CD003094_Anaemia Review 2007

Treatments for iron deficiency anaemia in pregnancy (Review)

Cuervo LG, Mahomed K

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

2007, Issue 1

http://www.thecochranelibrary.com

1Treatments for iron deficiency anaemia in pregnancy (Review)

Copyright © 2007 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

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

1PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .

4SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .

4METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .

7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13Comparison 01. Oral iron vs placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13Comparison 02. Oral iron with vitamin A vs placebo . . . . . . . . . . . . . . . . . . . . . .

13Comparison 03. Oral iron + vitamin A vs oral iron . . . . . . . . . . . . . . . . . . . . . . .

14Comparison 04. Controlled release oral iron vs regular oral iron . . . . . . . . . . . . . . . . . . .

14Comparison 05. Intramuscular iron sorbito-citric acid vs intramuscular dextran . . . . . . . . . . . . .

14Comparison 06. Intramuscular iron dextran vs intravenous iron dextran . . . . . . . . . . . . . . . .

14Comparison 07. Intramuscular iron sorbitol citric acid vs intravenous iron dextran . . . . . . . . . . . .

15Comparison 08. Intravenous iron vs placebo . . . . . . . . . . . . . . . . . . . . . . . . .

15Comparison 09. Intravenous iron vs regular oral iron . . . . . . . . . . . . . . . . . . . . . .

15Comparison 10. Intravenous iron vs controlled release oral iron . . . . . . . . . . . . . . . . . . .

16Comparison 11. Intravenous iron + hydrocortisone vs intravenous iron . . . . . . . . . . . . . . . .

16Comparison 12. 2/3 dose intravenous iron vs full dose intravenous iron . . . . . . . . . . . . . . . .

16INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17Analysis 01.01. Comparison 01 Oral iron vs placebo, Outcome 01 Anaemic during 2nd trimester. . . . . . . .

18Analysis 01.02. Comparison 01 Oral iron vs placebo, Outcome 02 Haemoglobin levels (g/dl) . . . . . . . .

18Analysis 01.03. Comparison 01 Oral iron vs placebo, Outcome 03 Ferritin levels (ln ug/l) . . . . . . . . . .

18Analysis 01.04. Comparison 01 Oral iron vs placebo, Outcome 04 Serum iron (mg/l) . . . . . . . . . . .

19Analysis 01.05. Comparison 01 Oral iron vs placebo, Outcome 05 Side effects . . . . . . . . . . . . . .

19Analysis 01.06. Comparison 01 Oral iron vs placebo, Outcome 06 Nausea and vomiting . . . . . . . . . .

20Analysis 01.07. Comparison 01 Oral iron vs placebo, Outcome 07 Constipation . . . . . . . . . . . . .

20Analysis 01.08. Comparison 01 Oral iron vs placebo, Outcome 08 Abdominal cramps . . . . . . . . . . .

21Analysis 02.01. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 01 Anaemic during 2nd trimester. .

21Analysis 02.02. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 02 Haemoglobin levels (g/dl) . . .

21Analysis 02.03. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 03 Ferritin levels (ln ug/l) . . . .

22Analysis 02.04. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 04 Serum iron (mg/l) . . . . . .

22Analysis 03.01. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 01 Anaemia during second trimester .

22Analysis 03.02. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 02 Haemoglobin levels (g/dl) . . . .

23Analysis 03.03. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 03 Ferritin (ln ug/l) . . . . . . .

iTreatments for iron deficiency anaemia in pregnancy (Review)


23Analysis 03.04. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 04 Serum iron (mg/l) . . . . . .

23Analysis 04.01. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 01 Side effects . . . .

24Analysis 04.02. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 02 Nausea and vomiting .

24Analysis 04.03. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 03 Constipation . . . .

25Analysis 04.04. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 04 Abdominal cramps . .

25Analysis 05.01. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 01 Pain at

injection site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26Analysis 05.02. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 02 Skin

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

26Analysis 05.03. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 03 Venous

thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27Analysis 05.04. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 04 Nausea or

vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27Analysis 05.05. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 05 Headaches

28Analysis 05.06. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 06 Shivering

28Analysis 05.07. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 07 Itching

29Analysis 05.08. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 08 Metallic

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

29Analysis 06.01. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 01 Pain at injection

site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30Analysis 06.02. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 02 Skin discolouration

at injection site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30Analysis 06.03. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 03 Venous thrombosis

31Analysis 06.04. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 04 Nausea or vomiting

31Analysis 06.05. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 05 Headaches . .

32Analysis 06.06. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 06 Shivering . .

32Analysis 06.07. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 07 Itching . . .

33Analysis 06.08. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 08 Metallic taste in

mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33Analysis 07.01. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 01 Pain at

injection site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34Analysis 07.02. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 02 Skin

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

34Analysis 07.03. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 03 Venous

thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35Analysis 07.04. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 04 Nausea

or vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35Analysis 07.05. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 05

Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36Analysis 07.06. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 06 Shivering

36Analysis 07.07. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 07 Itching

37Analysis 07.08. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome 08 Metallic

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

37Analysis 08.01. Comparison 08 Intravenous iron vs placebo, Outcome 01 Side effects . . . . . . . . . . .

38Analysis 08.02. Comparison 08 Intravenous iron vs placebo, Outcome 02 Nausea or vomiting . . . . . . . .

38Analysis 08.03. Comparison 08 Intravenous iron vs placebo, Outcome 03 Constipation . . . . . . . . . .

39Analysis 08.04. Comparison 08 Intravenous iron vs placebo, Outcome 04 Abdominal cramps . . . . . . . .

39Analysis 09.01. Comparison 09 Intravenous iron vs regular oral iron, Outcome 01 Side effects . . . . . . . .

40Analysis 09.02. Comparison 09 Intravenous iron vs regular oral iron, Outcome 02 Nausea or vomiting . . . . .

40Analysis 09.03. Comparison 09 Intravenous iron vs regular oral iron, Outcome 03 Constipation . . . . . . .

41Analysis 09.04. Comparison 09 Intravenous iron vs regular oral iron, Outcome 04 Abdominal cramps . . . . .

41Analysis 09.05. Comparison 09 Intravenous iron vs regular oral iron, Outcome 05 Diarrhoea . . . . . . . .

41Analysis 09.06. Comparison 09 Intravenous iron vs regular oral iron, Outcome 06 Haemoglobin at 36 weeks . . .

iiTreatments for iron deficiency anaemia in pregnancy (Review)


42Analysis 09.09. Comparison 09 Intravenous iron vs regular oral iron, Outcome 09 Maternal haemoglobin at delivery

42Analysis 09.10. Comparison 09 Intravenous iron vs regular oral iron, Outcome 10 Maternal haemoglobin at 6 weeks

42Analysis 09.13. Comparison 09 Intravenous iron vs regular oral iron, Outcome 13 Maternal mortality . . . . .

43Analysis 09.14. Comparison 09 Intravenous iron vs regular oral iron, Outcome 14 Preterm labour . . . . . . .

43Analysis 09.15. Comparison 09 Intravenous iron vs regular oral iron, Outcome 15 Caesarean section . . . . . .

44Analysis 09.16. Comparison 09 Intravenous iron vs regular oral iron, Outcome 16 Operative vaginal delivery . . .

44Analysis 09.17. Comparison 09 Intravenous iron vs regular oral iron, Outcome 17 Postpartum haemorrhage . . .

45Analysis 09.18. Comparison 09 Intravenous iron vs regular oral iron, Outcome 18 Low birth weight (under 2,500g)

45Analysis 09.19. Comparison 09 Intravenous iron vs regular oral iron, Outcome 19 Neonatal birth weight . . . .

46Analysis 09.20. Comparison 09 Intravenous iron vs regular oral iron, Outcome 20 Small for gestational age . . .

46Analysis 09.21. Comparison 09 Intravenous iron vs regular oral iron, Outcome 21 Five minute Apgar score under seven

47Analysis 09.22. Comparison 09 Intravenous iron vs regular oral iron, Outcome 22 Neonatal mortality . . . . .

47Analysis 10.01. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 01 Side effects . . . .

48Analysis 10.02. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 02 Nausea or vomiting .

48Analysis 10.03. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 03 Constipation . . . .

49Analysis 10.04. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 04 Abdominal cramps . .

49Analysis 11.01. Comparison 11 Intravenous iron + hydrocortisone vs intravenous iron, Outcome 01 Tenderness or

erythema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50Analysis 11.02. Comparison 11 Intravenous iron + hydrocortisone vs intravenous iron, Outcome 02 Venous thrombosis

50Analysis 12.01. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 01 Allergic reaction

during infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51Analysis 12.02. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 02 Allergic reaction

after infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51Analysis 12.03. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 03 Life threatening

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

52Analysis 12.04. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 04 Discomfort needing

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

52Analysis 12.05. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 05 Immobilised by

painful joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53Analysis 12.06. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 06 Non-live births

53Analysis 12.07. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 07 Neonatal death

54Analysis 12.08. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 08 Stillbirth . .

54Analysis 12.09. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 09 Spontaneous

abortion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiiTreatments for iron deficiency anaemia in pregnancy (Review)


Treatments for iron deficiency anaemia in pregnancy (Review)

Cuervo LG, Mahomed K

This record should be cited as:

Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Cochrane Database of Systematic Reviews 2001, Issue

2. Art. No.: CD003094. DOI: 10.1002/14651858.CD003094.

This version first published online: 23 April 2001 in Issue 2, 2001.

Date of most recent substantive amendment: 31 January 2001

A B S T R A C T

Background

Iron deficiency is the most common cause of anaemia in pregnancy worldwide. Iron treatment can be given by mouth, intramuscular

or intravenous injection. Alternatively, blood transfusions and recombinant erythropoietin are also used.

Objectives

To assess the effectiveness of different treatments for iron deficiency anaemia in pregnancy (defined as haemoglobin less than 11 g/dl)

on maternal and neonatal morbidity and mortality.

Search strategy

Cochrane Pregnancy and Childbirth Group Specialised Register of Trial was searched. Date of last search: December 2000.

Selection criteria

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

Data collection and analysis

The search identified 54 trials. Five trials, involving approximately 1234 women, met the inclusion criteria. Trial quality was assessed.

Study authors were contacted for additional information.

Main results

Oral iron treatment in pregnancy was assessed in one small trial (n=125), where it was compared with placebo. This showed a reduction

in the number of women with haemoglobins under 11g/dl (odds ratio (OR) 0.12, 95% confidence interval (CI) 0.06 to 0.24) and a

greater mean haemoglobin level 11.3g/dl compared to 10.5 g/dl (weighted mean difference 0.80, 95% CI 0.62 to 0.98). However, there

were no data on clinically relevant outcomes. When comparing different iron treatments, the intravenous (IV) route of administration

was associated with an increased risk of venous thrombosis (1 trial, n=74. Iron dextran intramuscularly (IM) versus IV (n=49) OR 0.13,

95% CI 0.02-1.02. IM iron sorbitol-citric acid versus IV iron dextran, OR 0.12, 95% CI 0.02-0.94). Intravenous iron treatments were

compared with placebo in one trial (n=54) but only scarce data on adverse outcomes were suitable for inclusion in this review.

Authors’ conclusions

This review provides inconclusive evidence on the effects of treating iron deficiency anaemia in pregnancy due to the shortage of good

quality trials.

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

Not enough evidence to know the best way to treat iron deficiency anaemia in pregnancy

Anaemia happens when there are not enough red cells in the blood to carry oxygen to the tissues. Anaemia can be due to a number of

causes, including certain diseases or a shortage of iron, folic acid or vitamin B12. The most common cause of anaemia in pregnancy

is due to iron shortage. Iron treatment can be given by mouth, an injection into the muscle or into the vein, or by giving a blood



transfusion. There are not enough studies to show which way is best for women with anaemia in pregnancy but the route into the vein

can cause blockages in the veins. More research is needed.

B A C K G R O U N D

Anaemia is the reduction in the normal number of red blood cells

and quantity of haemoglobin in the blood. Anaemia in pregnancy

is defined by the World Health Organisation as a haemoglobin

value below 11 g/dl (WHO 1992). Haemoglobin is the protein in

the red blood cell which carries oxygen to the tissues. However, the

estimation of the haemoglobin concentration in the blood is not a

particularly sensitive indicator of anaemia because the delivery of

oxygen to the tissues depends on the concentration of haemoglobin

in the blood, the capacity of haemoglobin to bind oxygen and the

blood flow through the tissue. A high haemoglobin concentration

causes increased blood viscosity which decreases the blood flow

through the tissues. In some cases, for example in pre-eclampsia,

increased haemoglobin concentration is caused by poor increase

in plasma volume which is under independent control from the

red cell mass.

The common causes of anaemia include iron deficiency, fo-

late deficiency, vitamin B12 deficiency, bone marrow suppres-

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

blood loss (e.g. hook worm infestation) and underlying malig-

nancies (WHO 1992), with iron deficiency anaemia being the

most common cause of anaemia in pregnant women worldwide

(Williams 1992; Lops 1995; Goroll 1997). However, neither

blood haemoglobin 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 haemoglobin levels and

serum iron fluctuates depending on recent iron intake. Serum fer-

ritin may be a better indicator of iron status as the examination of

iron stores in the bone marrow is impractical. However, histori-

cally, blood haemoglobin levels have been used, the test being sim-

ple and inexpensive to undertake and the WHO define anaemia

in pregnancy as haemoglobin levels less than 11 g/dl.

During pregnancy there is an increase in both red cell mass and

plasma volume to accommodate the needs of the growing uterus

and fetus. The plasma volume increases more than the red cell

mass leading to a fall in the concentration of haemoglobin in the

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

drop in haemoglobin 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 haemoglobin women and babies would benefit from

iron treatment. As discussed below, some studies suggest that the

physiological decrease in haemoglobin is associated with improved

outcomes for the baby (Steer 1995; Mahomed 1989), whilst others

have identified adverse long term outcomes for the baby (Walter

1994).

Anaemia has been associated with general weakness, tiredness and

dizziness but the level of haemoglobin associated with these symp-

toms in pregnancy is unknown. It is suggested that the iron stores

of the woman’s body become reduced during pregnancy (as a re-

sult 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 haemoglobin levels. Some will argue that this is

a well designed mechanism to continue to deliver oxygen to the

tissues in the presence of lowered iron stores. An observational

study done in London UK found that low levels of haemoglobin,

commonly considered as mild anaemia, were associated with a

better prognosis for the fetus, although figures did not appear to

be corrected for women with pre-eclampsia (Steer 1995). How-

ever, others argue that reduced iron stores are a health problem for

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

considered anaemia (haemoglobin levels between 7 g/dl and 10

g/dl) as a risk factor for fetal death, premature delivery, low birth

weight and other adverse outcomes (Williams 1992). Some sug-

gest a link between maternal anaemia in pregnancy on the later

developmental problems of the children (Williams 1992; Letsky

2001). There is evidence that when maternal haemoglobin levels

are under 7 g/dl, there is a higher risk in the mother of develop-

ing cardiac heart failure which has adverse consequences on the

mother and fetus (WHO 1992; Williams 1992; Lops 1995). The

suggestion that low iron stores in the mother during pregnancy

may affect the child’s later development, means that long term

outcomes on the baby should be outcome measures in any study

on the treatment of anaemia in pregnancy. There is also a strong

case for studying separately physiological anaemia, mild anaemia

and severe anaemia in pregnancy.

In developing countries anaemia in pregnancy is high and this is

attributed to poor nutrition and the high incidence of diseases, and

it can be associated with increased problems including postpartum

haemorrhage which is a major contributor to maternal mortality

in many developing countries (WHO 1992). However, anaemia

may only be a marker of various social and nutritional conditions,

and the changes on haemoglobin levels could have a minor effect

on morbidity or mortality if other conditions are not changed

(Goroll 1997).

There are various possible forms of treatment for iron deficiency

anaemia. Iron can be given by mouth, by intramuscular injection

or intravenous injection. It is also possible to give iron by giving

a blood transfusion, and recombinant erythropoietin in conjunc-

tion with iron is a further possibility. Anecdotal evidence suggests



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

is associated with the gastrointestinal side effects of nausea and

constipation. Intramuscular or intravenous iron is thought to be

associated with allergic reactions and anaphylactic shock as well

as venous thrombosis and occasionally cardiac arrest and death.

Blood transfusion runs the risk of possible parasitic or viral infec-

tion transmissions such as HIV and hepatitis, despite screening.

There is also the possibility of bovine spongioform encephalitis

(BSE) and as yet unknown viral infections. Oral iron is often the

choice of route of administration for mild anaemia, with intra-

muscular and intravenous routes used in cases of extreme anaemia

where side effects may need to be balanced against the possibility

of cardiac failure due to severe anaemia. Recommendations for

the treatment of anaemia are currently based on expert opinions

rather than systematic reviews of randomised clinical trials, and

may not take into account possible side effects of the treatment

such as allergic reactions, viral or parasitic transmission from blood

transfusions and discomfort generated by common side effects of

iron.

The aim of this review is, therefore, to search systematically for,

and combine the evidence from all relevant randomised controlled

trials of iron treatment for anaemia due to iron deficiency in preg-

nancy, in order to provide the best reliable and valid evidence to

guide clinical practice.

O B J E C T I V E S

The principal objective was to determine the overall effect of

iron therapy on iron deficiency anaemia in pregnancy, measuring

neonatal and maternal morbidity and mortality, haematological

parameters and side effects of treatment. The review also com-

pared different forms of iron therapy for iron deficiency anaemia

on neonatal and maternal morbidity and mortality, haematologi-

cal parameters and side effects on mothers and babies.

The review did not discuss the need for iron supplementation of

non-anaemic women since this issue has been addressed in another

review (Mahomed 2000). Similarly, it did not focus on vitamin

A, vitamin B12, folate deficiency, infectious or genetic anaemia,

which will be covered in other reviews.

C R I T E R I A F O R C O N S I D E R I N G

S T U D I E S F O R T H I S R E V I E W

Types of studies

Randomised controlled trials related to the treatment of iron de-

ficiency anaemia in pregnancy were considered for this review.

When information was not clear or complete in the abstract, the

’materials and methods’ of the reports were reviewed. Quasi-ran-

dom studies were not eligible for this review.

Iron deficiency anaemia definitions may be problematic due to the

controversy about which diagnostic tests are sufficient and reliable

enough to rule out other causes of anaemia, and to the fact that

anaemia causes are frequently combined. Therefore, for this review

we accepted the authors’ definition of iron deficiency anaemia.

Types of participants

Pregnant women with a diagnosis of anaemia (haemoglobin levels

under 11 g/dl) attributed to iron deficiency.

Types of intervention

(1) All types of iron preparations versus placebo/no treatment.

(2) Different forms of oral iron preparations used for the treatment

of anaemia.

(3) Oral iron in combination with other haematinics versus regular

oral iron.

(4) Oral iron in combination with substances that could increase

its absorption versus regular oral iron.

(5) Slow release preparations versus regular oral iron.

(6) Intramuscular iron versus regular oral iron.

(7) Intravenous iron versus regular oral iron.

(8) Intravenous versus intramuscular iron therapies.

(9) Different dosages of above combinations.

(10) Blood transfusion versus oral iron therapy.

(11) Blood transfusion versus parenteral iron.

(12) Recombinant erythropoietin versus oral iron therapy.

(13) Recombinant erythropoietin versus parenteral iron therapy.

(14) Parenteral iron versus oral iron.

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

preparations different from controlled release oral iron.

Types of outcome measures

1. Women

1.1Clinical Outcomes

1.1.1 Mortality

1.1.2 Morbidity

1.1.2.1 Preterm labour

1.1.2.2 Premature delivery

1.1.2.3 Puerperal sepsis

1.1.2.4 Systemic bacterial infection after delivery

1.1.2.5 Fever

1.1.2.6 Pneumonia

1.1.2.7 Postpartum haemorrhage (equal to or more than 500 ml)

1.1.2.8 Heart failure

1.1.2.9 Incapacity to work due to disease

1.1.2.10 Days in intensive care unit (ICU)

1.1.2.11 Days hospitalized during pregnancy

1.1.2.12 Hypertensive disorders of pregnancy

1.1.2.13 Malaria

1.1.2.14 Urinary tract infection

1.2 Haematological outcomes

1.2.1 Maternal serum ferritin

1.2.2 Maternal serum iron



1.2.3 Haemoglobin levels

1.3 Long term haematological outcomes (not pre-specified in orig-

inal protocol)

2 Newborn

2.1 Clinical Outcomes

2.1.1 Mortality

2.1.2 Morbidity

2.1.2.1 Low birth weight (less than 2,500 g)

2.1.2.2 Jaundice requiring hospital admission or plasmapheresis

2.1.2.3 Respiratory disease requiring ventilation

2.1.2.4 Admission to neonatal intensive care unit

2.1.2.5 Five minute Apgar score under seven

2.1.2.6 Days hospitalized

2.1.2.7 Small for gestational age

2.1.3 Haematological outcomes

2.1.3.1 Cord serum ferritin

2.1.3.2 Cord haemoglobin

2.1.4 Long term outcomes (not pre-specified in original protocol)

2.1.4.1 Haemoglobin levels at 1 year (not pre-specified in original

protocol)

2.1.4.2 Serum ferritin at 1 year (not pre-specified in original pro-

tocol)

2.1.4.3 Neurological development at 1 year (not pre-specified in

original protocol)

3. Maternal side effects

3.1 Gastrointestinal effects

3.1.1 Nausea

3.1.2 Vomiting

3.1.3 Diarrhoea

3.1.4 Epigastric pain

3.1.5 Constipation

3.2 Local symptoms

3.2.1 Pain or tenderness

3.2.2 Discolouration

3.2.3 Pigmentation or staining of injection site

3.2.4 Erythema

3.3 Systemic symptoms

3.3.1 Myalgia

3.3.2 Arthralgia

3.3.3 Abscess formation at injection site

3.3.4 Fever following treatment (> 37.5ºC)

3.3.5 Allergic reactions

3.3.6 Anaphylactic shock

3.4 Incapacity to work due to an adverse effect of medication.

S E A R C H M E T H O D S F O R

I D E N T I F I C A T I O N O F S T U D I E S

See: methods used in reviews.

The following sources of information were used initially:

This review has drawn on the search strategy developed for the

Cochrane Pregnancy and Childbirth Group as a whole. The

full list of journals and conference proceedings, as well as the

search strategies for the electronic databases, which are searched

by the Group on behalf of its reviewers, is given in detail in

the ’Search strategies for the identification of studies’ section

within the editorial information about the Cochrane Pregnancy

and Childbirth Group. Briefly, the Group’s electronic searches

include MEDLINE and the Cochrane Controlled Trials Register.

Date of last search: December 2000.

Relevant trials, which are identified through the Group’s search

strategy, are entered into the Group’s Specialised Register of

Controlled Trials. Please see Review Group’s details for more

information.

In addition, MEDLINE on PubMed was searched in September

1998, for the period 1966 to September 1998, using the

following terms:

(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)

Iron/therapeutic use

Pregnancy complications/prevention and control

Haematinics/adverse effects.

References in published material were checked.

M E T H O D S O F T H E R E V I E W

Trials under consideration were evaluated for methodological

quality and appropriateness for inclusion without consideration of

their results. Data from included trials were processed as described

in The Cochrane Collaboration Handbook (Clarke 2000). The

papers that passed this first screening were appraised using the

strategy proposed by Sackett (Sackett 1997).

When flaws in the study compromised validity, these flaws were

described and the study was excluded. Specifically, studies were

excluded if there was more than 20% of participants lost to follow-

up (with no explanation of cause) or if there was a difference

in the percentage lost to follow-up between compared groups of

more than 15%. Trials that combined anaemic with non-anaemic

women were excluded when more that 40% of the women were

non-anaemic and there was no significant difference in the baseline



distribution. Inclusion and exclusion criteria were established prior

to the initiation of the review.

D E S C R I P T I O N O F S T U D I E S

From the search, 54 trials were identified: two unpublished trials,

two congress abstracts and 50 published trials. Twenty eight were

excluded after first review as they were not randomised clinical tri-

als, included mostly non-anaemic women, evaluated postpartum

iron treatments or were focused on non iron deficiency anaemia.

Sixteen were excluded after critical appraisal due to methodologi-

cal flaws that compromised validity. Only 10 studies were eligible

for inclusion, but seven provided insufficient information so their

authors were actively searched and mailed, using data provided

in the paper and through active search of the Internet. Authors

for the papers by Singh (Singapore 1998), Visca (Visca 1996) and

Suharno (West Java 1993) were contacted through active Inter-

net search. The authors for the papers by Visca and Suharno re-

sponded to the queries. The authors of papers by Al Momen (Al

Momen 1996) were faxed but no reply was received. Authors for

the paper by Stein (Stein 1991) were not contactable.

Five trials were included in the review (Australia 1969; Singapore

1998; Tanzania 1988; UK 1965; West Java 1993). Most papers

focused on laboratory values rather than on clinical outcomes.

Clinical outcomes were assessed by Singh although these data were

unpublished; these data were provided by the author and have

been incorporated into this review.

M E T H O D O L O G I C A L Q U A L I T Y

We found studies that had both valid information and also data

with validity problems. Withdrawal rates were high, therefore, data

for some outcomes were incomplete. We used only the information

that fulfilled our pre-stated inclusion criteria.

The paper from West Java (West Java 1993) evaluated results at

the end of treatment during the second trimester of pregnancy.

We consider that this information would have been much more

valuable if outcomes had been evaluated at term or at least in the

third trimester, since positive increments in outcomes could subse-

quently disappear. This study provided information of good ran-

domisation process with concealment of allocation (other papers

lacked detail on this issue). This was the only paper that provided

sample size considerations. Its overall quality was good. There were

concerns about the clinical significance of the outcomes evalu-

ated after eight weeks of treatment, long before delivery was due.

Women were not followed until delivery and clinical outcomes

were not published.

The study in Singapore (Singapore 1998) provided data on haema-

tological measurements done at some clinically important ’mile-

stones’ such as the end of pregnancy, at delivery and in the post-

partum period. The authors also provided unpublished informa-

tion on relevant clinical outcomes. The overall quality of the paper

was graded as good. No sample size considerations were provided

and masking was not possible because the control group did not

receive a placebo. Information on randomisation was insufficient

in the published paper, but additional details were provided by the

authors upon request. This trial had no withdrawals. Published

baseline data suggest that the compared groups were similar at

baseline except for the mean haemoglobin level which was lower

for the parenteral iron group. However, we decided to include this

study in the review because such a difference would act to lower

the effect for the parenteral therapy, so the effects found may be

underestimated rather than overestimated.

The study in Tanzania (Tanzania 1988) provided insufficient in-

formation about the randomisation procedure. There was a high

rate of dropouts for most outcomes so the only information used

was that on side effects.

In a similar way, the study in the United Kingdom (UK 1965) had

inappropriate randomisation strategies and no care was taken to

conceal the allocation of interventions. It had high rates of women

who did not have follow-up. The study was used to obtain data

on side effects of interventions.

The study in Australia (Australia 1969) had some methodological

flaws that made the inclusion of two of the four analysis groups

inappropriate. Researchers masked two intervention groups and

kept unmasked the other two groups for one month. Afterwards

they unmasked the whole trial. We used only data obtained during

the first month of treatment in the two masked groups. Useful data

were restricted to side effects. The authors provided insufficient

data to incorporate other outcomes in the analysis and overall it

was also a study with methodological flaws that compromised the

validity of other data.

R E S U L T S

The search identified 54 trials. Five trials, involving approximately

1234 women, met the inclusion criteria. Globally, results for in-

cluded outcomes were unsatisfactory and susceptible to bias due

to the fact that most of them were extracted from one or two trials

and these trials had small sample sizes.

When oral treatments were compared with placebo, data provided

from one trial showed that the risk of being anaemic during the

second trimester would be reduced for women receiving iron (odds

ratio (OR) 0.12, 95% confidence interval (CI) 0.06-0.24) . In the

iron-treated group, the mean haemoglobin level was greater, 11.3

g/dl compared to 10.5g/dl (weighted mean difference (WMD)

0.80, 95% CI 0.62-0.98), as was the mean serum ferritin level.

There were trends towards increased side effects (nausea, vomit-

ing, constipation and abdominal cramps) but numbers were too



small to be of value. There were no measurements of other clin-

ical outcomes, so the possible benefits to women and babies are

unclear. Also, conclusions should be approached with care as they

are drawn from a small population of participants (n=125). Fur-

thermore, one trial assessed outcomes during the second trimester

(West Java 1993) and we cannot be sure that those women sus-

tained similar haemoglobin status during the rest of their preg-

nancy. There was no assessment of the haematological condition

of the women at delivery. For the population considered in that

same trial, the addition of vitamin A to regular iron improved the

results of iron therapy. This is an interesting result that could be

taken as the best evidence available, but should be applied only

to populations of similar characteristics. Results may not apply to

other populations with different nutritional status, or with appro-

priate vitamin A intake in the diet.

Controlled release oral iron compared with other iron prepara-

tions was assessed in only one trial (Australia 1969). This trial

provided data on side effects but data on effectiveness were not

included due to high withdrawal rates. It found no differences

between controlled release iron and regular oral iron. This could

be explained by a real absence of clinically relevant differences or

because this small trial may have had insufficient power to find

such differences.

When comparing two intramuscular preparations, women receiv-

ing intramuscular iron-sorbitol complex had lower rates of skin

discoloration at injection sites (one trial, n=48, OR 0.14, 95%

CI 0.04-0.48) and headaches (one trial, n=48, OR 0.16, 95% CI

0.03 -0.70) when compared with intramuscular iron dextran. As

in previous studies, results should be interpreted with care as they

come from a single small trial but, in this particular case, random

allocation and concealment were appropriately done.

Comparing intramuscular treatments with intravenous treatment,

the intramuscular route produced more frequent pain at the injec-

tion site. The relevant trial had a factorial design, where data from

active treatments were compared to a single control group. No ad-

justments for multiple comparisons were done. Skin discoloration

was more frequently observed in people receiving intramuscular

iron-dextran.

Also, intravenous iron treatment was associated with a higher risk

of venous thrombosis compared with intramuscular iron. These

data were obtained from one trial done in United Kingdom (UK

1965). The same trial showed that headaches were more frequent

with iron-dextran when injected intramuscularly than when given

by intravenous infusion (n=49, OR 4.42, 95% CI 1.05-18.54).

Women complained of nausea more frequently when given oral

iron than when receiving intravenous preparations. This was found

in two different trials and, in both, the magnitude of the effect was

similar. The Australian trial (Australia 1969) compared controlled

release preparations with regular intravenous preparations and ob-

tained similar results to those for regular oral iron preparations -

a higher risk of nausea or vomiting compared with intravenous

infusion.

Comparing oral and intravenous treatments, the review found a

significantly higher risk of having constipation with regular oral

treatments when compared with intravenous treatments. Statisti-

cal significant differences were not found when the comparison

was made against controlled release iron. Data for this compari-

son were obtained from a single trial. One trial (Singapore 1998)

found higher haemoglobin values at the end of gestation were ob-

tained with intravenous treatments than with oral treatments. The

study population were mostly Malayan and Chinese women. No

maternal or neonatal deaths were recorded in the trial, the only one

assessing such outcomes in women receiving oral or intravenous

therapies.

When a comparison was made between iron-dextran infusion and

iron-dextran with an added dose of hydrocortisone, the addition

of hydrocortisone lowered the risk for venous thrombosis (UK

1965).

Two different doses of intravenous iron-dextran were compared

(Tanzania 1988). The lower dose had a statistically significant

lower rate of allergic reactions after the infusion had ended. Life

threatening allergic reactions were more frequent in the low dose

group, but this difference did not reach statistical significance.

Data required to evaluate effectiveness were not obtained from

this trial because it did not fulfil our quality criteria.

D I S C U S S I O N

The objective of this review was to address the effects of anaemia

treatments on maternal and neonatal morbidity and mortality.

Few of the included trials in this review considered those outcomes

and no important differences were found with the data provided.

Moreover, the available data were unlikely to give a different result,

as the number of people with available data on these outcomes was

so small that even if the treatments are effective, it is improbable

that differences would have shown up in such small groups. The

evidence found suggests that gastrointestinal side effects are more

common with oral iron treatments than with other preparations.

Iron treatments seem to increase haematological values. There is

inconclusive evidence on the benefits of controlled release iron

preparations compared with standard oral preparations, except for

a diminished frequency of constipation.

Intravenous treatments were associated with a higher risk of venous

thrombosis and a lower risk of changes in skin pigmentation. The

risk of venous thrombosis may be modified by the addition of

hydrocortisone to the infusion but there are no data to address

if this alters the effectiveness of the iron therapy. Evidence of a

relationship between doses of intravenous iron and risk of adverse



allergic reactions is inconclusive. No effectiveness measurements

were done for the compared doses.

None of the included trials were designed to evaluate time-to-

resolution of anaemia.

There is poor quality evidence from randomised trials to support

advice on whether clinical outcomes may be modified using avail-

able treatments in women with iron deficiency anaemia during

pregnancy.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

With the available data, we are unable to give evidence-based ad-

vice on whether, or how, to treat iron deficiency anaemia. While it

seems sensible to treat severe iron deficiency anaemia in pregnancy

with clinical symptoms, there is no good evidence to support any

specific treatment, except that the intravenous route is associated

with venous thrombosis. Whether to treat pregnant women with

mild anaemia remains controversial.

Implications for research

Severe iron deficiency anaemia affects a large number of pregnant

women in developing countries and may have considerable im-

pact on maternal and neonatal health. Considerable resources are

used to treat this condition, however, available evidence is insuf-

ficient to prove that the effort is worthwhile. This review is an

invitation for researchers in developing countries to initiate rele-

vant, high quality research that will fill the knowledge gaps about

this common condition, particularly looking at different degrees

of anaemia and measuring long term effects on both mothers and

babies.

N O T E S

This study was done in its majority while Luis Gabriel Cuervo

worked as assistant professor at the Clinical Epidemiology Unit of

the Pontificia Universidad Javeriana in Bogota, Colombia. Kassam

Mahomed worked with the Obstetrics and Gyneacology Depart-

ment at the University of Zimbabwe. During the second semester

of 2000, when the search was updated, Luis Gabriel Cuervo moved

to London, where he works for the British Medical Association

and Kassam Mahomed moved to Australia where he works for the

University of Adelaide.

P O T E N T I A L C O N F L I C T O F

I N T E R E S T

None known.

A C K N O W L E D G E M E N T S

Accommodation and financial support were provided by the

Cochrane Pregnancy and Childbirth Group in Liverpool (UK)

and the Pontificia Universidad Javeriana in Bogota (Colombia).

Special thanks to Prof Jim Neilson for his academic support and

to Sonja Henderson, Lynn Hampson and Claire Winterbottom

for their support as well. Also, thanks to Elizabeth Letsky and Gill

Gyte for commenting on draft manuscripts.

S O U R C E S O F S U P P O R T

External sources of support

• Financial support was given by

HRP-UNDP/UNFPA/WHO/World Bank Special Programme

in Human Reproduction, Geneva. SWITZERLAND

• Cochrane Pregnancy and Childbirth Group UK

Internal sources of support

• Pontificia Universidad Javeriana at Bogota COLOMBIA

R E F E R E N C E S

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Symonds E, Radden H, Cellier K. Controlled-release iron therapy

in pregnancy. Aust NZ J Obstet Gynaecol 1969;9(1):21–5. [MedLine:

1969188811].

Singapore 1998 {published and unpublished data}

Singh K, Fong YF, Kuperan P. A comparison between intravenous

iron polymaltose complex (Ferrum Hausmann) and oral ferrous fu-

marate in the treatment of iron deficiency anaemia in pregnancy. Eur

J Haematol 1998;60:119–24. [MedLine: 1998167778].

Tanzania 1988 {published data only}

Kaisi M, Ngwalle EWK, Runyoro DE, Rogers J. Evaluation of toler-

ance of and response to iron dextran (Imferon) adminisered by total

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UK 1965 {published data only}

Dawson D, Goldthorp W, Spencer D. Parenteral iron therapy in

pregnancy. J Obstet Gynaecol Br Cmmwlth 1965;72:89–93.



West Java 1993 {published data only}

Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplemen-

tation with vitamin A and iron for nutritional anaemia in pregnant

women in West Java, Indonesia. Lancet 1993;342:1325–8. [Med-

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References to studies excluded from this review

Al Momen 1996

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. Eur J Obstet Gynecol

Reprod Biol 1996;69:121–4. [MedLine: 1997058115].

Allaire 1961

Allaire B, Campagna F. Iron-deficiency anemia in pregnancy. Evalu-

ation of diagnosis and therapy by bone marrow hemosiderin. Obstet

Gynecol 1961;17:605–10.

Bare 1960

Bare W, Sullivan A. Comparison of intravenous saccharated iron ox-

ide and whole blood in treatment of hypochromic anemia of preg-

nancy. Am J Obstet Gynecol 1960;79:279–85.

Barrada 1991

Barrada M, Pateisky N, Schatten C, Salzer H, Vavra N, Spona

J, et al.Ferritin levels in newborn after prepartal iron med-

ication. Geburtshilfe Frauenheilkd 1991;51(5):366–8. [MedLine:

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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; Singapore, 1991:38.

Basu 1973

Basu RN, Sood SK, Ramachandan K, Mathur M, Ramalingaswami

V. Ethiopathogenesis of nutritional anemia in pregnancy: a ther-

apeutic approach. Am J Clin Nutr 1973;26(6):591–4. [MedLine:

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Breymann 1998

Breymann C. rhEPO/parenteral iron vs parenteral iron only in

the treatment of severe pregnancy anemia. Personal communication

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Breymann C, Visca E, Huch R, Huch A. Recombinant human ery-

thropoietin (rhEPO) for the therapy of severe iron deficiency anaemia

during pregnancy. 21st Conference of the Swiss Society of Gynecol-

ogy and Obstetrics, 1998:24.

Chanarin 1965

Chanarin I, Rothman D. Response to folic and folinic acid in mega-

loblastic anaemia in pregnancy. Journal of Obstetrics and Gynaecology

of the British Commonwealth 1965;72:374–5.

Fochi 1985

Fochi F, Ciampini M, Ceccarelli G. Efficacy of iron therapy: a

comparative evaluation of four iron preparations administered to

anaemic pregnant women. J Int Med Res 1985;13(1):1–11. [Med-

Line: 1985154970].

Hamilton 1973

Hamilton PJS, Gebbie DAM. Antenatal clinics as trial units in evalu-

ating 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. Nairobi:

East African Literature Bureau, 1973:463–6.

Hampel 1974

Hampel K, Roetz R. Influence of a long-time substitution with fo-

late-iron combination in pregnancy on serum folate and serum iron

and on hematological parameters. Geburtshilfe Frauenheilkd 1974;

34:409–17. [MedLine: 1974293872].

Hawkins 1970

Hawkins DF. Relative efficacy of sustained release iron and iron with

folic acid treatment in pregnancy. Personal communication 1987.

Holly 1955

Holly R. Anemia in pregnancy. Obstet Gynecol 1955;5:562–9.

Izak 1973

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. Scand J Haematol 1973;11(3):

236–40. [MedLine: 1974063093].

Jackson 1982

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Africa: a therapeutic trial. Am J Clin Nutr 1982;35:710–4. [MedLine:

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Jaud 1979

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Frauenheilkd 1979;39(4):317–23. [MedLine: 1979170627].

Mahale 1993

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istration for pregnant women. Asia Oceania J Obstet Gynaecol 1993;

19:141–4. [MedLine: 1993393475].

Preziosi 1997

Preziosi P, Prual A, Galan P, Daouda H, Boureima H, Hercberg

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82. [MedLine: 1998019349].

Sood 1975

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Stein 1991

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Christiansen 1961

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T A B L E S

Characteristics of included studies

Study Australia 1969

Methods Women were assigned randomly although the method is not clearly specified. Baseline data for the four

groups compared are very similar.

Participants Women attending the Queen Elizabeth Hospital in Woodville, Australia. Inclusion criteria were a gestational

age of 32 weeks or less and a haemoglobin level of 10.8 g/dl or less.

Interventions Four treatment groups were assembled:



ignorespaces http://dx.doi.org/10.1002/14651858.CD000117.pub2unskip unskip

Characteristics of included studies (Continued )

1. Ferrous gluconate 108 mg of elemental iron daily divided in three 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. Intravenous iron -dextran 2% solution. Initial test dose of 2 ml IV followed by 5 injections of 5 ml

(100mg).

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 two months and only for these two 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 Haemoglobin results were presented as increases in haemoglobin. Since standard deviations for the values

cannot be added to baseline data, the data was not included.

Allocation concealment B – Unclear

Study Singapore 1998

Methods Women were allocated using sealed envelopes with consecutive numbers.

Participants The first 100 women with diagnosed iron deficiency anaemia while attending for antenatal care at the National

University Hospital, Singapore. Data provided by one 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 infusion vs oral therapy with 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.

Allocation concealment A – Adequate

Study Tanzania 1988

Methods A randomisation list was used to generate the randomisation sequence.

Participants The study was done in a population of indigenous women. Inclusion criteria were:

1. Diagnosis of iron deficiency anaemia defined as haemoglobin under 10 g/dl; MCHC under 32%; hypochro-

mia; poikilocytosis and anisocytosis.

2. Age 16 years and above.

3. Gestational age under 36 wks.

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



Characteristics of included studies (Continued )

7. Rheumatoid arthritis.

8. Fever.

314 women received the full dose while 309 women received the 2/3 dose. Age, gravidity, parity, duration

of pregnancy and basal haemoglobin levels were similar for the groups. Nearly one forth of the women had

haemoglobin levels under 7.0 g/dl in both groups.

Interventions The dose of the two studied treatments was determined according to the recommendations of providers. In

the intervention group patients 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 post-partum. Infants were examined at the time of birth. Maternal haemoglobin levels were assessed

at each visit to the antenatal clinic and 6 and 16 weeks after delivery. Cord haemoglobin was measured as

well.

Notes Women were analysed by intention to treat. Loss to follow-up for haemoglobin 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.


Study UK 1965

Methods Method of allocation was a random number table. It is not clearly stated how allocation was concealed.

Participants Pregnant women in the third trimester with haemoglobin with less than 10 g/dl, MCHC under 30 % and a

marrow aspiration indicating iron deficiency. Patients with toxemia, infection or ante-partum 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.

Interventions Iron sorbitrol-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 discoloration

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 drop-out rate. Haemoglobin level data are not included

due to 81% drop-outs at pre-delivery. 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.


Study West Java 1993

Methods Allocation was done using a random number list from 1 to 305 and allocating patients 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 The study was conducted from April to September 1992 in 20 rural villages in three 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.

Haemoglobin 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. 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 Four different groups received two active treatments at most (factorial design). All preparations were given

daily for eight 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 Haemoglobin, 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 >10.9g/dl) was counted as a

dichotomic 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 intention to treat.

Allocation concealment A – Adequate

Abbreviations:

IV - intravenous

MCHC - mean corpuscular haemoglobin concentration

vs - versus

Characteristics of excluded studies

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.

Bare 1960 They allocated patients 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 posed. No information is provided regarding blinding or number of women that

completed the trial or that were accounted for each result.

Breymann 1998 Randomised open label trial.

Chanarin 1965 This study addressed megaloblastic anaemia.

Fochi 1985 Randomisation is not well balanced. The paper does not explain unbalanced groups.

Hamilton 1973 Allocation was done using a haphazard strategy, not a random one.

Hampel 1974 Used a haphazard allocation method (day of diagnosis).

Hawkins 1970 The study evaluates the use of medication in women with hemoglobin levels over 10.5 g/dl and uses non random

strategy for allocation.

Holly 1955 The study is in women with haemoglobin levels over 10 g/dl. Treatment allocation was not random.



Characteristics of excluded studies (Continued )

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.

Mahale 1993 This study has drop-outs that surpasses the limit established for this review.

Preziosi 1997 No fundamental data to assess validity.

Sood 1975 This study has a high proportion of women lost to follow-up exceding 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.

Valli Rani 1995 They used sequential strategy for allocation and not a random one.

Visca 1996 No fundamental data to assess validity.

A N A L Y S E S

Comparison 01. Oral iron vs placebo

Outcome titleNo. of

studies

No. of

participants Statistical method Effect size

01 Anaemic during 2nd trimester. 1 125 Peto Odds Ratio 95% CI 0.12 [0.06, 0.24]

02 Haemoglobin levels (g/dl) 1 125 Weighted Mean Difference (Fixed) 95% CI 0.80 [0.62, 0.98]

03 Ferritin levels (ln ug/l) 1 125 Weighted Mean Difference (Fixed) 95% CI 0.70 [0.52, 0.88]

04 Serum iron (mg/l) 1 125 Weighted Mean Difference (Fixed) 95% CI 0.04 [0.03, 0.05]

05 Side effects 1 51 Peto Odds Ratio 95% CI 2.30 [0.61, 8.63]

06 Nausea and vomiting 1 51 Peto Odds Ratio 95% CI 4.21 [0.67, 26.26]

07 Constipation 1 51 Peto Odds Ratio 95% CI 1.15 [0.26, 5.13]

08 Abdominal cramps 1 51 Peto Odds Ratio 95% CI 8.74 [0.53, 144.48]

Comparison 02. Oral iron with vitamin A vs placebo

Outcome titleNo. of

studies

No. of


01 Anaemic during 2nd trimester. 1 125 Peto Odds Ratio 95% CI 0.04 [0.02, 0.08]


03 Ferritin levels (ln ug/l) 1 125 Weighted Mean Difference (Fixed) 95% CI 0.70 [0.52, 0.88]


Comparison 03. Oral iron + vitamin A vs oral iron

Outcome titleNo. of

studies

No. of


01 Anaemia during second

trimester

1 126 Peto Odds Ratio 95% CI 0.14 [0.06, 0.35]


03 Ferritin (ln ug/l) 1 126 Weighted Mean Difference (Fixed) 95% CI 0.00 [-0.17, 0.17]




Comparison 04. Controlled release oral iron vs regular oral iron

Outcome titleNo. of

studies

No. of



02 Nausea and vomiting 1 49 Peto Odds Ratio 95% CI 0.95 [0.21, 4.27]



Comparison 05. Intramuscular iron sorbito-citric acid vs intramuscular dextran

Outcome titleNo. of

studies

No. of


01 Pain at injection site 1 48 Peto Odds Ratio 95% CI 0.99 [0.32, 3.05]

02 Skin discolouration at injection

site


03 Venous thrombosis 1 48 Peto Odds Ratio 95% CI Not estimable

04 Nausea or vomiting 1 48 Peto Odds Ratio 95% CI 0.92 [0.06, 15.16]

05 Headaches 1 48 Peto Odds Ratio 95% CI 0.16 [0.03, 0.70]

06 Shivering 1 48 Peto Odds Ratio 95% CI 0.12 [0.00, 6.27]

07 Itching 1 48 Peto Odds Ratio 95% CI 0.91 [0.20, 4.08]

08 Metallic taste in mouth 1 48 Peto Odds Ratio 95% CI 3.40 [0.54, 21.26]

Comparison 06. Intramuscular iron dextran vs intravenous iron dextran

Outcome titleNo. of

studies

No. of




site


03 Venous thrombosis 1 49 Peto Odds Ratio 95% CI 0.13 [0.02, 1.02]






Comparison 07. Intramuscular iron sorbitol citric acid vs intravenous iron dextran

Outcome titleNo. of

studies

No. of




site










Comparison 08. Intravenous iron vs placebo

Outcome titleNo. of

studies

No. of





04 Abdominal cramps 1 54 Peto Odds Ratio 95% CI Not estimable

Comparison 09. Intravenous iron vs regular oral iron

Outcome titleNo. of

studies

No. of






05 Diarrhoea 1 100 Peto Odds Ratio 95% CI 0.13 [0.01, 1.28]

06 Haemoglobin at 36 weeks 1 100 Weighted Mean Difference (Fixed) 95% CI 1.10 [1.09, 1.11]

09 Maternal haemoglobin at

delivery

1 100 Weighted Mean Difference (Fixed) 95% CI 0.60 [0.59, 0.61]

10 Maternal haemoglobin at 6

weeks

1 100 Weighted Mean Difference (Fixed) 95% CI 0.60 [0.59, 0.61]

13 Maternal mortality 1 100 Peto Odds Ratio 95% CI Not estimable

14 Preterm labour 1 100 Peto Odds Ratio 95% CI Not estimable

15 Caesarean section 1 100 Peto Odds Ratio 95% CI 1.27 [0.33, 4.98]

16 Operative vaginal delivery 1 100 Peto Odds Ratio 95% CI 1.52 [0.25, 9.08]

17 Postpartum haemorrhage 1 100 Peto Odds Ratio 95% CI 0.84 [0.26, 2.68]

18 Low birth weight (under

2,500g)

1 100 Peto Odds Ratio 95% CI Not estimable

19 Neonatal birth weight 1 100 Weighted Mean Difference (Fixed) 95% CI -119.30 [-312.10,

73.50]

20 Small for gestational age 1 100 Peto Odds Ratio 95% CI 1.69 [0.53, 5.39]

21 Five minute Apgar score under

seven


22 Neonatal mortality 1 100 Peto Odds Ratio 95% CI Not estimable

Comparison 10. Intravenous iron vs controlled release oral iron

Outcome titleNo. of

studies

No. of








Comparison 11. Intravenous iron + hydrocortisone vs intravenous iron

Outcome titleNo. of

studies

No. of


01 Tenderness or erythema 1 30 Peto Odds Ratio 95% CI 7.94 [0.47, 133.26]


Comparison 12. 2/3 dose intravenous iron vs full dose intravenous iron

Outcome titleNo. of

studies

No. of


01 Allergic reaction during

infusion


02 Allergic reaction after infusion 1 623 Peto Odds Ratio 95% CI 0.56 [0.38, 0.83]

03 Life threatening allergic

reaction during infusion


04 Discomfort needing analgesics

after infusion


05 Immobilised by painful joints 1 623 Peto Odds Ratio 95% CI 0.79 [0.29, 2.12]

06 Non-live births 1 507 Peto Odds Ratio 95% CI 0.85 [0.35, 2.08]

07 Neonatal death 1 507 Peto Odds Ratio 95% CI 0.53 [0.14, 1.98]

08 Stillbirth 1 507 Peto Odds Ratio 95% CI 0.69 [0.25, 1.93]

09 Spontaneous abortion 1 507 Peto Odds Ratio 95% CI 2.86 [0.40, 20.42]

I N D E X T E R M S

Medical Subject Headings (MeSH)

Anemia, Iron-Deficiency [∗therapy]; Iron [∗administration & dosage]; Pregnancy Complications, Hematologic [∗ therapy]; Randomized

Controlled Trials

MeSH check words

Female; Humans; Pregnancy

C O V E R S H E E T

Title Treatments for iron deficiency anaemia in pregnancy

Authors Cuervo LG, Mahomed K

Contribution of author(s) Both reviewers appraised the papers independently. Luis Gabriel Cuervo took the lead on

writing the review with Kassam Mahomed providing comments on the various drafts.

Issue protocol first published 1999/4

Review first published 2001/2

Date of most recent amendment 02 March 2001

Date of most recent

SUBSTANTIVE amendment

31 January 2001

What’s New This review was done in 1998 and updated for publication on January 2000.

Date new studies sought but

none found

Information not supplied by author



Date new studies found but not

yet included/excluded


Date new studies found and

included/excluded


Date authors’ conclusions

section amended


Contact address A/Prof Luis Gabriel Cuervo-Amore

Research Promotion and Development Unit (IKM/RC)

Pan American Health Organization

525 23rd St

NW

Washington

DC 20037-2895

USA

E-mail: [email protected]

Tel: +1 202 9743135

DOI 10.1002/14651858.CD003094

Cochrane Library number CD003094

Editorial group Cochrane Pregnancy and Childbirth Group

Editorial group code HM-PREG

G R A P H S A N D O T H E R T A B L E S

Analysis 01.01. Comparison 01 Oral iron vs placebo, Outcome 01 Anaemic during 2nd trimester.

Review: Treatments for iron deficiency anaemia in pregnancy

Comparison: 01 Oral iron vs placebo

Outcome: 01 Anaemic during 2nd trimester.

Study Oral iron Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

West Java 1993 20/63 52/62 100.0 0.12 [ 0.06, 0.24 ]

Total (95% CI) 63 62 100.0 0.12 [ 0.06, 0.24 ]

Total events: 20 (Oral iron), 52 (Placebo)

Test for heterogeneity: not applicable

Test for overall effect z=5.87 p<0.00001

0.1 0.2 0.5 1 2 5 10

Oral Iron Better Oral Iron Worse



Analysis 01.02. Comparison 01 Oral iron vs placebo, Outcome 02 Haemoglobin levels (g/dl)



Outcome: 02 Haemoglobin levels (g/dl)

Study Oral iron Placebo Weighted Mean Difference (Fixed) Weight Weighted Mean Difference (Fixed)

N Mean(SD) N Mean(SD) 95% CI (%) 95% CI

West Java 1993 63 11.30 (0.52) 62 10.50 (0.51) 100.0 0.80 [ 0.62, 0.98 ]

Total (95% CI) 63 62 100.0 0.80 [ 0.62, 0.98 ]



-10.0 -5.0 0 5.0 10.0

Oral iron worse Oral iron better

Analysis 01.03. Comparison 01 Oral iron vs placebo, Outcome 03 Ferritin levels (ln ug/l)



Outcome: 03 Ferritin levels (ln ug/l)



West Java 1993 63 3.30 (0.50) 62 2.60 (0.50) 100.0 0.70 [ 0.52, 0.88 ]

Total (95% CI) 63 62 100.0 0.70 [ 0.52, 0.88 ]



-10.0 -5.0 0 5.0 10.0


Analysis 01.04. Comparison 01 Oral iron vs placebo, Outcome 04 Serum iron (mg/l)



Outcome: 04 Serum iron (mg/l)



West Java 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 ]



-10.0 -5.0 0 5.0 10.0




Analysis 01.05. Comparison 01 Oral iron vs placebo, Outcome 05 Side effects



Outcome: 05 Side effects


n/N n/N 95% CI (%) 95% CI

Australia 1969 7/24 4/27 100.0 2.30 [ 0.61, 8.63 ]

Total (95% CI) 24 27 100.0 2.30 [ 0.61, 8.63 ]



Test for overall effect z=1.23 p=0.2

0.1 0.2 0.5 1 2 5 10

Oral iron better Oral iron worse

Analysis 01.06. Comparison 01 Oral iron vs placebo, Outcome 06 Nausea and vomiting



Outcome: 06 Nausea and vomiting


n/N n/N 95% CI (%) 95% CI

Australia 1969 4/24 1/27 100.0 4.21 [ 0.67, 26.26 ]

Total (95% CI) 24 27 100.0 4.21 [ 0.67, 26.26 ]




0.1 0.2 0.5 1 2 5 10




Analysis 01.07. Comparison 01 Oral iron vs placebo, Outcome 07 Constipation



Outcome: 07 Constipation


n/N n/N 95% CI (%) 95% CI

Australia 1969 4/24 4/27 100.0 1.15 [ 0.26, 5.13 ]

Total (95% CI) 24 27 100.0 1.15 [ 0.26, 5.13 ]




0.1 0.2 0.5 1 2 5 10


Analysis 01.08. Comparison 01 Oral iron vs placebo, Outcome 08 Abdominal cramps



Outcome: 08 Abdominal cramps


n/N n/N 95% CI (%) 95% CI

Australia 1969 2/24 0/27 100.0 8.74 [ 0.53, 144.48 ]

Total (95% CI) 24 27 100.0 8.74 [ 0.53, 144.48 ]




0.1 0.2 0.5 1 2 5 10




Analysis 02.01. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 01 Anaemic during 2nd

trimester.


Comparison: 02 Oral iron with vitamin A vs placebo

Outcome: 01 Anaemic during 2nd trimester.

Study Oral iron + Vit A Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

West Java 1993 2/63 52/62 100.0 0.04 [ 0.02, 0.08 ]

Total (95% CI) 63 62 100.0 0.04 [ 0.02, 0.08 ]

Total events: 2 (Oral iron + Vit A), 52 (Placebo)



0.1 0.2 0.5 1 2 5 10

Iron + Vit A better Iron + Vit A worse

Analysis 02.02. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 02 Haemoglobin levels (g/dl)




Study Oral iron + Vit A Placebo Weighted Mean Difference (Fixed) Weight Weighted Mean Difference (Fixed)


West Java 1993 63 11.80 (0.55) 62 10.50 (0.51) 100.0 1.30 [ 1.11, 1.49 ]

Total (95% CI) 63 62 100.0 1.30 [ 1.11, 1.49 ]



-10.0 -5.0 0 5.0 10.0

Iron + Vit A worse Iron + Vit A better

Analysis 02.03. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 03 Ferritin levels (ln ug/l)



Outcome: 03 Ferritin levels (ln ug/l)



West Java 1993 63 3.30 (0.50) 62 2.60 (0.50) 100.0 0.70 [ 0.52, 0.88 ]

Total (95% CI) 63 62 100.0 0.70 [ 0.52, 0.88 ]



-10.0 -5.0 0 5.0 10.0




Analysis 02.04. Comparison 02 Oral iron with vitamin A vs placebo, Outcome 04 Serum iron (mg/l)






West Java 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 ]



-10.0 -5.0 0 5.0 10.0


Analysis 03.01. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 01 Anaemia during second

trimester


Comparison: 03 Oral iron + vitamin A vs oral iron

Outcome: 01 Anaemia during second trimester

Study oral iron + vit A oral iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

West Java 1993 2/63 20/63 100.0 0.14 [ 0.06, 0.35 ]

Total (95% CI) 63 63 100.0 0.14 [ 0.06, 0.35 ]

Total events: 2 (oral iron + vit A), 20 (oral iron)



0.1 0.2 0.5 1 2 5 10

Iron + Vit A better Iron + Vit A worse

Analysis 03.02. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 02 Haemoglobin levels (g/dl)




Study Oral iron + Vit A Oral iron Weighted Mean Difference (Fixed) Weight Weighted Mean Difference (Fixed)


West Java 1993 63 11.80 (0.55) 63 11.30 (0.52) 100.0 0.50 [ 0.31, 0.69 ]

Total (95% CI) 63 63 100.0 0.50 [ 0.31, 0.69 ]



-10.0 -5.0 0 5.0 10.0




Analysis 03.03. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 03 Ferritin (ln ug/l)



Outcome: 03 Ferritin (ln ug/l)



West Java 1993 63 3.30 (0.50) 63 3.30 (0.50) 100.0 0.00 [ -0.17, 0.17 ]

Total (95% CI) 63 63 100.0 0.00 [ -0.17, 0.17 ]


Test for overall effect z=0.00 p=1

-10.0 -5.0 0 5.0 10.0


Analysis 03.04. Comparison 03 Oral iron + vitamin A vs oral iron, Outcome 04 Serum iron (mg/l)






West Java 1993 63 0.47 (0.04) 63 0.43 (0.04) 100.0 0.04 [ 0.03, 0.05 ]

Total (95% CI) 63 63 100.0 0.04 [ 0.03, 0.05 ]



-10.0 -5.0 0 5.0 10.0


Analysis 04.01. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 01 Side effects


Comparison: 04 Controlled release oral iron vs regular oral iron


Study Ctrl release iron Regular oral iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

Australia 1969 7/25 7/24 100.0 0.95 [ 0.28, 3.23 ]

Total (95% CI) 25 24 100.0 0.95 [ 0.28, 3.23 ]

Total events: 7 (Ctrl release iron), 7 (Regular oral iron)



0.1 0.2 0.5 1 2 5 10

Ctrl rel iron better Ctrl rel iron worse



Analysis 04.02. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 02 Nausea and

vomiting



Outcome: 02 Nausea and vomiting


n/N n/N 95% CI (%) 95% CI

Australia 1969 4/25 4/24 100.0 0.95 [ 0.21, 4.27 ]

Total (95% CI) 25 24 100.0 0.95 [ 0.21, 4.27 ]




0.1 0.2 0.5 1 2 5 10


Analysis 04.03. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 03 Constipation





n/N n/N 95% CI (%) 95% CI

Australia 1969 1/25 4/24 100.0 0.26 [ 0.04, 1.61 ]

Total (95% CI) 25 24 100.0 0.26 [ 0.04, 1.61 ]




0.1 0.2 0.5 1 2 5 10




Analysis 04.04. Comparison 04 Controlled release oral iron vs regular oral iron, Outcome 04 Abdominal

cramps





n/N n/N 95% CI (%) 95% CI

Australia 1969 1/25 2/24 100.0 0.48 [ 0.05, 4.82 ]

Total (95% CI) 25 24 100.0 0.48 [ 0.05, 4.82 ]




0.1 0.2 0.5 1 2 5 10


Analysis 05.01. Comparison 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran, Outcome 01

Pain at injection site


Comparison: 05 Intramuscular iron sorbito-citric acid vs intramuscular dextran

Outcome: 01 Pain at injection site

Study Iron sorb-cit acid Iron dextran Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

UK 1965 13/25 12/23 100.0 0.99 [ 0.32, 3.05 ]

Total (95% CI) 25 23 100.0 0.99 [ 0.32, 3.05 ]

Total events: 13 (Iron sorb-cit acid), 12 (Iron dextran)



0.1 0.2 0.5 1 2 5 10

Iron sorb-cit better Iron sorb-cit worse




Skin discolouration at injection site



Outcome: 02 Skin discolouration at injection site


n/N n/N 95% CI (%) 95% CI

UK 1965 3/25 13/23 100.0 0.14 [ 0.04, 0.46 ]

Total (95% CI) 25 23 100.0 0.14 [ 0.04, 0.46 ]




0.1 0.2 0.5 1 2 5 10



Venous thrombosis



Outcome: 03 Venous thrombosis


n/N n/N 95% CI (%) 95% CI

x UK 1965 0/25 0/23 0.0 Not estimable

Total (95% CI) 25 23 0.0 Not estimable



Test for overall effect: not applicable

0.1 0.2 0.5 1 2 5 10





Nausea or vomiting



Outcome: 04 Nausea or vomiting


n/N n/N 95% CI (%) 95% CI

UK 1965 1/25 1/23 100.0 0.92 [ 0.06, 15.16 ]

Total (95% CI) 25 23 100.0 0.92 [ 0.06, 15.16 ]




0.1 0.2 0.5 1 2 5 10



Headaches



Outcome: 05 Headaches


n/N n/N 95% CI (%) 95% CI

UK 1965 1/25 7/23 100.0 0.16 [ 0.03, 0.70 ]

Total (95% CI) 25 23 100.0 0.16 [ 0.03, 0.70 ]




0.1 0.2 0.5 1 2 5 10





Shivering



Outcome: 06 Shivering


n/N n/N 95% CI (%) 95% CI

UK 1965 0/25 1/23 100.0 0.12 [ 0.00, 6.27 ]

Total (95% CI) 25 23 100.0 0.12 [ 0.00, 6.27 ]




0.1 0.2 0.5 1 2 5 10



Itching



Outcome: 07 Itching


n/N n/N 95% CI (%) 95% CI

UK 1965 4/25 4/23 100.0 0.91 [ 0.20, 4.08 ]

Total (95% CI) 25 23 100.0 0.91 [ 0.20, 4.08 ]




0.1 0.2 0.5 1 2 5 10





Metallic taste in mouth



Outcome: 08 Metallic taste in mouth


n/N n/N 95% CI (%) 95% CI

UK 1965 4/25 1/23 100.0 3.40 [ 0.54, 21.26 ]

Total (95% CI) 25 23 100.0 3.40 [ 0.54, 21.26 ]




0.1 0.2 0.5 1 2 5 10


Analysis 06.01. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 01 Pain at

injection site


Comparison: 06 Intramuscular iron dextran vs intravenous iron dextran


Study IM iron dextran IV iron dextran Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

UK 1965 12/23 3/26 100.0 6.51 [ 1.95, 21.73 ]

Total (95% CI) 23 26 100.0 6.51 [ 1.95, 21.73 ]

Total events: 12 (IM iron dextran), 3 (IV iron dextran)



0.1 0.2 0.5 1 2 5 10

IM Iron better IM iron worse



Analysis 06.02. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 02 Skin

discolouration at injection site





n/N n/N 95% CI (%) 95% CI

UK 1965 13/23 1/26 100.0 12.53 [ 3.67, 42.85 ]

Total (95% CI) 23 26 100.0 12.53 [ 3.67, 42.85 ]




0.1 0.2 0.5 1 2 5 10

IM iron better IM iron worse

Analysis 06.03. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 03 Venous

thrombosis





n/N n/N 95% CI (%) 95% CI

UK 1965 0/23 4/26 100.0 0.13 [ 0.02, 1.02 ]

Total (95% CI) 23 26 100.0 0.13 [ 0.02, 1.02 ]




0.1 0.2 0.5 1 2 5 10




Analysis 06.04. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 04 Nausea

or vomiting





n/N n/N 95% CI (%) 95% CI

UK 1965 1/23 2/26 100.0 0.57 [ 0.06, 5.73 ]

Total (95% CI) 23 26 100.0 0.57 [ 0.06, 5.73 ]




0.1 0.2 0.5 1 2 5 10


Analysis 06.05. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 05

Headaches





n/N n/N 95% CI (%) 95% CI

UK 1965 7/23 2/26 100.0 4.42 [ 1.05, 18.54 ]

Total (95% CI) 23 26 100.0 4.42 [ 1.05, 18.54 ]




0.1 0.2 0.5 1 2 5 10




Analysis 06.06. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 06

Shivering





n/N n/N 95% CI (%) 95% CI

UK 1965 1/23 2/26 100.0 0.57 [ 0.06, 5.73 ]

Total (95% CI) 23 26 100.0 0.57 [ 0.06, 5.73 ]




0.1 0.2 0.5 1 2 5 10


Analysis 06.07. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 07 Itching



Outcome: 07 Itching


n/N n/N 95% CI (%) 95% CI

UK 1965 4/23 3/26 100.0 1.60 [ 0.33, 7.81 ]

Total (95% CI) 23 26 100.0 1.60 [ 0.33, 7.81 ]




0.1 0.2 0.5 1 2 5 10




Analysis 06.08. Comparison 06 Intramuscular iron dextran vs intravenous iron dextran, Outcome 08 Metallic

taste in mouth





n/N n/N 95% CI (%) 95% CI

UK 1965 1/23 1/26 100.0 1.13 [ 0.07, 18.76 ]

Total (95% CI) 23 26 100.0 1.13 [ 0.07, 18.76 ]




0.1 0.2 0.5 1 2 5 10


Analysis 07.01. Comparison 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran, Outcome

01 Pain at injection site


Comparison: 07 Intramuscular iron sorbitol citric acid vs intravenous iron dextran


Study IM iron sorb-cit IV iron dextran Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

UK 1965 13/25 3/26 100.0 6.31 [ 1.96, 20.37 ]

Total (95% CI) 25 26 100.0 6.31 [ 1.96, 20.37 ]

Total events: 13 (IM iron sorb-cit), 3 (IV iron dextran)



0.1 0.2 0.5 1 2 5 10

IM sorb-cit better IM sorb-cit worse




02 Skin discolouration at injection site





n/N n/N 95% CI (%) 95% CI

UK 1965 3/25 1/26 100.0 3.02 [ 0.40, 22.83 ]

Total (95% CI) 25 26 100.0 3.02 [ 0.40, 22.83 ]




0.1 0.2 0.5 1 2 5 10



03 Venous thrombosis





n/N n/N 95% CI (%) 95% CI

UK 1965 0/25 4/26 100.0 0.12 [ 0.02, 0.94 ]

Total (95% CI) 25 26 100.0 0.12 [ 0.02, 0.94 ]




0.1 0.2 0.5 1 2 5 10





04 Nausea or vomiting





n/N n/N 95% CI (%) 95% CI

UK 1965 1/25 2/26 100.0 0.52 [ 0.05, 5.24 ]

Total (95% CI) 25 26 100.0 0.52 [ 0.05, 5.24 ]




0.1 0.2 0.5 1 2 5 10



05 Headaches





n/N n/N 95% CI (%) 95% CI

UK 1965 1/25 2/26 100.0 0.52 [ 0.05, 5.24 ]

Total (95% CI) 25 26 100.0 0.52 [ 0.05, 5.24 ]




0.1 0.2 0.5 1 2 5 10





06 Shivering





n/N n/N 95% CI (%) 95% CI

UK 1965 0/25 2/26 100.0 0.14 [ 0.01, 2.22 ]

Total (95% CI) 25 26 100.0 0.14 [ 0.01, 2.22 ]




0.1 0.2 0.5 1 2 5 10



07 Itching



Outcome: 07 Itching


n/N n/N 95% CI (%) 95% CI

UK 1965 4/25 3/26 100.0 1.45 [ 0.30, 7.02 ]

Total (95% CI) 25 26 100.0 1.45 [ 0.30, 7.02 ]




0.1 0.2 0.5 1 2 5 10





08 Metallic taste in mouth





n/N n/N 95% CI (%) 95% CI

UK 1965 4/25 1/26 100.0 3.85 [ 0.62, 23.94 ]

Total (95% CI) 25 26 100.0 3.85 [ 0.62, 23.94 ]




0.1 0.2 0.5 1 2 5 10


Analysis 08.01. Comparison 08 Intravenous iron vs placebo, Outcome 01 Side effects


Comparison: 08 Intravenous iron vs placebo


Study Intravenous iron Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

Australia 1969 3/27 4/27 100.0 0.72 [ 0.15, 3.49 ]

Total (95% CI) 27 27 100.0 0.72 [ 0.15, 3.49 ]

Total events: 3 (Intravenous iron), 4 (Placebo)



0.1 0.2 0.5 1 2 5 10

IV iron better IV iron worse



Analysis 08.02. Comparison 08 Intravenous iron vs placebo, Outcome 02 Nausea or vomiting





n/N n/N 95% CI (%) 95% CI

Australia 1969 0/27 1/27 100.0 0.14 [ 0.00, 6.82 ]

Total (95% CI) 27 27 100.0 0.14 [ 0.00, 6.82 ]




0.1 0.2 0.5 1 2 5 10


Analysis 08.03. Comparison 08 Intravenous iron vs placebo, Outcome 03 Constipation





n/N n/N 95% CI (%) 95% CI

Australia 1969 1/27 4/27 100.0 0.27 [ 0.04, 1.69 ]

Total (95% CI) 27 27 100.0 0.27 [ 0.04, 1.69 ]




0.1 0.2 0.5 1 2 5 10




Analysis 08.04. Comparison 08 Intravenous iron vs placebo, Outcome 04 Abdominal cramps





n/N n/N 95% CI (%) 95% CI

x Australia 1969 0/27 0/27 0.0 Not estimable





0.1 0.2 0.5 1 2 5 10


Analysis 09.01. Comparison 09 Intravenous iron vs regular oral iron, Outcome 01 Side effects


Comparison: 09 Intravenous iron vs regular oral iron


Study IV iron Oral regular iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

Australia 1969 3/27 7/24 100.0 0.33 [ 0.08, 1.28 ]

Total (95% CI) 27 24 100.0 0.33 [ 0.08, 1.28 ]

Total events: 3 (IV iron), 7 (Oral regular iron)



0.1 0.2 0.5 1 2 5 10




Analysis 09.02. Comparison 09 Intravenous iron vs regular oral iron, Outcome 02 Nausea or vomiting





n/N n/N 95% CI (%) 95% CI

Australia 1969 0/27 4/27 56.2 0.12 [ 0.02, 0.90 ]

Singapore 1998 0/50 3/50 43.8 0.13 [ 0.01, 1.28 ]

Total (95% CI) 77 77 100.0 0.12 [ 0.03, 0.56 ]


Test for heterogeneity chi-square=0.00 df=1 p=0.96 I =0.0%


0.1 0.2 0.5 1 2 5 10


Analysis 09.03. Comparison 09 Intravenous iron vs regular oral iron, Outcome 03 Constipation





n/N n/N 95% CI (%) 95% CI

Australia 1969 1/27 4/24 28.6 0.24 [ 0.04, 1.48 ]

Singapore 1998 0/50 13/50 71.4 0.10 [ 0.03, 0.33 ]

Total (95% CI) 77 74 100.0 0.13 [ 0.05, 0.35 ]


Test for heterogeneity chi-square=0.58 df=1 p=0.45 I =0.0%


0.1 0.2 0.5 1 2 5 10




Analysis 09.04. Comparison 09 Intravenous iron vs regular oral iron, Outcome 04 Abdominal cramps





n/N n/N 95% CI (%) 95% CI

Australia 1969 0/27 2/24 100.0 0.11 [ 0.01, 1.89 ]

Total (95% CI) 27 24 100.0 0.11 [ 0.01, 1.89 ]




0.1 0.2 0.5 1 2 5 10


Analysis 09.05. Comparison 09 Intravenous iron vs regular oral iron, Outcome 05 Diarrhoea



Outcome: 05 Diarrhoea


n/N n/N 95% CI (%) 95% CI

Singapore 1998 0/50 3/50 100.0 0.13 [ 0.01, 1.28 ]

Total (95% CI) 50 50 100.0 0.13 [ 0.01, 1.28 ]




0.1 0.2 0.5 1 2 5 10


Analysis 09.06. Comparison 09 Intravenous iron vs regular oral iron, Outcome 06 Haemoglobin at 36 weeks



Outcome: 06 Haemoglobin at 36 weeks

Study IV iron Oral regular iron Weighted Mean Difference (Fixed) Weight Weighted Mean Difference (Fixed)


Singapore 1998 50 11.00 (0.01) 50 9.90 (0.02) 100.0 1.10 [ 1.09, 1.11 ]

Total (95% CI) 50 50 100.0 1.10 [ 1.09, 1.11 ]



-10.0 -5.0 0 5.0 10.0

IV iron worse IV iron better



Analysis 09.09. Comparison 09 Intravenous iron vs regular oral iron, Outcome 09 Maternal haemoglobin at

delivery



Outcome: 09 Maternal haemoglobin at delivery



Singapore 1998 50 11.80 (0.02) 50 11.20 (0.02) 100.0 0.60 [ 0.59, 0.61 ]

Total (95% CI) 50 50 100.0 0.60 [ 0.59, 0.61 ]



-10.0 -5.0 0 5.0 10.0


Analysis 09.10. Comparison 09 Intravenous iron vs regular oral iron, Outcome 10 Maternal haemoglobin at 6

weeks



Outcome: 10 Maternal haemoglobin at 6 weeks



Singapore 1998 50 12.50 (0.01) 50 11.90 (0.02) 100.0 0.60 [ 0.59, 0.61 ]

Total (95% CI) 50 50 100.0 0.60 [ 0.59, 0.61 ]



-10.0 -5.0 0 5.0 10.0


Analysis 09.13. Comparison 09 Intravenous iron vs regular oral iron, Outcome 13 Maternal mortality



Outcome: 13 Maternal mortality


n/N n/N 95% CI (%) 95% CI

x Singapore 1998 0/50 0/50 0.0 Not estimable





0.1 0.2 0.5 1 2 5 10




Analysis 09.14. Comparison 09 Intravenous iron vs regular oral iron, Outcome 14 Preterm labour



Outcome: 14 Preterm labour


n/N n/N 95% CI (%) 95% CI






0.1 0.2 0.5 1 2 5 10


Analysis 09.15. Comparison 09 Intravenous iron vs regular oral iron, Outcome 15 Caesarean section



Outcome: 15 Caesarean section


n/N n/N 95% CI (%) 95% CI

Singapore 1998 5/50 4/50 100.0 1.27 [ 0.33, 4.98 ]

Total (95% CI) 50 50 100.0 1.27 [ 0.33, 4.98 ]




0.1 0.2 0.5 1 2 5 10




Analysis 09.16. Comparison 09 Intravenous iron vs regular oral iron, Outcome 16 Operative vaginal delivery



Outcome: 16 Operative vaginal delivery


n/N n/N 95% CI (%) 95% CI

Singapore 1998 3/50 2/50 100.0 1.52 [ 0.25, 9.08 ]

Total (95% CI) 50 50 100.0 1.52 [ 0.25, 9.08 ]




0.1 0.2 0.5 1 2 5 10


Analysis 09.17. Comparison 09 Intravenous iron vs regular oral iron, Outcome 17 Postpartum haemorrhage



Outcome: 17 Postpartum haemorrhage


n/N n/N 95% CI (%) 95% CI

Singapore 1998 6/50 7/50 100.0 0.84 [ 0.26, 2.68 ]

Total (95% CI) 50 50 100.0 0.84 [ 0.26, 2.68 ]




0.1 0.2 0.5 1 2 5 10




Analysis 09.18. Comparison 09 Intravenous iron vs regular oral iron, Outcome 18 Low birth weight (under

2,500g)



Outcome: 18 Low birth weight (under 2,500g)


n/N n/N 95% CI (%) 95% CI






0.1 0.2 0.5 1 2 5 10


Analysis 09.19. Comparison 09 Intravenous iron vs regular oral iron, Outcome 19 Neonatal birth weight



Outcome: 19 Neonatal birth weight



Singapore 1998 50 2966.70 (540.90) 50 3086.00 (437.30) 100.0 -119.30 [ -312.10, 73.50 ]

Total (95% CI) 50 50 100.0 -119.30 [ -312.10, 73.50 ]



-10.0 -5.0 0 5.0 10.0




Analysis 09.20. Comparison 09 Intravenous iron vs regular oral iron, Outcome 20 Small for gestational age



Outcome: 20 Small for gestational age


n/N n/N 95% CI (%) 95% CI

Singapore 1998 8/50 5/50 100.0 1.69 [ 0.53, 5.39 ]

Total (95% CI) 50 50 100.0 1.69 [ 0.53, 5.39 ]




0.1 0.2 0.5 1 2 5 10


Analysis 09.21. Comparison 09 Intravenous iron vs regular oral iron, Outcome 21 Five minute Apgar score

under seven



Outcome: 21 Five minute Apgar score under seven


n/N n/N 95% CI (%) 95% CI

Singapore 1998 1/50 1/50 100.0 1.00 [ 0.06, 16.21 ]

Total (95% CI) 50 50 100.0 1.00 [ 0.06, 16.21 ]




0.1 0.2 0.5 1 2 5 10




Analysis 09.22. Comparison 09 Intravenous iron vs regular oral iron, Outcome 22 Neonatal mortality



Outcome: 22 Neonatal mortality


n/N n/N 95% CI (%) 95% CI






0.1 0.2 0.5 1 2 5 10


Analysis 10.01. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 01 Side effects


Comparison: 10 Intravenous iron vs controlled release oral iron


Study IV iron Control release iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

Australia 1969 3/27 7/25 100.0 0.34 [ 0.09, 1.35 ]

Total (95% CI) 27 25 100.0 0.34 [ 0.09, 1.35 ]

Total events: 3 (IV iron), 7 (Control release iron)



0.1 0.2 0.5 1 2 5 10




Analysis 10.02. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 02 Nausea or

vomiting





n/N n/N 95% CI (%) 95% CI

Australia 1969 0/27 4/25 100.0 0.11 [ 0.01, 0.83 ]

Total (95% CI) 27 25 100.0 0.11 [ 0.01, 0.83 ]




0.1 0.2 0.5 1 2 5 10


Analysis 10.03. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 03 Constipation





n/N n/N 95% CI (%) 95% CI

Australia 1969 1/27 1/25 100.0 0.92 [ 0.06, 15.22 ]

Total (95% CI) 27 25 100.0 0.92 [ 0.06, 15.22 ]




0.1 0.2 0.5 1 2 5 10




Analysis 10.04. Comparison 10 Intravenous iron vs controlled release oral iron, Outcome 04 Abdominal

cramps





n/N n/N 95% CI (%) 95% CI

Australia 1969 0/27 1/25 100.0 0.12 [ 0.00, 6.31 ]

Total (95% CI) 27 25 100.0 0.12 [ 0.00, 6.31 ]




0.1 0.2 0.5 1 2 5 10


Analysis 11.01. Comparison 11 Intravenous iron + hydrocortisone vs intravenous iron, Outcome 01

Tenderness or erythema


Comparison: 11 Intravenous iron + hydrocortisone vs intravenous iron

Outcome: 01 Tenderness or erythema

Study IV iron + hydrocort IV iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

UK 1965 2/15 0/15 100.0 7.94 [ 0.47, 133.26 ]

Total (95% CI) 15 15 100.0 7.94 [ 0.47, 133.26 ]

Total events: 2 (IV iron + hydrocort), 0 (IV iron)



0.1 0.2 0.5 1 2 5 10

IV iron + hc better IV iron + hc worse



Analysis 11.02. Comparison 11 Intravenous iron + hydrocortisone vs intravenous iron, Outcome 02 Venous

thrombosis


Comparison: 11 Intravenous iron + hydrocortisone vs intravenous iron


Study IV iron + hydrocort IV iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

UK 1965 0/15 5/15 100.0 0.10 [ 0.01, 0.65 ]

Total (95% CI) 15 15 100.0 0.10 [ 0.01, 0.65 ]

Total events: 0 (IV iron + hydrocort), 5 (IV iron)



0.1 0.2 0.5 1 2 5 10

IV iron + hc better IV iron + hc worse

Analysis 12.01. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 01 Allergic

reaction during infusion


Comparison: 12 2/3 dose intravenous iron vs full dose intravenous iron

Outcome: 01 Allergic reaction during infusion

Study 2/3 dose IV iron Full dose IV iron Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N 95% CI (%) 95% CI

Tanzania 1988 15/309 23/314 100.0 0.65 [ 0.34, 1.25 ]

Total (95% CI) 309 314 100.0 0.65 [ 0.34, 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

2/3 dose better 2/3 dose worse



Analysis 12.02. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 02 Allergic

reaction after infusion



Outcome: 02 Allergic reaction after infusion


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 47/309 77/314 100.0 0.56 [ 0.38, 0.83 ]

Total (95% CI) 309 314 100.0 0.56 [ 0.38, 0.83 ]




0.1 0.2 0.5 1 2 5 10


Analysis 12.03. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 03 Life

threatening allergic reaction during infusion



Outcome: 03 Life threatening allergic reaction during infusion


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 5/309 2/314 100.0 2.42 [ 0.54, 10.70 ]

Total (95% CI) 309 314 100.0 2.42 [ 0.54, 10.70 ]




0.1 0.2 0.5 1 2 5 10




Analysis 12.04. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 04

Discomfort needing analgesics after infusion



Outcome: 04 Discomfort needing analgesics after infusion


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 15/309 31/314 100.0 0.48 [ 0.26, 0.88 ]

Total (95% CI) 309 314 100.0 0.48 [ 0.26, 0.88 ]




0.1 0.2 0.5 1 2 5 10



Immobilised by painful joints



Outcome: 05 Immobilised by painful joints


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 7/309 9/314 100.0 0.79 [ 0.29, 2.12 ]

Total (95% CI) 309 314 100.0 0.79 [ 0.29, 2.12 ]




0.1 0.2 0.5 1 2 5 10




Analysis 12.06. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 06 Non-live

births



Outcome: 06 Non-live births


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 9/248 11/259 100.0 0.85 [ 0.35, 2.08 ]

Total (95% CI) 248 259 100.0 0.85 [ 0.35, 2.08 ]




0.1 0.2 0.5 1 2 5 10


Analysis 12.07. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 07 Neonatal

death



Outcome: 07 Neonatal death


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 3/248 6/259 100.0 0.53 [ 0.14, 1.98 ]

Total (95% CI) 248 259 100.0 0.53 [ 0.14, 1.98 ]




0.1 0.2 0.5 1 2 5 10




Analysis 12.08. Comparison 12 2/3 dose intravenous iron vs full dose intravenous iron, Outcome 08 Stillbirth



Outcome: 08 Stillbirth


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 6/248 9/259 100.0 0.69 [ 0.25, 1.93 ]

Total (95% CI) 248 259 100.0 0.69 [ 0.25, 1.93 ]




0.1 0.2 0.5 1 2 5 10



Spontaneous abortion



Outcome: 09 Spontaneous abortion


n/N n/N 95% CI (%) 95% CI

Tanzania 1988 3/248 1/259 100.0 2.86 [ 0.40, 20.42 ]

Total (95% CI) 248 259 100.0 2.86 [ 0.40, 20.42 ]




0.1 0.2 0.5 1 2 5 10




CD003094_Anaemia Review 2007

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