Cochrane Database of Systematic Reviews (Reviews) || Treatments for iron-deficiency anaemia in...

Treatments for iron-deficiency anaemia in pregnancy (Review)

Reveiz L, Gyte GML, Cuervo LG, Casasbuenas A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 1

http://www.thecochranelibrary.com

Treatments for iron-deficiency anaemia in pregnancy (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Oral iron versus placebo, Outcome 1 Anaemic during 2nd trimester. . . . . . . . 69

Analysis 1.2. Comparison 1 Oral iron versus placebo, Outcome 2 Haemoglobin levels (g/dL). . . . . . . . . 69

Analysis 1.3. Comparison 1 Oral iron versus placebo, Outcome 3 Ferritin levels (ug/l). . . . . . . . . . . . 70

Analysis 1.4. Comparison 1 Oral iron versus placebo, Outcome 4 Serum iron (mg/l). . . . . . . . . . . . 70

Analysis 1.5. Comparison 1 Oral iron versus placebo, Outcome 5 Side effects. . . . . . . . . . . . . . . 71

Analysis 1.6. Comparison 1 Oral iron versus placebo, Outcome 6 Nausea and vomiting. . . . . . . . . . . 71

Analysis 1.7. Comparison 1 Oral iron versus placebo, Outcome 7 Constipation. . . . . . . . . . . . . . 72

Analysis 1.8. Comparison 1 Oral iron versus placebo, Outcome 8 Abdominal cramps. . . . . . . . . . . . 72

Analysis 2.1. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 1 Anaemic during 2nd trimester. . . . 73

Analysis 2.2. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 2 Haemoglobin levels (g/dL). . . . . 73

Analysis 2.3. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 3 Ferritin levels (ug/l). . . . . . . 74

Analysis 2.4. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 4 Serum iron (mg/l). . . . . . . . 74

Analysis 3.1. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 1 Side effects. . . . . 75

Analysis 3.2. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 2 Nausea and vomiting. . 75

Analysis 3.3. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 3 Constipation. . . . . 76

Analysis 3.4. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 4 Abdominal cramps. . . 76

Analysis 4.1. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 1 Pain at

injection site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Analysis 4.2. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 2 Skin

discolouration at injection site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Analysis 4.3. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 3 Venous

thrombosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Analysis 4.4. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 4 Nausea or

vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Analysis 4.5. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 5 Headaches. 79

Analysis 4.6. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 6 Shivering. 79

Analysis 4.7. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 7 Itching. 80

Analysis 4.8. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 8 Metallic taste

in mouth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Analysis 5.1. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 1 Pain at injection site. 81

Analysis 5.2. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 2 Skin discolouration at

injection site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Analysis 5.3. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 3 Venous thrombosis. 82

Analysis 5.4. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 4 Nausea or vomiting. 82

Analysis 5.5. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 5 Headaches. . . 83

Analysis 5.6. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 6 Shivering. . . 83

iTreatments for iron-deficiency anaemia in pregnancy (Review)


Analysis 5.7. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 7 Itching. . . . 84

Analysis 5.8. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 8 Metallic taste in

mouth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Analysis 5.9. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 9 Severe delayed allergic

reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Analysis 6.1. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 1 Pain at

injection site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Analysis 6.2. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 2 Skin

discolouration at injection site. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Analysis 6.3. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 3 Venous

thrombosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Analysis 6.4. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 4 Nausea or

vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Analysis 6.5. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 5 Headaches. 87

Analysis 6.6. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 6 Shivering. 88

Analysis 6.7. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 7 Itching. 88

Analysis 6.8. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran, Outcome 8 Metallic

taste in mouth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Analysis 7.1. Comparison 7 Intravenous iron versus placebo, Outcome 1 Side effects. . . . . . . . . . . . 89

Analysis 7.2. Comparison 7 Intravenous iron versus placebo, Outcome 2 Nausea or vomiting. . . . . . . . . 90

Analysis 7.3. Comparison 7 Intravenous iron versus placebo, Outcome 3 Constipation. . . . . . . . . . . 90

Analysis 7.4. Comparison 7 Intravenous iron versus placebo, Outcome 4 Abdominal cramps. . . . . . . . . 91

Analysis 8.1. Comparison 8 Intravenous iron versus regular oral iron, Outcome 1 Side effects. . . . . . . . . 91

Analysis 8.2. Comparison 8 Intravenous iron versus regular oral iron, Outcome 2 Nausea or vomiting or epigastric

discomfort. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Analysis 8.3. Comparison 8 Intravenous iron versus regular oral iron, Outcome 3 Constipation. . . . . . . . 92

Analysis 8.4. Comparison 8 Intravenous iron versus regular oral iron, Outcome 4 Abdominal cramps. . . . . . 93

Analysis 8.5. Comparison 8 Intravenous iron versus regular oral iron, Outcome 5 Diarrhoea. . . . . . . . . . 93

Analysis 8.6. Comparison 8 Intravenous iron versus regular oral iron, Outcome 6 Blood transfusion required. . . . 94

Analysis 8.7. Comparison 8 Intravenous iron versus regular oral iron, Outcome 7 Neonates mean hemoglobin. . . 94

Analysis 8.8. Comparison 8 Intravenous iron versus regular oral iron, Outcome 8 Maternal haemoglobin at birth. . 95

Analysis 8.10. Comparison 8 Intravenous iron versus regular oral iron, Outcome 10 Neonates ferritin level. . . . . 95

Analysis 8.11. Comparison 8 Intravenous iron versus regular oral iron, Outcome 11 Mean maternal haemoglobin at 4

weeks ( g/dL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Analysis 8.12. Comparison 8 Intravenous iron versus regular oral iron, Outcome 12 Maternal mortality. . . . . . 96

Analysis 8.13. Comparison 8 Intravenous iron versus regular oral iron, Outcome 13 Preterm labour. . . . . . . 97

Analysis 8.14. Comparison 8 Intravenous iron versus regular oral iron, Outcome 14 Caesarean section. . . . . . 97

Analysis 8.15. Comparison 8 Intravenous iron versus regular oral iron, Outcome 15 Operative vaginal birth. . . . 98

Analysis 8.16. Comparison 8 Intravenous iron versus regular oral iron, Outcome 16 Postpartum haemorrhage. . . 98

Analysis 8.17. Comparison 8 Intravenous iron versus regular oral iron, Outcome 17 Low birthweight (under 2500 g). 99

Analysis 8.18. Comparison 8 Intravenous iron versus regular oral iron, Outcome 18 Neonatal birthweight. . . . . 99

Analysis 8.19. Comparison 8 Intravenous iron versus regular oral iron, Outcome 19 Small-for-gestational age. . . . 100

Analysis 8.20. Comparison 8 Intravenous iron versus regular oral iron, Outcome 20 Five minute Apgar score under

seven. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Analysis 8.21. Comparison 8 Intravenous iron versus regular oral iron, Outcome 21 Neonatal mortality. . . . . . 101

Analysis 8.22. Comparison 8 Intravenous iron versus regular oral iron, Outcome 22 Haemoglobin level > 12 g/dL at 30

days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Analysis 8.23. Comparison 8 Intravenous iron versus regular oral iron, Outcome 23 Gestational hypertension. . . 102

Analysis 8.24. Comparison 8 Intravenous iron versus regular oral iron, Outcome 24 Gestational diabetes. . . . . 102

Analysis 8.25. Comparison 8 Intravenous iron versus regular oral iron, Outcome 25 Haemoglobin level > 11 g/dL at

birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Analysis 8.26. Comparison 8 Intravenous iron versus regular oral iron, Outcome 26 Severe delayed allergic reaction. 103

Analysis 8.27. Comparison 8 Intravenous iron versus regular oral iron, Outcome 27 Arthralgia. . . . . . . . . 104

iiTreatments for iron-deficiency anaemia in pregnancy (Review)


Analysis 9.1. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 1 Side effects. . . . . . 104

Analysis 9.2. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 2 Nausea or vomiting. . . 105

Analysis 9.3. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 3 Constipation. . . . . 105

Analysis 9.4. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 4 Abdominal cramps. . . 106

Analysis 10.1. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 1 Allergic reaction

during infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Analysis 10.2. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 2 Allergic reaction

after infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Analysis 10.3. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 3 Life-threatening

allergic reaction during infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Analysis 10.4. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 4 Discomfort needing

analgesics after infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Analysis 10.5. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 5 Immobilised by

painful joints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Analysis 10.6. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 6 Non-live births. 109

Analysis 10.7. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 7 Neonatal death. 109

Analysis 10.8. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 8 Stillbirth. . . 110

Analysis 10.9. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 9 Spontaneous

abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Analysis 11.1. Comparison 11 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus

intravenous iron sucrose, Outcome 1 Hb < 11 g/dL at 4 weeks. . . . . . . . . . . . . . . . . . 111


intravenous iron sucrose, Outcome 2 Mean corpuscular volume. . . . . . . . . . . . . . . . . 111


intravenous iron sucrose, Outcome 3 Caesarean section. . . . . . . . . . . . . . . . . . . . 112


intravenous iron sucrose, Outcome 4 Metallic taste. . . . . . . . . . . . . . . . . . . . . . 112


intravenous iron sucrose, Outcome 5 Warm feeling. . . . . . . . . . . . . . . . . . . . . . 113


intravenous iron sucrose, Outcome 6 Birthweight. . . . . . . . . . . . . . . . . . . . . . 113


intravenous iron sucrose, Outcome 7 Birth < 37 weeks. . . . . . . . . . . . . . . . . . . . 114


intravenous iron sucrose, Outcome 8 Maternal mean blood pressure. . . . . . . . . . . . . . . . 114


intravenous iron sucrose, Outcome 9 Need transfusion. . . . . . . . . . . . . . . . . . . . 115

Analysis 12.1. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 1 Not anaemic at term. 115

Analysis 12.2. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 2 Mean maternal

haemoglobin at birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Analysis 12.3. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 3 Mean maternal hematocrit

level at birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Analysis 12.4. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 4 Caesarean section. 117

Analysis 12.5. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 5 Haematocrit (%) at 4

weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117







Analysis 13.1. Comparison 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid, Outcome 1

Haematocrit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

iiiTreatments for iron-deficiency anaemia in pregnancy (Review)


Analysis 13.2. Comparison 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid, Outcome 2 Not

anaemic at 6 weeks (packed cell volume > 33%). . . . . . . . . . . . . . . . . . . . . . . 120

Analysis 14.1. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 1 Mean

haemoglobin at 36 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Analysis 14.2. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 2 Haemoglobin

> 11 g/dL at 36 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Analysis 14.3. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 3 Caesarean

section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Analysis 14.4. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 4 Mean

birthweight (kg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Analysis 14.5. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 5 Diarrhoea. 122

Analysis 14.6. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 6

Constipation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Analysis 14.7. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 7 Dyspepsia. 123

Analysis 14.8. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 8 Local site

mainly pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Analysis 14.9. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 9 Staining. 124


Arthralgia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Analysis 14.11. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 11 Itching and

rash. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Analysis 14.12. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 12 Fever. 126

Analysis 14.13. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 13 Malaise. 126

Analysis 14.14. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 14 Vaso-vagal

due to apprehension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Analysis 14.15. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome 15 Systemic

ache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127


Haemoglobin > 12 g/dL at 36 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Analysis 15.1. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 1 Haemoglobin level at 4 weeks. 128




Analysis 15.5. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 5 Haemoglobin level > 11 g/dL at 16


Analysis 15.6. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 6 Treatment failure (haemoglobin <

10 g/dL) at 16 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Analysis 16.1. Comparison 16 Oral iron daily versus oral iron once week, Outcome 1 Haemoglobin level at 16 weeks. 131

Analysis 16.2. Comparison 16 Oral iron daily versus oral iron once week, Outcome 2 Haemoglobin level > 11 g/dL at 16


Analysis 16.3. Comparison 16 Oral iron daily versus oral iron once week, Outcome 3 Treatment failure (haemoglobin < 10

g/dL) at 16 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Analysis 17.1. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 1 Haemoglobin level at 16

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Analysis 17.2. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 2 Haemoglobin level > 11 g/dL

at 16 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Analysis 17.3. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 3 Treatment Failure (haemoglobin

< 10 g/dL) at 16 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Analysis 18.1. Comparison 18 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 1

Haemoglobin level at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134


Haemoglobin level > 11g/dL at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . 135

ivTreatments for iron-deficiency anaemia in pregnancy (Review)



Moderate abdominal pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Analysis 19.1. Comparison 19 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol, Outcome 1 Maternal

haemoglobin level at birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Analysis 19.2. Comparison 19 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol, Outcome 2

Haemoglobin level > 11g/dL at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . 136


Haemoglobin level at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137


Haemoglobin level > 11 g/dL at delivery. . . . . . . . . . . . . . . . . . . . . . . . . 137

Analysis 21.1. Comparison 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day, Outcome 1 Haematocrit (%) at

4 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Analysis 21.2. Comparison 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day, Outcome 2 Haematocrit (%) at

8 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Analysis 23.1. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran, Outcome 1 Haematocrit

(%) at 4 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

Analysis 23.2. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran, Outcome 2 Haematocrit

(%) at 8 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

Analysis 23.3. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran, Outcome 3 Neonatal

jaundice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Analysis 23.4. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran, Outcome 4 Viral

hepatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Analysis 23.5. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran, Outcome 5 Severe

allergic reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Analysis 24.1. Comparison 24 Oral iron polymaltose complex (100mg) versus ferrous sulphate (120mg), Outcome 1

Haemoglobin level at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141


Constipation at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142


Haemoglobin > 11 g/dL at 8 weeks of treatment. . . . . . . . . . . . . . . . . . . . . . 142


Gastrointestinal intolerance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143


Metallic taste. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143


Diarrhea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144


Rashes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144


Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Analysis 24.9. Comparison 24 Oral iron polymaltose complex (100mg) versus ferrous sulphate (120mg), Outcome 9 Cost

due to hospital visits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145


Cost due to loss of work. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

Analysis 25.1. Comparison 25 Oral bovine lactoferrin versus ferrous sulphate, Outcome 1 Mean haemoglobin levels at 1

month. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

Analysis 26.1. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 1 Haemoglobin level at 8

weeks (or until birth). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Analysis 26.2. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 2 Rate of anaemia at 8

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Analysis 26.3. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 3 Rate of moderate anaemia

at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Analysis 26.4. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 4 Nausea at 8 weeks. . 148

vTreatments for iron-deficiency anaemia in pregnancy (Review)


Analysis 26.5. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 5 Heartburn at 8 weeks. 149

Analysis 26.6. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 6 Stomach pain at 8 weeks. 149

Analysis 26.7. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 7 Vomiting at 8 weeks. 150

Analysis 26.8. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 8 Bowel habit: < 3 per

week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Analysis 26.9. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 9 Hard stool at 8 weeks. 151

Analysis 26.10. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 10 Feeling unwell at 8

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Analysis 26.11. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 11 Need transfusion. 152

Analysis 26.12. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 12 Caesarean section. 152

Analysis 26.13. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 13 Birthweight. . . 153

Analysis 26.14. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 14 Preterm birth. . . 153

Analysis 26.15. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 15 Small-for-gestational

age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Analysis 26.16. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 16 Fetal distress. . . 154



Analysis 27.2. Comparison 27 Ferrous sulphate (elementary iron) 20 mg vs 80 mg, Outcome 2 Rate of patients with

anaemia at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155


at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156






week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158



weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159






age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162




Analysis 28.2. Comparison 28 Ferrous sulphate (elementary iron) 40 mg vs 80 mg, Outcome 2 Rate of anaemia at 8

weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163


at 8 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164






week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166



weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167


viTreatments for iron-deficiency anaemia in pregnancy (Review)






age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170


Analysis 29.1. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 1 Mean predelivery maternal

haemoglobin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Analysis 29.2. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 2 Mean maternal haemoglobin after

delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Analysis 29.3. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 3 Tolerate oral iron. . . . . 172

172ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

173APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

176CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

177DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

177INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

viiTreatments for iron-deficiency anaemia in pregnancy (Review)


[Intervention Review]

Treatments for iron-deficiency anaemia in pregnancy

Ludovic Reveiz1, Gillian ML Gyte2, Luis Gabriel Cuervo3, Alexandra Casasbuenas4

1Research Promotion and Development Team, Health Systems Based on Primary Health Care (HSS), Pan American Health Organiza-

tion, Washington DC, USA. 2Cochrane Pregnancy and Childbirth Group, Department of Women’s and Children’s Health, The Univer-

sity of Liverpool, Liverpool, UK. 3Research Promotion Team and Development, Pan American Health Organization (PAHO/WHO),

Washington DC, USA. 4Maternal and Fetal Medicine - Obstetrics and Gynecology, Fundación Santa Fe de Bogotá, Bogotá, Colombia

Contact address: Ludovic Reveiz, Research Promotion and Development Team, Health Systems Based on Primary Health Care

(HSS), Pan American Health Organization, 525, 23rd St, NW, Washington DC, 20037-2895, USA. [email protected].

[email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2012.

Review content assessed as up-to-date: 24 August 2011.

Citation: Reveiz L, Gyte GML, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Databaseof Systematic Reviews 2011, Issue 10. Art. No.: CD003094. DOI: 10.1002/14651858.CD003094.pub3.


A B S T R A C T

Background

Iron deficiency, the most common cause of anaemia in pregnancy worldwide, can be mild, moderate or severe. Severe anaemia can have

very serious consequences for mothers and babies, but there is controversy about whether treating mild or moderate anaemia provides

more benefit than harm.

Objectives

To assess the effects of different treatments for anaemia in pregnancy attributed to iron deficiency (defined as haemoglobin less than

11 g/dL or other equivalent parameters) on maternal and neonatal morbidity and mortality.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (7 June 2011), CENTRAL (2011, Issue 5), PubMed (1966

to June 2011), the International Clinical Trials Registry Platform (ICTRP) (2 May 2011), Health Technology Assessment Program

(HTA) (2 May 2011) and LATINREC (Colombia) (2 May 2011).

Selection criteria

Randomised controlled trials comparing treatments for anaemia in pregnancy attributed to iron deficiency.

Data collection and analysis

We identified 23 trials, involving 3.198 women. We assessed their risk of bias. Three further studies identified are awaiting classification.

Main results

Many of the trials were from low-income countries; they were generally small and frequently methodologically poor. They covered a

very wide range of differing drugs, doses and routes of administration, making it difficult to pool data. Oral iron in pregnancy showed

a reduction in the incidence of anaemia (risk ratio 0.38, 95% confidence interval 0.26 to 0.55, one trial, 125 women) and better

haematological indices than placebo (two trials). It was not possible to assess the effects of treatment by severity of anaemia. A trend was

found between dose and reported adverse effects. Most trials reported no clinically relevant outcomes nor adverse effects. Although the

1Treatments for iron-deficiency anaemia in pregnancy (Review)


mailto:[email protected]

mailto:[email protected]

intramuscular and intravenous routes produced better haematological indices in women than the oral route, no clinical outcomes were

assessed and there were insufficient data on adverse effects, for example, on venous thrombosis and severe allergic reactions. Daily low-

dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with higher

doses.

Authors’ conclusions

Despite the high incidence and burden of disease associated with this condition, there is a paucity of good quality trials assessing clinical

maternal and neonatal effects of iron administration in women with anaemia. Daily oral iron treatment improves haematological indices

but causes frequent gastrointestinal adverse effects. Parenteral (intramuscular and intravenous) iron enhances haematological response,

compared with oral iron, but there are concerns about possible important adverse effects (for intravenous treatment venous thrombosis

and allergic reactions and for intramuscular treatment important pain, discolouration and allergic reactions). Large, good quality trials,

assessing clinical outcomes (including adverse effects) as well as the effects of treatment by severity of anaemia are required.

P L A I N L A N G U A G E S U M M A R Y

Treatments for anaemia in pregnancy thought to be due to iron deficiency

When the blood has insufficient red cells, or the red cells carry insufficient haemoglobin to deliver adequate oxygen to the tissues, this

is called anaemia. There is normally a reduction in the haemoglobin concentrations in the mother’s blood during pregnancy, and this

allows a better blood flow around the womb (uterus) and to the baby. This is sometime called physiological anaemia and needs no

treatment. True anaemia, however, can be mild, moderate or severe and can cause weakness, tiredness and dizziness. Severe anaemia

makes women at risk of cardiac failure and is very common in low-income countries Anaemia has many causes including a shortage

or iron, folic acid or vitamin B12. These are all required for making red cells and are available in a good diet. Iron shortage, however,

is the most common cause of anaemia during pregnancy. Iron treatment can be given by mouth (oral), by injection into the muscle

(intramuscular) or injection into the vein (intravenous). Blood transfusion or giving something which stimulates the body to produce

more red cells (erythropoietin) are also possible treatments.

In this review, we identified 23 trials involving 3198 pregnant women. Many of the trials were in low-income countries and many

treatment variations were studied. Oral iron reduced the incidence of anaemia but is known to sometimes cause constipation and

nausea. Although the intramuscular and intravenous routes produced better levels of red cells and iron stores than the oral route,

no clinical outcomes (such as pre-eclampsia, preterm births, postpartum haemorrhage) were assessed and there were insufficient data

on adverse effects. Intravenous treatment can cause venous thrombosis (blockages in the veins) and intramuscular treatment causes

important pain and discolouration at the injection site. It was unclear if women and babies were healthier when women were given

iron for mild or moderate anaemia during pregnancy. There were no studies on using blood transfusions.

Overall, there was insufficient evidence to say when or how anaemia in pregnancy needs to or should be treated.

B A C K G R O U N D

Description of the condition

Iron deficiency, and particularly iron deficiency anaemia, is one

of the most severe and important nutritional deficiencies world-

wide. Iron deficiency is defined as “a condition in which there are

no mobilizable iron stores and in which signs of a compromised

supply of iron to tissues, including the erythron, are noted. The

more severe stages of iron deficiency are associated with anaemia”

(WHO 2001). Anaemia is a reduction in the normal number of

circulating red blood cells and in the quantity of haemoglobin

(Hb) in the blood. More than half of the pregnant women in

low-income countries suffer from anaemia and iron deficiency is

the most common cause of anaemia in pregnancy (WHO 2001).

Using data from the World Health Organization (WHO) Vita-

min and Mineral Nutrition Information System for 1993 to 2005,

global anaemia prevalence was estimated to be 41.8% (95% confi-

dence interval (CI) 39.9 to 43.8 %) in pregnant women (McLean



2009). The high prevalence of anaemia has been associated with

low socio-economic status (odds ratio (OR) 1.419, 95% CI 1.05

to 1.90) (Noronha 2010).

More than half a million maternal deaths occur each year, ap-

proximately 90% of which are in low-income countries, mak-

ing evident a large discrepancy between high- and low-income

countries. The common causes of anaemia include iron deficiency,

folate deficiency, vitamin B12 deficiency, bone marrow suppres-

sion, haemolytic diseases (sickle cell disease and malaria), chronic

blood loss (for example, hook worm infestation) and underlying

malignancies (WHO 1992), with iron-deficiency being the most

common cause of anaemia in pregnant women worldwide (Goroll

1997; Lops 1995; Williams 1992). The diverse main preventable

factors relating to maternal mortality have been described, and

include chronic anaemia, infections, bleeding, hypertensive disor-

ders, obstructed labour and unsafe abortions (WHO 2000).

Haemoglobin is the protein in the red blood cell which carries oxy-

gen to the tissues and iron is part of the Hb molecule. There are a

variety of indicators of iron status such as bone marrow iron, serum

ferritin, transferrin saturation, erythrocyte protoporphyrin, trans-

ferrin receptors and also red cell mean corpuscular volume (MCV),

red cell mean corpuscular haemoglobin (MCH) and red cell mean

corpuscular haemoglobin concentration (MCHC). However, nei-

ther blood Hb concentration nor serum iron are thought to be

good indicators of anaemia because there can be depletion of body

iron stores in the presence of normal Hb levels and serum iron

fluctuates depending on recent iron intake. Serum ferritin may be

a better indicator of iron status as the examination of iron stores

in the bone marrow is impractical. Historically, blood Hb levels

have been used as indicators of anaemia, the test being simple

and inexpensive to undertake. Anaemia is associated with general

weakness, tiredness and dizziness but the level of Hb associated

with these symptoms in pregnancy is unknown. These symptoms

are nonspecific and frequently appear in cases of severe anaemia

too and in association with other medical problems. Anaemia in

pregnancy is defined by the WHO as a Hb value below 11 g/

dL (WHO 1992; WHO 2001). Although anaemia is frequently

graded as “mild”, “moderate”, or “severe”, the Hb values at which

the division into these three categories is made vary and are ar-

bitrary. Standardised cut-off values are difficult to define because

populations, geographic settings and needs are different according

to specific areas. Some authors suggest that Hb values at sea level

should be categorised as follows (WHO 1989): (1) mild anaemia

(Hb 10 to 10.9 g/dL); (2) moderate anaemia (Hb 7 to 9.9 g/dL);

(3) severe anaemia (Hb less than 7 g/dL). However, other criteria

have been widely used in the literature to define anaemia cut-off

values: (1) mild (Hb 9 to 10.9 g/dL), (2) moderate (Hb 7 to 8.9

g/dL) and (3) severe (Hb below 7 g/dL) (Adam 2005); and (1)

mild anaemia (Hb 7 to 11 g/dL), moderate anaemia (5 to 7 g/

dL) and severe anaemia (below 5 g/dL) (Brabin 2001). The in-

terpretation of Hb concentrations in pregnancy is sometimes dif-

ficult because of the normal physiological decrease in blood Hb

concentration in pregnancy and in certain conditions where water

balance is affected (i.e. pre-eclampsia) Hb concentrations may be

overestimated as a result of dehydration (Letsky 1991).

It is suggested that the iron stores of the woman’s body become

reduced during pregnancy (as a result of the increased red cell mass

and the demands of the fetus exceeding iron intake), and that this

can take place in the presence of normal blood Hb levels. Some

will argue that this is a well-designed physiological mechanism to

continue to deliver oxygen to the tissues in the presence of low-

ered blood Hb levels in pregnancy. An observational study under-

taken in London, UK, found that low levels of Hb, commonly

considered as mild anaemia, were associated with a better progno-

sis for the fetus, although figures did not appear to be corrected

for women with pre-eclampsia (Steer 1995). However, others ar-

gue that reduced iron stores are a health problem for pregnant

women and their babies (Letsky 2001). Several studies considered

anaemia (Hb levels between 7 g/dL and 10 g/dL) as a risk fac-

tor for fetal death, premature delivery, low birthweight and other

adverse outcomes (Williams 1992). Some suggest a link between

maternal anaemia in pregnancy on the later developmental prob-

lems of the children (Letsky 2001; Williams 1992). There is evi-

dence indicating that maternal Hb levels under 7 g/dL are associ-

ated with a higher risk in the mother of developing cardiac heart

failure, which has adverse consequences on the mother and fetus

(Lops 1995; WHO 1992; Williams 1992). A cohort study done

in Pakistan found that the risk of low birthweight and preterm

delivery among anaemic women (Hb under 11 g/dL) was 1.9 and

four times higher, respectively, than non-anaemic women. In ad-

dition, the neonates of anaemic women had a 3.7 greater risk of

intrauterine fetal death and 1.8 times increased risk having low Ap-

gar scores at one minute when compared to non-anaemic women

(Lone 2004). There is a strong case for studying separately physi-

ological anaemia, mild anaemia and severe anaemia in pregnancy.

In low-income countries, anaemia in pregnancy is frequent and

has been attributed to poor nutrition and a high incidence of con-

current diseases, and can potentially complicate conditions such

as postpartum haemorrhage which is a major contributor to ma-

ternal mortality in many developing countries (WHO 1992). A

case control study, conducted in India, evaluated maternal mor-

tality risk factors from 25,926 households in 411 villages. The

authors reported that the major related causes of maternal deaths

were haemorrhage, severe anaemia, puerperal sepsis, and abortion

(Gupta 2010). However, anaemia may only be a marker of various

social and nutritional conditions, and raising Hb levels could have

little, if any, effect on morbidity or mortality if those conditions

are not improved (Goroll 1997).

Description of the intervention

There are various considerations that need to be taken into account

when treating iron-deficiency anaemia:



Iron can be given by mouth, by intramuscular (IM) injection or

intravenous (IV) injection. It is also possible to deliver iron by

giving a blood transfusion, and recombinant erythropoietin in

conjunction with iron is a further possibility. Some evidence sug-

gests that oral iron given to anaemic pregnant and non-pregnant

women is associated with gastrointestinal side effects such as nau-

sea and constipation (WHO 2000 ). IM or IV iron are thought

to be associated with allergic reactions and anaphylactic shock,

as well as venous thrombosis and occasionally cardiac arrest and

death. Blood transfusion carries the risk of transmitting parasitic

or viral infections including HIV, hepatitis, and Chagas disease

(trypanosomiasis), despite preventive blood screening. There is

also the possibility of bovine spongiform encephalitis, and as yet

unknown viral infections. Oral iron is often the preferred route

of administration for mild anaemia, while IM and IV routes are

more frequently used in people with severe anaemia when the risks

of cardiac failure due to severe anaemia are perceived to outweigh

the risks of potential adverse effects.

There are also variations in the doses used (e.g. low or high

doses), differing regimens (e.g. single, daily, monthly or intermit-

tent doses), differing forms of iron (e.g. dextran, fumarate) and

sometimes adjuncts given (e.g. vitamin A, erythropoietin).

How the intervention might work

Physiological changes during pregnancy may affect laboratory pa-

rameters such as the haematocrit and the Hb (Klajnbard 2010).

Transfer of iron from the mother to the fetus is regulated by the

placenta (Allen 2000). During pregnancy, there is an increase in

maternal iron absorption and also an increase in both red cell mass

and plasma volume to accommodate the needs of the growing

uterus and fetus. However, plasma volume increases more than

the red cell mass leading to a fall in the concentration of Hb in

the blood, despite the increase in the total number of red cells

(Letsky 1991). This drop in Hb concentration decreases the blood

viscosity and it is thought this enhances the placental perfusion

providing a better maternal-fetal gas and nutrient exchange (Mani

1995). There is controversy around the significance for women

and their babies of this physiological haemodilution of pregnancy

and at what level of Hb women and babies would benefit from iron

treatment. As discussed below, some studies suggest that the phys-

iological decrease in Hb is associated with improved outcomes for

the baby (Mahomed 1989; Steer 1995), whilst others have iden-

tified adverse long-term outcomes for the baby (Walter 1994).

For pathological changes, treatment for iron deficiency focuses on

increasing the iron stores and blood Hb levels, so they reach normal

levels and can provide a normal oxygen supply to the tissues. In

anaemia in pregnancy, the treatment should not only normalise

iron stores and blood Hb levels, but should also be shown to

improves clinical outcomes for both mother and baby.

Why it is important to do this review

Iron is the most common strategy currently used to control iron

deficiency and anaemia in low-income countries (WHO 2001).

Recommendations for the treatment of anaemia are frequently

based on the expectation that they may be benevolent but are

seldom supported by reproducible robust studies, especially ran-

domised controlled trials. Furthermore, they may not take into

account important adverse effects such as allergic reactions, viral

or parasitic transmission from blood transfusions, gastrointestinal

complications, and discomfort generated by common side effects

of iron (Table 1). Therefore, it is difficult to balance the benefits

and harms of treatments, let alone determine if there is a case to

recommend a particular anaemia treatment for all women with

anaemia in pregnancy.

The aim of this review was to use a systematic approach to identify

and synthesise the evidence of randomised controlled trials evalu-

ating the effects of treatments for anaemia in pregnancy, and pro-

vide robust valid and useful evidence to inform clinical practice.

O B J E C T I V E S

The principal objective was to determine the overall effects of dif-

ferent forms of iron therapy given to pregnant women diagnosed

with anaemia attributed to iron-deficiency, measuring neonatal

and maternal morbidity and mortality, haematological parameters

and side effects, especially adverse effects of treatment. The re-

view aimed to assess the effects of iron treatments when delivered

to women categorised in three groups (mild, moderate or severe

anaemia, as defined by trialists) at inception into the randomised

controlled trial.

The review did not address the need for iron supplementation of

non-anaemic women; this question has been addressed in several

other reviews and evidence summaries. Similarly, it did not fo-

cus vitamin B12, micronutrients, folate deficiency, infectious or

genetic anaemia, which will be or are covered by other reviews

(Pena-Rosas 2009; Van den Broek 2010).

M E T H O D S

Criteria for considering studies for this review

Types of studies

This review considered randomised controlled trials assessing the

effects of treatments for anaemia in pregnancy attributed to iron

deficiency. When information in the abstract was unclear or in-

complete, we reviewed the ’materials and methods’ of the reports.

Quasi-random studies were not eligible for this review.



As previously mentioned, the use of Hb <11g/dL (at sea level)

only helps to diagnose anaemia but not iron deficiency anaemia.

Iron-deficiency anaemia definitions may be problematic due to

the controversy about which diagnostic tests are sufficient and reli-

able enough to rule out other causes of anaemia, and that anaemia

causes are frequently combined. Therefore, for this review we ac-

cepted the diagnosis of anaemia defined by the authors of the stud-

ies.

Types of participants

Pregnant women with a diagnosis of anaemia (Hb levels under 11

g/dL, or other tests for anaemia as described by trialists) attributed

to iron deficiency.

Types of interventions

We included the following interventions.

1. Oral iron.

2. Oral iron plus adjuncts.

3. Intramuscular (IM) iron.

4. Intravenous (IV) iron.

5. Blood transfusion.

6. Recombinent erythropoietin.

We looked for studies that compared these intervention against

placebo and against each other. We also looked at different doses,

routes of administration and regimens.

* For the purpose of this review, regular oral iron will include

preparations different from controlled-release oral iron.

Types of outcome measures

Primary outcomes

Women

Clinical outcomes

Mortality

Morbidity

Puerperal sepsis

Systemic bacterial infection after delivery

Days in intensive care unit

Days hospitalised during pregnancy

Newborn

Clinical outcomes

Mortality

Morbidity

Days hospitalised

Admission to neonatal intensive care unit

Secondary outcomes

Women

Clinical outcomes

Preterm labour

Premature delivery

Pneumonia

Postpartum haemorrhage (equal to or more than 500 ml)

Heart failure

Haematological outcomes

Maternal serum ferritin

Maternal serum iron

Hb levels

Long-term haematological outcomes (not pre-specified in original

protocol)

Maternal side effects

General symptoms (e.g. weakness,

tiredness, dizziness)Gastrointestinal effects (e.g. nausea, vomiting,

diarrhoea, epigastric pain, constipation)

Local symptoms (e.g. pain or tenderness, erythema)

Systemic symptoms (e.g. myalgia, arthralgia, abscess formation at

injection site, allergic reactions etc)

Newborn

Clinical outcomes

Low birthweight (less than 2500 g)

Respiratory disease requiring ventilation

Small-for-gestational age



Haematological outcomes

Cord serum ferritin

Cord Hb

Other long-term outcomes

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Tri-

als Register by contacting the Trials Search Co-ordinator (7 June

2011).

The Cochrane Pregnancy and Childbirth Group’s Trials Register

is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. quarterly searches of the Cochrane Central Register of

Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of EMBASE;

4. handsearches of 30 journals and the proceedings of major

conferences;

5. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE,

the list of handsearched journals and conference proceedings, and

the list of journals reviewed via the current awareness service can

be found in the ‘Specialized Register’ section within the edito-

rial information about the Cochrane Pregnancy and Childbirth

Group.

Trials identified through the searching activities described above

are each assigned to a review topic (or topics). The Trials Search

Co-ordinator searches the register for each review using the topic

list rather than keywords.

In addition, we searched CENTRAL (The Cochrane Library 2011,

Issue 2 of 4) and PubMed (1966 to June 2011) using the search

strategies given in Appendix 1.

In order to further identify ongoing RCTs and unpublished studies

we searched the following trials registers (2 May 2011) using the

terms and phrases detailed in Appendix 1.

• Search Portal of the International Clinical Trials Registry

Platform (ICTRP; www.who.int/ictrp/) for appropriate ongoing

and recently completed studies

• Health Technology Assessment Program (HTA) (

www.hta.ac.uk/) (United Kingdom)

• LATINREC [www.latinrec.net], Colombia

For details of searching carried out in the previous version of the

review, see: Appendix 2

Searching other resources

We searched the bibliographies of all papers identified by these

strategies.

We did not apply any language restrictions.

Data collection and analysis

For the methods used when assessing the trials identified in the

previous version of this review, see Appendix 3.

For this update, we used the following methods when assessing

the reports identified by the updated search.

Selection of studies

Two review authors (Ludovic Reveiz (LR), Alexandra Casasbuenas

(AC)) independently assessed for inclusion all the potential studies

we identified as a result of the search strategy. We resolved any

disagreement through discussion or, if required, we consulted a

third person (Luis Gabriel Cuervo (LGC)).

Data extraction and management

We designed a form to extract data. For eligible studies, two review

authors (LR, AC) extracted the data using the agreed form. We

resolved discrepancies through discussion or, if required, we con-

sulted another review author (LGC). We entered data into Review

Manager software (RevMan 2011) and checked for accuracy.

When information regarding any of the above was unclear, we

attempted to contact authors of the original reports to provide

further details.

Assessment of risk of bias in included studies

Two review authors (LR, AC) independently assessed risk of bias

for each study using the criteria outlined in the Cochrane Handbookfor Systematic Reviews of Interventions (Higgins 2011). We resolved

any disagreement by discussion.

(1) Sequence generation (checking for possible selection

bias)

We described for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment

of whether it should produce comparable groups.

We assessed the method as:

• low risk (any truly random process, e.g. random number

table; computer random number generator);

• high risk (any non-random process, e.g. odd or even date of

birth; hospital or clinic record number);

• unclear risk.



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/PREG/frame.html





http://www.who.int/ictrp/


http://www.hta.ac.uk/

http://www.latinrec.net

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the method used to conceal

the allocation sequence and determine whether intervention allo-

cation could have been foreseen in advance of, or during recruit-

ment, or changed after assignment.

We assessed the methods as:

• low risk (e.g. telephone or central randomisation;

consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non-opaque

envelopes, alternation; date of birth);

• unclear risk.

(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which

intervention a participant received. We considered that studies

were at low risk of bias if they were blinded, or if we judged that the

lack of blinding could not have affected the results. We assessed

blinding separately for different outcomes or classes of outcomes.


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

• low risk, high risk or unclear risk for personnel;

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

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome or

class of outcomes, the completeness of data including attrition

and exclusions from the analysis. We stated whether attrition and

exclusions were reported, the numbers included in the analysis at

each stage (compared with the total randomised participants), rea-

sons for attrition or exclusion where reported, and whether miss-

ing data were balanced across groups or were related to outcomes.

Where sufficient information was reported, or could be supplied

by the trial authors, we re-included missing data in the analyses

which we undertook. We assessed methods as:

• low risk;

• high risk;

• unclear risk.

(5) Selective reporting bias

We described for each included study how we investigated the

possibility of selective outcome reporting bias and what we found.


• low risk (where it is clear that all of the study’s pre-specified

outcomes and all expected outcomes of interest to the review

have been reported);

• high risk (where not all the study’s pre-specified outcomes

have been reported; one or more reported primary outcomes

were not pre-specified; outcomes of interest were reported

incompletely and so could not be used; study failed to include

results of a key outcome that would have been expected to have

been reported);

• unclear risk.

(6) Other sources of bias

We described for each included study any important concerns we

have about other possible sources of bias.

We assessed whether each study was free of other problems that

could put it at risk of bias:

• low risk;

• high risk;

• unclear risk.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high

risk of bias, according to the criteria given in the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2011). With

reference to (1) to (6) above, we assessed the likely magnitude and

direction of the bias and whether we considered it was likely to

impact on the findings. We explored the impact of the level of bias

through undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio

(RR) with 95% confidence intervals (CIs).

Continuous data

For continuous data, we used the mean difference (MD) if out-

comes were measured in the same way between trials. We used

the standardised mean difference (SMD) to combine trials that

measured the same outcome, but used different methods.

Dealing with missing data

For included studies, we noted levels of attrition. We explored the

impact of including studies with high levels of missing data in the

overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on

information about retaining participants in their original assigned

groups, i.e. we attempted to include all participants randomised

to each group in the analyses, and all participants were analysed

in the group to which they were allocated, regardless of whether

or not they received the allocated intervention. The denominator



for each outcome in each trial was the number randomised minus

any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using

the T², I² and Chi² statistics. We regarded heterogeneity as sub-

stantial if T² was greater than zero and either I² was greater than

30% or there is a low P value (less than 0.10) in the Chi² test for

heterogeneity.

Assessment of reporting biases

If there had been 10 or more studies in the meta-analysis we

planned to investigate reporting biases (such as publication bias)

using funnel plots. We would have assessed funnel plot asymme-

try visually, and used formal tests for funnel plot asymmetry. For

continuous outcomes we would have used the test proposed by

Egger 1997, and for dichotomous outcomes, the test proposed by

Harbord 2006. If asymmetry had been detected in any of these

tests, or was suggested by a visual assessment, we would have per-

formed exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager soft-

ware (RevMan 2011). We used fixed-effect meta-analysis for com-

bining data where it was reasonable to assume that studies were

estimating the same underlying treatment effect: i.e. where trials

were examining the same intervention, and the trials’ populations

and methods were judged sufficiently similar. If there was clinical

heterogeneity sufficient to expect that the underlying treatment ef-

fects differed between trials, or if substantial statistical heterogene-

ity was detected, we used random-effects meta-analysis to produce

an overall summary if an average treatment effect across trials was

considered clinically meaningful. The random-effects summary

was treated as the average range of possible treatment effects and

we discussed the clinical implications of treatment effects differing

between trials. If the average treatment effect was not clinically

meaningful, we did not combine trials.

Where we used random-effects analyses, the results were presented

as the average treatment effect with its 95% CI, and the estimates

of T² and I².

Subgroup analysis and investigation of heterogeneity

Had we identify substantial heterogeneity, we would have investi-

gated it using subgroup analyses and sensitivity analyses. We would

have considered whether an overall summary was meaningful, and

if it was, used random-effects analysis to produce it.

We had planned to carry out the following subgroup analyses:

1. level of anaemia (mild, moderate, severe).

The following outcomes would have been used in subgroup anal-

ysis:

1. maternal and newborn mortality;

2. maternal and newborn morbidity (puerperal sepsis, days

hospitalised during pregnancy, low birthweight, newborn

hospitalisations days);

3. Hb levels.

For fixed-effect inverse variance meta-analyses, we would have as-

sessed differences between subgroups by interaction tests. For ran-

dom-effects and fixed-effect meta-analyses using methods other

than inverse variance, we would have assessed differences between

subgroups by inspection of the subgroups’ CIs; non-overlapping

CIs indicate a statistically significant difference in treatment effect

between the subgroups.

Sensitivity analysis

We had planned to carry out the following sensitivity analyses but

there were insufficient data:

1. according to risk of bias assessment.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of

excluded studies; Characteristics of studies awaiting classification;

Characteristics of ongoing studies.

Results of the search

The search identified 117 references: two unpublished trials,

six congress abstracts, and 109 published trials. An initial trawl

through this list (LR excluded 17 references of non-randomised

controlled trials (RCTs). This left 100 trials for a more detailed

evaluation. Seventy three studies were further excluded after first

review because they were not RCTs; included mostly non-anaemic

women; evaluated postpartum iron treatments; focused on non

iron-deficiency anaemia; or had methodological flaws that seri-

ously compromised their validity or resulted in insufficient useful

reliable information (Characteristics of excluded studies). Two re-

view authors (LR and AC) independently checked the trials against

the inclusion criteria, and a third author (LGC) acted as the arbiter.

We actively tried to contact the authors using contact informa-

tion provided in their articles and on the Internet. We contacted

and received responses from the authors listed in the following

articles: Breymann 2001; De Souza 2004; Mumtaz 2000; Singh

1998; Suharno 1993; Visca 1996. We did not receive a response

to our communications from the authors of the articles listed as

Al Momen 1996; Khalafallah 2010; Sarkate 2007; Ruangvutilet



2009. We were unable to contact the authors for two articles (Stein

1991; Wu 1998).

Included studies

We included 23 RCTs in the review involving 3198 women (Al

2005; Bayoumeu 2002; Breymann 2001; Dawson 1965; De Souza

2004; Digumarthi 2008; Kaisi 1988; Khalafallah 2010; Komolafe

2003; Kumar 2005; Mumtaz 2000; Nappi 2009; Ogunbode 1980;

Oluboyede 1980; Saha 2007; Singh 1998; Sood 1979; Suharno

1993;Sun 2010; Symonds 1969; Wali 2002; Zhou 2007; Zutschi

2004). Most focused on laboratory results rather than clinical out-

comes. Clinical outcomes were assessed in seven RCTs (Al 2005;

Bayoumeu 2002; Breymann 2001; Oluboyede 1980; Singh 1998;

Zhou 2007; Zutschi 2004).Although Breymann and Singh’s data

were unpublished, these data were provided by the main author

of Singh 1998 and have been incorporated into the review. LR

and AC independently extracted data from the articles. LGC was

expected to act as arbiter if differences arose in the data extraction,

but this did not happen. LR performed data entry, and G Gyte

(GG) and AC checked data entries for accuracy. Six RCTs were in-

cluded in this update (Digumarthi 2008; Khalafallah 2010; Nappi

2009; Saha 2007; Sun 2010; Zhou 2007). In addition, we have

added three reports to Studies awaiting classification because au-

thors did not provide useful data for analysis (Paleru 2011; Pandit

2009; Sarkate 2007) and one study was ongoing (Ruangvutilet

2009). We contacted authors by email but only the authors of the

ongoing RCT replied informing us that they were still at the stage

of analysis (Ruangvutilet 2009).

Seven groups of RCTs were described according to the type of

intervention. However, groups were further divided according to

co-interventions, dose, regimen, route, or type of chemical com-

ponents of the intervention (i.e. iron sucrose, dextran), as follows.

(1) Oral iron

• Oral iron versus placebo (Suharno 1993;Sun 2010;

Symonds 1969)

• Oral iron plus vitamin A versus placebo (Suharno 1993)

• Oral iron plus vitamin A versus oral iron (Suharno 1993)

• Oral iron versus bovine lactoferrin (Nappi 2009)

(2) Different regimens of oral iron treatment

• Daily oral iron versus twice-weekly (De Souza 2004;

Mumtaz 2000)

• Daily oral iron versus once a week (De Souza 2004)

• Twice-weekly iron versus once weekly iron (De Souza 2004)

• 600 mg oral iron versus 1200 mg oral iron (Ogunbode

1980)

• Controlled-release oral iron versus regular oral iron

(Symonds 1969)

• Iron polymaltose versus ferrous sulphate (Saha 2007)

• Elemental iron 20; 40 or 80 mg (Zhou 2007)

(3) Intramuscular (IM) iron

• IM iron sorbitol versus IM dextran (Dawson 1965)

• IM iron sorbitol versus intravenous (IV) iron dextran

(Oluboyede 1980)

(4) Intravenous (IV) iron

• IV route versus placebo (Symonds 1969)

(5) Parenteral route (IM or IV) versus oral route

• IM versus oral iron treatment (Komolafe 2003; Kumar

2005; Ogunbode 1980; Zutschi 2004)

• IV versus oral iron treatment (Al 2005; Bayoumeu 2002;

Digumarthi 2008; Khalafallah 2010; Singh 1998; Sood 1979;

Symonds 1969)

(6) IV iron versus IM iron with different regimens of parenteral

iron treatment

• IV iron versus IM iron (Oluboyede 1980)

• Different IM preparations (Dawson 1965)

• IV iron versus IM iron (Dawson 1965)

• IV iron with hydrocortisone versus IV iron (Dawson 1965)

• Two differing IV doses (Kaisi 1988)

• IV iron versus IM iron (Wali 2002)

(7) IV administered iron sucrose with and without adjuvant re-

combinant human erythropoietin (Breymann 2001)

For details of included studies see: Characteristics of included

studies table. We have two studies awaiting classification, see

Characteristics of studies awaiting classification). There is one on-

going study (Ruangvutilet 2009).

Excluded studies

The reasons for excluding studies are reported in Characteristics

of excluded studies.

Risk of bias in included studies

We (LR, AC) assessed the risk of bias of the included studies in-

dependently as described in the Cochrane Handbook for SystematicReviews of Interventions (Higgins 2011). We resolved differences

in interpretations by consensus among three review authors (LR,

AC, LGC), after checking the criteria agreed in the original re-

view protocol. When RCTs had potential validity or interpretation

problems and just part of the data were deemed useful, we would

only use such data. For example, when RCTs had high withdrawal

rates, and therefore, incomplete data on outcomes at the end of

follow-up, but still offered complete data at a given time that ful-

filled our pre-defined inclusion criteria, we used the later data. A

summary of the assessment can be viewed in Figure 1 and Figure

2.



Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.



Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.



Allocation

Twelve out of 23 RCTs reported on how the randomisation se-

quence was generated (Al 2005; Bayoumeu 2002; Breymann 2001;

Dawson 1965; Kaisi 1988; Khalafallah 2010; Komolafe 2003;

Mumtaz 2000; Nappi 2009 ; Singh 1998; Suharno 1993; Zhou

2007); no information was available for the remaining RCTs.

Seven out of 23 studies reported adequate allocation concealment

(Al 2005; Breymann 2001; Khalafallah 2010; Mumtaz 2000;

Singh 1998; Suharno 1993; Zhou 2007). Published details of the

randomisation were insufficient in the Singh 1998 and Breymann

2001 articles, but additional details were provided by the authors

upon request.

The allocation strategy and concealment were considered adequate

in six of the 23 studies (Al 2005; Breymann 2001; Khalafallah

2010; Mumtaz 2000; Suharno 1993; Zhou 2007).

Blinding

In most RCTs, blinding was not used; these were open RCTs.

Six RCTs described blinding (masking), three of which were ade-

quately reported (Nappi 2009; Saha 2007; Zhou 2007). However,

in two RCTs it was unclear whether the participants or healthcare

providers were blinded to the interventions (Mumtaz 2000; Sun

2010; Suharno 1993); both RCTs assessed oral administration.

Incomplete outcome data

Withdrawal rates (drop outs and losses to follow up) were reported

in eleven RCTs (Al 2005; Breymann 2001;Khalafallah 2010;

Komolafe 2003; Nappi 2009; Ogunbode 1980; Singh 1998;Sun

2010; Symonds 1969; Zhou 2007; Zutschi 2004).

• Less than 5%: withdrawal rates were lower than 5% in five

RCTs (Nappi 2009; Oluboyede 1980; Sood 1979; Sun 2010;

Zhou 2007).

• 5% to 9.9%: an RCT from Pakistan (Wali 2002) had five

withdrawals (8.3%) due to intolerance in the IM iron group. An

RCT from France had three withdrawals (6%) (Bayoumeu 2002)

and the RCT from Australia had 17 withdrawals (8.5%)

(Khalafallah 2010).

• 10% to 19.9%: the West Java RCT (Suharno 1993) had

complete data available on 251 (83%) women: reasons for

withdrawals are further described in the article.

• More than 20%: an RCT from Pakistan (Mumtaz 2000)

recruited 191 women; of these, 160 were successfully followed

for at least four weeks and supplemented for an average of 10.9

weeks. Fifty-five per cent completed the entire duration of

follow-up; 15% of the women recruited did not return for a

single visit and were excluded from the analysis. The remaining

30% did not complete the entire 12 weeks of planned follow-up.

No significant differences were found for population

characteristics (age, socio-economic status score, parity, time

since last pregnancy, body mass index, initial Hb, dependants or

family and the duration of follow-up) between women who

withdrew and those who completed the study. The RCT from

Brazil (De Souza 2004) had 41 (21.5%) women who withdrew

or were lost to follow up; the reasons were described in the

article. The analysis was done using data at 16 weeks of

treatment. The UK RCT (Dawson 1965) had high rates of losses

to follow up. The RCT focused on assessing adverse effects. The

RCT from Tasmania (Kaisi 1988) had high withdrawal rates for

most outcomes (loss to follow up for Hb result was 47%) and

only data on adverse effects were used for this review. The RCT

from India (Kumar 2005) recruited 220 women of whom 150

(68%) completed the study. No significant differences were

found on data of initial haematological parameters, gestation,

parity or literacy between women who completed the study and

women who withdrew. However, withdrawals were different for

women receiving oral treatment (13.5%) and those receiving IM

treatment (38.5%).

A number of studies did not adequately report the outcomes (i.e.

standard deviations were not reported) (see Risk of bias in included

studies).

Selective reporting

Relevant neonatal and maternal outcomes were not frequently

reported by most studies (see Risk of bias in included studies). The

protocol was not available in any study (Figure 1; Figure 2). Only

two studies (Khalafallah 2010; Zhou 2007) were registered in an

international clinical trial registry.

Effects of interventions

Twenty-three RCTs, involving 3198 women, met the inclusion

criteria. Overall, we found insufficient assessment of the outcomes

relevant to the focus of this review, especially of clinical out-

comes. Most results were provided by one or two small RCTs with

methodological limitations. The effect size for these are repre-

sented in this review using the risk ratio (RR) and mean difference

(MD). Uncertainty levels are quantified using 95% confidence in-

tervals (CI).

(1) Oral iron

Oral iron versus placebo (comparison 01)



We found three RCTs involving 266 women (Suharno 1993; Sun

2010; Symonds 1969). Data from the first RCT showed that

women receiving iron (ferrous sulphate) had a lower risk of being

anaemic during the second trimester (RR 0.38; 95% CI 0.26 to

0.55, one RCT, 125 women, Analysis 1.1). In the group receiving

iron, the mean Hb level was higher (MD 1.34; 95% CI 0.0.27

to 2.41; two RCT, 215 women;I2 98% Analysis 1.2) (Suharno

1993; Sun 2010); both trials had individual significant differences

favouring oral iron treatments. Similarly, the mean serum ferritin

was higher for women receiving iron (MD 0.70; 95% CI 0.52

to 0.88; one RCT, 125 women; Analysis 1.3). A trend towards

increased adverse effects (for example, nausea, vomiting, consti-

pation and abdominal cramps) was also noticed in the second

RCT (ferrous gluconate), but figures were small to allow worthy

comparisons (11/51 women with adverse effects). No other as-

sessments were found for clinical outcomes. Hence, it is difficult

to establish the clinical effects of treatments in women and new-

borns. Conclusions need to be approached with care because they

are drawn from a small sample of participants. Furthermore, one

RCT assessed outcomes at the second trimester (Suharno 1993)

and it is unclear if those women sustained similar Hb levels during

the rest of their pregnancy, and no assessment of haematological

results was done at delivery.

Oral iron plus vitamin A versus placebo (comparison 02)

We found one RCT involving 125 women (Suharno 1993). It

included anaemic women with a high risk of suffering vitamin A

deficiency. Adding vitamin A to regular iron (ferrous sulphate), re-

sulted in improved Hb levels. Anaemia during the second trimester

was lower with oral iron plus vitamin A, compared with placebo

(RR 0.04; 95% CI 0.01 to 0.15; one RCT, 125 women; Analysis

2.1). The difference was not as large when the comparator was iron

therapy only (see below). The applicability of these results may be

limited to women in populations with vitamin A deficiency.

Oral iron versus bovine lactoferrin (comparison 25)

One RCT involving 97 women (Nappi 2009) found a significant

reduction in the mean level of anaemia at one month with oral fer-

rous sulphate compared with bovine lactoferrin (MD -0.30 95%

CI -0.52 to -0.08; one RCT, 97 women, Analysis 25.1).

(2) Different regimens of oral iron treatment

(comparisons 15, 16, 17 and 21)

Daily oral iron versus twice-weekly (comparison 15)

An RCT from Pakistan had a loss to follow up greater than 20%

for most of the outcomes and so validity of the findings is unclear

(Mumtaz 2000). The study found that daily oral iron (ferrous

sulphate) significantly increased Hb levels at four weeks, eight

weeks, and 12 weeks, compared with twice-weekly oral iron. At 12

weeks, the mean Hb level was 11.36 g/dL compared with 10.09 g/

dL, respectively (MD 1.27; 95% CI 0.68 to 1.86; one RCT, 105

women; Analysis 15.3). In women receiving daily versus twice-

weekly oral iron therapy (ferrous sulphate), an RCT from Brazil

(De Souza 2004) found no significant difference in Hb levels (MD

0.30; 95% CI -0.01 to 0.61; one RCT, 102 women; Analysis

15.4) or anaemia (RR 1.38; 95% CI 0.86 to 2.23; one RCT, 102

women; Analysis 15.5) at 16 weeks of treatment. A trend was

found between higher doses of iron and reported adverse effects

(19/48 (40%) for 1/week, 24/53 (45%) for twice/week and 35/

49 (71%) for daily treatment). No further description of adverse

effects was provided.

Daily oral iron versus once-weekly (comparison 16)

One RCT from Brazil also had a loss to follow up greater than

20% and so the findings also have uncertain validity (De Souza

2004). The study found that daily oral treatment (ferrous sulphate)

increased Hb levels after 16 weeks of treatment, compared with

weekly oral iron (MD 0.70; 95% CI 0.36 to 1.04; one RCT, 97

women; Analysis 16.1), the proportion of women non-anaemic

at the end of the follow-up (RR 1.73; 95% CI 1.00 to 3.01; one

RCT, 97 women; Analysis 16.2) and reduced treatment failure


16.3).

Twice-weekly iron versus once-weekly iron (comparison 17)

The same RCT from Brazil (De Souza 2004) found that a twice-

weekly regimen of ferrous sulphate resulted in a modest increase in

Hb levels, compared with a weekly iron regimen (MD 0.40; 95%

CI 0.03 to 0.77; one RCT, 101 women; Analysis 17.1) and reduced

treatment failure (RR 0.32; 95% CI 0.15 to 0.68; one RCT, 101

women; Analysis 17.3). However, no significant differences were

found in the proportion of women non-anaemic at 16 weeks of

treatment (RR 1.25; 95% CI 0.69 to 2.28; one RCT, 101 women;

Analysis 17.2). There is again a high risk of bias due to a loss to

follow up of greater than 20%.

600 mg oral iron versus 1200 mg oral iron (comparison 21)

An RCT conducted in Nigeria (Ogunbode 1980) found no signif-

icant differences in Hb levels at four weeks ( MD 0.37; 95% CI -

0.77 to 1.51; one RCT, 56 women; Analysis 21.1) and eight weeks

(MD 0.02; 95% CI -1.03 to 1.07; one RCT, 56 women; Analysis

21.2) of treatment between women receiving 600 mg versus 1200

mg of oral ferrous sulphate. All women received daily 5 mg of folic

acid and 25 mg of pyrimethamine daily, in addition to ferrous

sulphate.



Controlled-release oral iron versus regular oral iron

(comparison 03)

One RCT conducted in Australia (Symonds 1969) compared con-

trolled-release oral iron versus other iron preparations. It provided

information on adverse effects, but data on effectiveness were not

included because it had a very high withdrawal rate. It found no

differences in nausea and vomiting, constipation and abdominal

cramps at one month between controlled-release iron and regu-

lar oral iron. The small sample size and broad CIs illustrate that

the sample size is clearly insufficient to rule out any difference

(Analysis 3.1 to Analysis 3.4).

Iron polymaltose versus ferrous sulphate (comparison 24)

One RCT from India (Saha 2007) that included 100 women com-

pared iron polymaltose (100 mg elemental iron + folic acid 500

mcg for eight weeks versus ferrous sulphate (60 mg elemental iron

+ folic acid 500 mcg for eight weeks). No significant differences

were found in the mean level of Hb and in the proportion of

women with Hb greater than 11 g/dL between groups. Concern-

ing adverse events, a significant difference was found in consti-

pation (RR 0.30; 95% CI 0.14 to 0.64; one RCT, 100 women,

Analysis 24.2), gastrointestinal intolerance (RR 0.41; 95% CI 0.25

to 0.69; one RCT, 100 women, Analysis 24.3) that favoured the

iron polymaltose groups. However, no significant differences were

found for other adverse events (metallic taste, diarrhoea, rashes),

compliance, the cost due to hospital visits and the cost due to loss

of work.

Ferrous sulphate (elemental iron 20 versus 40 versus 80 mg)

(comparisons 26, 27 and 28)

One RCT conducted in Australia (Zhou 2007) that included 180

women compared three different doses of ferrous sulphate elemen-

tal iron.

(3) Intramuscular (IM) iron

We found no RCTs comparing IM iron versus placebo.

IM iron sorbitol versus IM dextran (comparison 04)

We found one RCT that recruited 74 women (Dawson 1965).

It did not provide effectiveness figures and had high withdrawal

rates, so the findings are at high risk of bias. It found that iron

sorbitol produced less skin discolouration (RR 0.21; 95% CI 0.07

to 0.65; one RCT, 48 women; Analysis 4.2) and fewer headaches


4.5) than IM dextran. These findings are inconclusive given the

limitations of this single study and the high loss to follow up.

IM iron sorbitol versus intravenous (IV) iron dextran

(comparison 23)

We found one RCT involving 63 women conducted in Nige-

ria (Oluboyede 1980). It found that IM iron sorbitol increased

haematocrit after four weeks of treatment (MD 2.18; 95% CI

0.77 to 3.59; one RCT, 59 women; Analysis 23.1) and after eight

weeks of treatment (MD 1.48; 95% CI 0.15 to 2.81; one RCT,

43 women; Analysis 23.2), compared with IV iron dextran.

(4) Intravenous (IV) iron

IV route versus placebo (comparison 07)

We found one small RCT involving 54 women and conducted

in Australia (Symonds 1969). The RCT provided data on adverse

effects. Data on effectiveness were not included. It found no sig-

nificant differences between IV iron and placebo for: nausea and

vomiting (RR 0.33; 95% CI 0.01 to 7.84; one RCT, 54 women;

Analysis 7.2), abdominal cramps (not estimable), and constipation


7.3). However, the small sample size and broad CIs illustrate that

the sample size is clearly insufficient to rule out any such adverse

effects.

(5) Parenteral route (IM or IV) versus oral route

IM versus oral iron treatment (comparisons 12, 13 and 14)

We found four RCTs (571 women) comparing IM and oral ad-

ministration of iron (Komolafe 2003; Kumar 2005; Ogunbode

1980; Zutschi 2004).

The first RCT, from India, (Zutschi 2004) evaluated 150 mg IM

iron sorbitol (via three injections a day) at four-weekly intervals

versus 100 mg of elemental oral iron for at least 100 days. IM iron

significantly increased Hb (MD 0.54; 95% CI 0.30 to 0.78; one

RCT, 200 women; Analysis 12.2), and haematocrit levels (MD

1.40; 95% CI 0.67 to 2.13; one RCT, 200 women; Analysis 12.3),

compared with oral iron. A higher proportion of women were

found to be non-anaemic at labour (RR 1.23; 95% CI 1.01 to

1.48; one RCT, 200 women; Analysis 12.1). Adverse effects were

not included in the reports of the article.

The second RCT, from India, compared IM sorbitol citric acid

dose versus oral ferrous sulphate (100 mg of elemental iron) plus 5

mg of folic acid at 36 weeks of pregnancy (Kumar 2005). Women

receiving oral iron plus folic acid had a higher Hb level (MD 0.26;

95% CI 0.04 to 0.48; one RCT, 150 women; Analysis 14.1). No

significant differences were found for caesarean section rates or

mean birthweight. Adverse effects were reported by 40 women

receiving IM treatment versus 16 receiving oral treatment at 36

weeks of treatment (Analysis 14.3 to Analysis 14.15). Gastroin-

testinal side effects (dyspepsia, constipation, diarrhoea, vomiting)



were observed predominately in the oral group, while systemic

reactions (local pain, staining, fever, systemic ache, arthralgia, it-

ching and rash, immediate headache, malaise and vaso-vagal due

to apprehension (it is unclear what the authors meant by this and

what diagnostic criteria they used) were more frequently found

in women receiving IM iron. No anaphylactic reaction or abscess

formation were observed, but too few women participated in the

RCT to assess these and other important adverse effects.

The third RCT, from Nigeria, (Ogunbode 1980) was a three-arm

RCT comparing iron sorbitol versus 600 mg oral ferrous sulphate

versus 1200 mg oral ferrous sulphate. All women received a daily

supplement of 5 mg of folic acid and 25 mg of pyrimethamine.

After eight weeks, IM iron sorbitol had significantly improved

haematocrit levels compared with 600 mg of oral iron (MD 2.62;

95% CI 1.26 to 3.98; one RCT, 59 women; Analysis 12.6), and

compared with 1200 mg of oral iron (MD 2.60; 95% CI 1.02 to

4.18; one RCT, 59 women; Analysis 12.8). Adverse effects were

not assessed.

The fourth RCT, conducted in Nigeria, compared IM iron dex-

tran (250 mg iron dextran thrice-weekly until total calculated dose

was given) versus 600 mg of oral ferrous sulphate plus vitamin C

and folic acid (Komolafe 2003). It found that iron dextran sig-

nificantly improved haematocrit levels after six weeks (MD 4.47;

95% CI 3.67 to 5.27; one RCT, 60 women; Analysis 13.1) and

the proportion of non-anaemic women after six weeks (RR 11.00;

95% CI 1.51 to 79.96; one RCT, 60 women; Analysis 13.2).

IV versus oral iron treatment (comparisons 08 and 09)

Pooled estimates (Al 2005; Bayoumeu 2002; Digumarthi 2008)

for Hb levels at four weeks favoured IV iron (average MD 0.44;

95% CI 0.05 to 0.82; random-effects [X² = 3.43; T² = 0.05; P =

0.18; I² 42%]; three RCTs, 167 women; Analysis 8.11). Diarrhoea

was less frequent in women receiving IV iron (RR 0.16; 95% CI

0.03 to 0.86; three RCTs, 237 women; Analysis 8.5).

A French RCT compared IV iron sucrose given in six slow IV

injections on days one, four, eight, 12, 15 and 21 according to a

formula described in the article, with 240 mg of elemental iron

sulphate tablets (Bayoumeu 2002); all women received 15 mg of

folic acid in addition to iron. No significant differences were found

in maternal Hb levels at four weeks of treatment, Hb levels in

excess of 12 g/dL, neonatal Hb, ferritin levels, and birthweight.

Similarly, no significant differences were found in the incidence of

diarrhoea, postpartum haemorrhage, blood transfusion required,

or neonatal mortality. The RCTs were underpowered to assess

these outcomes properly.

An RCT conducted in Turkey (Al 2005) compared IV iron su-

crose calculated according to a formula described in the article

(total dose was administered over five days and maximum daily

dose administered was 400 mg elemental iron) versus 300 mg of

elemental iron (polymaltose complex); all women were given 5

mg of folic acid daily. It found that IV iron significantly increased

maternal Hb at four weeks (MD 0.68; 95% CI 0.39 to 0.97; one

RCT, 90 women; Analysis 8.11) and at birth (MD 0.75; 95% CI

0.34 to 1.16; one RCT, 90 women; Analysis 8.8) and increased the

proportion of non-anaemic women - those with Hb levels equal or

greater than 11 g/dL (RR 1.54; 95% CI 1.21 to 1.94; one RCT, 90

women; Analysis 8.25). No significant differences were found for

caesarean section rates, neonatal birthweight, gestational hyper-

tension, gestational diabetes and arthralgias (Analysis 8.2; Analysis

8.14; Analysis 8.18; Analysis 8.23; Analysis 8.24; Analysis 8.27).

A comparison of oral ferrous fumarate 200 mg three times a day

versus IV iron dextrin (calculated according to described formula)

found that oral treatments increased constipation, compared with

IV treatments (Singh 1998) (RR 0.04; 95% CI 0.00 to 0.61;

one RCT, 100 women; Analysis 8.3). No significant differences

were found for constipation when IV iron was compared with

controlled-release iron. However, only one small RCT (Symonds

1969) assessed this and it seemed to be underpowered to rule

out clinically important effects (RR 0.22; 95% CI 0.03 to 1.85;

one RCT, 51 women; Analysis 8.3). One RCT, recruiting mostly

Malayan and Chinese women, found that higher Hb levels were

found at the end of gestation with IV versus oral treatments (

Singh 1998). However, the standard deviations are 50 to 100 times

narrower than those found in other studies, raising questions about

their validity (Al 2005; Suharno 1993). We excluded data from the

analysis pending a response from the trial’s authors. No maternal

or neonatal deaths were recorded in this RCT, which was the only

one specifically assessing these outcomes in women receiving oral

or IV treatments.

Three RCTs (Al 2005; Singh 1998; Symonds 1969), including

one that assessed controlled-release iron (Symonds 1969), found

that oral iron was more frequently associated with complaints of

nausea than IV preparations, and the magnitude of the effects was

consistent across all three RCTs (RR 0.33; 95% CI 0.15 to 0.74;

three trials, 244 women; Analysis 8.2).

Two women were reported as suffering severe allergic reactions

with IV dextran in an RCT comparing the latter with oral ferrous

sulphate (Sood 1979). Data on other relevant outcomes were not

available for comparison.

IV + oral iron versus oral iron (comparisons 29)

One RCT (Khalafallah 2010) assessed daily oral ferrous sulphate

250mg (elemental iron 80 mg) with or without a single intra-

venous iron polymaltose infusion. The combined treatment sig-

nificantly increased the mean Hb (MD 0.48 95% CI 0.21 to 0.75,

one trial, 183 women; Analysis 29.1) and in the proportion of

women with mild or moderate anaemia predelivery (RR 0.55 95%

CI 0.31 to 0.98) when compared with the oral treatment. Follow-

ing delivery, the combined treatment also significantly increased

the mean Hb (MD 0.39 95% CI 0.02 to 0.76, one trial, 183



women, Analysis 29.2). No significant differences were found in

the newborn weights, gestational age at delivery, placental cord

Hb or iron status between the two treatment groups. Two patients

developed urticarial reactions after commencement of IV iron in-

fusion. Trialist reported that there was a significant benefit in the

IV plus oral iron group in terms of amelioration of symptoms at-

tributed to anaemia (energy level, well being and physical activity)

within a shorter period of time

(6) IV iron versus IM iron with different regimens of

parenteral iron treatment (comparisons 04, 05, 06,

18, 20 and 23)

IV iron versus IM iron (comparison 23)

An RCT from Nigeria (Oluboyede 1980) found that IM sorbitol

increased haematocrit levels compared with the IV dextran group

at four weeks (MD 2.18; 95% CI 0.77 to 3.59, one RCT, 59

women, Analysis 23.1) and eight weeks (MD 1.48; 95% CI 0.15 to

2.81; one RCT, 43 women; Analysis 23.2). One women receiving

IV iron suffered a severe allergic reaction whereas one participant

of the IM group had viral hepatitis three months later. Authors

reported that no significant differences in newborn weight and

Apgar score at birth were found between the groups (no data were

provided). Neonates were assessed for any complication at birth

and within the first week of life; one neonate in each treatment

group developed neonatal jaundice. Maternal outcomes were not

reported for each group of treatment.

Different IM preparations (comparison 04)

One RCT compared two IM preparations (Dawson 1965). It

found that women receiving IM iron-sorbitol complex had a lower

incidence of skin discolouration at injection sites at eight weeks


4.2) and fewer headaches (RR 0.13; 95% CI 0.02 to 0.99; one

RCT, 48 women; Analysis 4.5) compared with IM iron dextran.

Results should be interpreted with care as they come from a single,

small RCT. However, this particular RCT had a robust randomi-

sation and concealment strategy.

IV iron versus IM iron (comparison 05)

One factorial RCT conducted in the UK compared IM treatments

with IV treatment (Dawson 1965). It found that IM iron was more

frequently associated with pain in the injection site. This factorial

design had some problems that were not addressed during the anal-

ysis: active treatments were compared with a single control group

and no adjustments for multiple comparisons were done. This in-

creases the possibilities of finding spurious associations. The RCT

found a higher risk of skin discolouration in women receiving IM

iron dextran compared with IV iron. Findings suggested a trend

towards a higher risk of venous thrombosis with IV iron versus

IM iron, but no statistical differences were found (RR 0.13; 95%

CI 0.01 to 2.20; 4/26 with IV iron dextran (15%) versus 0/23

with IM iron; one RCT, 49 women; Analysis 5.3). However, this

raises concern and an association can not be ruled out; the RCTs

were underpowered to assess these outcomes properly, and these

are very serious adverse effects.

The RCT found that IM iron dextran was not associated with

higher complaints of headaches, compared with IV infusion of iron

dextran (RR 3.96; 95% CI 0.91 to 17.17; one RCT, 49 women;

Analysis 5.5). The RCT was too small to rule out important clinical

differences in measured adverse effects outcomes such as shivering,

itching, metallic taste in mouth, severe delayed allergic reaction

(Analysis 5.4 to Analysis 5.9).

Two differing IV doses of iron dextran (comparison 11)

An RCT conducted in Tanzania compared two doses of IV iron

dextran by total dose infusion (Kaisi 1988). All participants were

given the full dose recommended by the manufacturer; group A

received an additional 10 ml whereas group B was given two-thirds

of that total dose. It found that allergic reactions after the infusion

had finished were reduced with the lower dose (RR 0.62; 95% CI

0.45 to 0.86; one RCT, 623 women; Analysis 10.2). No significant

differences were found for life threatening allergic reactions. This

RCT was not used to assess effectiveness as it failed to fulfil our

quality criteria.

IV iron versus IM iron (comparisons 19 and 20)

An RCT conducted in Pakistan (Wali 2002) evaluated two doses

of IV iron sucrose (500 mg versus 200 mg) and IM iron sorbitol.

The participants were divided into three groups. In group A (n =

15), IV iron sucrose was administered intravenously according to

the following formula: total iron deficit = body weight x (target Hb

- actual Hb) x 0.24 + 500; in group B (n = 20) IV iron sucrose was

administered using the same formula but 200 mg of iron being

given for storage instead of 500 mg; in group C, iron was admin-

istered IM daily or alternate days; after parenteral administration,

oral iron therapy (ferrous gluconate 250 mg) was continued un-

til the time of giving birth. No significant differences were found

regarding Hb levels and the proportion of non-anaemic women

(with Hb levels greater than 11 g/dL at delivery) when the two

different doses of IV iron were compared. Abdominal pain was

reported by one woman in each group. Administration of IV iron

sucrose (500 mg) significantly increased Hb levels (MD 1.60; 95%

CI 0.87 to 2.33; one RCT, 40 women; Analysis 19.1) and the

proportion of women with Hb greater than 11 g/dL at delivery


20.2) compared with IM iron sorbitol. Similarly, significant results

favouring IV treatment were found when comparing IV iron su-

crose (200 mg) and IM iron sorbitol for the same outcomes (MD



1.10; 95% CI 0.49 to 1.71; Analysis 20.1), and (RR 2.50; 95%

CI 1.25 to 4.99; one RCT, 45 women; Analysis 20.2). In the IV

groups 2/35 (5.7%) women had shivering and feeling of weakness

within a few hours, and 3/35 (8.6%) had phlebitis at the site where

IV canula was retained. In the IM group, 5/25 (20%) withdrew

from the study due to intolerance (no further description was pro-

vided) and the majority complained of pain at the injection site.

(7) IV administered iron sucrose with and without

adjuvant recombinant human erythropoietin

(comparison 11)

One small size study evaluated adjuvant recombinant human ery-

thropoietin when iron sucrose was administered intravenously

(Breymann 2001). No statistically significant differences were

found in the number of women with a rise of Hb greater than

11 g/dL or caesarean delivery. The author provided unpublished

data concerning birthweight and mean maternal blood pressure at

the end of therapy; no significant differences were found (Analysis

11.6 and Analysis 11.8) for these outcomes. None of the women

required additional antepartum or postpartum blood transfusion.

D I S C U S S I O N

Summary of main results

Although iron treatments consistently increase maternal haema-

tological indices in women diagnosed with anaemia in pregnancy

attributed to iron deficiency, we found no evidence that these lab-

oratory improvements reflected in clinical improvements such as

reduced preterm delivery, reduced infant low birthweight, lower

rates of pre-eclampsia, sepsis or postpartum haemorrhage and its

complications (Scholl 1992; Scholl 2000). We found very few ran-

domised controlled trials (RCTs) assessing clinical outcomes, and

these RCTs were too small to estimate important clinical effects.

Moreover, the studied populations turned out to be too small to

deliver clear-cut answers to this review’s questions.

The findings suggest that gastrointestinal adverse effects are more

frequent with oral iron treatments, compared with other routes

of iron administration, although these gastrointestinal effects may

be considered less problematic than the adverse effects of intra-

venous and intramuscular iron (see below). The results of one RCT

suggest that daily iron treatment is better than intermittent iron

supplementation in increasing Hb at delivery in pregnant women

based in developing countries. Higher doses of iron were not asso-

ciated with improved haematological values. In one RCT (Zhou

2007), daily low-dose iron supplements were effective at treating

anaemia in pregnancy with less gastrointestinal side effects com-

pared with higher doses. Although women with higher iron doses

had a higher mean Hb concentration at the end of intervention,

all groups of treatment (low, intermediate and high doses) were

within the normal reference range for women. The neonatal and

maternal outcomes were similar among groups of intervention.

The assessment of the effects of controlled versus regular oral iron

were mostly inconclusive; there seems to be a reduced incidence

of constipation. Most oral iron studies were marred by high with-

drawal rates, highlighting the importance of assessing adverse ef-

fects and compliance issues with these frequently-prescribed treat-

ments.

The findings of this review suggest that adding vitamin A to regular

iron (ferrous sulphate) resulted in improved Hb levels for women

with vitamin A deficiency. Another Cochrane review that focused

on vitamin A supplementation during pregnancy suggested ben-

eficial effects for women in areas of poor nutritional intake (Van

den Broek 2010).

Compared with oral iron, intramuscular (IM) iron sorbitol and

iron dextran improved haematological values, reduced the propor-

tion of women without anaemia, and resulted in lower gastroin-

testinal side effects. But these preparations were associated with

higher rates of systemic reactions.

The findings of this review also suggest that intravenous (IV) iron

sucrose is effective, but there is uncertainty whether it may in-

crease the incidence of serious adverse effects such as thrombo-

sis, which was frequent (9/41; 22%). Similarly, there are worrying

trends towards an increased risk of severe allergic reaction with IV

dextran iron, but data were few. One study suggests that the risk

of venous thrombosis may be lowered by adding hydrocortisone

to the infusion, but it is unclear what the real impact of this might

be and whether it has any other effects. Evidence of a relation-

ship between doses of IV iron and risk of adverse allergic reactions

is inconclusive. No effectiveness assessments were done for the

compared doses of IV drugs. Compared with IM iron sucrose, IV

iron sucrose significantly increased haematological indices but it is

unclear what the effects are on maternal and neonatal morbidity.

RCTs were insufficient to determine the clinical effects of treat-

ments in women with iron-deficiency anaemia during pregnancy.

Overall completeness and applicability ofevidence

Although there were a reasonable number of RCTs and women in

this review, the data are incomplete for a number of clinically im-

portant outcomes. In addition, there were multiple comparisons

with few RCTs leading to limited opportunities to pool data. The

applicability of the evidence outside the research setting is reason-

able as all these studies were conducted in the clinical settings that

are quite similar. The comparisons in the review are commonly

undertaken and not difficult to apply. The 23 RCTs came from

many different countries.



Quality of the evidence

The objective of this review was to address the effects of iron

anaemia treatments on maternal and neonatal morbidity and mor-

tality. The review included 23 RCTs, most of which were small

and with significant methodological flaws. These RCTs assessed

many different questions and a broad range of treatments resulting

in very limited opportunities to pool useful data. The paucity of

robust studies assessing clinical effects of treatments makes it im-

possible to balance the benefits and harms of differing treatments

for different levels of anaemia in pregnancy, in a meaningful and

useful way. Many questions remain open. We cannot determine

if women with mild anaemia, but otherwise healthy, will benefit

from anaemia treatment; adverse effects can potentially outweigh

benefits. It also remains unclear which treatments are safer and

more effective in women with moderate or severe anaemia with

and without associated illness.

Potential biases in the review process

We have produced updated coverage of randomised controlled

trials of treatments for anaemia in pregnancy attributed to iron-

deficiency by summarising the best available evidence using quan-

titative methods. We have endeavoured to provide information to

help clinicians and stakeholders choose the most appropriate treat-

ment. Several sources were searched to identify RCTs. However,

we cannot ensure that all available RCTs were located. We had

to impute data (i.e. standard deviation) from a number of RCTs.

Using this technique may lead to introduce bias. In addition, a

number of pooled outcomes may have been measured in different

ways within RCTs (i.e. adverse events).

Agreements and disagreements with otherstudies or reviews

Another Cochrane review that evaluated the effects and safety

of preventive oral iron or iron + folic acid supplementation for

women during pregnancy found that routine supplementation

raised Hb levels although the authors found no evidence of the

significant reduction in substantive maternal and neonatal adverse

clinical outcomes (Pena-Rosas 2009). Those findings are similar

to those presented in this review.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Avoidable limitations in the included randomised controlled trials

(RCTs) resulted in these failing to provide sound evidence that

currently available treatments for iron-deficiency anaemia in preg-

nant women are beneficial for women or their children. We found

no scientific basis to suggest that in otherwise healthy women, the

benefits of treatments for mild anaemia in pregnancy will outweigh

the adverse effects associated with them. We found no evidence

that in women with iron-deficiency anaemia in pregnancy, im-

provement in women’s haematological indices translate into clini-

cal improvements for them or their children. However, treatments

are associated with frequent adverse effects such as gastrointestinal

disturbances and poor compliance. Compared with oral iron, in-

tramuscular (IM) iron improves haematological indices. But again,

the support from clinical research seems to be missing and adverse

effects remain poorly evaluated despite indications that treatments

can result in important adverse outcomes. Intravenous (IV) iron

sorbitol improves haematological values compared with IM or oral

iron, but serious adverse effects are possible and remain poorly

studied; knowledge of their magnitude and mitigation strategies is

missing. Potential adverse effects may include venous thrombosis

and severe allergic reactions. Treatment of mild anaemia in preg-

nancy remains controversial and unsupported by scientific proof.

It is also unclear what treatments work better for severe anaemia

in pregnancy. In one RCT (Zhou 2007) daily low-dose iron sup-

plements were effective at treating anaemia in pregnancy with less

gastrointestinal side effects compared with higher doses.

Iron-deficiency anaemia in pregnancy is frequently diagnosed and

treated, but the effects of these treatments remain largely un-

known. Severe iron-deficiency anaemia affects many pregnant

women in developing countries and may have considerable impact

on maternal and neonatal health.

Implications for research

Considerable resources are being used globally to diagnose and

treat anaemia in pregnant women, but it remains unclear if these

efforts are worthy and beneficial to individuals or populations.

Also, it is unclear if there is a positive return for this investment,

and if it improves people’s lives. This review is an invitation for

researchers, especially those working towards the improvement

of health of communities in under-resourced settings, to imple-

ment high-quality RCTs addressing knowledge gaps (such as those

flagged up by this review), for this common condition. In partic-

ular, determining when treatments are worthwhile, and providing

sufficient information to allow better balancing of the benefits and

harms of treatments. The authors of this systematic review con-

sider that a solution to this would be to conduct a large multicen-

ter RCT assessing the clinical effects of a selection of commonly-

used treatments in different regions of the world. The sample and

duration of the follow-up in such an RCT should be estimated to

allow the identification of important, frequent, and long-term ef-

fects in women and babies. Large RCTs such as the MAGPIE trial

(Magpie 2002) or the CRASH trial (Edwards 2005) illustrate how

gaps in knowledge can be effectively addressed through research,



and how this can reduce harmful practices and inappropriate use

of resources. We found a compelling case for a similar approach

to be taken on iron-deficiency anaemia in pregnancy.

Some important considerations for future research are as follows.

1. There is an urgent need to determine what treatments

improve maternal and neonatal prognosis in women with severe

and moderate anaemia in poorly-resourced settings.

2. The effects of different doses, regimens and routes of

administrations for commonly-used treatments remain to be

determined. The suitability of the route of administration may

be influenced by the setting or cultural background.

3. Stratification according to anaemia severity can help address

questions of the effects in different populations, and balance

differently the benefits and harms.

4. Women with additional factors contributing to their

anaemia, such as vitamin A deficiency, need to be studied as a

different population.

5. Clinical outcomes, including adverse effects and quality of

life, need to be better addressed and considered for study sample

size calculations.

6. Offspring outcomes are particularly important given the

possibility that iron has been associated with adverse effects in

some observational studies.

7. RCTs need to have sample sizes big enough to allow

assessing adverse effects such as venous thrombosis, allergic

reactions, infections, and rare but serious adverse effects, as well

as long-term outcomes.

8. For women with mild iron-deficiency anaemia, it would be

helpful to assess whether oral iron is overall beneficial compared

with placebo or no treatment. Researchers need to remain aware

about the clinical effects of high iron on Hb levels, and possible

overdosing.

9. We found no studies on oral erythropoietin or transfusions;

these need to be evaluated in populations where they remain

likely to be used. But providing scientific support for commonly-

used treatments seems to be the priority; we do not know if more

harm then good is being done and yet these interventions remain

widely prescribed and used.

10. Studies are needed to determine the effects in specific

populations such as pregnant women who are anaemic and also

infected with human immunodeficiency virus.

11. To use the CONSORT statement to improve the quality of

reports of randomised trials (Schulz 2010: http://www.consort-

statement.org/).

[Note: The three citations in the awaiting classification section of

the review may alter the conclusions of the review once assessed.]

A C K N O W L E D G E M E N T S

We are grateful to Lynn Hampson, from the Cochrane Pregnancy

and Childbirth Group, for her assistance with trials search. We

thank Professor Jianping Liu, from the Evidence-Based Chinese

Medicine Center for Clinical Research and Evaluation (Beijing

University of Chinese Medicine), for translating a Chinese trial.

We thank the Cochrane Pregnancy and Childbirth Group editorial

staff for arranging commentaries to improve this manuscript.

As part of the pre-publication editorial process, this review has

been commented on by three peers (an editor and two referees

who are external to the editorial team), a member of the Pregnancy

and Childbirth Group’s international panel of consumers and the

Group’s Statistical Adviser.

R E F E R E N C E S

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Bayoumeu F, Subiran-Buisset C, Baka NE, Legagneur H,

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Dawson 1965 {published data only}

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Zhou SJ, Gibson RA, Crowther CA, Makrides M. Efficacy

and side effects of iron supplements for the correction of

anaemia in pregnancy: a comparison of high dose vs. low

dose iron [abstract]. Journal of Paediatrics and Child Health

2007;43(Suppl 1):A30.∗ Zhou SJ, Gibson RA, Crowther CA, Makrides M.

Should we lower the dose of iron when treating anaemia in

pregnancy? A randomized dose-response trial. European

Journal of Clinical Nutrition 2009;63(2):183–90.

Zhou SJ, Gibson RA, Makrides M. Routine iron

supplementation in pregnancy has no effect on iron status

of children at six months and four years of age. Journal of

Pediatrics 2007;151(4):438–40.

Zutschi 2004 {published data only}

Zutschi V, Batra S, Ahmad SS, Khera N, Chauhan G,

Ghandi G, et al.Injectable iron supplementation instead of

oral therapy for antenatal care. Journal of Obstetrics and

Gynecology of India 2004;54(1):37–8.

References to studies excluded from this review

Al Momen 1996 {published data only}

Al-Momen A, Al-Meshari A, Al-Nuaim L, Saddique A,

Abotalib Z, Khashogji T, et al.Intravenous iron sucrose

complex in the treatment of iron deficiency anemia during

pregnancy. European Journal of Obstetrics & Gynecology

and Reproductive Biology 1996;69:121–4. [MEDLINE:

1997058115]

Allaire 1961 {published data only}

Allaire B, Campagna F. Iron-deficiency anemia in pregnancy.

Evaluation of diagnosis and therapy by bone marrow

hemosiderin. Obstetrics & Gynecology 1961;17:605–10.

Amir 1983 {published data only}

Amir M, Ahmad SH, Ansari Z, Dutta AK, Husain I. Total

dose iron infusion during third trimester to iron deficient

mothers and its influences on anemia of early infancy.

Indian Pediatrics 1983;20(5):335–9.

Ayub 2008 {published data only}

Ayub R, Tariq N, Adil MM, Iqbal M, Junaid A, Jaferry T.

Efficacy and safety of total dose infusion of low molecular

weight iron dextran in the treatment of iron deficiency

anemia during pregnancy. Journal of the College of Physicians

and Surgeons Pakistan 2008;18(7):424–7.

Bare 1960 {published data only}

Bare W, Sullivan A. Comparison of intravenous saccharated

iron oxide and whole blood in treatment of hypochromic

anemia of pregnancy. American Journal of Obstetrics and

Gynecology 1960;79:279–85.

Barrada 1991 {published data only}∗ Barrada M, Pateisky N, Schatten C, Salzer H, Vavra N,

Spona J, et al.Ferritin levels in newborn after prepartal iron

medication. Geburtshilfe und Frauenheilkunde 1991;51(5):

366–8. [MEDLINE: 1991331243]

Barrada M, Salzer H, Schatten C, Pateisky N, Vavra N,

Spona J, et al.Influence of prepartal iron-medication on

newborns. Proceedings of the 13th World Congress of

Gynaecology and Obstetrics (FIGO); 1991 September 15-

20; Singapore. 1991:38.

Basu 1973 {published data only}

Basu RN, Sood SK, Ramachandan K, Mathur M,

Ramalingaswami V. Ethiopathogenesis of nutritional anemia

in pregnancy: a therapeutic approach. American Journal

of Clinical Nutrition 1973;26(6):591–4. [MEDLINE:

1973186956]

Bencaiova 2009 {published data only}∗ Bencaiova G, von Mandach U, Zimmermann R. Iron

prophylaxis in pregnancy: intravenous route versus oral

route. European Journal Obstetrics & Gynecology and

Reproductive Biology 2009;144(2):135–9.

Bencaiova G, von Mandach U, Zimmerman R. Optimal

prophylaxis of iron deficiency and iron-deficiency anemia

during pregnancy: a randomized study. Gynakologisch-

Geburtshilfliche Rundschau 2007;47:140.

Bhatla 2009 {published data only}

Bhatla N, Kaul N, Lal N, Kriplani A, Agarwal N, Saxena

R, et al.Comparison of effect of daily versus weekly iron

supplementation during pregnancy on lipid peroxidation.

Journal of Obstetrics and Gynaecology Research 2009;35(3):

438–45.

Bhutta 2006 {published data only}

Bhutta Z. Severe anemia treatment trials, Pakistan.

ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 21

March 2006).


Breymann C. rhEPO/parenteral iron vs parenteral iron

only in the treatment of severe pregnancy anemia. Personal

communication 1999.∗ Breymann C, Visca E, Huch R, Huch A. Recombinant

human erythropoietin (rhEPO) for the therapy of severe

iron deficiency anaemia during pregnancy. 21st Conference

of the Swiss Society of Gynecology and Obstetrics; 1988;

Switzerland. 1998:24.


Breymann C. Iron deficiency and anaemia in pregnancy:

modern aspects of diagnosis and therapy. Blood Cells,

Molecules, & Diseases 2002;29(3):506–16.

Buglanov 1984 {published data only}

Buglanov AA, Saiapina EV, Turaev AT. A comparative study

of the effectiveness of iron preparations in the treatment of

iron deficiency anemias in pregnant women. Akusherstvo i

Ginekologiia 1994;6:16–8.

Chan 2009 {published data only}

Chan KK, Chan BC, Lam KF, Tam S, Lao TT. Iron

supplement in pregnancy and development of gestational



diabetes: a randomised placebo-controlled trial. BJOG: an

international journal of obstetrics and gynaecology 2009;116

(6):789–97.

Chanarin 1965 {published data only}

Chanarin I, Rothman D. Response to folic and folinic acid

in megaloblastic anaemia in pregnancy. Journal of Obstetrics

and Gynaecology of the British Commonwealth 1965;72:

374–5.

Christiansen 1961 {published data only}

Christiansen TC, Koszewski BJ, Grier ME. Evaluation of a

new cobalt chelate with iron in pregnancy anemia. American

Journal of Obstetrics and Gynecology 1961;82:213–8.

Coelho 2000 {published data only}

Coelho K, Ramdas S, Pillai S. A comparative study of

changes in haemoglobin with high and low dose iron

preparations in pregnant women. Journal of Obstetrics and

Gynecology of India 2000;50(2):37–9.

De Souza 2009 {published data only}

De Souza AI, Batista Filho M, Bresani CC, Ferreira LO,

Figueiroa JN. Adherence and side effects of three ferrous

sulfate treatment regimens on anemic pregnant women

in clinical trials. Cadernos de Saude Publica 2009;25(6):

1225–33.

Dede 2005 {published data only}

Dede D, Uygur B, Yilmaz T, Mungan M, Ugur M.

Intravenous iron sucrose complex vs. oral ferrous sulfate for

postpartum iron deficiency anemia. International Journal of

Gynecology & Obstetrics 2005;90:238–9.

Dochi 1988 {published data only}

Dochi T. Clinical evaluation of combined therapy with

slow-releasing iron preparations and Aldioxa (Isalon) in

pregnant women with anemia [Nimpu Hinketsu ni Taisuru

Johosei Seizai to Arujiokisa Seizai (Isaron) Heiyo Ryoho].

Kiso to Rinsho (The Clinical Report) 1988;22(9):2855–9.

Dommisse 1982 {published data only}

Dommisse J, Du Toit ED, Nicholson N. Folic acid - has it a

role in the treatment of severe iron deficiency anaemia in

pregnancy?. South African Medical Journal 1982;61:831–2.

Ekstrom 2002 {published data only}

Ekstrom EC, Hyder SM, Chowdhury AM, Chowdhury SA,

Lonnerdal B, Habicht JP, et al.Efficacy and trial effectiveness

of weekly and daily iron supplementation among pregnant

women in rural Bangladesh: disentangling the issues.

American Journal of Clinical Nutrition 2002;76:1392–400.

Finzi 1972 {published data only}

Finzi C, Bailo U. Treatment of anemia in pregnancy:

comparison of an iron delayed-action preparation and

conventional preparations. Minerva Medica 1972;63(43):

2445–9.

Fochi 1985 {published data only}

Fochi F, Ciampini M, Ceccarelli G. Efficacy of iron

therapy: a comparative evaluation of four iron preparations

administered to anaemic pregnant women. Journal

of International Medical Research 1985;13(1):1–11.

[MEDLINE: 1985154970]

Govan 2005 {published data only}

Govan AD, Scott JM. Intravenous iron in the treatment of

anemia of pregnancy. 1949. European Journal Obstetrics

& Gynecology and Reproductive Biology 2005;23(Suppl 2):

S33–S35.

Graham 2007 {published data only}

Graham JM, Haskell MJ, Pandey P, Shrestha RK, Brown

KH, Allen LH. Supplementation with iron and riboflavin

enhances dark adaptation response to vitamin A-fortified

rice in iron-deficient, pregnant, nightblind Nepali women.

American Journal of Clinical Nutrition 2007;85(5):1375–84.

Halksworth 2003 {published data only}

Halksworth G, Moseley L, Carter K, Worwood M. Iron

absorption from spatone (a natural mineral water) for

prevention of iron deficiency in pregnancy. Clinical &

Laboratory Haematology 2003;25(4):227–31.

Hamilton 1973 {published and unpublished data}

Hamilton PJS, Gebbie DAM. Antenatal clinics as trial units

in evaluating treatment of anaemia in pregnancy. The

use and abuse of drugs and chemicals in Tropical Africa.

Proceedings of the 1973 Annual Scientific Conference of

the East African Research Council; 1973; Nairobi, Kenya.

Nairobi: East African Literature Bureau, 1973:463–6.

Hampel 1974 {published data only}

Hampel K, Roetz R. Influence of a long-time substitution

with folate-iron combination in pregnancy on serum

folate and serum iron and on hematological parameters.

Geburtshilfe und Frauenheilkunde 1974;34:409–17.

[MEDLINE: 1974293872]

Hancock 1968 {published data only}

Hancock KW, Walker PA, Harper TA. Mobilisation of iron

in pregnancy. Lancet 1968;2:1055–8.

Harrison 1971 {published data only}

Harrison KA, Ajabor LN, Lawson JB. Ethacrynic acid

and packed-blood-cell transfusion in treatment of severe

anaemia in pregnancy. Lancet 1971;1(7688):11–4.

Hawkins 1970 {unpublished data only}

Hawkins DF. Relative efficacy of sustained release iron

and iron with folic acid treatment in pregnancy. Personal

communication 1987.

Holly 1955 {published data only}

Holly R. Anemia in pregnancy. Obstetrics & Gynecology

1955;5:562–9.

Hosokawa 1989 {published data only}

Hosokawa K. Studies on anemia in pregnant women:

therapeutic efficacy of iron monotherapy vs. combination

therapy with iron and vitamin C [Nimpu Hinketsu ni

Kansuru Kenkyu: Tetsuzai Tandoku Narabini Tetsuzai to

Bitamin C Heiyo Ryoho no Chiryo Koka ni Tsuite]. Rinsho

to Kenkyu (The Japanese Journal of Clinical and Experimental

Medicine) 1989;66(10):3329–35.

Izak 1973 {published data only}

Izak G, Levy S, Rachmilewitz M, Grossowicz N. The

effect of iron and folic acid therapy on combined iron and

folate deficiency anaemia: the results of a clinical trial.



Scandinavian Journal of Haematology 1973;11(3):236–40.

[MEDLINE: 1974063093]

Jackson 1982 {published data only}

Jackson RT, Latham MC. Anemia of pregnancy in Liberia,

West Africa: a therapeutic trial. American Journal of Clinical

Nutrition 1982;35:710–4. [MEDLINE: 1982179371]

Jaud 1979 {published data only}

Jaud W. Folate- and iron- deficiency in pregnancy.

Geburtshilfe und Frauenheilkunde 1979;39(4):317–23.

[MEDLINE: 1979170627]

Juarez-Vazquez 2002 {published data only}

Juarez-Vazquez J, Bonizzoni E, Scotti A. Iron plus folate

is more effective than iron alone in the treatment of iron

deficiency anaemia in pregnancy: a randomised, double

blind clinical trial. BJOG: an international journal of

obstetrics and gynaecology 2002;109:1009–14.

Kore 2006 {published data only}

Kore SJ, Ambiye VR, Gandewar. Improving compliance of

oral iron. Role of modified drug release system [abstract].

49th All India Congress of Obstetrics and Gynaecology;

2006 January 6-9; Cochin, Kerala State, India. 2006:41.

Krafft 2009 {published data only}

Krafft A, Bencaiova G, Breymann C. Selective use of

recombinant human erythropoietin in pregnant patients

with severe anemia or nonresponsive to iron sucrose alone.

Fetal Diagnosis and Therapy 2009;25(2):239–45.

Ma 2008 {published data only}

Ma AG, Schouten EG, Zhang FZ, Kok FJ, Yang F, Jiang

DC, et al.Retinol and riboflavin supplementation decreases

the prevalence of anemia in chinese pregnant women taking

iron and folic acid supplements. Journal of Nutrition 2008;

138(10):1946–50.

Mahale 1993 {published data only}

Mahale AR, Shah SH. New schedule of intramuscular iron

administration for pregnant women. Asia-Oceania Journal

of Obstetrics and Gynaecology 1993;19:141–4. [MEDLINE:

1993393475]

Mahmoudian 2005 {published data only}

Mahmoudian A, Khademloo MD. The effect of

simultaneous administration of zinc sulfate and ferrous

sulfate in the treatment of anemic pregnant women. Journal

of Research in Medical Sciences 2005;10(4):205–9.

Mathan 1979 {published data only}

Mathan BVI, Baker SH, Sood SK, Ramachandran K,

Ramalingaswami V. WHO sponsored collaborative studies

on nutritional anaemia in India. The effects of ascorbic acid

and protein supplementation on the response of pregnant

women to iron, pteroyglutamic acid and cyanocobalamin

therapy. British Journal of Nutrition 1979;42:391–8.

Milman 2006 {published data only}

Milman N, Byg KE, Bergholt T, Eriksen L. Side effects of

oral iron prophylaxis in pregnancy--myth or reality?. Acta

Haematologica 2006;115(1-2):53–7.

Minganti 1995 {published data only}

Minganti E, Farina A, Farina F, Calora A, d Aloja P,

Dossi L, et al.Clinical study on the therapeutic efficacy

and tolerability of ferrimannitol-albumin in pregnancy

[Indagine clinica sull efficacia terapeutica e sulla tollerabilita

della ferri–mannitol–albumina in gravidanza]. Giornale

Italiano di Ostetricia e Ginecologia 1995;10:597–600.

Mukhopadhyay 2004 {published data only}

Mukhopadhyay A, Bhatla N, Kriplani A, Pandey RM,

Saxena R. Erythrocyte indices in pregnancy: effect of

intermittent iron supplementation. National Medical

Journal of India 2004;17(3):135–7.

Mukhopadhyay 2004a {published data only}

Mukhopadhyay A, Bhatla N, Kriplani A, Pandey RM,

Saxena R. Daily versus intermittent iron supplementation in

pregnant women: hematological and pregnancy outcome.

Journal of Obstetrics and Gynaecology Research 2004;30(6):

409–17.

Ogunbode 1984 {published data only}

Ogunbode O, Damole IO. Treatment of anaemia in

obstetric patients with sustained-release (Ferrograd Folic

500 Plus) and conventional fersolate and folic acid as

separate drugs. Current Therapeutic Research, Clinical and

Experimental 1984;35(6):1038–42.

Preziosi 1997 {published data only}

Preziosi P, Prual A, Galan P, Daouda H, Boureima H,

Hercberg S. Effect of iron supplementation on the iron

status of pregnant women: consequences for newborns.


[MEDLINE: 1998019349]

Reddy 2000 {published data only}

Reddy PS, Adsul BB, Gandewar K, Desai A. Mumfer (iron

polymaltose complex) in the management of anaemia in

pregnancy--an Indian study. Journal of the Indian Medical

Association 2000;98(6):343, 346.

Ridwan 1996 {published data only}

Ridwan E, Schultink W, Dillon D, Gross R. Effects of

weekly iron supplementation on pregnant indonesian

women are similar to those of daily supplementation.


Sagaonkar 2009 {published data only}

Sagaonkar S, Sukhija S, Tayal R, Sagaonkar PD. Pregnancy

induced iron deficiency and the evaluation and comparison

of the efficacy and safety of ferrous fumarate and carbonyl

iron in its treatment - PERFECT trial. Journal of Obstetrics

and Gynecology of India 2009;59(6):552–62.

Schoyerer 1975 {published data only}

Schoyerer W. The addition of folic acid to the iron

substitution during pregnancy. Schweizerische Rundschau

fur Medizin Praxis//Revue Suisse de Medecine Praxis 1975;64

(28):903–7.

Scott 2005 {published data only}

Scott JM, Govan AD. Anemia of pregnancy treated with

intravenous iron. 1951. European Journal of Obstetrics &

Gynecology and Reproductive Biology 2005;123(Suppl 2):

S29–S32.



Sharma 2004 {published data only}

Sharma JB, Jain S, Mallika V, Singh T, Kumar A, Arora

R, et al.A prospective, partially randomized study of

pregnancy outcomes and hematologic responses to oral

and intramuscular iron treatment in moderately anemic

pregnant women. American Journal of Clinical Nutrition

2004;79(1):116–22.

Siega-Riz 2001 {published data only}

Siega-Riz A, Hartzema A, Turnbull C, Thorp JJ, McDonald

T. A trial of selective versus routine iron supplementation to

prevent third trimester anemia during pregnancy. American

Journal of Obstetrics and Gynecology 2001;185(6 Suppl):

S119.

Siega-Riz 2006 {published data only}

Siega-Riz AM, Hartzema AG, Turnbull C, Thorp J,

McDonald T, Cogswell ME. The effects of prophylactic

iron given in prenatal supplements on iron status and birth

outcomes: a randomized controlled trial. American Journal

of Obstetrics and Gynecology 2006;194(2):512–9.

Sigridov 2005 {published data only}

Sigridov I, Ivanov S. Ferro-folgamma--a good alternative in

the treatment of iron deficiency anemia and depleted iron

stores in pregnant women. Akusherstvo i Ginekologiia 2005;

44(7):22–7.

Sood 1975 {published data only}

Sood SK, Ramachandran K, Mathur M, Gupta K,

Ramalingaswami V, Swarnabai C, et al.WHO sponsored

collaborative studies on nutritional anaemia in India. 1.

The effects of supplemental oral iron administration to

pregnant women. Quarterly Journal of Medicine 1975;44

(174):241–58. [MEDLINE: 1976053828]

Stein 1991 {published data only}

Stein ML, Gunston KD, May RM. Iron dextran in

the treatment of iron-deficiency anaemia of pregnancy.

Haematological response and incidence of side-effects. South

African Medical Journal 1991;79:195–6. [MEDLINE:

1991142847]

Steiner 1977 {published data only}

Steiner H, Hilgarth M. Treatment of anemia in pregnancy.

Fortschritte der Medizin 1977;95:753–6. [MEDLINE:

1977163809]

Szarfarc 2001 {published data only}

Szarfarc SC, de Cassana LM, Fujimori E, Guerra-Shinohara

EM, de Oliveira IM. Relative effectiveness of iron bis-

glycinate chelate (Ferrochel) and ferrous sulfate in the

control of iron deficiency in pregnant women. Archivos

Latinoamericanos de Nutricion 2001;51(1 Suppl 1):42–7.

Tange 1993 {published data only}

Tange E, Weigand E, Mbofung CM. Effect of iron

supplementation on anemic and non-anemic pregnant

teenagers in Cameroon. TEMA 8: Proceedings of the

Eighth International Symposium on Trace Elements in Man

and Animals; 1993 May 16-22; Dresden, Germany 1993:

220–3.

Thirunavukkarasu 2009 {published data only}

Thirunavukkarasu S, Bhandary A. A novel short-course

regimen of intramuscular iron therapy for anaemic pregnant

women. Tropical Doctor 2009;39(4):227–8.

Tomar 2006 {published data only}

Tomar R, Dubey K, Pandit U. Comparative study - efficacy,

safety, compliance of intravenous iron and intra muscular

iron in severe iron deficiency [abstract]. 49th All India

Congress of Obstetrics and Gynaecology; 2006 January 6-9;

Cochin, Kerala State, India. 2006:3.

Valli Rani 1995 {published data only}

Valli Rani N, Pandey J, Das B, Shruti, Talib VH, Singh K,

et al.Pregnancy associated anemia and iron: a pilot study.

Indian Journal of Pathology and Microbiology 1995;38(3):

293–7. [MEDLINE: 1996416871]

Van den Broek 2006 {published data only}

Van den Broek NR, White SA, Flowers C, Cook JD, Letsky

EA, Tanumihardjo SA, et al.Randomised trial of vitamin

A supplementation in pregnant women in rural Malawi

found to be anaemic on screening by HemoCue. BJOG: an

international journal of obstetrics and gynaecology 2006;113

(5):569–76.

Visca 1996 {published data only}

Visca E, Breymann CC, Huch R, Huch A. Recombinant

erythropoietin (rhEPO) and iron vs. parenteral iron only

for the treatment of pregnancy anemia; a prospective and

randomised study. 15th European Congress of Perinatal

Medicine; 1996 September 10-13; Glasgow, Scotland, UK.

1996:184.

Von Peiker 1986 {published data only}

Von Peiker G, Muller B, Schwarz A, Dawcsynski H, Linke

E. The diagnosis and treatment of iron deficiency anaemia

in pregnancy. Zentralblatt fur Gynakologie 1986;108:

1487–92.

Wu 1998 {published data only}

Wu Y, Weng L, Wu L. Clinical experience with iron

supplementation in pregnancy. Chinese Journal of Obstetrics

& Gynecology 1998;33(4):206–8.

Young 2000 {published data only}

Young MW, Lupafya E, Kapenda E, Bobrow EA. The

effectiveness of weekly iron supplementation in pregnant

women of rural northern malawi. Tropical Doctor 2000;30

(2):84–8.

Zhou 2006 {published data only}

Zhou SJ, Gibson RA, Crowther CA, Baghurst P, Makrides

M. Effect of iron supplementation during pregnancy on

the intelligence quotient and behavior of children at 4 y of

age: long-term follow-up of a randomized controlled trial.

American Journal of Clinical Nutrition 2006;83(5):1112–7.

References to studies awaiting assessment

Paleru 2011 {published data only}

Paleru N, Anagani M, Sree J. Intravenous iron sucrose

versus oral iron supplementation for treatment of iron

deficiency anaemia in pregnancy. 54th All India Congress of



Obstetrics and Gynaecology; 2011 January 5-9; Hyderabad,

Andhra Pradesh, India. 2011:64.

Pandit 2009 {published data only}

Pandit S, Deshmukh P. A random prospective comparative

study to evaluate the efficacy of intravenous iron sucrose

versus oral ferrous sulphate in the treatment of iron

deficiency anaemia of pregnancy. International Journal of

Gynecology & Obstetrics 2009;107(Suppl 2):S424.

Sarkate 2007 {published data only}

Sarkate P, Patil A, Parulekar S, Rege NN, Samant BD,

Lokhande J, et al.A randomised double-blind study

comparing sodium feredetate with ferrous fumarate in

anaemia in pregnancy. Journal of the Indian Medical

Association 2007;105(5):278, 280-1, 284.

References to ongoing studies

Ruangvutilet 2009 {published data only}

Ruangvutilet P. Comparison study of intravenous (IV)

versus oral iron (Fe) for iron deficiency anemia treatment

in late pregnancy (EIVF). ClinicalTrials.gov (http://

clinicaltrials.gov/) (accessed 4 January 2009).

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Scholl TO, Reilly T. Anemia, iron and pregnancy outcome.

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Schulz 2010

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for reporting parallel-group randomized trials. BMJ 2010;

340:c332.

Steer 1995

Steer P, Alam MA, Wadsworth J, Welch A. Relation between

maternal haemoglobin concentration and birth weight in

different ethnic groups. BMJ 1995;310(6978):489–91.

Van den Broek 2010

Van den Broek N, Dou L, Othman M, Neilson JP, Gates

S, Gülmezoglu AM. Vitamin A supplementation during

pregnancy for maternal and newborn outcomes. Cochrane

Database of Systematic Reviews 2010, Issue 11. [DOI:

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Walter 1994

Walter T. Effect of iron-deficiency anaemia on cognitive

skills in infancy and childhood. Baillieres Clinical

Haematology 1994;7:815–27.

WHO 1989

World Health Organization. Preventing and controlling iron

deficiency anaemia through primary health care. Geneva:

WHO, 1989.

WHO 1992

World Health Organization. The prevalence of anaemia in

women: a tabulation of available information (WHO/MCH/

MSM/92). 2nd Edition. Geneva: WHO, Maternal Health

and Safe Motherhood Programme, Division of Family

Health, 1992.

WHO 2000

World Health Organization. Maternal mortality in 2000.

Estimates developed by WHO, UNICEF and UNFPA.

www.who.int (accessed 2004).

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World Health Organization. Iron deficiency anaemia,

assessment, prevention, and control: a guide for programme

managers. http://www.who.int/reproductive-health/docs/

anaemia.pdf (accessed February 14 2007).

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Clinics of North America 1992;76:631–47. [MEDLINE:

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References to other published versions of this review

Cuervo 2001

Cuervo LG, Mahomed K. Treatments for iron

deficiency anaemia in pregnancy. Cochrane Database

of Systematic Reviews 2001, Issue 2. [DOI: 10.1002/

14651858.CD003094]

Reveiz 2007

Reveiz L, Gyte GML, Cuervo LG. Treatments for iron-

deficiency anaemia in pregnancy. Cochrane Database

of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/

14651858.CD003094.pub2]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Al 2005

Methods Group allocation was predetermined by one of the authors who was not involved with

women’s care. Authors used opaque envelopes that were consecutively-numbered by

means of a computer-generated randomisation table. As each woman gave consent for

the study, the next envelope was opened to assign the participant to either of the 2

groups.

A sample-size analysis was performed before initiation of the study. The analysis was

based on the ITT principle.

No participants were lost to follow up, and there were no dropouts

Participants 90 pregnant women, between the 26th and 34th weeks of gestation, with established

iron-deficiency anaemia who had Hb levels between 8 and 10.5 g/dL and ferritin levels

less than 13 g/ L.

Women were excluded when serum folate and vitamin B12 levels were found to be less

than 4 pg/mL and 100 pg/mL respectively.

Anaemia from causes other than iron-deficiency, multiple pregnancy, previous blood

transfusion, history of haematological disease, risk of preterm labour, intolerance to iron

derivatives, recent administration of iron for the treatment of iron-deficiency anaemia,

or current usage of iron supplement

were the reasons for other exclusions.

Interventions Experimental group: the dose for total iron sucrose was calculated from the following

formula: weight x (target Hb - actual Hb) x 0.24 + 500 mg. In each infusion, the

maximum total dose administered was 200 mg elemental iron in 100 mL 0.9% NaCl,

infused in 20-30 minutes. Total dose was administered over 5 days and maximum daily

dose administered was 400 mg elemental iron. Most of the women received iron sucrose

at the rate of 200 mg every other day

Control group: 3 x 100 mg iron polymaltose complex (300 mg elemental iron per day)

tablets per day orally administered iron were given throughout pregnancy

Both groups were supplemented by 0.5 mg folic acid treatment per day

Outcomes The primary outcome measure was Hb concentration on day 28 and at birth. Secondary

outcome measures included ferritin levels, the recorded adverse effects, and fetal birth-

weight

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Group allocation was predetermined by

one of the authors who was not involved

with patient care. Opaque envelopes were

consecutively numbered by means of a



Al 2005 (Continued)

computer-generated randomisation table.

As each patient gave consent for the study,

the next envelope was opened to assign the

patient to either of the 2 groups

Allocation concealment (selection bias) Low risk Consecutive numbered opaque envelopes.

Blinding (performance bias and detection

bias)

All outcomes

High risk Not done.

Incomplete outcome data (attrition bias)

All outcomes

Low risk The analysis was based on the ITT prin-

ciple. No participants were lost to follow

up, and there were no dropouts. Relevant

neonatal outcomes were not reported

Selective reporting (reporting bias) Unclear risk Protocol of the study is not available.

Other bias Low risk Maternal and infant baseline characteristics

were provided.

Competing interests and funding were not

declared.

Bayoumeu 2002

Methods Women were assigned to the group treatment by a randomisation table.

Sample size and power calculation were described. Neither the women nor caregivers

were blinded to the interventions. It is unclear if the outcome assessor was blinded to the

interventions. The trialists reported that 3 (6%) women were excluded from the study

and that 2 others where lost to follow up

Participants 50 pregnant women.

Inclusion criteria: pregnant women at 6 months of pregnancy > 18 years, with Hb 8-10

g/dL at 6 months; MCV < 100 fl; ferritin < 50 ug/l (corresponds to iron store of < 500

mg)

Exclusion criteria: anaemia not linked to iron deficiency; asthma; cirrhosis; viral hepatitis;

multiple pregnancy; risk of premature birth; suspected acute infection; parenteral iron

treatment before inclusion; intolerance to iron. Also transport problems, etc

Interventions Experiment group: IV iron sucrose. Total dose calculated from weight before pregnancy

in kg x (target Hb - actual Hb) x 0.24 + 500 mg rounded up to nearest 100 mg. Target

Hb set at 120 g/L because of physiological haemodilution during pregnancy. Given in

6 slow IV injections (days 1, 4, 8, 12, 15 and 21)

Control group: oral iron. 3 x 80 mg iron sulphate tablets (Tardyferon) per day for 4

weeks (i.e. 240 mg elemental iron a day for 4 weeks). Women asked to note compliance

in calendar.

“Women were also given 15 mg folic acid per day to prevent an eventual folic-acid

deficiency and to eliminate the influence of such a deficiency on the results.”



Bayoumeu 2002 (Continued)

“After 4 weeks, physician or midwife decided duration and dose of any continuing iron

treatment.”

Outcomes The trial measured haematological response, transferrin level and saturation coefficient,

erythrocytic folates, ferritin level, baby’s ferritin level and full blood cell count and adverse

reactions

Notes

Risk of bias



bias)

Low risk Women were assigned to the group treat-

ment by a randomisation table

Allocation concealment (selection bias) Unclear risk Not described.


bias)

All outcomes

High risk Neither the women nor caregivers were

blinded to the interventions. It is unclear

if the outcome assessor was blinded to the

interventions


All outcomes

Low risk The trialists reported that 3 (6%) women

were excluded from the study and that 2

others where lost to follow up. No clinical

outcomes were measured


Other bias Low risk Baseline characteristics were provided. Sup-

ported by Maternity Hospital Nano. Com-

peting interests not declared

Breymann 2001

Methods Women randomly assigned to 2 treatment groups by means of a computer-generated

list. It is unclear whether participants, clinicians and outcome assessor were blinded to

the interventions. Trial had no withdrawals. No description of the sample size or power

calculation was recorded

Participants 40 pregnant women. Inclusion criteria: pregnant women with Hb < 10 g/dL in 2nd

trimester and < 11 g/dL in 3rd trimester; ferritin < 15 ug/l

Exclusion criteria: women with anaemia not caused by iron deficiency, e.g. B12 or folate

deficiency; chronic bleeding; renal failure

Interventions Women were randomised to receive IV administered iron sucrose (200 mg IV adminis-

tered twice weekly 72 to 96 hours apart) with vs. without adjuvant recombinant human

erythropoietin (300 U/kg body weight). All women received orally administered iron



Breymann 2001 (Continued)

sulphate (80 mg twice daily) for = 2 weeks before starting. Random assignment was

initiated when the Hb dropped to < 10.0 g/dL despite orally administered iron supple-

mentation. Median durations of therapy were 18 days in group 1 and 25 days in group

2

Outcomes Blood index values, maternal outcomes (which cannot be obtained separately for both

groups of treatment) and safety were reported

Notes

Risk of bias



bias)

Low risk Women randomly assigned to 2 treatment

groups by means of a computer-generated

list

Allocation concealment (selection bias) Low risk Not described in the article but the author

provided additional information upon re-

quest


bias)

All outcomes

Unclear risk It is unclear whether participants, clinicians

and outcome assessor were blinded to the

interventions. Probably not done


All outcomes

Low risk Trial had no withdrawals.


Other bias Low risk Baseline characteristics were provided.


declared

Dawson 1965

Methods Method of allocation was a random-number table. It is not clearly stated how allocation

was concealed.

Loss to follow up: at 2 weeks: loss: A = 24%; B = 9%; C = 27%.

At 4 weeks: loss: A = 48%; B = 39%; C = 38%.

At 8 weeks: loss: A = 88%; B = 70%; C = 85%.

Participants 74 pregnant women in the 3rd trimester with Hb less than 10 g/dL, MCHC under 30%

and a marrow aspiration indicating iron deficiency. Women with toxemia, infection or

antepartum haemorrhage were excluded. All women received prophylactic folate and

oral iron was stopped prior to randomisation.

Women were followed for 8 weeks and outcomes assessed at admission, 2, 4 and 8 weeks.

Side effects were assessed during the treatment period



Dawson 1965 (Continued)

Interventions Iron sorbitol-citric acid complex (Jectofer) IM 25 women.

Iron dextran (Imferon) IM 23 women.

Iron dextran (Imferon) IV 26 women.

Dosages of all preparations were calculated to replace iron stores

Outcomes Side effects:

1. pain at injection site;

2. skin discolouration;

3. venous thrombosis;

4. nausea or vomiting;

5. headaches;

6. shivering;

7. itching;

8. metallic taste in mouth.

Notes Other outcomes were not considered due to a high dropout rate. Hb level data are not

included due to 81% dropouts at predelivery. The authors made an additional trial of

iron dextran IV vs. iron dextran + 50 mg of hydrocortisone in the infusion to assess if

this had any effect on the rate of side effects

Risk of bias



bias)

Low risk Method of allocation was a random-num-

ber table.



bias)

All outcomes

High risk Not done.


All outcomes

High risk Loss to follow up: at 2 weeks: loss: A = 24%;

B = 9%; C = 27%.

At 4 weeks: loss: A = 48%; B = 39%; C =

38%.

At 8 weeks: loss: A = 88%; B = 70%; C =

85%.


Other bias Low risk Competing interests and funding were not

declared.



De Souza 2004

Methods Method of allocation generation and concealment are unclear.

Neither the women nor treating physicians were blinded to the interventions. Trialists

reported that the laboratory was blind to the interventions. 41 (21.5%) women were

reported to drop the trial or were lost to follow up and the reasons described. ITT analysis

was not used.

Sample size and power calculation were described.

Participants 150 pregnant women at 16-20 weeks of gestation, with an initial Hb of < 11 g/dL and

> 8 g/dL

Interventions Women were randomly distributed into 3 groups, 1 receiving daily (300 mg of ferrous

sulphate), the 2nd twice-weekly and the 3rd once-weekly iron supplementation for 16

weeks

Outcomes The trial measured Hb concentration, MCV and ferritin before and after the treatment

Notes

Risk of bias



bias)

Unclear risk Not described.



bias)

All outcomes

High risk Neither the women nor treating physicians

were blinded to the interventions. Trialists

reported that the laboratory was blind to

the interventions


All outcomes

Low risk 21.5% of women were reported to drop the

trial or were lost to follow up. The reasons

were described




declared

Digumarthi 2008

Methods Open randomised controlled trial.

Participants 30 pregnant women with moderate anaemia. Singleton pregnancy, 20 to 32 weeks with

Hb from 7.1 to 9 g/dL



Digumarthi 2008 (Continued)

Interventions IV iron sucrose (Weight in kg x (target Hb - actual Hb) x 0.25 + 500) vs. oral ferrous

fumerate (300 mg of iron + 1.5 mg folic acid, twice day)

Outcomes Hb rise, serum ferritin, serum iron, transferrin saturation.

Notes Abstract publication.

Risk of bias



bias)

Unclear risk “Randomized”. Not described.



bias)

All outcomes

High risk Not done.


All outcomes

Unclear risk Losses to follow up not reported. No clinical out-

comes were reported


Other bias High risk No baseline characteristics were reported. Com-

peting interests and funding were not declared

Kaisi 1988

Methods A randomisation list was used to generate the randomisation sequence

Participants 630 pregnant women. The study was done in a population of indigenous women. In-

clusion criteria were:

1. diagnosis of iron-deficiency anaemia defined as Hb under 10 g/dL; MCHC under

32%; hypochromia; poikilocytosis and anisocytosis;

2. age 16 years and above;

3. gestational age under 36 weeks.

Exclusion criteria were:

1. history of reaction to parenteral iron;

2. hypersensitivity to iron dextran;

3. asthma history;

4. allergic conditions;

5. hepatic impairment;

6. renal impairment;

7. rheumatoid arthritis;

8. fever.



Kaisi 1988 (Continued)

314 women received the full dose while 309 women received the 2/3 dose. Age, gravidity,

parity, duration of pregnancy and basal Hb levels were similar for the groups. Nearly one

fourth of the women had Hb levels under 7.0 g/dL in both groups

Interventions The dose of the 2 studied treatments was determined according to the recommendations

of providers. In the intervention group, women received 2/3 of the total dose calculated

of iron dextran ’Imferon’ while in the control group they received the total dose of iron

dextran plus 10 additional ml as suggested for pregnant women. The iron dextran was

diluted in 500 ml of 5% dextrose and infused at a steady rate of 40 drops per minute.

A test dose was given at the start of each infusion. This test dose was administered at a

rate of 5 drops per minute over 10 minutes

Outcomes Women were followed up regularly throughout the remaining part of their pregnancy,

during delivery and for 16 weeks postpartum. Infants were examined at the time of birth.

Maternal Hb levels were assessed at each visit to the antenatal clinic and 6 and 16 weeks

after delivery. Cord Hb was measured as well

Notes Women were analysed by ITT. Loss to follow up for Hb result was 47% so these results

were not included in this review. For other clinical outcomes, loss to follow up was 18%

and 20% so they were included

Risk of bias



bias)

Low risk Randomisation list.



bias)

All outcomes

High risk Not done.


All outcomes

High risk High rate of loss to follow up.

Selective reporting (reporting bias) Unclear risk Protocol of the study is not available. . Loss

to follow up for Hb result was 47% so these

results were not included in this review. For

other clinical outcomes, loss to follow up

was 18% and 20% so they were included

Other bias Unclear risk Baseline characteristics were reported.


declared



Khalafallah 2010

Methods Single site, prospective, non blinded randomised-controlled trial

Participants Two hundred women matched for Hb concentration and serum ferritin level were re-

cruited. Women aged 18 years or above were identified with moderate iron deficiency

anaemia defined as Hb <115 g L and low iron stores based on a serum ferritin level <

30 lg L. Most of the women (75%) had ferritin levels below 20 lg L and were equally

distributed in both groups

Interventions Patients were randomised to daily oral ferrous sulphate 250 mg (elemental iron 80 mg)

with or without a single intravenous iron polymaltose infusion. The IV arm required a

single intravenous infusion of iron polymaltose (Ferrosig, Sigma Pharmaceuticals, Syd-

ney, Australia) within 1 week after booking followed by oral iron identical to the other

arm

Outcomes Primary outcomes were Hb level and mean serum ferritin level. Secondary outcomes

were tolerability, safety and compliance and the effect of iron therapy on birth weight

and gestational age at delivery. Cord blood Hb and iron studies data were collected at

37 consecutive deliveries to assess the effects of IV plus oral iron

Notes

Risk of bias



bias)

Low risk “Central randomisation by computer will

follow thereafter” (data from the Australian

New Zealand clinical trials Registry. The

trial was retrospectively registered: AC-

TRN12609000177257)

Allocation concealment (selection bias) Low risk “If the patients agree to participate in the

trial, randomisation will follow in different

department by the Pharmacy clinical trial

personnel where a special computer pro-

gramme will assign the treatment in ran-

dom fashion without influence of treating

team. This is usually conducted in blocks

until full recruitment occurs”


bias)

All outcomes

Low risk Not done.


All outcomes

Low risk 8.5% of participants did not complete the

trial (8 and 9 participants in the oral and

IV iron group respectively)

Selective reporting (reporting bias) Unclear risk The protocol was not available.



Khalafallah 2010 (Continued)

Other bias Low risk All authors declare no financial conflicts of

interest.

Komolafe 2003

Methods The women were assigned randomly by offering them a choice from sealed envelopes

containing computer-generated random numbers. No description of the sample size or

power calculation was described and neither the participants nor treating physicians were

blinded to the interventions. This trial had no withdrawals

Participants 60 women at 14-32 weeks of pregnancy were included.

Inclusion criteria: PCV 22% to 26% due to iron-deficiency anaemia. Iron-deficiency

anaemia defined as: Hb genotype AA; MCV < 75 pg; MCHC < 32 g/dL; blood film -

picture of iron-deficiency anaemia

Exclusion criteria: symptomatic anaemia; acute malaria; acute urinary tract infec-

tion; history of allergy to parenteral iron; multiple pregnancy atopic individual and

haemoglobinopathy

Interventions Experiment group: 30 women.

IM iron dextran. 50 mg iron dextran into buttock preceded by 25 mg promethazine

tablet 30 minutes before. If no untoward reaction after 48 hours, 250 mg (5 ml) iron

dextran thrice weekly I = until total dose given.

Total dose = iron (mg) = weight (kg) x Hb deficit (g/dL) x 4.4 + 500

Control group: 30 women.

Oral Fe: 200 mg ferrous sulphate 3 times daily between meals, with vitamin C 100 mg

3 times daily and 5 mg folic acid.

Both groups were treated for 6 weeks.

Outcomes The trial measured the mean PCV, corrected anaemia at the end of the follow-up period,

the cost of the treatment and the side effects

Notes Results given in % and not specific numbers.

Risk of bias



bias)

Low risk Computer-generated random numbers.

Allocation concealment (selection bias) Unclear risk “Sealed envelopes”.


bias)

All outcomes

High risk Neither the participants nor treating physi-

cians were blinded to the interventions


All outcomes

Low risk This trial had no withdrawals.



Komolafe 2003 (Continued)



Kumar 2005

Methods Participants were randomly allocated to 2 groups. Method of allocation generation and

allocation concealment were unclear.

Both the participants and treating physicians were not blinded to the interventions.

Sample size considerations were not provided. 47 women in parenteral iron group and

23 women in oral iron group were lost to follow up

Participants 220 pregnant women were including according to the following criteria

Inclusion criteria: women with gestation period of 16-24 weeks, were selected according

to the following inclusion criteria: singleton pregnancy, moderate anaemia (Hb 8-11 g%)

by cyanmethaemoglobin method, microcytic hypochromic blood smear and willingness

for enrolment to the study

Exclusion criteria: the women with anaemia due to haemoglobinopathies, chronic bleed-

ing, parasitosis, diseases of liver, cardiovascular system and kidney; medical disorders like

tuberculosis, diabetes mellitus; women who had any form of parenteral iron therapy for

anaemia during pregnancy; women with antepartum haemorrhage and intolerance to

test dose (0.5 ml) of IM administration of iron were excluded from the study

Interventions Experiment group: IM iron: parenteral iron group were given 2 IM injections of 250 mg

elemental iron as iron sorbitol citric acid in a injection volume of 5 ml at an interval of

4-6 weeks in the antenatal clinic. An initial test dose of 0.5 ml was given. If there was no

adverse reaction to the test dose, then a full 250 mg dose was given deeply in the outer

quadrant of the buttock using Z-tract technique

Control group: oral iron: tablets of 100 mg elemental iron (ferrous sulphate) and 500

Ag of folic acid daily

Outcomes The trial measured values of blood indices at 36 weeks as well as mean birthweight, mode

of delivery and side effects

Notes

Risk of bias



bias)

Unclear risk Not reported.

Allocation concealment (selection bias) Unclear risk Not reported.


bias)

All outcomes

High risk Both the participants and treating physi-

cians were not blinded to the interventions



Kumar 2005 (Continued)


All outcomes

Unclear risk 47 women in parenteral iron group and 23

women in oral iron group were lost to fol-

low up




declared

Mumtaz 2000

Methods Randomisation was performed using a random-number generator, and each women

was assigned a unique identifier. The women and the investigator were blinded to the

allocation of treatment group (daily vs. twice weekly) at initial recruitment and the 3

follow-up visits. The appearance of the capsules and the blister packs of the 2 groups

were identical. The randomisation code was opened only after the follow-up for all

participants had been completed. Sample size considerations were provided. This trial

had 86 participants, (45%) that did not complete the entire duration of follow up (i.e. 4

follow-up visits). However, data on 83.8% of the participants were available for 4 weeks

of follow-up.

Analysis by ITT.

Participants 191 pregnant women between the age of 17-35 years, with an initial Hb of < 110 g/L

were included.

Uneventful obstetric history.

All given health education materials on importance of diet in pregnancy

Interventions Experiment group: daily iron - plus daily folate. 200 mg iron sulphate (60 mg elemental

iron) each day and 1 mg folate.

Control group: twice weekly iron - plus daily folate. 200 mg iron sulphate (60 mg

elemental) twice weekly and 1 mg folate. Placebo was given for the rest of the days

Outcomes Venous blood samples were taken for complete blood count at each visit and for serum

ferritin at the 1st, 3rd and 4th visits. A peripheral film was made to rule out congenital

disorders such as thalassaemia minor.

No information about maternal and fetal outcomes and side effects was provided

Notes There was no difference between the women who dropped out compared with those

who continued in the trial in terms of age, initial Hb, parity and in the 2 treatment

groups (41 versus 45)

Risk of bias




Mumtaz 2000 (Continued)


bias)

Low risk Random-number generator.

Allocation concealment (selection bias) Low risk Randomisation was performed using a ran-

dom-number generator, and each women

was assigned a unique identifier. The ran-

domisation code was opened only after the

follow up for all participants had been com-

pleted


bias)

All outcomes

Low risk The women and the investigator were

blinded to the allocation of treatment

group. The appearance of the capsules and

the blister packs of the 2 groups were iden-

tical


All outcomes

Unclear risk This trial had 86 participants, (45%) that

did not complete the entire duration of

follow up (i.e. 4 follow-up visits). How-

ever data on 83.8% of the participants were

available for 4 weeks of follow-up


Other bias Low risk Characteristics of the women at the begin-

ning of the study were provided. Compet-

ing interests and funding were not declared

Nappi 2009

Methods Prospective, randomised, controlled, double blind trial.

Participants 100 pregnant women with iron deficiency anaemia. Inclusion criteria were: physiological

course of pregnancy, singleton pregnancy, gestational age 12 weeks and 36 weeks, Hb

values11 mg/dl, serum iron 30 µg/dl, serum ferritin12 µg/dl and TIBC 450 µg/dl.

Exclusion criteria were: gestational (such as hypertension, gestational diabetes) or pre-

existent maternal diseases and fetal abnormalities

Interventions Group A received bovine lactoferrin at the oral dose of one capsule of 100 mg twice a

day for 4 weeks

Group B received ferrous sulphate at the daily oral dose of one tablet of 520 mg (con-

taining 100 mg elementary iron) for 4 weeks

Both groups received an additional supplementation with calcium mefolinate at the daily

oral dose of 1 x 15 mg tablet

Outcomes The primary outcome measure was the Hb level before and after 1 month of treatment.

Secondary outcomes were serum ferritin, serum iron and TIBC levels and the difference

in symptom scores between groups



Nappi 2009 (Continued)

Notes

Risk of bias



bias)

Low risk Computer-generated randomisation list.



bias)

All outcomes

Low risk Both researchers and patients were blinded

to group assignment. The tablets were sim-

ilar and neither the researchers nor the pa-

tients could differentiate the treatment as-

signed


All outcomes

Unclear risk 2 patients (4%) from the group assigned to

ferrous sulphate were lost to follow up. No

clinical outcomes were collected. The total

number of adverse events were not reported

for each group; only the median gastroin-

testinal side effects score were presented


Other bias Low risk Baseline characteristics were provided. The

authors report no conflicts of interest.

Funding was not reported

Ogunbode 1980

Methods There was no information on methods of randomisation. No description of the sample

size or power calculation was described and both the participants and treating physicians

were blinded to the interventions. No participants were reported to have dropped out

or were lost to follow up

Participants 91 women in the first or second trimester of pregnancy with a PCV of 33% or less were

randomly allocated to 3 treatment groups

Interventions In group A, 32 participants received 200 mg of oral ferrous sulphate thrice daily; in

group B 28 participants received 400 mg of oral ferrous sulphate 3 times daily; in group

C, 31 women received IM iron poly (sorbitol gluconic acid) complex ferastral (500 mg

iron) on alternate days until completion of the required dose (between 1250 to 2500 mg

of iron). No formal formula to calculate the dose was described. All participants received

5 mg of folic acid and 25 mg of pyrimethamine once weekly



Ogunbode 1980 (Continued)

Outcomes The trial measured the reticulocyte response and haematocrit level

Notes

Risk of bias



bias)




bias)

All outcomes

Low risk Both the participants and treating physi-



All outcomes

Low risk No participants were reported to have

dropped out or were lost to follow up



Oluboyede 1980

Methods Participants were allocated by restricted random allocation. There was no further infor-

mation on methods of randomisation. No description of the sample size or power calcu-

lation was described and neither the participants nor treating physicians were blinded to

the interventions. 1 participant from the imferon group was reported to have dropped

out due to a severe reaction

Participants 63 pregnant women with established iron-deficiency anaemia defined as a PCV of 30%

or less were included. Hb AA genotype only.

Exclusion criteria: if previously had iron therapy.

Interventions Experiment group: 32 women. IM ferastral (sorbitol gluconic acid). 500 mg ferastral (5

ml in each buttock) IM on alternate days until completion of required dose.

Control group: 31 women. IV imferon (iron dextran). Calculated dose given in 540 ml

normal saline and 50 ml promethazine hydrochloride (phenegran) was given IM before

infusion. Drip ran slowly for first 30 minutes then 60 drops a minute until completion.

Discharged home though 10 kept in.

All women received anti-malarial of 25 mg pyrimethamine and 5 mg of folic acid

throughout pregnancy

Outcomes Weekly or 2-weekly PCV estimations were done on all participants, after 4 weeks of

treatment liver function tests were repeated and after 6 weeks bone marrow aspirations

were repeated on 21 women. The trial also measured the reticulocyte response in 10



Oluboyede 1980 (Continued)

women randomly selected from each group and babies birth weights and any complica-

tion within the first week of life

Notes

Risk of bias



bias)

Unclear risk “Restricted random allocation.”



bias)

All outcomes




All outcomes

Low risk 1 participant from the imferon group was

reported to have dropped out due to a se-

vere reaction


Other bias Unclear risk Competing interests and funding were not

declared.

Saha 2007

Methods A double blinded randomised control trial.

Participants 100 pregnant women between 20 and 40 years; gestation 14-27 weeks; Hb < 9 and > 7

g/dL; and serum ferritin < mcg/L. Patients with a history of anaemia due to any other

causes were excluded (i.e. chronic blood loss, haemolytic anaemia, thalassaemia). Women

with other chronic or severe diseases were also excluded (hepatic, renal, cardiovascular

etc.)

Interventions Group 1 (48 participants): iron polymaltose, 100 mg elemental iron + folic acid 500

mcg for 8 weeks (1 tablet orally once day) + placebo (1 tablet orally once day)

Gourp 2 (52 participants): 60 mg elemental iron + folic acid 500 mcg for 8 weeks (1

tablet orally twice day)

Outcomes The primary efficacy parameter was the proportion of women achieving normal Hb level

(> 11 g/dL). Adverse events and costs were also collected. No clinical outcomes were

collected

Notes

Risk of bias



Saha 2007 (Continued)



bias)

Unclear risk “Randomized.”

Allocation concealment (selection bias) Unclear risk Not reported.


bias)

All outcomes

Low risk Participants and outcome assessors were

blind. Both of the drugs were dispensed in

identical capsules to ensure blinding


All outcomes

Low risk No losses to follow up or discontinuation

were reported. No clinical outcomes were

reported



Competing interests were declared

Singh 1998

Methods Women were allocated using sealed envelopes with consecutive numbers

Participants First 100 women with diagnosed iron-deficiency anaemia while attending for antenatal

care at the National University Hospital, Singapore. Data provided by 1 of the authors

reveals that compared groups had similar age distribution, parity, mean total income,

weight, height, history of anaemia in previous pregnancies, history of intrauterine growth

retardation in previous pregnancies and similar time-gap between pregnancies.

Races were distributed as follows: Chinese (10% parenteral and 6% of oral iron therapy)

, Malayan (46% and 78% in the same order), Indian (16 and 8%). History of preterm

delivery was seen in 16% of the parenteral treatment group and 12% of oral iron group

Interventions Total dose iron polymaltose complex - iron dextrin (ferrum Hausmann) infusion vs. oral

therapy with 3 x 200 mg/day iron fumarate. The dose was determined according to the

body weight and estimated iron deficiency

Outcomes This paper provided data at 36 weeks, delivery and 6 weeks’ postpartum. The paper

provided haematological outcomes. In addition, the publication mentioned some side

effects and similar clinical outcomes in both groups. The authors were contacted and

provided precise data on clinical outcomes and side effects that were included too

Notes Dr Kuldip Singh at the National University Hospital - University of Singapore was the

contacted author. Contact was established through a search on Internet. Further contact

is being undertaken to check the units used for serum iron and ferritin estimations, then

further comparison tables can be added to this review



Singh 1998 (Continued)

Risk of bias



bias)

Unclear risk Randomised.

Allocation concealment (selection bias) Low risk Sealed envelopes with consecutive num-

bers.


bias)

All outcomes

Unclear risk No sufficient detail to decide.


All outcomes

Low risk The paper provided haematological out-

comes. In addition, the publication men-

tioned some side effects and similar clini-

cal outcomes in both groups. The authors

were contacted and provided precise data

on clinical outcomes and side effects that

were included too


Other bias Low risk Data provided by 1 of the authors re-

veals that compared groups had similar

age distribution, parity, mean total income,

weight, height, history of anaemia in pre-

vious pregnancies, history of intrauterine

growth retardation in previous pregnancies

and similar time-gap between pregnancies

Sood 1979

Methods There was no information on methods of randomisation. No description of the sample

size or power calculation was described and researchers kept unmasked the 5 groups.

2 women were reported to have dropped in the group receiving IV iron due to severe

delayed adverse allergic reaction

Participants 151 pregnant women.

Inclusion criteria: pregnant women, 26 + 2 weeks’ gestation. Divided into 3 strata ac-

cording to their Hb concentration: 50-79; 80-109; 110 or above.

Exclusion criteria: women with chronic illness; with Hb < 50 g/L; who had received

haematinics during the last months

Interventions Within each stratum they were randomised to 1 of the following groups. 1. Oral ferrous

sulphate providing 120 mg of 120 mg elemental iron, given once per day 6 weeks.

2. Iron dextran complex providing 100 mg iron given IM twice per week. 3. Iron as in



Sood 1979 (Continued)

group 1 + pteroylmonoglutamic acid (5 mg, 6 day/week) + cyanocobalamin (100 µg IM

once per 14 day). 4. Iron IM as in group 2 + pteroylmonoglutamic acid + cyanocobalamin

as in group 3.

5. Iron dextran complex given IV as a single total dose infusion according to the formula

(15 - women’s Hb (g/dL)) x (body-weight (kg) x 3) + pteroylmonoglutamic acid +

cyanocobalamin as in group 3. Treatment was continued for 10-12 weeks

Outcomes Hb, PCV was estimated 48 before the treatment was started and at least 48 hours after

the last injection or tablet was given

Notes

Risk of bias



bias)




bias)

All outcomes

High risk Not done.


All outcomes

Unclear risk The paper provided haematological out-

comes.



declared.

Suharno 1993

Methods Allocation was done using a random-number list from 1 to 305 and allocating women

sequentially in the list. The manufacturers of the active treatments provided placebos. An

independent researcher randomly labelled the active and placebo preparations. Coding

colours were given to the preparations and these codes were opened once the data for all

analyses had been entered in the computer and cleaned

Participants 305 pregnant women. The study was conducted from April to September 1992 in 20

rural villages in 3 sub districts of Bogor, West Java. Participants came from middle and

low socio-economic groups. They were aged between 17 and 35 years, with parity in the

ranges of 0 to 4 and gestational age of 16 to 25 weeks.

572 women met inclusion criteria. 305 participated in the study.

Hb levels of participants were in the range of 8.0 to 10.9 g/dL. Women receiving iron

or vitamin A treatments or supplements in the 6 months prior to study were excluded.



Suharno 1993 (Continued)

Outcomes were assessed 2 and 7 days after the last dose of treatment was given (24 to 33

weeks). Participants had similar age, height, weight, pregnancies, parity and gestational

age at admission

Interventions 4 different groups received 2 active treatments at most (factorial design). All preparations

were given daily for 8 weeks.

1. 60 mg elemental oral iron (as ferrous sulphate) + vitamin A (2.4 mg of retinol as

retinyl palmitate).

2. 60 mg elemental oral iron (as ferrous sulphate ) + placebo of vitamin A.

3. Placebo of oral iron + vitamin A (2.4 mg of retinol as retinyl palmitate).

4. Placebo or oral iron + placebo or vitamin A.

Outcomes Hb, ferritin and serum iron mean values and standard deviations were extracted for this

review from the published paper. Percentage of women that became non-anaemic (Hb

> 10.9 g/dL) was counted as a dichotomised variable. Numbers needed to treat were

calculated by the authors of this review

Notes Results for vitamin A + placebo were not considered since this is part of a different review.

Vitamin A combined with iron was included in this review. Serum iron levels were given

in umol/l and converted to mg/l by the authors (umol/l x 0.056 = mg/l). Loss to follow

up accounted for 17% of the women. Analysis was done by ITT

Risk of bias



bias)

Low risk Random-number list.

Allocation concealment (selection bias) Low risk An independent researcher randomly la-

belled the active and placebo preparations.

Coding colours were given to the prepara-

tions and these codes were opened once the

data for all analyses had been entered in the

computer and cleaned


bias)

All outcomes

Low risk An independent researcher randomly la-

belled the active and placebo preparations.

Coding colours were given to the prepara-

tions and these codes were opened once the

data for all analyses had been entered in the

computer and cleaned


All outcomes

Unclear risk Some outcomes not fully reported.




Suharno 1993 (Continued)


Sun 2010

Methods Double-blind randomised trial

Participants Pregnant women, 12 to 24-week gestation, age between 20-30 years, were examined for

eligibility. Of these women, 186 anaemic pregnant women with Hb concentration ≥ 80

and < 110 g/L were included

Interventions Group I (n=47) was supplemented daily with 60 mg iron as ferrous sulfate

Group II (n=46) with 60 mg iron and 0.4 mg folic acid.

Group III (n=46) with 60 mg iron, 2.0 mg retinol and 0.4 mg folic acid

Group C (n=47) was the placebo control group.

Only group 1 and 4 were included for analysis in the review.

Outcomes - Hb concentration at 2 months of treatment

- Plasma ferritin

- Plasma iron concentrations

- Peripheral blood lymphocytes

No clinical outcomes or adverse events were reported

Notes

Risk of bias



bias)

Unclear risk “Randomized”. Not described.



bias)

All outcomes

Unclear risk “The capsules were coloured red, yellow, green and

blue during manufacture by Hurun (a Chinese food-

additive company, Beijing). Both trial participants and

the research team were unaware of the group assign-

ment. The trial was decoded after analysis of the pri-

mary outcomes”


All outcomes

Unclear risk Few participants were lost to follow up. Standard de-

viations of placebo group were not provided and had

to be calculated.

Selective reporting (reporting bias) High risk No clinical outcomes and adverse events were in-

formed.



Sun 2010 (Continued)


Symonds 1969

Methods Women were assigned randomly although the method is not clearly specified. Baseline

data for the 4 groups compared are very similar

Participants 103 women attending the Queen Elizabeth Hospital in Woodville, Australia. Inclusion

criteria were a gestational age of 32 weeks or less and a Hb level of 10.8 g/dL or less

Interventions 4 treatment groups were assembled.

1. Ferrous gluconate 108 mg of elemental iron daily divided in 3 doses given orally

throughout pregnancy.

2. Ferrogradumet tablets (controlled-release) iron tablets with 105 mg elemental iron

given once daily throughout pregnancy.

3. Placebo for the controlled-release iron tablets provided by the same pharmaceutical

laboratory.

4. IV iron-dextran 2% solution. Initial test dose of 2 ml IV followed by 5 injections of

5 ml (100 mg)

Participants received controlled-release iron or placebo for the first month. After that

time side effects were evaluated, and then all participants were given a daily dose of active

controlled-release oral iron. The trial was masked only the first 2 months and only for

these 2 groups

Outcomes For this review, side effects were considered. The other data were incomplete, without

reported standard deviations of mean values and irrelevant due to important flaws in the

design of the study

Notes Hb results were presented as increases in Hb. Since standard deviations for the values

cannot be added to baseline data, the data were not included

Risk of bias



bias)

Unclear risk “Randomly”.



bias)

All outcomes

Unclear risk The trial was masked only the first 2

months and only for these 2 groups


All outcomes

High risk For this review, side effects were considered.

The other data were incomplete, without

reported standard deviations of mean val-



Symonds 1969 (Continued)

ues


Other bias Low risk Baseline characteristics of participants were

provided.

Wali 2002

Methods There was no information on methods of randomisation described and neither the

participants nor treating physicians were blinded to the interventions. No description of

the sample size or power calculation was provided

Participants 60 pregnant women with anaemia were included in the study.

Inclusion criteria: pregnant women; 12-34 weeks; iron-deficiency anaemia; Hb 5-10 g/

dL; PCV < 30%; MCV < 80 fl; MCH < 28 pg.

Women with Hb < 7 g/dL (n = 2) were given IV iron sucrose (Venofer) as an alternative

to blood transfusion; those with Hb 7-10 g/dL were randomised for IV iron or IM iron.

Exclusion criteria: chronic diseases; anaemic failure.

Interventions Experiment group A: 15 women.

IV iron sucrose 500 mg for iron storage.

Experiment group B: 20 women.

IV iron sucrose 200 mg iron.

Experiment group C: 25 women

IM iron sorbitol with varying doses depending on Hb level; 5 g/dL - 24 injections; 6 g/

dL - 22 injections; 7 g/dL - 20 injections; 8 g/dL - 17 injections; 9 g/dL - 14 injections;

10 g/dL - 12 injections; 11 g/dL - 10 injections

After parenteral iron, oral iron given till birth of baby.

Outcomes The trial outcomes focused on laboratory values (Hb) and side effects

Notes

Risk of bias



bias)

Unclear risk No description other than “randomised”.

Allocation concealment (selection bias) Unclear risk No description.


bias)

All outcomes





Wali 2002 (Continued)


All outcomes

Unclear risk The trial outcomes focused on laboratory

values (Hb) and side effects



declared.

Zhou 2007

Methods Double blind randomised controlled trial.

Participants Pregnant women (N = 180) diagnosed with anaemia (Hb < 110 g/L) at the routine

mid-pregnancy blood test were approached to take part in our study. They were eligible

if between 24 and 32 weeks’ gestation and had a singleton pregnancy. Women were

excluded if they were taking iron or vitamin and mineral supplements containing iron,

other causes of anaemia, history of thalassaemia or drug and alcohol abuse and had

diabetes requiring insulin or a known fetal abnormality

Interventions Ferrous sulphate containing 20, 40 or 80 mg of elemental iron per tablet, which did not

contain other micronutrients (1 tablet daily between meals from enrolment for 8 weeks

or until birth)

Outcomes The primary outcomes of the study were Hb levels and incidence of anaemia at the end of

the intervention, and gastro-intestinal side effects during treatment. Secondary outcomes

included incidence of iron deficiency, iron-deficiency anaemia and haemoconcentration

at the end of treatment as well as pregnancy outcomes

Notes

Risk of bias



bias)

Low risk ”Computer-generated randomizations

schedule was generated by an independent

consultant with stratification for Hb (Hb <

100 or > 100 g/L) to ensure that there were

equal proportions of women with more se-

vere anaemia in all groups.“

Allocation concealment (selection bias) Low risk ”The iron tablets were packed in bottles

with childproof lids, which were labelled

with a unique study number according to

the randomizations schedule by the Phar-

macy Department at the CYWHS.“



Zhou 2007 (Continued)


bias)

All outcomes

Low risk ”Trial participants and the research team

were unaware of the treatment group as-

signment“. The trial was unblinded after

the analysis of the primary outcomes.”

“The tablets were identical in size, colour

and shape.”


All outcomes

Low risk Only 1 patient was lost to follow up. Preg-

nancy outcomes and neonatal complica-

tions at birth were reported

Selective reporting (reporting bias) Unclear risk Protocol of the study is not available. The

Australian Clinical Trials Registry (ACTR)

(Reference no. 12606000357550)


“Funding from the Adelaide Women’s &

Children’s Hospital Research Foundation.

The iron and placebo tablets used in

the trial were manufactured and donated

by Soul Pattinson Manufacturing, Kings-

grove, NSW, Australia. The funding orga-

nizations had no role in the design and con-

duct of the study, the analysis and interpre-

tation of the data, or the preparation, re-

view and approval of the manuscript. MM

and RAG occasionally provide advice to

manufacturers of nutritional supplements.

SJZ and CAC have no known conflict of

interest.”

Zutschi 2004

Methods There was no information on methods of randomisation. No women were reported to

have dropped out or were lost to follow up. Neither the women nor treating physicians

were blinded to the interventions. No description of the sample size or power calculation

was described

Participants 200 women with uncomplicated pregnancy enrolled at 24-26 weeks of gestation with a

Hb of > 8 gm% but < 11 gm% were included

Women dropped out of study if Hb fell below 8 g/l or if severe problems arose

Interventions Group A (100 women) received injectable iron-sorbitol-citrate in 3 IM doses of 150 mg

each at 4-weekly intervals and group B (100 women) were given oral iron having 100

mg elemental iron daily for at least 100 days

Outcomes The trial measured Hb levels at the time of inclusion into the study, 4-weekly thereafter

and at delivery as well as the proportion of caesarean delivery



Zutschi 2004 (Continued)

Notes

Risk of bias



bias)

Unclear risk No description other than “randomized”.

Allocation concealment (selection bias) Unclear risk No description.


bias)

All outcomes

High risk Neither the women nor treating physicians

were blinded to the interventions


All outcomes

Low risk No dropout or lost to follow up were re-

ported. Few clinical outcomes were pro-

vided


Other bias Unclear risk Baseline characteristics were partially pre-

sented. Competing interests and funding

were not declared

Hb: haemoglobin

IM: intramuscular

ITT: intention-to-treat

IV: intravenous

MCH: mean corpuscular haemoglobin

MCHC: mean corpuscular haemoglobin concentration

MCV: mean corpuscular volume

PCV: packed cell volume

TIBC: total iron binding capacity

vs: versus

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Al Momen 1996 Not a randomised controlled trial. Sequential allocation.

Allaire 1961 Loss to follow up of 56%. Used quasi-random allocation.



(Continued)

Amir 1983 Excluded: inclusion criteria Hb < 12 g/dL. No baseline characteristics that lead to infer levels of Hb at the

beginning of the study

Ayub 2008 Non-randomised study.

Bare 1960 They allocated participants using alternate order. This is not considered random

Barrada 1991 Insufficient information for critical appraisal was provided. There are no explicit inclusion or exclusion

criteria

Basu 1973 Randomisation method not provided. No information is provided regarding blinding or number of women

that completed the trial or that were accounted for each result

Bencaiova 2009 Non-anaemic pregnant women.

Bhatla 2009 Non-anaemic women.

Bhutta 2006 Mebendazol and multivitamin trial. Ongoing.

Breymann 1998 Randomised open-label trial.

Breymann 2002 Not a randomised controlled trial.

Buglanov 1984 No mention of randomisation.

Chan 2009 Iron supplementation from early pregnancy in anaemic and non-anaemic women. No subgroup data

Chanarin 1965 This study addressed megaloblastic anaemia.

Christiansen 1961 Alternate participants; not Hb < 11.0 g/d/L.

Coelho 2000 No mention that women were anaemic.

De Souza 2009 A convenience sample was used and allocation was consecutively and casually unblinded by the main

researcher to each of the three experimental groups

Dede 2005 Postpartum iron-deficiency anaemia.

Dochi 1988 Non-iron trial.

Dommisse 1982 Folic acid trial.

Ekstrom 2002 Centers were randomly assign (not women) and only some women had Hb < 11.5 g/dL

Finzi 1972 No random allocation.

Fochi 1985 Randomisation is not well balanced. The paper does not explain unbalanced groups



(Continued)

Govan 2005 Case series.

Graham 2007 A vitamin A-fortified rice curry dish with iron + vitamins vs. placebo

Halksworth 2003 No randomisation method. Evaluated the absorption of iron.

Hamilton 1973 Allocation was done using a haphazard strategy, not a random one

Hampel 1974 Used a haphazard allocation method (day of diagnosis).

Hancock 1968 Non randomised trial.

Harrison 1971 Non-iron RCT.

Hawkins 1970 The study evaluates the use of medication in women with Hb levels over 10.5 g/dL and uses non-random

strategy for allocation

Holly 1955 The study is in women with Hb levels over 10 g/dL. Treatment allocation was not random

Hosokawa 1989 Vitamin C trial.

Izak 1973 Although the authors state that allocation was random, the groups are very different (184, 76 and 22). The

authors used an inappropriate control group of healthy women. They do not explain the randomisation

method

Jackson 1982 More than 50% of their women were lost to follow up.

Jaud 1979 Used open-randomisation list. We tried to contact to verify data but it was impossible. Open-randomisation

lists are considered inadequate since there is no concealment and it is prone to bias

Juarez-Vazquez 2002 The trial evaluated folic acid + iron versus iron.

Kore 2006 Non randomised study. Only the abstract was available.

Krafft 2009 Non randomised study. No comparison.

Ma 2008 Retinol and Riboflavin supplementation trial.

Mahale 1993 This study has dropouts that surpasses the limit established for this review

Mahmoudian 2005 Zinc trial.

Mathan 1979 The trial evaluated group 1 iron + pteroylmonoglutamic acid and cyanocobalamin versus group 1 +

ascorbic acid versus group 1 + calcium caseinate

Milman 2006 Non-anaemic pregnant women.



(Continued)

Minganti 1995 Sample size: 15 participants. Data not available.

Mukhopadhyay 2004 The trial excludes women with Hb level < 10 g/dL. The mean baseline Hb was 11.3 and 11.6 g/dL in

both groups of treatment

Mukhopadhyay 2004a Double publication.

Ogunbode 1984 Folic acid trial.

Preziosi 1997 No fundamental data to assess validity.

Reddy 2000 No comparison group.

Ridwan 1996 Health centres were randomised, rather than individuals.

Sagaonkar 2009 Assessed two different iron drugs and varied types of vitamins at the same time

Schoyerer 1975 Folic acid trial.

Scott 2005 Series of cases description.

Sharma 2004 No randomisation.

Siega-Riz 2001 Trialists reported that a subgroup of anaemic patients (women with Hb > 9 g/dL and ferritin < 40 g/l) was

randomised to receive prenatal supplements with 30 or 60 mg of iron. A subsequent publication only

focus on the non-anaemic group (Siega-Riz 2006). The principal author was contacted to get data on the

subgroup of anaemic patients. The author said “that it will not be possible”

Siega-Riz 2006 Non-anaemic pregnant women.

Sigridov 2005 Not randomised.

Sood 1975 This study has a high proportion of women lost to follow up exceeding the cut-off point established for

this review

Stein 1991 No fundamental data to assess validity.

Steiner 1977 No information regarding random allocation or allocation concealment. Insufficient baseline data provided

Szarfarc 2001 Non-anaemic women.

Tange 1993 Non-randomised trial. The number of anaemic participant was not provided for each group of treatment

Thirunavukkarasu 2009 Not a controlled trial.

Tomar 2006 Non-randomised study. Only the abstract was available.



(Continued)

Valli Rani 1995 They used sequential strategy for allocation and not a random one

Van den Broek 2006 Non-iron trial.

Visca 1996 No fundamental data to assess validity.

Von Peiker 1986 The differences between the groups was not iron, but vitamins

Wu 1998 The numbers of participants in the 3 groups are not similar (93 for maternal, 50 for ferrous sulphate and

35 for ferroids) and is higher at follow-up than at the beginning of the trial. It is unclear how they were

allocated to the groups and whether therefore they are similar at baseline

Young 2000 A weekly iron/folate supplement was compared with a standard daily iron/folate supplement in pregnant

women living in rural Malawi. Acid folic trial

Zhou 2006 Non-anaemic women.

Hb: haemoglobin

vs: versus

Characteristics of studies awaiting assessment [ordered by study ID]

Paleru 2011

Methods Randomised open label controlled trial. No further details on the methods to generate randomisation and allocation

concealment were provided

Participants 80 antenatal women with anaemia (Hb levels between 8 and 10.5 g/dL) and serum ferritin < 13 mcg/L

Interventions 300 mg oral iron sulphate per day vs. IV iron sucrose

Outcomes Levels of Hb and ferritin on the day 28th and at delivery. No data on findings were provided.

Notes Poster presentation. No numerical data were provided for analysis

Pandit 2009

Methods Randomised controlled trial. No further details on the methods to generate randomisation and allocation concealment

were provided

Participants 100 anaemic pregnant women were recruited. All women were selected between 16 to 24 weeks of gestational age,

irrespective of their parity, socio-economic status and dietary habits



Pandit 2009 (Continued)

Interventions Women were randomly divided into study and control groups and were given study group (N = 50) - IV iron sucrose

injections. Control group (N = 50) - oral ferrous sulphate tablets

Outcomes The outcome of pregnancy, birthweight of babies and side effects of both methods were also studied

Notes Poster presentation. No numerical data were provided for analysis. We attempted to find the authors on the Web but

this strategy was unsuccessful

Sarkate 2007

Methods Double blind randomised controlled trial.

Participants Pregnant women with gestation period between 12 and 26 weeks having serum Hb < 10 g/dL, serum ferritin < 12

mcg/L

Interventions Group 1: sodium feredetate (33 mg elemental iron) + vitamin B12 (15 mcg) + folic acid (1.5 mcg), twice day

Group 2: sodium feredetate (66 mg elemental iron) + vitamin B12 (15 mcg) + folic acid (1.5 mcg), twice day

Group 3: Ferrous fumarate (100 mg elemental iron) + vitamin B12 (15 mcg) + folic acid (1.5 mcg), twice day

Outcomes Haematological levels; adverse events. 77% of patients completed all the visits. 11 patients withdrawn due to treatment

failure at day 45. The data for their subsequent follow-up visits were computed using the principle of last observation.

More patients were recruited due to drop-outs. Trialists did not report the total number of patients that were finally

enrolled. Data of 48 patients were available for analysis

Notes Trialist did not report the total number of participants that were analysed in each group and no further analysis was

possible. We attempted to contact some of the authors by electronic email but no response was obtained

Hb: haemoglobin

IV: intravenous

vs: versus

Characteristics of ongoing studies [ordered by study ID]

Ruangvutilet 2009

Trial name or title

Methods Open randomised controlled trial. Phase IV study. No further details on the methods to generate randomi-

sation and allocation concealment were provided

Participants Women aged between 18 and 45 years old, singleton pregnancy at 32 weeks’ gestation, having anaemia (less

than 11 g/dL). No underlying disease

Interventions Intravenous versus oral iron (Venofer vs Ferli-6). No further detail was provided



Ruangvutilet 2009 (Continued)

Outcomes Serum ferritin, Hb level.

Starting date

Contact information

Notes Ongoing study. We attempted to contact some of the authors by electronic email but no response was obtained

Hb: haemoglobin



D A T A A N D A N A L Y S E S

Comparison 1. Oral iron versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Anaemic during 2nd trimester 1 125 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.26, 0.55]

2 Haemoglobin levels (g/dL) 2 215 Mean Difference (IV, Random, 95% CI) 1.34 [0.27, 2.42]

3 Ferritin levels (ug/l) 1 125 Mean Difference (IV, Fixed, 95% CI) 0.70 [0.52, 0.88]

4 Serum iron (mg/l) 1 125 Mean Difference (IV, Fixed, 95% CI) 0.04 [0.03, 0.05]

5 Side effects 1 51 Risk Ratio (M-H, Fixed, 95% CI) 1.97 [0.66, 5.91]

6 Nausea and vomiting 1 51 Risk Ratio (M-H, Fixed, 95% CI) 4.5 [0.54, 37.54]

7 Constipation 1 51 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.32, 4.01]

8 Abdominal cramps 1 51 Risk Ratio (M-H, Fixed, 95% CI) 5.6 [0.28, 111.15]

Comparison 2. Oral iron + vitamin A versus placebo


studies

No. of


1 Anaemic during 2nd trimester 1 125 Risk Ratio (M-H, Fixed, 95% CI) 0.04 [0.01, 0.15]

2 Haemoglobin levels (g/dL) 1 125 Mean Difference (IV, Fixed, 95% CI) 1.30 [1.11, 1.49]

3 Ferritin levels (ug/l) 1 125 Mean Difference (IV, Fixed, 95% CI) 0.70 [0.52, 0.88]

4 Serum iron (mg/l) 1 125 Mean Difference (IV, Fixed, 95% CI) 0.08 [0.07, 0.09]

Comparison 3. Controlled-release oral iron versus regular oral iron


studies

No. of



2 Nausea and vomiting 1 49 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.27, 3.41]





Comparison 4. Intramuscular iron sorbito-citric acid versus intramuscular dextran


studies

No. of


1 Pain at injection site 1 48 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.58, 1.72]

2 Skin discolouration at injection

site

1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.07, 0.65]

3 Venous thrombosis 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Nausea or vomiting 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.06, 13.87]

5 Headaches 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.02, 0.99]

6 Shivering 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.01, 7.20]

7 Itching 1 48 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.26, 3.26]

8 Metallic taste in mouth 1 48 Risk Ratio (M-H, Fixed, 95% CI) 3.68 [0.44, 30.56]

Comparison 5. Intramuscular iron dextran versus intravenous iron dextran


studies

No. of




site








9 Severe delayed allergic reaction 1 62 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.01, 4.26]

Comparison 6. Intramuscular iron sorbitol citric acid versus intravenous iron dextran


studies

No. of




site










Comparison 7. Intravenous iron versus placebo


studies

No. of






Comparison 8. Intravenous iron versus regular oral iron


studies

No. of



2 Nausea or vomiting or epigastric

discomfort


3 Constipation 2 151 Risk Ratio (M-H, Random, 95% CI) 0.11 [0.02, 0.71]


5 Diarrhoea 3 237 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.03, 0.86]

6 Blood transfusion required 3 167 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.05, 1.59]

7 Neonates mean hemoglobin 1 47 Mean Difference (IV, Fixed, 95% CI) -0.15 [-1.37, 1.07]

8 Maternal haemoglobin at birth 1 90 Mean Difference (IV, Fixed, 95% CI) 0.75 [0.34, 1.16]

9 Maternal haemoglobin at 6

weeks

0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

10 Neonates ferritin level 1 47 Mean Difference (IV, Fixed, 95% CI) -2.0 [-62.36, 58.36]

11 Mean maternal haemoglobin at

4 weeks ( g/dL)

3 167 Mean Difference (IV, Random, 95% CI) 0.44 [0.05, 0.82]

12 Maternal mortality 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

13 Preterm labour 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

14 Caesarean section 2 190 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.46, 1.67]

15 Operative vaginal birth 1 100 Risk Ratio (M-H, Fixed, 95% CI) 1.5 [0.26, 8.60]

16 Postpartum haemorrhage 2 147 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.34, 2.26]

17 Low birthweight (under 2500

g)


18 Neonatal birthweight 3 237 Mean Difference (IV, Random, 95% CI) 54.29 [-170.11, 278.

68]

19 Small-for-gestational age 1 100 Risk Ratio (M-H, Fixed, 95% CI) 1.6 [0.56, 4.56]

20 Five minute Apgar score under

seven


21 Neonatal mortality 2 147 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

22 Haemoglobin level > 12 g/dL

at 30 days


23 Gestational hypertension 1 90 Risk Ratio (M-H, Fixed, 95% CI) 5.0 [0.25, 101.31]

24 Gestational diabetes 1 90 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.01, 4.05]

25 Haemoglobin level > 11 g/dL

at birth




26 Severe delayed allergic reaction 1 67 Risk Ratio (M-H, Fixed, 95% CI) 5.45 [0.27, 109.49]

27 Arthralgia 1 90 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.06, 15.50]

Comparison 9. Intravenous iron versus controlled-release oral iron


studies

No. of






Comparison 10. 2/3 dose intravenous iron versus full dose intravenous iron


studies

No. of


1 Allergic reaction during infusion 1 623 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.35, 1.25]

2 Allergic reaction after infusion 1 623 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.45, 0.86]

3 Life-threatening allergic reaction

during infusion


4 Discomfort needing analgesics

after infusion


5 Immobilised by painful joints 1 623 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.30, 2.10]

6 Non-live births 1 507 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.36, 2.03]

7 Neonatal death 1 507 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.13, 2.07]

8 Stillbirth 1 507 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.25, 1.93]

9 Spontaneous abortion 1 507 Risk Ratio (M-H, Fixed, 95% CI) 3.13 [0.33, 29.92]

Comparison 11. Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous

iron sucrose


studies

No. of


1 Hb < 11 g/dL at 4 weeks 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.03, 1.56]

2 Mean corpuscular volume 1 40 Mean Difference (IV, Fixed, 95% CI) 6.30 [2.96, 9.64]


4 Metallic taste 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.05, 5.08]

5 Warm feeling 1 40 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.07, 14.90]

6 Birthweight 1 40 Mean Difference (IV, Fixed, 95% CI) -130.0 [-380.44,

120.44]

7 Birth < 37 weeks 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.72]



8 Maternal mean blood pressure 1 40 Mean Difference (IV, Fixed, 95% CI) -0.20 [-5.02, 4.62]

9 Need transfusion 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 12. Intramuscular iron sorbitol citric acid versus oral iron


studies

No. of


1 Not anaemic at term 1 200 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [1.01, 1.48]

2 Mean maternal haemoglobin at

birth


3 Mean maternal hematocrit level

at birth



5 Haematocrit (%) at 4 weeks of

treatment

1 56 Mean Difference (IV, Fixed, 95% CI) 1.25 [-0.03, 2.53]


treatment



treatment



treatment


Comparison 13. Intramuscular iron dextran versus oral iron + vitamin C + folic acid


studies

No. of


1 Haematocrit 1 60 Mean Difference (IV, Fixed, 95% CI) 4.47 [3.67, 5.27]

2 Not anaemic at 6 weeks (packed

cell volume > 33%)


Comparison 14. Intramuscular iron sorbitol citric acid versus oral iron + folic acid


studies

No. of


1 Mean haemoglobin at 36 weeks 1 150 Mean Difference (IV, Fixed, 95% CI) -0.26 [-0.48, -0.04]

2 Haemoglobin > 11 g/dL at 36

weeks



4 Mean birthweight (kg) 1 150 Mean Difference (IV, Fixed, 95% CI) -20.0 [-164.35, 124.

35]

5 Diarrhoea 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 1.62]




7 Dyspepsia 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.05 [0.00, 0.89]

8 Local site mainly pain 1 150 Risk Ratio (M-H, Fixed, 95% CI) 125.0 [7.87, 1984.

19]

9 Staining 1 150 Risk Ratio (M-H, Fixed, 95% CI) 113.0 [7.11, 1795.

82]

10 Arthralgia 1 150 Risk Ratio (M-H, Fixed, 95% CI) 13.0 [0.75, 226.73]

11 Itching and rash 1 150 Risk Ratio (M-H, Fixed, 95% CI) 29.0 [1.76, 477.47]

12 Fever 1 150 Risk Ratio (M-H, Fixed, 95% CI) 17.0 [1.00, 289.34]

13 Malaise 1 150 Risk Ratio (M-H, Fixed, 95% CI) 15.0 [0.87, 258.02]

14 Vaso-vagal due to apprehension 1 150 Risk Ratio (M-H, Fixed, 95% CI) 9.0 [0.49, 164.29]

15 Systemic ache 1 150 Risk Ratio (M-H, Fixed, 95% CI) 23.0 [1.38, 383.37]


weeks


Comparison 15. Oral iron daily versus oral iron twice weekly


studies

No. of


1 Haemoglobin level at 4 weeks 1 160 Mean Difference (IV, Fixed, 95% CI) 0.54 [0.14, 0.94]



4 Haemoglobin level at 16 weeks 1 102 Mean Difference (IV, Fixed, 95% CI) 0.30 [-0.01, 0.61]

5 Haemoglobin level > 11 g/dL at

16 weeks of treatment


6 Treatment failure (haemoglobin

< 10 g/dL) at 16 weeks


Comparison 16. Oral iron daily versus oral iron once week


studies

No. of






3 Treatment failure (haemoglobin





Comparison 17. Oral iron twice week versus oral iron once week


studies

No. of






3 Treatment Failure (haemoglobin



Comparison 18. Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg


studies

No. of


1 Haemoglobin level at delivery 1 35 Mean Difference (IV, Fixed, 95% CI) 0.5 [-0.18, 1.18]

2 Haemoglobin level > 11g/dL at

delivery


3 Moderate abdominal pain 1 35 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.09, 19.64]

Comparison 19. Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol


studies

No. of


1 Maternal haemoglobin level at

birth


2 Haemoglobin level > 11g/dL at

delivery


Comparison 20. Intravenous iron sucrose 200 mg versus intramuscular iron sorbitol


studies

No. of


1 Haemoglobin level at delivery 1 45 Mean Difference (IV, Fixed, 95% CI) 1.10 [0.49, 1.71]


delivery




Comparison 21. Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day


studies

No. of



treatment



treatment


Comparison 23. Intramuscular iron sorbitol-glu acid versus intravenous iron dextran


studies

No. of



treatment



treatment


3 Neonatal jaundice 1 62 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.06, 14.33]

4 Viral hepatitis 1 62 Risk Ratio (M-H, Fixed, 95% CI) 2.82 [0.12, 66.62]

5 Severe allergic reaction 1 62 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.01, 7.40]

Comparison 24. Oral iron polymaltose complex (100mg) versus ferrous sulphate (120mg)


studies

No. of


1 Haemoglobin level at 8 weeks 1 100 Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.30, 0.20]

2 Constipation at 8 weeks 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.14, 0.64]


weeks of treatment


4 Gastrointestinal intolerance 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.25, 0.69]

5 Metallic taste 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.02, 1.04]

6 Diarrhea 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.01, 4.39]

7 Rashes 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.02, 8.64]

8 Compliance 1 100 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.92, 1.21]

9 Cost due to hospital visits 1 100 Mean Difference (IV, Fixed, 95% CI) -7.05 [-116.16, 102.

06]

10 Cost due to loss of work 1 100 Mean Difference (IV, Fixed, 95% CI) 10.28 [-2.77, 23.33]



Comparison 25. Oral bovine lactoferrin versus ferrous sulphate


studies

No. of


1 Mean haemoglobin levels at 1

month

1 97 Mean Difference (IV, Fixed, 95% CI) -0.30 [-0.52, -0.08]

Comparison 26. Ferrous sulphate (elementary iron) 20 mg vs 40 mg


studies

No. of


1 Haemoglobin level at 8 weeks

(or until birth)

1 114 Mean Difference (IV, Fixed, 95% CI) -0.30 [-0.74, 0.14]

2 Rate of anaemia at 8 weeks 1 114 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.84, 2.52]

3 Rate of moderate anaemia at 8

weeks


4 Nausea at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.67, 1.12]

5 Heartburn at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.72, 1.13]

6 Stomach pain at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.36, 0.88]

7 Vomiting at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.39, 1.30]

8 Bowel habit: < 3 per week 1 120 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.42, 2.57]

9 Hard stool at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.64, 1.87]

10 Feeling unwell at 8 weeks 1 120 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.50, 0.97]



13 Birthweight 1 119 Mean Difference (IV, Fixed, 95% CI) -32.0 [-206.02, 142.

02]

14 Preterm birth 1 119 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.12, 4.05]


16 Fetal distress 1 119 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.25, 2.23]



studies

No. of



(or until birth)


2 Rate of patients with anaemia at

8 weeks



weeks


4 Nausea at 8 weeks 1 119 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.59, 0.95]












83]






studies

No. of



(or until birth)


2 Rate of anaemia at 8 weeks 1 110 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [0.87, 2.79]


weeks


4 Nausea at 8 weeks 1 121 Odds Ratio (M-H, Fixed, 95% CI) 0.54 [0.23, 1.26]










82]




Comparison 29. Intravenous iron + oral iron versus oral iron


studies

No. of


1 Mean predelivery maternal

haemoglobin


2 Mean maternal haemoglobin

after delivery




3 Tolerate oral iron 1 183 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.06, 1.32]

Analysis 1.1. Comparison 1 Oral iron versus placebo, Outcome 1 Anaemic during 2nd trimester.

Review: Treatments for iron-deficiency anaemia in pregnancy

Comparison: 1 Oral iron versus placebo

Outcome: 1 Anaemic during 2nd trimester

Study or subgroup Oral iron Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Suharno 1993 20/63 52/62 100.0 % 0.38 [ 0.26, 0.55 ]

Total (95% CI) 63 62 100.0 % 0.38 [ 0.26, 0.55 ]

Total events: 20 (Oral iron), 52 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 5.04 (P < 0.00001)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours oral iron Favours placebo

Analysis 1.2. Comparison 1 Oral iron versus placebo, Outcome 2 Haemoglobin levels (g/dL).



Outcome: 2 Haemoglobin levels (g/dL)

Study or subgroup Oral iron PlaceboMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Suharno 1993 63 11.3 (0.52) 62 10.5 (0.51) 50.5 % 0.80 [ 0.62, 0.98 ]

Sun 2010 44 11.8 (0.77) 46 9.9 (0.55) 49.5 % 1.90 [ 1.62, 2.18 ]

Total (95% CI) 107 108 100.0 % 1.34 [ 0.27, 2.42 ]

Heterogeneity: Tau2 = 0.59; Chi2 = 42.40, df = 1 (P<0.00001); I2 =98%

Test for overall effect: Z = 2.45 (P = 0.014)


-10 -5 0 5 10

Favours placebo Favours oral iron



Analysis 1.3. Comparison 1 Oral iron versus placebo, Outcome 3 Ferritin levels (ug/l).



Outcome: 3 Ferritin levels (ug/l)



Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Suharno 1993 63 3.3 (0.5) 62 2.6 (0.5) 100.0 % 0.70 [ 0.52, 0.88 ]

Total (95% CI) 63 62 100.0 % 0.70 [ 0.52, 0.88 ]




-10 -5 0 5 10


Analysis 1.4. Comparison 1 Oral iron versus placebo, Outcome 4 Serum iron (mg/l).



Outcome: 4 Serum iron (mg/l)



Difference


Suharno 1993 63 0.43 (0.04) 62 0.39 (0.02) 100.0 % 0.04 [ 0.03, 0.05 ]

Total (95% CI) 63 62 100.0 % 0.04 [ 0.03, 0.05 ]




-10 -5 0 5 10




Analysis 1.5. Comparison 1 Oral iron versus placebo, Outcome 5 Side effects.



Outcome: 5 Side effects



Symonds 1969 7/24 4/27 100.0 % 1.97 [ 0.66, 5.91 ]

Total (95% CI) 24 27 100.0 % 1.97 [ 0.66, 5.91 ]





0.1 0.2 0.5 1 2 5 10


Analysis 1.6. Comparison 1 Oral iron versus placebo, Outcome 6 Nausea and vomiting.



Outcome: 6 Nausea and vomiting



Symonds 1969 4/24 1/27 100.0 % 4.50 [ 0.54, 37.54 ]

Total (95% CI) 24 27 100.0 % 4.50 [ 0.54, 37.54 ]





0.01 0.1 1 10 100




Analysis 1.7. Comparison 1 Oral iron versus placebo, Outcome 7 Constipation.



Outcome: 7 Constipation



Symonds 1969 4/24 4/27 100.0 % 1.13 [ 0.32, 4.01 ]

Total (95% CI) 24 27 100.0 % 1.13 [ 0.32, 4.01 ]





0.1 0.2 0.5 1 2 5 10


Analysis 1.8. Comparison 1 Oral iron versus placebo, Outcome 8 Abdominal cramps.



Outcome: 8 Abdominal cramps



Symonds 1969 2/24 0/27 100.0 % 5.60 [ 0.28, 111.15 ]

Total (95% CI) 24 27 100.0 % 5.60 [ 0.28, 111.15 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 2.1. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 1 Anaemic during 2nd trimester.


Comparison: 2 Oral iron + vitamin A versus placebo

Outcome: 1 Anaemic during 2nd trimester

Study or subgroup Oral iron + vit A Placebo Risk Ratio Weight Risk Ratio


Suharno 1993 2/63 52/62 100.0 % 0.04 [ 0.01, 0.15 ]

Total (95% CI) 63 62 100.0 % 0.04 [ 0.01, 0.15 ]

Total events: 2 (Oral iron + vit A), 52 (Placebo)




0.1 0.2 0.5 1 2 5 10

Favours iron + vit A Favours placebo

Analysis 2.2. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 2 Haemoglobin levels (g/dL).



Outcome: 2 Haemoglobin levels (g/dL)

Study or subgroup Oral iron + vit A PlaceboMean


Difference


Suharno 1993 63 11.8 (0.55) 62 10.5 (0.51) 100.0 % 1.30 [ 1.11, 1.49 ]

Total (95% CI) 63 62 100.0 % 1.30 [ 1.11, 1.49 ]




-10 -5 0 5 10

Favours placebo Favours iron + vit A



Analysis 2.3. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 3 Ferritin levels (ug/l).



Outcome: 3 Ferritin levels (ug/l)



Difference


Suharno 1993 63 3.3 (0.5) 62 2.6 (0.5) 100.0 % 0.70 [ 0.52, 0.88 ]

Total (95% CI) 63 62 100.0 % 0.70 [ 0.52, 0.88 ]




-10 -5 0 5 10


Analysis 2.4. Comparison 2 Oral iron + vitamin A versus placebo, Outcome 4 Serum iron (mg/l).



Outcome: 4 Serum iron (mg/l)



Difference


Suharno 1993 63 0.47 (0.04) 62 0.39 (0.02) 100.0 % 0.08 [ 0.07, 0.09 ]

Total (95% CI) 63 62 100.0 % 0.08 [ 0.07, 0.09 ]




-10 -5 0 5 10




Analysis 3.1. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 1 Side effects.


Comparison: 3 Controlled-release oral iron versus regular oral iron


Study or subgroup Ctrl release iron Regular oral iron Risk Ratio Weight Risk Ratio


Symonds 1969 7/25 7/24 100.0 % 0.96 [ 0.40, 2.33 ]

Total (95% CI) 25 24 100.0 % 0.96 [ 0.40, 2.33 ]

Total events: 7 (Ctrl release iron), 7 (Regular oral iron)




0.1 0.2 0.5 1 2 5 10

Favours ctrl rel Fe Favours reg oral Fe

Analysis 3.2. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 2 Nausea and

vomiting.



Outcome: 2 Nausea and vomiting



Symonds 1969 4/25 4/24 100.0 % 0.96 [ 0.27, 3.41 ]

Total (95% CI) 25 24 100.0 % 0.96 [ 0.27, 3.41 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.3. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 3 Constipation.






Symonds 1969 1/25 4/24 100.0 % 0.24 [ 0.03, 2.00 ]

Total (95% CI) 25 24 100.0 % 0.24 [ 0.03, 2.00 ]





0.01 0.1 1 10 100


Analysis 3.4. Comparison 3 Controlled-release oral iron versus regular oral iron, Outcome 4 Abdominal

cramps.






Symonds 1969 1/25 2/24 100.0 % 0.48 [ 0.05, 4.95 ]

Total (95% CI) 25 24 100.0 % 0.48 [ 0.05, 4.95 ]





0.01 0.1 1 10 100




Analysis 4.1. Comparison 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran, Outcome 1

Pain at injection site.


Comparison: 4 Intramuscular iron sorbito-citric acid versus intramuscular dextran

Outcome: 1 Pain at injection site

Study or subgroup IM iron sorb-cit IM iron dextran Risk Ratio Weight Risk Ratio


Dawson 1965 13/25 12/23 100.0 % 1.00 [ 0.58, 1.72 ]

Total (95% CI) 25 23 100.0 % 1.00 [ 0.58, 1.72 ]

Total events: 13 (IM iron sorb-cit), 12 (IM iron dextran)




0.1 0.2 0.5 1 2 5 10

Favours IM sorb-cit Favours IM dextran


Skin discolouration at injection site.



Outcome: 2 Skin discolouration at injection site



Dawson 1965 3/25 13/23 100.0 % 0.21 [ 0.07, 0.65 ]

Total (95% CI) 25 23 100.0 % 0.21 [ 0.07, 0.65 ]





0.01 0.1 1 10 100





Venous thrombosis.



Outcome: 3 Venous thrombosis

Study or subgroup IM iron sorb-cit IM iron dextran Risk Ratio Risk Ratio


Dawson 1965 0/25 0/23 0.0 [ 0.0, 0.0 ]

Total (95% CI) 25 23 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10



Nausea or vomiting.



Outcome: 4 Nausea or vomiting



Dawson 1965 1/25 1/23 100.0 % 0.92 [ 0.06, 13.87 ]

Total (95% CI) 25 23 100.0 % 0.92 [ 0.06, 13.87 ]





0.01 0.1 1 10 100





Headaches.



Outcome: 5 Headaches



Dawson 1965 1/25 7/23 100.0 % 0.13 [ 0.02, 0.99 ]

Total (95% CI) 25 23 100.0 % 0.13 [ 0.02, 0.99 ]





0.01 0.1 1 10 100



Shivering.



Outcome: 6 Shivering



Dawson 1965 0/25 1/23 100.0 % 0.31 [ 0.01, 7.20 ]

Total (95% CI) 25 23 100.0 % 0.31 [ 0.01, 7.20 ]





0.01 0.1 1 10 100





Itching.



Outcome: 7 Itching



Dawson 1965 4/25 4/23 100.0 % 0.92 [ 0.26, 3.26 ]

Total (95% CI) 25 23 100.0 % 0.92 [ 0.26, 3.26 ]





0.1 0.2 0.5 1 2 5 10

Favours iron sorb-ci Favours IM dextran


Metallic taste in mouth.



Outcome: 8 Metallic taste in mouth



Dawson 1965 4/25 1/23 100.0 % 3.68 [ 0.44, 30.56 ]

Total (95% CI) 25 23 100.0 % 3.68 [ 0.44, 30.56 ]





0.01 0.1 1 10 100

Favours iron sorb-ci Favours IM dextran



Analysis 5.1. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 1 Pain at

injection site.


Comparison: 5 Intramuscular iron dextran versus intravenous iron dextran


Study or subgroup IM iron dextran IV iron dextran Risk Ratio Weight Risk Ratio


Dawson 1965 12/23 3/26 100.0 % 4.52 [ 1.45, 14.05 ]

Total (95% CI) 23 26 100.0 % 4.52 [ 1.45, 14.05 ]

Total events: 12 (IM iron dextran), 3 (IV iron dextran)




0.01 0.1 1 10 100

Favours IM dextran Favours IV dextran

Analysis 5.2. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 2 Skin

discolouration at injection site.






Dawson 1965 13/23 1/26 100.0 % 14.70 [ 2.08, 103.81 ]

Total (95% CI) 23 26 100.0 % 14.70 [ 2.08, 103.81 ]





0.001 0.01 0.1 1 10 100 1000

Fvaours IM dextran Favours IV dextran



Analysis 5.3. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 3 Venous

thrombosis.






Dawson 1965 0/23 4/26 100.0 % 0.13 [ 0.01, 2.20 ]

Total (95% CI) 23 26 100.0 % 0.13 [ 0.01, 2.20 ]





0.001 0.01 0.1 1 10 100 1000


Analysis 5.4. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 4

Nausea or vomiting.






Dawson 1965 1/23 2/26 100.0 % 0.57 [ 0.05, 5.83 ]

Total (95% CI) 23 26 100.0 % 0.57 [ 0.05, 5.83 ]





0.01 0.1 1 10 100





Headaches.






Dawson 1965 7/23 2/26 100.0 % 3.96 [ 0.91, 17.17 ]

Total (95% CI) 23 26 100.0 % 3.96 [ 0.91, 17.17 ]





0.01 0.1 1 10 100



Shivering.






Dawson 1965 1/23 2/26 100.0 % 0.57 [ 0.05, 5.83 ]

Total (95% CI) 23 26 100.0 % 0.57 [ 0.05, 5.83 ]





0.01 0.1 1 10 100




Analysis 5.7. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 7 Itching.



Outcome: 7 Itching



Dawson 1965 4/23 3/26 100.0 % 1.51 [ 0.38, 6.04 ]

Total (95% CI) 23 26 100.0 % 1.51 [ 0.38, 6.04 ]





0.1 0.2 0.5 1 2 5 10



Metallic taste in mouth.






Dawson 1965 1/23 1/26 100.0 % 1.13 [ 0.07, 17.07 ]

Total (95% CI) 23 26 100.0 % 1.13 [ 0.07, 17.07 ]





0.01 0.1 1 10 100




Analysis 5.9. Comparison 5 Intramuscular iron dextran versus intravenous iron dextran, Outcome 9 Severe

delayed allergic reaction.



Outcome: 9 Severe delayed allergic reaction



Sood 1979 0/30 2/32 100.0 % 0.21 [ 0.01, 4.26 ]

Total (95% CI) 30 32 100.0 % 0.21 [ 0.01, 4.26 ]





0.01 0.1 1 10 100


Analysis 6.1. Comparison 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran,

Outcome 1 Pain at injection site.


Comparison: 6 Intramuscular iron sorbitol citric acid versus intravenous iron dextran


Study or subgroup IM iron sorb-cit IV iron dextran Risk Ratio Weight Risk Ratio


Dawson 1965 13/25 3/26 100.0 % 4.51 [ 1.46, 13.94 ]

Total (95% CI) 25 26 100.0 % 4.51 [ 1.46, 13.94 ]

Total events: 13 (IM iron sorb-cit), 3 (IV iron dextran)




0.01 0.1 1 10 100

Favours IM sorb-cit Favours IV dextran




Outcome 2 Skin discolouration at injection site.






Dawson 1965 3/25 1/26 100.0 % 3.12 [ 0.35, 28.03 ]

Total (95% CI) 25 26 100.0 % 3.12 [ 0.35, 28.03 ]





0.01 0.1 1 10 100



Outcome 3 Venous thrombosis.






Dawson 1965 0/25 4/26 100.0 % 0.12 [ 0.01, 2.04 ]

Total (95% CI) 25 26 100.0 % 0.12 [ 0.01, 2.04 ]





0.001 0.01 0.1 1 10 100 1000





Outcome 4 Nausea or vomiting.






Dawson 1965 1/25 2/26 100.0 % 0.52 [ 0.05, 5.38 ]

Total (95% CI) 25 26 100.0 % 0.52 [ 0.05, 5.38 ]





0.01 0.1 1 10 100



Outcome 5 Headaches.






Dawson 1965 1/25 2/26 100.0 % 0.52 [ 0.05, 5.38 ]

Total (95% CI) 25 26 100.0 % 0.52 [ 0.05, 5.38 ]





0.01 0.1 1 10 100





Outcome 6 Shivering.






Dawson 1965 0/25 2/26 100.0 % 0.21 [ 0.01, 4.12 ]

Total (95% CI) 25 26 100.0 % 0.21 [ 0.01, 4.12 ]





0.01 0.1 1 10 100



Outcome 7 Itching.



Outcome: 7 Itching



Dawson 1965 4/25 3/26 100.0 % 1.39 [ 0.34, 5.58 ]

Total (95% CI) 25 26 100.0 % 1.39 [ 0.34, 5.58 ]





0.1 0.2 0.5 1 2 5 10





Outcome 8 Metallic taste in mouth.






Dawson 1965 4/25 1/26 100.0 % 4.16 [ 0.50, 34.71 ]

Total (95% CI) 25 26 100.0 % 4.16 [ 0.50, 34.71 ]





0.01 0.1 1 10 100


Analysis 7.1. Comparison 7 Intravenous iron versus placebo, Outcome 1 Side effects.


Comparison: 7 Intravenous iron versus placebo


Study or subgroup IV iron Placebo Risk Ratio Weight Risk Ratio


Symonds 1969 3/27 4/27 100.0 % 0.75 [ 0.19, 3.04 ]

Total (95% CI) 27 27 100.0 % 0.75 [ 0.19, 3.04 ]

Total events: 3 (IV iron), 4 (Placebo)




0.1 0.2 0.5 1 2 5 10

Favours IV iron Favours placebo



Analysis 7.2. Comparison 7 Intravenous iron versus placebo, Outcome 2 Nausea or vomiting.






Symonds 1969 0/27 1/27 100.0 % 0.33 [ 0.01, 7.84 ]

Total (95% CI) 27 27 100.0 % 0.33 [ 0.01, 7.84 ]





0.01 0.1 1 10 100


Analysis 7.3. Comparison 7 Intravenous iron versus placebo, Outcome 3 Constipation.






Symonds 1969 1/27 4/27 100.0 % 0.25 [ 0.03, 2.09 ]

Total (95% CI) 27 27 100.0 % 0.25 [ 0.03, 2.09 ]





0.01 0.1 1 10 100




Analysis 7.4. Comparison 7 Intravenous iron versus placebo, Outcome 4 Abdominal cramps.




Study or subgroup IV iron Placebo Risk Ratio Risk Ratio


Symonds 1969 0/27 0/27 0.0 [ 0.0, 0.0 ]

Total (95% CI) 27 27 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.1. Comparison 8 Intravenous iron versus regular oral iron, Outcome 1 Side effects.


Comparison: 8 Intravenous iron versus regular oral iron


Study or subgroup IV iron Oral regular iron Risk Ratio Weight Risk Ratio


Symonds 1969 3/27 7/24 100.0 % 0.38 [ 0.11, 1.31 ]

Total (95% CI) 27 24 100.0 % 0.38 [ 0.11, 1.31 ]

Total events: 3 (IV iron), 7 (Oral regular iron)




0.1 0.2 0.5 1 2 5 10

Favours IV iron Favours oral iron



Analysis 8.2. Comparison 8 Intravenous iron versus regular oral iron, Outcome 2 Nausea or vomiting or

epigastric discomfort.



Outcome: 2 Nausea or vomiting or epigastric discomfort



Al 2005 6/45 13/45 61.9 % 0.46 [ 0.19, 1.11 ]

Singh 1998 0/50 3/50 16.7 % 0.14 [ 0.01, 2.70 ]

Symonds 1969 0/27 4/27 21.4 % 0.11 [ 0.01, 1.97 ]

Total (95% CI) 122 122 100.0 % 0.33 [ 0.15, 0.74 ]


Heterogeneity: Chi2 = 1.41, df = 2 (P = 0.49); I2 =0.0%



0.001 0.01 0.1 1 10 100 1000


Analysis 8.3. Comparison 8 Intravenous iron versus regular oral iron, Outcome 3 Constipation.




Study or subgroup Favours IV iron Oral regular iron Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Singh 1998 0/50 13/50 38.5 % 0.04 [ 0.00, 0.61 ]

Symonds 1969 1/27 4/24 61.5 % 0.22 [ 0.03, 1.85 ]

Total (95% CI) 77 74 100.0 % 0.11 [ 0.02, 0.71 ]

Total events: 1 (Favours IV iron), 17 (Oral regular iron)

Heterogeneity: Tau2 = 0.27; Chi2 = 1.17, df = 1 (P = 0.28); I2 =14%



0.001 0.01 0.1 1 10 100 1000




Analysis 8.4. Comparison 8 Intravenous iron versus regular oral iron, Outcome 4 Abdominal cramps.






Symonds 1969 0/27 2/24 100.0 % 0.18 [ 0.01, 3.54 ]

Total (95% CI) 27 24 100.0 % 0.18 [ 0.01, 3.54 ]





0.001 0.01 0.1 1 10 100 1000


Analysis 8.5. Comparison 8 Intravenous iron versus regular oral iron, Outcome 5 Diarrhoea.



Outcome: 5 Diarrhoea



Al 2005 0/45 4/45 47.2 % 0.11 [ 0.01, 2.01 ]

Bayoumeu 2002 0/24 1/23 16.1 % 0.32 [ 0.01, 7.48 ]

Singh 1998 0/50 3/50 36.7 % 0.14 [ 0.01, 2.70 ]

Total (95% CI) 119 118 100.0 % 0.16 [ 0.03, 0.86 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 8.6. Comparison 8 Intravenous iron versus regular oral iron, Outcome 6 Blood transfusion

required.



Outcome: 6 Blood transfusion required



Al 2005 0/45 1/45 27.1 % 0.33 [ 0.01, 7.97 ]

Bayoumeu 2002 0/24 1/23 27.7 % 0.32 [ 0.01, 7.48 ]

Digumarthi 2008 0/15 2/15 45.2 % 0.20 [ 0.01, 3.85 ]

Total (95% CI) 84 83 100.0 % 0.27 [ 0.05, 1.59 ]





0.01 0.1 1 10 100


Analysis 8.7. Comparison 8 Intravenous iron versus regular oral iron, Outcome 7 Neonates mean

hemoglobin.



Outcome: 7 Neonates mean hemoglobin

Study or subgroup IV iron Oral regular IronMean


Difference


Bayoumeu 2002 24 15.15 (2.1) 23 15.3 (2.17) 100.0 % -0.15 [ -1.37, 1.07 ]

Total (95% CI) 24 23 100.0 % -0.15 [ -1.37, 1.07 ]




-10 -5 0 5 10

Favours oral iron Favours IV iron



Analysis 8.8. Comparison 8 Intravenous iron versus regular oral iron, Outcome 8 Maternal haemoglobin at

birth.



Outcome: 8 Maternal haemoglobin at birth

Study or subgroup IV iron Oral regular ironMean


Difference


Al 2005 45 12.01 (0.88) 45 11.26 (1.1) 100.0 % 0.75 [ 0.34, 1.16 ]

Total (95% CI) 45 45 100.0 % 0.75 [ 0.34, 1.16 ]




-10 -5 0 5 10


Analysis 8.10. Comparison 8 Intravenous iron versus regular oral iron, Outcome 10 Neonates ferritin level.



Outcome: 10 Neonates ferritin level

Study or subgroup IV iron Oral regular IronMean


Difference


Bayoumeu 2002 24 132 (104) 23 134 (107) 100.0 % -2.00 [ -62.36, 58.36 ]

Total (95% CI) 24 23 100.0 % -2.00 [ -62.36, 58.36 ]




-100 -50 0 50 100




Analysis 8.11. Comparison 8 Intravenous iron versus regular oral iron, Outcome 11 Mean maternal

haemoglobin at 4 weeks ( g/dL).



Outcome: 11 Mean maternal haemoglobin at 4 weeks ( g/dL)



Difference


Al 2005 45 11.08 (0.72) 45 10.4 (0.68) 53.2 % 0.68 [ 0.39, 0.97 ]

Bayoumeu 2002 24 11.11 (1.3) 23 11 (1.25) 20.5 % 0.11 [ -0.62, 0.84 ]

Digumarthi 2008 15 10.6 (0.8) 15 10.4 (0.9) 26.3 % 0.20 [ -0.41, 0.81 ]

Total (95% CI) 84 83 100.0 % 0.44 [ 0.05, 0.82 ]




-10 -5 0 5 10


Analysis 8.12. Comparison 8 Intravenous iron versus regular oral iron, Outcome 12 Maternal mortality.



Outcome: 12 Maternal mortality

Study or subgroup IV iron Oral regular iron Risk Ratio Risk Ratio


Singh 1998 0/50 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 50 50 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 8.13. Comparison 8 Intravenous iron versus regular oral iron, Outcome 13 Preterm labour.



Outcome: 13 Preterm labour



Singh 1998 0/50 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 50 50 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.14. Comparison 8 Intravenous iron versus regular oral iron, Outcome 14 Caesarean section.



Outcome: 14 Caesarean section



Al 2005 9/45 12/45 75.0 % 0.75 [ 0.35, 1.60 ]

Singh 1998 5/50 4/50 25.0 % 1.25 [ 0.36, 4.38 ]

Total (95% CI) 95 95 100.0 % 0.88 [ 0.46, 1.67 ]





0.1 0.2 0.5 1 2 5 10




Analysis 8.15. Comparison 8 Intravenous iron versus regular oral iron, Outcome 15 Operative vaginal birth.



Outcome: 15 Operative vaginal birth



Singh 1998 3/50 2/50 100.0 % 1.50 [ 0.26, 8.60 ]

Total (95% CI) 50 50 100.0 % 1.50 [ 0.26, 8.60 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.16. Comparison 8 Intravenous iron versus regular oral iron, Outcome 16 Postpartum

haemorrhage.



Outcome: 16 Postpartum haemorrhage



Bayoumeu 2002 1/24 1/23 12.7 % 0.96 [ 0.06, 14.43 ]

Singh 1998 6/50 7/50 87.3 % 0.86 [ 0.31, 2.37 ]

Total (95% CI) 74 73 100.0 % 0.87 [ 0.34, 2.26 ]





0.01 0.1 1 10 100




Analysis 8.17. Comparison 8 Intravenous iron versus regular oral iron, Outcome 17 Low birthweight (under

2500 g).



Outcome: 17 Low birthweight (under 2500 g)



Singh 1998 0/50 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 50 50 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.18. Comparison 8 Intravenous iron versus regular oral iron, Outcome 18 Neonatal birthweight.



Outcome: 18 Neonatal birthweight



Difference


Al 2005 45 3498 (452) 45 3439 (451) 40.0 % 59.00 [ -127.56, 245.56 ]

Bayoumeu 2002 24 3595 (785) 23 3220 (570) 20.6 % 375.00 [ -16.02, 766.02 ]

Singh 1998 50 2967 (541) 50 3086 (437) 39.3 % -119.00 [ -311.77, 73.77 ]

Total (95% CI) 119 118 100.0 % 54.29 [ -170.11, 278.68 ]




-1000 -500 0 500 1000




Analysis 8.19. Comparison 8 Intravenous iron versus regular oral iron, Outcome 19 Small-for-gestational

age.



Outcome: 19 Small-for-gestational age



Singh 1998 8/50 5/50 100.0 % 1.60 [ 0.56, 4.56 ]

Total (95% CI) 50 50 100.0 % 1.60 [ 0.56, 4.56 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.20. Comparison 8 Intravenous iron versus regular oral iron, Outcome 20 Five minute Apgar

score under seven.



Outcome: 20 Five minute Apgar score under seven



Singh 1998 1/50 1/50 100.0 % 1.00 [ 0.06, 15.55 ]

Total (95% CI) 50 50 100.0 % 1.00 [ 0.06, 15.55 ]





0.01 0.1 1 10 100




Analysis 8.21. Comparison 8 Intravenous iron versus regular oral iron, Outcome 21 Neonatal mortality.



Outcome: 21 Neonatal mortality



Bayoumeu 2002 0/24 0/23 0.0 [ 0.0, 0.0 ]

Singh 1998 0/50 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 74 73 0.0 [ 0.0, 0.0 ]


Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%



0.1 0.2 0.5 1 2 5 10


Analysis 8.22. Comparison 8 Intravenous iron versus regular oral iron, Outcome 22 Haemoglobin level > 12

g/dL at 30 days.



Outcome: 22 Haemoglobin level > 12 g/dL at 30 days



Bayoumeu 2002 3/24 4/23 100.0 % 0.72 [ 0.18, 2.87 ]

Total (95% CI) 24 23 100.0 % 0.72 [ 0.18, 2.87 ]





0.1 0.2 0.5 1 2 5 10




Analysis 8.23. Comparison 8 Intravenous iron versus regular oral iron, Outcome 23 Gestational

hypertension.



Outcome: 23 Gestational hypertension



Al 2005 2/45 0/45 100.0 % 5.00 [ 0.25, 101.31 ]

Total (95% CI) 45 45 100.0 % 5.00 [ 0.25, 101.31 ]





0.001 0.01 0.1 1 10 100 1000


Analysis 8.24. Comparison 8 Intravenous iron versus regular oral iron, Outcome 24 Gestational diabetes.



Outcome: 24 Gestational diabetes



Al 2005 0/45 2/45 100.0 % 0.20 [ 0.01, 4.05 ]

Total (95% CI) 45 45 100.0 % 0.20 [ 0.01, 4.05 ]





0.001 0.01 0.1 1 10 100 1000

Favours IV iron Favours oral



Analysis 8.25. Comparison 8 Intravenous iron versus regular oral iron, Outcome 25 Haemoglobin level > 11

g/dL at birth.



Outcome: 25 Haemoglobin level > 11 g/dL at birth



Al 2005 43/45 28/45 100.0 % 1.54 [ 1.21, 1.94 ]

Total (95% CI) 45 45 100.0 % 1.54 [ 1.21, 1.94 ]





0.1 0.2 0.5 1 2 5 10


Analysis 8.26. Comparison 8 Intravenous iron versus regular oral iron, Outcome 26 Severe delayed allergic

reaction.



Outcome: 26 Severe delayed allergic reaction



Sood 1979 2/32 0/35 100.0 % 5.45 [ 0.27, 109.49 ]

Total (95% CI) 32 35 100.0 % 5.45 [ 0.27, 109.49 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 8.27. Comparison 8 Intravenous iron versus regular oral iron, Outcome 27 Arthralgia.



Outcome: 27 Arthralgia



Al 2005 1/45 1/45 100.0 % 1.00 [ 0.06, 15.50 ]

Total (95% CI) 45 45 100.0 % 1.00 [ 0.06, 15.50 ]





0.01 0.1 1 10 100


Analysis 9.1. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 1 Side effects.


Comparison: 9 Intravenous iron versus controlled-release oral iron


Study or subgroup IV iron Control release iron Risk Ratio Weight Risk Ratio


Symonds 1969 3/27 7/25 100.0 % 0.40 [ 0.12, 1.37 ]

Total (95% CI) 27 25 100.0 % 0.40 [ 0.12, 1.37 ]

Total events: 3 (IV iron), 7 (Control release iron)




0.1 0.2 0.5 1 2 5 10

Favours IV iron Favours ctrl rel Fe



Analysis 9.2. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 2 Nausea or

vomiting.






Symonds 1969 0/27 4/25 100.0 % 0.10 [ 0.01, 1.82 ]

Total (95% CI) 27 25 100.0 % 0.10 [ 0.01, 1.82 ]





0.001 0.01 0.1 1 10 100 1000


Analysis 9.3. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 3 Constipation.






Symonds 1969 1/27 1/25 100.0 % 0.93 [ 0.06, 14.03 ]

Total (95% CI) 27 25 100.0 % 0.93 [ 0.06, 14.03 ]





0.01 0.1 1 10 100




Analysis 9.4. Comparison 9 Intravenous iron versus controlled-release oral iron, Outcome 4 Abdominal

cramps.






Symonds 1969 0/27 1/25 100.0 % 0.31 [ 0.01, 7.26 ]

Total (95% CI) 27 25 100.0 % 0.31 [ 0.01, 7.26 ]





0.01 0.1 1 10 100


Analysis 10.1. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 1

Allergic reaction during infusion.


Comparison: 10 2/3 dose intravenous iron versus full dose intravenous iron

Outcome: 1 Allergic reaction during infusion

Study or subgroup 2/3 dose IV iron Full dose IV iron Risk Ratio Weight Risk Ratio


Kaisi 1988 15/309 23/314 100.0 % 0.66 [ 0.35, 1.25 ]

Total (95% CI) 309 314 100.0 % 0.66 [ 0.35, 1.25 ]

Total events: 15 (2/3 dose IV iron), 23 (Full dose IV iron)




0.1 0.2 0.5 1 2 5 10

Favours 2/3 dose Favours full dose




Allergic reaction after infusion.



Outcome: 2 Allergic reaction after infusion



Kaisi 1988 47/309 77/314 100.0 % 0.62 [ 0.45, 0.86 ]

Total (95% CI) 309 314 100.0 % 0.62 [ 0.45, 0.86 ]





0.1 0.2 0.5 1 2 5 10


Analysis 10.3. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 3 Life-

threatening allergic reaction during infusion.



Outcome: 3 Life-threatening allergic reaction during infusion



Kaisi 1988 5/309 2/314 100.0 % 2.54 [ 0.50, 13.00 ]

Total (95% CI) 309 314 100.0 % 2.54 [ 0.50, 13.00 ]





0.01 0.1 1 10 100





Discomfort needing analgesics after infusion.



Outcome: 4 Discomfort needing analgesics after infusion



Kaisi 1988 15/309 31/314 100.0 % 0.49 [ 0.27, 0.89 ]

Total (95% CI) 309 314 100.0 % 0.49 [ 0.27, 0.89 ]





0.1 0.2 0.5 1 2 5 10



Immobilised by painful joints.



Outcome: 5 Immobilised by painful joints



Kaisi 1988 7/309 9/314 100.0 % 0.79 [ 0.30, 2.10 ]

Total (95% CI) 309 314 100.0 % 0.79 [ 0.30, 2.10 ]





0.1 0.2 0.5 1 2 5 10




Analysis 10.6. Comparison 10 2/3 dose intravenous iron versus full dose intravenous iron, Outcome 6 Non-

live births.



Outcome: 6 Non-live births



Kaisi 1988 9/248 11/259 100.0 % 0.85 [ 0.36, 2.03 ]

Total (95% CI) 248 259 100.0 % 0.85 [ 0.36, 2.03 ]





0.1 0.2 0.5 1 2 5 10



Neonatal death.



Outcome: 7 Neonatal death



Kaisi 1988 3/248 6/259 100.0 % 0.52 [ 0.13, 2.07 ]

Total (95% CI) 248 259 100.0 % 0.52 [ 0.13, 2.07 ]





0.1 0.2 0.5 1 2 5 10





Stillbirth.



Outcome: 8 Stillbirth



Kaisi 1988 6/248 9/259 100.0 % 0.70 [ 0.25, 1.93 ]

Total (95% CI) 248 259 100.0 % 0.70 [ 0.25, 1.93 ]





0.1 0.2 0.5 1 2 5 10



Spontaneous abortion.



Outcome: 9 Spontaneous abortion



Kaisi 1988 3/248 1/259 100.0 % 3.13 [ 0.33, 29.92 ]

Total (95% CI) 248 259 100.0 % 3.13 [ 0.33, 29.92 ]





0.01 0.1 1 10 100




Analysis 11.1. Comparison 11 Intravenous iron sucrose with adjuvant recombinant human erythropoietin

versus intravenous iron sucrose, Outcome 1 Hb < 11 g/dL at 4 weeks.


Comparison: 11 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose

Outcome: 1 Hb < 11 g/dL at 4 weeks

Study or subgrouprhEPO +IVFe sucrose IV Fe sucrose Risk Ratio Weight Risk Ratio


Breymann 2001 1/20 5/20 100.0 % 0.20 [ 0.03, 1.56 ]

Total (95% CI) 20 20 100.0 % 0.20 [ 0.03, 1.56 ]

Total events: 1 (rhEPO +IV Fe sucrose), 5 (IV Fe sucrose)




0.01 0.1 1 10 100

Favours rhEPO+IV Fe Favours IV Fe


versus intravenous iron sucrose, Outcome 2 Mean corpuscular volume.



Outcome: 2 Mean corpuscular volume

Study or subgrouprhEPO +IVFe sucrose IV Fe sucrose

MeanDifference Weight

MeanDifference


Breymann 2001 20 91.1 (4.3) 20 84.8 (6.3) 100.0 % 6.30 [ 2.96, 9.64 ]

Total (95% CI) 20 20 100.0 % 6.30 [ 2.96, 9.64 ]




-10 -5 0 5 10

Favours IV Fe Favours rhEPO+IV Fe




versus intravenous iron sucrose, Outcome 3 Caesarean section.






Breymann 2001 6/20 6/20 100.0 % 1.00 [ 0.39, 2.58 ]

Total (95% CI) 20 20 100.0 % 1.00 [ 0.39, 2.58 ]





0.1 0.2 0.5 1 2 5 10



versus intravenous iron sucrose, Outcome 4 Metallic taste.



Outcome: 4 Metallic taste



Breymann 2001 1/20 2/20 100.0 % 0.50 [ 0.05, 5.08 ]

Total (95% CI) 20 20 100.0 % 0.50 [ 0.05, 5.08 ]





0.01 0.1 1 10 100





versus intravenous iron sucrose, Outcome 5 Warm feeling.



Outcome: 5 Warm feeling



Breymann 2001 1/20 1/20 100.0 % 1.00 [ 0.07, 14.90 ]

Total (95% CI) 20 20 100.0 % 1.00 [ 0.07, 14.90 ]





0.01 0.1 1 10 100



versus intravenous iron sucrose, Outcome 6 Birthweight.



Outcome: 6 Birthweight

Study or subgroup Iron + EPO IronMean


Difference


Breymann 2001 20 3332 (282) 20 3462 (497) 100.0 % -130.00 [ -380.44, 120.44 ]

Total (95% CI) 20 20 100.0 % -130.00 [ -380.44, 120.44 ]




-10 -5 0 5 10

Favours treatment Favours control




versus intravenous iron sucrose, Outcome 7 Birth < 37 weeks.



Outcome: 7 Birth < 37 weeks

Study or subgroup Iron + EPO Iron Risk Ratio Weight Risk Ratio


Breymann 2001 0/20 1/20 100.0 % 0.33 [ 0.01, 7.72 ]

Total (95% CI) 20 20 100.0 % 0.33 [ 0.01, 7.72 ]

Total events: 0 (Iron + EPO), 1 (Iron)




0.1 0.2 0.5 1 2 5 10



versus intravenous iron sucrose, Outcome 8 Maternal mean blood pressure.



Outcome: 8 Maternal mean blood pressure

Study or subgroup Iron + EPO IronMean


Difference


Breymann 2001 20 75.8 (8.3) 20 76 (7.2) 100.0 % -0.20 [ -5.02, 4.62 ]

Total (95% CI) 20 20 100.0 % -0.20 [ -5.02, 4.62 ]




-10 -5 0 5 10





versus intravenous iron sucrose, Outcome 9 Need transfusion.



Outcome: 9 Need transfusion

Study or subgroup Iron + EPO Iron Risk Ratio Risk Ratio


Breymann 2001 0/20 0/20 0.0 [ 0.0, 0.0 ]

Total (95% CI) 20 20 0.0 [ 0.0, 0.0 ]

Total events: 0 (Iron + EPO), 0 (Iron)




0.1 0.2 0.5 1 2 5 10


Analysis 12.1. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 1 Not

anaemic at term.


Comparison: 12 Intramuscular iron sorbitol citric acid versus oral iron

Outcome: 1 Not anaemic at term

Study or subgroup IM iron Oral iron Risk Ratio Weight Risk Ratio


Zutschi 2004 76/100 62/100 100.0 % 1.23 [ 1.01, 1.48 ]

Total (95% CI) 100 100 100.0 % 1.23 [ 1.01, 1.48 ]

Total events: 76 (IM iron), 62 (Oral iron)




0.1 0.2 0.5 1 2 5 10

Favours oral iron Favours IM iron



Analysis 12.2. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 2 Mean

maternal haemoglobin at birth.



Outcome: 2 Mean maternal haemoglobin at birth

Study or subgroup IM iron Oral ironMean


Difference


Zutschi 2004 100 10.5 (0.84) 100 9.96 (0.89) 100.0 % 0.54 [ 0.30, 0.78 ]

Total (95% CI) 100 100 100.0 % 0.54 [ 0.30, 0.78 ]




-10 -5 0 5 10


Analysis 12.3. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 3 Mean

maternal hematocrit level at birth.



Outcome: 3 Mean maternal hematocrit level at birth

Study or subgroup IM iron Oral ironMean


Difference


Zutschi 2004 100 31.2 (2.6) 100 29.8 (2.7) 100.0 % 1.40 [ 0.67, 2.13 ]

Total (95% CI) 100 100 100.0 % 1.40 [ 0.67, 2.13 ]




-10 -5 0 5 10




Analysis 12.4. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 4 Caesarean

section.




Study or subgroup IM iron Oral iron Risk Ratio Weight Risk Ratio


Zutschi 2004 24/100 22/100 100.0 % 1.09 [ 0.66, 1.81 ]

Total (95% CI) 100 100 100.0 % 1.09 [ 0.66, 1.81 ]

Total events: 24 (IM iron), 22 (Oral iron)




0.1 0.2 0.5 1 2 5 10

Favours IM iron Favours oral iron

Analysis 12.5. Comparison 12 Intramuscular iron sorbitol citric acid versus oral iron, Outcome 5

Haematocrit (%) at 4 weeks of treatment.



Outcome: 5 Haematocrit (%) at 4 weeks of treatment

Study or subgroup IM iron Oral iron (600 mg)Mean


Difference


Ogunbode 1980 28 32.5 (2.65) 28 31.25 (2.22) 100.0 % 1.25 [ -0.03, 2.53 ]

Total (95% CI) 28 28 100.0 % 1.25 [ -0.03, 2.53 ]




-10 -5 0 5 10











Difference


Ogunbode 1980 31 35.29 (3.6) 28 32.67 (1.3) 100.0 % 2.62 [ 1.26, 3.98 ]

Total (95% CI) 31 28 100.0 % 2.62 [ 1.26, 3.98 ]




-10 -5 0 5 10









Difference


Ogunbode 1980 28 32.5 (2.65) 28 31.25 (2.22) 100.0 % 1.25 [ -0.03, 2.53 ]

Total (95% CI) 28 28 100.0 % 1.25 [ -0.03, 2.53 ]




-10 -5 0 5 10











Difference


Ogunbode 1980 31 35.29 (3.6) 28 32.69 (2.53) 100.0 % 2.60 [ 1.02, 4.18 ]

Total (95% CI) 31 28 100.0 % 2.60 [ 1.02, 4.18 ]




-10 -5 0 5 10


Analysis 13.1. Comparison 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid, Outcome

1 Haematocrit.


Comparison: 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid

Outcome: 1 Haematocrit

Study or subgroup IM iron dextran Oral Fe+vitC+folic aMean


Difference


Komolafe 2003 30 32.67 (1.58) 30 28.2 (1.58) 100.0 % 4.47 [ 3.67, 5.27 ]

Total (95% CI) 30 30 100.0 % 4.47 [ 3.67, 5.27 ]




-10 -5 0 5 10

Favours Fe+vitC+FA Favours IM iron



Analysis 13.2. Comparison 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid, Outcome

2 Not anaemic at 6 weeks (packed cell volume > 33%).


Comparison: 13 Intramuscular iron dextran versus oral iron + vitamin C + folic acid

Outcome: 2 Not anaemic at 6 weeks (packed cell volume > 33%)

Study or subgroup IM iron dextran Oral Fe+vitC+folic a Risk Ratio Weight Risk Ratio


Komolafe 2003 11/30 1/30 100.0 % 11.00 [ 1.51, 79.96 ]

Total (95% CI) 30 30 100.0 % 11.00 [ 1.51, 79.96 ]

Total events: 11 (IM iron dextran), 1 (Oral Fe+vitC+folic a)




0.01 0.1 1 10 100

Favours Fe+vitC+FA Favours IM iron


Mean haemoglobin at 36 weeks.


Comparison: 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid

Outcome: 1 Mean haemoglobin at 36 weeks

Study or subgroup IM iron Oral iron+folic acMean


Difference


Kumar 2005 75 10.94 (0.56) 75 11.2 (0.82) 100.0 % -0.26 [ -0.48, -0.04 ]

Total (95% CI) 75 75 100.0 % -0.26 [ -0.48, -0.04 ]




-10 -5 0 5 10

Favours oral Fe+FA Favours IM iron




Haemoglobin > 11 g/dL at 36 weeks.



Outcome: 2 Haemoglobin > 11 g/dL at 36 weeks

Study or subgroup IM iron Oral iron+folic acid Risk Ratio Weight Risk Ratio


Kumar 2005 42/75 51/75 100.0 % 0.82 [ 0.64, 1.06 ]

Total (95% CI) 75 75 100.0 % 0.82 [ 0.64, 1.06 ]

Total events: 42 (IM iron), 51 (Oral iron+folic acid)




0.1 0.2 0.5 1 2 5 10



Caesarean section.






Kumar 2005 5/75 3/75 100.0 % 1.67 [ 0.41, 6.73 ]

Total (95% CI) 75 75 100.0 % 1.67 [ 0.41, 6.73 ]





0.1 0.2 0.5 1 2 5 10

Favours IM iron Favours oral Fe+FA




Mean birthweight (kg).



Outcome: 4 Mean birthweight (kg)

Study or subgroup IM Iron Oral iron+folic acidMean


Difference


Kumar 2005 75 2610 (420) 75 2630 (480) 100.0 % -20.00 [ -164.35, 124.35 ]

Total (95% CI) 75 75 100.0 % -20.00 [ -164.35, 124.35 ]




-1000 -500 0 500 1000

Favours oral Fe+FA Favours IM iron


Diarrhoea.



Outcome: 5 Diarrhoea



Kumar 2005 0/75 5/75 100.0 % 0.09 [ 0.01, 1.62 ]

Total (95% CI) 75 75 100.0 % 0.09 [ 0.01, 1.62 ]





0.001 0.01 0.1 1 10 100 1000





Constipation.






Kumar 2005 0/75 8/75 100.0 % 0.06 [ 0.00, 1.00 ]

Total (95% CI) 75 75 100.0 % 0.06 [ 0.00, 1.00 ]





0.001 0.01 0.1 1 10 100 1000



Dyspepsia.



Outcome: 7 Dyspepsia



Kumar 2005 0/75 9/75 100.0 % 0.05 [ 0.00, 0.89 ]

Total (95% CI) 75 75 100.0 % 0.05 [ 0.00, 0.89 ]





0.001 0.01 0.1 1 10 100 1000





Local site mainly pain.



Outcome: 8 Local site mainly pain



Kumar 2005 62/75 0/75 100.0 % 125.00 [ 7.87, 1984.19 ]

Total (95% CI) 75 75 100.0 % 125.00 [ 7.87, 1984.19 ]





0.001 0.01 0.1 1 10 100 1000



Staining.



Outcome: 9 Staining



Kumar 2005 56/75 0/75 100.0 % 113.00 [ 7.11, 1795.82 ]

Total (95% CI) 75 75 100.0 % 113.00 [ 7.11, 1795.82 ]





0.001 0.01 0.1 1 10 100 1000




Analysis 14.10. Comparison 14 Intramuscular iron sorbitol citric acid versus oral iron + folic acid, Outcome

10 Arthralgia.



Outcome: 10 Arthralgia



Kumar 2005 6/75 0/75 100.0 % 13.00 [ 0.75, 226.73 ]

Total (95% CI) 75 75 100.0 % 13.00 [ 0.75, 226.73 ]





0.001 0.01 0.1 1 10 100 1000



11 Itching and rash.



Outcome: 11 Itching and rash



Kumar 2005 14/75 0/75 100.0 % 29.00 [ 1.76, 477.47 ]

Total (95% CI) 75 75 100.0 % 29.00 [ 1.76, 477.47 ]





0.001 0.01 0.1 1 10 100 1000





12 Fever.



Outcome: 12 Fever



Kumar 2005 8/75 0/75 100.0 % 17.00 [ 1.00, 289.34 ]

Total (95% CI) 75 75 100.0 % 17.00 [ 1.00, 289.34 ]





0.001 0.01 0.1 1 10 100 1000



13 Malaise.



Outcome: 13 Malaise



Kumar 2005 7/75 0/75 100.0 % 15.00 [ 0.87, 258.02 ]

Total (95% CI) 75 75 100.0 % 15.00 [ 0.87, 258.02 ]





0.001 0.01 0.1 1 10 100 1000





14 Vaso-vagal due to apprehension.



Outcome: 14 Vaso-vagal due to apprehension



Kumar 2005 4/75 0/75 100.0 % 9.00 [ 0.49, 164.29 ]

Total (95% CI) 75 75 100.0 % 9.00 [ 0.49, 164.29 ]





0.001 0.01 0.1 1 10 100 1000



15 Systemic ache.



Outcome: 15 Systemic ache



Kumar 2005 11/75 0/75 100.0 % 23.00 [ 1.38, 383.37 ]

Total (95% CI) 75 75 100.0 % 23.00 [ 1.38, 383.37 ]





0.001 0.01 0.1 1 10 100 1000





16 Haemoglobin > 12 g/dL at 36 weeks.



Outcome: 16 Haemoglobin > 12 g/dL at 36 weeks

Study or subgroup IMiron Oral iron+folic acid Risk Ratio Weight Risk Ratio


Kumar 2005 11/75 21/75 100.0 % 0.52 [ 0.27, 1.01 ]

Total (95% CI) 75 75 100.0 % 0.52 [ 0.27, 1.01 ]

Total events: 11 (IMiron), 21 (Oral iron+folic acid)




0.01 0.1 1 10 100


Analysis 15.1. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 1 Haemoglobin level

at 4 weeks.


Comparison: 15 Oral iron daily versus oral iron twice weekly

Outcome: 1 Haemoglobin level at 4 weeks

Study or subgroup Oral iron daily

Oral irontwiceweek


MeanDifference


Mumtaz 2000 84 10.16 (1.52) 76 9.62 (1.05) 100.0 % 0.54 [ 0.14, 0.94 ]

Total (95% CI) 84 76 100.0 % 0.54 [ 0.14, 0.94 ]




-10 -5 0 5 10

Favours twice a week Favours daily




at 8 weeks.





Oral irontwiceweek


MeanDifference


Mumtaz 2000 68 10.87 (1.72) 61 9.7 (1.14) 100.0 % 1.17 [ 0.67, 1.67 ]

Total (95% CI) 68 61 100.0 % 1.17 [ 0.67, 1.67 ]




-10 -5 0 5 10



at 12 weeks.





Oral irontwiceweek


MeanDifference


Mumtaz 2000 55 11.36 (1.83) 50 10.09 (1.23) 100.0 % 1.27 [ 0.68, 1.86 ]

Total (95% CI) 55 50 100.0 % 1.27 [ 0.68, 1.86 ]




-10 -5 0 5 10





at 16 weeks.





Oral irontwiceweek


MeanDifference


De Souza 2004 49 11 (0.7) 53 10.7 (0.9) 100.0 % 0.30 [ -0.01, 0.61 ]

Total (95% CI) 49 53 100.0 % 0.30 [ -0.01, 0.61 ]




-10 -5 0 5 10


Analysis 15.5. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 5 Haemoglobin level >

11 g/dL at 16 weeks of treatment.



Outcome: 5 Haemoglobin level > 11 g/dL at 16 weeks of treatment


Oral irontwiceweek Risk Ratio Weight Risk Ratio


De Souza 2004 23/49 18/53 100.0 % 1.38 [ 0.86, 2.23 ]

Total (95% CI) 49 53 100.0 % 1.38 [ 0.86, 2.23 ]

Total events: 23 (Oral iron daily), 18 (Oral iron twice week)




0.1 0.2 0.5 1 2 5 10




Analysis 15.6. Comparison 15 Oral iron daily versus oral iron twice weekly, Outcome 6 Treatment failure

(haemoglobin < 10 g/dL) at 16 weeks.



Outcome: 6 Treatment failure (haemoglobin < 10 g/dL) at 16 weeks


Oral irontwiceweek Risk Ratio Weight Risk Ratio


De Souza 2004 1/49 7/53 100.0 % 0.15 [ 0.02, 1.21 ]

Total (95% CI) 49 53 100.0 % 0.15 [ 0.02, 1.21 ]

Total events: 1 (Oral iron daily), 7 (Oral iron twice week)




0.01 0.1 1 10 100

Favours daily Favours twice a week

Analysis 16.1. Comparison 16 Oral iron daily versus oral iron once week, Outcome 1 Haemoglobin level at

16 weeks.


Comparison: 16 Oral iron daily versus oral iron once week


Study or subgroup Oral iron daily Oral iron once weekMean


Difference


De Souza 2004 49 11 (0.7) 48 10.3 (1) 100.0 % 0.70 [ 0.36, 1.04 ]

Total (95% CI) 49 48 100.0 % 0.70 [ 0.36, 1.04 ]




-10 -5 0 5 10

Favours weekly Favours daily



Analysis 16.2. Comparison 16 Oral iron daily versus oral iron once week, Outcome 2 Haemoglobin level >

11 g/dL at 16 weeks of treatment.




Study or subgroup Oral iron daily Oral iron once week Risk Ratio Weight Risk Ratio


De Souza 2004 23/49 13/48 100.0 % 1.73 [ 1.00, 3.01 ]

Total (95% CI) 49 48 100.0 % 1.73 [ 1.00, 3.01 ]

Total events: 23 (Oral iron daily), 13 (Oral iron once week)




0.1 0.2 0.5 1 2 5 10

Favours weekly Favours daily

Analysis 16.3. Comparison 16 Oral iron daily versus oral iron once week, Outcome 3 Treatment failure

(haemoglobin < 10 g/dL) at 16 weeks.



Outcome: 3 Treatment failure (haemoglobin < 10 g/dL) at 16 weeks

Study or subgroup Oral iron daily Oral iron once week Risk Ratio Weight Risk Ratio


De Souza 2004 1/49 20/48 100.0 % 0.05 [ 0.01, 0.35 ]

Total (95% CI) 49 48 100.0 % 0.05 [ 0.01, 0.35 ]

Total events: 1 (Oral iron daily), 20 (Oral iron once week)




0.001 0.01 0.1 1 10 100 1000

Favours daily Favours weekly



Analysis 17.1. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 1 Haemoglobin

level at 16 weeks.


Comparison: 17 Oral iron twice week versus oral iron once week


Study or subgroup Oral iron twice week Oral iron once weekMean


Difference


De Souza 2004 53 10.7 (0.9) 48 10.3 (1) 100.0 % 0.40 [ 0.03, 0.77 ]

Total (95% CI) 53 48 100.0 % 0.40 [ 0.03, 0.77 ]




-10 -5 0 5 10

Favours once week Favours twice week

Analysis 17.2. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 2 Haemoglobin

level > 11 g/dL at 16 weeks of treatment.




Study or subgroup Oral iron twice week Oral iron once week Risk Ratio Weight Risk Ratio


De Souza 2004 18/53 13/48 100.0 % 1.25 [ 0.69, 2.28 ]

Total (95% CI) 53 48 100.0 % 1.25 [ 0.69, 2.28 ]

Total events: 18 (Oral iron twice week), 13 (Oral iron once week)




0.1 0.2 0.5 1 2 5 10

Favours once week Favours twice week



Analysis 17.3. Comparison 17 Oral iron twice week versus oral iron once week, Outcome 3 Treatment

Failure (haemoglobin < 10 g/dL) at 16 weeks.



Outcome: 3 Treatment Failure (haemoglobin < 10 g/dL) at 16 weeks

Study or subgroup Oral iron twice week Oral iron once week Risk Ratio Weight Risk Ratio


De Souza 2004 7/53 20/48 100.0 % 0.32 [ 0.15, 0.68 ]

Total (95% CI) 53 48 100.0 % 0.32 [ 0.15, 0.68 ]

Total events: 7 (Oral iron twice week), 20 (Oral iron once week)




0.1 0.2 0.5 1 2 5 10

Favours twice week Favours once week

Analysis 18.1. Comparison 18 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg,

Outcome 1 Haemoglobin level at delivery.


Comparison: 18 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg

Outcome: 1 Haemoglobin level at delivery

Study or subgroup IV iron sucrose 500 IV iron sucrose 200Mean


Difference


Wali 2002 15 11.8 (1.1) 20 11.3 (0.9) 100.0 % 0.50 [ -0.18, 1.18 ]

Total (95% CI) 15 20 100.0 % 0.50 [ -0.18, 1.18 ]




-10 -5 0 5 10

Favours 200 mg dose Favours 500 mg dose




Outcome 2 Haemoglobin level > 11g/dL at delivery.



Outcome: 2 Haemoglobin level > 11g/dL at delivery

Study or subgroup IV iron sucrose 500 IV iron sucrose 200 Risk Ratio Weight Risk Ratio


Wali 2002 12/15 14/20 100.0 % 1.14 [ 0.78, 1.68 ]

Total (95% CI) 15 20 100.0 % 1.14 [ 0.78, 1.68 ]

Total events: 12 (IV iron sucrose 500), 14 (IV iron sucrose 200)




0.1 0.2 0.5 1 2 5 10



Outcome 3 Moderate abdominal pain.



Outcome: 3 Moderate abdominal pain

Study or subgroup IV iron sucrose 500 IV iron sucrose 200 Risk Ratio Weight Risk Ratio


Wali 2002 1/15 1/20 100.0 % 1.33 [ 0.09, 19.64 ]

Total (95% CI) 15 20 100.0 % 1.33 [ 0.09, 19.64 ]

Total events: 1 (IV iron sucrose 500), 1 (IV iron sucrose 200)




0.01 0.1 1 10 100




Analysis 19.1. Comparison 19 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol,

Outcome 1 Maternal haemoglobin level at birth.


Comparison: 19 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol

Outcome: 1 Maternal haemoglobin level at birth

Study or subgroup IV iron sucrose 500 IM iron sorbitolMean


Difference


Wali 2002 15 11.8 (1.1) 25 10.2 (1.2) 100.0 % 1.60 [ 0.87, 2.33 ]

Total (95% CI) 15 25 100.0 % 1.60 [ 0.87, 2.33 ]




-10 -5 0 5 10

Favours IM iron Favours IV iron


Outcome 2 Haemoglobin level > 11g/dL at delivery.



Outcome: 2 Haemoglobin level > 11g/dL at delivery

Study or subgroup IV iron sucrose 500 IM iron sorbitol Risk Ratio Weight Risk Ratio


Wali 2002 12/15 7/25 100.0 % 2.86 [ 1.45, 5.63 ]

Total (95% CI) 15 25 100.0 % 2.86 [ 1.45, 5.63 ]

Total events: 12 (IV iron sucrose 500), 7 (IM iron sorbitol)




0.1 0.2 0.5 1 2 5 10

Favours IM Favours IV




Outcome 1 Haemoglobin level at delivery.



Outcome: 1 Haemoglobin level at delivery

Study or subgroup IV iron sucrose 200 IM iron sorbitolMean


Difference


Wali 2002 20 11.3 (0.9) 25 10.2 (1.2) 100.0 % 1.10 [ 0.49, 1.71 ]

Total (95% CI) 20 25 100.0 % 1.10 [ 0.49, 1.71 ]




-10 -5 0 5 10



Outcome 2 Haemoglobin level > 11 g/dL at delivery.



Outcome: 2 Haemoglobin level > 11 g/dL at delivery

Study or subgroup IV iron sucrose 200 IM iron sorbitol Risk Ratio Weight Risk Ratio


Wali 2002 14/20 7/25 100.0 % 2.50 [ 1.25, 4.99 ]

Total (95% CI) 20 25 100.0 % 2.50 [ 1.25, 4.99 ]

Total events: 14 (IV iron sucrose 200), 7 (IM iron sorbitol)




0.1 0.2 0.5 1 2 5 10




Analysis 21.1. Comparison 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day, Outcome 1



Comparison: 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day


Study or subgroup Oral iron 1200 mg Oral iron 600 mgMean


Difference


Ogunbode 1980 28 31.62 (2.14) 28 31.25 (2.22) 100.0 % 0.37 [ -0.77, 1.51 ]

Total (95% CI) 28 28 100.0 % 0.37 [ -0.77, 1.51 ]




-10 -5 0 5 10


Analysis 21.2. Comparison 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day, Outcome 2



Comparison: 21 Oral ferrous sulphate iron 1200 mg/day versus 600 mg/day


Study or subgroup Oral iron 1200 mg Oral iron 600 mgMean


Difference


Ogunbode 1980 28 32.69 (2.53) 28 32.67 (1.3) 100.0 % 0.02 [ -1.03, 1.07 ]

Total (95% CI) 28 28 100.0 % 0.02 [ -1.03, 1.07 ]




-10 -5 0 5 10




Analysis 23.1. Comparison 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran,

Outcome 1 Haematocrit (%) at 4 weeks of treatment.


Comparison: 23 Intramuscular iron sorbitol-glu acid versus intravenous iron dextran


Study or subgroup IM iron sorb-gluc IV iron dextranMean


Difference


Oluboyede 1980 31 32.39 (2.16) 28 30.21 (3.19) 100.0 % 2.18 [ 0.77, 3.59 ]

Total (95% CI) 31 28 100.0 % 2.18 [ 0.77, 3.59 ]




-10 -5 0 5 10

Favours IV iron Favours IM iron


Outcome 2 Haematocrit (%) at 8 weeks of treatment.




Study or subgroup IM iron sorb-gluc IV iron dextranMean


Difference


Oluboyede 1980 21 34.43 (2.31) 22 32.95 (2.13) 100.0 % 1.48 [ 0.15, 2.81 ]

Total (95% CI) 21 22 100.0 % 1.48 [ 0.15, 2.81 ]




-10 -5 0 5 10

Favours IV iron Favours IM iron




Outcome 3 Neonatal jaundice.



Outcome: 3 Neonatal jaundice

Study or subgroup IM iron sorb-gluc IV iron dextran Risk Ratio Weight Risk Ratio


Oluboyede 1980 1/32 1/30 100.0 % 0.94 [ 0.06, 14.33 ]

Total (95% CI) 32 30 100.0 % 0.94 [ 0.06, 14.33 ]

Total events: 1 (IM iron sorb-gluc), 1 (IV iron dextran)




0.01 0.1 1 10 100



Outcome 4 Viral hepatitis.



Outcome: 4 Viral hepatitis



Oluboyede 1980 1/32 0/30 100.0 % 2.82 [ 0.12, 66.62 ]

Total (95% CI) 32 30 100.0 % 2.82 [ 0.12, 66.62 ]





0.01 0.1 1 10 100





Outcome 5 Severe allergic reaction.



Outcome: 5 Severe allergic reaction



Oluboyede 1980 0/32 1/30 100.0 % 0.31 [ 0.01, 7.40 ]

Total (95% CI) 32 30 100.0 % 0.31 [ 0.01, 7.40 ]





0.01 0.1 1 10 100


Analysis 24.1. Comparison 24 Oral iron polymaltose complex (100mg) versus ferrous sulphate (120mg),

Outcome 1 Haemoglobin level at 8 weeks.


Comparison: 24 Oral iron polymaltose complex (100mg) versus ferrous sulphate (120mg)


Study or subgroup

Ironpolymaltose

complex Ferrous sulphateMean


Difference


Saha 2007 48 11.19 (0.67) 52 11.24 (0.61) 100.0 % -0.05 [ -0.30, 0.20 ]

Total (95% CI) 48 52 100.0 % -0.05 [ -0.30, 0.20 ]




-100 -50 0 50 100

Favours experimental Favours control




Outcome 2 Constipation at 8 weeks.



Outcome: 2 Constipation at 8 weeks

Study or subgroup

Ironpolymaltose

complex Ferrous sulphate Risk Ratio Weight Risk Ratio


Saha 2007 7/48 25/52 100.0 % 0.30 [ 0.14, 0.64 ]

Total (95% CI) 48 52 100.0 % 0.30 [ 0.14, 0.64 ]

Total events: 7 (Iron polymaltose complex), 25 (Ferrous sulphate)




0.01 0.1 1 10 100



Outcome 3 Haemoglobin > 11 g/dL at 8 weeks of treatment.



Outcome: 3 Haemoglobin > 11 g/dL at 8 weeks of treatment

Study or subgroup

Ironpolymaltose



Saha 2007 33/48 33/52 100.0 % 1.08 [ 0.82, 1.43 ]

Total (95% CI) 48 52 100.0 % 1.08 [ 0.82, 1.43 ]





0.01 0.1 1 10 100





Outcome 4 Gastrointestinal intolerance.



Outcome: 4 Gastrointestinal intolerance

Study or subgroup

Ironpolymaltose



Saha 2007 13/48 34/52 100.0 % 0.41 [ 0.25, 0.69 ]

Total (95% CI) 48 52 100.0 % 0.41 [ 0.25, 0.69 ]





0.01 0.1 1 10 100



Outcome 5 Metallic taste.



Outcome: 5 Metallic taste

Study or subgroup

Ironpolymaltose



Saha 2007 1/48 8/52 100.0 % 0.14 [ 0.02, 1.04 ]

Total (95% CI) 48 52 100.0 % 0.14 [ 0.02, 1.04 ]





0.01 0.1 1 10 100





Outcome 6 Diarrhea.



Outcome: 6 Diarrhea

Study or subgroup

Ironpolymaltose



Saha 2007 0/48 2/52 100.0 % 0.22 [ 0.01, 4.39 ]

Total (95% CI) 48 52 100.0 % 0.22 [ 0.01, 4.39 ]





0.01 0.1 1 10 100



Outcome 7 Rashes.



Outcome: 7 Rashes

Study or subgroup

Ironpolymaltose



Saha 2007 0/48 1/52 100.0 % 0.36 [ 0.02, 8.64 ]

Total (95% CI) 48 52 100.0 % 0.36 [ 0.02, 8.64 ]





0.01 0.1 1 10 100





Outcome 8 Compliance.



Outcome: 8 Compliance

Study or subgroup

Ironpolymaltose



Saha 2007 44/48 45/52 100.0 % 1.06 [ 0.92, 1.21 ]

Total (95% CI) 48 52 100.0 % 1.06 [ 0.92, 1.21 ]





0.01 0.1 1 10 100



Outcome 9 Cost due to hospital visits.



Outcome: 9 Cost due to hospital visits

Study or subgroup

Ironpolymaltose



Difference


Saha 2007 48 310.25 (245.54) 52 317.3 (309.6) 100.0 % -7.05 [ -116.16, 102.06 ]

Total (95% CI) 48 52 100.0 % -7.05 [ -116.16, 102.06 ]




-100 -50 0 50 100





Outcome 10 Cost due to loss of work.



Outcome: 10 Cost due to loss of work

Study or subgroup

Ironpolymaltose



Difference


Saha 2007 48 213.54 (30.83) 52 203.26 (35.7) 100.0 % 10.28 [ -2.77, 23.33 ]

Total (95% CI) 48 52 100.0 % 10.28 [ -2.77, 23.33 ]




-100 -50 0 50 100


Analysis 25.1. Comparison 25 Oral bovine lactoferrin versus ferrous sulphate, Outcome 1 Mean

haemoglobin levels at 1 month.


Comparison: 25 Oral bovine lactoferrin versus ferrous sulphate

Outcome: 1 Mean haemoglobin levels at 1 month

Study or subgroup

OralBovine

lactoferrin

Oralferrous

sulphateMean


Difference


Nappi 2009 49 11.2 (0.5) 48 11.5 (0.6) 100.0 % -0.30 [ -0.52, -0.08 ]

Total (95% CI) 49 48 100.0 % -0.30 [ -0.52, -0.08 ]




-100 -50 0 50 100




Analysis 26.1. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 1

Haemoglobin level at 8 weeks (or until birth).


Comparison: 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg

Outcome: 1 Haemoglobin level at 8 weeks (or until birth)

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate

40mgMean


Difference


Zhou 2007 56 11.1 (1.3) 58 11.4 (1.1) 100.0 % -0.30 [ -0.74, 0.14 ]

Total (95% CI) 56 58 100.0 % -0.30 [ -0.74, 0.14 ]




-100 -50 0 50 100


Analysis 26.2. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 2 Rate of

anaemia at 8 weeks.



Outcome: 2 Rate of anaemia at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate

40mg Risk Ratio Weight Risk Ratio


Zhou 2007 21/56 15/58 100.0 % 1.45 [ 0.84, 2.52 ]

Total (95% CI) 56 58 100.0 % 1.45 [ 0.84, 2.52 ]

Total events: 21 (Ferrous sulphate 20mg), 15 (Ferrous sulphate 40mg)




0.01 0.1 1 10 100





moderate anaemia at 8 weeks.



Outcome: 3 Rate of moderate anaemia at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 8/56 5/58 100.0 % 1.66 [ 0.58, 4.76 ]

Total (95% CI) 56 58 100.0 % 1.66 [ 0.58, 4.76 ]





0.01 0.1 1 10 100


Analysis 26.4. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 4 Nausea at 8

weeks.



Outcome: 4 Nausea at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 36/59 43/61 100.0 % 0.87 [ 0.67, 1.12 ]

Total (95% CI) 59 61 100.0 % 0.87 [ 0.67, 1.12 ]





0.01 0.1 1 10 100




Analysis 26.5. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 5 Heartburn

at 8 weeks.



Outcome: 5 Heartburn at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 40/59 46/61 100.0 % 0.90 [ 0.72, 1.13 ]

Total (95% CI) 59 61 100.0 % 0.90 [ 0.72, 1.13 ]





0.01 0.1 1 10 100


Analysis 26.6. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 6 Stomach

pain at 8 weeks.



Outcome: 6 Stomach pain at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 18/59 33/61 100.0 % 0.56 [ 0.36, 0.88 ]

Total (95% CI) 59 61 100.0 % 0.56 [ 0.36, 0.88 ]





0.01 0.1 1 10 100




Analysis 26.7. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 7 Vomiting at

8 weeks.



Outcome: 7 Vomiting at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 13/59 19/61 100.0 % 0.71 [ 0.39, 1.30 ]

Total (95% CI) 59 61 100.0 % 0.71 [ 0.39, 1.30 ]





0.01 0.1 1 10 100


Analysis 26.8. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 8 Bowel habit:

< 3 per week.



Outcome: 8 Bowel habit: < 3 per week

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 8/59 8/61 100.0 % 1.03 [ 0.42, 2.57 ]

Total (95% CI) 59 61 100.0 % 1.03 [ 0.42, 2.57 ]





0.01 0.1 1 10 100




Analysis 26.9. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 9 Hard stool

at 8 weeks.



Outcome: 9 Hard stool at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 19/59 18/61 100.0 % 1.09 [ 0.64, 1.87 ]

Total (95% CI) 59 61 100.0 % 1.09 [ 0.64, 1.87 ]





0.01 0.1 1 10 100


Analysis 26.10. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 10 Feeling

unwell at 8 weeks.



Outcome: 10 Feeling unwell at 8 weeks

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 27/59 40/61 100.0 % 0.70 [ 0.50, 0.97 ]

Total (95% CI) 59 61 100.0 % 0.70 [ 0.50, 0.97 ]





0.01 0.1 1 10 100




Analysis 26.11. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 11 Need

transfusion.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 1/59 1/61 100.0 % 1.03 [ 0.07, 16.15 ]

Total (95% CI) 59 61 100.0 % 1.03 [ 0.07, 16.15 ]





0.01 0.1 1 10 100


Analysis 26.12. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 12 Caesarean

section.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 14/58 14/61 100.0 % 1.05 [ 0.55, 2.01 ]

Total (95% CI) 58 61 100.0 % 1.05 [ 0.55, 2.01 ]





0.01 0.1 1 10 100





Birthweight.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate

40mgMean


Difference


Zhou 2007 58 3464 (444) 61 3496 (523) 100.0 % -32.00 [ -206.02, 142.02 ]

Total (95% CI) 58 61 100.0 % -32.00 [ -206.02, 142.02 ]




-100 -50 0 50 100


Analysis 26.14. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 14 Preterm

birth.



Outcome: 14 Preterm birth

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 2/58 3/61 100.0 % 0.70 [ 0.12, 4.05 ]

Total (95% CI) 58 61 100.0 % 0.70 [ 0.12, 4.05 ]





0.01 0.1 1 10 100




Analysis 26.15. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 15 Small-for-

gestational age.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 2/58 6/61 100.0 % 0.35 [ 0.07, 1.67 ]

Total (95% CI) 58 61 100.0 % 0.35 [ 0.07, 1.67 ]





0.01 0.1 1 10 100


Analysis 26.16. Comparison 26 Ferrous sulphate (elementary iron) 20 mg vs 40 mg, Outcome 16 Fetal

distress.



Outcome: 16 Fetal distress

Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 5/58 7/61 100.0 % 0.75 [ 0.25, 2.23 ]

Total (95% CI) 58 61 100.0 % 0.75 [ 0.25, 2.23 ]





0.01 0.1 1 10 100









Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80

mgMean


Difference


Zhou 2007 56 11.1 (1.3) 54 11.9 (1.2) 100.0 % -0.80 [ -1.27, -0.33 ]

Total (95% CI) 56 54 100.0 % -0.80 [ -1.27, -0.33 ]




-100 -50 0 50 100



patients with anaemia at 8 weeks.



Outcome: 2 Rate of patients with anaemia at 8 weeks

Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80

mg Risk Ratio Weight Risk Ratio


Zhou 2007 21/56 13/54 100.0 % 1.56 [ 0.87, 2.79 ]

Total (95% CI) 56 54 100.0 % 1.56 [ 0.87, 2.79 ]

Total events: 21 (Ferrous sulphate 20 mg), 13 (Ferrous sulphate 80 mg)




0.01 0.1 1 10 100









Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 5/54 3/57 100.0 % 1.76 [ 0.44, 7.01 ]

Total (95% CI) 54 57 100.0 % 1.76 [ 0.44, 7.01 ]





0.01 0.1 1 10 100



weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 36/59 49/60 100.0 % 0.75 [ 0.59, 0.95 ]

Total (95% CI) 59 60 100.0 % 0.75 [ 0.59, 0.95 ]





0.01 0.1 1 10 100





at 8 weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 40/59 43/60 100.0 % 0.95 [ 0.75, 1.20 ]

Total (95% CI) 59 60 100.0 % 0.95 [ 0.75, 1.20 ]





0.01 0.1 1 10 100



pain at 8 weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 18/59 34/60 100.0 % 0.54 [ 0.35, 0.84 ]

Total (95% CI) 59 60 100.0 % 0.54 [ 0.35, 0.84 ]





0.01 0.1 1 10 100





8 weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 13/59 25/60 100.0 % 0.53 [ 0.30, 0.93 ]

Total (95% CI) 59 60 100.0 % 0.53 [ 0.30, 0.93 ]





0.01 0.1 1 10 100



< 3 per week.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 8/59 9/60 100.0 % 0.90 [ 0.37, 2.18 ]

Total (95% CI) 59 60 100.0 % 0.90 [ 0.37, 2.18 ]





0.01 0.1 1 10 100





at 8 weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 19/59 23/60 100.0 % 0.84 [ 0.51, 1.37 ]

Total (95% CI) 59 60 100.0 % 0.84 [ 0.51, 1.37 ]





0.01 0.1 1 10 100



unwell at 8 weeks.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 27/59 37/60 100.0 % 0.74 [ 0.53, 1.04 ]

Total (95% CI) 59 60 100.0 % 0.74 [ 0.53, 1.04 ]





0.01 0.1 1 10 100





transfusion.




Study or subgroup

Ferroussulphate 20

mg

Ferroussulphate 80



Zhou 2007 1/59 2/60 100.0 % 0.51 [ 0.05, 5.46 ]

Total (95% CI) 59 60 100.0 % 0.51 [ 0.05, 5.46 ]





0.01 0.1 1 10 100



section.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 14/58 17/60 100.0 % 0.85 [ 0.46, 1.57 ]

Total (95% CI) 58 60 100.0 % 0.85 [ 0.46, 1.57 ]





0.01 0.1 1 10 100





Birthweight.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate

80mgMean


Difference


Zhou 2007 58 3464 (444) 61 3503 (522) 100.0 % -39.00 [ -212.83, 134.83 ]

Total (95% CI) 58 61 100.0 % -39.00 [ -212.83, 134.83 ]




-100 -50 0 50 100



birth.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 2/58 5/60 100.0 % 0.41 [ 0.08, 2.05 ]

Total (95% CI) 58 60 100.0 % 0.41 [ 0.08, 2.05 ]





0.01 0.1 1 10 100





gestational age.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 2/58 2/60 100.0 % 1.03 [ 0.15, 7.10 ]

Total (95% CI) 58 60 100.0 % 1.03 [ 0.15, 7.10 ]





0.01 0.1 1 10 100



distress.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 5/58 9/60 100.0 % 0.57 [ 0.20, 1.61 ]

Total (95% CI) 58 60 100.0 % 0.57 [ 0.20, 1.61 ]





0.01 0.1 1 10 100









Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80

mgMean


Difference


Zhou 2007 58 11.4 (1.1) 54 11.9 (1.2) 100.0 % -0.50 [ -0.93, -0.07 ]

Total (95% CI) 58 54 100.0 % -0.50 [ -0.93, -0.07 ]




-100 -50 0 50 100



anaemia at 8 weeks.



Outcome: 2 Rate of anaemia at 8 weeks

Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 21/56 13/54 100.0 % 1.56 [ 0.87, 2.79 ]

Total (95% CI) 56 54 100.0 % 1.56 [ 0.87, 2.79 ]





0.01 0.1 1 10 100









Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 5/54 3/53 100.0 % 1.64 [ 0.41, 6.50 ]

Total (95% CI) 54 53 100.0 % 1.64 [ 0.41, 6.50 ]





0.01 0.1 1 10 100



weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80

mg Odds Ratio Weight Odds Ratio


Zhou 2007 43/61 49/60 100.0 % 0.54 [ 0.23, 1.26 ]

Total (95% CI) 61 60 100.0 % 0.54 [ 0.23, 1.26 ]





0.01 0.1 1 10 100





at 8 weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 46/61 43/60 100.0 % 1.05 [ 0.85, 1.30 ]

Total (95% CI) 61 60 100.0 % 1.05 [ 0.85, 1.30 ]





0.01 0.1 1 10 100



pain at 8 weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 33/61 34/60 100.0 % 0.95 [ 0.69, 1.31 ]

Total (95% CI) 61 60 100.0 % 0.95 [ 0.69, 1.31 ]





0.01 0.1 1 10 100





8 weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 19/61 25/60 100.0 % 0.75 [ 0.46, 1.21 ]

Total (95% CI) 61 60 100.0 % 0.75 [ 0.46, 1.21 ]





0.01 0.1 1 10 100



< 3 per week.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 8/61 9/60 100.0 % 0.87 [ 0.36, 2.11 ]

Total (95% CI) 61 60 100.0 % 0.87 [ 0.36, 2.11 ]





0.01 0.1 1 10 100





at 8 weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 18/61 23/60 100.0 % 0.77 [ 0.47, 1.27 ]

Total (95% CI) 61 60 100.0 % 0.77 [ 0.47, 1.27 ]





0.01 0.1 1 10 100



unwell at 8 weeks.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 40/61 37/60 100.0 % 1.06 [ 0.81, 1.39 ]

Total (95% CI) 61 60 100.0 % 1.06 [ 0.81, 1.39 ]





0.01 0.1 1 10 100





transfusion.




Study or subgroup

Ferroussulphate 40

mg

Ferroussulphate 80



Zhou 2007 1/61 2/60 100.0 % 0.49 [ 0.05, 5.28 ]

Total (95% CI) 61 60 100.0 % 0.49 [ 0.05, 5.28 ]





0.01 0.1 1 10 100



section.




Study or subgroup

Ferroussulphate

40mg

Ferroussulphate



Zhou 2007 14/61 17/60 100.0 % 0.81 [ 0.44, 1.49 ]

Total (95% CI) 61 60 100.0 % 0.81 [ 0.44, 1.49 ]





0.01 0.1 1 10 100





Birthweight.




Study or subgroup

Ferroussulphate

40mg

Ferroussulphate

80mgMean


Difference


Zhou 2007 58 3496 (523) 61 3503 (522) 100.0 % -7.00 [ -194.82, 180.82 ]

Total (95% CI) 58 61 100.0 % -7.00 [ -194.82, 180.82 ]




-100 -50 0 50 100



birth.




Study or subgroup

Ferroussulphate

40mg

Ferroussulphate



Zhou 2007 3/61 5/60 100.0 % 0.59 [ 0.15, 2.36 ]

Total (95% CI) 61 60 100.0 % 0.59 [ 0.15, 2.36 ]





0.01 0.1 1 10 100





gestational age.




Study or subgroup

Ferroussulphate

20mg

Ferroussulphate



Zhou 2007 6/61 2/60 100.0 % 2.95 [ 0.62, 14.04 ]

Total (95% CI) 61 60 100.0 % 2.95 [ 0.62, 14.04 ]





0.01 0.1 1 10 100



distress.




Study or subgroup

Ferroussulphate

40mg

Ferroussulphate



Zhou 2007 7/61 9/60 100.0 % 0.77 [ 0.30, 1.92 ]

Total (95% CI) 61 60 100.0 % 0.77 [ 0.30, 1.92 ]





0.01 0.1 1 10 100




Analysis 29.1. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 1 Mean predelivery

maternal haemoglobin.


Comparison: 29 Intravenous iron + oral iron versus oral iron

Outcome: 1 Mean predelivery maternal haemoglobin

Study or subgroup IV + Oral iron Oral ironMean


Difference


Khalafallah 2010 92 12.66 (0.97) 91 12.18 (0.87) 100.0 % 0.48 [ 0.21, 0.75 ]

Total (95% CI) 92 91 100.0 % 0.48 [ 0.21, 0.75 ]




-100 -50 0 50 100


Analysis 29.2. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 2 Mean maternal

haemoglobin after delivery.



Outcome: 2 Mean maternal haemoglobin after delivery

Study or subgroup IV + Oral iron Oral ironMean


Difference


Khalafallah 2010 92 11.55 (1.08) 91 11.16 (1.42) 100.0 % 0.39 [ 0.02, 0.76 ]

Total (95% CI) 92 91 100.0 % 0.39 [ 0.02, 0.76 ]




-100 -50 0 50 100




Analysis 29.3. Comparison 29 Intravenous iron + oral iron versus oral iron, Outcome 3 Tolerate oral iron.



Outcome: 3 Tolerate oral iron

Study or subgroup IV + Oral iron Oral iron Risk Ratio Weight Risk Ratio


Khalafallah 2010 2/92 7/91 100.0 % 0.28 [ 0.06, 1.32 ]

Total (95% CI) 92 91 100.0 % 0.28 [ 0.06, 1.32 ]

Total events: 2 (IV + Oral iron), 7 (Oral iron)




0.01 0.1 1 10 100


A D D I T I O N A L T A B L E S

Table 1. FDA iron adverse effects description

Drug substance Adverse effect

Iron Oral preparations: produces gastrointestinal irritation and abdom-

inal pain with nausea and vomiting, when administered orally.

The effect is usually dose related to the amount of elemental

iron, rather than the preparation. Diarrhoea and constipation.

Better to administer with foods, and to increase doses gradu-

ally. Oral liquid preparations may stain teeth. Oral preparations

should not be given concomitantly with parenteral preparations.

Parenteral preparations: anaphylactoid reactions, peripheral vas-

cular flushing with intravenous administration, tachycardia, hy-

potension and syncope, thrombophlebitis (higher if given with

glucose 5% versus sodium chloride 0.9%), nausea, vomiting, taste

disturbance. Delayed reactions may include arthralgia, myalgia,

regional lymphadenopathy, chills, fever, paraesthesia, dizziness,

malaise, headache, nausea, vomiting and haematuria. Intramus-

cular use in animals has resulted in the development of sarcomas

at the injection site. It interacts with enalapril (potentiates adverse

systemic reactions) and chloramphenicol

Iron sulphate (oral)

Ferrous gluconate (oral)

Iron fumarate (oral)



Table 1. FDA iron adverse effects description (Continued)

Iron sucrose (intravenous) In addition to the adverse effects for parenteral preparations: bron-

chospasm, dyspnoea, myalgia, pruritus, urticaria, rash, reactions

in the injection site

Iron sorbitol In addition to the adverse effects for parenteral preparations: severe

systemic reactions with potentially fatal cardiac complications.

Dark urine. Do not administer intravenously

Iron dextran (intramuscular)

Iron polymaltose complex -iron dextrin-

Adjuvant recombinant human erythropoietin Epoetin: recombinant human erythropoietin.

Darbepoetin: derivative of epoetin.

Headache, hypertension and seizures, specially in people with

poor renal function. Thrombosis at vascular access sites, flu-like

symptoms, hyperkalaemia, skin rashes, and rare reports of ana-

phylactoid reactions

Iron polymaltose complex (oral)

†Martindale, The Complete Drug reference. Pharmaceutical

Press. 32 ed. London 1999. ‡British National Formulary. Royal

Pharmaceutical Society. 49 ed. London, March 2005

‡British National Formulary. Royal Pharmaceutical Society. 49

ed. London, March 2005

†Martindale, The Complete Drug reference. Pharmaceutical

Press. 32 ed. London 1999

A P P E N D I C E S

Appendix 1. Search strategy

PubMed (Jan 2005 to June 2011)

(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR

randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT (humans [mh] AND animals [mh])) AND (Pregnant

Women [mh] OR Pregnancy [mh] OR Pregnan* OR Prenatal Care [mh]) AND (Iron OR ferrous OR ferric OR iron [mh]) AND

(Anemia* OR anaemia* OR anemic OR anaemic OR anemia [mh])

CENTRAL (2011, Issue 2 of 4)

#1 mesh descriptor Pregnant Women explode all trees

#2 mesh descriptor Pregnancy explode all trees

#3 mesh descriptor Prenatal care explode all trees

#4 Iron OR ferrous OR ferric OR mesh descriptor Iron explode all trees



#5 Anemia* OR anaemia* OR anemic OR anaemic OR mesh descriptor Anemia explode all trees

#6 #1 OR #2 OR #3

#7 #6 AND #5 AND #4

Health Technology Assessment Program (HTA) (www.hta.ac.uk/) [United Kingdom]; and LATINREC [www.latinrec.org, Colom-

bia] (searched 2 May 2011):

(anemia OR anaemia OR anemic OR anaemic) AND (pregnant OR pregnancy) AND (iron OR ferrous) AND (random OR randomized

OR randomised OR aleatory).

Search Portal of the International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/) (searched 2 May 2011)

anemia AND pregnant AND ferrous

anaemia AND pregnant AND ferrous

anemic AND pregnant AND ferrous

anemia AND pregnancy AND ferrous

anaemia AND pregnancy AND ferrous

anemic AND pregnancy AND ferrous

anemia AND pregnant AND iron

anaemia AND pregnant AND iron

anemic AND pregnant AND iron

anemia AND pregnancy AND iron

anaemia AND pregnancy AND iron

anemic AND pregnancy AND iron

Appendix 2. Search strategy used in the previous version of the review

Authors searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to

December 2005), EMBASE (1976 to December 2005), LILACS (1982 to 40 edition), and BIOSIS Previews (from 1980 to June 2002)

using the following strategy (adapted for each database):

(Randomized-controlled-trial:PT OR Randomized-clinical-trials:PT)

AND

(Pregnancy in Mesh OR Prenatal care in Mesh)

(Anemia, Hypochromic/drug therapy in MESH OR

Anemia, Hypochromic/prevention and control in MESH OR

Anemia, Hypochromic/therapy in MESH OR

Anemia, Iron deficiency/drug therapy in MESH OR

Anemia, Iron deficiency/prevention and control in MESH OR

Anemia, Iron deficiency/therapy in MESH)

Pregnancy complications/prevention and control

Iron/therapeutic use

Haematinics/adverse effects.

Appendix 3. Methods used to assess trials included in previous versions of this review

(1) Study selection

Two review authors (L Reveiz (LR) and LG Cuervo (LGC)) checked the titles and abstracts identified from the searches. If it was clear

that the study did not refer to a randomised controlled trial on iron-deficiency anaemia in pregnancy, it was excluded. If it was unclear,

then we obtained the full text of the study for independent assessment by LR and G Gyte (GG). LR and GG assessed each trial for

inclusion and resolved any disagreements through discussion, with referral to a third author (LGC) when necessary. Excluded studies

and reasons for exclusion are described in the ’Characteristics of excluded studies’ table.



http://www.hta.ac.uk/

http://www.latinrec.org



(2) Assessment of methodological quality

We assessed trials under consideration for methodological quality and for appropriateness for inclusion without consideration of their

results. We processed data from included trials as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins

2005). We undertook quality assessment by evaluating the following components for each included study, since there was some evidence

that these are associated with biased estimates of treatment effect:

(a) the method of generation of the randomisation sequence; if it delivered a known chance allocation to each given group but individual

allocation could not be anticipated;

(b) the method of allocation concealment, which was considered ’adequate’ when the assignment could not be foreseen;

(c) who was blinded or not blinded (participants, clinicians, outcome assessors);

(d) participants lost to follow up in each arm of the study (split into postrandomisation exclusions and later losses if possible), and

whether participants were analysed in the groups to which they were originally randomised (intention to treat).

The information was recorded in a table of quality criteria and a description of the quality of each study was given based on a summary

of these components.

(3) Data extraction

Data extraction was carried out independently by one author (LR) using a data extraction form. Data were extracted for all outcomes

for all relevant drugs, paying particular attention to the dosage and periodicity of treatment. GG checked the data extraction. We

resolved disagreements by discussion until we reached consensus. We obtained missing data from the trial authors, when possible.

(4) Analysis

To estimate differences between treatments, we pooled the results of randomised controlled trials (RCTs) that evaluated similar

interventions (and controls), and calculated a weighted treatment effect across RCTs using a fixed-effect model. The results were

expressed as relative risk, and 95% confidence intervals (CI)) for dichotomous outcomes, and weighted mean difference (and 95% CI)

for continuous outcomes. Results were expressed as number needed to treat where appropriate. We summarised the information we

found available. Quasi-randomised and non-randomised controlled studies were identified and listed, but were not further discussed.

A qualitative description was provided for adverse effects when this was available.

W H A T ’ S N E W

Last assessed as up-to-date: 24 August 2011.

Date Event Description

5 December 2011 Amended Corrected typographical error.

H I S T O R Y

Protocol first published: Issue 4, 1999

Review first published: Issue 2, 2001



Date Event Description

7 June 2011 New search has been performed This update is based on a search run in June 2011,

which identified six new randomised controlled trials

(RCTs). There are now a total of 23 RCTs included in

the review. The inclusion of the 6 new included studies

did not change the overall conclusions (Digumarthi

2008; Khalafallah 2010; Nappi 2009; Saha 2007; Sun

2010; Zhou 2007). In addition, a ’risk of bias’ assess-

ment was performed for all RCTs

7 June 2011 New citation required but conclusions have not

changed

New author joined the review team.

9 February 2010 Amended Search updated. Fifteen reports added to Studies await-

ing classification

12 May 2009 Amended Contact details updated.

20 September 2008 Amended Converted to new review format.

13 February 2007 New search has been performed An updated search of the Pregnancy and Childbirth

Group’s Trials Register on 31 January 2007 identified

seven new trial reports which have been added to the

awaiting assessment section for assessment in the next

update

This update is based on a search run in Decem-

ber 2005, which identified twelve new trials (Al

2005; Bayoumeu 2002; Breymann 2001; De Souza

2004; Komolafe 2003; Kumar 2005; Mumtaz 2000;

Ogunbode 1980; Oluboyede 1980; Sood 1979; Wali

2002; Zutschi 2004).

1 February 2007 New citation required but conclusions have not

changed

There are now a total of 17 trials included in the review.

The inclusion of these trials have generally not changed

the conclusions although there are now concerns about

possible important adverse effects.

Ludovic Reveiz is now the guarantor of the review.



C O N T R I B U T I O N S O F A U T H O R S

For the 2011 update, Ludovic Reveiz and Alexandra Casasbuenas appraised the papers independently. Ludovic Reveiz took the lead

on writing the review, with Gill Gyte, Alexandra Casasbuenas and Luis Gabriel Cuervo providing comments on the various drafts, and

revised the review in response to the editorial feedback.

The first published review was prepared by Luis Gabriel Cuervo and Kassam Mahomed (Cuervo 2001). The second published review

was prepared by Ludovic Reveiz, Gill Gyte and Luis Gabriel Cuervo (Reveiz 2007).

D E C L A R A T I O N S O F I N T E R E S T

Ludovic Reveiz and Luis Gabriel Cuervo have contributed to this systematic review in a personal capacity and during their spare time.

Most of their contributions were made before joining the Pan American Health Organization. The Pan American Health Organization

does not assume responsibility for the statements contained therein.

S O U R C E S O F S U P P O R T

Internal sources

• None, Not specified.

External sources

• None, Not specified.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We have modified the ’Outcome measures’ as a result of suggestions from a referee.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Anemia, Iron-Deficiency [∗therapy]; Injections, Intramuscular; Injections, Intravenous; Iron Compounds [∗administration & dosage;

adverse effects]; Pregnancy Complications, Hematologic [∗therapy]; Randomized Controlled Trials as Topic

MeSH check words

Female; Humans; Pregnancy



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