebo. After each 2-wks treatment period women were questioned about possible side effects. No side effects are reported by group assigned. No comparisons are allowed within the scope of this review.

Sachdeva 1993In this study carried out in rural India 66 pregnant women from low and middle income groups in an area where Government practice recommends the provision of iron and folic acid for the last 100 days of pregnancy. In addition to iron and folic acid supplements women in the experimental group received a calcium supplement, individual and group counselling and a booklet about nutrition in pregnancy. "Nutrient supplements in the form of Folifer (iron and folic acid) and Calcium Sandoz tablets were supplied regularly to the subjects of E group from the fifth month of pregnancy till delivery. On the other hand, some of the subjects of the C group who visited the subsidiary health centre.. consumed only Folifer tablets as these are supplied free of cost." This study was not included as all women received iron and folic acid supplements (the dose and regimen were not clear); the focus of the study was on nutritional education and extra contacts with women in the experimental group. It was not clear that allocation to groups was random, "Sixty six pregnant women were equally divided into two groups".

Sandstad 2003233 pregnant women attending their second antenatal care visit at the University Health Services of Oslo, Norway with serum ferritin concentration < 60 ug/L were randomised to two different iron preparations, group 1 received one tablet containing 60 mg of elemental iron (as ferrous sulphate) daily; group 2 received three tablets each containing 1.2 mg of heme iron from porcine blood plus 8 mg of elemental iron (as ferrous fumarate) per tablet (total 3.6 heme iron and 24 mg elemental iron) daily. A third group (n = 93) of pregnant women who had been given advice to take or not the iron supplements according to the centre recommendations were enrolled in the trial at 6 wks postpartum and served as control. The study groups were not randomised to the interventions and no comparisons can be made within the scope of this review.

Seck 2008221 apparently healthy pregnant women, had not used iron supplements prior to enrolment, who were 12 to 16 wks were recruited from six health centres in Dakar, Senegal during their first prenatal visit, and randomly assigned to receive either a prescription to purchase iron/folic acid tablets to be taken daily, according to official policy, or to receive free tablets. Compliance was assessed 20 wks after enrolment through interviews and pill count. the study compares prescribed iron daily to free tablets to be taken daily. No comparisons allowed within the scope of this review.

Shatrugna 1999115 healthy pregnant women with 20-28 wks of gestation attending the antenatal clinic of the National Institute of Nutrition, Government Maternity Hospital, India were randomly assigned to one of 11 different formulations and doses of iron and then undergo iron tolerance tests. They received ferrous sulphate tablets containing 60 mg, 12 mg, and 180 mg of elemental iron; formulations containing 60 mg of elemental iron as pure ferrous sulphate salt, ferrous fumarate tablets, ferrous fumarate syrup, excipients added to pure ferrous sulphate salts; powdered ferrous sulphate tablets, iron tablets distributed by the National Nutritional Anaemia Prophylaxis Programme and pure ferrous salt in gelatin capsules.

Siega-Riz 2001429 non anaemic iron replete women with less than 20 wks of gestation attending the prenatal clinic at the Wake County Human services in Raleigh, North Carolina, USA. Women were randomly assigned to one of two groups: group 1 received multivitamin/mineral supplements containing 30 mg of iron (as ferrous sulphate) daily or group 2 received multivitamin/mineral supplements containing 0 mg of iron (no iron) until 29 wks of gestation. Supplementation started on average at 12 wks. Folic acid supplements were prescribed for all women who had received the positive pregnancy test until the first prenatal visit.

Simmons 1993376 pregnant women with ages between 16-35 y, with mild anaemia (Hb concentrations between 80-110 g/L) attending eight maternal and child health centres in Kingston, St. Andrews and Spanish Town, Jamaica, with gestational age between 14-22 wks were randomly assigned to one of three groups: group 1 received one placebo tablet daily; group 2 received 100 mg of elemental iron (as ferrous sulphate) daily; group 3 received 50 mg elemental iron (as gastric delivery system capsule) daily. All women received 400 μg (0.4 mg) folic acid. Outcomes measure included Hb, haematocrit, MCV, white cell count, serum iron, total iron binding capacity, serum ferritin, serum transferrin receptor, at baseline, at 6 wks and at 12 wks after start of supplementation as well as side effects. No prespecified outcomes are presented in the paper as gestational ages differed in the participants.

Sinha 201150 pregnant women between 16-20 wk of gestation with haemoglobin equal or greater than 100 g/L in Allahabad, in the north Indian state of Uttar Pradesh, India were randomly assigned to one of two groups: group 1 (n = 22): women received two doses of 400 mg iron sucrose infusion, one at 16-20 wk gestation and a second infusion at 28-32 wks gestation; group 2 (n = 28): women received 100 mg oral ferrous ascorbate daily starting at 16-20 wk gestation.

The type of intervention is outside the scope of this review.

Sjostedt 1977300 pregnant women attending the Maternity Welfare Center, in Oulu, Finland before the 5th month of pregnancy were randomly assigned to one of three interventions: group 1 received 100 mg of elemental iron daily as sustained-release tablets daily; group 2 received 200 mg of elemental iron daily (as sustained-release tablets) and group 3 received 200 mg of elemental iron daily (as rapidly disintegrating ferrous sulphate tablets). All groups received daily iron in different doses and formulations.

Sood 1979151 healthy pregnant women with Hb > 50 g/L who had not received iron supplements during the last 6 months from Delhi and Vellore, India were divided in one of three strata according to Hb concentration (50-79 g/L; 80-109 g/L;110 g/L and above) and within each strata were allocated randomly to one of five interventions: group 1 received 120 mg of elemental iron (as ferrous sulphate) 6 days a week; group 2 received 100 mg of elemental iron (as iron dextran complex) intramuscular twice per week; group 3 received iron as group 1 + pteroylmonoglutamic acid 5 mg/d 6 days a week + cyanocobalamin 100 μg intramuscular once per 14 d; group 4 received 100 mg of elemental iron intramuscular + pteroylmonoglutamic acid + cyanocobalamin 100 ug intramuscular; and group 5 received iron dextran complex intramuscular in a single total dose infusion + 5 mg/d pteroylmonoglutamic acid + 100 μg intramuscular cyanocobalamin once per 14 days. All groups received iron at different doses and routes. No comparisons allowed within the scope of this review.

Steer 1992Trial abandoned. No data available.

Stone 1975248 healthy pregnant women attending hospital antenatal clinic in London, England, were allocated randomly to receive a slow-release dose of 105 mg of elemental iron (as ferrous sulphate) and 350 μg (0.35 mg) folic acid daily or 80 mg of elemental iron (as ferrous fumarate) and 400 μg (0.4 mg) folic acid daily in a standard preparation. Both groups received daily iron and folic acid in different doses and preparations. No comparisons allowed within the scope of this review.

Suharno 1993251 pregnant women aged 17-35 years, parity 0-4 and Hb concentrations between 80 and 109 g/L were randomly allocated to one of four groups: group 1 received 2.4 mg of retinol and one placebo iron tablet daily; group 2 received 60 mg of elemental iron (as ferrous sulphate) and a placebo vitamin A tablet daily; group 3 received 2.4 mg of retinol and 60 mg of elemental iron (as ferrous sulphate); and group 4 received two placebos for 8 wks. Outcomes measured include: Hb, haematocrit, serum ferritin, serum iron, total iron binding capacity, serum retinol, transferrin saturation, at baseline and after 8 wks of supplementation. None of the pre-specified outcomes in this review can be extracted from this paper.

Svanberg 197560 healthy primiparous women attending antenatal care clinic in Goteborg, Sweden and less than 14 wks of gestation and with Hb concentrations above 120 g/L who had not received iron supplements in the previous 6 months. Women whose Hb concentration fell below 100 g/L during the study period were excluded and received immediate therapy. Women were randomly allocated to receive 200 mg of elemental iron (as a sustained release preparation of ferrous sulphate) daily or placebo from 12 wks of gestation until 9 wks postdelivery.

Swain 2011100 women with uncomplicated pregnancy were assigned to received either injectable iron sucrose (400 mg diluted in 400 ml of normal saline) over 2-3 hours or to receive oral dose of 100 mg elemental iron daily. The interventions in this trial are outside of the scope of this review.

Tampakoudis 199682 pregnant women with haemoglobin concentrations 140 g/L or above attending clinic in Thessaloniki, Greece were randomised to receive 80 mg iron protein succinylate daily or a placebo. Serial Hb, haematocrit and serum erythropoietin were measured from maternal blood and cord blood on delivery; serum ferritin measured in frequent intervals. Abstract only available. Insufficient information to assess characteristics of the trial.

Tan 1995285 healthy middle-class pregnant women with Hb concentration above 100 g/L attending antenatal clinic at the University Hospital at Kuala Lumpur, Malaysia were assigned to receive daily iron supplements or no treatment. Abstract only available. No additional information was available, including doses, regimens and other characteristics of the trial.

Tange 1993128 anaemic and non-anaemic pregnant females aged 10-19 years old, with an average gestation of 16 wks, were grouped for three levels of iron supplementation: group 1 (n = 42 non-anaemic participants) received placebo (no iron); group 2 (n = 41 anaemic and non-anaemic participants) received 22 mg of elemental iron daily and group 3 (n = 45 anaemic and non-anaemic participants) received 55 mg elemental iron daily. Women were supplemented from 16 wks until delivery. Outcomes assessed included Hb, haematocrit, red cell count, mean corpuscular volume, serum iron, serum transferring and serum, ferritin measured every four wks. The study is not reported as randomised and is excluded in the first screening for eligibility.  

Taylor 198248 healthy pregnant women with no adverse medical or obstetric history attending antenatal care clinic in Newcastle, England, United Kingdom before 12 wks of gestation.Women were randomly allocated to one of two groups: group 1 receive 65 mg elemental iron (as 325 mg of ferrous sulphate) and 350 μg (0.35 mg) folic acid daily from 12 wks until delivery and group 2 received no supplements.

Thane-Toe 1982135 healthy pregnant women between 22-28 wks of gestation attending antenatal clinic in Burma, were randomly assigned to receive a daily dose of 60 mg, 120 mg or 240 mg of elemental iron (as ferrous sulphate). A control group was composed by 47 apparently healthy adults (17 males and 30 single women). Control groups are not appropriate. No comparisons allowed within the scope of this review.

Tholin 199383 healthy nulliparous non vegetarian, non-anaemic pregnant women with serum ferritin concentrations above 10 ug/L were randomly assigned to one of three groups: group 1 received 100 mg of elemental iron (as ferrous sulphate) daily; group 2 received placebo, and group 3 received dietary advice only. Blood Hb, serum ferritin and blood manganese were determined at baseline before 15th week of gestation, between 25-28 wks, and between 35-40 wks of gestation. Median and ranges are presented. No outcomes were extractable from this report for this review.

Thomsen 199352 healthy non-anaemic nulliparous women with normal singleton pregnancy and serum ferritin levels above 15 mg/L at 16th week in Herlev, Denmark were randomly assigned to receive either a daily tablet containing 18 mg elemental iron and also a tablet containing 300 μg (0.3 mg) of folic acid daily or a daily tablet containing 100 mg of elemental iron from 16 wks until delivery and 300 μg (0.3 mg) of folic acid daily. All women received daily iron in different doses. This comparison is not within the scope of this review.

Tura 1989254 non-anaemic non-iron deficient healthy pregnant women from multiple centres in Italy. Women were randomly assigned to receive 40 mg of elemental iron containing 250 g of ferritin in a microgranulated gastric resistant capsule daily or no treatment from 12-16 wks of gestation until the end of puerperium.

Van Eijk 197830 pregnant women with uncomplicated pregnancies attending antenatal care clinic at the University Hospital Obstetric Unit in Rotterdam, Netherlands. Women received 100 mg of elemental iron (as ferrous sulphate) daily or no treatment from the third month of gestation until delivery. Follow-up was until 12 wks after delivery.

Vogel 1963191 consecutive pregnant when attending antenatal care clinics and at 32 wks of gestation were divided in two groups by alternate allocation by clinic: group 1 received 140 mg of elemental iron daily (as ferrous gluconate) in four tablets; group 2 received 150 mg elemental iron daily (as ferrous glutamate) in 3 tablets. All women received iron in different dose and number of tablets. No comparisons allowed within the scope of this review.

Wali 200260 iron deficiency anaemic pregnant women with the gestational age of 12-34 wks were randomly assigned to one of 3 groups: group 1 (n = 15) received intravenous 500 mg of iron sucrose for storage; group 2 (n = 20) received intravenous iron sucrose according to deficit calculated as per formula with 200 mg of iron was given for storage and group 3 received intra muscular iron Sorbitol in the dose used as practice. All groups received iron intravenous or intramuscular.

Wallenburg 198344 non-anaemic women with singleton pregnancy attending the University Hospital Obstetrical Clinic of the Erasmus University in Rotterdam who had not received iron supplementation during their first visit. Women were randomly assigned to one of two groups:group 1: received 105 mg of elemental iron (as ferrous sulphate in a sustained release preparation ) daily and group 2: received no iron supplement. Supplementation started at 14-16th week of gestation until delivery.

Willoughby 1966350 consecutive pregnant women attending antenatal care clinic were allocated to one of five groups: group 1 received no hematinic supplements; group 2 received 105 mg of elemental iron daily (as iron chelate aminoates); group 3 received 105 mg of elemental iron daily with 100 μg (0.1 mg) folic acid; group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) folic acid; and group 5 received 105 mg of elemental iron daily th 450 μg (0.45 mg) folic acid. All women received a multivitamin preparation (Vivatel) free of folic acid.

Willoughby 19673599 pregnant women with Hb above 100 g/L at their antenatal care clinic visit at Queen's Mother's Hospital in Glasgow, Scotland, United Kingdom. Women were randomly allocated to one of five interventions: group 1 received no prophylactic supplements; group 2 received 105 mg of elemental iron daily (as chelated iron aminoates); group 3 received 105 mg of elemental iron with 100 μg (0.1 mg) folic acid; group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) folic acid; and group 5 received 105 mg elemental iron daily with 450 μg (0.45 mg) folic acid. Starting and ending time of supplementation variable.

Willoughby 196868 pregnant women attending antenatal care clinic in Queen Mother's Hospital in Scotland, were randomly allocated to receive 195 mg of elemental iron alone daily or 195 mg of elemental iron in conjunction with 300 μg (0.3 mg) folic acid daily.

Wills 1947500 pregnant women attending antenatal care clinic at the Royal Free Hospital in London, England, United Kingdom during wartime, with ages between 18-43 years. Women with severe anaemic or rheumatoid arthritis were excluded. Women were alternatively allocated to receive 580 mg of elemental iron (as ferrous gluconate) daily or placebo from their first visit. Supplementation starting variable and ending time unclear.

Wu 1998369 pregnant women attending antenatal care at Beijing Hospital, China were divided into two groups according to their initial Hb concentrations. Women with Hb 110 g/L or above were randomly assigned to one of two groups: group 1 (n = 96) received one daily tablet of maternal supplement containing 60 mg of elemental iron in addition to other micronutrients including calcium and magnesium ; group 2 (n = 95) served as control and received no supplements. Another group of women with Hb < 110 g/L (treatment group) were randomly assigned to one of three groups: group 1 received 1 tablet of maternal supplement daily; group 2 received 0.9 g of ferrous sulphate daily; and group 3 received one tablet of Ferroids, a sustained released preparation daily. In the preventive group, women entered the study from 20-24 gestational wks. In the treatment groups, women less than 36 gestational wks were accepted. No comparisons allowed due to the addition of other micronutrients in the treatment.

Zeng 2008In this cluster randomised trial 5828 pregnant women in rural north west China were randomised to one of 3 groups: group 1 received daily supplements of 400 μg (0.4 mg) folic acid alone; group 2 received 60 mg elemental iron and 400 μg (0.4 mg) folic acid; and group 3 received a multi-micronutrient (containing both iron and folic acid).

Zhou 2009180 anaemic women (Hb < 110 g/L) attending antenatal care at the Children, Youth and Women's Health Service, Adelaide, Australia with 24-32 wks of gestation and a singleton pregnancy. Women were excluded if they were taking iron or vitamin and mineral supplements, had presumptive diagnosis of non iron deficiency related anaemia, history of thalassaemia, drug or alcohol abuse and/or diabetes requiring insulin or a known fetal abnormality. Women were randomly assigned to receive a daily dose of 20, 40 or 80 mg of elemental iron (as ferrous sulphate) for 8 wks or until birth. The primary outcomes measured were Hb levels, anaemia at the end of the intervention and gastrointestinal side effects during treatment. All women received iron at different doses. No comparisons allowed within the scope of this review.

Ziaei 2007750 non-anaemic (with Hb higher or equal to 132 g/L) pregnant women in early stage of second trimester attending prenatal care in Tehran, Iran. Women were randomly assigned to one of two groups: group 1 received 50 mg of elemental iron (as ferrous sulphate) with 1000 μg (1 mg) folic acid daily and group 2 received placebo and 1000 μg (1 mg) of folic acid daily.

Ziaei 2008244 pregnant women attending prenatal care in Tehran, Iran, 13-18 wks of gestation and non-anaemic (Hb 132 g/L or higher) and normal serum ferritin (15 ug/L or higher). Women were randomly assigned to one of two groups: group 1 received 50 mg of elemental iron (as ferrous sulphate) daily and group 2 received placebo from 20th week of gestation until delivery. All women received 50 mg elemental iron (as ferrous sulphate) after delivery for 6 wks.

Zittoun 1983203 pregnant women attending antenatal clinic in Paris, France, with 28 +/- 2 wks of gestation were studied. Women with Hb below 110 g/L (n = 48) were provided 105 mg of elemental iron and 500 mg of ascorbic acid daily. Women with Hb concentration above 110 g/L were randomly assigned to receive 105 mg of elemental iron and 500 mg of ascorbic acid daily until delivery or placebo. Iron was provided in conjunction with vitamin C. No comparisons allowed within the scope of this review.

Zutshi 2004200 apparently pregnant women with 24-26 wks of gestation, with singleton pregnancy with moderate anaemia (Hb > 80 g/L and < 110 g/L) were randomly assigned to receive injectable iron-sorbitol-citrate in three intramuscular doses of 150 mg each at 4 wks intervals or 100 mg of elemental iron daily. Haemoglobin concentrations were measured at baseline, every 4 wks and at delivery. The study compares two routes of iron administration. Both groups receive iron. No comparisons allowed within the scope of this review.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Alizadeh 2010

MethodsRCT, 2-arm trial.

Participants281 non anaemic pregnant women aged 18-35 with singleton pregnancy and normal body mass index in Teheran, Iran.

Exclusion criteria: haemoglobin less than 105 g/L, preterm delivery before week 34, any condition that needs medical or surgical intervention.

InterventionsParticipants were randomly assigned to 1 of 2 groups: .group 1 received 1 tablet containing 60 mg elemental iron (as ferrous sulphate) 1 tablet per day, since 20th gestational week till the end of pregnancy; group 2 received 1 tablet containing 60 mg elemental iron (as ferrous sulphate) twice a week on Mondays and Thursdays, since 20th gestational week till the end of pregnancy.

OutcomesHaemoglobin and ferritin in cord blood, birthweight.and anaemia indices and side effects in mother during pregnancy.

NotesAbstract with limited information. Date of first enrolment: 07 December 2008. Recruitment complete.

Contact information:

Dr Azita Goshtasbi  

University Tarbiat Modares Tehran

Nasr bridge University campus Tehran 14117-13116 Tehran, Islamic Republic of Iran

Phone: +98 2182883589

Email: goshtasebi@modares.ac.ir

Viteri 2010

MethodsCross-over design with 2 interventions.

Participants100 apparently healthy pregnant women with no disease or addictions (including tobacco), no nutritional supplements taken before gestational week 20, single-fetus pregnancy, and blood Hb > 115 g/L (equivalent to 105 g/L at sea level) at gestational week 20 were recruited during their first visit for prenatal care at the Instituto Nacional de Perinatología Isidro Espinosa de los Reyes (INPerIER) in Mexico City, Mexico located at an altitude of 2240 m above sea level.  

InterventionsParticipants were randomly assigned, without replacement, to 1 of 2 groups: group 1 received daily supplementation from gestational week 20 to week 28 with a tablet containing 60 mg elemental iron, 200 μg (0.2 mg) of folic acid, and 1 mg of vitamin B12, and then, weekly supplementation with 2 tablets (providing 120 mg of elemental iron, 400 μg (0.4 mg) of folic acid, and 2 mg of vitamin B12) from week 28 to week 36; group 2 received the supplementation scheme inverted, that is the weekly regimen from gestational week 20 to week 28, followed by daily supplementation up to week 36.

OutcomesHb values at different gestational ages, serum ferritin, serum iron concentrations, serum malon-di-aldehyde (MDA) equivalent values (µmoles/L) as Thio-Barbituric-Acid-Reacting-Substances (TBARS), abortion, birthweight, gestational age at birth and maternal iron status.

Notes

 
Characteristics of ongoing studies [ordered by study ID]
Agrawal 2012

Trial name or titleImpact of two oral iron supplementation regimens (intermittently and continuously/daily) for prevention of anaemia in pregnancy in women with normal haemoglobin levels.

MethodsRandomised controlled trial. Stratified block randomisation with sequentially numbered, sealed, opaque envelopes.

Participants150 apparently healthy pregnant women 19-40 years of age with normal haemoglobin levels between 13-16 weeks gestation attending antenatal care clinic, Department of Obstetrics and Gynecology, Kasturba Medical College, Maniopal, India. Exclusion criteria: suspected acute infection (upper respiratory tract and urinary tract infections, gastroenteritis), pre-existing chronic illness, like chronic renal disease, hepatic cirrhosis, viral hepatitis, Inflammatory bowel disease, recent blood transfusion, beta-thalassaemia and other haemoglobinopathies.

InterventionsParticipants will be randomised to one of two groups: group 1 will receive an oral intake with water of a capsule of Autrin® daily containing 98.6 mg elemental iron (as ferrous fumarate); group 2 will receive oral intake with water of the same capsule Autrin® only during 4 days a week (Monday-Thursday). Oral iron in both the groups will be continued throughout pregnancy.

OutcomesHaemoglobin (more than 105 g/L), serum ferritin at 28 and 38 weeks gestation, side effects of oral iron: nausea, vomiting, constipation, heartburn, diarrhoea, metallic taste, pre-eclampsia, IUGR in 3rd trimester, preterm labor, birthweight, placenta weight, compliance.

Starting dateDate of first enrolment: 01/01/2010. recruitment ongoing.

Contact informationNimisha Agrawal

Junior Resident

Kasturba Medical College, Manipal, Department of Obstetrics and Gynecology,

Kasturba Hospital, ManipalL-576104, Udupi  District, Karnataka, India 576104

Phone 0820-2932600

 Email:  nimisha_4u@yahoo.co.in

Notes

Biggs 2010

Trial name or titleA randomised controlled trial to compare the impact on birthweight of daily iron-folic acid, twice weekly iron-folic acid and twice weekly multiple micronutrient supplementation for pregnant women in Ha Nam province, Vietnam.

MethodsRandomised controlled trial.

ParticipantsHealthy pregnant women 16 weeks gestation or less.
Exclusion criteria: complicated pregnancies (e.g. twins, diabetes, other medical conditions), or Hb 80 g/L or lower.

InterventionsThe trial has three arms. Arms 1. and 2. will each receive a different intervention as follows: 1. Micronutrient supplement (60 mg elemental iron, 1500 μg (1.5 mg) folic acid taken orally twice weekly for the duration of pregnancy and three months postpartum. and 2. Micronutrient supplement (multiple micronutrients - modified 2xUNIMAPP) taken orally twice weekly for the duration of pregnancy and three months postpartum.

OutcomesPrimary: birthweight.

Secondary: Infant cognitive development, infant Hb, infant height, maternal ferritin, maternal Hb.

Starting date28/09/2010.

Contact informationDr. Beverley-Ann Biggs

Department of Medicine Royal Melbourne Hospital Parkville, Victoria, 3050, Australia

E-mail: babiggs@unimelbi.edu.au

NotesSponsors: National Health and Medical Research Council (NHMRC) and Research and Training Center for Community Development (RTCCD).

Gies 2010

Trial name or titleMalaria risk prior to and during early pregnancy in nulliparous women receiving long-term weekly iron and folic acid supplementation (WIFS): a non-inferiority randomised controlled trial.

MethodsRandomised double blind trial.

Participants1800 female participants 15-25 years of age at enrolment, who have never given birth, are resident within the 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).

InterventionsNon pregnant women will receive: group 1: 60 mg elemental iron and 2800 μg (2.8 mg) folic acid weekly for 18 months; group 2: placebo and 2800 μg (2.8 mg) folic acid weekly for 18 months.

Women who become pregnant will change to 60 mg elemental iron and 400 μg (0.4 mg) folic acid daily after the first antenatal care visit at 13-16 weeks of gestation.

OutcomesPrimary:

Prevalence of peripheral parasitaemia at first antenatal clinic visit (13-16 weeks gestation).

Secondary:

In the non-pregnant cohort: acceptability of weekly supplementation, adherence to supplementation, incidence of clinical malaria, gastrointestinal adverse events, prevalence of anaemia after at least 18 months supplementation, prevalence of iron deficiency after at least 18 months supplementation, prevalence of peripheral parasitaemia during the first rainy season after at least six months of supplementation.

In the pregnant cohort: incidence of adverse pregnancy outcomes, incidence of clinical malaria during the first and subsequent trimesters, mean birthweight and prevalence of low birthweight (< 2500 g), mean gestational age at delivery, prevalence of anaemia at first antenatal clinic visit, prevalence of iron deficiency at first antenatal visit, prevalence of placental malaria.

Starting dateJanuary 2011

Contact informationSabine GIES, PhD
Address: Liverpool School of Tropical Medicine
Telephone: +22670700738
Email: sgies@itg.be

NotesSponsors:

Centre Muraz

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Institut de Recherche en Sciences de la Sante-Direction Regionale de l'Ouest

Institute of Tropical Medicine, Belgium

National Institutes of Health (NIH)

University of Manchester

 
Comparison 2. Any intermittent iron regimen (with or without other vitamins and minerals) compared with daily regimen (with same vitamins and minerals)

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

 1 Low birthweight (less than 2500 g) (ALL)71111Risk Ratio (M-H, Random, 95% CI)0.96 [0.61, 1.52]

 2 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by weekly dose of iron71111Risk Ratio (M-H, Random, 95% CI)0.96 [0.61, 1.52]

    2.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
2397Risk Ratio (M-H, Random, 95% CI)0.90 [0.21, 3.75]

    2.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
6714Risk Ratio (M-H, Random, 95% CI)0.97 [0.60, 1.57]

 3 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by anaemia status71111Risk Ratio (M-H, Random, 95% CI)0.96 [0.61, 1.52]

    3.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
3341Risk Ratio (M-H, Random, 95% CI)1.12 [0.56, 2.24]

    3.2 Unspecified/mixed anaemia status at start of supplementation
4770Risk Ratio (M-H, Random, 95% CI)0.85 [0.47, 1.56]

 4 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by gestational age71111Risk Ratio (M-H, Random, 95% CI)0.96 [0.61, 1.52]

    4.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4716Risk Ratio (M-H, Random, 95% CI)1.17 [0.65, 2.12]

   4.2 Late gestational age (supplementation started at 20 weeks of gestation or later);
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Unspecified gestational age or mixed gestational ages at the start of supplementation
3395Risk Ratio (M-H, Random, 95% CI)0.72 [0.35, 1.47]

 5 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by intermittent regimen71181Risk Ratio (M-H, Random, 95% CI)0.96 [0.61, 1.51]

    5.1 Provision of iron once a week
6922Risk Ratio (M-H, Random, 95% CI)1.08 [0.66, 1.76]

    5.2 Other intermittent regimens
2259Risk Ratio (M-H, Random, 95% CI)0.46 [0.14, 1.55]

 6 Birthweight (g) (ALL)81152Mean Difference (IV, Random, 95% CI)-8.62 [-52.76, 35.52]

 7 Birthweight (g) SUBGROUP ANALYSIS by gestational age81152Mean Difference (IV, Random, 95% CI)-8.62 [-52.76, 35.52]

    7.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4716Mean Difference (IV, Random, 95% CI)-6.00 [-64.81, 52.80]

    7.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
4436Mean Difference (IV, Random, 95% CI)-11.99 [-78.80, 54.82]

 8 Birthweight (g) SUBGROUP ANALYSIS by anaemia status81152Mean Difference (IV, Random, 95% CI)-8.62 [-52.76, 35.52]

    8.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
3341Mean Difference (IV, Random, 95% CI)-14.45 [-100.14, 71.25]

    8.2 Unspecified/mixed anaemia status at start of supplementation
5811Mean Difference (IV, Random, 95% CI)-6.51 [-58.01, 44.99]

 9 Birthweight (g) SUBGROUP ANALYSIS by weekly dose of iron81152Mean Difference (IV, Random, 95% CI)-8.56 [-52.69, 35.57]

    9.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
4672Mean Difference (IV, Random, 95% CI)-26.45 [-93.80, 40.90]

    9.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
5480Mean Difference (IV, Random, 95% CI)4.90 [-53.51, 63.31]

 10 Birthweight (g) SUBGROUP ANALYSIS by intermittent regimen81222Mean Difference (IV, Random, 95% CI)-18.51 [-61.60, 24.57]

    10.1 Provision of iron once a week
6922Mean Difference (IV, Random, 95% CI)-20.47 [-73.66, 32.73]

    10.2 Other intermittent regimens
3300Mean Difference (IV, Random, 95% CI)-14.79 [-88.27, 58.69]

 11 Premature birth (less than 37 weeks of gestation) (ALL)4382Risk Ratio (M-H, Random, 95% CI)1.82 [0.75, 4.40]

 12 Premature birth (less than 37 weeks' gestation) SUBGROUP ANALYSIS by gestational age4382Risk Ratio (M-H, Random, 95% CI)1.82 [0.75, 4.40]

    12.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
3341Risk Ratio (M-H, Random, 95% CI)2.08 [0.82, 5.25]

    12.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
141Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 8.96]

 13 Premature birth (less than 37 weeks' gestation) SUBGROUP ANALYSIS by anaemia status4382Risk Ratio (M-H, Random, 95% CI)1.82 [0.75, 4.40]

    13.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
3341Risk Ratio (M-H, Random, 95% CI)2.08 [0.82, 5.25]

    13.2 Unspecified/mixed anaemia status at start of supplementation
141Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 8.96]

 14 Premature birth (less than 37 weeks' gestation) SUBGROUP ANALYSIS by weekly dose of iron4382Risk Ratio (M-H, Random, 95% CI)1.82 [0.75, 4.40]

    14.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
2242Risk Ratio (M-H, Random, 95% CI)1.74 [0.24, 12.56]

    14.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
2140Risk Ratio (M-H, Random, 95% CI)1.79 [0.64, 5.06]

 15 Premature birth (less than 37 weeks' gestation) SUBGROUP ANALYSIS by intermittent regimen4445Risk Ratio (M-H, Random, 95% CI)2.10 [0.92, 4.81]

    15.1 Provision of iron once a week
3272Risk Ratio (M-H, Random, 95% CI)2.13 [0.84, 5.43]

    15.2 Other intermittent regimens
2173Risk Ratio (M-H, Random, 95% CI)2.01 [0.34, 11.85]

16 Neonatal death (within 28 days after delivery) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

17 Congenital anomalies (including neural tube defects) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)4676Risk Ratio (M-H, Random, 95% CI)1.22 [0.84, 1.80]

 19 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by gestational age4676Risk Ratio (M-H, Random, 95% CI)1.22 [0.84, 1.80]

    19.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
1201Risk Ratio (M-H, Random, 95% CI)3.77 [0.20, 71.87]

   19.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    19.3 Unspecified gestational age or mixed gestational ages at the start of supplementation
3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 20 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by anaemia status4676Risk Ratio (M-H, Random, 95% CI)1.22 [0.84, 1.80]

    20.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
1201Risk Ratio (M-H, Random, 95% CI)3.77 [0.20, 71.87]

    20.2 Unspecified/mixed anaemia status at start of supplementation
3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 21 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by weekly dose of iron4676Risk Ratio (M-H, Random, 95% CI)1.22 [0.84, 1.80]

    21.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
2375Risk Ratio (M-H, Random, 95% CI)0.90 [0.52, 1.56]

    21.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
2301Risk Ratio (M-H, Random, 95% CI)1.51 [0.96, 2.37]

 22 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by intermittent regimen4746Risk Ratio (M-H, Random, 95% CI)1.25 [0.78, 1.99]

    22.1 Provision of iron once a week
4607Risk Ratio (M-H, Random, 95% CI)1.25 [0.78, 1.99]

    22.2 Other intermittent regimens
1139Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

23 Maternal iron deficiency at term (based on any indicator of iron status at 37 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 24 Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks gestation or more) (ALL)1156Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.63]

25 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 26 Side effects (any reported throughout intervention period) (ALL)111777Risk Ratio (M-H, Random, 95% CI)0.56 [0.37, 0.84]

 27 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by gestational age111777Risk Ratio (M-H, Random, 95% CI)0.56 [0.37, 0.84]

    27.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
3341Risk Ratio (M-H, Random, 95% CI)0.24 [0.11, 0.56]

    27.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
1172Risk Ratio (M-H, Random, 95% CI)1.0 [0.79, 1.27]

    27.3 Unspecified gestational age or mixed gestational ages at the start of supplementation
71264Risk Ratio (M-H, Random, 95% CI)0.56 [0.32, 0.97]

 28 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by anaemia status111777Risk Ratio (M-H, Random, 95% CI)0.56 [0.37, 0.84]

    28.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
4430Risk Ratio (M-H, Random, 95% CI)0.26 [0.14, 0.48]

    28.2 Unspecified/mixed anaemia status at start of supplementation
71347Risk Ratio (M-H, Random, 95% CI)0.70 [0.47, 1.05]

 29 Side effects (any reported throughout intervention period)SUBGROUP ANALYSIS by weekly dose of iron111777Risk Ratio (M-H, Random, 95% CI)0.54 [0.36, 0.81]

    29.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
61101Risk Ratio (M-H, Random, 95% CI)0.59 [0.32, 1.10]

    29.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
6676Risk Ratio (M-H, Random, 95% CI)0.45 [0.23, 0.90]

 30 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by intermittent regimen111978Risk Ratio (M-H, Random, 95% CI)0.56 [0.37, 0.84]

    30.1 Provision of iron once a week
101657Risk Ratio (M-H, Random, 95% CI)0.56 [0.37, 0.86]

    30.2 Other intermittent regimens
2321Risk Ratio (M-H, Random, 95% CI)0.52 [0.19, 1.40]

 31 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 32 Severe anaemia at any time during the 2nd and 3rd trimesters SUBGROUP ANALYSIS by gestational age61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    32.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
2459Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    32.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
4781Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Severe anaemia at any time during the 2nd and 3rd trimesters SUBGROUP ANALYSIS by anaemia status61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    33.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
180Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    33.2 Unspecified/mixed anaemia status at start of supplementation
51160Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 34 Severe anaemia at any time during the 2nd and 3rd trimesters SUBGROUP ANALYSIS by weekly dose of iron61381Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    34.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
51049Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    34.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
2332Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 35 Severe anaemia at any time during the 2nd and 3rd trimesters SUBGROUP ANALYSIS by intermittent regimen61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    35.1 Provision of iron once a week
61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   35.2 Other intermittent regimens
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

36 Maternal clinical malaria00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

37 Maternal infection during pregnancy (including urinary tract infections and others)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 38 Very low birthweight (less than 1500 g) (ALL)4737Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 39 Very premature birth (less than 34 weeks of gestation) (ALL)2227Risk Ratio (M-H, Random, 95% CI)0.98 [0.06, 15.31]

 40 Infant ferritin concentration in the first 6 months (μg/L, counting the last reported measure after birth within this period) (ALL)188Mean Difference (IV, Random, 95% CI)0.09 [0.05, 0.13]

 41 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks gestation or more) (ALL)81385Risk Ratio (M-H, Random, 95% CI)1.66 [1.09, 2.53]

 42 Maternal iron deficiency at or near term (based on any indicator of iron status at 34 weeks' gestation or more) (ALL)3587Risk Ratio (M-H, Random, 95% CI)2.38 [1.30, 4.36]

 43 Maternal iron deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks gestation or more) (ALL)2278Risk Ratio (M-H, Random, 95% CI)2.06 [0.65, 6.61]

 44 Maternal haemoglobin concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)71231Mean Difference (IV, Random, 95% CI)-3.26 [-5.79, -0.72]

 45 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)132047Risk Ratio (M-H, Random, 95% CI)0.48 [0.35, 0.67]

 46 Moderate anaemia at any time during second or third trimester (Hb between 70 and 99 g/L)(ALL)91291Risk Ratio (M-H, Random, 95% CI)2.50 [0.84, 7.48]

 47 Severe anaemia at term (Hb less than 70 g/L at 37 weeks' gestation or more) (ALL)3475Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 48 Severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)61050Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 49 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)0.43 [0.04, 4.64]

 50 Antepartum haemorrhage (ALL)1110Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.59]

 51 Diarrhoea (ALL)5613Risk Ratio (M-H, Random, 95% CI)0.80 [0.32, 2.00]

 52 Constipation (ALL)6733Risk Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.59]

 53 Nausea (ALL)71034Risk Ratio (M-H, Random, 95% CI)0.60 [0.37, 0.97]

 54 Heartburn (ALL)4533Risk Ratio (M-H, Random, 95% CI)0.75 [0.31, 1.81]

 55 Vomiting (ALL)6954Risk Ratio (M-H, Random, 95% CI)1.30 [0.79, 2.15]

 56 Placental abruption (ALL)1110Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]

 57 Premature rupture of membranes (ALL)180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]

 
Comparison 6. Intermittent oral iron alone supplementation versus daily iron alone supplementation

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

 1 Low birthweight (less than 2500 g) (ALL)1201Risk Ratio (M-H, Random, 95% CI)0.53 [0.03, 8.41]

 2 Birthweight (g) (ALL)2242Mean Difference (IV, Random, 95% CI)-58.22 [-176.20, 59.76]

 3 Premature birth (less than 37 weeks of gestation) (ALL)2242Risk Ratio (M-H, Random, 95% CI)1.74 [0.24, 12.56]

4 Neonatal death (within 28 days after delivery) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

5 Congenital anomalies (including neural tube defects)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)1201Risk Ratio (M-H, Random, 95% CI)3.77 [0.20, 71.87]

7 Maternal iron deficiency at term (based on any indicator of iron status at 37 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

8 Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)(ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

9 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Side effects (any reported throughout intervention period) (ALL)1201Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 11 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)264Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

12 Maternal clinical malaria00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

13 Maternal infection during pregnancy (including urinary tract infections and others)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 14 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks gestation or more) (ALL)1201Risk Ratio (M-H, Random, 95% CI)3.77 [0.20, 71.87]

 15 Maternal haemoglobin concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)1201Mean Difference (IV, Random, 95% CI)-2.58 [-5.17, 0.01]

 16 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)3265Risk Ratio (M-H, Random, 95% CI)0.50 [0.26, 0.96]

 
Comparison 7. Intermittent oral iron+folic acid supplementation versus daily iron+folic acid supplementation

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

 1 Low birthweight (less than 2500 g) (ALL)6910Risk Ratio (M-H, Random, 95% CI)0.98 [0.61, 1.55]

 2 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by gestational age6910Risk Ratio (M-H, Random, 95% CI)0.98 [0.61, 1.55]

    2.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
3515Risk Ratio (M-H, Random, 95% CI)1.22 [0.66, 2.24]

    2.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
3395Risk Ratio (M-H, Random, 95% CI)0.72 [0.35, 1.47]

 3 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by anaemia status6910Risk Ratio (M-H, Random, 95% CI)0.98 [0.61, 1.55]

    3.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
2140Risk Ratio (M-H, Random, 95% CI)1.18 [0.57, 2.41]

    3.2 Unspecified/mixed anaemia status at start of supplementation
4770Risk Ratio (M-H, Random, 95% CI)0.85 [0.47, 1.56]

 4 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by weekly dose of iron6910Risk Ratio (M-H, Random, 95% CI)0.98 [0.61, 1.55]

    4.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
1197Risk Ratio (M-H, Random, 95% CI)1.10 [0.21, 5.87]

    4.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
6713Risk Ratio (M-H, Random, 95% CI)0.97 [0.60, 1.57]

 5 Low birthweight (less than 2500 g) SUBGROUP ANALYSIS by intermittent regimen6910Risk Ratio (M-H, Random, 95% CI)0.98 [0.61, 1.55]

    5.1 Provision of iron once a week
5790Risk Ratio (M-H, Random, 95% CI)1.08 [0.66, 1.77]

    5.2 Other intermittent regimens
1120Risk Ratio (M-H, Random, 95% CI)0.49 [0.13, 1.80]

 6 Birthweight (g) (ALL)6910Mean Difference (IV, Random, 95% CI)-0.54 [-48.14, 47.06]

 7 Birthweight (g) SUBGROUP ANALYSIS by gestational age6910Mean Difference (IV, Random, 95% CI)-0.54 [-48.14, 47.06]

    7.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
3515Mean Difference (IV, Random, 95% CI)8.05 [-58.40, 74.50]

    7.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
3395Mean Difference (IV, Random, 95% CI)-9.60 [-77.82, 58.62]

 8 Birthweight (g) SUBGROUP ANALYSIS by anaemia status6910Mean Difference (IV, Random, 95% CI)-0.54 [-48.14, 47.06]

    8.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
2140Mean Difference (IV, Random, 95% CI)21.67 [-94.98, 138.31]

    8.2 Unspecified/mixed anaemia status at start of supplementation
4770Mean Difference (IV, Random, 95% CI)-4.98 [-57.12, 47.16]

 9 Birthweight (g) SUBGROUP ANALYSIS by weekly dose of iron6910Mean Difference (IV, Random, 95% CI)-0.49 [-48.07, 47.09]

    9.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
3472Mean Difference (IV, Random, 95% CI)-14.34 [-93.79, 65.11]

    9.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
4438Mean Difference (IV, Random, 95% CI)7.26 [-52.16, 66.68]

 10 Birthweight (g) SUBGROUP ANALYSIS by intermittent regimen6910Mean Difference (IV, Random, 95% CI)-0.54 [-48.14, 47.06]

    10.1 Provision of iron once a week
5790Mean Difference (IV, Random, 95% CI)-1.21 [-58.12, 55.71]

    10.2 Provision of iron by three times on non-consecutive days or other intermittent regimens
1120Mean Difference (IV, Random, 95% CI)1.0 [-85.81, 87.81]

 11 Premature birth (less than 37 weeks of gestation) (ALL)2140Risk Ratio (M-H, Random, 95% CI)1.79 [0.64, 5.06]

12 Neonatal death (within 28 days after delivery) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

13 Congenital anomalies (including neural tube defects) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 14 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 15 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by gestational age3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

   15.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   15.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    15.3 Unspecified gestational age or mixed gestational ages at the start of supplementation
3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 16 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by anaemia status3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

   16.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Unspecified/mixed anaemia status at start of supplementation
3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 17 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by weekly dose of iron3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

    17.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
1174Risk Ratio (M-H, Random, 95% CI)0.86 [0.49, 1.50]

    17.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
2301Risk Ratio (M-H, Random, 95% CI)1.51 [0.96, 2.37]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) SUBGROUP ANALYSIS by intermittent regimen3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

    18.1 Provision of iron once a week
3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

   18.2 Other intermittent regimens
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

19 Maternal iron deficiency at term (based on any indicator of iron status at 37 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 20 Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more (ALL)1156Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.63]

21 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Side effects (any reported throughout intervention period) (ALL)91487Risk Ratio (M-H, Random, 95% CI)0.60 [0.40, 0.91]

 23 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by gestational age91487Risk Ratio (M-H, Random, 95% CI)0.60 [0.40, 0.91]

    23.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
2140Risk Ratio (M-H, Random, 95% CI)0.24 [0.11, 0.56]

    23.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
1172Risk Ratio (M-H, Random, 95% CI)1.0 [0.79, 1.27]

    23.3 Unspecified gestational age or mixed gestational ages at the start of supplementation
61175Risk Ratio (M-H, Random, 95% CI)0.62 [0.36, 1.08]

 24 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by anaemia status91487Risk Ratio (M-H, Random, 95% CI)0.60 [0.40, 0.91]

    24.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
2140Risk Ratio (M-H, Random, 95% CI)0.24 [0.11, 0.56]

    24.2 Unspecified/mixed anaemia status at start of supplementation
71347Risk Ratio (M-H, Random, 95% CI)0.70 [0.47, 1.05]

 25 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by weekly dose of iron91487Risk Ratio (M-H, Random, 95% CI)0.58 [0.39, 0.87]

    25.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
4812Risk Ratio (M-H, Random, 95% CI)0.72 [0.40, 1.29]

    25.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
6675Risk Ratio (M-H, Random, 95% CI)0.45 [0.23, 0.90]

 26 Side effects (any reported throughout intervention period) SUBGROUP ANALYSIS by intermittent regimen91487Risk Ratio (M-H, Random, 95% CI)0.60 [0.40, 0.91]

    26.1 Provision of iron once a week
81367Risk Ratio (M-H, Random, 95% CI)0.61 [0.40, 0.94]

    26.2 Other intermittent regimens
1120Risk Ratio (M-H, Random, 95% CI)0.52 [0.19, 1.40]

 27 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 28 Severe anaemia at any time during the 2nd and 3rd trimesters (Hb less than 70 g/L) SUBGROUP ANALYSIS by gestational age61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    28.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
2459Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    28.2 Unspecified gestational age or mixed gestational ages at the start of supplementation
4781Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 29 Severe anaemia at any time during the 2nd and 3rd trimesters (Hb less than 70 g/L) SUBGROUP ANALYSIS by anaemia status61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    29.1 Non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation
180Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    29.2 Unspecified/mixed anaemia status at start of supplementation
51160Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 30 Severe anaemia at any time during the 2nd and 3rd trimesters (Hb less than 70 g/L) SUBGROUP ANALYSIS by intermittent regimen61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    30.1 Provision of iron once a week
61240Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   30.2 Other intermittent regimens
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 31 Severe anaemia at any time during the 2nd and 3rd trimesters (Hb less than 70 g/L) SUBGROUP ANALYSIS by weekly dose of iron61381Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    31.1 Low weekly dose of iron in the weekly group (120 mg elemental iron or less per week)
51049Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    31.2 High weekly dose of iron in the weekly group (more than 120 mg elemental iron per week)
2332Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

32 Maternal clinical malaria00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

33 Maternal infection during pregnancy (including urinary tract infections or others)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 34 Very low birthweight (less than 1500 g) (ALL)4737Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 35 Very premature birth (less than 34 weeks of gestation) (ALL)1111Risk Ratio (M-H, Random, 95% CI)0.98 [0.06, 15.31]

 36 Infant ferritin concentration in the first 6 months (μg/L, counting the last reported measured after birth within this period) (ALL)188Mean Difference (IV, Random, 95% CI)0.09 [0.05, 0.13]

 37 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)5976Risk Ratio (M-H, Random, 95% CI)1.24 [0.97, 1.59]

 38 Maternal iron deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks gestation or more) (ALL)1156Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.63]

 39 Maternal haemoglobin concentration at or near term (g/L, at 34 weeks' gestation or more) (ALL)4535Mean Difference (IV, Random, 95% CI)-1.91 [-5.53, 1.71]

 40 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)91457Risk Ratio (M-H, Random, 95% CI)0.51 [0.33, 0.79]

 41 Moderate anaemia at any time during second or third trimester (Hb between 70 and 99 g/L)(ALL)61111Risk Ratio (M-H, Random, 95% CI)2.54 [0.63, 10.17]

 42 Moderate anaemia at postpartum (Hb between 80 and 109 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)1.14 [0.26, 4.95]

 43 Severe anaemia at term (Hb less than 70 g/L at 37 weeks' gestation or more) (ALL)4555Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 44 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)0.43 [0.04, 4.64]

 45 Antepartum haemorrhage (ALL)1110Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.59]

 46 Diarrhoea (ALL)5613Risk Ratio (M-H, Random, 95% CI)0.80 [0.32, 2.00]

 47 Constipation (ALL)6733Risk Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.59]

 48 Nausea (ALL)71034Risk Ratio (M-H, Random, 95% CI)0.60 [0.37, 0.97]

 49 Heartburn (ALL)4533Risk Ratio (M-H, Random, 95% CI)0.75 [0.31, 1.81]

 50 Vomiting (ALL)6954Risk Ratio (M-H, Random, 95% CI)1.30 [0.79, 2.15]

 51 Placental abruption (ALL)1110Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]

 52 Premature rupture of membranes (ALL)180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]

 
Comparison 8. Intermittent oral iron+vitamins and minerals supplementation versus daily iron+vitamins and minerals supplementation

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

1 Low birthweight (less than 2500 g) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

2 Birthweight (g) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

3 Premature birth (less than 37 weeks of gestation) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

4 Neonatal death (within 28 days after delivery) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

5 Congenital anomalies (including neural tube defects) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)2208Risk Ratio (M-H, Random, 95% CI)4.62 [2.18, 9.76]

7 Maternal iron deficiency at term (based on any indicator of iron status at 37 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

8 Maternal iron deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

9 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Side effects (any reported throughout intervention period) (ALL)189Risk Ratio (M-H, Random, 95% CI)0.28 [0.12, 0.70]

11 Maternal clinical malaria00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

12 Maternal infection during pregnancy (including urinary tract infections and others)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 13 Very premature birth (less than 34 weeks of gestation) (ALL)1116Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 14 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)2208Risk Ratio (M-H, Random, 95% CI)4.62 [2.18, 9.76]

 15 Maternal iron deficiency at or near term (based on any indicator of iron status at 34 weeks' gestation or more) (ALL)2208Risk Ratio (M-H, Random, 95% CI)2.45 [0.70, 8.66]

 16 Maternal haemoglobin concentration at or near term (g/L, at 34 weeks' gestation or more) (ALL)1116Mean Difference (IV, Random, 95% CI)-9.50 [-13.19, -5.81]

 17 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)1116Risk Ratio (M-H, Random, 95% CI)0.37 [0.12, 1.12]

 18 Severe anaemia at term (Hb less than 70 g/L at 37 weeks' gestation or more) (ALL)1116Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 19 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)1116Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Any intermittent oral iron supplementation versus any daily iron supplementation for women during pregnancy-infant outcomes

Any Intermittent oral iron supplementation versus any daily iron supplementation for women during pregnancy

Patient or population: women during pregnancy
Settings: community settings
Intervention: any intermittent oral iron supplementation versus any daily iron supplementation

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

Low birthweight (less than 2500 g)RR 0.96
(0.61 to 1.52)
1111
(7 studies)
⊕⊝⊝⊝
very low1

Birthweight (g)MD -8.62 (-52.76 to 35.52)1152
(8 studies)
⊕⊝⊝⊝
very low2

Premature birth (less than 37 weeks of gestation)RR 1.82
(0.75 to 4.40)
382
(4 studies)
⊕⊝⊝⊝
very low3

Neonatal death (death within first 28 days of life)Not estimable0
(0)
See commentNo studies reported data for this outcome.

Congenital anomalies (including neural tube defects)Not estimable0
(0)
See commentNo studies reported data for this outcome.

CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Six of the studies contributing data had high levels of attrition, none had blinding and five had high or unclear risk of bias for allocation concealment. Proportion of events was low and there was some imprecision in the estimate. The results were consistent and statistical heterogeneity was nil (I2 = 0%).
2 Seven of the studies contributing data had high levels of attrition, none had blinding and five had high or unclear risk of bias for allocation concealment. 95% confidence intervals were wide for this outcome, although the results were consistent and statistical heterogeneity was nil (I2 = 0%).
3 Three of the included studies had high attrition, lacked blinding and five had unclear of high risk of bias for allocation concealment. Proportion of events was low. The results were consistent and statistical heterogeneity was nil (I2 = 0%).
 
Summary of findings 2. Any intermittent oral iron supplementation versus any daily iron supplementation for women during pregnancy-maternal outcomes

Any Intermittent oral iron supplementation versus any daily iron supplementation for women during pregnancy

Patient or population: women during pregnancy
Settings: community settings
Intervention: any intermittent oral iron supplementation versus any daily iron supplementation

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

Anaemia at term (Hb < 110 g/L at 37 wk gestation or more)RR 1.22
(0.84 to 1.80)
676
(4 studies)
⊕⊝⊝⊝
very low1

Iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 wk gestation or more)Not estimable0
(0)
See commentNo studies reported data for this outcome.

Iron-deficiency anaemia at term (as defined by trialists)RR 0.71
(0.08 to 6.63)
156
(1 study)
⊕⊝⊝⊝
very low2

Maternal deathNot estimable0
(0)
See commentNo studies reported data for this outcome.

Side effects (any reported throughout intervention period)RR 0.56
(0.37 to 0.84)
1777
(11 studies)
⊕⊝⊝⊝
very low3

Severe anaemia at any time during second and third trimester (Hb less than 70 g/L)Not estimable1240
(6 studies)
See commentWhile this outcome was reported in six studies there were no events.

Maternal clinical malariaNot estimable0
(0)
See commentThis outcome was not reported in any of the included studies.

Maternal infection during pregnancyNot estimable0
(0)
See commentThis outcome was not reported in any of the included studies.

CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Half of the studies contributing data had high risk of bias for attrition, one had unclear allocation concealment. 95% confidence intervals were wide for all of these studies. The results were consistent and statistical heterogeneity was nil (I2 = 10%).
2 The single study contributing data had unclear methods to generate the random sequences and no blinding. 95% confidence intervals were wide.
3 Several studies were at had high or unclear risk of allocation and attrition.The size and direction of treatment effect varied in these studies and heterogeneity was high (I2 = 87%).