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Daily 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: 12 DEC 2012

Assessed as up-to-date: 1 NOV 2012

DOI: 10.1002/14651858.CD004736.pub4


How to Cite

Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily oral iron supplementation during pregnancy. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD004736. DOI: 10.1002/14651858.CD004736.pub4.

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. juanpablopenarosas@outlook.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 12 DEC 2012

SEARCH

 
Characteristics of included studies [ordered by study ID]
Barton 1994

MethodsRCT, 2-arm trial with individual randomisation.


Participants97 healthy women attending prenatal care at National Maternity Hospital, Dublin, Ireland with singleton pregnancy, during their first trimester of pregnancy, and with Hb equal or higher than 140 g/L were assigned to the groups. Women were excluded if they had a recent blood transfusion, chronic respiratory disease, chronic hypertension, renal disease, diabetes mellitus, history of haematologic disorder and alcohol dependence.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1: received 60 mg elemental iron and 500 μg (0.5 mg) of folic acid to be taken by mouth twice daily; group 2: placebo tablets also to be taken by mouth twice daily.
Supplementation started at 12 weeks until delivery. No postpartum supplementation.

Setting and health worker cadre: the intervention was performed by physicians at the National Maternity Hospitalin Dublin, Ireland.


OutcomesMaternal: Hb, HCT, serum erythropoietin concentrations at baseline and at 24, 28, 32, 36 and 40 weeks; serum ferritin at baseline and at 36 weeks; number of hypertensive disorders, antepartum haemorrhage, caesarean delivery.
Infant: perinatal death, birthweight below 10th percentile, Apgar score, need for neonatal resuscitation and admission to neonatal intensive care unit data recorded but not reported in paper. Cord blood values of Hb, HCT, serum ferritin, and erythropoietin concentrations.


NotesUnsupervised.
No participants were withdrawn because of anaemia.
Compliance not reported.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks of gestation) (12 weeks until delivery).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (60 mg elemental iron or more) (120 mg elemental iron).

Iron release formulation: normal release/not specified.

Iron compound: not specified.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Unclear riskInsufficient information reported on the method used to conceal the allocation sequence.

Blinding (performance bias and detection bias)
All outcomes
Low riskReported as double blind. The placebo tablets were identical in size, colour and shape to the iron and folic acid supplements and contained the same excipients.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5% lost to follow-up.

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

Other biasLow riskNo baseline imbalance apparent.

Batu 1976

MethodsRCT, 4-arm trial with individual randomisation.


Participants133 women referred to investigators from a population of women attending an antenatal clinic for the fist time in Yangoon (also known as Rangoon), Myanmar (Burma). Women with severe anaemia were excluded from the trial during the intervention for treatment.


InterventionsParticipants were randomly assigned to 1 of 4 groups starting at 22-25 weeks: group 1: 60 mg of elemental iron (as ferrous sulphate), and 1 placebo tablets twice daily; group 2: 1 tablet containing 60 mg of elemental iron (as ferrous sulphate), and 1 tablet containing 500 μg (0.5 mg) of folic acid twice daily; group 3: 2 placebo tablets twice daily; group 4: 1 placebo tablet and 1 tablet containing 500 μg (0.5 mg) of folic acid twice daily. Administration of the treatments was carefully supervised. Supplementation started at 22-25 weeks until term.

Setting and health worker cadre: the intervention was performed by physicians at an antenatal clinic in Rangoon, Burma.


OutcomesMaternal: Hb concentrations at baseline, at term (38-40th week) and 4-7 week postpartum, serum iron, serum and red cell folate activity and hypersegmented polymorph count at baseline, at 38-40th week and postpartum.


NotesSupervised.

32 women who had taken other supplements or whose Hb level at full term was not available were excluded from the analysis. 3 women from group 3 and 2 from group 4 developed severe anaemia and were also withdrawn from analysis.

Gestational age at start of supplementation: late gestational age (more than 20 weeks at the start of supplementation) (22-25 weeks' gestation)

Anaemic status at start of supplementation: unspecified/mixed anaemia status at the start of supplementation (women with severe anaemia excluded)

Daily iron dose: higher daily dose (60 mg elemental iron or more) (120 mg of elemental iron)

Iron release formulation: normal release iron supplement/not specified

Iron compound: ferrous sulphate

Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year at altitudes below 1000 m, excluding the main urban areas of Mandalayand Yangon. Risk is highest in remote rural, hilly and forested areas. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Mefloquine resistance reported in Kayin state and the eastern part of Shan state. P. vivax resistance to chloroquine reported. Human P. knowlesi infection reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not stated; "randomly placed in one of four treatment regimens".

Allocation concealment (selection bias)Unclear riskInsufficient information reported on the method used to conceal the allocation sequence.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant blinded by provision of placebos. Provider/assessor not stated or unclear.

Incomplete outcome data (attrition bias)
All outcomes
High risk37 women (28%) were excluded for analysis. 133 women randomised "32 women who had taken other hematinics or whose Hb level at full term was not available were excluded". 5 women developed anaemia and were given treatment. Loss was not balanced across groups.

Selective reporting (reporting bias)High risk32 women who had taken other supplements or whose Hb level at full term was not available were excluded from the analysis. 3 women from group 3 and 2 from group 4 developed severe anaemia and were also withdrawn from analysis.

Other biasLow riskNo baseline imbalance apparent.

Butler 1968

MethodsRCT, 3-arm trial with individual randomisation.


Participants200 women before 20th week of gestation and Hb above 100 g/L attending antenatal clinic at the Maternity Hospital in Glossop Terrace, Cardiff, United Kingdom were studied. Exclusion criteria included urinary infection and threatened miscarriage, confusion over therapy, intercurrent illness and difficult veins, intolerant to the iron form, premature labor.


InterventionsParticipants were randomly allocated to 1 of 3 groups: group 1: received 122 mg of elemental iron (as ferrous sulphate) daily; group 2: received 122 mg of elemental iron (as ferrous sulphate) + 3400 μg (3.4 mg) of folic acid daily; group 3: received no intervention. A group 4 was formed as some participants (n = 38) from group 3 received iron supplements for treatment of anaemia in the course of the intervention. They are excluded from the analysis. Women were supplemented from week 20 to 40 of gestation.

Setting and health worker cadre: the intervention was performed by obstetricians and hematologists at the antenatal clinic, Cardiff Maternity Hospital in Cardiff, United Kingdom.


OutcomesMaternal: Hb concentrations, blood and plasma volume, HCT (not reported), red cell volume, albumin and globulin fractions at weeks 20, 28, 36 and 40 of gestation and at the first postanal visit, oedema, intrapartum haemorrhage.


NotesUnsupervised.
154 women were followed through to the postnatal visit. Only 16 women (30%) in the no-treatment group remained untreated.
Compliance not reported.

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

Anaemic status at start of supplementation: mixed anaemia status (Hb above 100 g/L).

Daily iron dose: higher daily dose (60 mg of elemental iron or more) (122 mg elemental iron).

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

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised list stratified by age, parity and initial Hb level.

Allocation concealment (selection bias)Low riskThe code was not opened for the iron and iron + folic acid group until the end of the investigation, thus clinical staff could not anticipate the randomisation sequence. There was no treatment for 1 group.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and provider were blinded to treatment for groups 1 and 2. The control group received no treatment and did not get a placebo.

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

154 women were randomised and for many outcomes there were missing data. 70% of the 54 women initially allocated to the no treatment group received iron supplements for anaemia (as there was no placebo, staff would be aware that women were not receiving supplements). Results for those women treated or not treated in the control group were reported separately. Results are therefore difficult to interpret.

Selective reporting (reporting bias)Low riskAuthors provided the full database for this review.

Other biasLow riskNo baseline imbalance apparent.

Buytaert 1983

MethodsRCT, 2-arm trial with individual randomisation.


Participants45 non-anaemic women with singleton pregnancy and no major illnesses attending the University Hospital Obstetric and Gynaecologic Clinic in Antwerp, Belgium.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1: received 105 mg of elemental iron (as ferrous sulphate sustained release preparation) daily and group 2: received no iron supplement.
Supplementation started at 14-16th week of gestation and continued until delivery.

Setting and health worker cadre: the intervention was performed by obstetricians at the University Hospital Obstetrical Clinic of the Erasmus University at Rotterdam, The Netherlands or the University Hospital Obstetric and Gynecologic Clinic in Antwerp, Belgium.


OutcomesMaternal: Hb, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 weeks, delivery and 6 weeks postpartum.


NotesUnsupervised. The randomisation was made for each clinic in Antwerp, and the results are presented separately by clinic. Compliance not reported.

We treated this study carried out collaboratively in 2 different sites as 2 different trials, 1 conducted in Rotterdam (Wallenburg 1983) and 1 conducted in Antwerp (Buytaert 1983).

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation) (14th-16th week).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher dose of iron (60 mg of elemental iron or more) (105 mg elemental iron).

Iron release formulation: sustained release preparation.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom table numbers.

Allocation concealment (selection bias)Low riskBy means of sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant nor provider blinded. No placebo used.

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

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

Other biasUnclear riskNo other bias apparent.

Cantlie 1971

MethodsRCT, 2-arm trial with individual randomisation.


Participants27 apparently healthy 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 120 g/L or higher in first trimester and 110 g/L or higher in second trimester. Women with history of pathological blood loss or gross dietary imbalance were excluded.


InterventionsParticipants were randomly assigned to 2 groups: group 1 received 39 mg elemental iron (Mol-Iron®, ferrous iron) to be taken twice daily with meals (total daily 78 mg elemental iron) or group 2 who received no iron tablets. As a co-intervention, both groups received 1 tablet of multiple micronutrient supplement daily containing: 2 mg copper citrate, 6 mg magnesium stearate, 0.3 mg manganese carbonate, 1000 IU vitamin A , 500 IU vitamin D, bone flour 130 mg, 1 mg vitamin B1, 1 mg vitamin B2, 50 mg brewer yeast concentrate, 5 mg niacinamide, 25 mg vitamin C, 0.2 mg sodium iodide and 0.049 μg folate (naturally occurring). Duration of supplementation unclear.

Setting and health worker cadre: the intervention was performed by obstetricians and hematologists at the McGill University Medical Clinic, Royal Victoria Hospital in Montreal, Canada. Participant, of higher socioeconomic status, were of recruited from private obstetrical practices.


OutcomesMaternal: Hb concentration, PCV, reticulocyte count, sedimentation rate, total white blood cell and differential counts, serum iron, unsaturated and total iron binding capacity, serum B12, serum and RBC folate at baseline and at 32, 36, 39th weeks and 7 days postpartum.


NotesSupervision unclear.
Compliance not reported.

Gestational age at start of supplementation: mixed gestational age (1-5th month of pregnancy).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (60 mg elemental iron or more) (78 mg elemental iron).

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

Iron compound: Mol-Iron®, ferrous iron.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not stated; "divided randomly".

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot mentioned.

Incomplete outcome data (attrition bias)
All outcomes
High risk27 women were randomised. 26 mentioned in the discussion; denominators were not provided for the results.

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

Other biasUnclear riskWomen in the intervention group had higher median serum folate levels at baseline (not sig).

Chan 2009

MethodsRCT (placebo controlled) 2-arm trial, individual randomisation.


Participants1164 pregnant women with singleton pregnancies with a gestational age of 16 weeks or less able to understand English or Chinese attending their first antenatal care visit at Queen Mary Hospital, Hong Kong between April 2005 and March 2007.

Exclusion criteria: women with existing diabetes, haemoglobinopathies, Hb levels  < 80 g/L or >140 g/L, women with possible thalassaemia (MCV < 80), women diagnosed with gestational diabetes at booking.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1: (n = 565 women) received 60 mg of elemental iron orally (as 300 mg ferrous sulphate) daily ; group 2: (n = 599 women) received daily placebo indistinguishable in appearance from the active supplements. Women in both groups were provided with a supply for 16 weeks. At 28-30 weeks further supplements were provided (up to 36 weeks) as long as women had not developed gestational diabetes mellitus or Hb level was > 140 g/L. If women in the placebo group developed anaemia (Hb < 80 g/L) they were given iron supplements as clinically indicated.

Baseline investigations included a full blood count including Hb and HCT, MCV, white cells and platelets along with serum ferritin concentration. A OGIT was carried out at baseline for women with risk factors for gestational diabetes (e.g. advanced maternal age, family history of diabetes).  Otherwise women in both groups received standard antenatal care.

Setting and health worker cadre: the intervention was performed by physicians at a regional university teaching hospital in Hong Kong.


OutcomesFollow-up at 28 weeks and 36 weeks' gestation and delivery and 3 days pp.

Main outcome: development of gestational diabetes at 28 or 36 weeks.  (According to WHO criteria for impaired glucose tolerance test (OGTT 2-hour value > or = 7.8 < 11.1 mmol/L) or diabetes (OGTT 2-hour value> or = 11.1 mmol) both were considered as gestational diabetes mellitus). Other maternal outcomes: Hb (g/L), 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/L), ferritin of cord blood (pmol/L), jaundice, birth trauma, infection, congenital abnormality or metabolic disorder.


NotesVery high attrition (> 50% for outcomes at 36 weeks).  45.6% of controls and 43.1% of women in the study group were taking additional vitamin supplements.

As the results reported in the paper were not completely clear to us we preferred not to use the reported SDs and removed the information from this trial for continuous variables, while awaiting clarification from the authors.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks) (16 weeks or less).

Anaemic status at start of supplementation: mixed anaemia status (Hb levels > 80 and < 140 g/L).

Daily iron dose: higher dose (60 mg elemental iron).

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

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was carried out by a research nurse who was not involved in patient recruitment. Block randomisation with computer generation of sequence.  The block size was 100.

Allocation concealment (selection bias)Low riskSealed opaque envelopes. The envelopes were sequentially numbered and sealed ( By nurse A who did the block randomisation ) and all the envelopes were accounted for.  The research assistant who recruited the patients (nurse B) would sequentially open the numbered envelopes after the patient had consented to participate in the study.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants blinded; placebo controlled.

After randomisation “The participants but not the research assistants were blinded to group assignment”. Staff and research nurses were aware of the group allocation.

Outcomes were assessed by the principle investigator (the outcomes are mainly objective outcomes such as OGTT results, blood counts, birthweight, etc).

Incomplete outcome data (attrition bias)
All outcomes
High risk1164 women were randomised. It was stated that an ITT analysis was performed but data tables suggest there were missing data for most outcomes at 28 and 36 weeks and at delivery; e.g. at 28 weeks 90.3% attended for follow-up. Neonatal outcome data were available for 74% of those randomised. There were very high levels (> 50%) of missing data for lab values at 36 weeks.

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

Other biasLow riskNo baseline imbalance between groups apparent.

Chanarin 1965

MethodsRandomised controlled trial with 3 arms.


Participants190 pregnant women before 16 week of gestational age attending antenatal clinic for the first time in St Mary's Hospital in London, England, United Kingdom were invited to participate in the study and 189 accepted.


InterventionsParticipants were randomly assigned to 1 of 3 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).

Setting and health worker cadre: the intervention was performed by obstetricians and pathologists at the antenatal clinic of St. Mary's Hospital in London, United Kingdom.


OutcomesThe outcomes measured include full blood count at 20th, 30th, 35th and 39th week of gestation and 6th day after delivery.


NotesThe paper does not report SDs in the variables measured and no data can be extracted. The trial is included but does not contribute data for the analysis.

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

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

Daily iron dose: higher daily dose (60 mg of elemental iron or more).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous fumarate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethods not described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant and care provider blinded during the trial. tablets had green, red or blue labels to differentiate among the groups.

Incomplete outcome data (attrition bias)
All outcomes
High risk189 women were randomised but only 154 completed the study but not all samples could be obtained from every participant. 35 women were further withdrawn from the trial. 9 participants in the placebo group and 1 in the iron + folic acid group required parenteral iron nutrition and were withdrawn from the analysis.

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

Other biasUnclear riskNo other bias apparent.

Chanarin 1971

MethodsQuasi RCT. 5-arm trial with individual randomisation.


Participants251 women attending antenatal clinic at St Mary's Hospital, London, United Kingdom before 20th week of gestation.


InterventionsParticipants were allocated by sequence to 1 of 5 groups: group 1: oral dose of 30 mg of elemental iron (as ferrous fumarate) daily; 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 (not included in this review).
Supplementation started at 20th week until 37th week. Only the data related to comparisons of group 1: oral dose of 30 mg of elemental iron daily with group 4: placebo are used in this review given that no data for the other groups could be desegregated.

Setting and health worker cadre: the intervention was performed by obstetricians and pathologists at the antenatal clinic of St. Mary's Hospital in London, United Kingdom.


OutcomesMaternal: full blood count, serum iron at 20, 25, 30 and 37th week. Sternal marrow aspiration at 37 weeks; antepartum haemorrhage, threatened abortion, urinary tract infection, fetal abnormalities, pregnancy hypertension, premature delivery and puerperal infection measured but not reported by groups.
Infant: birthweight (not reported by groups).


NotesCompliance not reported.

Gestational age at start of supplementation: late gestational age (supplementation started at 20 week's gestation).

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

Daily iron dose: different doses in different arms of trial (group 1 lower daily dose: 30 mg; group 2 and 3 higher daily dose 60 mg or more).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous fumarate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised study, assignment by sequence.

Allocation concealment (selection bias)High riskWomen were "allocated in sequence to one of five groups"; allocation order could therefore be anticipated.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded. A placebo was provided.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIt was not clear exactly how many women were randomised; there were approximately 50 in each of 5 groups. 11 women (9 from the placebo group) were withdrawn and given treatment for anaemia "after allowance had been made for the subjects dropping out of the study... there were just under 50 subjects in each group".

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

Other biasUnclear riskNo other bias apparent.

Charoenlarp 1988

MethodsRCT. Series of treatment conditions.


Participants325 pregnant women with Hb (AA) and 232 pregnant women with Hb (AE) attending midwife centres in 80 villages from the Varin Chamrab district of Ubon Province, Thailand. Chronic illness, complicated pregnancy, severe anaemia (Hb < 80 g/L), haemoglobinopathies Hb (EE) and (EF), and unwillingness to co-operate were reason for exclusion. Individuals with Hb (AA) have normal Hb genes. Individuals with Hb (AE) have a heterozygous Hb E trait with normal Hb gene (A-adults) and an abnormal Hb gene (E). This is usually a clinically insignificant condition.


InterventionsParticipants were divided into 2 groups according to Hb (AA) and Hb (AE) and studied separately.

Women from each group were randomly assigned to 1 of the following 11 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 1 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 and 5000 μg (5 mg) of folic acid daily, motivated but unsupervised.
Starting and ending time of supplementation not stated.

Setting and health worker cadre: the intervention was performed by community health workers under the supervision of a midwife and was delivered to the home of participants living in villages near Ubon, Thailand. Intervention was coordinated from village midwife centres.


OutcomesMaternal: Hb, serum ferritin after 10 and 15 weeks of supplementation, and side effects.


NotesGroups 1, 2, 3, 4, 7, 8, 9 supervised. Groups 5, 6, 10 and 11 motivated but unsupervised. For purposes of analysis, the groups were merged by iron alone or iron-folic acid, and included as daily higher doses in both cases.
Compliance not reported.

Gestational age at start of supplementation: gestational age not specified.

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

Daily iron dose: higher daily dose (60 mg or more of elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria: 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 the main tourist resorts of Phuket island. However, there is a risk in some other areas and islands. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Resistance to mefloquine and to quinine reported from areas near the borders with Cambodia and Myanmar. P. vivax resistance to chloroquine reported. Human P. knowlesi infection reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSet of random tables.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and outcome assessor blinded. Provider blinding unclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskRanged from 10%-15%.

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

Other biasUnclear riskNo other bias apparent.

Chisholm 1966

MethodsRCT, 6 arms.


Participants360 non-anaemic women attending antenatal clinic at Radcliffe Infirmary, Oxford, United Kingdom before 28th week of gestation, who had not taken iron supplements in the preceding 8 weeks and with Hb >= 102 g/L or a normal serum iron reading. Exclusion criteria: Hb < 110 g/L and serum iron less than 60 μg/L.


InterventionsParticipants were randomly assigned to 1 of various combinations of elemental iron as ferrous gluconate and folic acid, as follows:group 1: 900 mg elemental iron alone daily; group 2: 900 mg elemental iron and 500 μg (0.5 mg) folic acid daily; group 3: 900 mg elemental iron and 5000 μg (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.

Setting and health worker cadre: the intervention was performed by physicians at the antenatal clinic of The Radcliffe Infirmary, Oxford, United Kingdom.


OutcomesMaternal: Hb, HCT, serum iron, serum folic acid activity, serum vitamin B12 estimation at 28 weeks of gestation and before delivery.


NotesUnsupervised.
For purposes of this review, placebo group was the group who received neither iron nor folic acid. Groups 2 and 3 were merged for iron-folic acid comparisons.
Compliance not reported.

Gestational age at start of supplementation: late gestational age (from 28 weeks' gestation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (60 mg or more of elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskExternal randomisation.

Allocation concealment (selection bias)Low riskBottles containing the tablets had been numbered by random selection at source and the code was unknown during trial.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up apparent.

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

Other biasUnclear riskNo other bias apparent.

Christian 2003 (C)

MethodsCluster-randomised trial with 5 treatment arms.


Participants4998 married pregnant women (with positive pregnancy test) living in the south eastern plains district of Sarlahi, Nepal. Widows were excluded.


InterventionsParticipants were randomly assigned to 1 of 5 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 μg (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. Only groups 1, 2 and 3 are considered in this review. Supplementation started at recruitment and continued until 3 months postpartum in the case of live births of 5 weeks 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.
Supplementation lasted 257.5 days in group 1 (control) and 251.7 days in the group 3 receiving vitamin A, iron and folic acid.

Comparisons: group 3 vs group 1: effect of iron supplementation with folic acid; group 3 vs group 2: effect of iron supplementation alone.

Setting and health worker cadre: the intervention was performed by community health workers in the home of the participants in remote villages in Sarlahi, Nepal. In Nepal, 8% of women received assistance from an auxiliary nurse midwife or doctor. Dosing and supplement replenishment was done by 426 local female workers, 1 per sector, or about 40 households.


OutcomesMaternal: premature delivery, Hb and iron status at baseline in the third trimester (scheduled at 32 wk of gestation) and Hb at 6 weeks postpartum, prevalence of anaemia in third trimester and at 6-week postpartum, severe anaemia postpartum, moderate anaemia during third trimester, moderate anaemia postpartum, moderate high Hb concentrations during third trimester
Infant: birthweight, prevalence of low birthweight, perinatal mortality, neonatal mortality, infant deaths, small-for-gestational age.


NotesSupplementation with 1000 μg retinol equivalents vitamin A (control) daily and deworming treatment (albendazole 400 mg single dose) in the second and third trimester at were co-interventions for purposes of the analysis.

Unsupervised but trial personnel visited women twice each week to monitor supplement intake.
Compliance during pregnancy measured by pill count was high (median 88%) and did not vary by groups.
98% of the women accepted the albendazole treatment at both times (second and third trimesters)

Approximate 50% of women started supplementation before 9 weeks of gestational age.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 week's gestation)

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

Daily iron dose: higher daily dose (60 mg or more elemental iron)

Iron release formulation: normal release preparation/not specified

Iron compound: ferrous fumarate

Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. vivax exists throughout the year in rural areas of the 20 Terai districts bordering India, with occasional outbreaks of P. falciparum from July to October inclusive. Seasonal transmission of P. vivax takes place in 45 districts of the inner Terai and mid hills. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported.  


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCluster-randomisation.

Allocation concealment (selection bias)Low riskCoded.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant, provider and outcome assessors blinded.

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

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

Other biasLow riskBaseline characteristics did not differ by treatment group in age at baseline, socioeconomic status, parity, gestational age at enrolment, previous miscarriage. The level of compliance did not differ by groups.

Cogswell 2003

MethodsRCT, 2 arms with individual randomisation.


Participants275 legally competent, non-imprisoned, non-anaemic, low-income pregnant women at < 20 weeks of gestation with ferritin levels above 20 μg/L enrolled at the Cuyahoga County, MetroHealth Center, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, USA.


InterventionsParticipants were randomly assigned to 1 of 2 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 weeks of gestation until delivery.


OutcomesMaternal: prevalence of anaemia at 28 and 38 weeks, side effects, compliance to treatment, maternal weight gain, iron status (MCV, Hb concentration, serum ferritin, erythrocyte protoporphyrin concentrations at 28 and 38 weeks.
Infant: birthweight, birth length, proportion of low birthweight, low birthweight and premature, small-for-gestational age.

Setting and health worker cadre: the intervention was performed by a dietician at the Cuyahoga County, MetroHealth Medical Center, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, United States of America.


NotesUnsupervised. Women were re-evaluated at 28 weeks of gestation, and according to Hb concentrations at that time were prescribed treatment following the Institute of Medicine guidelines for iron supplementation during pregnancy.
Compliance was 63.4% and 65.2% in groups 1 and 2 respectively.

Gestational age at start of supplementation: early gestational age (supplementation started before 20 weeks' gestation)

Anaemic status at start of supplementation: non-anaemic

Daily iron dose: lower daily dose (30 mg of elemental iron)

Iron release formulation: normal release preparation/unspecified

Iron compound: ferrous sulphate

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskPlacebo controlled trial. Randomisation by study data manager. The placebo and active treatment were indistinguishable and all staff were blind to group allocation.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and care provider blinded. Laboratory and other staff assessing outcomes 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 biasUnclear riskNo other bias apparent.

Corrigan 1936

MethodsQuasi-randomised trial with allocation by odd or even numbers. 2-arm trial.


Participants200 normal pregnant women attending antenatal care clinic with 3-7 months of gestational age at Boston City Hospital, Boston, USA.


InterventionsParticipants were assigned a number in order. Patients who had been assigned an odd number received 0.2 g of ferrous sulphate (3 tablets daily to be taken after meals - total daily dose 0.6 g); patients with even numbers received placebo that were identical in appearance and size and contained lactose but not ferrous sulphate.

Supplements were from recruitment until delivery.

Women who took less than 1 of the 2 tablets prescribed daily were excluded.

Setting and health worker cadre: the intervention was performed by physicians at the antepartum clinic of Boston City Hospital, Boston, Massachusetts, United States of America.


OutcomesNumber of women with anaemia at 1-week postpartum. (Figures were also provided for the mean Hb level at 1-week postpartum but no SD was provided and we were not able to include these data in the analysis).


NotesMean Hb in the intervention group 117 g/L and 112 g/L in the control group.

Gestational age at start of supplementation: mixed gestational age.

Anaemic status at start of supplementation: not specified.

Daily iron dose: higher daily dose (60 mg or more).

Iron release formulation: not specified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised trial, odd/even numbers.

Allocation concealment (selection bias)High riskAlternate allocation.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskA placebo was provided which was identical in appearance to the active treatment but it was not clear whether investigators were aware of group allocation.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk200 women were randomised and it was stated that women that did not comply (that took on average less than 1 of the prescribed tablets daily) or in whom sepsis or haemorrhage developed during pregnancy, birth or the early postnatal period were excluded. It was not clear how many women were excluded for these reasons and it was not clear whether or not there was any ITT analysis.

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

Other biasUnclear riskMost of the results were provided in graphs and were not simple to interpret and we have included all of these results in the analyses.

Women were described as similar at baseline.

The denominators for results were not clear.

De Benaze 1989

MethodsRCT, 2-arm trial with individual randomisation.


Participants191 non-anaemic pregnant women with 12-18 weeks of gestation attending antenatal care clinic at the Maternity at Poissy Hospital, Paris, France. Exclusion criteria included women who had taken iron or folate supplements in the prior 6 months and those with language barriers for proper communication.
Supplementation started at 12-18 weeks until delivery.


InterventionsParticipants were randomly allocated to 1 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 tablets.

Setting and health worker cadre: the intervention was performed by physicians at the Maternity Ward of Poissy Hospital, Poissy, France


OutcomesMaternal: Hb, MCV, serum iron, total iron binding capacity, transferrin saturation, serum ferritin at baseline, at 5 months, at 7 months, at delivery and 2 months postpartum.


NotesUnsupervised.
Serum ferritin values presented as arithmetic and geometric means. No SD in transformed ferritin values is presented. Women in the placebo group were prescribed treatment after delivery thus not allowing comparisons at 2 months postpartum among the groups.
Compliance reported as good.

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: medium daily dose (45 mg elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous betainate hydrochloride.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised but method used unclear.

Allocation concealment (selection bias)Low riskPlacebo controlled trial. Active and placebo tablets were in identical packaging and packages were provided randomly.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% losses to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Dommisse 1983

MethodsRCT, 2-arm trial with individual randomisation.


Participants146 pregnant women with less than 20 weeks of gestation who had not received iron therapy recently attending the Peninsula Maternity Service, Department of Obstetrics and Gynecology, University of Cape Town, Groote Schuur Hospital, South Africa.


InterventionsParticipants 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.

Setting and health worker cadre: the intervention was performed by obstetricians and professional staff at the Peninsula Maternity Service of the Department of Obstetrics and Gynecology of the University of Cape Town and Groote Schuur Hospital in Cape Town, South Africa.


OutcomesHb, PCV, MCV, MCHC, serum iron, transferrin, red cell folate, ferritin, iron storage depletion at baseline and at 36 weeks' gestation, compliance.


NotesMean Hb and other outcomes at term were reported, but no SDs were provided. We have therefore not been able to include data from this trial in the review.

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

Anaemic status at start of supplementation: mixed/not specified.

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the low altitude areas of Mpumalanga Province (including the Kruger National Park), Northern Province and north-eastern KwaZulu-Natal as far south as the Tugela River. Risk is highest from October to May inclusive. Resistance to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomly allocated."

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
High risk146 were randomised but when compliance was assessed as poor or doubtful, the participant was excluded from the trial. 21 patients were excluded for poor or doubtful compliance and 20 patients delivered before 36th weeks' gestation. Only 105 completed the trial.

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

Other biasUnclear riskNo other bias apparent.

Eskeland 1997

MethodsRCT, 3-arm trial with individual randomisation.


Participants90 healthy non-anaemic pregnant women with singleton pregnancy of less than 13 weeks, attending an inner city maternity centre in Bergen, Norway and willing to participate. Exclusion criteria: uncertain gestational age according to menstrual history, Hb concentration < 110 g/L, chronic disease or pregnancy complications (hypertension, diabetes, bleeding), multiple pregnancy, liver enzymes out of normal range and logistic difficulties foreseen at baseline (moving out of area).


InterventionsParticipants were randomly allocated to 1 of the following: group 1: 3 tablets containing 1.2 mg heme iron from porcine blood and 9 mg of elemental iron (as ferrous fumarate) (Hemofer®) and 1 placebo tablet (total 27 mg elemental iron a day); group 2: 1 tablet containing 27 mg elemental iron (as iron fumarate) with 100 mg vitamin C (Collet®) and 3 placebo tablets; or group 3: 4 placebo tablets.
Supplementation started at 20th week until 38-40th week.

Setting and health worker cadre: the intervention was performed by midwives and physicians at an inner city maternity centre in Bergen, Norway.


OutcomesMaternal: Hb, erythrocytes count, HCT, MCV, MCH, MCHC, reticulocytes, serum iron, total iron binding capacity, serum transferrin, erythrocyte protoporphyrin at baseline and at 20, 28, 38 weeks, 8 weeks postpartum, and 6 months postpartum; pregnancy complications: hypertension, pre-eclampsia, forceps, postpartum haemorrhage, maternal well being and breastfeeding duration.
Infant: birthweight and length.


NotesUnsupervised.
Only groups 1 and 3 (placebo) were included in this review.
Compliance was 81% and 82% in groups 1 and 3 respectively.

Gestational age at start of supplementation: late gestational age (supplementation started at or after 20 weeks' gestation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: lower daily dose (less than 30 mg elemental iron daily).

Iron release formulation: normal release preparation/not specified.

Iron compound: iron fumarate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskThis was a placebo controlled trial.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and care provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
High risk23% and 21% in groups included.

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

Other biasUnclear riskNo other bias apparent.

Falahi 2010

MethodsRCT-2 arms with individual randomisation


Participants148 non-anaemic pregnant women, 20-35 years of age with gestational age less than 20 wk, primigravidae, body mass index less than 25 and less than 30 and Hb concentrations lower than 110 g/L and serum ferritin higher than 20 μg/L who visited the gynaecology centre in Khorramabad city, Lorestan Province, Western Iran. Participants who had diabetes mellitus, renal disease, coronary heart disease, or reported having used multivitamins and minerals, drugs or being on a special diet were excluded.


InterventionsParticipants were randomly allocated to 1 of to groups: group 1 (n = 70) received tablets containing 60 mg elemental iron (as ferrous sulphate) and group 2 (n = 78) received placebo tablets until delivery. Women who were anaemic or iron deficient were referred for medical evaluation and treated.

Setting and heath worker cadre: the intervention was performed by physicians at a gynaecology centre in Khorramabad city, Lorestan Province, Western Iran.


OutcomesHb concentration, serum ferritin at baseline, week 28 and at delivery; birth weight, birth length, pregnancy duration.


NotesGestational age at start of supplementation: early gestational age (supplementation started less than 20 weeks' gestation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: high daily dose (60 mg elemental iron daily).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. 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. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Low riskThis was a placebo controlled trial.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo controlled trial. It was described as "triple-blind".

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk148 women were randomised. It was not clear whether any women were lost to follow-up or if there were any missing data.

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

Other biasUnclear riskGroups appeared comparable at baseline.

Fenton 1977

MethodsQuasi-randomised trial, 2 arms with individual randomisation.


Participants154 pregnant women with less than 14 weeks of gestation, and who had not received or were receiving treatment for a blood disorder at clinic in Cardiff, United Kingdom


InterventionsParticipants 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 no iron supplement.

Setting and health worker cadre: the intervention was performed by physicians at the Antenatal Clinic of the Welsh National School of Medicine at the University Hospital of Wales, Cardiff, United Kingdom.


OutcomesHb concentration, MCV, serum ferritin, serum iron and total iron binding capacity were measured at 10-14 week and at term.


NotesThe data in the paper are presented with no SD values. No data can be extracted from the publication for this review.

Gestational age at start of supplementation: early gestational age.

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

Daily iron dose: higher daily dose (60 mg or elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskBy day of clinic attendance.

Allocation concealment (selection bias)High riskBy day of clinic attendance.

Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll women appear to be accounted for in the analyses; separate figures are provided for women in the control arm who received supplements.

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

Other biasUnclear riskNo other bias apparent.

Fleming 1974

MethodsRCT with randomisation by blocks of 50 consecutive participants into 5 arms.


Participants146 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. Women with Hb < 100.0 g/L were excluded.


InterventionsParticipants were randomly assigned in sequences of 50 to 1 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 the 20th week.

Setting and health worker cadre: the intervention was performed by obstetricians at a public antenatal clinic in western Australia. Patients were of a low socio-economic status.


OutcomesHb, serum and red cell folate, serum vitamin B12 at first attendance, and at 20 week, 28, 35 week and at delivery, and 6 weeks postpartum; pregnancy complications, anaemia defined as Hb lower than 100 g/L, premature delivery, abortion, compliance; birthweight, placental weight, Apgar score at delivery (full outcome data were not reported for group 5, which received a higher dose of folic acid).


NotesMore than 20% of the women were lost to follow-up. We decided not to include outcome data for mean Hb at term, as the SDs provided in the paper represent a single SD for all groups and this assumes that distributions were similar in each treatment group.

Gestational age at start of supplementation: late gestational age (supplementation started at or after 20 weeks' gestation).

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

Daily iron dose: higher daily dose (60 mg elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"they were allotted according to randomised sequences of 50".

Allocation concealment (selection bias)Unclear riskNot clear, women were provided with colour-coded packages which identified the regimes.

Blinding (performance bias and detection bias)
All outcomes
Low riskIt was stated that the contents of the treatment packages were not known to women or investigators until after the completion of the trial.

Incomplete outcome data (attrition bias)
All outcomes
High risk146 women randomised., 89 women completed the trial and women were removed from the trial for reasons that may have related to outcomes (e.g. women developed anaemia).

Selective reporting (reporting bias)Unclear riskThere was high attrition in this trial and data were not reported for all treatment groups.

Other biasUnclear riskNo other bias apparent.

Fleming 1985

MethodsRCT, 5 arms with individual randomisation.


Participants200 apparently healthy primigravidae Hausa women living in Zaria, Nigeria and planning to deliver in Zaria, with less than 24 weeks of gestation, who had not taken any antimalarial treatment or iron supplements in current pregnancy.


InterventionsParticipants were randomly assigned to 1 of 5 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.

Setting and health worker cadre: the intervention was performed by an obstetrician working with a Hausa-speaking social worker in Zaria.


OutcomesFull blood count, malarial parasites, serum and red cell folate, at first attendance, 28 week and 36 weeks gestational age, at delivery, and at 6 week postpartum, serum vitamin B12 at first attendance and at 36 weeks gestational age, Hb electrophoresis and fetal microscopy once, and bone marrow at delivery, clinical malaria.


NotesRelevant groups are:

group 3 vs group 2 for comparison 2: daily oral supplementation with iron alone vs no treatment/placebo.

group 4 vs group 5 for comparison 4: daily oral iron + folic acid supplementation vs daily oral folic acid alone (without iron) supplementation.

Results were not reported separately for each randomised group and we have been unable to include data from this trial in the review.

Gestational age at start of supplementation: mixed gestational age (up to 24 weeks' gestation).

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

Daily iron dose: higher daily dose (60 mg elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: not clear.

Malaria setting: yes. Described as a malaria endemic area: 28% of P falciparum in the sample and 40% of those anaemic. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the whole country. Resistance to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table.

Allocation concealment (selection bias)Low riskTreatment allocation code; "Neither the researchers nor the patients were aware of the treatment allocated until after the completion of the study."

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and researchers blinded. Placebos were provided which were packaged so that they "could not be distinguished by sight".

Incomplete outcome data (attrition bias)
All outcomes
High riskWomen that were excluded because they developed anaemia or "defaulted"; were replaced. Further loss to follow up occurred during the trial; it was not clear how many women were followed up at each data collection point. 89 out of 200 women randomised delivered in the hospital and no complete, clear data could be extracted for the outcomes of interest in this review.

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

Other biasUnclear riskNo other bias apparent.

Foulkes 1982

MethodsQuasi-randomised trial, 2 arms with individual randomisation.


Participants568 apparently healthy pregnant women with less than 20 weeks of pregnancy and no prior iron supplementation.


InterventionsParticipants were allocated alternatively to receive 100 mg of elemental iron and 350 μg (0.35 mg) folic acid daily or no treatment.


OutcomesFerritin and Hb concentrations were measured at baseline and at 28 and 36 weeks of gestation and 2 days postpartum. MCV and MCH were measured at 2 days postpartum. Number of women developing anaemia in the 2nd and 3rd trimester was reported (Hb < 105 g/L).

Setting and health worker cadre: the intervention was performed by obstetricians at Southmead Hospital in Bristol, United Kingdom.


NotesOnly means and median are presented for continuous outcomes. No SDs are reported and for ferritin concentrations no ln-transformed data are presented. Limited data were extractable from the paper and subsequent communication with the author. The paper reported the number of women developing Hb < 105 g/L from the start of supplementation to delivery. No data were extracted from this trial.

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

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

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: not clear.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAlternation.

Allocation concealment (selection bias)High riskAlternate allocation.

Blinding (performance bias and detection bias)
All outcomes
High riskNo placebos provided.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk537 women randomised, then 67 excluded post-randomisation for reasons that may have related to outcomes (non-compliance). Subsequent loss to follow-up was not clear as denominators were not reported in the text or figures.

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

Other biasUnclear riskNo other bias apparent.

Freire 1989

MethodsRCT, 2 arms with individual randomisation.


Participants412 non-black pregnant women with 26 ± 2 weeks of gestation, who had not received iron supplements in the previous 6 months, from low SES using the prenatal unit of public obstetric hospital in Quito, Ecuador.


InterventionsParticipants were randomly assigned to receive 2 tablets containing 78 mg of elemental iron (as ferrous sulphate) daily or placebo during a period of 2 months.

Setting and health worker cadre: the intervention was performed by physicians in the Prenatal Unit of Quito's public obstetric hospital in Quito, Ecuador.


OutcomesHb, 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.


NotesApart from mean Hb levels at term no other prespecified outcomes from this review are presented in the paper. No data can be extracted from this trial.

Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation).

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

Daily iron dose: high daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. The study was conducted in Quito where there is no risk of malaria. As of 2011: Malaria risk – P. vivax (87%), P. falciparum (13%) – exists throughout the year below 1500 m, with moderate transmission risk in coastal provinces. There is no risk in Guayaquil, Quito and other cities of the inter-Andean region. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described ("randomly assigned").

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as "double-blind", placebo tablets provided.

Incomplete outcome data (attrition bias)
All outcomes
High risk412 women were recruited and 240 followed up. Loss to follow-up was 41.7% and there were missing data for some outcomes.

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

Other biasUnclear riskNo other bias apparent.

Groner 1986

MethodsRCT, 2 arms, individual randomisation.


Participants40 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 weeks of pregnancy with HCT equal or above 31%. 2 women objected to the randomisation and 13 dropped out of the study. Both groups received multiple micronutrients. Supplementation lasted a month.


InterventionsParticipants were randomly assigned to 1 of 2 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.

Setting and health worker cadre: the intervention was performed by physicians at the Adolescent Pregnancy Clinic and Obstetrics Clinic of Johns Hopkins and Sinai Hospitals in Baltimore, Maryland, United States of America.


OutcomesPsychometric tests (arithmetic, total digit span, digit symbol, vocabulary and others) were performed and hematologic status was measured at baseline and after a month.


NotesHaematologic outcomes cannot be extracted from the paper. None of the other outcomes were sought.

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

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

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous fumarate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low risk"Each subject was handed an unlabeled bottle of capsules... The test administrator was also unaware of the content of the capsules distributed."

Incomplete outcome data (attrition bias)
All outcomes
High risk15 of the 40 women randomised were not followed up. Group size at follow up was not balanced (16 vs 9).

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

Other biasUnclear riskNo other bias apparent.

Han 2011

MethodsQuasi-randomised control trial with 3 arms and individual allocation to groups by order of enrolment.


Participants153 anaemic pregnant women 12 to 24-wk gestation, age range 20-30 years, with 80≤ Hb <110 g/L, no dietary supplements use during the previous 2 months and no abnormal pregnancy response recruited from the communities of Shen county, Shandong province, China.


InterventionsParticipants were allocated to 1 of the 3 groups in the order of enrolment: group 1 (n = 51) was the placebo control; group 2 (n = 51) received supplement daily containing 60 mg elemental iron (as ferrous sulphate); group 3 (n = 51) received a supplement daily containing 60 mg elemental iron (as NaFeEDTA). The capsules were labelled in red, yellow and blue colour and manufactured by Hurun’s company (a Chinese food-additive company, Beijing). The intervention lasted 2 months. Women were visited at home once each week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken.

Setting and health worker cadre: the intervention was performed by village nurses in house visits to the participants in the communities of Shen county, Shandong province, China.


OutcomesHb concentration; plasma iron; soluble transferrin receptor; total iron-binding.
capacity; Malondialdehyde; superoxide dismutase; glutathione peroxidase


NotesThe participants in the placebo group in this study were given iron supplementation with NaFeEDTA or foods rich in iron, such as the hemachrome-iron from animal foodstuff, such as meat, fish and sea foods, immediately after the trial.

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

Anaemic status at start of supplementation: anaemic status.

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate and iron EDTA.

Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskIndividual allocation to groups by order of enrolment.

Allocation concealment (selection bias)High riskThe capsules were labelled in red, yellow and blue colour and manufactured by Hurun’s company (a Chinese food-additive company, Beijing).

Blinding (performance bias and detection bias)
All outcomes
Low riskTrial participants and the research team were unaware of the treatment assignment. The trial was unblinded after analysis of the primary outcomes.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete data were available for 147 women, 96.1% of the original number of 153 pregnant women

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

Other biasLow riskThe groups did not differ in age, gestational stage, gravidity, haematological status, levels of MDA, SOD and GSH-Px at baseline.

Hankin 1963

MethodsQuasi-randomised trial, 2 arms with individual randomisation.


Participants174 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.


InterventionsParticipants 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 un supplemented.
Supplementation started during 2nd trimester and ending time is unclear.

Setting and health worker cadre: the intervention was performed by physicians at the Queen Elisabeth Hospital in Woodville, South Australia.


OutcomesMaternal: Hb and HCT at 20-30 week, 30-40 week, at 5 days, at 6 week and at 3 months postpartum.
Infant: Hb from umbilical cord, at 6 week, at 3 months and at 6 months of age (not reported).


NotesUnsupervised.
Compliance not reported.

Gestational age at start of supplementation: mixed/unspecified gestational age.

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

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised, alternate by day of the week.

Allocation concealment (selection bias)High riskAlternate allocation.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5% excluded.

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

Other biasUnclear riskNo other bias apparent.

Harvey 2007

MethodsRCT, 2 arms, individual randomisation.


Participants13 apparently healthy non-anaemic non-smokers pregnant women aged 18-40 years and < 14 weeks of gestation with singleton pregnancy recruited through local medical practitioners and the Maternity Department of the Norfolk and Norwich University Hospital, England, United Kingdom.


InterventionsParticipants were randomly assigned to 1 of 2 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.

Setting and health worker cadre: The intervention was performed by midwives and obstetricians at Maternity Department of the Norfolk and Norwich University Hospital in Norwich, United Kingdom.


OutcomesMaternal: Hb, serum ferritin, transferrin receptor, plasma zinc, exchangeable zinc pool, zinc excretion and zinc absorption at 16, 24 and 34 weeks of gestation.
Infant: birthweight (not reported).


NotesUnsupervised.
Compliance not reported.

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCoded bottles were provided by manufacturer.

Allocation concealment (selection bias)Low riskSupplied in coded opaque bottles.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant blinded. Care provider and outcome assessor unblinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Hemminki 1991

MethodsRCT, 2 arms, individual randomisation.


Participants2994 pregnant women with less than 16 weeks of gestation attending 15 communal maternity centres and 12 centres in 5 neighbouring communities in Tampere, Finland who consented to participate. Exclusion criteria included: chronic illness, anaemia (HCT under 0.32 or Hb < 110 g/L), late arrival, likelihood of moving away from the area before child birth, or twin pregnancies.


InterventionsParticipants were randomly assigned to 1 of 2 policy 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 of gestation; or group 2 (selective) who received no iron supplements. Women in the selective group who had a HCT of < 0.30 (Hb < 100 g/L) on 2 consecutive visits were provided 100 mg elemental iron (as ferrous sulphate) to be taken 1 tablet (50 mg) twice a day for 2 months or until HCT increased to 0.31 (Hb 100 g/L).

Setting and health worker cadre: the intervention was performed by general practitioners, midwives and public health nurses at no-cost communal maternity centres in towns surrounding Tampere, Finland.


OutcomesMaternal: HCT at 28th and 36th week of gestation, weight increase (kg), systolic and systolic blood pressure at 36th week, proteinuria, HCT at 28th and 36th week of gestation,  overall estimation of health, symptoms of tiredness, sick days, fever, adverse effects from iron supplements, symptoms related to iron supplements, duration of first stage of labor, caesarean section, blood transfusion, fever I hospital, postpartum stay in hospital for more than 7 days, not breastfeeding in postpartum check up, spontaneous abortions, length of gestation in week, proportion of premature births.

Infant: birthweight, low birthweight, death, perinatal mortality, 1 min Apgar score < 7, special care unit, malformations, infections, hyperviscosity as a discharge diagnosis, weight gain, overall health.


NotesAverage iron intake in the routine group was 124 mg elemental iron a day. 32 women were excluded: 20 twin pregnancies, 4 discovered not to be pregnant, and 8 for other (unintentional) reasons. Of the remaining 2912, 218 participants miscarried. Final samples were therefore 2694: 1336 women in the routine iron group and 1358 women in the selective group.

The limit to prescribe treatment on the selective group was changed in the middle of the study to HCT < 0.31 (Hb < 105 g/L) after the 33rd week of gestation.

Compliance assessed daily through self-reporting. Women in the routine group who reported not having taken the iron supplements during the preceding 2 weeks was only 8.2% at 28th week of gestation and 14% at 36 weeks.

It is reported that 7.4% of mothers in the selective group (i.e. no iron unless anaemic) reported having taken iron either regularly or "every now and then" in the preceding 2 weeks, at 28th week of gestation, while this proportion increased to 14% in the 36th week.

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

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

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: not clear/varied.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom codes created by computer in blocks of 10 by maternity centre.

Allocation concealment (selection bias)Low riskSealed numbered envelopes stored in containers from which midwives were asked to take them in order.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5% lost to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Hoa 2005 (C)

MethodsRandomisation may have been by cluster (communes) rather than individual women. Block randomised trial with 4 arms.


Participants202 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 weeks of gestation who agreed to participate in the study were selected to participate.


InterventionsParticipants were assigned through block randomly assigned to 1 of 4 interventions: group 1 (n = 44) received 400 ml fortified milk with iron (ferrous fumarate), 17.5 mg vitamin C and 200 μg (0.2 mg) folic acid daily; group 2 (n = 41) received 400 ml of fortified milk containing 17.5 mg vitamin C and 200 μg (0.2 mg) folic acid but no iron daily; group 3 (n = 40) received 1 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 1 placebo tablet daily.

Setting and health worker cadre: the intervention was performed by community health workers working from a commune health centre operated by the National Ministry of Health in the rural delta area of the Red River in northern Vietnam (Dong Hung District, Thai Binh Province).


OutcomesHb at baseline, 5 , 10, 16 weeks after start of the study, total iron-binding capacity, serum transferrin saturation, anaemia, iron deficiency, weight, presence of hookworms.


NotesFor purposes of this review groups 3 vs group 4 comparing iron and folic acid supplements are relevant. However, no data on outcomes of interest could be extracted from the published report. It was reported in the paper that the "decrease in haemoglobin concentration in the supplemented groups was significantly less"; and that, "the transferrin saturation level increased slightly in the supplement group".

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

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

Daily iron dose: higher dose (60 mg of elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk due predominantly to P. falciparum exists in the whole country, excluding urban centres, the Red River delta, the Mekong delta, and the coastal plain areas of central Viet Nam. High-risk areas are the highland areas below 1500 m south of 18˚N, notably in the 4 central highlands provinces Dak Lak, Dak Nong, Gia Lai and Kon Tum, Binh Phuoc province, and the western parts of the coastal provinces Khanh Hoa, Ninh Thuan, Quang Nam and Quang Tri. Resistance to chloroquine, sulphadoxine–pyrimethamine and mefloquine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskIt was not clear whether individual women or communes were randomised "For practical reasons it was possible to implement only 1 type of intervention per commune (block randomly adjusted)".

Allocation concealment (selection bias)Unclear riskLittle information about study methods was provided.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo supplements were provided but it was not clear whether the health workers supervising distribution were aware of whether the women were receiving active or placebo treatment. Outcome assessment may have been partly blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up not described.

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

Other biasLow riskGroups appeared comparable at baseline.

Holly 1955

MethodsRCT, 3 arms with individual randomisation.


Participants207 pregnant women with less than 26 weeks of gestation and Hb > 100 g/L attending antenatal care clinic in Nebraska, USA.


InterventionsParticipants were randomly assigned to 1 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 for each of the participants until delivery.

Setting and health worker cadre: the intervention was performed by obstetricians at the Department of Obstetrics and Gynecology of the Univeristy of Nebraska, College of Medicine in Omaha, Nebraska, United States of America.


OutcomesMaternal: Hb, HCT, serum iron, erythrocyte protoporphyrin at 3-6 months and pre-delivery.


NotesUnsupervised.
3 iron compounds (n = 94) were used: ferrous gluconate (n = 40), ferrous sulphate (n = 32) and Mol-Iron® (n = 22). The iron treated groups with different iron salts were merged together by the author as iron treated group since the results were comparable. The iron and cobalt treatment group is not included in this review.
Compliance not reported.

Gestational age at start of supplementation: mixed gestational age at the start of supplementation (before 26 weeks).

Anaemic status at start of supplementation: mixed anaemia status (Hb > 100 g/L).

Daily iron dose: higher daily dose (60 mg or more elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: mixed (groups merged in analysis).

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskNeither participants nor provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up not described.

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

Other biasUnclear riskNo other bias apparent.

Hood 1960

MethodsRCT, 3 arms, individual randomisation.


Participants75 consecutive apparently healthy pregnant women with 32-34 weeks of gestation attending the maternity clinic at St Anthony's Hospital, Oklahoma City, Oklahoma, USA.


InterventionsParticipants were randomly divided in 3 groups: group 1 served as control and received no treatment; group 2 received 220 mg elemental iron (as ferrous sulphate) daily; and group 3 received 55 mg elemental iron (as sustained release ferrous sulphate) daily.
Supplementation started at 32-34 week of gestation until delivery.

Setting and health worker cadre: the intervention was performed by obstetricians at the Department of Obstetrics and Gynecology of St. Anthony's Hospital in Oklahoma City, Oklahoma, United States of America.


OutcomesMaternal: Hb, HCT, incidence and severity of side effects on a weekly basis until delivery.


NotesUnsupervised.
For any iron vs no treatment comparison groups were merged.
Compliance not reported.

Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation).

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

Daily iron dose: medium dose (55 mg elemental iron) and higher dose (220 mg elemental iron).

Iron release formulation: sustained release preparation and normal release preparation/not specified.

Iron compound: ferrous sulphate and sustained release ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% losses to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Kerr 1958

MethodsRCT, 4 arms with individual randomisation.


Participants430 apparently healthy women with 24-25 weeks of singleton pregnancy and Hb equal or above 104 g/L attending antenatal clinic at Simpson Memorial Maternity Pavillion, Edinburgh, United Kingdom.


InterventionsParticipants were randomly allocated to 1 of 4 groups: group 1 received 35 mg of elemental iron (as ferrous sulphate) 3 times a day; group 2 received 35 mg of elemental iron (as ferrous gluconate) 3 times a day; group 3 received 35 mg of elemental iron (as ferrous gluconate) with 25 mg of ascorbic acid, 3 times a day; group 4 received placebo.
Supplementation started at 24-25th week of gestation until term.

Setting and health worker cadre: the intervention was performed by physicians at the Simpson Memorial Maternity Pavilion in Edinburgh, United Kingdom.


OutcomesMaternal: Hb, red cell count, HCT at baseline and at 37th week.


NotesUnsupervised.
Groups 1 and 2 were merged for analysis. Group 3 was not used in this review.
Compliance not measured.

Gestational age at start of supplementation: late gestational age (supplementation started after 20 weeks' gestation).

Anaemic status at start of supplementation: unspecified/mixed anaemia status (no severe anaemia, all had Hb equal or above 104 g/L).

Daily iron dose: higher iron dose (all treatment groups received more than 60 mg of elemental iron daily (105 mg)).

Iron release formulation: norm,al release preparation/unspecified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: no risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy cards shuffle.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant blinded. Provider blinded to treatments but not to controls. Outcome assessor unclear.

Incomplete outcome data (attrition bias)
All outcomes
High risk23% of participants were lost to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Kuizon 1979

MethodsRCT, 4 groups (with supplementation depending on Hb levels at baseline) individual randomisation.


Participants385 pregnant women attending antenatal care at government health centres in Greater Manila area, Philippines. Mean gestation at recruitment was approximately 21 weeks until delivery. Women were assessed at baseline and women with anaemia ( Hb < 120 g/L in 1st and < 110 g/L in 2nd trimester) received a higher dose of supplements.


InterventionsParticipants were randomly assigned to 1 of 4 groups: group 1 received placebo (anaemic and non-anaemic women received 1 placebo capsule); group 2 received 65 mg of elemental iron ( as 325 mg ferrous sulphate) women received either 1 or 3 oral tablets daily; group 3 received 100 mg ascorbic acid (either 1 or 3 oral tablets daily); group 4 received 65 mg elemental oral iron (as ferrous sulphate) plus 100 mg ascorbic acid - women received either 1 or 3 tablets.

Supplementation started from recruitment in 1st and second trimester until delivery.

Setting and health worker cadre: the intervention was performed by health centre staff at government health centres and maternity clinics in the greater Manila area, Manila, Phillipines.


OutcomesMean Hb concentration at 32 and 39 weeks (for women anaemic and not anaemic at baseline) Haematiocrit at 32 and 39 weeks, serum iron at 32 and 39 weeks, transferring saturation levels at 32 and 39 weeks.


NotesAttrition in this study was very high (half of the women were lost to follow-up by 32 weeks' gestation and more than 75% by term). For this reason we have not included data from this study in our data and analyses tables.

Gestational age at start of supplementation: mixed gestational age at the start of supplementation (mean gestation at start of supplementation was 21 weeks).

Anaemic status at start of supplementation: mixed anaemia status (dose depended on Hb level at baseline).

Daily iron dose: higher daily dose (greater than 60 mg of elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk exists throughout the year in areas below 600 m, except in the 22 provinces of Aklan, Albay, Benguet, Biliran, Bohol, Camiguin, Capiz, Catanduanes, Cavite, Cebu, Guimaras, Iloilo, Northern Leyte, Southern Leyte, Marinduque, Masbate, Eastern Samar, Northern Samar, Western Samar, Siquijor, Sorsogon, Surigao Del Norte and metropolitan Manila. No risk is considered to exist in urban areas or in the plains. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. Human P. knowlesi infection reported in the province of Palawan.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear risk"randomly assigned".

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo was provided but women received different doses (and number of tablets). It was not clear if outcome assessment was blind.

Incomplete outcome data (attrition bias)
All outcomes
High riskVery high attrition.

679 women recruited. In non-anaemic women, 189/385 followed up (49%). In anaemic group  146/294 (50%) followed up at 32 weeks by 39 weeks only 94/385 non-anaemic women followed up (24%) and 60 in anaemic group (20%).

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

Other biasHigh riskThe reasons for the very high levels of attrition were not explained (except that some women delivered before term). The very high loss to follow-up means that results are very difficult to interpret.

Lee 2005

MethodsRCT, 5 arms with individual randomisation.


Participants154 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.


InterventionsParticipants were randomly allocated to 1 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) of folic acid from first trimester until delivery; group 3 received 30 mg elemental iron (as ferrous sulphate) and 175 μg (0.17 mg) of 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) of folic acid from 20th week of gestation until delivery; or control group with no supplement.

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


OutcomesMaternal: Hb, HCT, serum ferritin, serum soluble transferrin receptor concentrations at baseline and during first, second, third trimester of pregnancy and at delivery.


NotesUnsupervised.
Compliance not reported.

included in comparison 3: daily iron + folic acid vs no treatment/placebo and only different groups included in the subgroup analysis by gestational age at start of supplementation (early (group 1+ group 2); late (group 3 + group 4); and by iron dose: low (group 1 + group 3); higher (group 2 + group 4).

Gestational age at start of supplementation: mixed gestational ages (different arms started supplementation before or after 20 weeks' gestation).

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

Daily iron dose: mixed (with different arms receiving lower (30 mg) and higher (60 mg) of elemental iron daily.

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Limited malaria risk due exclusively to P. 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)Low riskDescribed as "truly random" but the method was not stated.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant, provider and outcome assessor blinding unclear.

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

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

Other biasUnclear riskNo other bias apparent.

Liu 2000

MethodsRCT with 3-arms, and individual randomisation.


Participants300 pregnant women with 24 - 28 weeks of gestation with no had organic disease and Hb level higher than 100 g/L who received antenatal examinations in Second Affiliated Hospital, Zhujiang Hospital, the First Military Medical University, Guangzhou, China from January 1998 to January 1999.


InterventionsParticipants were randomly assigned to 1 of 3 groups: group 1 received 1 table daily containing 100 mg elemental iron (as ferrous sulphate sustained-release) with 500 mg vitamin C and B-complex vitamins (amounts not reported) administered orally for 4 consecutive weeks; group 2 received conventional iron supplement (as 300 mg ferrous sulphate) administered 3 times a day to meals for 4 consecutive weeks; and group 3 did not receive any iron supplementation.

Setting and health worker cadre: intervention and outcome assessment were conducted by physicians from the Obstetric & Gynecology Department, Zhujiang Hospital, the First Military Medical University, Guangzhou, China.


OutcomesRBC, Hb and serum ferritin at baseline at after 4 weeks of intervention and before delivery. Anaemia, iron deficiency, fatigue, dizziness, shortness of breath, and pale mucous membranes and skin, tinnitus, presence of stomatitis or glossitis, premature birth, average Apgar score, congenital malformations. Side effects reported: nausea and loss of appetite, severe gastrointestinal reactions including vomiting, abdominal pain, and diarrhoea, metallic taste in the mouth, black staining of their teeth. Blood tests and serum ferritin measurement were performed for the gravidas after 4 and 8 weeks of supplementation and before delivery. The Apgar scoring and physical examinations were performed for the newborns after delivery.


NotesGestational age at start of supplementation: late gestational age (supplementation started at 20 weeks' gestation or later). Only groups included in the comparisons are group 2 and group 3 who did not receive supplements.

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: high daily dose (60 mg or more mg iron daily).

Iron release formulation: normal and slow release preparation for group 1 (not included in the comparisons in this review).

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as randomised but method unclear.

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

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported in the paper.

Incomplete outcome data (attrition bias)
All outcomes
Low riskData reported as complete for all the participants reported as randomised.

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

Other biasLow risk There were no significant differences in terms of age, gestational age, body weight, and H level among the 3 groups (all P > 0.05).

Ma 2010

MethodsRCT with 4 arms including a placebo and individual randomisation.


Participants164 anaemic pregnant women (80 g/L , Hb ,110 g/L), 12–24 weeks gestation and 20–35 years old recruited between March 2004 and September 2006 from the community hospitals of Shen County in the central area of China.


InterventionsParticipants were randomly allocated to 1 of 4 groups for this 2-month intervention in the order of recruitment: group 1 (n = 41) received placebo; group 2 (n = 41) received 60 mg elemental iron (as ferrous sulphate); group 3 (n = 41) received 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid daily; and group 4 (n = 41) received 60 mg elemental iron (as ferrous sulphate), and 400 μg (0.4 mg) folic acid, 2 mg retinol and 1 mg riboflavin daily.

Setting and health worker cadre: In each community, a local female community health worker called ‘village nurse’ was responsible for the recruitment and distribution of the supplements. Women were recruited from the community hospitals and then home-visited once a week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken. The nurse also provided counselling about the possible side effects.


OutcomesHb, plasma iron, ferritin, folic acid, retinol riboflavin after the 2 months intervention. Other outcomes included membrane fluidity, oxidative stress markers such as GSH-Px, SOD, and MDA.


NotesThis study is included but does not provide any data that can be useful; for purposes of this review.

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

Anaemic status at start of supplementation: anaemic.

Daily iron dose: high daily dose (60 mg or more mg iron daily).

Iron release formulation: normal.

Iron compound: ferrous sulphate.

Malaria setting: yes. Malaria as of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasi-randomised as participants were randomly allocated to 1 of 4 groups for this 2-months intervention in the order of recruitment: group

Allocation concealment (selection bias)Unclear riskTretaments were colour coded. It was stated that the code was not revealed until after the analysis.

Blinding (performance bias and detection bias)
All outcomes
Low riskIt was stated that women and staff were blind to treatment.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk164 women were randomised and 145 (88%) were included in the analysis.

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

Other biasUnclear riskNo other bias apparent.

Makrides 2003

MethodsRCT, 2 arms with individual randomisation.


Participants430 non-anaemic pregnant women attending antenatal clinics at Women's and Children's Hospital in Adelaide, Australia with singleton or twin pregnancies and informed consent. 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.


InterventionsParticipants were randomly assigned to receive 1 tablet containing 20 mg of elemental iron daily between meals from week 20 until delivery or a placebo tablet.

Setting and health worker cadre: the intervention was performed by Pediatricians and Obstetricians in a maternity hospital in Adelaide, Australia.


OutcomesMaternal: Hb concentration at 28 week, at delivery, and at 6 months postpartum; ferritin concentration at delivery and at 6 months postpartum; maternal gastrointestinal side effects at 24 and 36 weeks of gestation; serum zinc at delivery and at 6 months postpartum; maternal well being at 36 week of gestation, at 6 weeks and at 6 months postpartum; pregnancy outcomes: type of birth, blood loss at delivery, gestational age. At 4 years postpartum: general health of mothers using the SF-36, a self-administered questionnaire that assesses 8 concepts of health.
Infant: birthweight, birth length, birth head circumference, Apgar scores, and level of nursery care. Follow-up at 4 years: intelligence quotient (IQ) using Stanford-Binet Intelligence Scale, child behaviour using Strength and Difficulties Questionnaire parent report form.


NotesUnsupervised but monthly phone calls to encourage compliance.
If anaemia was detected in the routine 28 week blood sample or if the clinician considered her Hb too low the woman was advised to purchase and take a high-dose iron supplement (containing > 80 mg elemental iron per tablet) until the end of pregnancy.
Compliance was 86% and 85% in the iron and placebo groups respectively.

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: lower daily dose (less than 30 mg iron daily) (20 mg).

Iron release formulation: normal release preparation.

Iron compound: not clear.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence with balanced blocks and stratified for parity.

Allocation concealment (selection bias)Low riskOpaque bottles marked with sequential numerical code prepared by the Pharmacy Department of Women's & Children's Hospital.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and care provider blinded.

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

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

Other biasUnclear riskNo other bias apparent.

Meier 2003

MethodsRCT, 2 arms with individual randomisation.


Participants144 non-iron deficient adolescents 15-18 years old in their first pregnancy and adult women 19 or older in their first or greater pregnancy attending prenatal care at Marshfield Clinic, Wisconsin, USA.


InterventionsParticipants were randomly assigned to receive once daily 60 mg of elemental iron (as ferrous sulphate) or a placebo. All women received 1000 μg (1 mg) of folic acid daily.


OutcomesMaternal: prevalence of iron-deficiency anaemia, compliance to treatment, side effects, vomiting, nausea, constipation, diarrhoea, caesarean section, serum ferritin and Hb concentrations at 24-28 weeks' gestation and at 36-40 weeks' gestation.
infant: perinatal morbidity and mortality, birthweight, birth length, Apgar scores at 1 and 5 minutes, admission to neonatal unit, prevalence of birthweight.

Setting and health worker cadre: the intervention was performed at multicenter clinic in central Wisconsin.


NotesUnsupervised.
All adolescents and adult pregnant women who developed iron-deficiency anaemia at 24-28 weeks' gestation were offered 60 mg elemental iron 3 times a day.
Compliance was assessed through pill counts and ranged from 32% to 124% (median 95.5% in iron supplemented group and 87.4% in placebo group.

Gestational age at start of supplementation: unspecified/mixed gestational age.

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskStratified by age group.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded. Outcome assessor unclear.

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 biasUnclear riskNo other bias apparent.

Menendez 1994 (C)

MethodsCluster randomised trial, 2-arm trial.


Participants550 multi gravidae pregnant women with less than 34 weeks 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.


InterventionsParticipants were allocated randomly by compound of residence to receive 60 mg of elemental iron (as ferrous sulphate) or placebo. All pregnant women received a weekly tablet of 5000 μg (5 mg) of folic acid but no antimalarial chemoprophylaxis.
Supplementation started at 23-24 weeks until delivery.

Setting and health worker cadre: the intervention was performed by traditional birth attendants in villages in the North Bank Division of The Gambia within the national village-based primary health care program.


OutcomesMaternal: Hb concentrations at baseline, 4-6 weeks before delivery and 1 week postpartum; plasma iron, total iron binding capacity, transferrin saturation, deposition of malaria pigment in placenta.
Infant: birthweight within 7 days of delivery.


NotesUnsupervised.
Malaria prophylaxis is provided to primigravidae in The Gambia. 30 women with PCV less than 25% after enrolment (17 in iron group and 13 in placebo) were treated and withdrawn from study and analysis. Additionally 29 women (7 in iron and 22 in placebo group) had PCV below 25% at the second visit and were also withdrawn from study. No differences in the prevalence and severity of peripheral blood or placental malaria infection. No increase in the susceptibility to malaria infection in the 2 groups.
Compliance: estimated tablet consumption was 81.1 and 81.7 tablets in the iron and placebo groups respectively.

Gestational age at start of supplementation: late gestational age (more than 20 week's gestation at the start of supplementation).

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

Daily iron dose: higher daily dose (60 mg daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: high malaria risk area. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the whole country. Resistance to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised but method unclear.

Allocation concealment (selection bias)High riskNot described. Active treatment and placebo were different colours.

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.

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

Other biasUnclear riskNo other bias apparent.

Milman 1991

MethodsRCT 2 arms with individual randomisation.


Participants248 healthy Caucasian Danish women attending Birth Clinic in Copenhagen, Denmark within 9-18 weeks of gestation and normal pregnancy. Exclusion criteria: complicated delivery, excessive smoking (> 9 cigarettes/day).


InterventionsParticipants 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.

Setting and health worker cadre: the intervention was performed by obstetricians at the Birth Clinic of the Department of Obstetrics, Herning Hospital in Copenhagen, Denmark.


OutcomesMaternal: Hb, HCT, erythrocyte indices, iron status, serum ferritin, serum transferrin saturation, serum erythropoietin at baseline and every 4th week until delivery, and 1-8 weeks after delivery in subsample; pregnancy complications.
Infant: birthweight, serum ferritin, transferrin saturation and serum erythropoietin in umbilical cord.


NotesUnsupervised.
Of the 248 women, 20 placebo and 21 iron treated were excluded by the authors in some of the analysis for the following reasons: withdrawn consent, 10; uterine bleeding episodes, 5; placental insufficiency, placenta praevia and abruptio placenta, 7; pre-eclampsia, 3; partus prematurus, 5; excessive smoking, 3. Sample size has been adjusted for ITT.
Compliance: number of tablets consumed was 159 +/- 38 and 93 +/-43 tablets in the iron treated and placebo groups respectively.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

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

Daily iron dose: higher daily dose (60 mg or more of elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous fumarate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded. Outcome assessor unclear.

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

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

Other biasUnclear riskNo other bias apparent.

Ouladsahebmadarek 2011

MethodsRCT with 2-arms and individual randomisation


Participants960 healthy women at first trimester of pregnancy with Hb > 120 g/L and blood pressure < 140/90
mmHg from Alzahra University dependent hospital in Vanak,Tehran, Iran.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received daily 1 multiple micronutrient + 30 mg elemental iron from week 13 of gestation until delivery; group 2 received daily 1 daily multiple micronutrient + placebo tablet from 13 weeks of pregnancy until delivery.

Setting and health worker cadre: the intervention was conducted by obstetricians and gynaecologists from the Alzahra hospital, in Iran.


OutcomesHb concentrations, HCT, serum iron, serum ferritin, total iron binding capacity at baseline and at delivery , birth weight, gestational age at birth, prematurity, Intrauterine growth retardation, 1' Apgar score, 5 min Apgar score, admission duration in neonatal care intensive unit, premature rupture of membranes, placenta abruption, pre-eclampsia, periventricular-intraventricular haemorrhage (PIH), gestational diabetes, intrauterine fetal death (IUFD), oligohydramnios.


NotesBoth groups were matched for mother's age, body mass index, parity, previous obstetric history and iron parameters.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

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

Daily iron dose: 30 mg elemental iron.

Iron release formulation: normal release preparation/not specified.

Iron compound: not specified.

Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. 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. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and care provider were blinded to the intervention groups. Outcome assessor not described,

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were 56 loses to follow-up in the group 1 (iron) in comparison to 49 participants lost to follow-up in the placebo group. 70/480 (14.6%) were excluded in the group 1 in comparison to 108/480 (22.5%) in the placebo group. Overall attrition was 18%

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

Other biasUnclear riskNo other bias apparent.

Paintin 1966

MethodsRCT, 3 arms with individual randomisation.


Participants180 primigravidae women with less than 20 weeks' gestation and Hb > 100 g/L attending antenatal clinic in Aberdeen Maternity Hospital, United Kingdom.


InterventionsParticipants were randomly assigned to 1 of 3 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.

Setting and health worker cadre: the intervention was performed by clinic and laboratory staff of the Obstetric Medicine Research Unit of Aberdeen Maternity Hospital and Castle Terrace Antenatal Clinic in Aberdeen, United Kingdom.


OutcomesMaternal: Hb, HCT at baseline, and at weeks 20, 30, 36 of gestation and 7-13 days postpartum; plasma volume at 30 weeks, total red cell volume, serum iron and total iron binding capacity at 30 weeks, subjective health and side effects at 30 weeks.


NotesUnsupervised.
Compliance estimated by measuring tablets returned. Authors report good compliance.

Gestational age at start of supplementation: late gestational age (20 weeks' gestation at the start of supplementation).

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

Daily iron dose: mixed doses (lower dose group - 12 mg daily; higher dose group 105 mg daily).

Iron release formulation: normal release preparation/not specified.

Iron compound: not specified.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Low riskPlacebo controlled with sequentially numbered packages.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5%.

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

Other biasUnclear riskNo other bias apparent.

Preziosi 1997

MethodsRCT 2 arms with individual randomisation.


Participants197 healthy pregnant women 17-40 years of age, with 28 +/- 3 weeks of gestation attending antenatal care clinic in a Mother-Child Health Center in Niamey, Niger.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received 100 mg of elemental iron (as ferrous betainate) daily; group 2 received placebo.
Supplementation was from 28 +/- 3 weeks of gestation until delivery.

Setting and health worker cadre: the intervention was performed by physicians at an isolated, urban maternal and child health centre serving low- or middle-class villagers in Niger.


OutcomesMaternal: Hb concentration, MCV, HCT, erythrocyte protoporphyrin, serum iron, transferrin, total iron binding capacity, serum ferritin concentrations, at baseline and at the first stage of labor and at 3 and 6 months postpartum, prevalence of iron deficiency and iron-deficiency anaemia.
Infant: birthweight and length, Hb concentration, MCV, erythrocyte protoporphyrin, serum iron, transferrin saturation, serum ferritin concentrations at birth and at 3 and 6 months; Apgar scores.


NotesSupervised by physicians who recorded tablet consumption.
Compliance not reported.

Gestational age at start of supplementation: late gestational age (more than 20 weeks' gestation)

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

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous betainate.

Malaria setting: high risk malaria setting. As of 2011: Malaria risk due predominantly to P. falciparum exists throughout the year in the whole country. Chloroquine-resistant P. falciparum reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskPackages of tablets numbered by manufacturer.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and provider blinded. Outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up not described.

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

Other biasUnclear riskNo other bias apparent.

Pritchard 1958

MethodsRCT 3 arms with individual randomisation.


Participants172 pregnant women believed to be in the second trimester of pregnancy by date of last menstrual period attending antenatal care clinic in Parland Memorial Hospital, Dallas, Texas, USA.


InterventionsParticipants were randomly assigned to 1 of 3 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.

Setting and health worker cadre: the intervention was performed by physicians at a prenatal clinic in the United States of America.


OutcomesMaternal: Hb concentration at baseline and at delivery.


NotesUnsupervised.
Only groups 2 (oral iron) and 3 (placebo) were included in this review.
Compliance not reported.

Gestational age at start of supplementation: mixed gestational age at the start of supplementation (2nd trimester).

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

Daily iron dose: higher daily dose (more than 60 mg elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
High riskNeither participant no provider blinded. Outcome assessor not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up not described (no loss to follow-up apparent).

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

Other biasHigh riskNo other bias apparent.

Puolakka 1980

MethodsRCT, 2 arms with individual randomisation.


Participants32 healthy non-anaemic pregnant women attending antenatal care at maternity centres of Oulu University Central Hospital, Finland with uncomplicated pregnancy of less than 16 weeks, and no earlier haematological problems.


InterventionsParticipants were randomly assigned to 1 of 2 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 1 month postpartum.

Setting and health worker cadre: the intervention was performed by obstetricians at maternity centres in Oulu, Finland.


OutcomesMaternal: Hb, HCT, red cell count, leucocyte count, reticulocytes, MCV, MCH, serum iron, total iron binding capacity, transferrin, vitamin B12, whole folate, and serum ferritin concentration at baseline, and at weeks, 16, 20, 24, 28, 32, 36, 40 and 5 days, 1, 2, and 6 months postpartum. Bone marrow aspirates at 16th and 32nd week and at 2 months postpartum.
Infant: birthweight, Apgar scores at 5 minutes.


NotesUnsupervised.
Compliance not reported.

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear risk"randomly divided into two groups".

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% lost to follow-up. It was stated that no women discontinued the study.

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

Other biasUnclear riskNo other bias apparent.

Romslo 1983

MethodsRCT, 2 arms with individual randomisation.


Participants52 healthy pregnant women attending outpatient Women's clinic at Haukeland Hospital, Bergen, Norway within first 10 weeks of a normal singleton pregnancy with uncomplicated delivery at 37-42 weeks.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received 200 mg of elemental iron (as ferrous sulphate) daily; group 2 received placebo.
Supplementation started at 10 weeks of gestation.

Setting and health worker cadre: the intervention was performed by physicians at the outpatient clinic of the Women's Clinic, Haukeland Hospital in Bergen, Norway.


OutcomesMaternal: Hb, HCT, PCV, erythrocyte count, leucocyte count, MCV, MCH, MCHC, serum iron, iron binding capacity, erythrocyte protoporphyrin, serum ferritin at baseline and every month during 2nd trimester and every 2 weeks until delivery.
Infant: birthweight and Apgar scores.


NotesUnsupervised.
Compliance measured by tablet count was 55% in the iron-treated group.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear risk"randomly divided into two groups".

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant blinded. Provider and outcome assessor unclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20%. (7/52 lost to follow-up).

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

Other biasUnclear riskNo other bias apparent.

Siega-Riz 2001

MethodsRCT, 2 arms with individual randomisation.


Participants429 non-anaemic iron replete women with less than 20 weeks of gestation attending who had not taken supplements containing iron in the last month, with a singleton pregnancy attending the prenatal clinic at the Wake County Human services in Raleigh, North Carolina, USA.


InterventionsParticipants were randomly assigned to 1 of 2 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 weeks of gestation. Supplementation started on average at 12 weeks. The multivitamin/mineral supplement contained the following: 4000 IU vitamin A; 400 IU vitamin D; 70 mg vitamin C; 500 μg (0.5 mg) folic acid;1.5 mg thiamine; 1.6 mg riboflavin; 17 mg niacin; 2.6 mg vitamin B6 ; 2.5 μg vitamin B1; 200 mg calcium; 100 mg magnesium; 1.5 mg copper; 15 mg zinc. Folic acid supplements were prescribed for all women who had received the positive pregnancy test until the first prenatal visit.

Setting and health worker cadre: the intervention was performed by physicians at a clinic serving patients of a low socioeconomic group in Raleigh, North Carolina, United States of America.


OutcomesMaternal: prevalence of anaemia, iron repletion and iron-deficiency anaemia at 26-29 weeks, side effects, compliance to treatment, iron status (Hb concentration, serum ferritin at 26-29 weeks, preterm delivery.
Infant: birthweight, proportion of low birthweight, small-for-gestational age.


NotesUnsupervised.
Compliance measured by pill counts and a questionnaire and was 66% in the iron group and 63% in the control group. Compliance was also measured by the Medication Event Monitoring System (MEMS) in a subsample of 100 women.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: lower daily dose (30 mg or less elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound:ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy using random number generator.

Allocation concealment (selection bias)Low riskTretament provided in coded bottles by pharmacy.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant, provider and outcome assessor blinded to treatment.

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 biasUnclear riskNo other bias apparent.

Simmons 1993

MethodsRCT, 3 arms with individual randomisation


Participants376 pregnant women with ages between 16-35 years, with mild anaemia (Hb concentrations between 80-110 g/L) attending 8 maternal and child health centres in Kingston, St. Andrews and Spanish Town, Jamaica, with gestational age between 14-22 weeks.


InterventionsParticipants were randomly assigned to 1 of 3 groups: group 1 received 1 placebo tablet daily; group 2 received 100 mg of elemental iron (as ferrous sulphate) daily; group 3 received 50 mg of elemental iron (in a gastric delivery system capsule) daily. All women received 400 μg (0.4 mg) of folic acid.

Setting and health worker cadre: the intervention was performed by clinic nurses and field workers at maternal and child health centres in urban areas of Jamaica.


OutcomesHb, HCT, MCV, white cell count, serum iron, total iron binding capacity, serum ferritin, serum transferrin receptor, at baseline, at 6 weeks and at 12 weeks after start of supplementation as well as side effects.


NotesGestational ages differed in the participants and we have not included outcome data from this trial in the review.

Gestational age at start of supplementation: mixed gestational age (up to 22 weeks' gestation at recruitment).

Anaemic status at start of supplementation: anaemic at the start of supplementation (mild anaemia Hb 80-110 g/L).

Daily iron dose: mixed dose (medium dose group - 50 mg elemental iron in gastric delivery system capsule; higher dose group 100 mg of elemental iron).

Iron release formulation: gastric delivery system capsule (controlled release preparation).

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Very limited risk of P. falciparum malaria may occur in the Kingston St Andrew Parish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy random number table.

Allocation concealment (selection bias)Low riskSealed envelopes distributed to clinics (not clear if envelopes were opaque).

Blinding (performance bias and detection bias)
All outcomes
High riskWomen may have been unaware of group allocation but the 2 supplements and the placebo differed in appearance and this would be apparent to staff.

Incomplete outcome data (attrition bias)
All outcomes
High risk376 women were recruited. 275 women were followed up (73.1%) but laboratory results were available for 66% of the original sample.

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

Other biasLow riskThe 3 groups were reported to have similar characteristics at baseline.

Suharno 1993

MethodsRCT 4 arms with individual randomisation.


Participants305 women randomised and follow-up data were available for 251 pregnant women aged 17-35 years, parity 0-4 and Hb concentrations between 80 and 109 g/L from rural villages in Bogor, West Java, Indonesia. Women recruited at 16-24 weeks' gestation.


InterventionsParticipants were randomly allocated to 1 of 4 groups: group 1 received 2.4 mg of retinol and 1 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 2 placebos for 8 weeks.

Setting and health worker cadre: the intervention was performed by village workers among middle and low socioeconomic groups in rural villages in Bogor, West Java, Indonesia.


OutcomesHb, HCT, serum ferritin, serum iron, total iron binding capacity, serum retinol, transferrin saturation, at baseline and after 8 weeks of supplementation (2nd and 3rd trimester).


NotesRelevant comparison in this review:

group 3 (iron + vit A) vs group 1 (vit A but no iron) for comparison 5: daily oral iron + other vitamins and minerals supplementation vs daily oral same other vitamins and minerals (without iron) supplementation.

group 2 (iron + placebo) vs group 4 (placebo) for comparison 2: daily oral supplementation with iron alone vs no treatment/placebo.

No prespecified outcome available for extraction. No data included.

Gestational age at start of supplementation: mixed gestational age at the start of supplementation (16-24 weeks' gestation).

Anaemic status at start of supplementation: anaemic at the start of supplementation (Hb < 110 g/L).

Daily iron dose: higher daily dose (60 mg elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: high malaria risk area. As of 2011: Malaria risk exists throughout the year in all areas of the 5 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, in big cities. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported. P. vivax resistant to chloroquine reported. Human P. knowlesi infection reported in the province of Kalimantan.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCarried out by independent researcher.

Allocation concealment (selection bias)Low risk"Subjects were allocated a sequential number from 1 to 305. An independent researcher randomly labelled the iron and placebo preparations" which were colour coded.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo controlled trial "the code was revealed once the data or all analyses had been entered in the computer and cleaned up".

Incomplete outcome data (attrition bias)
All outcomes
Low risk305 women were randomised and follow-up data were available for 251 (83%). Reasons for loss to follow-up were described and were similar across groups.

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

Other biasLow riskGroups appeared similar at baseline.

Sun 2010

MethodsQuasi-randomised trial with individual assignment in order of enrolment.


Participants186 anaemic pregnant women, 12 to 24-wk gestation, age between 20-30 y with Hb concentration ≥ 80 and < 110 g/L, no dietary supplements during the previous 2 months and no abnormal pregnancy response from the communities of Shen County in a central rural area of China.


InterventionsParticipants were randomly allocated in the order of enrolment to 1 of 4 groups: group 1 (n = 47) was supplemented daily with 60 mg elemental iron (as ferrous sulphate); group 2 (n = 46) received with 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid; group 3 (n = 46) with 60 mg elemental iron (as ferrous sulphate), 2 mg retinol and 400 μg (0.4 mg) folic acid, and group 4 (n = 47) was the placebo control group. The capsules were coloured red, yellow, green and blue during manufacture by Hurun (a Chinese food-additive company, Beijing). The capsules were to be taken daily for 2 months.

Setting and health worker cadre: the study was carried out in communities of Shen County in a central rural area of China. Women were home-visited once a week by the village nurse to replenish supplements and to monitor compliance by counting and recording the number of supplements that were taken.


OutcomesHb concentration; plasma iron; plasma retinol and plasma folate; erythrocyte protoporphyrin; interleukin 2; lymphocyte proliferation at baseline and after 2 months intervention.


NotesRelevant comparisons for this review:

group 1 (n = 47) was supplemented daily with 60 mg elemental iron (as ferrous sulphate) vs group 4 (n = 47) was the placebo control group.

group 2 (n = 46) received with 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid vs group 4 (n = 47) was the placebo control group.

Gestational age at start of supplementation: mixed gestational age at the start of supplementation (12-24 weeks' gestation).

Anaemic status at start of supplementation: anaemic at the start of supplementation (Hb < 110 g/L).

Daily iron dose: higher daily dose (60 mg elemental iron).

Iron release formulation: normal release preparation/not specified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.

Supported by Danone Nutrition Institute China.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as randomly assigned but method unclear. It is reported that the assignment to the groups was done in order of enrolment.

Allocation concealment (selection bias)High riskThe capsules were coloured red, yellow, green and blue during manufacture and the assignment was done in order of enrolment.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants, care providers and outcome assessors were blinded to the intervention groups.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow losses to followed up and they were balanced among the groups.

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

Other biasLow riskThere were no substantial differences between the groups in any of the baseline characteristics.

Svanberg 1975

MethodsRCT, 2 arms with individual randomisation.


Participants60 healthy primiparous women attending antenatal care clinic in Goteborg, Sweden with uncomplicated pregnancy and less than 14 weeks of gestation and with Hb concentrations above 120 g/L who had not received iron supplements in the previous 6 months or parenteral iron at any previous time. Women whose Hb concentration fell below 100 g/L during the study period were excluded and received immediate therapy.


InterventionsParticipants were randomly allocated to receive 200 mg of elemental iron (as a sustained release preparation of ferrous sulphate) daily or placebo from 12 weeks of gestation until 9 weeks post delivery.

Setting and health worker cadre: the intervention was performed by physicians at the University of Göthenburg in Sweden.


OutcomesMaternal: iron absorption measurements; Hb concentration, HCT, bone marrow haemosiderin, MCHC, total iron binding capacity, transferrin saturation at baseline, and at weeks 16, 20, 24, 28, 32, and 35; and 8-10 weeks after delivery.


NotesUnsupervised.
Compliance measured by remaining pills count was 86 +/- 3%.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher dose (more than 60 mg elemental iron daily).

Iron release formulation: sustained release preparation of ferrous sulphate.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants blind, care provider blind and outcome assessor blinded.

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

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

Other biasUnclear riskNo other bias apparent.

Taylor 1982

MethodsRCT, 2 arms with individual randomisation


Participants48 healthy pregnant women with no adverse medical or obstetric history attending antenatal care clinic in Newcastle, England, United Kingdom before 12 weeks of gestation.


InterventionsParticipants were randomly allocated to 1 of 2 groups: group 1 receive about 65 mg elemental iron (as 325 mg of ferrous sulphate) and 350 μg (0.35 mg) of folic acid daily from 12 weeks until delivery and group 2 received no supplements.

Setting and health worker cadre: the intervention was performed by physicians at the Princess Mary Maternity Hospital in Newcastle upon Tyne, United Kingdom.


OutcomesMaternal: Hb concentration, serum ferritin, MCV at 12 weeks and every 4 weeks until delivery, and at 6 days, 6 weeks and 6 months after delivery; plasma volume at 12 and 36 weeks of gestation.
Infant: birthweight, infant death, admission to special care unit.


NotesUnsupervised.
Compliance not reported.

Gestational age at start of supplementation: early gestational age (less than 20 weeks' gestation at the start of supplementation).

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

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear risk"Randomly assigned".

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

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

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

Other biasUnclear riskNo other bias apparent.

Tholin 1993

MethodsRCT, 3-arm trial with individual randomisation.


Participants83 healthy nulliparous non-vegetarian, non-anaemic pregnant women with serum ferritin concentrations above 10 μg/L


InterventionsParticipants were randomly assigned to 1 of 3 groups: group 1 received 100 mg of elemental iron (as ferrous sulphate) daily; group 2 received placebo, and group 3 received dietary advice only.

Setting and health worker cadre: the intervention was performed by physicians at the Maternal Health Unit of Ostersund Hospital in Ostersund, Sweden.


OutcomesBlood Hb, serum ferritin and blood manganese were determined at baseline before 15th week of gestation, between 25-28 weeks, and between 35-40 weeks of gestation. Median and ranges are presented.


NotesThe aim of this study was to examine the relationship between iron and zinc levels during pregnancy. No outcomes were extractable from this report for this review. Median serum zinc levels were reported by randomisation group "levels did not differ between groups". Median Hb levels were reported for women who had normal vs complicated deliveries (rather than by randomisation group. Results for mean Hb and serum ferritin levels were depicted in graphs.

Gestational age at start of supplementation: early gestational age at the start of supplementation (supplementation started before 20 weeks' gestation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as "randomly assigned".

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo controlled trial with outcome assessment by an obstetrician blind to group assignment.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThere were some discrepancies in the figures reported in 2 study publications. (We have not included data from this trial in the review.)

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

Other biasHigh riskResults were not simple to interpret and some results were not reported according to randomisation group.

Tura 1989

MethodsRCT, 2 arms with individual randomisation.


Participants254 non-anaemic non-iron deficient healthy pregnant women from multiple centres in Italy between 12-16 week of gestation. Exclusion criteria: acquired or congenital anaemia, haemoglobinopathies, thalassaemia, medically or surgically treated cardiopathy, abortion, hypertension, gastric resection, metabolic or endocrine disorder, hepatic or renal disease, epilepsy or another neurological disease, previously treated for cancer, alcohol or substance dependence.


InterventionsParticipants were randomly assigned to receive 40 mg of elemental iron (containing 250 g of ferritin in a micro granulated gastric resistant capsule) daily or no treatment from 12-16 weeks of gestation until the end of puerperium.

Setting and health worker cadre: The intervention was performed by physicians in health centres in Italy.


OutcomesMaternal: Hb concentration, red cell count, MCV, serum iron, total transferrin, transferrin saturation, serum ferritin at 12-16 weeks, 2 times during pregnancy, at 38-42 weeks, and at puerperium 48-52 weeks.


NotesUnsupervised.
The study included another sample of women who were iron deficient and received 2 forms of iron preparation. This sample is not used in this review.
Compliance reported as higher than 98.5%.

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: medium iron dose (more than 30 and less than 60 mg).

Iron release formulation: micro granulated gastric resistant capsule.

Iron compound: not specified.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy random number lists.

Allocation concealment (selection bias)Low riskSealed envelopes progressively numbered.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% loss to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Van Eijk 1978

MethodsRCT, 2 arms with individual randomisation.


Participants30 pregnant women with uncomplicated pregnancies and deliveries attending antenatal care clinic at the University Hospital Obstetric Unit in Rotterdam, Netherlands.


InterventionsParticipants 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 weeks after delivery.

Setting and health worker cadre: the intervention was performed by physicians at the Univeristy Hospital Obstetrical Clinic in Rotterdam, the Netherlands.


OutcomesMaternal: Hb concentration, serum iron, serum ferritin, transferrin concentration at baseline and every 3-4 weeks until delivery, and 3 months after delivery.
Infant: Hb concentration, transferrin, serum iron, serum ferritin in cord blood at term.


NotesUnsupervised.
Compliance not reported.

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

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

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)High riskNot used.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% loss to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Wallenburg 1983

MethodsRCT, 2 arms with individual randomisation.


Participants44 non-anaemic Caucasian women with singleton pregnancy and no major illnesses attending the University Hospital Obstetrical Clinic of the Erasmus University in Rotterdam who had not received iron supplementation during their first visit.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1: received 105 mg of elemental iron (as ferrous sulphate) daily in a sustained release preparation and group 2: received no iron supplement.
Supplementation started at 14-16th week of gestation until delivery.

Setting and health worker cadre: the intervention was performed by physicians at the Antenatal Clinic of the University Hospital Dijkzigt in Rotterdam, the Netherlands.


OutcomesMaternal: Hb, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 weeks, delivery, 6 and 12 weeks postpartum.


NotesUnsupervised.
Compliance not reported.

We treated this study carried out collaboratively in 2 different sites as 2 different trials, 1 conducted in Rotterdam (Wallenburg 1983) and 1 conducted in Antwerp (Buytaert 1983).

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

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskBy means of sealed envelopes.

Blinding (performance bias and detection bias)
All outcomes
High riskParticipant nor provider blinded. No placebo used.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 20% losses to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Willoughby 1967

MethodsRCT. 5-arm trial.


Participants3599 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 who reported not taken the tablets regularly were excluded as well as those diagnosed with anaemia during the study.


InterventionsParticipants were randomly allocated to 1 of 5 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) of folic acid; group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) of folic acid; and group 5 received 105 mg elemental iron daily with 450 μg (0.45 mg) of folic acid.
Starting and ending time of supplementation variable.

Setting and health worker cadre: the intervention was performed by a team of nurses and physicians at the Antenatal Clinic of the Queen Mother's Hospital in Glasgow, United Kingdom.


OutcomesMaternal: Hb concentration at baseline and in every visit, at early puerperium and during postnatal visit; incidence of obstetric complications. incidence of megaloblastic anaemia.
Infant: Hb and whole blood folate levels a 6 weeks of age. Incidence of neonatal complications.


NotesUnsupervised.
Groups 3-5 were merged for the purposes of this review.
Women were excluded from the trial and the analysis if they were diagnosed as anaemic.
Compliance not reported.

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

Anaemic status at start of supplementation: mixed anaemia status (Hb > 100 g/L).

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: Not clear? normal release preparation/unspecified.

Iron compound: chelated iron aminoates.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLess than 20% losses to follow-up. However, women were excluded from the trial and the analysis if they were diagnosed as anaemic.

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

Other biasUnclear riskNo other bias apparent.

Wills 1947

MethodsQuasi-randomised trial with 2 arms with individual randomisation.


Participants500 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.


InterventionsParticipants 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.

Setting and health worker cadre: the intervention was performed by nurses and physicians at the Antenatal Clinic of the Obstetrical Department at the Roryal Free Hspital in London, United Kingdom.


OutcomesMaternal: Hb concentration using the Haldane method at baseline and every 4 weeks until delivery, then 1 day, 2-4 days, 5-16 days and 6 weeks postpartum; serum protein and pregnancy complications (not reported by group).
Infant: birthweight (not reported).


NotesUnsupervised.
The study was conducted during wartime and a bomb incident interrupted the work allowing only a small portion of original sample studied and reported. Women were receiving special food rations.
Compliance not reported.

Gestational age at start of supplementation: mixed gestational age (variable).

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

Daily iron dose: higher daily dose (more than 60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous gluconate.

Malaria setting: non-malarial setting. As of 2011: Malaria: No risk.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuasirandomised, alternate.

Allocation concealment (selection bias)High riskAlternate allocation.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipant and care provider blinded. Outcome assessor blinded.

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

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

Other biasUnclear riskNo other bias apparent.

Zeng 2008 (C)

MethodsCluster-randomised trial (3 arms) Villages were assigned to interventions. Villages were stratified and there was block randomisation to ensure geographical balance in 2 participating counties.


Participants5828 eligible pregnant women with less than 28 weeks and resident in 2 poor rural counties in Shaanxi Province of north west China participated in the study. Village doctors recruited women by active surveillance. In the study areas there were no specific policies for the distribution of multiple micronutrients or iron-folic acid supplements even in disadvantaged areas although folic acid supplements were promoted to prevent NTDs.Their villages were randomly assigned for women to receive 1 of 3 groups.


InterventionsTheir villages were randomly assigned for participants to receive 1 of 3 groups: group 1, daily antenatal multiple micronutrients containing 30 mg elemental iron, 400 µg (0.4 mg) folic acid and 15 mg zinc, 2 mg copper, 65 µg selenium, 150 µg iodine, 800 µg vitamin A, 1.4 mg vitamin B1 (thiamine), 1.4 mg vitamin B2 (riboflavin), 1.9 mg vitamin B6, 2.6 µg vitamin B12, 5 µg vitamin D, 70 mg vitamin C, 10 mg vitamin E, and 18 mg niacin; group 2 who received a tablet containing 60 mg elemental iron and 400 μg (0.4 mg) of folic acid; and group 3 received a tablet containing 400 μg (0.4 mg) folic acid alone (control).

Setting and health worker cadre: the intervention was performed by local maternal and child health workers in rural, antenatal clinics and local health facilities in Shaanxi Province, China.


OutcomesBirthweight within 1 hour of delivery, low birthweight, birth length, gestational age at birth, preterm delivery, small-for-gestational age babies, maternal Hb concentration in the third trimester (gestation 28-32 weeks), anaemia in the third trimester, fetal losses during pregnancy, birth outcome, delivery information, neonatal and maternal deaths; neonatal survival at the 6 weeks, perinatal deaths, neonatal deaths, stillbirths.


NotesWe have included groups 2 (iron + folic acid) and 3 (folic acid alone) in the analyses.

In the data tables we have adjusted the raw data presented in the paper to take account of the cluster design effect. We have calculated an effective sample size by dividing figures by the design effect calculated using the ICC for the trial’s primary outcome: birthweight ICC = 0.03. We have used the same sample adjustment for all outcomes.

65.9 of women in group 2 (iron + folic acid) and 65.2% of women in group 3 (folic acid) started supplementation before 16 weeks of gestational age.

Gestational age at start of supplementation: mixed/unspecified gestational age.

Anaemic status at start of supplementation: mixed anaemia status.

Daily iron dose: higher dose group (60 mg elemental iron daily).

Iron release formulation: normal release preparation/unspecified.

Iron compound: unspecified.

Malaria setting: yes. As of 2011: Malaria risk, including P. falciparum malaria, exists in Yunnan and to a lesser extent in Hainan. P. falciparum resistance to chloroquine and sulphadoxine–pyrimethamine reported. Limited risk of P. vivax malaria exists in southern and some central provinces, including Anhui, Ghuizhou, Henan, Hubei, Jiangsu. There is no malaria risk in urban areas.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“The randomisation schedule was generated off site with a pseudo-random number generator.”

Allocation concealment (selection bias)Low riskOff-site randomisation.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskCluster trial all women in village received the same intervention.

Incomplete outcome data (attrition bias)
All outcomes
Low riskTotal clusters  (531). Total women  5828 (in 3 groups, 2 groups included in the analyses ? total randomised 3929). Overall 133 women lost to follow-up and 279 stopped taking supplements and were excluded (7% lost to follow-up).

3270 women in groups 1 and 2 had live births (3306 babies). Approximately 6% further missing data for primary outcome (infant birthweight). Further missing data for other outcomes.

Available case analysis for primary outcome (LBW).

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

Other biasUnclear riskThe trial was stopped early because of funding constraints.

The treatment groups appeared similar at baseline.

Results were adjusted for cluster design effect.

Ziaei 2007

MethodsRCT 2 arms with individual randomisation.


Participants750 apparently healthy non-smoking non-anaemic (with Hb higher or equal to 132 g/L) pregnant women in early stage of second trimester, BMI 19.8-26 kg/m2 and age 17-35 years with singleton pregnancy attending prenatal care in Tehran, Iran. Women with history of threatened abortion in the present pregnancy or diseases related with polycythaemia such as asthma and chronic hypertension were not included.


InterventionsParticipants were randomly assigned to 1 of 2 groups: group 1 received 50 mg of elemental iron (as ferrous sulphate) + 1000 μg (1 mg) folic acid daily and group 2 received placebo and 1000 μg (1 mg) of folic acid daily.

Setting and health worker cadre: the intervention was performed by midwives and physicians at multiple urban clinical centres in Tehran, Iran.


OutcomesMaternal: Hb at 24-28 week, 32-36 week, premature delivery, weight gain, caesarean sections, hypertensive disorders, severe anaemia, high Hb concentrations, iron deficiency, iron-deficiency anaemia, MCV, MCH and MCHC at term, severe anaemia and high Hb concentrations at any time during 2-3 trimesters, symptomatic tract infection, puerperal infection, antepartum and postpartum haemorrhage, transfusion provided, side effects (any), diarrhoea, constipation, nausea, heartburn, vomiting, placental abruption, premature rupture of membranes.

Infant: birthweight, perinatal mortality rate, low Apgar at 10th minute, small-for-gestational age.


NotesUnsupervised.
Supplementation started 13.07 ± 2.02 weeks' gestation for group 1 and 13.66 ± 3.45 weeks' gestation for the placebo group and lasted until after delivery.
No compliance reported.

Gestational age at start of supplementation: early gestational age at the start of supplementation (supplementation started before 20 weeks' gestation).

Anaemic status at start of supplementation: non-anaemic.

Daily iron dose: medium iron dose (50 mg elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. 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. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy means of table of random numbers.

Allocation concealment (selection bias)Low riskCoded bottles.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and care provider and outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5% lost to follow-up.

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

Other biasUnclear riskNo other bias apparent.

Ziaei 2008

MethodsRCT 2 arms with individual randomisation


Participants244 pregnant women 17-35 years of age attending prenatal care in Tehran, Iran, with BMI between 19.8-26 kg/m2, and 13-18 weeks of gestation, with singleton pregnancy and non-anaemic (Hb 132 g/L or higher) and normal serum ferritin (15 μg/L or higher). Women who smoked, had history of diseases such as polycythaemia, asthma, or chronic hypertension, or a history or threatened abortion in the present pregnancy were excluded.


InterventionsParticipants were randomly assigned to 1 of 2 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 weeks.

Setting and health worker cadre: the intervention was performed by midwives and physicians at a prenatal clinic in Tehran, Iran.


OutcomesMaternal: Hb, HCT, serum ferritin at baseline, at time of delivery, 1 week postpartum and 6 weeks postpartum, postpartum haemorrhage, caesarean sections.


NotesUnsupervised.
No compliance reported.

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

Anaemic status at start of supplementation: non anaemic.

Daily iron dose: medium dose (50 mg elemental iron).

Iron release formulation: normal release preparation/unspecified.

Iron compound: ferrous sulphate.

Malaria setting: yes. As of 2011: Malaria risk due to P. vivax and P. 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. P. falciparum resistant to chloroquine and sulphadoxine–pyrimethamine reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBy means of table of random numbers.

Allocation concealment (selection bias)Low riskCoded bottles.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and care provider blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLess than 5% lost to follow-up.

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

Other biasUnclear riskNo other bias apparent.

 
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 daily regimen of either 100 mg Fe or 15 mg Fe.

Both groups received iron at different doses. No comparisons allowed 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. The type of study is not eligible for inclusion in this review.

Adhikari 2009320 pregnant women attending the Tribhuvan University Teaching Hospital, Nepal for antenatal care were randomised to 1 of 4 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 4 intervention groups received daily iron supplements.

The type 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 1 of 2 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 type 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 type of interventions do not allow for comparisons within the scope of this review.

Angeles-Agdeppa 2003744 apparently healthy pregnant (with less than 20 weeks) 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 2 preparations of iron-folic acid supplements. Women with severe anaemia or history of malaria were excluded. Non-pregnant women were prescribed 4 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 4 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 weeks 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, mean corpuscular volume, mean corpuscular Hb concentration, 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. The type of comparisons are not relevant for the scope of this review.

Babior 198515 healthy pregnant women 22-32 years old, in the first trimester of pregnancy from Boston, Massachusetts, USA were randomly assigned to 3 different multiple micronutrient preparations to assess absorption of iron.

All women received iron in the multiple micronutrient supplements. The type of interventions is not relevant for the scope of this review.

Balmelli 197442 pregnant women attending antenatal care clinic at the Hospital University of Berne, Switzerland were randomly assigned to one of two groups: group 1 received 37 mg elemental iron (as ferrous sulphate) and succinic acid three times daily (total daily dose of 111 mg elemental iron and 555 mg succinic acid); group 2 received 37 mg elemental iron (as ferrous sulphate) and succinic acid three times daily (total daily dose of 111 mg elemental iron and 555 mg succinic acid) and one tablet three times a day containing 100 μg (0.1 mg) folic acid and 100 μg vitamin B12. Both groups received iron supplements. The type of interventions is outside the scope of this review.

Bencaiova 2007260 women with singleton pregnancy in Zurich, Switzerland, were randomised at 21-24 weeks of gestation to receive either intravenous iron group (further divided into 2 doses of 200 mg iron saccharate or 3 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 1 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 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.

Bhatla 2009109 pregnant non-anaemic women between 14 and 18 weeks (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 randomly allocated into 1 of 3 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 2 tablets on any 1 day of the week; 1 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 1 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.

All groups received iron with different regimens. The type of interventions are not within the scope of this review.

Blot 1980203 pregnant women attending prenatal care clinics in Antonie Beclere Hospital, Paris, France during their 6th month visit were randomly allocated to either 105 mg of elemental iron with 500 mg of ascorbic acid or a placebo.

The intervention group received iron with ascorbic acid in comparison to placebo. The type of intervention do not allow for comparisons within the scope of this review.

Bokhari 201133 healthy non-smokers Caucasian, primiparous, with singleton pregnancy (wk 20 to wk 30) pregnant women with pre pregnancy BMI between 19.8 and 26 not taking medicines known to influence iron status nor iron supplements and free from gastrointestinal disorders or allergies were randomised to eat 3–4 slices of iron-rich or control bread daily for 6 weeks. Women with Hb concentrations not within the normal range (below 70 g/L or over 160 g/L) were excluded. Low versus high iron fortified breads were compared. Two 24-h prompted (multiple-pass) dietary recalls were completed, and validated algorithms were used to determine the amount of ‘available iron’ from the diet.  Findings from this study show that iron-rich staple foods can help women reach dietary targets for iron. Further research using fortified staple foods containing higher levels of iron is now warranted to establish physiological benefits. The study was excluded because food fortification is out of the scope of this review.

The intervention is outside of the scope of this review.

Brown 1972109 pregnant women attending prenatal care clinics in Manchester, England, United Kingdom were randomly allocated to 1 of 3 groups: group 1 received 1 tablet daily given in 'reminder packs', group 2 received 1 tablet daily given in loose forms, or group 3 received 2 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 type of interventions do not allow for comparisons within the scope of this review.

Burslem 1968472 pregnant women attending the booking clinic in Manchester, England, United Kingdom were alternatively allocated to 2 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 daily; group 2 received 3 tablets of combined conventional 60 mg elemental iron (as ferrous sulphate) and 1 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 type 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 type of interventions do not allow for comparisons within the scope of this review.

Carrasco 19622 liquid preparations were used in this study: 1 with D-sorbitol and the other without.

Both preparations contained vitamin B12, vitamin B6, ferric pyrophosphate and folic acid.The type of interventions do not allow for comparisons within the scope of this review.

Casanueva 2003a120 singleton pregnant women attending the Instituto Nacional de Perinatologia in Mexico City, Mexico with Hb concentrations higher than 115 g/L at 20 weeks of gestation (equivalent to 105 g/L at sea level) were randomly 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. No comparisons allowed within the scope of this review.

Castren 1968126 healthy pregnant women attending Maternity Centres of Turku, Finland were assigned to one of two groups: group 1 (n=63) received three tablets a day providing a total 120 mg elemental iron (as ferrous sulphate) daily; group 2 (n = 63) received three tablets a day providing total 120 mg elemental iron (as ferrous sulphate) + 9000 μg (9 mg) folic acid daily from their first visit at 10-20th wk of gestation until term. Both groups received iron. The type of intervention is outside the scope of this review.

Chanarin 1968206 women attending the antenatal clinic at St. Mary's Hospital, London, United Kingdom with less than 16 weeks pregnant at the first attendance. At the 20th week they were allotted to one of two groups: group 1 received tablets to be taken once daily containing 260 mg ferrous fumarate ; and group 2 received tablets to be taken daily containing 260 mg ferrous fumarate and 100 μg (0.1 mg) of folic acid. Iron deficiency was largely eliminated by giving 1 g of intravenous iron dextran as four 250-mg. doses at weekly intervals to all participants in early pregnancy. Both groups received iron. the type of comparison is not within the scope of this review.

Chawla 199581 pregnant women with 20 +/- weeks of gestation from Ludhiana City, India were divided to 1 of 3 groups: group 1 received 60 mg of elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) 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 weeks. Outcomes measured included Hb, red blood cell count, total iron binding capacity, transferrin saturation, serum iron, serum vitamin A at baseline and at 36 +/- 2 weeks of gestation. Poor methodological quality.

Pregnant women who were willing to go to the hospital or centre once a week to collect the iron supplements were included in the groups 1 and 2. The rest of the participants were included in the control group. This is not a randomised trial.

Chew 1996a256 clinically healthy pregnant women from low socioeconomic status attending 1 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. Participants were randomly assigned to 1 of 2 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 weeks until 38th week.

All groups received iron with different regimens. The type of interventions are not within the scope of this review

Chew 1996b120 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. Participants 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 0.5 mg folic acid; or group 4: weekly unsupervised intake of 180 mg of elemental iron (as ferrous sulphate) and 3.5 mg of folic acid in 1 intake once a week. Supplementation started at an average of 20.5 weeks of gestation until 38th week.

All groups received iron with different regimens. The type of interventions are not within the scope of this review.

Coelho 2000100 pregnant women with 20-34 weeks of gestation attending the antenatal clinic at The Bandra Holy Family Hospital, Bandra, Mumbai India were randomly assigned to 1 of 2 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 birthweight 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.

Cook 1990200 women at Kansas University Medical Center, Kansas, USA were randomly assigned to receive 50 mg elemental iron daily given either as Gastric Delivery System (GDS) or conventional ferrous sulphate . Gastrointestinal side effects were evaluated.

The participants were non-pregnant women.

Dawson 19622498 pregnant women attending antenatal care clinic in Crumpsal Hospital, Manchester United Kingdom were grouped to receive folic acid or as controls. The assignment was not randomised. Participants whose Hb fell below 100 g/L after 28th week received oral iron if they had not previously received oral iron, had not reached the 36th wk of gestation and had a mean corpuscular Hb concentration of less than 30%. If these participants had been receiving oral iron, iron was then provided parenterally. The type of interventions and comparisons are outside the scope of this review.

Dawson 198742 healthy women with less than 16 weeks of pregnancy entering prenatal care at the Department of Obstetrics and Gynecology, University of Texas, Texas, USA were randomly assigned to receive either a multiple micronutrient supplement containing 65 mg of elemental iron or 1 multiple micronutrient supplement with no iron, calcium, zinc and copper and pantothenic acid.

Both groups received different multiple micronutrient supplement formulations. No comparisons allowed within the scope of this review.

Dijkhuizen 2004170 pregnant women with less than 20 weeks' 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.

Edgar 1956179 pregnant women with Hb levels below 105 g/L and more than 16 weeks of gestation volunteered for this study and were divided into 4 supplementation groups according to the stage of pregnancy at which iron was introduced: 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.

This is not a randomised trial.

Ekstrom 1996176 pregnant women attending Ilula Lutheran Health Center's antenatal service in Iringa region, Tanzania with 21-26 weeks 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.

Ekstrom 2002209 apparently healthy women attending antenatal care clinics in rural areas of Mymemsingh thana, Bangladesh, with fundal height of 14-22 cm (18-24 weeks of gestation), who had not used iron supplements prior to the study. Exclusion criteria: women with Hb concentrations < 80 g/L. Each 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 weeks postpartum. Supplementation started at baseline for 12 weeks.

All groups received iron with different regimens. The type of interventions are not within the scope of this review.

Fletcher 1971643 pregnant women attending antenatal clinic in London, England, United Kingdom were randomly assigned to 1 of 2 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.

Giles 1971????

Gomber 200240 apparently healthy women with singleton pregnancy in their second trimester (between 16-24 weeks of gestation), living in urban slums, from low socioeconomic status attending Guru Teg Bahadur Hospital, Delhi, India were randomly assigned to receive 1 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 weeks, 8 weeks and 14 weeks of supplementation, serum ferritin concentration, at baseline, at 14 weeks of supplementation and at delivery.

Both groups received iron and folic acid in different regimens (daily versus weekly). The type of interventions do not allow for comparisons within the scope of this review.

Goonewardene 200192 pregnant women from 14-24 weeks of gestation attending the university antenatal clinic, in Galle, Sri Lanka were randomly assigned to 1 of 3 regimens: group 1 (n = 26) received a tablet containing 100 mg of elemental iron (as ferrous fumarate), with additional micronutrients once a week; group 2 (n = 35) received the same tablet but 3 times a week; and group 3 (n = 31) received the same supplement in a daily fashion.

All groups were receiving iron and multiple micronutrients with different regimens (daily, weekly, 3 times a week). The type of interventions do not allow for comparisons within the scope of this review.

Gopalan 2004900 pregnant women of poor socioeconomic status females attending government antenatal care clinics in New Delhi, India were grouped in 3 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 birthweight, low birthweight, 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 in Cheschire, England, United Kingdom 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.

Grover 1998200 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 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. The type of interventions do not allow for comparisons within the scope of this review.

Guldholt 1991192 pregnant women in Horsens Hospital, Denmark were consecutively randomised to receive 1 of 2 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.

Hartman-Craven 2009In this cross-over study 2 types of multivitamin supplements were compared: 18 healthy pregnant women 24-32 weeks' gestation attending a Toronto hospital were recruited and received 2 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.

Hawkins 1987No report available of the study results.

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.

Horgan 196642 apparently healthy pregnant women attending 2 antenatal care clinics in London, England were assigned to 1 of 3 interventions: group 1 received 200 mg ferrous sulphate with 5000 μg (5 mg) of folic acid 3 times a day; group 2 received 350 mg of ferrous aminoate with 50 μg (0.05 mg) folic acid 3 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 weeks.

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 weeks.

Both groups received daily iron. No comparisons allowed within the scope of this review.

Iyengar 1970800 pregnant women with less than 24 weeks of gestation and Hb > 85 g/L in India were assigned by rotation to 1 of 4 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%.

This is not a randomised trial.

Kaestel 20052100 pregnant women (22 +/- 7 weeks' 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 1 RDA of 15 micronutrients, or daily multi micronutrients containing 2 times the RDA except for iron that was maintained at 1 RDA or a conventional prenatal daily iron (60 mg elemental iron) and 400 μg (0.4 mg) folic acid supplement.

In a follow-up analysis (Andersen 2010), of the previous study a two-year follow-up examined the effects of the interventions on fetal loss ans under 2 mortality. 2169 women were recruited from four suburban districts followed by the Bandim Health project in collaboration with the Danish Epidemiology Science Centre in Guinea-Bissau. Women with severe anaemia (Hb less than 70 g/L) received 60 mg elemental iron daily in addition to the intervention. All participants received impregnated bed net at inclusion ans were provided weekly anti-malarial prophylaxis with chloroquine phosphate (300 mg base) throughout pregnancy. Also women with more than 10 parasite per 200 leucocytes were offered anti-malarial treatment with chloroquine.

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 1 of 4 groups: group 1 received a tablet (Stuartnatal® 1 + 1) containing 65 mg elemental iron, 1000 μg (1 mg) folic acid and 12 additional micronutrients daily; group 2 received a tablet (Stuart Prenatal®) containing 60 mg elemental iron, 800 μg (0.8 mg) folic acid and 11 additional micronutrients; group 3 received a tablet (Materna®) containing 60 mg elemental iron, 1000 μg (1 mg) folic acid and 17 additional micronutrients daily; and group 4 received a tablet (Natalins Rx®) containing 60 mg elemental iron, 1000 μg (1 mg) folic acid and 14 additional micronutrients daily.

All participants received iron and multiple micronutrients. No comparisons allowed within the scope of this review.

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 women were followed up for 9 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.

Kulkarni 2010This study was secondary analysis of the data from the Christian 2003 (C) study included in the review.

Kumar 2005220 pregnant women with a singleton pregnancy and Hb between 80-110 g/L at 16-24 weeks' 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 weeks.

This trial compares the effects of daily oral iron with 2 injections of high dose parenteral iron. No comparisons allowed within the scope of this review.

Lira 1989199 pregnant women with less than 16 wk gestation attending antenatal care at the Hospital clinica Universidad Catolica ein Santiago, Chile were randomly assigned to one of two groups: group 1 (n = 78) received 105 mg elemental iron (as ferrous sulphate) and 500 mg ascorbic acid; group 2 (n = 75) received 105 mg elemental iron (as ferrous sulphate), 500 mg ascorbic acid and 350 ug (0.35 mg) folic acid daily. There were 36 losses to follow-up. Both groups received iron. The type of interventions provided is outside the scope of this review.

Liu 1996395 healthy, anaemic and non-anaemic, pregnant women attending prenatal care at 2 outpatient clinics in Xianjiang, China. Women with Hb < 80 g/L were excluded. Maternal age was 25.15 ± 2.28 years. Women were randomly assigned to 1 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.

All women randomised to treatments received iron. 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.

Ma 2008366 pregnant women between 20-35 years of age women in rural China with 12–24 wk gestation; with Hb 105 g/L or lower, all receiving 60 mg elemental iron and 400 μg (0.4 mg) folic acid were randomly assigned to one of 4 groups: group 1 (n = 93) received daily 60 mg elemental iron (as ferrous sulphate) and 400 μg (0.4 mg) folic acid; group 2 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid + 2000 μg retinol (as retinyl palmitate); group 3 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid + 1.0 mg riboflavin and group 4 (n = 91) received daily 60 mg elemental iron (as ferrous sulphate), 400 μg (0.4 mg) folic acid, 2000 μg retinol (as retinyl palmitate) + 1.0 mg riboflavin. The intervention lasted 2 months. All groups received iron. The type of comparisons are outside the scope of this review.

Madan 1999109 apparently healthy pregnant women with 16-24 weeks of gestation who had not received iron supplements were randomly assigned to 1 of 3 groups: group 1 received 60 mg of elemental iron + 500 μg (0.5 mg) of folic acid once daily; group 2 received 120 mg of elemental iron + 500 μg (0.5 mg) of folic acid once daily; group 3 received 120 mg of elemental iron twice daily + 500 μg (0.5 mg) of folic acid. Duration of supplementation was 12-14 weeks.

All participants received iron and folic acid daily. No comparisons are allowed within the scope of this review.

Mbaye 20061035 pregnant women attending mother and child health clinics near the town of Farafenni, The 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 3 tablets of SP (25 mg of pyrimethamine and 500 mg of sulphadoxine).

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 Hb > 104 g/L and known gestational age of less than 20 weeks 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 2 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.

The intervention is not an iron supplement but an iron-fortified water product.

Menon 1962273 healthy pregnant women with 16-24 weeks 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 3 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.

Metz 1965355 Bantu and White pregnant women attending antenatal clinics at the Baragwanath and South Rand Hospitals, Johannesburg, South Africa were allocated by random numbers to one of three groups. Group 1 received 200 mg of iron by mouth; group 2 received 5000 μg (5 mg) of folic acid daily by mouth in addition to the iron, and group 3 received 50 μg of vitamin B12 by mouth in addition to the folic acid and iron. In the White participants supplementation was started after the 24th week while Bantu participants started after the 28th. Both groups received iron. The type of comparisons are outside the scope of this review,

Milman 2005427 healthy Danish pregnant women living in the northeastern 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 weeks of gestation. Hb, serum ferritin, and serum soluble transferrin receptor concentrations were measured at 18 weeks (inclusion), 32 weeks, and 39 weeks of gestation and 8 weeks postpartum.

All women received iron daily. No comparisons allowed within the scope of this review.

Morgan 1961356 pregnant women attending 2 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 1 of 4 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) of folic acid.

All groups received iron daily. No comparisons allowed within the scope of this review.

Mukhopadhyay 2004111 apparently healthy pregnant women with less than 20 weeks 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 were randomly assigned to 1 of 2 groups: group 1 received 2 tablets of 100 mg elemental iron 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 weeks until delivery. Deworming, if required, was carried out with Mebendazole 100 mg twice a day for 3 days in the second trimester.

Both groups received iron and folic acid in different regimens (daily versus weekly).

Mumtaz 2000191 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 were randomly assigned to 1 of 2 interventions: group 1 received 40 mg elemental iron (as ferrous sulphate) with 1000 μg (1 mg) of folic acid once daily; and group 2 received 40 mg elemental iron (as ferrous sulphate) with 1000 μg (1 mg) of folic acid on 2 days of the week and placebo the rest of the days. Participants and care providers were blinded to the treatments. Outcomes 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 from different gestational ages and duration of intervention.

Both groups received iron and folic acid in different regimens (daily versus bi-weekly).

Nguyen 2008167 pregnant women with less than 20 weeks 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 1 of 2 groups: group 1 were provided,  a small-size supplement (PregVit® ), containing 35 mg elemental iron (as ferrous fumarate) and multivitamins; or group 2 who received high iron content, small size supplement (Orifer F® ) 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 5 groups: group 1 received 120 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) 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) of 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) of folic acid daily.

All groups received iron and 2 groups received zinc in addition to iron and folic acid. 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 1 of 2 groups: group 1 (n = 39) received 1 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. 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 4 prenatal care clinics in 4 geographical areas of Nigeria with mild to moderate anaemia (as defined by haematocrit between 26%-34%) and 18-28 weeks of gestation, single pregnancies, no complications and who consented to participate in the study were randomly allocated to 1 of 2 groups: group 1 (n = 159) received 1 daily capsule of a multiple micronutrient supplement Chemiron® containing 300 mg of ferrous fumarate, 5000 μg (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 chloroquine 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 were assigned to 1 of 2 groups: group 1 received 100 mg of elemental iron daily (as ferric maltosate), and group 2 received no treatment.
Supplementation started at 21 +/- 7 weeks 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 weeks' gestation attending an antenatal clinic at Janakpur zonal hospital in Nepal, were randomly assigned to receive routine 60 mg elemental iron daily and 400 μg (0.4 mg) folic acid supplements or a multiple micronutrient supplement containing 15 vitamins and minerals including 30 mg elemental iron and 400 μg (0.4 mg) folic acid.

Both groups received iron and folic acid. No comparisons allowed within the scope of this review.

Payne 1968200 pregnant women attending antenatal clinics in Glasgow, Scotland with less than 20 weeks' 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) of folic acid daily throughout pregnancy.

Both groups received iron. No comparisons allowed within the scope of this review.

Pena-Rosas 2003116 pregnant women of 10-30 week of gestational age attended antenatal care clinics in Trujillo, Venezuela were randomly allocated to receive a 120 mg oral dose of iron (as ferrous sulphate) and 500 μg (0.5 mg) of folic acid weekly (n = 52) or 60 mg elemental iron (as ferrous sulphate) and 250 μg (0.25 mg) folic acid and a placebo twice weekly (n = 44). Hb, HCT , serum ferritin and transferrin saturation were estimated at baseline and at 36-39 week of gestation.

All groups received iron and folic acid in 2 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.

Pita Martin 1999203 healthy pregnant women with normal blood pressure at first visit, attending antenatal care clinic at Diego Paroissien Hospitalin 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. Participants 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 3 days; and group 3 received no treatment. Supplementation started at 8-28 weeks until 34-37 weeks of gestation. Outcomes: maternal: Hb, haematocrit, erythroporphyrin, serum ferritin concentration at baseline and at 34-37 weeks' gestation, premature delivery, birthweight. Unsupervised. Compliance not reported.

 

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.

Powers 1985Eighty-one pregnant 14-36 wk of gestation or lactating (1-20 months post partum) women with Hb less than 140 g/L living in a village in The Gambia were allocated to one of four groups: group 1 received daily placebo; group 2 received 5 mg riboflavin; group 3 received 30 mg ferrous sulphate; group 4 received 30 mg ferrous sulphate + 5 mg riboflavin. At the beginning of the study and at 3 and 6 weeks thereafter women were examined clinically and blood samples collected for haematological and biochemical measurements. This is not a randomised trial.

Quintero 2004107 healthy pregnant women with 6-20 weeks of gestation who had not received iron supplements during the current pregnancy attending 19 health units in the State of Morelos, Mexico were randomly assigned by block pairs to receive either 120 mg of elemental iron (as ferrous sulphate) in a single dose daily or once weekly. Hb concentration, prevalence of anaemia and nutrient consumption at baseline and after 10 weeks of supplementation were measured.

Both groups received iron in different regimens (daily versus weekly). Gestational ages were variable among the participants.

Rae 1970In this quasi-randomised trial, pregnant women attending antenatal clinic at the Department of Obstetrics and Department of Haematology, Walton Hospital, Liverpool, United Kingdom were assigned to one of two groups: group 1 received 200 mg ferrous gluconate three times a day throughout pregnancy; group 2 received 200 mg ferrous gluconate + 5000 μg (5 mg) three times a day. Both groups received iron daily. The type of comparison is outside of the scope of this review.

Ramakrishnan 2003873 pregnant women living near Cuernavaca, Morelos, Mexico with less than 13 weeks 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 weeks of gestation and singleton pregnancy from Fuentalabra, Spain were randomly assigned to 1 of 2 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 weeks of gestation were randomly assigned to 1 of 3 groups: group 1 received 60 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) of 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 500 μg (0.5 mg) of folic acid daily.

All groups received iron daily. No comparisons allowed within the scope of this review.

Ridwan 1996176 pregnant women with 8-24 weeks of gestation attending antenatal care at 6 health centres in West Java, Indonesia. Health 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 weeks until 28-32 weeks of gestation.

Both groups received iron in different regimens.

Robinson 1998680 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 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.

Groups 1 and 2 both received iron in different regimens. The control group was not assigned the traditional iron supplement.

Rolschau 197936 pregnant women were selected consecutively, paired two and two, and allotted to two groups, one of which was supplied daily with 5000 ug (5 mg) folic acid, and the second with tablets without folic acid, from the 23rd week of pregnancy. The type of comparison is outside the scope of this review.

Roth 198023 pregnant women were assigned to one of two groups during August 1976 and September 1977: group 1 (n = 11) received a supplement daily 'Tardyferon-Fol ®" containing 80 mg ferrous sulphate and 350 ug (0.35 mg) folic acid; group 2 (n = 12) received a supplement daily' Tardyferon®" containing 80 mg ferrous sulphate. Both groups received iron. The type of intervention is outside the scope of this review.

Roztocil 199484 non-anaemic pregnant women at Mazarik University Brno in Czech Republic were treated from 20-24 weeks with 1 capsule of Actiferrin Compositum®, and from 36 weeks 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.

This is not a randomised trial. No comparisons allowed within the scope of this review.

Rybo 1971117 pregnant women between 20-29 weeks of gestation were alternatively assigned during 3 consecutive 2 weeks 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-week 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 received nutritional supplements. Women in both groups received both iron and folic acid supplements. In addition, women in the experimental group received a calcium supplement, individual and group counselling and a booklet about nutrition in pregnancy.

All women received iron and folic acid supplements (the dose and regimen were not clear) and it was not clear that allocation to groups was random.

Saha 2007100 pregnant women aged 20-40 years at 14 to 27 weeks' gestation, with Hb < 90 g/L, and serum ferritin <12 μg/L, attending the Department of Pharmacology and the Department of Obstetrics and Gynaecology at the Postgraduate Institute of Medical Education and Research, Chandigarh, India were randomly assigned to 1 of 2 groups: group 1 received 100 mg elemental iron (as iron polymaltose complex) and 500 μg (0.5 mg) folic acid daily, and group 2 received 120 mg elemental iron (as ferrous sulphate) and 500 μg (0.5 mg) folic acid daily for 8 weeks.

Both groups received iron and folic acid. No comparisons can be made within the scope of this review.

Sandstad 2003233 pregnant women attending their second antenatal care visit at the University Health Services of Oslo, Norway with serum ferritin concentration < 60 μg/L were randomised to 2 different iron preparations: group 1 received 1 tablet containing 60 mg of elemental iron (as ferrous sulphate) daily; group 2 received 3 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 weeks 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 weeks were recruited from 6 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 weeks after enrolment through interviews and pill count.

All women received iron. No comparisons allowed within the scope of this review.

Shatrugna 1999115 healthy pregnant women with 20-28 weeks of gestation attending the antenatal clinic of the National Institute of Nutrition, Government Maternity Hospital, India were randomly assigned to 1 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.

All women received iron. No comparisons allowed within the scope of this review.

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 1 of 3 groups: group 1 received 100 mg of elemental iron (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 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 1 of 3 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 1 of 5 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 μg 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.

Srisupandit 1983567 pregnant women 16-30 years of age with 18-26 wks gestation attending antenatal care clinic, in the department of Obstetrics and Gynecology of the Siriraj Hospital, Thailand were randomly assigned to one opf three groups; group 1 received 60 mg elemental iron daily; group 2 received 180 mg elemental iron daily; and group 3 received 180 mg elemental iron and 5000 ug (5 mg) folic acid daily. The intervention lasted three months. THere were 101 losses to follow-up. All participants received iron. The type of interventions is outside 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 105 mg of elemental iron (as ferrous sulphate slow release dose) and 350 μg (0.35 mg) of folic acid daily or 80 mg of elemental iron (as ferrous fumarate) and 400 μg (0.4 mg) of folic acid daily in a standard preparation.

Both groups received iron in different doses and preparations. No comparisons allowed within the scope of this review.

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 Hb 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 or any other characteristics of the trial.

Tange 1993128 anaemic and non-anaemic pregnant females aged 10-19 years old, with an average gestation of 16 weeks, were grouped for 3 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 weeks until delivery. Outcomes assessed included Hb, haematocrit, red cell count, mean corpuscular volume, serum iron, serum transferring and serum, ferritin measured every 4 weeks.

The study is not reported as randomised and is excluded in the first screening for eligibility.  

Thane-Toe 1982135 healthy pregnant women between 22-28 weeks 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.

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 or a daily tablet containing 100 mg of elemental iron from 16 weeks until delivery. All women received 300 μg (0.3 mg) of folic acid daily. All women received iron in different doses. No comparisons allowed within the scope of this review.

Trigg 1976158 pregnant women seeking antenatal care with general practitioners in the former South-east England Faculty of the Royal College of General Practitioners, in South England, United Kingdom were assigned to one of two groups: group 1 (n = 76) received 50 mg ferrous sulphate daily to 76 pregnant women was compared with giving ferrous sulphate 50 mg daily + 500 μg (0.5 mg) folic acid. After the first test patients were randomly allocated to one of the two treatments which was either a minimum of 50 mg of ferrous sulphate daily or a minimum of 50 mg of ferrous sulphate plus 500 μg (0.5 mg) of folic acid daily, and afterwards allocation was in sequence. Both groups received iron. The type of comparison is not within the scope of this review.

Vogel 1963191 consecutive pregnant when attending antenatal care clinics and at 32 weeks of gestation were divided in 2 groups by alternate allocation by clinic: group 1 received 140 mg of elemental iron daily (as ferrous gluconate) in 4 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-deficient anaemic pregnant women with the gestational age of 12-34 weeks were randomly assigned to 1 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 intramuscular iron Sorbitol in the dose used as practice. All groups received iron intravenous or intramuscular.

Weil 197729 attending a clinic at University of Basel, Switzerland between May and November 1976 with 20 wk gestation were randomly assigned in one of two groups: group 1 (n = 15) received 80 mg elemental iron slow release as ferrous sulphate (Tardyferon®); group 2 (n = 14) received 80 mg elemental iron slow release as ferrous sulphate + 350 μg (0.35 mg) folic acid (gino-Tardyferon®) until term. Women who had already taken multiple micronutrient supplements containing folic acid were excluded from the study. Both groups received iron. The type of interventions is outside the scope of this review.

Willoughby 1966350 consecutive pregnant women attending antenatal care clinic were allocated to 1 of 5 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) of folic acid; group 4 received 105 mg of elemental iron daily with 300 μg (0.3 mg) of folic acid; and group 5 received 105 mg of elemental iron daily with 450 μg (0.45 mg) of folic acid. All women received a multivitamin preparation (Vivatel®) free of folic acid.

This is not a randomised trial.

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) of folic acid daily.

Both groups received iron. No comparisons allowed within the scope of this review.

Winichagoon 2003484 healthy pregnant women with 13-17 weeks 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.

The 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 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 weeks until delivery.

All groups receive iron in different regimens (weekly versus daily) or doses. No comparisons allowed within the scope of this review.

Wu 1998369 pregnant women attending antenatal care at Beijing Hospital, China were divided into 2 groups according to their initial Hb concentrations. Women with Hb 110 g/L or above were randomly assigned to 1 of 2 groups: group 1 (n = 96) received 1 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 1 of 3 groups: group 1 received 1 tablet of maternal supplement daily; group 2 received 0.9 g of ferrous sulphate daily; and group 3 received 1 tablet of Ferroids, a sustained released preparation daily. In the preventive group, women entered the study from 20-24 gestational weeks. In the treatment groups, women less than 36 gestational weeks were accepted. No comparisons allowed within the scope of this review.

This is not a randomised trial.

Yecta 2011210 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 healthcare clinics between September 2007 and February 2009 in the urban regions of Urmia city North West Iran 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 sulfate); group 2 (n = 70) received one tablet twice weekly providing 100 mg elemental iron per week (as ferrous sulfate); and group 3 (n = 70) received one tablet daily containing 50 mg elemental iron per day (as ferrous sulfate). No additional micronutrients were supplied. Hb and serum ferritin levels were measured at 20, 28, and 38 weeks. Pregnancy and birth outcomes (pregnancy termination, method of delivery, birth weight, stillbirth) were reported. All participants received iron in different regimens. The type of interventions is outside the scope of this review.

Young 2000413 healthy non-severely anaemic pregnant women attending antenatal care at Ekwendeni Hospital or its mobile clinics in northern Malawi with less than 30 weeks of gestation at their first visit, stratified by initial Hb concentration before randomisation. Supplementation starting time variable (22.2 +/- 4.8 weeks) and ending time variable (32.2 +/- 4.4 weeks of gestation). Participants 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 ?g (0.5 mg) of folic acid once a week; group 2 received 60 mg of elemental iron (as ferrous sulphate) with 250 ?g (0.25 mg) of folic acid daily. Outcomes: maternal: Hb concentration at baseline and after 8 weeks of supplementation; compliance, presence of side effects, and prevalence of anaemia.

All women received iron and folic acid in  different regimens (daily versus weekly). No comparisons allowed within the scope of this review.

Young 2010This trial examines the relative differences in heme (animal based) and non-heme (ferrous sulphate) iron utilisation in 20 non-smoking, pregnant women (19 y or older; n = 10) and adolescents
(18 years of age or younger; n = 10) from the Strong Midwifery Group and the Rochester Adolescent Maternity Program in Rochester, NY, USA and 12 healthy, nonsmoking, non-pregnant women ages 18–27 y recruited in 2009 from Ithaca, NY, USA. Women were randomly assigned to receive both an animal-based heme meal (intrinsically labelled 58Fe pork) and labelled ferrous sulphate (57Fe) fed on alternate days.

The type of design and the comparisons of this study are outside the scope of this review.

Yu 199851 healthy pregnant women with 18-22 weeks of gestation who had not taken supplements or medication in the previous 6 months attending public health centre in Ulsan, South Korea 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 weeks and 20.2 weeks of gestation for groups 1 and 2 respectively.

Both groups receive iron in different regimens (weekly versus daily). No comparisons allowed within the scope of this review.

Zamani 2008152 healthy, non-anaemic pregnant women aged 18-38 years, 15-16 weeks’ gestation (gestation estimated by menstrual dates and ultrasound) attending 2 clinics for prenatal care in Isfahan, Iran. ("In Iran, it is mandatory to prescribe iron (1 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. Participants were assigned to 1 of 2 groups: group 1 (experimental group) received 2 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, 1 in the morning and 1 before dinner” i.e. 90 mg of “elemental iron (as ferrous sulphate) 1 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 1 tablet containing 45 mg elemental iron (as ferrous sulphate) daily for 16 weeks (from recruitment at 16-18 weeks). Supplied as 28 tablets every 4 weeks.

Both groups receive iron in different regimens (weekly versus daily). No comparisons allowed within the scope of this review.

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 weeks of gestation and a singleton pregnancy. Women were excluded if they were taking iron or vitamins and minerals 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 weeks 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.

Zutshi 2004200 apparently pregnant women with 24-26 weeks of gestation, with singleton pregnancy and moderate anaemia (Hb > 80 g/L and < 110 g/L) were randomly assigned to receive injectable iron-sorbitol-citrate in 3 intramuscular doses of 150 mg each at 4 weeks intervals or 100 mg of elemental iron daily. Hb concentrations were measured at baseline, every 4 weeks and at delivery. The study compares 2 routes of iron administration. Both groups receive iron. No comparisons allowed within the scope of this review.

 
Characteristics of ongoing studies [ordered by study ID]
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 3 arms. Arms 1. and 2. will each receive a different intervention as follows: 1. micronutrient supplement (elemental iron 60 mg, folic acid 1.5 mg) taken orally twice weekly for the duration of pregnancy and 3 months postpartum. and 2. micronutrient supplement (multiple micronutrients - modified 2xUNIMAPP) taken orally twice weekly for the duration of pregnancy and 3 months postpartum.

OutcomesPrimary: birthweight.

Secondary: infant cognitive development, infant haemoglobin, 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).

Cogswell 2006

Trial name or titleImpact of iron/folic acid versus multi micronutrient versus folic acid supplements during pregnancy on mortality, morbidity, and complications during pregnancy, labor, and delivery: a randomised controlled trial in China.

MethodsRandomised controlled trial.

ParticipantsPregnant women 20 years or older who live in 1 of the study counties (Laoting, Mancheng, Fengrun, Xianghe, Yuanshi), who can follow instructions and can swallow pills.

InterventionsDaily prenatal supplements that contain 400 μg (0.4 mg) folic acid alone, or daily supplements that contain 30 mg iron and 400 μg (0.4 mg) folic acid.
Daily supplements that contain 30 mg iron and 400 μg (0.4 mg) folic acid or daily supplement containing 30 mg iron, 400 μg (0.4 mg) folic acid and other vitamins and minerals (UNICEF formulation).

OutcomesPerinatal mortality, i.e., the number of stillbirths (fetal deaths of 28 weeks or more of gestation) and the number of deaths within the first 0-6 days of life per 1000 births (live births and stillbirths); gastrointestinal side effects at monthly visits.

Starting dateMay 2006; expected completion: December 2010.

Contact informationMary E Cogswell, DrPH, RN 770-488-6053 MCogswell@cdc.gov
Mei Zuguo, MD, MPH 770-488-5864 ZMei@cdc.gov

NotesPrincipal Investigator: Mei Zuguo, MD, MPH 770-488-5864 ZMei@cdc.gov

Dibley 2012

Trial name or titleA trial to evaluate the impact of an early start to iron/folic acid supplementation in pregnancy on deaths of newborns in rural Bangladesh.

MethodsCommunity-based cluster-randomised controlled trial. The interventions will be assigned to eligible clusters using a fixed randomisation scheme with uniform allocation ratio of treatments, stratified by Sub-Districts (upazilla) and in blocks of 5 or 10 to ensure geographic balance across each geographic area. The random allocation sequence will be generated using SAS software.

Participants32000 pregnant women registered in the 202 study clusters trained by Bangladesh Rural Advancement Committee, an NGO based in Bangladesh. Exclusion criteria: 1) clusters on the sampling frame will be excluded if there are other interventions to improve antenatal iron/folic acid distribution currently being implemented either by government or non-government sectors. 2) clusters located in areas where access is extremely difficult, for example, low land areas which are prone to flooding for extended periods of the year, will also be excluded. 3) cohort evaluation: pregnant women with more than 16 weeks of gestational age at enrolment will be excluded from ‘cohort’ follow-up.

InterventionsClusters will be assigned to 1 of 2 interventions: group 1: women in this group will receive a daily dose of 60 mg elemental iron + 400 μg (0.4 mg) folic acid supplementation early in pregnancy (in the first trimester) to be taken orally and sustained for at least 180 days, ensure resupply of supplements through fortnightly visits, and provide counselling in support of early uptake, continued use of the supplements until delivery, and compliance with the supplementation regimen; group 2: women receive standard treatment, the usual antenatal and postnatal care services provided by the Bangladesh Ministry of Health, which are supported by BRAC Essential Health Care Program.

OutcomesPrimary: infant deaths occurring in the first month of life assessed by the data collected by the trained research field worker visits. at 4 weeks and 6 weeks after delivery.

Secondary: percentage of women using iron/folic acid as prescribed in the first trimester of pregnancy assessed by data collected by trained research field worker visits; percentage of live births with low birthweight (weighing < 2500 g) (intensive); percentage of live births with preterm delivery (intensive). Preterm delivery is defined as a birth occurring with gestational age before 37 weeks of gestation and includes early preterm delivery (< 34 weeks) based on maternal report of the date of last menstrual period; percentage of neonatal deaths attributable to preterm delivery asphyxia; percentage of neonatal deaths attributable to preterm delivery; mean marginal additional expenditure associated with early iron/folic acid supplementation, and the mean cost per neonatal death prevented referring to health service costs;

Starting dateAnticipated or actual date of first participant enrolment:1/12/2012

Contact informationDr Tanvir Huda

CHNRI Secretariat Coordinator, Centre for Child and Adolescent Health, ICDDR,B; Mohakhali, Dhaka 1212 Bangladesh

Phone: +880 2 9840523-32/Ext. 3820

Email: thuda@icddrb.org

Prof Michael Dibley

Sydney School of Public Health, Room: 307A, Edward Ford Building (A27), University of Sydney, NSW 2006 Australia

Phone: +61 2 9351 3620  and +61 2 9351 5049

E-mail: michael.dibley@sydney.edu.au

NotesFunded by the National Health & Medical Research Council of Australia.

Primary sponsors:  The University of Sydney, Australia and the International Centre for Diarrhoeal Disease Research, Bangladesh. Collaborator: Bangladesh Rural Advancement Committee (BRAC).

Fawzi 2010

Trial name or titlePrenatal iron supplements: safety and efficacy in Tanzania.

MethodsRandomised clinical trial.

ParticipantsInclusion criteria: - at or before 19 weeks of gestation - primigravida or secundigravidae - not-anaemic (defined as Hb < 85 g/L) - not iron deficient (defined as serum ferritin < 12 µg/L) - HIV-uninfected - intend to stay in Dar es Salaam until delivery and for at least 6 weeks thereafter. Exclusion criteria: - after 19 weeks' gestation - not primigravida or secundigravidae - anaemic - iron deficient - HIV-infected - high iron stores at baseline (i.e., serum ferritin > 200 µg/L) - do not intend to stay in Dar es Salaam until delivery and for at least 6 weeks thereafter.

Interventions60 mg elemental iron (as ferrous sulphate) versus placebo.

OutcomesPrimary: incidence of placental malaria (time frame: delivery); infant birthweight (time frame: delivery); maternal Hb (time frame: 20 weeks' gestation); maternal Hb (time frame: 30 weeks' gestation); maternal Hb (time frame: 6 weeks postpartum); maternal Hb (time frame: delivery); placental malaria parasite density (time frame: delivery). 

Secondary: low birthweight (time frame: delivery); maternal anaemia (time frame: 20 weeks' gestation); maternal anaemia (time frame: 30 weeks' gestation); maternal anaemia (time frame: 6 weeks postpartum); maternal anaemia (time frame: delivery); maternal malaria infection (time frame: 20 weeks' gestation); maternal malaria infection (time frame: 30 weeks' gestation); maternal malaria infection (time frame: 6 weeks postpartum); maternal malaria infection (time frame: delivery).

Starting dateDate of first enrolment: June 2010.

Contact informationWafaie W Fawzi, MD, DrPh

Telephone:  +1 617 432-5299

Email:  mina@hsph.harvard.edu

Affiliation:   Harvard School of Public Health

 

Zul Premji, MD, MSC, PhD

Affiliation:   Muhimbili University of Health and Allied Sciences

NotesScientific title: Prenatal iron supplements: safety and efficacy in Tanzania.

Hemminki 2008

Trial name or titleRoutine Iron Prophylaxis During Pregnancy (PROFEG).

MethodsA pragmatic randomised controlled trial with non-blind design. Total intended sample size is 4000 women. Hypothesis: group 2 will have better health outcomes. Study site: Mozambique, Maputo City.

ParticipantsPregnant women 18 years of age or older attending prenatal care in 2 health centres, 1 in Maputo city and 1 in Maputo province. The women are followed in prenatal visits and until delivery.

InterventionsWomen will be randomised individually and allocated into 2 different groups: group 1, women in the routine iron prophylaxis will receive 65 mg ferrous sulphate and 400 μg (0.4 mg) of folic acid daily; group 2, women will be screened in the antenatal visits with measurements of Hb. If Hb is lower than 90 g/L women will receive a monthly supply of 130 mg of iron to be taken daily and folic acid. If Hb is 90 g/L or higher then women receive 1 tablet containing 1 mg of folic acid.

OutcomesPrimary outcomes: preterm delivery, low birthweight, malaria reactivation during pregnancy (mother) (time frame: until birth). Secondary outcome measures: perinatal mortality, complications during pregnancy and birth (time frame: pregnancy and neonatal period).

Starting dateThe project consists of 3 interlinked phases: the preparatory phase, pilot study and trial as such. The research project started in April 2005 with the preparatory phase, the pilot study of the second phase tested the data collection methods and procedures in the study protocol. The third phase is currently ongoing.

Contact informationPrincipal Investigator: Elina Hemminki

Study Director: Baltazar Chilundo

Elina Hemminki, Research Professor
THL (National Institute for Health and Welfare)
P.O.Box 30, 00271 Helsinki, Finland
E-mail: elina.hemminki@thl.fi
Phone: +358-20-6107307
fax  +358-20 6107227
http://groups.stakes.fi/thp/en       

Baltazar Chilundo, MD, PhD

Universidade Eduardo Mondlande,

Faculty of Medicine, Department of Community Health  

Phone: +258 84 3158350    

E-mail: chilubal@yahoo.com

Notes

Mwangi 2011

Trial name or titleA randomised trial to assess the safety and efficacy or iron supplementation in Kenyan pregnant women.

MethodsRandomised, placebo control double blind trial.

ParticipantsPregnant women aged 15-45 years, with gestational age < 23 weeks resident in the predefined study area in Kenya.

Exclusion criteria

  • Failure to provide a blood sample.
  • Initial Hb concentration < 90 g/L.
  • Reported medical history suggestive of sickle cell anaemia, epilepsy, diabetes.
  • Obstetric history suggestive of eclampsia or pre-eclampsia.
  • Obvious mental retardation or metabolic disorder.
  • No written consent.
  • Carrying multiples.
  • Woman planning to leave the homestead or to be absent for prolonged periods in the course of the pregnancy or within a 1-month period thereafter.
  • Woman planning to deliver outside the research clinic.

InterventionsDaily supplementation with 60 mg elemental iron (as ferrous sulphate) or placebo.

OutcomesPrimary: maternal Plasmodium infection at parturition. 
Secondary: serum non-transferrin bound iron concentration at 3 hours after ingestion of first supplement with either iron or placebo; neonatal iron stores at 1 month of age (assessed by plasma ferritin concentration, restricted to infants without inflammation); maternal iron status at 1 month after delivery (assessed by haemoglobin concentrations, prevalence of iron-deficiency anaemia (plasma ferritin concentration < 12 µg/L) and iron stores (ratio of ferritin:transferrin receptor concentrations); indicators based on ferritin and/or transferrin receptor will be restricted to those without inflammation; maternal intestinal pathogens at 1 month after delivery.

Starting dateStarting date April 2011.

Estimated study completion date: May 2013.

Contact informationContact: Martin N Mwangi, MSc +254 734 018863 martinndegwa.mwangi@wur.nl
Contact: Pauline EA Andang'o, PhD +254 728 485729 paulango@hotmail.com

NotesSponsors and Collaborators: London School of Hygiene and Tropical Medicine; University of Nairobi; Maseno University, Kenya; Wageningen University.

 
Comparison 1. Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo)

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

 1 Low birthweight (less than 2500 g) (ALL)118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    2.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
65379Risk Ratio (M-H, Random, 95% CI)0.74 [0.55, 1.00]

    2.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3665Risk Ratio (M-H, Random, 95% CI)1.05 [0.50, 2.19]

    2.3 Unspecified or mixed gestational age at the start of supplementation
22436Risk Ratio (M-H, Random, 95% CI)0.87 [0.61, 1.24]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at the start of supplementation
84710Risk Ratio (M-H, Random, 95% CI)0.75 [0.49, 1.16]

    3.3 Unspecified or mixed anaemia status
33770Risk Ratio (M-H, Random, 95% CI)0.82 [0.72, 0.94]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    4.1 Low daily dose of iron (30 mg or less of elemental iron)
41031Risk Ratio (M-H, Random, 95% CI)0.57 [0.23, 1.41]

    4.2 Medium daily dose of iron (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    4.3 Higher daily dose of iron (60 mg elemental iron or more)
66722Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.94]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    5.1 Malarial setting
54645Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.94]

    5.2 Non-malarial setting
63835Risk Ratio (M-H, Random, 95% CI)0.70 [0.40, 1.24]

 6 Birthweight (g) (ALL)149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

    7.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
106378Mean Difference (IV, Random, 95% CI)38.63 [3.26, 73.99]

    7.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3681Mean Difference (IV, Random, 95% CI)-0.19 [-77.46, 77.08]

    7.3 Unspecified or mixed gestational age at the start of supplementation
12326Mean Difference (IV, Random, 95% CI)20.20 [-15.13, 55.53]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at the start of supplementation
105426Mean Difference (IV, Random, 95% CI)31.13 [-8.90, 71.15]

    8.3 Unspecified or mixed anaemia status
43959Mean Difference (IV, Random, 95% CI)33.02 [3.65, 62.38]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron149385Mean Difference (IV, Random, 95% CI)30.63 [7.05, 54.22]

    9.1 Low daily dose (30 mg or less of elemental iron)
61902Mean Difference (IV, Random, 95% CI)52.87 [-11.51, 117.26]

    9.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    9.3 Higher daily dose (60 mg elemental iron or more)
86756Mean Difference (IV, Random, 95% CI)27.56 [2.59, 52.54]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

    10.1 Malarial setting
65443Mean Difference (IV, Random, 95% CI)33.48 [10.58, 56.37]

    10.2 Non-malarial setting
83942Mean Difference (IV, Random, 95% CI)25.96 [-42.06, 93.97]

 11 Premature birth (less than 37 weeks of gestation) (ALL)1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

 12 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    12.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
107345Risk Ratio (M-H, Random, 95% CI)0.93 [0.80, 1.08]

    12.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
2477Risk Ratio (M-H, Random, 95% CI)0.58 [0.29, 1.13]

    12.3 Unspecified or mixed`gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.79 [0.57, 1.09]

 13 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at the start of supplementation
105699Risk Ratio (M-H, Random, 95% CI)0.74 [0.59, 0.94]

    13.3 Unspecified/ mixed anaemia status
34449Risk Ratio (M-H, Random, 95% CI)0.96 [0.81, 1.14]

 14 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    14.1 Low daily dose (30 mg or less of elemental iron)
51817Risk Ratio (M-H, Random, 95% CI)0.70 [0.50, 0.98]

    14.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    14.3 Higher daily dose (60 mg elemental iron or more)
77604Risk Ratio (M-H, Random, 95% CI)0.91 [0.78, 1.06]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    15.1 Malarial setting
76406Risk Ratio (M-H, Random, 95% CI)0.95 [0.82, 1.11]

    15.2 Non-malarial setting
63742Risk Ratio (M-H, Random, 95% CI)0.69 [0.52, 0.91]

 16 Neonatal death (within 28 days after delivery) (ALL)47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

 17 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

    17.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
34970Risk Ratio (M-H, Random, 95% CI)1.01 [0.67, 1.53]

   17.2 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]

    17.3 Unspecified or mixed gestational age at the start of supplementation
12495Risk Ratio (M-H, Random, 95% CI)0.81 [0.56, 1.19]

 18 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

   18.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    18.2 Non-anaemic at the start of supplementation
23421Risk Ratio (M-H, Random, 95% CI)0.94 [0.37, 2.39]

    18.3 Unspecified or mixed anaemia status
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 19 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

   19.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    19.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    19.3 Higher daily dose (60 mg elemental iron or more)
36738Risk Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.23]

 20 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

    20.1 Malarial setting
34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    20.2 Non-malarial setting
12694Risk Ratio (M-H, Random, 95% CI)1.32 [0.58, 3.00]

 21 Congenital anomalies (ALL)32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 22 Congenital anomalies: SUBGROUP ANALYSIS by gestational age at the start of supplementation)32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

    22.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

   22.2 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]

   22.3 Unspecified or mixed gestational age at the start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 23 Congenital anomalies: SUBGROUP ANALYSIS by anaemia status at the start of supplementation32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

   23.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.2 Non-anaemic at the start of supplementation
1300Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.3 Unspecified or mixed anaemia status
22402Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 24 Congenital anomalies: SUBGROUP ANALYSIS by dose of iron32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

   24.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   24.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    24.3 Higher daily dose (60 mg elemental iron or more)
32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 25 Congenital anomalies: SUBGROUP ANALYSIS by malarial status of setting32699Risk Ratio (M-H, Random, 95% CI)0.87 [0.60, 1.26]

    25.1 Malarial setting
32699Risk Ratio (M-H, Random, 95% CI)0.87 [0.60, 1.26]

   25.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 26 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

 27 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation):142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    27.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
7749Risk Ratio (M-H, Random, 95% CI)0.28 [0.12, 0.70]

    27.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
51178Risk Ratio (M-H, Random, 95% CI)0.36 [0.22, 0.61]

    27.3 Unspecified or mixed gestational age
2272Risk Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.59]

 28 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

   28.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    28.2 Non-anaemic at the start of supplementation
81295Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]

    28.3 Unspecified or mixed anaemia status
6904Risk Ratio (M-H, Random, 95% CI)0.24 [0.12, 0.49]

 29 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    29.1 Low daily dose (30 mg or less of elemental iron)
3590Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.03]

    29.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
169Risk Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.73]

    29.3 Higher daily dose (60 mg elemental iron or more)
101540Risk Ratio (M-H, Random, 95% CI)0.25 [0.14, 0.45]

 30 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    30.1 Malarial setting
3530Risk Ratio (M-H, Random, 95% CI)0.61 [0.45, 0.82]

    30.2 Non-malarial setting
111669Risk Ratio (M-H, Random, 95% CI)0.18 [0.10, 0.34]

 31 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks's gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 32 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    32.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4653Risk Ratio (M-H, Random, 95% CI)0.45 [0.22, 0.93]

    32.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3603Risk Ratio (M-H, Random, 95% CI)0.36 [0.18, 0.72]

   32.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

   33.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    33.2 Non-anaemic at the start of supplementation
51092Risk Ratio (M-H, Random, 95% CI)0.56 [0.39, 0.82]

    33.3 Unspecified/ mixed anaemia status
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

 34 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    34.1 Low daily dose (30 mg or less of elemental iron)
3703Risk Ratio (M-H, Random, 95% CI)0.52 [0.34, 0.78]

    34.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.17]

    34.3 Higher daily dose (60 mg elemental iron or more)
3312Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.41]

 35 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    35.1 Malarial setting
2192Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.53]

    35.2 Non-malarial setting
51064Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.78]

 36 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)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 37 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    37.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4660Risk Ratio (M-H, Random, 95% CI)0.39 [0.13, 1.11]

    37.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
2428Risk Ratio (M-H, Random, 95% CI)0.25 [0.11, 0.58]

   37.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 38 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): SUBGROUP ANALYSIS by anaemia status at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

   38.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    38.2 Non-anaemic at the start of supplementation
5968Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    38.3 Unspecified or mixed anaemia status
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 39 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): SUBGROUP ANALYSIS by dose of iron61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    39.1 Low daily dose (30 mg or less of elemental iron)
3579Risk Ratio (M-H, Random, 95% CI)0.38 [0.13, 1.11]

    39.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.34 [0.16, 0.70]

    39.3 Higher daily dose (60 mg elemental iron or more)
2268Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 40 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): SUBGROUP ANALYSIS by malarial status of setting61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    40.1 Malarial setting
1148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    40.2 Non-malarial setting
5940Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 41 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 42 Side effects (any reported throughout the intervention period) (ALL)114418Risk Ratio (M-H, Random, 95% CI)2.36 [0.96, 5.82]

 43 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation:114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

    43.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
53181Risk Ratio (M-H, Random, 95% CI)2.44 [0.34, 17.39]

    43.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
51032Risk Ratio (M-H, Random, 95% CI)1.43 [0.89, 2.29]

    43.3 Unspecified or mixed gestational age
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

 44 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

   44.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    44.2 Non-anaemic at the start of supplementation
73643Risk Ratio (M-H, Random, 95% CI)1.87 [0.64, 5.45]

    44.3 Unspecified or mixed anaemia status
4775Risk Ratio (M-H, Random, 95% CI)5.16 [0.78, 34.29]

 45 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron114418Risk Ratio (M-H, Random, 95% CI)2.36 [1.06, 5.24]

    45.1 Low daily dose (30 mg or less of elemental iron)
5973Risk Ratio (M-H, Random, 95% CI)1.01 [0.84, 1.21]

    45.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
2225Risk Ratio (M-H, Random, 95% CI)2.00 [0.66, 6.02]

    45.3 Higher daily dose (60 mg elemental iron or more)
63220Risk Ratio (M-H, Random, 95% CI)6.52 [1.13, 37.69]

 46 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

    46.1 Malarial setting
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

    46.2 Non-malarial setting
104213Risk Ratio (M-H, Random, 95% CI)2.02 [0.88, 4.65]

 47 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

 48 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    48.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
51417Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.47]

    48.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3559Risk Ratio (M-H, Random, 95% CI)0.48 [0.00, 46.15]

    48.3 Unspecified or mixed gestational age
1149Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 49 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

   49.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    49.2 Non-anaemic at the start of supplementation
51394Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    49.3 Unspecified or mixed anaemia status
4731Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

 50 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    50.1 Low daily dose (30 mg or less of elemental iron)
3654Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    50.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    50.3 Higher daily dose (60 mg elemental iron or more)
5744Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

 51 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    51.1 Malarial setting
31102Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

    51.2 Non-malarial setting
61023Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

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

 53 Infection during pregnancy (including urinary tract infections) (ALL)23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

 54 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by gestational age at the start of supplementation23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

    54.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   54.2 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]

   54.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 55 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by anaemia status at the start of supplementation23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   55.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    55.2 Non-anaemic at the start of supplementation
23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   55.3 Unspecified or mixed anaemia status
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 56 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by dose of iron23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   56.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    56.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

    56.3 Higher daily dose (60 mg elemental iron or more)
12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 57 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by malarial status of setting23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

    57.1 Malarial setting
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

    57.2 Non-malarial setting
12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 58 Very low birthweight (less than 1500 g) (ALL)52687Risk Ratio (M-H, Random, 95% CI)0.73 [0.31, 1.74]

 59 Very premature birth (less than 34 weeks' gestation) (ALL)53743Risk Ratio (M-H, Random, 95% CI)0.51 [0.29, 0.91]

 60 Infant Hb concentration within the first 6 months (in g/L counting the last reported measure after birth within this period) (ALL)2533Mean Difference (IV, Random, 95% CI)-1.25 [-8.10, 5.59]

 61 Infant serum ferritin concentration within first 6 months (in μg/L counting the last reported measure after birth within this period) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]

 62 Admission to special care unit (ALL)22805Risk Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.23]

 63 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)154893Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.45]

 64 Maternal iron deficiency at or near term (as defined by as defined by trialists, based on any indicator of iron status at 34 weeks's gestation or more)) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 65 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)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 66 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)193704Mean Difference (IV, Random, 95% CI)8.88 [6.96, 10.80]

 67 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)7956Mean Difference (IV, Random, 95% CI)7.61 [5.50, 9.72]

 68 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)104882Risk Ratio (M-H, Random, 95% CI)2.26 [1.40, 3.66]

 69 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)94850Risk Ratio (M-H, Random, 95% CI)3.08 [1.28, 7.41]

 70 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)81819Risk Ratio (M-H, Random, 95% CI)0.47 [0.01, 44.11]

 71 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)81339Risk Ratio (M-H, Random, 95% CI)0.04 [0.01, 0.28]

 72 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3766Risk Ratio (M-H, Random, 95% CI)0.55 [0.12, 2.51]

 73 Puerperal infection (ALL)44374Risk Ratio (M-H, Random, 95% CI)0.68 [0.50, 0.92]

 74 Antepartum haemorrhage (ALL)21157Risk Ratio (M-H, Random, 95% CI)1.48 [0.51, 4.31]

 75 Postpartum haemorrhage (ALL)41488Risk Ratio (M-H, Random, 95% CI)0.93 [0.59, 1.49]

 76 Transfusion provided (ALL)33453Risk Ratio (M-H, Random, 95% CI)0.61 [0.38, 0.96]

 77 Diarrhoea (ALL)31088Risk Ratio (M-H, Random, 95% CI)0.55 [0.32, 0.93]

 78 Constipation (ALL)41495Risk Ratio (M-H, Random, 95% CI)0.95 [0.62, 1.43]

 79 Nausea (ALL)41377Risk Ratio (M-H, Random, 95% CI)1.21 [0.72, 2.03]

 80 Heartburn (ALL)31323Risk Ratio (M-H, Random, 95% CI)1.19 [0.86, 1.66]

 81 Vomiting (ALL)41392Risk Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.30]

 82 Maternal wellbeing/satisfaction (ALL)22604Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.09]

 83 Placental abruption (ALL)32951Risk Ratio (M-H, Random, 95% CI)1.41 [0.56, 3.59]

 84 Premature rupture of membranes (ALL)21509Risk Ratio (M-H, Random, 95% CI)0.95 [0.72, 1.24]

 85 Pre-eclampsia (ALL)41704Risk Ratio (M-H, Random, 95% CI)1.63 [0.87, 3.07]

 
Comparison 2. Any supplements containing iron and folic acid versus same supplements without iron nor folic acid (no iron nor folic acid or placebo)

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

 1 Low birthweight (less than 2500 g) (ALL)21311Risk Ratio (M-H, Random, 95% CI)1.07 [0.31, 3.74]

 2 Birthweight (ALL)21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]

 3 Premature birth (less than 37 weeks of gestation) (ALL)31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 4 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestation at the start of supplementation3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

   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 or mixed gestational age at start of supplementation
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3Risk Ratio (M-H, Random, 95% CI)Subtotals only

   5.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   5.2 Non-anaemic at the start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Unspecified or mixed anaemic status at start of supplementation
31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 6 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    6.1 Low daily dose (30 mg elemental iron or less)
1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   6.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Higher daily dose (60 mg elemental iron and above)
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 7 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of settings31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    7.1 Malarial setting
21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]

    7.2 Non-malarial setting
148Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

 8 Neonatal death (within 28 days after delivery) (ALL)31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 9 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestation at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    9.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

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

   9.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   10.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

    10.3 Unspecified or mixed anaemic status at start of supplementation
21696Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

 11 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   11.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   11.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Higher daily dose (60 mg elemental iron and above)
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 12 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    12.1 Malarial setting
11648Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

    12.2 Non-malarial setting
2145Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

 13 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 14 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 15 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestation at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    15.3 Unspecified or mixed gestational age at start of supplementation
1183Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 16 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   16.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Non-anaemic at start of supplementation
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

    16.3 Unspecified or mixed anaemic status at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

 17 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   17.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   17.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    17.3 Higher daily dose (60 mg elemental iron and above)
3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    18.1 Malarial setting
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    18.2 Non-malarial setting
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 19 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 20 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)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 21 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Side effects (any reported throughout the intervention period) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]

 23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 24 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestation at the start of supplementation4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    24.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3456Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.83]

    24.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
150Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

   24.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 25 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

   25.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Unspecified or mixed anaemic status at start of supplementation
3409Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 26 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    26.1 Low daily dose (30 mg elemental iron or less)
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   26.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    26.3 Higher daily dose (60 mg elemental iron and above)
3462Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 27 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    27.1 Malarial setting
3409Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    27.2 Non-malarial setting
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

 29 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]

 30 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 31 Very premature birth (less than 34 weeks' gestation) (ALL)292Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 32 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 34 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 35 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)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 36 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)3140Mean Difference (IV, Random, 95% CI)16.13 [12.74, 19.52]

 37 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)2459Mean Difference (IV, Random, 95% CI)10.07 [7.33, 12.81]

 38 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]

 39 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)2314Risk Ratio (M-H, Random, 95% CI)4.37 [0.58, 32.71]

 40 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.33 [0.17, 0.65]

 41 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more ) (ALL)3191Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

 42 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.76]

 43 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]

 44 Antepartum haemorrhage (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]

45 Postpartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 46 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]

 47 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.16]

 
Comparison 3. Supplementation with iron alone versus no treatment/placebo

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

 1 Low birthweight (less than 2500 g) (ALL)73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
33055Risk Ratio (M-H, Random, 95% CI)0.53 [0.22, 1.23]

    2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3665Risk Ratio (M-H, Random, 95% CI)1.05 [0.50, 2.19]

    2.3 Unspecified or mixed gestational age at the start of supplementation
1110Risk Ratio (M-H, Random, 95% CI)1.79 [0.17, 19.20]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at start of supplementation
63649Risk Ratio (M-H, Random, 95% CI)0.72 [0.39, 1.32]

    3.3 Unspecified or mixed anaemic status at start of supplementation
1181Risk Ratio (M-H, Random, 95% CI)0.57 [0.14, 2.31]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    4.1 Low daily dose (30 mg elemental iron or less)
3697Risk Ratio (M-H, Random, 95% CI)0.59 [0.12, 2.96]

   4.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Higher daily dose (60 mg elemental iron and above)
43133Risk Ratio (M-H, Random, 95% CI)0.83 [0.56, 1.23]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    5.1 Malarial setting
2329Risk Ratio (M-H, Random, 95% CI)0.52 [0.20, 1.35]

    5.2 Non-malarial setting
53501Risk Ratio (M-H, Random, 95% CI)0.77 [0.38, 1.57]

 6 Birthweight (g) (ALL)93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

    7.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
53099Mean Difference (IV, Random, 95% CI)30.74 [-83.78, 145.25]

    7.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
4854Mean Difference (IV, Random, 95% CI)-8.70 [-74.71, 57.31]

   7.3 Unspecified or mixed gestational age at the start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at start of supplementation
73583Mean Difference (IV, Random, 95% CI)22.44 [-54.15, 99.03]

    8.3 Unspecified or mixed anaemic status at start of supplementation
2370Mean Difference (IV, Random, 95% CI)0.90 [-86.32, 88.12]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron93953Mean Difference (IV, Random, 95% CI)15.73 [-33.92, 65.38]

    9.1 Low daily dose (30 mg elemental iron or less)
4785Mean Difference (IV, Random, 95% CI)46.83 [-76.57, 170.22]

   9.2 Medium daily dose (31 to 59 mg elemental iron)
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    9.3 Higher daily dose (60 mg elemental iron and above)
63168Mean Difference (IV, Random, 95% CI)12.51 [-25.07, 50.10]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

    10.1 Malarial setting
2345Mean Difference (IV, Random, 95% CI)33.74 [-61.16, 128.65]

    10.2 Non-malarial setting
73608Mean Difference (IV, Random, 95% CI)10.18 [-65.06, 85.42]

 11 Premature birth (less than 37 weeks of gestation) (ALL)74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

 12 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    12.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
53930Risk Ratio (M-H, Random, 95% CI)0.81 [0.61, 1.07]

    12.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2477Risk Ratio (M-H, Random, 95% CI)0.58 [0.29, 1.13]

   12.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 13 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at start of supplementation
63545Risk Ratio (M-H, Random, 95% CI)0.71 [0.53, 0.97]

    13.3 Unspecified or mixed anaemic status at start of supplementation
1862Risk Ratio (M-H, Random, 95% CI)0.95 [0.58, 1.57]

 14 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    14.1 Low daily dose (30 mg elemental iron or less)
3690Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.24]

   14.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    14.3 Higher daily dose (60 mg elemental iron and above)
43717Risk Ratio (M-H, Random, 95% CI)0.78 [0.57, 1.05]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    15.1 Malarial setting
21010Risk Ratio (M-H, Random, 95% CI)0.87 [0.54, 1.39]

    15.2 Non-malarial setting
53397Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.99]

 16 Neonatal death (within 28 days after delivery) (ALL)12694Risk Ratio (M-H, Random, 95% CI)1.32 [0.58, 3.00]

 17 Congenital anomalies (ALL)22402Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)142136Risk Ratio (M-H, Random, 95% CI)0.29 [0.19, 0.47]

 19 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation144693Risk Ratio (M-H, Random, 95% CI)0.26 [0.17, 0.40]

    19.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
73243Risk Ratio (M-H, Random, 95% CI)0.24 [0.12, 0.50]

    19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
61301Risk Ratio (M-H, Random, 95% CI)0.32 [0.20, 0.53]

    19.3 Unspecified or mixed gestational age at start of supplementation
1149Risk Ratio (M-H, Random, 95% CI)0.03 [0.00, 0.18]

 20 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation144630Risk Ratio (M-H, Random, 95% CI)0.26 [0.16, 0.41]

   20.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    20.2 Non-anaemic at start of supplementation
93938Risk Ratio (M-H, Random, 95% CI)0.23 [0.13, 0.41]

    20.3 Unspecified or mixed anaemic status at start of supplementation
5692Risk Ratio (M-H, Random, 95% CI)0.34 [0.18, 0.64]

 21 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron144693Risk Ratio (M-H, Random, 95% CI)0.26 [0.17, 0.40]

    21.1 Low daily dose (30 mg elemental iron or less)
3590Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.03]

    21.2 Medium daily dose (31 to 59 mg elemental iron)
169Risk Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.73]

    21.3 Higher daily dose (60 mg elemental iron and above)
104034Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.37]

 22 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting144630Risk Ratio (M-H, Random, 95% CI)0.26 [0.16, 0.41]

    22.1 Malarial setting
2267Risk Ratio (M-H, Random, 95% CI)0.58 [0.46, 0.72]

    22.2 Non-malarial setting
124363Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.34]

 23 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 24 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    24.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4653Risk Ratio (M-H, Random, 95% CI)0.45 [0.22, 0.93]

    24.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3603Risk Ratio (M-H, Random, 95% CI)0.36 [0.18, 0.72]

   24.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 25 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

   25.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.2 Non-anaemic at start of supplementation
51092Risk Ratio (M-H, Random, 95% CI)0.56 [0.39, 0.82]

    25.3 Unspecified or mixed anaemic status at start of supplementation
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

 26 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    26.1 Low daily dose (30 mg elemental iron or less)
3703Risk Ratio (M-H, Random, 95% CI)0.52 [0.34, 0.78]

    26.2 Medium daily dose (31 to 59 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.17]

    26.3 Higher daily dose (60 mg elemental iron and above)
3312Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.41]

 27 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    27.1 Malarial setting
2192Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.53]

    27.2 Non-malarial setting
51064Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.78]

 28 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)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 29 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): SUBGROUP ANALYSIS by gestational age at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    29.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4660Risk Ratio (M-H, Random, 95% CI)0.39 [0.13, 1.11]

    29.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2428Risk Ratio (M-H, Random, 95% CI)0.25 [0.11, 0.58]

   29.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 30 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): SUBGROUP ANALYSIS by anaemia status at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

   30.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    30.2 Non-anaemic at start of supplementation
5968Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    30.3 Unspecified or mixed anaemic status at start of supplementation
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 31 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): SUBGROUP ANALYSIS by dose of iron61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    31.1 Daily low dose (60 mg elemental iron or less)
3579Risk Ratio (M-H, Random, 95% CI)0.38 [0.13, 1.11]

    31.2 Medium dose (31 to 59 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.34 [0.16, 0.70]

    31.3 High dose (60 mg elemental iron and above)
2268Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 32 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): SUBGROUP ANALYSIS by malarial status of setting61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    32.1 Malarial setting
1148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    32.2 Non-malarial setting
5940Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 33 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 34 Side effects (any reported throughout the intervention period) (ALL)104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

 35 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

    35.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
42993Risk Ratio (M-H, Random, 95% CI)3.65 [0.40, 33.51]

    35.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
51034Risk Ratio (M-H, Random, 95% CI)1.42 [0.89, 2.28]

    35.3 Unspecified or mixed gestational age at start of supplementation
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

 36 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

   36.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    36.2 Non-anaemic at start of supplementation
63455Risk Ratio (M-H, Random, 95% CI)2.25 [0.57, 8.93]

    36.3 Unspecified or mixed anaemic status at start of supplementation
4777Risk Ratio (M-H, Random, 95% CI)5.11 [0.78, 33.60]

 37 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron104232Risk Ratio (M-H, Random, 95% CI)2.75 [1.10, 6.89]

    37.1 Low daily dose (30 mg elemental iron or less)
4785Risk Ratio (M-H, Random, 95% CI)1.07 [0.90, 1.26]

    37.2 Medium daily dose (31 to 59 mg elemental iron)
2225Risk Ratio (M-H, Random, 95% CI)2.00 [0.66, 6.02]

    37.3 Higher daily dose (60 mg elemental iron and above)
63222Risk Ratio (M-H, Random, 95% CI)7.95 [1.38, 45.72]

 38 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

    38.1 Malarial setting
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

    38.2 Non-malarial setting
94027Risk Ratio (M-H, Random, 95% CI)2.35 [0.89, 6.24]

 39 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

 40 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    40.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3416Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    40.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3513Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    40.3 Unspecified or mixed gestational age at start of supplementation
1149Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 41 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status age at the start of supplementation71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

   41.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    41.2 Non-anaemic at start of supplementation
5816Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    41.3 Unspecified or mixed anaemic status at start of supplementation
2262Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

 42 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    42.1 Low daily dose (30 mg elemental iron or less)
3654Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

   42.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    42.3 Higher daily dose (60 mg elemental iron and above)
4424Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

 43 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    43.1 Malarial setting
155Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

    43.2 Non-malarial setting
61023Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

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

 45 Infection during pregnancy (including urinary tract infections) (ALL)12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 46 Very low birthweight (less than 1500 g) (ALL)3697Risk Ratio (M-H, Random, 95% CI)0.55 [0.03, 9.07]

 47 Very premature birth (less than 34 weeks' gestation) (ALL)3690Risk Ratio (M-H, Random, 95% CI)0.32 [0.10, 1.09]

 48 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)2533Mean Difference (IV, Random, 95% CI)-1.25 [-8.10, 5.59]

 49 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]

 50 Admission to special care unit (ALL)22805Risk Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.23]

 51 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)144390Risk Ratio (M-H, Random, 95% CI)0.29 [0.19, 0.45]

 52 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 53 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)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 54 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)161851Mean Difference (IV, Random, 95% CI)8.95 [6.37, 11.53]

 55 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)6659Mean Difference (IV, Random, 95% CI)7.26 [4.78, 9.74]

 56 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)83840Risk Ratio (M-H, Random, 95% CI)1.81 [1.21, 2.71]

 57 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)83883Risk Ratio (M-H, Random, 95% CI)3.67 [2.23, 6.04]

 58 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3453Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 13.91]

 59 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)71046Risk Ratio (M-H, Random, 95% CI)0.74 [0.02, 27.81]

 60 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)7953Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.33]

 61 Puerperal infection (ALL)22292Risk Ratio (M-H, Random, 95% CI)0.65 [0.41, 1.03]

 62 Antepartum haemorrhage (ALL)1430Risk Ratio (M-H, Random, 95% CI)2.97 [0.12, 72.56]

 63 Postpartum haemorrhage (ALL)3761Risk Ratio (M-H, Random, 95% CI)0.82 [0.51, 1.34]

 64 Transfusion provided (ALL)22726Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.94]

 65 Diarrhoea (ALL)1173Risk Ratio (M-H, Random, 95% CI)0.98 [0.09, 10.61]

 66 Constipation (ALL)2580Risk Ratio (M-H, Random, 95% CI)0.88 [0.18, 4.40]

 67 Nausea (ALL)3650Risk Ratio (M-H, Random, 95% CI)2.38 [0.49, 11.52]

 68 Heartburn (ALL)1408Risk Ratio (M-H, Random, 95% CI)1.0 [0.82, 1.22]

 69 Vomiting (ALL)2477Risk Ratio (M-H, Random, 95% CI)0.88 [0.38, 2.07]

 70 Maternal wellbeing/satisfaction (ALL)22604Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.09]

 71 Placental abruption (ALL)11442Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 70.53]

72 Premature rupture of membranes (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 73 Pre-eclampsia (ALL)147Risk Ratio (M-H, Random, 95% CI)0.96 [0.06, 14.43]

 
Comparison 4. Supplementation with iron+folic acid versus no treatment/placebo

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

 1 Low birthweight (less than 2500 g) (ALL)21311Risk Ratio (M-H, Random, 95% CI)1.07 [0.31, 3.74]

 2 Birthweight (ALL)21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]

 3 Premature birth (less than 37 weeks of gestation) (ALL)31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 4 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation31410Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

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

    4.3 Unspecified or mixed gestational age at start of supplementation
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

   5.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   5.2 Non-anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Unspecified or mixed anaemic status at start of supplementation
31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 6 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    6.1 Low daily dose (30 mg elemental iron or less)
1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   6.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Higher daily dose (60 mg elemental iron and above)
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 7 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    7.1 Malarial setting
21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]

    7.2 Non-malarial setting
148Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

 8 Neonatal death (within 28 days after delivery) (ALL)31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 9 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    9.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

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

   9.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   10.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

    10.3 Unspecified or mixed anaemic status at start of supplementation
21696Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

 11 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   11.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   11.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Higher daily dose (60 mg elemental iron and above)
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 12 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    12.1 Malarial setting
11648Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

    12.2 Non-malarial setting
2145Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

 13 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 14 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 15 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2249Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   15.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   16.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Non-anaemic at start of supplementation
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

    16.3 Unspecified or mixed anaemic status at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

 17 Maternal anaemia at term (Hb less than 110 g/Lat 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   17.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   17.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    17.3 Higher daily dose (60 mg elemental iron and above)
3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    18.1 Malarial setting
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    18.2 Non-malarial setting
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 19 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 20 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)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 21 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Side effects (any reported throughout the intervention period) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]

 23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

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

 25 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]

 26 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 27 Very premature birth (less than 34 weeks' gestation) (ALL)292Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

28 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

29 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 30 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 31 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 32 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 33 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)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 34 Maternal Hb concentration at term or near term (in g/L, at 34 weeks' gestation or more) (ALL)3140Mean Difference (IV, Random, 95% CI)16.13 [12.74, 19.52]

 35 Maternal Hb concentration within 6 wk postpartum (g/L) (ALL)2459Mean Difference (IV, Random, 95% CI)10.07 [7.33, 12.81]

 36 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]

 37 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)2314Risk Ratio (M-H, Random, 95% CI)4.37 [0.58, 32.71]

 38 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)2458Risk Ratio (M-H, Random, 95% CI)0.34 [0.17, 0.69]

 39 Maternal severe anaemia at term or near (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)3191Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

 40 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.76]

 41 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]

 42 Antepartum haemorrhage (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]

43 Postpartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 44 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]

 45 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.16]

 
Comparison 5. Supplementation with iron+folic acid versus folic acid alone (without iron) supplementation

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

 1 Low birthweight (less than 2500 g) (ALL)34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21990Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.96]

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

    2.3 Unspecified or mixed gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.85 [0.59, 1.22]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    3.3 Unspecified or mixed anaemia status
23589Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.94]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   4.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    4.3 Higher daily dose (60 mg elemental iron and above)
23589Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.94]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

    5.1 Malarial setting
34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   5.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Birthweight (g) (ALL)34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

    7.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21990Mean Difference (IV, Random, 95% CI)41.19 [-12.23, 94.60]

   7.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    7.3 Unspecified or mixed gestational age at the start of supplementation
12326Mean Difference (IV, Random, 95% CI)20.20 [-15.13, 55.53]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at start of supplementation
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    8.3 Unspecified or mixed anaemic status at start of supplementation
23589Mean Difference (IV, Random, 95% CI)39.61 [-3.90, 83.13]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

   9.1 Low daily dose (30 mg elemental iron or less)
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    9.2 Medium daily dose (31 to 59 mg elemental iron)
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    9.3 Higher daily dose (60 mg elemental iron and above)
23589Mean Difference (IV, Random, 95% CI)39.61 [-3.90, 83.13]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

    10.1 Malarial setting
34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

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

 11 Premature birth (less than 37 weeks of gestation) (ALL)34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

 12 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

    12.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21988Risk Ratio (M-H, Random, 95% CI)1.06 [0.87, 1.29]

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

    12.3 Unspecified or mixed gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.79 [0.57, 1.09]

 13 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    13.3 Unspecified or mixed anaemic status at start of supplementation
23587Risk Ratio (M-H, Random, 95% CI)0.93 [0.71, 1.22]

 14 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   14.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    14.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    14.3 Higher daily dose (60 mg elemental iron and above)
23587Risk Ratio (M-H, Random, 95% CI)0.93 [0.71, 1.22]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

    15.1 Malarial setting
34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   15.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 Neonatal death (within 28 days after delivery) (ALL)34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

 17 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    17.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
22276Risk Ratio (M-H, Random, 95% CI)0.92 [0.57, 1.49]

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

    17.3 Unspecified or mixed gestational age at the start of supplementation
12495Risk Ratio (M-H, Random, 95% CI)0.81 [0.56, 1.19]

 18 Neonatal death (within 28 days after delivery) : SUBGROUP ANALYSIS by anaemia status at the start of supplementation34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   18.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    18.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    18.3 Unspecified or mixed anaemic status at start of supplementation
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 19 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   19.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    19.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    19.3 Higher daily dose (60 mg elemental iron and above)
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 20 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    20.1 Malarial setting
34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   20.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 21 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 22 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

 23 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   23.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   23.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 24 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   24.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    24.2 Non-anaemic at start of supplementation
1240Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.61]

    24.3 Unspecified or mixed anaemic status at start of supplementation
163Risk Ratio (M-H, Random, 95% CI)0.39 [0.23, 0.67]

 25 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by dose of iron2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   25.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   25.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Higher daily dose (60 mg elemental iron and above)
2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

 26 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by malarial status of setting2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

    26.1 Malarial setting
163Risk Ratio (M-H, Random, 95% CI)0.39 [0.23, 0.67]

    26.2 Non-malarial setting
1240Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.61]

27 Maternal iron deficiency at term (as defined by trialists, 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]

 28 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)1727Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

29 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]

 30 Side effects (any reported throughout the intervention period) (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.10 [0.55, 2.23]

 31 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)31047Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.47]

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

 33 Infection during pregnancy (including urinary tract infections) (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

 34 Very low birthweight (