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Daily oral iron supplementation during pregnancy

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

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 12 DEC 2012

Assessed as up-to-date: 1 NOV 2012

DOI: 10.1002/14651858.CD004736.pub4


How to Cite

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

Author Information

  1. 1

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

  2. 2

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

  3. 3

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

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

Publication History

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

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

 
Summary of findings for the main comparison. Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo) for women during pregnancy

Patient or population: women during pregnancy
Settings: settings including malaria endemic areas
Intervention: any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo)

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

Low birthweight (less than 2500 g)RR 0.81
(0.68 to 0.97)
8480
(11 studies)
moderate1 

Birthweight (g)The mean birthweight (g) in the intervention groups was
30.81
(5.94 to 55.68) 
9385
(14 studies)
low2 

Premature birth (less than 37 weeks of gestation)RR 0.88
(0.77 to 1.01)
10148
(13 studies)
moderate3 

Neonatal death (within 28 days after delivery)RR 0.90
(0.68 to 1.19)
7465
(4 studies)
low4 

Congenital anomaliesRR 0.86
(0.55 to 1.35)
2702
(3 studies)
low5 

Maternal anaemia at term (Hb less than 110 g/L at 37 weeks gestation or more)RR 0.30
(0.19 to 0.46)
2199
(14 studies)
moderate6 

Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)RR 0.43
(0.27 to 0.66)
1256
(7 studies)
moderate7 

Maternal death (death while pregnant or within 42 days of termination of pregnancy)Not estimable47
(1 study)
low8 

Side effects (any reported throughout the intervention period)RR 2.36
(0.96 to 5.82)
4418
(11 studies)
very low9 

Maternal severe anaemia at any time during 2nd or 3rd trimester (Hb less than 70 g/L)RR 0.22
(0.01 to 3.20)
2125
(9 studies)
low10 

Infection during pregnancy (including urinary tract infections and others) (ALL)RR 1.16
(0.83 to 1.63)
3421
(2 studies)
low11 

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

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

1 Some of the trials contributing data had high levels of attrition and in several studies the method of allocation concealment was unclear. Low heterogeneity (16%). No serious imprecision.
2 Some of the trials contributing data had high levels of attrition and in several studies the method of allocation concealment was unclear. There was no serious heterogeneity in the magnitude of the effect (23%) and most of the trials favoured iron supplementation. Wide confidence intervals.

3 Some of the trials contributing data had high levels of attrition and in several studies the method of allocation concealment was unclear. Nil heterogeneity (0%). No serious imprecision.

4 Some of the trials contributing data had high levels of attrition or the method of allocation concealment was unclear. Event rates in some trials were low and the 95% CI was very broad in these trials. Nil heterogeneity (0%). Some imprecision.

5 No serious risk of bias in the trials contributing data. Event rates in one study were low and the 95% CI were broad. Nil heterogeneity (0%).  Some imprecision.

6 Some of the trials contributing data had high levels of attrition and in various studies the method of allocation concealment was unclear. Although the direction of the effect was the same in all these trials, the effect size varied considerably resulting in high heterogeneity (80%). No serious imprecision. Assessors refrained from downgrading due to the high magnitude of the effect.
7 Some of the trials contributing data had high levels of attrition and in various studies the method of allocation concealment was unclear. Although the direction of the effect was the same in all these trials, the effect size varied considerably resulting in high heterogeneity (85%). No serious imprecision. Assessors refrained from downgrading due to the high magnitude of the effect.

8 A single high quality trial assessed this outcome reporting zero events for both study arms.

9 Some of the trials contributing data had high levels of attrition and in various studies the method of allocation concealment was unclear. There was serious heterogeneity in the magnitude of the effect (96%) but most of the trials favoured no intervention/placebo. Wide confidence intervals.

10 Some of the trials contributing data had high levels of attrition and in various studies the method of allocation concealment was unclear. Nil heterogeneity (0%). Wide confidence intervals.

11 Some of the trials contributing data had high levels of attrition and in various studies the method of allocation concealment was unclear.

Nil heterogeneity (0%). Event rates in both studies were low and the 95% CI broad.

 Summary of findings 2 Any supplements containing iron and folic acid versus same supplements without iron nor folic acid (no iron nor folic acid or placebo) for women during pregnancy

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Description of the condition

Iron deficiency is thought to be the most common nutrient deficiency among pregnant women (WHO 1992). Iron deficiency involves an insufficient supply of iron to the cells following depletion of the body's reserves. Its main causes are a diet poor in absorbable iron, an increased requirement for iron (e.g. during pregnancy) not covered through the diet, a loss of iron due to parasitic infections, particularly hookworm, and other blood losses (Crompton 2002; INACG 2002a). Chronic iron deficiency frequently turns into iron deficiency anaemia. While iron deficiency is the most common cause of anaemia, other causes such as acute and chronic infections that cause inflammation; deficiencies of folate and of vitamins B2, B12, A, and C; and genetically inherited traits such as thalassaemia and drepanocytosis (sickle-cell anaemia) may be independent or superimposed causal factors (WHO 2001; WHO 2012a). According to the most recent estimate, the global prevalence of anaemia among pregnant women is 41.8% (WHO/CDC 2008).

 

Diagnosis of iron deficiency and anaemia during pregnancy

Anaemia during pregnancy is diagnosed if a woman's haemoglobin (Hb) concentration is lower than 110 g/L at sea level, although it is recognized that during the second trimester Hb concentrations naturally decrease by approximately 5 g/L (WHO 2011a). Although Hb and, less frequently, hematocrit tests are used to screen for iron deficiency, low Hb or hematocrit values are not specific to iron deficiency.

Iron deficiency in non-pregnant populations can be measured quite precisely using laboratory tests such as serum ferritin, serum iron, transferrin, transferrin saturation and transferrin receptors. However, these tests are often not readily available and their results may be of limited value in some settings where different infections (e.g. malaria, HIV/AIDS, vaginosis) are highly prevalent. Furthermore, the results of those tests do not correlate closely with one another because each reflects a different aspect of iron metabolism. For example, serum ferritin concentration is an indicator of iron reserves. During pregnancy, however, serum ferritin levels as well as levels of bone marrow iron fall even in women who ingest daily supplements with high amounts of iron, which casts doubts about their true significance in pregnancy and suggests the need to review cut-off values (Puolakka 1980; Romslo 1983; Svanberg 1975). Currently, a serum ferritin concentration of less than 15 µg/L in healthy adults is an accepted cut-off of depleted iron stores, even among pregnant women (WHO 2011b). Interestingly, the nadir of maternal serum ferritin occurs by week 28, before higher iron demands are believed to occur, a decrease only partially explained by the normal plasma volume expansion that occurs during pregnancy (Taylor 1982).

The ratio of serum transferrin receptors to serum ferritin has been suggested as a good indicator of iron nutrition among pregnant and non-pregnant women (Cook 2003). Data from the United States National Health and Nutrition Examination Survey (NHANES) in 1999–2006 for 1171 pregnant women using this composed indicator showed that pregnant women in the first trimester had the highest mean total body iron compared with that of pregnant women in the second or third trimesters, and that the prevalence of iron deficiency in pregnant women increased with trimester (Mei 2011). However, the lack of a standard soluble transferrin receptor (sTfR) assay method and a standard reference material, limit the use and comparability of this indicator with other studies. There is still a need to improve the definition of the distribution of serum transferrin receptors during pregnancy in populations with different iron status (Nair 2004) in various environments (Milman 2007).

After considering all these indicators, a World Health Organization (WHO) and Centres for Disease Control (CDC) Technical Consultation on the Assessment of Iron Status at the Population Level concluded that Hb and ferritin were the most efficient combination of indicators for monitoring change in the iron status of a population as a consequence of iron supplementation (WHO/CDC 2005). Unfortunately, only two of the very varied studies on pregnant women were included, and only one of them demonstrated changes with iron supplementation. The use of multiple indicators (Hb, ferritin and sTfRs) is useful for population-based assessments of iron-deficiency anaemia, when this is feasible.

 

Low and high Hb concentrations, iron status and pregnancy outcomes

The consequences of iron-deficiency anaemia are serious, and can include diminished intellectual and productive capacity (Hunt 2002), and possibly increased susceptibility to infections (Oppenheimer 2001). The lowest rates of low birthweight and premature birth appear to occur when maternal Hb levels are between 95 and 105 g/L during the second trimester of gestation (Murphy 1986; Steer 2000) and between 95 and 125 g of Hb/L at term (Hytten 1964; Hytten 1971). However, the results of several studies suggest that near-term Hb levels below 95 g/L or even below 110 g/L may be associated with low birthweight, heavier placentas and increased frequency of premature births (Garn 1981; Godfrey 1991; Kim 1992; Klebanoff 1989; Klebanoff 1991; Murphy 1986). There is evidence that maternal Hb levels below 95 g/L before or during the second trimester of gestation are associated with increased risk of giving birth to a low birthweight infant and with premature delivery. During pregnancy, low Hb levels, indicative of moderate (between 70 and 90 g/L) or severe (less than 70 g/L) anaemia, are associated with increased risk of maternal and child mortality and infectious diseases (INACG 2002b). Favourable pregnancy outcomes occur 30% to 45% less often in anaemic mothers, and it has been estimated that their infants have less than one-half of normal iron reserves (Bothwell 1981).

Unfortunately, the time between birth and umbilical cord clamping has not been considered in the estimates of impact of maternal iron status and anaemia on the infant's iron reserves, even though late cord clamping (between one and three minutes) has been shown to improve them significantly (Chaparro 2006; Chaparro 2007; Grajeda 1997; McDonald 2008; Mercer 2001; Van Rheenen 2004) and is recommended to prevent maternal postpartum haemorrhage (WHO 2012b). Iron deficiency may adversely affect the cognitive performance, development and physical growth of infants (WHO 2001) even in the long term (Lozoff 2006). Moderate or severe iron deficiency during infancy has been shown to have irreversible cognitive effects (Gleason 2007). Studies in animal models suggest that suffering anaemia during the intrauterine period can lead to long-term chronic diseases such as hypertension, as part of a phenomenon known as fetal programming (Andersen 2006).

Haemoglobin levels greater than 130 g/L at sea level have also been associated with negative pregnancy outcomes (Hytten 1964; Hytten 1971; Murphy 1986; Scholl 1997; Steer 2000). Large epidemiologic retrospective studies (Murphy 1986; Steer 2000; Xiong 2000) and one prospective study in China (Zhou 1998) have shown that both low and high prenatal Hb concentrations are associated with increased risks for premature delivery and low birthweight. In fact, the incidence of these negative consequences increases dramatically when women's Hb levels, at sea level, are below 95 to 105 g/L at any time in pregnancy or above 130 to 135 g/L after mid-pregnancy. A randomised clinical trial in Mexico showed associations between prenatal daily iron supplement intake at recommended doses to be associated with high Hb concentrations and the risk for both low birthweight and premature delivery (Casanueva 2003a). A study (Ziaei 2007) also showed that women whose Hb concentration at gestational weeks 32 to 36 was greater than 132 g/L had more low birthweight babies and also higher blood pressure than women with lower Hb concentrations. Unfortunately, any women considered anaemic were excluded from the study. Observational studies have shown that among iron supplemented pregnant women, and particularly among those who are anaemic early in pregnancy, a failure of Hb and/or ferritin levels to decline during the second and third trimesters, and overall high ferritin levels during pregnancy, not due to infection, are associated with adverse pregnancy outcomes. However, when some confounding factors are controlled for, the association between high serum ferritin concentrations and the risk for premature delivery was not significant (Scholl 1998; Scholl 2000; Scholl 2005).

The association between iron deficiency without anaemia and adverse perinatal outcomes is less clear, although some studies have shown iron deficiency to be associated with inadequate pregnancy weight gain, decreased defence against infections, preterm delivery and low birthweight (Garn 1981; Kandoi 1991; Prema 1982; Scholl 1992).

 

Description of the intervention

The Institute of Medicine recommends that women consume 27 mg/day of iron during pregnancy (IOM 2001). Most women need additional iron as well as sufficient iron stores to prevent iron deficiency (Bothwell 2000), and so direct iron supplementation for pregnant women has been used extensively in most low- and middle-income countries as an intervention to prevent and correct iron deficiency and anaemia during pregnancy. It has been recommended that iron supplements also contain folic acid, an essential B-vitamin, because of the increased requirements of pregnancy, due to the rapidly dividing cells in the fetus and elevated urinary losses. Other vitamins and minerals for which deficiencies are documented, and when requirements during pregnancy are higher, this may justify their addition to the supplementation formula, although this is an ongoing area of controversy, particularly with differing conclusions on maternal and infant benefits from various reviews (Christian 2010; Bhutta 2008; Haider 2006; Shrimptom 2009).

International organisations have been advocating routine iron and folic acid supplementation for every pregnant woman in areas where anaemia is highly prevalent (Beard 2000; Villar 1997). While iron supplementation with or without folic acid has been used in a variety of doses and regimens, some current recommendations for pregnant women include the provision of a standard daily dose of 60 mg of elemental iron and 400 μg of folic acid starting as soon as possible after gestation begins -no later than the third month- and continuing for the rest of the pregnancy. When this duration of six months of intervention cannot be achieved during pregnancy, either continued supplementation during the postpartum period or an increased dosage to 120 mg elemental iron daily during pregnancy is recommended (WHO 2006). Additionally, if iron deficiency prevalence in the country is high, or the pregnant women are anaemic (INACG 1998), the dose of 120 mg elemental iron is indicated. Recent data from national surveys from 46 countries during the years 2003 to 2009 estimated that 52% to 75% of mothers had received iron tablets during pregnancy, and that the duration of supplementation was usually short (Lutter 2011).

The dose of 60 mg of elemental iron was first established in 1959 and was based on estimated iron requirements for women during pregnancy (WHO 1959). This same dose was endorsed by subsequent expert consultations (INACG 1998; WHO 1968; WHO 2001). The use of folic acid during pregnancy was first suggested in 1967, during a technical consultation in Geneva, Switzerland. It was considered that a dose of 300 μg (0.3 mg) of folic acid per day throughout pregnancy would help prevent megaloblastic anaemia, which is associated with folate deficiency (WHO 2012a). This consultation was called three years after the start of a worldwide multi-country collaborative study in India, Israel, Mexico, Poland, South Africa, the United Kingdom, the United States of America, and Venezuela (WHO 1968). The recommended supplemental dose increased to 400 μg (0.4 mg) per day in 1998 after various studies supported its periconceptional use for prevention of neural tube defects (INACG 1998). At the time it was acknowledged that the rationale for providing folic acid supplementation after the first trimester of pregnancy would not be to prevent congenital anomalies but that the 400 µg (0.4 mg) daily dose of folic acid would provide a safe and healthy intake for women during pregnancy and lactation, although probably more than was actually required to produce an optimal Hb response in pregnant women (INACG 1998).

The tolerable upper intake level for iron has been set based on the gastrointestinal side effects associated with high levels of iron consumed on an empty stomach. Iron has the potential to cause direct erosion and irritation of the gastrointestinal mucosa, to cause oxidative damage of lipid membranes, proteins or DNA, can stimulate inflammation or, as an essential nutrient, fertilise the growth of pathogens. High-dose iron supplements are commonly associated with constipation and other gastrointestinal effects including nausea, vomiting and diarrhoea, with frequency and severity varying according to the amount of elemental iron released in the stomach. The Institute of Medicine has established the tolerable upper limit for iron during pregnancy as 45 mg/day of iron, a daily dose much lower than international recommendations (IOM 2001), although the methodology and assumptions used have been questionable (Schümann 2007). In most industrialised countries, the decision to prescribe or recommend antenatal iron with folic acid supplementation to women during pregnancy is left to the healthcare personnel, and is based on the individual maternal condition. In the United States, iron supplementation as a primary prevention intervention involves smaller daily iron doses (i.e. 30 mg/day) but therapeutic doses of up to 120 mg elemental iron daily are recommended for the treatment of anaemia (CDC 1998).

 

Why it is important to do this review

Several studies have shown that iron supplementation, with or without folic acid during pregnancy, helps cover the iron intake gap and results in a substantial reduction in women's risk of anaemia in late pregnancy, at delivery and six weeks postpartum (Mahomed 2000a; Mahomed 1997; Villar 2003). However, the overall impact of iron supplementation interventions under field conditions has been limited, and the effectiveness of these interventions has been questioned (Beaton 1999). The limited success has been attributed to inadequate infrastructure and poor compliance (Mora 2002), although few studies have evaluated these issues adequately. The effectiveness of iron supplementation for pregnant women has been evaluated mostly in terms of improvement in Hb concentration, rather than improvements in maternal or infant health (Beaton 2000). This narrow scope may have been an important omission in most studies addressing the efficacy, effectiveness and safety of iron and iron with folic acid supplementation during pregnancy.

An additional important consideration arises when providing iron supplements to women is the presence of malaria. Approximately 40% of the world population is exposed to the parasite and it is endemic in over 100 countries (WHO 2010). Of all the complications associated with this disease, anaemia is the most common and causes the highest number of malaria-related deaths. Malaria in pregnant women increases the risk of maternal death, miscarriage, stillbirth and low birthweight with an associated risk of neonatal death (WHO 2010; WHO 2011c). Provision of iron in malaria-endemic areas has been a long standing controversy due to concerns that iron therapy may exacerbate infections, in particular malaria in childhood (Oppenheimer 2001). Although the mechanisms by which additional iron can benefit the parasite are far from clear, it is possible that lower dose supplementation might be an effective intervention to prevent anaemia and improve malaria treatment in malaria endemic areas since less iron is available for the parasite (NIH 2011). The potential interaction between malaria interventions and iron interventions in pregnancy has not been well studied. Malaria intermittent preventive treatment (IPT) is recommended for pregnant women in areas of high transmission who are particularly vulnerable to contracting malaria or suffering its consequences. A total of 35 of 45 sub-Saharan African countries had adopted IPT for pregnant women as national policy by the end of 2008 (WHO 2011c).

This review updates a previously published Cochrane Review on iron and iron + folic acid supplementation (Peña-Rosas 2009) that has clearly shown improvements on biochemical and haematological parameters, and evaluates the issues related to dose and formulation as well as the potential benefits and hazards of daily iron supplementation as a preventive intervention for women during pregnancy.

The effectiveness of different iron treatments for anaemia among pregnant women in clinical practice (Reveiz 2011) and the effects of supplementation with iron and vitamin A during pregnancy (Van den Broek 2010) are covered in other Cochrane Reviews. A planned review will assess the effectiveness of oral folate supplementation alone during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes (Haider 2008). The effects and safety of periconceptional folate supplementation for preventing birth defects (De Regil 2010) and the effects of multiple vitamin and mineral supplements during pregnancy have also been reviewed elsewhere (Haider 2006). A separate review addresses the effectiveness of intermittent iron and folic acid supplementation regimens for women during pregnancy (Pena-Rosas 2012).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

To assess the effects of daily oral use of iron supplements by pregnant women, either alone or in conjunction with folic acid or with other vitamins and minerals as a public health intervention.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We reviewed randomised and quasi-randomised trials comparing the effects of daily oral prenatal supplements of iron, or iron + folic acid or iron + other vitamins and minerals supplements among pregnant women.

We excluded studies that assessed the effects of multiple combinations of vitamins and minerals, except studies that examined the 'additional effect' of iron or iron + folic acid supplements, i.e. when women in all arms of the trial were provided with the same other micronutrient supplements (with the exception of iron or iron + folic acid).

We have not reviewed the effects of supplementation with multiple micronutrients containing iron or iron + folic acid in comparison to supplementation with iron or iron + folic acid or in comparison to placebo or no treatment. We have excluded studies dealing specifically with iron supplementation as a medical treatment. We also excluded trials addressing the effects of intermittent (i.e. weekly, twice weekly) iron supplementation regimens in comparison to daily supplementation regimens.

 

Types of participants

Pregnant women of any gestational age and parity.

 

Types of interventions

We have included a range of interventions providing daily oral supplementation (e.g. tablets, capsules) containing iron alone, iron + folic acid or iron + other vitamins and minerals.

The oral supplements forms include tablets or capsules (WHO 2008). Tablets (soluble tablets, effervescent tablets, tablets for use in the mouth, and modified-release tablets) are solid dosage forms containing one or more active ingredients. They are obtained by single or multiple compression (in certain cases they are moulded) and may be uncoated or coated. Capsules are solid dosage forms with hard or soft shells, various shapes and sizes, that contain a single dose of one or more active ingredients. Capsules may be hard, soft, and modified-release capsules and are generally intended for oral administration.

Where data were available we planned to compare the following.

  1. Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo).
  2. Any supplements containing iron and folic acid versus same supplements without iron or folic acid (no iron + folic acid or placebo).
  3. Supplementation with iron alone versus no treatment/placebo.
  4. Supplementation with iron + folic acid versus no treatment/placebo.
  5. Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation.
  6. Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation.
  7. Supplementation with iron + folic acid + other vitamins and minerals versus folic acid + same other vitamins and minerals (without iron) supplementation.
  8. Supplementation with iron + folic acid + other vitamins and minerals versus same other vitamins and minerals (without iron + folic acid) supplementation.

Interventions that combined daily oral iron or iron + folic acid supplementation with co-interventions such as education or other approaches were included only if the other co-interventions were the same in both the intervention and comparison groups. Studies examining supplemental iron alone or vitamins and minerals provided from supplementary food based interventions (i.e. interventions with multiple micronutrient powders, lipid based supplements, fortified complementary foods, and other fortified foods) were excluded. Likewise, regimens providing iron supplements in intermittent regimens were excluded from this review.

 

Types of outcome measures

Maternal, perinatal and postpartum clinical and laboratory outcomes and infant clinical and laboratory outcomes as described below.

 

Primary

 
Infant

  1. Low birthweight (less than 2500 g).
  2. Birthweight (in g).
  3. Premature birth (less than 37 weeks' gestation).
  4. Neonatal death (within 28 days after delivery).
  5. Congenital anomalies, including neural tube defects (as defined by trialists).

 
Maternal

  1. Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more).
  2. Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more).
  3. Maternal iron deficiency anaemia at term (as defined by trialists at 37 weeks' gestation or more).
  4. Maternal death (death while pregnant or within 42 days of termination of pregnancy).
  5. Side effects (any reported throughout intervention period)*.
  6. Severe anaemia at any time during second or third trimesters (Hb less than 70 g/L).
  7. Clinical malaria (as defined by trialists).
  8. Infection during pregnancy (including urinary tract infections and others as specified by trialists).

 

Secondary

 
Infant

  1. Very low birthweight (less than 1500 g).
  2. Very premature birth (less than 34 weeks' gestation).
  3. Hb concentration in the first six months (in g/L, counting the last reported measure after birth within this period).
  4. Ferritin concentration in the first six months (in μg/L, counting the last reported measure after birth within this period).
  5. Development and motor skills (as defined by trialists).
  6. Admission to special care unit.

 
Maternal

  1. Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more).
  2. Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more).
  3. Maternal iron deficiency anaemia at or near term ((Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more).
  4. Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more).
  5. Maternal Hb concentration within 6 weeks postpartum (in g/L).
  6. Maternal high Hb concentrations at any time during second or third trimester (defined as Hb greater than 130 g/L).
  7. Maternal high Hb concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more)
  8. Moderate anaemia at postpartum (Hb between 80 and 109 g/L).
  9. Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more).
  10. Severe anaemia postpartum (Hb less than 80 g/L).
  11. Puerperal infection (as defined by trialists).
  12. Antepartum haemorrhage (as defined by trialists).
  13. Postpartum haemorrhage (intrapartum and postnatal, as defined by trialists).
  14. Transfusion given (as defined by trialists).
  15. Diarrhoea (as defined by trialists).
  16. Constipation (as defined by trialists).
  17. Nausea (as defined by trialists).
  18. Heartburn (as defined by trialists).
  19. Vomiting (as defined by trialists).
  20. Maternal well being/satisfaction (as defined by trialists).
  21. Placental abruption (as defined by trialists).
  22. Premature rupture of membranes (as defined by trialists).
  23. Pre-eclampsia (as defined by trialists).

* For trials reporting individual side effects separately but not specifying the number of women reporting any side effects, for our primary outcome, we have selected the side effect with the greatest number of women (in the intervention and control groups combined) reporting that particular problem. We did this to avoid double counting any women reporting more than one side effect.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (2 July 2012).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
  2. weekly searches of MEDLINE;
  3. weekly searches of EMBASE;
  4. handsearches of 30 journals and the proceedings of major conferences;
  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of hand searched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

In addition we searched the International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned trials (2 July 2012) using the search terms described in Appendix 1.

 

Searching other resources

For assistance in identifying ongoing or unpublished studies, we also contacted the Departments of Reproductive Health and Research and Nutrition for Health and Development from the World Health Organization (WHO), the nutrition section of the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the U.S. Centers for Disease Control and Prevention (CDC), the Micronutrient Initiative (MI), the Global Alliance for Improved Nutrition (GAIN), Hellen Keller International (HKI), and the Sight and Life.

We did not apply any language restrictions.

 

Data collection and analysis

 

Selection of studies

Two review authors independently assessed and selected the trials for inclusion in this review. We resolved any disagreement on eligibility for inclusion by discussion.

It was not possible for us to assess the relevance of the trials blinded because we knew the authors' names, institution, journal of publication and results, when we applied the inclusion criteria.

 

Data extraction and management

We designed a form to facilitate the process of data extraction and to request additional (unpublished) information from the authors of the original reports. We resolved any disagreements among us by discussion, and, if necessary, sought clarification from the authors of the original reports. We extracted data relating to the setting and cadre from all the included studies specifying whether the intervention was reported as being done by a physician, obstetrician, lay health worker, midwife, dietitian or a combination of health professionals. We also extracted the type of healthcare facility and the geographical location of the intervention, when this information was available.

We entered data onto Review Manager software (RevMan 2011) and checked for accuracy.

 

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion.

 

(1) Sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence. We assessed the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);
  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); or
  • unclear.   

 

 (2) Allocation concealment (checking for possible selection bias)

We have described for each included study the method used to conceal the allocation sequence and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  • unclear.   

 

(3) Blinding (checking for possible performance bias)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes and we have noted where there was partial blinding.

We assessed the methods as:

  • low, high or unclear risk of bias for women;
  • low, high or unclear risk of bias for clinical staff;
  • low, high or unclear risk of bias for outcome assessors.

We classified blinding "inadequate" if the blinding status of a trial was unclear or the trial was open.

 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We assessed losses to follow-up and post-randomisation exclusions systematically for each trial.

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.  We assessed methods as:

  • low risk of bias;
  • high risk of bias; or
  • unclear.

We considered follow-up to be adequate if more than 80% of participants initially randomised in a trial were included in the analysis and any loss was balanced across groups, unclear if the percentage of initially randomised participants included in the analysis was unclear, and inadequate if less than 80% of those initially randomised were included in the analysis or if loss was imbalanced in different treatment groups.

 

(5) Selective reporting bias

We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review had been reported);
  • high risk of bias (where not all the study’s pre-specified outcomes had been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);
  • unclear.

 

(6) Other sources of bias

We assessed whether each study was free of other problems that could put it at risk of bias. We have noted for each included study any important concerns we had about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

  • low risk of further bias;
  • high risk of further bias;
  • unclear whether there is a risk of further bias.

 

(7) Overall risk of bias

We have made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011) and for primary outcomes have explored the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

 

Measures of treatment effect

For dichotomous data, we present results as summary risk ratio (RR) with 95% confidence intervals (CI). 

For continuous data, we have used the mean difference (MD) if outcomes were measured in the same way between trials. We planned to use the standardised mean difference (SMD) to combine trials measuring the same outcome, but using different scales or methods.  

 

Unit of analysis issues

 

Cluster-randomised trials

We included cluster-randomised trials in the analyses along with individually-randomised trials. Cluster-randomised trials are labelled with a (C). Where possible we estimated the intracluster correlation co-efficient (ICC) from trials' original data sets and reported the design effect. On the basis of this information we used the methods set out in the Handbook to calculate the adjusted sample sizes (Higgins 2011).

We included four cluster-randomised trials (Christian 2003 (C); Hoa 2005 (C); Menendez 1994 (C); Zeng 2008 (C)). One of these trials did not contribute data to the analysis (Hoa 2005 (C)). For the remaining three cluster-randomised trials (Christian 2003 (C); Menendez 1994 (C); Zeng 2008 (C)) data have been adjusted to take account of the design effect. In the study by Christian 2003 (C) adjusted data were provided by the author using outcome specific ICCs. For the Zeng 2008 (C) trial, we adjusted the published results and calculated an effective sample size by dividing figures by the design effect calculated using the ICC for the trial’s primary outcome: birthweight ICC = 0.03. We used the same sample adjustment for all outcomes. We used the same method for the Menendez 1994 (C) trial, however in this case there was insufficient information in the study reports to allow us to calculate the design effect and so we estimated it using the ICC for Hb at term (ICC = 0.03) reported in another study with similar average cluster sizes (Winichagoon 2003).  We used this same ICC for all outcomes.

Where we have identified both cluster-randomised trials and individually-randomised trials reporting data for the same outcome, we considered that it was reasonable to combine the results from both if there was little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit was considered to be unlikely.

 

Cross-over trials

We did not include cross-over trials.

 

Dealing with missing data

For included studies, levels of attrition have been noted in the Characteristics of included studies tables. The impact of including studies with high levels of missing data in the overall assessment of treatment effect have been explored by using sensitivity analysis.

When possible, we conducted an available case analysis and reinstated previously excluded cases, i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial is the number randomised minus any participants whose outcomes are known to be missing.

 

Assessment of heterogeneity

We examined the forest plots for the analyses visually to assess any obvious heterogeneity in terms of the size or direction of treatment effect between studies. We used the I², and T² statistics and the P value of the Chi² test for heterogeneity to quantify heterogeneity among the trials in each analysis. The I² statistic quantifies inconsistency and describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance).

 

Assessment of reporting biases

For our primary outcomes, we investigated publication bias on outcomes with more than 10 trials by examining the funnel plots for signs of asymmetry, although we gave consideration to reasons other than publication bias that could explain the asymmetry, when present.

 

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011).

Because of our experience in conducting other reviews in this area we anticipated high heterogeneity among trials and we pooled trial results using a random-effects model and were cautious in our interpretation of the pooled results. We have indicated in the text that the random-effects model gives the average treatment effect. For statistically significant results where there are high levels of heterogeneity ((I² greater than 50%), we have given the values of I², T² and the P value of the Chi² test for heterogeneity and have provided an estimate of the 95% range of underlying intervention effects (prediction interval (PI)).

 

Subgroup analysis and investigation of heterogeneity

Where more than one trial was included in a comparison, we conducted both overall analysis of the effects of various supplementation regimens on primary outcomes and subgroup analysis on the primary outcomes based on the following criteria:

  1. by gestational age: early, if supplementation started before 20 weeks' gestation or prior to pregnancy; late if supplementation started at 20 weeks of gestation or later; or, unspecified or mixed gestational ages at the start of supplementation;
  2. by anaemic status at start of intervention: anaemic when Hb below 110 g/L during first and third trimesters or below 105 g/L in second trimester; non-anaemic if Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester; or unspecified/mixed anaemic status;
  3. by dose of iron: low daily dose of iron if 30 mg or less of elemental iron; medium daily dose of iron (more than 30 mg and less than 60 mg elemental iron) and higher daily dose of iron if dose is 60 mg elemental iron or more);
  4. by type of formulation: slow release iron supplement (as defined by trialists) or normal release iron supplement/not specified;
  5. by iron compound bioavailability in comparison to ferrous sulphate: higher bioavailability: NaFeEDTA; equivalent or lower relative bioavailability: ferrous sulphate, ferrous fumarate, ferrous gluconate; other/not specified;
  6. By malaria risk setting: study carried out in malaria risk-free countries or study carried out in countries with some malaria risk or explicitly described as a malaria risk study site.

In the subgroup analyses we have provided totals and subtotals and have carried out formal tests to examine whether there was any statistical evidence of differences between subgroups and, if so we have drawn attention to this in the text. However, for some outcomes few studies contributed data, and for some outcomes, all the trials were in the same subgroup; as more data become available, in updates of the review, we will explore possible subgroup differences as a means of exploring heterogeneity.

 

Sensitivity analysis

We conducted a sensitivity analysis based on the quality of the studies. We considered a study to be of high quality if it was graded as adequate in both the randomisation and allocation concealment and in either blinding or loss to follow-up.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

 

Results of the search

A single search was carried out for this and a related review examining intermittent iron and iron plus folic acid supplementation in pregnancy (Pena-Rosas 2012). The study flow is depicted in Figure 1. In this updated review, we have included 60 and excluded 119 trials. We confirmed that six trials are still ongoing. Forty-three trials involving more than 27,402 women contributed data for the comparisons in this review.

 FigureFigure 1. Study flow diagram.

Studies by Chanarin 1965, Dommisse 1983, Fenton 1977, Fleming 1974, Fleming 1985, Foulkes 1982, Freire 1989, Groner 1986, Han 2011, Hoa 2005 (C), Ma 2010, Simmons 1993, Suharno 1993, Sun 2010 and Tholin 1993 were all assessed as eligible for inclusion but these studies have not contributed data to the review. We were not able to include data either because the studies did not report data on any of the review's prespecified outcomes, or the results were not presented in a way that allowed us to enter them into the analyses (e.g. results were not reported separately for randomised groups or standard deviations or standard errors were not reported for continuous outcomes). In addition, two studies that were otherwise eligible for inclusion (Butler 1968; Kuizon 1979) had such serious attrition (up to 80% for some outcomes) that we considered results were difficult to interpret, and we have not included data from these trials in the review. Details of all included studies can be found in the Characteristics of included studies tables.

In addition to the published papers, abstracts and reports identified by the search, several trial authors provided additional unpublished information for inclusion in the review, including individual patient data sets for ad hoc statistical analysis (Butler 1968; Eskeland 1997; Hemminki 1991; Lee 2005); some authors provided reanalysed data for this review (Christian 2003 (C); Makrides 2003; Paintin 1966) or additional information useful for description and 'Risk of bias' assessment of the studies (Cogswell 2003; Freire 1989; Harvey 2007; Siega-Riz 2001; Zeng 2008 (C); Ziaei 2007; Ziaei 2008).

For the trials contributing to the analyses, we have treated a study carried out collaboratively in two different sites as two different trials, one conducted in Rotterdam (Wallenburg 1983) and one conducted in Antwerp (Buytaert 1983). Some trials included more than two arms and are therefore, included in more than one comparison.

 

Included studies

Sixty studies were included in this review.

 

Settings

The studies included in the review were carried out since 1936 in countries across the globe: 25 trials in Europe with 12 trials in United Kingdom (Butler 1968; Chanarin 1965; Chisholm 1966;.Chanarin 1971; Fenton 1977; Foulkes 1982; Harvey 2007; Kerr 1958; Paintin 1966; Taylor 1982  Willoughby 1967Wills 1947); two trials in Norway (Eskeland 1997; Romslo 1983); two trials in Finland (Hemminki 1991; Puolakka 1980), two trials in Sweden (Svanberg 1975; Tholin 1993), two trials in the  Netherlands.(Van Eijk 1978; Wallenburg 1983); one each in Denmark (Milman 1991); Ireland (Barton 1994); Belgium (Buytaert 1983); France (De Benaze 1989) and Italy (Tura 1989). Eleven trials were conducted in the Americas with eight trials conducted in the United States of America (Cogswell 2003; Corrigan 1936; Groner 1986; Holly 1955Hood 1960Meier 2003; Pritchard 1958; Siega-Riz 2001); one in  Canada (Cantlie 1971); one in Ecuador (Freire 1989) and one in Jamaica (Simmons 1993). Four trials were conducted in Africa with one trial in South Africa (Dommisse 1983), one in Nigeria (Fleming 1985); one in Gambia (Menendez 1994 (C)) and one in Niger (Preziosi 1997). Four trials were conducted in Iran (Falahi 2010; Ouladsahebmadarek 2011; Ziaei 2007; Ziaei 2008). One trial was conducted in Hong Kong (Chan 2009) and five in China (Han 2011; Liu 2000; Ma 2010Sun 2010; Zeng 2008 (C)). Three trials were conducted in Australia (Fleming 1974; Hankin 1963; Makrides 2003). Seven trials were conducted in Asia with one trial each in Myanmar (Burma) (Batu 1976); Thailand (Charoenlarp 1988); Nepal (Christian 2003 (C)); Vietnam (Hoa 2005 (C)); Philippines (Kuizon 1979); South Korea (Lee 2005) and Indonesia (Suharno 1993).

Most included trials were published in the between years 2000-2009 and 1980-1989. Two trials were published before 1950's, three trials in the period 1950-1959, seven trials between 1960-1969, eight trials between 1970-1979, 13 trials in the period 1980-1989, nine trials between 1990-1999, 13 trials in the period 2000-2009 and only five included trials have been published since 2010 to present.

Twenty-three studies were conducted in countries that in 2011 (WHO 2011c; WHO 2011d) had some malaria risk in parts of the country, of diverse characteristics (Batu 1976; Chan 2009; Charoenlarp 1988; Christian 2003 (C); Dommisse 1983; Falahi 2010; Fleming 1985; Freire 1989; Han 2011; Hoa 2005 (C); Kuizon 1979; Lee 2005; Liu 2000; Ma 2010; Menendez 1994 (C); Ouladsahebmadarek 2011; Preziosi 1997; Simmons 1993; Suharno 1993; Sun 2010; Zeng 2008 (C); Ziaei 2007; Ziaei 2008). Only two of these reported malaria outcomes (Fleming 1985; Menendez 1994 (C)). In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. In many countries, malaria has a seasonal pattern (WHO 2011d). These details as well as information on the predominant malaria species, status of resistance to antimalarial drugs for each country where an included study was conducted was extracted for 2011 (WHO 2011d) and provided in the notes section of the Characteristics of included studies tables. Thirty-seven of the included trials, mostly from Australia, Canada, United States of America, or countries in Europe were carried out in areas that generally are considered malaria-free.

 

Participants

In 23 trials it was specifically stated that all women recruited were non-anaemic at the start of supplementation (Barton 1994; Buytaert 1983; Cantlie 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Harvey 2007; Hemminki 1991; Liu 2000; Makrides 2003; Meier 2003; Ouladsahebmadarek 2011; Puolakka 1980; Romslo 1983; Siega-Riz 2001; Svanberg 1975; Tholin 1993; Tura 1989; Wallenburg 1983; Ziaei 2007; Ziaei 2008). For the remaining trials it was not always stated whether or not women were anaemic and some studies included some women with mild and moderate anaemia so samples were mixed in terms of women's anaemia status at the start of supplementation. In some of these trials it was specifically stated that women with severe anaemia were excluded (Batu 1976; Butler 1968; Chan 2009; Charoenlarp 1988; Kerr 1958; Paintin 1966; Willoughby 1967). Five studies specifically recruited women with mild and moderate anaemia (Hb between 80 to 110 g/L) but none of these trials contribute data to the review (Han 2011; Ma 2010; Simmons 1993; Suharno 1993; Sun 2010).

In most of the trials women began taking supplements before 20 weeks' gestation and continued taking supplements up until delivery. In 12 trials supplementation started at or after 20 weeks' gestation (Batu 1976; Chanarin 1965; Chisholm 1966; Eskeland 1997; Fleming 1974; Freire 1989; Hood 1960; Kerr 1958; Makrides 2003; Menendez 1994 (C); Paintin 1966; Preziosi 1997). In 16 studies it was not clear at what gestational age women started to take supplements or gestational ages were mixed and samples included both women who started supplements before and after the 20th week of pregnancy (Cantlie 1971; Charoenlarp 1988; Corrigan 1936; Fleming 1985; Hankin 1963; Holly 1955; Kuizon 1979; Lee 2005; Liu 2000; Ma 2010; Meier 2003; Pritchard 1958; Simmons 1993; Suharno 1993; Sun 2010; Willoughby 1967).

 

Interventions

 
Daily iron dose

The daily dose of elemental iron in some of the groups in the included trials ranged between 9-90 mg of elemental iron daily. One trial provided 9 mg elemental iron daily (Eskeland 1997); one trial provided 12 mg elemental iron (Paintin 1966);  one trial provided 20 mg elemental iron daily (Makrides 2003); one trial provided 27 mg elemental iron (Eskeland 1997); six trials provided 30 mg  elemental iron (Chanarin 1971; Cogswell 2003; Lee 2005; Ouladsahebmadarek 2011; Siega-Riz 2001; Zeng 2008 (C); one trial provided 40 mg elemental iron (Tura 1989); 45 mg elemental iron (De Benaze 1989); 50 mg elemental iron (Ziaei 2007, Ziaei 2008); 55 mg elemental iron (Hood 1960); 17 trials provided 60 mg elemental iron (Barton 1994; Batu 1976; Chan 2009Christian 2003 (C); Falahi 2010; Fenton 1977; Fleming 1974; Fleming 1985; Groner 1986; Han 2011; Hoa 2005 (C); Ma 2010; Meier 2003; Menendez 1994 (C); Suharno 1993; Sun 2010; Zeng 2008 (C)); two trials provided 65 mg of elemental iron (Kuizon 1979; Taylor 1982); 66 mg elemental iron (Milman 1991); two trials provided 78 mg elemental iron  (Cantlie 1971; Freire 1989); one trial provided 80 mg elemental iron (Wills 1947); nine trials provided 100 mg of elemental iron (Foulkes 1982Hankin 1963;  Harvey 2007; Hemminki 1991; Liu 2000; Preziosi 1997; Simmons 1993; Tholin 1993; Van Eijk 1978); five trials provided 105 mg of elemental iron daily (Buytaert 1983; Kerr 1958; Paintin 1966; Wallenburg 1983; Willoughby 1967); one trial provided 112 mg elemental iron  (Pritchard 1958); two trials provided 120 mg of elemental iron (Charoenlarp 1988; Dommisse 1983); one trial provided 122 mg of elemental iron  (Butler 1968); three trials provided 200 mg of elemental iron (Puolakka 1980; Romslo 1983; Svanberg 1975); 220 mg elemental iron (Hood 1960); 240 mg of elemental iron (Charoenlarp 1988) and 900 mg elemental iron (Chisholm 1966). One trial did not report the amount of iron as elemental iron and only referred the amount provided as a total daily dose 0.6 g of ferrous sulphate (Corrigan 1936) while another referred a dose of 1 g of iron salt daily (Holly 1955).

 
Folic acid daily dose

For trials providing folic acid daily as part of the intervention, the doses ranged from 10 μg (0.01 mg) folic acid to 5000 μg (5 mg) folic acid daily along with the iron. In one trial each the dosis of folic acid provided was 10 μg (0.01 mg) folic acid (Chanarin 1965); 30 μg (0.03 mg) folic acid (Chanarin 1965); 100 μg (0.1 mg) of folic acid (Willoughby 1967); 175 μg (0.17 mg) folic acid (Lee 2005); 250 μg (0.25 mg) folic acid (Hoa 2005 (C)); 300 μg (0.3 mg) of folic acid (Willoughby 1967). In three trials participants received a daily dosis pf 350 μg (0.35 mg) folic acid (Foulkes 1982; Lee 2005; Taylor 1982). In five trials the daily dose provided to participants in some of the groups were 400 μg (0.4 mg) folic acid (Christian 2003 (C); Ma 2010; Simmons 1993; Sun 2010; Zeng 2008 (C)); 450 μg (0.45 mg) folic acid (Willoughby 1967); three trials provided 500 μg (0.5 mg) folic acid daily (Chisholm 1966; Fleming 1974; Siega-Riz 2001); five trials provided participants in some of the groups with 1000 μg (1 mg) folic acid daily (Barton 1994; Batu 1976; Fleming 1985; Meier 2003; Ziaei 2007); and one trial provided participants in some of the groups 3400 μg (3.4 mg) of folic acid  daily (Butler 1968). Four trials of iron and folic acid supplementation provided 5000 μg (5 mg) folic acid daily (Charoenlarp 1988; Chisholm 1966; Fleming 1974; Menendez 1994 (C).

 
Type of iron compounds

With the exception of six trials that explicitly described the supplements as slow or sustained release (Buytaert 1983; Hood 1960; Liu 2000; Simmons 1993; Svanberg 1975; Wallenburg 1983), all other trials appeared to be standard preparations.

Nine trials did not specify the iron compound used in the trials and described the iron daily dose only in terms of elemental iron (Barton 1994; Fleming 1985; Foulkes 1982; Hemminki 1991; Holly 1955; Makrides 2003; Ouladsahebmadarek 2011; Paintin 1966; Zeng 2008 (C)).  

Most supplements used in trials were equivalent or lower, rather than high relative bioavailability iron compounds (ferrous sulphate and ferrous fumarate). Thirty-seven trials used iron supplements in one of the groups that was provided as ferrous sulphate (Batu 1976; Butler 1968; Buytaert 1983; Chan 2009; Charoenlarp 1988; Cogswell 2003; Corrigan 1936; Dommisse 1983; Falahi 2010; Fenton 1977; Fleming 1974; Freire 1989; Han 2011; Hemminki 1991; Hoa 2005 (C); Holly 1955; Hood 1960; Kerr 1958; Kuizon 1979; Lee 2005; Liu 2000; Ma 2010; Meier 2003; Menendez 1994 (C); Puolakka 1980; Romslo 1983; Siega-Riz 2001; Simmons 1993; Suharno 1993; Sun 2010; Svanberg 1975; Taylor 1982; Tholin 1993; Van Eijk 1978; Wallenburg 1983; Ziaei 2007; Ziaei 2008). Six trials used ferrous fumarate as the form of iron provided to the participants (Chanarin 1965; Chanarin 1971; Christian 2003 (C); Eskeland 1997; Groner 1986; Milman 1991). One trial used ferrous iron (Cantlie 1971). 

Ferrous gluconate was used in six included trials (Chisholm 1966; Hankin 1963; Harvey 2007; Kerr 1958; Pritchard 1958; Wills 1947). Two trials used ferrous betainate hydrochloride (De Benaze 1989; Preziosi 1997), one trial used heme iron from porcine blood (Eskeland 1997), one trial used ferritin in a micro granulated gastric resistant capsule (Tura 1989), one used chelated iron aminoates (Willoughby 1967) and one study (Han 2011) used iron EDTA.  

Bioavailability of iron compounds is assessed in comparison (relative) to ferrous sulphate.

 
Supervision and co-interventions

In most of the studies women took the supplements without supervision. Some trials report that intake of the supplements was supervised in all or some of the groups (Batu 1976; Charoenlarp 1988; Preziosi 1997). In Christian 2003 (C) the intake was unsupervised but trial personnel visited women twice each week to monitor supplement intake.

Some studies included co-interventions in addition to the iron or iron + folic acid supplement. For example, in the study by Cantlie 1971 participants from both groups received one tablet of multiple micronutrient supplement daily containing: 2 mg copper citrate, 6 mg magnesium stearate, 0.3 mg manganese carbonate, 1000 IU vitamin A , 500 IU vitamin D, bone flour 130 mg, 1 mg vitamin B1, 1 mg vitamin B2, 50 mg brewer yeast concentrate, 5 mg niacinamide, 25 mg vitamin C, 0.2 mg sodium iodide and 0.049 μg folate (naturally occurring) and in Christian 2003 (C) all participants were offered a 1000 μg retinol equivalents vitamin A supplement daily and deworming treatment (albendazole 400 mg single dose) in the second and third trimester. In Fleming 1974 all participants received 50 mg of ascorbic acid daily from the first visit until the 20th week. In Fleming 1985 the participants from the groups included in this review received chloroquine 600 mg base once, followed by proguanil 100 mg per day. In Menendez 1994 (C) all pregnant women received a weekly tablet of 5000 μg (5 mg) of folic acid but no antimalarial chemoprophylaxis. In the study by Siega-Riz 2001 folic acid supplements were prescribed for all women who had received the positive pregnancy test until the first prenatal visit. In Simmons 1993 all women received 400 μg (0.4 mg) of folic acid.

 
Intervention settings and health worker cadre

In the majority of these studies (52 studies, 86%), the intervention was delivered in hospital or community-based antenatal clinics usually by physicians or other healthcare professionals including midwives, dieticians or social workers. In eight of the studies the intervention was delivered by community workers, traditional birth attendants or village-based healthcare staff, and supplements were provided during visits to women's homes or in local community settings. The supplements were provided by village-based traditional birth attendants in the study by Menendez 1994 (C). In the Han 2011 trial village nurses made visits to women's homes to deliver supplements and monitor women's health. Community health or village workers were involved in delivering supplementation programmes in the trials by Charoenlarp 1988; Christian 2003 (C); Hoa 2005 (C); Ma 2010; Suharno 1993; and Sun 2010.

 

Comparisons

Comparison 1: forty-three trials that contributed data compared the effects of any daily oral supplements containing iron versus same daily oral supplements without iron. This included data from 34 trials that compared the effects of daily iron supplementation with the effects of no iron or placebo (Batu 1976; Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; Corrigan 1936; De Benaze 1989; Eskeland 1997; Falahi 2010; Hankin 1963; Harvey 2007; Hemminki 1991; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Ouladsahebmadarek 2011; Paintin 1966; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947; Ziaei 2008). Data from eight trials included in this comparison evaluated the effects of daily iron + folic acid supplementation with the effects of no treatment (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Lee 2005; Taylor 1982; Willoughby 1967). Data from one study (Christian 2003 (C)) which met the criteria for high quality examined groups receiving daily iron + folic acid versus women receiving folic acid (without iron), with vitamin A supplementation as co-intervention. Five studies provided data comparing the effects of daily iron + folic acid with daily folic acid alone (without iron) supplementation (Batu 1976; Chisholm 1966; Christian 2003 (C); Zeng 2008 (C); Ziaei 2007). Data from four studies compared women receiving oral iron + other vitamins and minerals with women receiving other vitamins and minerals (without iron) supplementation (Cantlie 1971; Liu 2000; Ouladsahebmadarek 2011; Siega-Riz 2001). Some trials provide data from different arms of the study for different comparisons. Of all the 43 studies that provided data in this comparison, 16 trials were of high quality according to our pre-established criteria (Barton 1994; Buytaert 1983; Chisholm 1966; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Makrides 2003; Preziosi 1997; Siega-Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C); Ziaei 2007; Ziaei 2008).

Comparison 2: eight trials compared the effects of daily iron + folic acid supplementation with the effects of same supplements without iron + folic acid (no iron + folic acid or placebo). Seven of them compared the effects of daily iron + folic acid supplementation with the effects of no treatment (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Lee 2005; Taylor 1982; Willoughby 1967). Only two of these (Barton 1994; Chisholm 1966) met the criteria for high quality. No studies compared women receiving daily oral iron + folic acid + other vitamins and minerals with women receiving other vitamins and minerals (without iron + folic acid). One study (Christian 2003 (C)) included a group that compared daily iron + folic acid supplementation in comparison to no treatment, considering the vitamin A supplementation and deworming as co-interventions in the compared groups.

Comparison 3: 35 trials compared the effects of daily iron supplementation with the effects of no iron or placebo (Batu 1976; Buytaert 1983; Chan 2009; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; Corrigan 1936; Christian 2003 (C); De Benaze 1989; Eskeland 1997; Falahi 2010; Hankin 1963; Harvey 2007; Hemminki 1991; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994 (C); Milman 1991; Ouladsahebmadarek 2011; Paintin 1966; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947; Ziaei 2008). Of these, 12 trials were of high quality according to our pre-established criteria (Buytaert 1983; Chisholm 1966, Cogswell 2003; Christian 2003 (C); Eskeland 1997; Harvey 2007; Hemminki 1991; Makrides 2003; Preziosi 1997;Tura 1989; Wallenburg 1983; Ziaei 2008).

Comparison 4: eight trials compared the effects of daily iron + folic acid supplementation with the effects of no treatment (Barton 1994; Batu 1976; Charoenlarp 1988; Chisholm 1966; Christian 2003 (C); Lee 2005; Taylor 1982; Willoughby 1967). Only three of them (Barton 1994; Chisholm 1966; Christian 2003 (C)) met the criteria for high quality. One study (Christian 2003 (C)) included a group that compared daily iron + folic acid supplementation in comparison to no treatment, considering the vitamin A supplementation and deworming as co-interventions in the compared groups.

Comparison 5: five studies compared the effects of daily iron + folic acid with daily folic acid alone (without iron) supplementation (Batu 1976; Chisholm 1966; Christian 2003 (C); Zeng 2008 (C); Ziaei 2007). Four of the trials met the criteria for high quality (Chisholm 1966; Christian 2003 (C)Zeng 2008 (C); Ziaei 2007). The study (Christian 2003 (C)) included a group that compared daily iron + folic acid supplementation in comparison daily folic acid alone, considering the vitamin A supplementation and deworming as co-interventions in the compared groups.

Comparison 6: three studies compared women receiving oral iron + other vitamins and minerals with women receiving other vitamins and minerals (without iron) supplementation (Cantlie 1971; Ouladsahebmadarek 2011; Siega-Riz 2001). One of the studies met the criteria for high quality (Siega-Riz 2001). One group in the study (Liu 2000) provided iron with vitamin C, but the comparison groups had different nutrients.

Comparison 7: no studies compared women receiving daily iron + folic acid + other vitamins and minerals versus women receiving folic acid and other vitamins and minerals (without iron).

Comparison 8: no studies compared women receiving daily oral iron + folic acid + other vitamins and minerals with women receiving same other vitamins and minerals (without iron + folic acid).

See the tables of Characteristics of included studies for a detailed description of all the studies. All included studies met the pre-stated inclusion criteria.

 

Excluded studies

Altogether, we excluded 119 studies; some studies were excluded for more than one reason. The main reason for excluding studies was that participants in all arms of trials received iron and were therefore not eligible for any of the comparisons included in this review. This reason applied to a total of 87 trials.

The second most frequent reason for exclusion was that the studies were not prospective, parallel, randomised controlled trials. A total of 18 trials were excluded for this reason (Abel 2000; Angeles-Agdeppa 2003; Berger 2003; Chawla 1995; Dawson 1962; Edgar 1956; Gopalan 2004; Iyengar 1970; Kulkarni 2010; Menon 1962; Morgan 1961; Ortega-Soler 1998; Powers 1985; Roztocil 1994; Sandstad 2003; Tange 1993; Wu 1998; Young 2010).

The remaining 14 studies were excluded for other reasons: the studies by Bergsjo 1987 and Steer 1992 were not completed, and results are not available for the Hawkins 1987 trial; studies by Hermsdorf 1986, Tampakoudis 1996 and Tan 1995 were reported as abstracts and there was insufficient information on methods to allow us to assess risk of bias; Cook 1990, Khambalia 2009 and Picha 1975 did not examine iron supplementation in pregnant women and Hampel 1974 recruited women, and reported outcomes at different gestational ages so we were unable to interpret results; Bokhari 2011 and McKenna 2002 looked at iron fortified food or drink; finally, Blot 1980 and Seck 2008 examined comparisons outside the scope of this review.

 

Risk of bias in included studies

See the 'Risk of bias' tables included in Characteristics of included studies for an assessment of the risk of bias for each included trial and Figure 2 and Figure 3 for an overall summary of the methodological quality of all included trials. In the description below we have summarised risk of bias only for those 43 trials contributing outcome data to the review.

 FigureFigure 2. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

In the summary of findings tables we examined risk of bias for each outcome separately, considering only those trials contributing data for each primary outcome.

 

Allocation

 

Sequence generation

We assessed 20 trials as having adequate methods for generating the randomisation sequence (Barton 1994; Buytaert 1983; Chan 2009 Charoenlarp 1988; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Kerr 1958; Lee 2005; Makrides 2003; Meier 2003; Preziosi 1997; Siega-Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C); Ziaei 2007; Ziaei 2008). Eighteen trials did not report or did not state clearly the randomisation method used (Batu 1976; Chanarin 1965; Cantlie 1971; Chisholm 1966; De Benaze 1989; Holly 1955; Hood 1960; Menendez 1994 (C); Milman 1991; Ouladsahebmadarek 2011; Paintin 1966; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982; Van Eijk 1978; Willoughby 1967). Five trials were quasi-randomised using alternate sequence allocation (Chanarin 1971; Corrigan 1936; Han 2011; Hankin 1963; Wills 1947).

In three of these trials clusters rather than individual women were randomised (Christian 2003 (C); Menendez 1994 (C); Zeng 2008 (C)).

 

Allocation concealment

We judged that 19 trials had adequate methods of allocation concealment (Barton 1994; Buytaert 1983; Chan 2009; Chisholm 1966; Christian 2003 (C); Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hemminki 1991; Makrides 2003; Paintin 1966; Preziosi 1997; Siega-Riz 2001; Tura 1989; Wallenburg 1983; Zeng 2008 (C); Ziaei 2007; Ziaei 2008). The method of concealing allocation used in the remaining trials was unclear (Batu 1976; Cantlie 1971; Chanarin 1965; Charoenlarp 1988; Holly 1955; Hood 1960; Kerr 1958; Lee 2005; Meier 2003; Milman 1991; Ouladsahebmadarek 2011; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982; Willoughby 1967). Some trials used an inadequate method or did not use any allocation concealment at all (Chanarin 1971; Corrigan 1936; Han 2011; Hankin 1963; Menendez 1994 (C); Van Eijk 1978; Wills 1947).

 

Blinding

 

Blinding of participants, staff and outcome assessors

Investigators in 25 trials attempted to blind participants and staff by using placebos of similar appearance to active treatment or coded or opaque bottles although it was not always clear whether or not outcome assessment was blinded (Barton 1994; Buytaert 1983; Chanarin 1971; Charoenlarp 1988 Chisholm 1966; Christian 2003 (C); Cogswell 2003; Corrigan 1936; De Benaze 1989; Eskeland 1997; Han 2011; Harvey 2007; Hemminki 1991; Makrides 2003; Meier 2003; Milman 1991; Paintin 1966; Preziosi 1997; Siega-Riz 2001; Svanberg 1975; Tura 1989; Wallenburg 1983; Wills 1947; Ziaei 2007; Ziaei 2008). In the remaining trials blinding was either not mentioned or not attempted.

 

Incomplete outcome data

We judged that trials with more than 20% loss to follow-up, or with imbalanced loss to follow-up in different arms of trials were inadequate in terms of completeness of outcome data. Ten trials were assessed as having high levels of attrition, or loss was not balanced across groups and may have occurred for reasons associated with treatment (for example, if women were withdrawn from trials if they developed anaemia or experienced side effects) (Barton 1994; Cantlie 1971; Chan 2009; Christian 2003 (C); Cogswell 2003; Eskeland 1997; Kerr 1958; Meier 2003; Menendez 1994 (C); Siega-Riz 2001).

 

Selective reporting

We did not formally assess outcome reporting bias; for most of the included trials we did not have access to study protocols and assessing outcome reporting bias from published reports alone can be difficult. However, we have noted in the Characteristics of included studies tables where we suspected a problem relating to outcome reporting. Although for most outcomes too few studies contributed data to allow us to examine possible publication bias through generating funnel plots, in the data and analyses tables and in the forest plots, we have arranged studies by weight to allow us to visually examine plots to decide whether there is any evidence of a greater effect size in smaller studies.

 

Other potential sources of bias

We have noted other concerns about studies in the notes and other risk of bias sections of the Characteristics of included studies tables.

 

Effects of interventions

See:  Summary of findings for the main comparison Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo) for women during pregnancy;  Summary of findings 2 Any supplements containing iron and folic acid versus same supplements without iron nor folic acid (no iron nor folic acid or placebo) for women during pregnancy

In this review we have included data from 43 trials, involving more than 27,402 women although in trials which included more than two treatment arms we may not have included all arms in our analyses. We have organised the summary of results by supplementation regimens compared and by primary and secondary outcomes. Most of the included studies focused on haematological indices and few reported on any of the other outcomes prespecified in the review protocol. Many of the findings showed heterogeneity that could not be explained by standard sensitivity analyses including quality assessment, and so we used a random-effects model to analyse the results.

See the Data and analyses section for detailed results on primary and secondary outcomes.

For each comparison we have indicated the number of studies contributing data to that comparison. Some studies, with more than two treatment arms are included in more than one comparison. For most outcomes only a relatively small proportion of studies included in the comparison reported data; for some outcomes a single study reported results; for this reason we have indicated for each outcome the number of studies contributing data and the number of women included in those studies. For those outcomes including data from cluster-randomised trials the number included is the effective sample size; that is, sample sizes and event rates have been adjusted for cluster-trials to take account of the design effect.

 

(1) Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo) (43 studies)

 

Infant outcomes

 
Low birthweight (less than 2500 g)

Overall, there was a statistically significant difference in the prevalence of low birthweight (less than 2500 g) between newborns of mothers in these two groups. Among 8480 women in 11 trials, 8.4% of those who took daily iron supplementation during pregnancy had a baby with birthweight below 2500 g versus 10.2% of those who received no iron or placebo (average risk ratio (RR) 0.81; 95% confidence interval (CI) 0.68 to 0.97) ( Analysis 1.1). There was no clear evidence of differences between subgroups ( Analysis 1.2;  Analysis 1.3;  Analysis 1.4;  Analysis 1.5) or obvious funnel plot asymmetry (Figure 4).

 FigureFigure 4. Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.1 Low birthweight (less than 2500 g) (ALL).

 
Birthweight (g)

We also found a significant difference in mean infant birthweight in the two groups. Among infants born to 9385 participants in 14 trials the mean difference (MD) in birthweight between those whose mothers had taken iron supplements and those whose mothers had not was 30.81 g (95% CI 5.94 to 55.68) ( Analysis 1.6). We did not find evidence of subgroup differences ( Analysis 1.7;  Analysis 1.8;  Analysis 1.9;  Analysis 1.10) or obvious funnel plot asymmetry (Figure 5).

 FigureFigure 5. Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.6 Birthweight (g) (ALL).

 
Premature birth (less than 37 weeks' gestation)

Thirteen trials with 10,148 women provided data on preterm birth (before 37 week's gestation); while women receiving iron supplements were less likely to experience premature delivery the difference between groups did not reach statistical significance (average RR 0.88; 95% CI 0.77 to 1.01).There was no evidence of differences between subgroups in terms of women's gestational age or anaemia status at the start of supplementation, or for the dose of iron, however, the treatment effect appeared to be greater in non-malarial settings ( Analysis 1.12;  Analysis 1.13;  Analysis 1.14;  Analysis 1.15). Visual inspection of the funnel plot for this outcome suggested that smaller studies tended to report more pronounced treatment effects (Figure 6).

 FigureFigure 6. Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.11 Premature birth (less than 37 weeks of gestation) (ALL).

 
Neonatal death

Four studies with 7465 participants reported neonatal mortality and there was no clear evidence of any difference between groups (average RR 0.90; 95% CI 0.68 to 1.19) ( Analysis 1.16). We did not find evidence of subgroup differences for this outcome ( Analysis 1.17;  Analysis 1.18;  Analysis 1.19;  Analysis 1.20).

 
Congenital anomalies

Three studies with 2702 women reported the number of infants with congenital anomalies; there was no clear evidence of any difference between groups (average RR 0.86; 95% CI 0.55 to 1.35) ( Analysis 1.21).

 
Other primary infant outcomes

No studies reported findings for infant anaemia or infant iron-deficiency anaemia at birth or soon after.

 

Maternal primary outcomes

 
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Among 2199 women in 14 trials (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Holly 1955; Liu 2000; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983), 13.06% of those who received daily iron supplements during pregnancy had anaemia at term in comparison with 35.71% who did not receive iron (average RR 0.30; 95% CI 0.19 to 0.46) ( Analysis 1.26). However, because the heterogeneity in study results was substantial our results have to be interpreted with caution (heterogeneity: T² = 0.40, I² = 80%, Chi² test for heterogeneity P < 0.00001. We did not find any differences between subgroups in most of the subgroup analyses although the treatment effect appeared more pronounced in non-malarial settings ( Analysis 1.27;  Analysis 1.28;  Analysis 1.29;  Analysis 1.30). Visual inspection of the funnel plot for this outcome suggested that the treatment effect was more pronounced in smaller studies (Figure 7).

 FigureFigure 7. Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.26 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL).

 
Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more )

Seven studies (1256 women) reported data for this outcome, with women in groups receiving iron as part of supplements being less likely to have iron deficiency at term (average RR 0.43; 95% CI 0.27 to 0.66) ( Analysis 1.31). Subgroup analyses suggested that gestational age greater than 20 weeks, mixed or unspecified anaemia status at the start of supplementation and higher doses of iron were associated with more pronounced treatment effects ( Analysis 1.32;  Analysis 1.33;  Analysis 1.34;  Analysis 1.35).

 
Maternal iron deficiency anaemia at term (Hb below 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

Data from six trials involving 1088 women showed that 4.4% of women who received daily iron supplements and 13.2% of those who did not had iron deficiency anaemia at term (average RR 0.33; 95% CI 0.16 to 0.69). We did not find evidence of differences between subgroups ( Analysis 1.37;  Analysis 1.38;  Analysis 1.39;  Analysis 1.40).

 
Side effects (any)

Data from 11 trials involving 4418 women suggest that women who receive daily oral iron supplementation are more likely to report side effects of any kind than women taking placebo or not taking any iron as part of supplements (25.3% versus 9.91% reporting side effects; average RR 2.36; 95% CI 0.96 to 5.82) (( Analysis 1.42). However, the heterogeneity between the treatment effects is substantial and the results have to be interpreted with caution (heterogeneity: T² = 1.72, I² = 96%, Chi² test for heterogeneity P < 0.00001, 95% PI 0.14 to 42.28).There were no differences between subgroups in terms of women's gestational age or anaemia status at the start of supplementation. The risk of side effects appeared greater with increased doses of iron and the test for subgroup differences was close to statistical significance (P = 0.06, I2 = 64.7%). There also appeared to be a difference between subgroups based on malarial setting: in one trial carried out in a malarial setting there appeared to be a huge disparity between treatment groups in terms of side effects and this led to an apparent difference between subgroups ( Analysis 1.43;  Analysis 1.44;  Analysis 1.45;  Analysis 1.46). There was no obvious funnel plot asymmetry for this outcome (Figure 8).

 FigureFigure 8. Funnel plot of comparison: 1 Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo), outcome: 1.42 Side effects (any reported throughout the intervention period) (ALL).

 
Severe (Hb < 70/L) anaemia at any time during the second or third trimester

Nine trials with 2125 women reported results for this outcome, but estimable data were available for only three trials involving 786 women, this showed that women who received iron supplements were as likely to become severely anaemic during second and third trimesters (average RR 0.22; 95% CI 0.01 to 3.20). In many cases, women who became anaemic were treated and excluded from the analysis in the trials, independently of the group assigned, so very few cases became severely anaemic. As only three trials contributed estimable data, this result and the associated subgroup analysis have to be interpreted with caution.

 
Other maternal primary outcomes

There was no clear difference between groups for maternal mortality, or infection during pregnancy ( Analysis 1.41;  Analysis 1.53).

Two studies reported on placental malaria and parasitaemia (Fleming 1985; Menendez 1994 (C)) and found no differences between groups.

 

Secondary infant outcomes

There was statistically significant evidence of differences between groups for the following infant secondary outcomes.

 
Very premature birth (less than 34 weeks' gestation)

This outcome was reported in five trials with 3743 women; results suggest that babies born to mothers receiving iron were less likely to be born before 34 weeks' gestation (average RR 0.51; 95% CI 0.29 to 0.91) ( Analysis 1.59).

 
Infant ferritin concentration at six months in μg/L

This outcome was measured in a single study with 197 participants; at six months the MD was 11.00 (95% CI 4.37 to 17.63) ( Analysis 1.61).

 
Other infant secondary outcomes

There was no evidence of statistically significant differences between groups for the following infant secondary outcomes: very low birthweight; infant small-for-gestational age; mean Apgar score or low Apgar score at five minutes; mean infant Hb levels at three and six months; admission to special care; head circumference at birth; stunting at long-term follow-up, and breast feeding at four months (not prespecified).

No trials reported on the remaining prespecified infant secondary outcomes.

 

Maternal secondary outcomes

There was statistically significant evidence of differences between groups for the following maternal secondary outcomes:

 
Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) and within six weeks postpartum period (in g/L)

Haemoglobin concentration at or near term was reported in 19 studies, involving 3704 participants. There were high levels of heterogeneity for this outcome and results should be interpreted with caution. Women who received iron were on average likely to have higher Hb levels at term (MD 8.88 g/L; 95% CI 6.96 to 10.80) (heterogeneity: T² = 13.92, I² = 87%, Chi² test for heterogeneity P < 0.00001 ( Analysis 1.66).

At six weeks postpartum the difference between groups remained significant with women receiving iron as part of supplements having higher Hb levels (MD 7.61; 95% CI 5.50 to 9.72; reported in seven studies with 956 women) (heterogeneity: T² = 3.09, I² = 40%, Chi² test for heterogeneity P = 0.12) ( Analysis 1.67).

 
Maternal high Hb concentrations (Hb greater than 130 g/L) at any time during second or third trimester

There was evidence from nine studies (4869 women) with estimable data that high Hb concentrations were more likely in the second and third trimesters in women who had received iron as part of supplements (average RR 2.26; 95% CI 1.40 to 3.66). There was high heterogeneity for this outcome (heterogeneity: T² = 0.44, I² = 89%, Chi² test for heterogeneity P < 0.00001, PI 0.44 to 11.54 ) ( Analysis 1.68).

 
Maternal high Hb concentrations at term (defined as Hb greater than 130 g/L at 37 weeks' gestation or more)

Women who received iron were at higher risk of haemoconcentration at term (RR 3.08; 95% CI 1.28 to 7.41; reported in nine studies 4850 women). Again, there was high heterogeneity for this outcome and results should be interpreted cautiously (heterogeneity: T² = 1.34, I² = 96%, Chi² test for heterogeneity P < 0.00001, 95% PI 0.19 to 39.15) ( Analysis 1.69).

 
Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

Data from eight trials involving 1819 reported results for this outcome; in six trials no cases of severe anaemia were identified so only two trials with 494 women contributed estimable data. Results from these two trials showed no significant difference between women who receive iron or not (average RR 0.47; 95% CI 0.01 to 44.11) ( Analysis 1.70).

 
Severe anaemia at postpartum (Hb less than 80 g/L)

While eight trials reported severe anaemia in the postnatal period only two studies with estimable data for 553 women contributed to this analysis; women receiving iron as part of supplements were less at risk of severe anaemia in the weeks after the birth (average RR 0.04; 95% CI 0.01 to 0.28) ( Analysis 1.71).

 
Transfusion provided

The number of women receiving transfusions was reported in three studies (3453 participants) with women who had iron being less likely to have a transfusion than women who had no iron as part of supplements (average RR 0.61; 95% CI 0.38 to 0.96) ( Analysis 1.76).

 
Puerperal infection

There was a statistically significant difference between groups in the number of women reported to have puerperal infection; with women receiving iron being at reduced risk, (four studies, 4374 participants) (average RR 0.68; 95% CI 0.50 to 0.92) ( Analysis 1.73).

 
Other secondary outcomes

There was no statistically significant evidence of differences between groups for the following secondary outcomes: ante- or postpartum haemorrhage, individual side effects, placental abruption, preterm rupture of the membranes, pre-eclampsia and moderate anaemia in the postpartum period. Several of these outcomes were reported in only a small number of studies.

No trials reported on the remaining prespecified secondary outcomes.

 

(2) Any supplements containing iron and folic acid versus same supplements without iron nor folic acid (no iron nor folic acid or placebo) (eight studies)

 

Infant primary outcomes

 
Low birthweight (less than 2500 g)

Two trials with 1311 participants examined this outcome (Christian 2003 (C);Taylor 1982). There was no clear evidence of significant differences between infants of women receiving daily iron + folic acid supplementation versus no supplements (RR 1.07; 95% CI 0.31 to 3.74) ( Analysis 2.1). Data from the same trials suggest that infant birthweight were similar in the two groups (MD 57.73; 95% CI 7.66 to 107.79) ( Analysis 2.2).

 
Premature birth (less than 37 weeks' gestation)

Three studies with 1497 women examined this outcome (Christian 2003 (C); Lee 2005; Taylor 1982). We found no evidence of differences in the numbers experiencing preterm birth between women who received daily iron and folic acid supplements and those receiving no treatment or placebo (RR 1.55, 95% CI 0.40 to 6.00). Only one of these trials met the criteria for high quality (Christian 2003 (C)) ( Analysis 2.3). There were no significant differences between subgroups ( Analysis 2.4;  Analysis 2.5;  Analysis 2.6;  Analysis 2.7).

 
Neonatal death

Three studies reported on this outcome (Barton 1994; Christian 2003 (C); Taylor 1982); there were a total of 69 perinatal deaths, and no clear evidence of any difference between groups (average RR 0.81; 95% CI 0.51 to 1.30) ( Analysis 2.8). No subgroup differences were apparent.

 
Congenital anomalies

One study with 1652 women reported the number of infants with congenital anomalies; and there was no clear evidence of any difference between groups (average RR 0.70; 95% CI 0.35 to 1.40) ( Analysis 2.13).

 

Maternal primary outcomes

 
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

The data from three trials including 346 women (Barton 1994; Batu 1976; Chisholm 1966) suggest that women who routinely receive daily iron and folic acid supplementation during pregnancy are less likely to have anaemia at term than those not taking any iron and folic acid supplements at all (defined as Hb less than 110 g/L) (7.2% versus 28.3%; average RR 0.34; 95% CI 0.21 to 0.54) ( Analysis 2.14). Only one study with no estimable data met the prespecified criteria for high quality. We did not identify any differences between subgroups.

 
Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

Data from one trial involving 131 women (Lee 2005) suggest that women who routinely receive daily oral supplementation with iron are less likely to have iron deficiency at term than women taking placebo or not taking any iron and folic acid supplements at all although the difference between groups did not reach statistical significance (3.6% versus 15%; RR 0.24; 95% CI 0.06 to 0.99) ( Analysis 2.19).

 
Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo in the single trial contributing data to this analysis (RR 0.43; 95% CI 0.17 to 1.09) ( Analysis 2.20). The study contributing data did not meet prespecified criteria for high quality.

 
Side effects (any)

One trial including 456 women (Charoenlarp 1988) suggests that women routinely receiving iron and folic acid supplementation are more likely to report any side effects; none of those receiving no supplementation reported side effects, however, the CI is very broad for this finding (RR 44.32; 95% CI 2.77 to 709.09) ( Analysis 2.22). This trial did not meet criteria for high methodological quality.

 
Severe anaemia at any time during second and third trimester (Hb less than 70 g/L)

Two studies had estimable data for this outcome; there was no evidence of a statistically significant difference between groups (RR 0.12, 95% CI 0.02 to 0.63) ( Analysis 2.23).

 
Other outcomes

One trial with 48 women reported on infection in pregnancy (Taylor 1982); there were four events in total, two in each group ( Analysis 2.29). A single study reported on maternal deaths and there were no estimable data ( Analysis 2.21).

There were no data on the remaining prespecified primary outcomes.

 

Infant secondary outcomes

No evidence of significant differences was found between infants from these groups of women receiving daily iron + folic acid supplementation and those taking placebo or not taking any supplements at all in the following secondary outcomes: very low birthweight (less than 1500 g), or admission to special care unit.

No trials reported on the remaining infant secondary outcomes.

 

Maternal secondary outcomes

 
Maternal Hb concentration at term (in g/L at 37 weeks' gestation or more)

The data from three trials including 140 women (Barton 1994; Batu 1976; Taylor 1982) suggest that women who routinely receive daily iron and folic acid supplementation reach term with higher Hb concentration than women taking placebo or not taking any iron and folic acid supplement at all (MD 16.13 g/L; 95% CI 12.74 to 19.52) ( Analysis 2.36). The effect of iron-folic acid supplementation was associated with higher Hb concentrations in the single high-quality trial (MD 17.10; 95% CI 8.44 to 25.76) (Barton 1994).

 
Maternal high Hb concentrations at term (defined as Hb greater than 130 g/L)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo ( Analysis 2.39).

 
Maternal high Hb concentrations at any time during second or third trimesters (defined as Hb greater than 130 g/L)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo (RR 1.78; 95% CI 0.63 to 5.04) ( Analysis 2.38).

 
Maternal Hb concentration within six weeks postpartum in g/L

Two studies (Christian 2003 (C); Taylor 1982) involving 459 women reported this outcome. The data from these trials suggest that women receiving daily iron + folic acid supplementation achieve a higher concentration of Hb at one month postpartum than women not taking any supplements at all (MD 10.07; 95% CI 7.33 to 12.81) ( Analysis 2.37) but no firm conclusions can be drawn given the scarcity of the data.

 
Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

Three trials reported severe anaemia at or near term; there were estimable data for only one trial and overall only three women were identified with severe anaemia ( Analysis 2.41).

 
Maternal severe or moderate anaemia at postpartum (Hb less than 80 g/L)

Two trials reported estimable data for moderate anaemia in the postpartum period and women receiving iron were less likely to have anaemia (RR 0.33; 95% CI 0.17 to 0.65) ( Analysis 2.40). For severe anaemia in the postpartum period only one trial reported estimable data with all cases of severe anaemia occurring in the women who did not receive supplements (RR 0.05; 95% CI 0.00 to 0.76) ( Analysis 2.42). The scarcity of data makes it difficult to draw any firm conclusions on these outcomes.

 

Other secondary maternal outcomes

No evidence of significant differences was found in the following secondary outcomes: very premature delivery, puerperal infection, antepartum haemorrhage, postpartum haemorrhage, placental abruption, and pre-eclampsia. No trials reported on the remaining maternal secondary outcomes.

 

(3) Supplementation with iron alone versus no treatment/placebo (35 studies)

 

Infant outcomes

 
Low birthweight (less than 2500 g)

Overall, we found no statistically significant difference in the prevalence of low birthweight (less than 2500 g) between newborns of mothers in these two groups ( Analysis 3.1). Among 3830 women in seven trials (Cogswell 2003; Eskeland 1997; Falahi 2010; Hemminki 1991; Makrides 2003; Meier 2003; Menendez 1994 (C)), 3.2% of those who took daily iron supplementation during pregnancy had a baby with birthweight below 2500 g versus 4.2% of those who received no iron or placebo (average RR 0.71; 95% CI 0.42 to 1.19) ( Analysis 3.1). When we limited our analysis to studies meeting criteria for high quality (Cogswell 2003; Eskeland 1997; Makrides 2003; Menendez 1994 (C)), the difference in the percentage of mothers with low birthweight babies remained non-significant (data not shown). There were no significant differences between subgroups  Analysis 3.2;  Analysis 3.3;  Analysis 3.4;  Analysis 3.5).

 
Birthweight (g)

We found no significant difference in birthweight ( Analysis 3.6) in children from mothers of the two groups. Among infants born to 3953 participants in nine trials (Cogswell 2003; Eskeland 1997; Falahi 2010; Harvey 2007; Hemminki 1991; Makrides 2003; Paintin 1966; Preziosi 1997; Puolakka 1980), the MD in birthweight between those whose mothers had taken iron supplements and those whose mothers had not was 16.43 g and was not statistically significant (95% CI -37.28 to 70.14) . When we temporarily removed from the analysis the studies that did not meet our criteria for high quality the results remained non-significant (data not shown). No subgroup differences were apparent ( Analysis 3.7;  Analysis 3.8;  Analysis 3.9;  Analysis 3.10).

 
Premature birth (less than 37 weeks' gestation)

Seven trials with 4407 women provided data on preterm birth (before 37 weeks' gestation); while women receiving iron supplements were less likely to experience premature delivery the difference between groups did not quite reach statistical significance (average RR 0.77; 95% CI 0.60 to 1.00) ( Analysis 3.11). When we temporarily removed from the analysis the one study that did not meet our criteria for high quality (Chan 2009), the results favouring women in the daily iron group reached statistical significance (average RR 0.71; 95% CI 0.53 to 0.97) (data not shown). We found no significant differences between subgroups ( Analysis 3.12;  Analysis 3.13;  Analysis 3.14;  Analysis 3.15).

 
Other primary infant outcomes

Only one study with 2694 participants reported neonatal mortality and there was no clear evidence of any difference between groups ( Analysis 3.16). A single study with 850 women reported the number of infants with congenital anomalies; again there was no clear evidence of any difference between groups ( Analysis 3.17).

No studies reported findings for infant anaemia or infant iron deficiency anaemia at birth or soon after.

 

Maternal primary outcomes

 
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

Among 2136 women in 14 trials (Batu 1976; Chanarin 1971; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Holly 1955; Liu 2000; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983), 12.5% of those who received daily iron supplements during pregnancy and 34.3% who did not receive iron had anaemia at term (average RR 0.29; 95% CI 0.19 to 0.47 ( Analysis 3.18). However, because the heterogeneity in study results was substantial our results have to be interpreted with caution (heterogeneity: T² = 0.44, I² = 80%, Chi² test for heterogeneity P < 0.0001. When we temporarily removed studies from the analyses that did not meet our criteria for high quality, the difference between groups remained significant and heterogeneity was reduced although it remained over 50% (data not shown). We did not find differences between subgroups in terms of women's gestational age or anaemia status at the start of supplementation, or for the dose of iron. The treatment effect appeared more pronounced in non-malarial settings, however only two of the trials contributing data to this analysis were carried out in a malarial setting so any difference between these subgroups may have occurred by chance ( Analysis 3.19;  Analysis 3.20;  Analysis 3.21;  Analysis 3.22).

 
Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

Data from seven trials involving 1256 women (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989) showed that 28.5% of women who received daily iron supplements had iron-deficiency at term, compared with 51.3% of those who received no iron supplements (average RR 0.43; 95% CI 0.27 to 0.66) ( Analysis 3.23). The heterogeneity between the treatment effects is high and the results should be interpreted with caution (heterogeneity: T² = 0.26, I² = 85%, Chi² test for heterogeneity P < 0.00001). Subgroup analyses indicated that gestational age greater than 20 weeks, mixed or unspecified anaemia status at the start of supplementation, malarial setting and higher doses of iron were associated with more pronounced treatment effects ( Analysis 3.24;  Analysis 3.25;  Analysis 3.26;  Analysis 3.27).

 
Maternal iron deficiency anaemia at term (Hb below 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

Data from six trials involving 1088 women (Cogswell 2003; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Tura 1989) showed that 4.4% of women who received daily iron supplements and 13.2% of those who did not, had iron-deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69). The heterogeneity between the treatment effects was moderate (I² 49%) ( Analysis 3.28). There were no differences identified between subgroups ( Analysis 3.29;  Analysis 3.30;  Analysis 3.31;  Analysis 3.32).

 
Side effects (any)

Data from 10 trials involving 4232 women (Charoenlarp 1988; Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hemminki 1991; Hood 1960; Kerr 1958; Makrides 2003; Paintin 1966) suggest that women who receive daily oral iron supplementation are more likely to report side effects of any kind than women taking placebo or not taking any iron supplements at all (26.03% versus 8.74%; RR 2.92; 95% CI 1.10 to 7.76) ( Analysis 3.34). However, the heterogeneity between the treatment effects is substantial and the results have to be interpreted with caution (heterogeneity: T² = 1.79, I² = 96%, Chi² test for heterogeneity P < 0.00001, 95% PI 0.11 to 78.56). Side effects were increased in women who received daily higher doses of elemental iron (more than 60 mg) and where supplementation started earlier ( Analysis 3.35;  Analysis 3.36;  Analysis 3.37;  Analysis 3.38). When we restricted the analyses to those trials meeting criteria for high quality, the difference between groups did not reach statistical significance (data not shown).

 
Maternal severe (Hb < 70 g/L) anaemia at any time during the second or third trimester

Data from seven trials involving 1078 women was available for this outcome, although only two trials with 466 women reported estimable data which showed that women who received iron supplements were as likely to become severely anaemic during second and third trimesters (RR 0.75; 95% CI 0.02 to 29.10) as those not receiving iron. However, results are difficult to interpret as very few trials reported events, and in many cases women who became anaemic were treated and excluded from the analysis in the trials. We found no differences between subgroups ( Analysis 3.40;  Analysis 3.41;  Analysis 3.42;  Analysis 3.43).

 
Other maternal primary outcomes

Maternal mortality was reported in one small trial including 47 women and no events were reported ( Analysis 3.33). Infection during pregnancy for 2694 women was reported by Hemminki 1991; there was no evidence of statistically significant differences between groups ( Analysis 3.45).

No studies reported findings for other maternal primary outcomes: malaria.

 

Secondary infant outcomes

 
Infant ferritin concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period)

The MD was 11.00 μg/L; 95% CI 4.37 to 17.63 μg/L (one trial involving 197 women) (Preziosi 1997) ( Analysis 3.49).

 
Very premature birth (less than 34 weeks' gestation)

This outcome was reported in three trials, involving 690 participants; results suggest that babies born to mothers receiving iron were less likely to be born before 34 weeks' gestation (average RR 0.32; 95% CI 0.10 to 1.09) ( Analysis 3.47)

 
Other infant secondary outcomes

We found no evidence of significant difference by treatment group in the following secondary outcomes: very low birthweight (less than 1500 g) ( Analysis 3.46); infant Hb concentration in the first six months (in g/L, counting the last reported measure after birth within this period) ( Analysis 3.48); admission to special care unit ( Analysis 3.50).

No trials reported on the remaining infant secondary outcomes.

 

Maternal secondary outcomes

 
Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more)

Among 1851 women who participated in 16 trials (Batu 1976; Buytaert 1983; Cantlie 1971; Chanarin 1971; Cogswell 2003; De Benaze 1989; Eskeland 1997; Falahi 2010; Makrides 2003; Milman 1991; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983; Ziaei 2008), those who took iron supplements had a mean Hb concentration 8.95 g/L higher at term in comparison to those who took no iron supplements at all (MD 8.95; 95% CI 6.37 to 11.53 g/L) ( Analysis 3.54). However, because the heterogeneity among the treatment effects found in individual studies was substantial our results have to be interpreted with caution (heterogeneity: T² = 21.70, I² = 89%, Chi² test for heterogeneity P < 0.00001). When we restricted the analysis to studies meeting the criteria for high quality the difference between groups remained significant (data not shown).

 
Maternal Hb concentration within six weeks postpartum (in g/L)

The data from six trials involving 659 women (Cantlie 1971; Hankin 1963; Lee 2005; Menendez 1994 (C); Milman 1991; Wills 1947) suggest that women that routinely receive daily iron supplementation have a higher concentration of Hb within six weeks postpartum than those taking placebo or not taking any iron supplements at all (MD 7.26 g/L; 95% CI 4.78 to 9.74 g/L). Heterogeneity of the results is T² = 3.99, I² = 44%, Chi² test for heterogeneity P < 0.0001 ( Analysis 3.55).

 
Maternal high Hb concentrations at any time during second or third trimester (Hb greater than 130 g/L)

Eight trials involving 3840 women evaluated the effects of oral routine supplementation with iron alone and high Hb concentrations at any time during the second or third trimesters (Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958). Among women who received daily iron supplements, 17.2% were found to have high Hb concentrations at some time during their second or third trimesters, compared with 8.9% of those who received no iron supplements (average RR 1.81; 95% CI 1.21 to 2.71) ( Analysis 3.56). However, because the heterogeneity between studies was substantial the results have to be interpreted with caution (heterogeneity: T² = 0.20, I² = 75%, Chi² test for heterogeneity P < 0.0005, 95% PI 0.54 to 6.04). The difference between groups remained significant when we temporarily removed from the analysis those studies which did not meet our criteria for high quality (data not shown).

 
Maternal high Hb concentrations at or near term (defined as Hb greater than 130 g/L, at 34 weeks' gestation or more)

Data from eight trials involving 3883 women (Chisholm 1966; Cogswell 2003; Eskeland 1997; Hemminki 1991; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958) indicated that 18.1% of women who took daily iron supplementation during pregnancy and 5.6% of those who did not had high Hb concentrations at term (average RR 3.67; 95% CI 2.23 to 6.04) ( Analysis 3.57). The heterogeneity between the treatment effects was substantial and the results have to be interpreted with caution (heterogeneity: T² = 0.23, I² = 63%, Chi² test for heterogeneity P < 0.008. The difference between groups remained significant when we restricted the analysis to studies meeting criteria for high quality (data not shown).

 
Transfusion provided

The data from two trials involving 2726 women (Hemminki 1991; Puolakka 1980) suggest that women that routinely receive daily iron supplementation have a lower risk of receiving transfusion in comparison with women who did not receive iron supplementation (2% versus 3.4%); RR 0.59; 95% CI 0.37 to 0.94) ( Analysis 3.64).

 
Maternal well being/satisfaction

A maternal index of well being was measured in one trial (Hemminki 1991) through the use of a self-administered questionnaire at 36 weeks' gestation and at six weeks and six months postpartum. There were no significant differences in any of the eight health concepts measured by this methodology between the women in the iron supplemented group or those in the placebo group at 36 weeks' gestation, six weeks and six months postpartum. Another trial (Eskeland 1997) assessed maternal well being at 28 and 36 weeks' gestation, and found no differences between the iron supplemented mothers or those receiving placebo ( Analysis 3.70).

 
Other secondary outcomes

There was no evidence of significant differences between women receiving daily iron supplementation and women receiving placebo or not taking any iron supplements at all, in the following secondary outcomes: diarrhoea, very premature delivery (less than 34 weeks' gestation), placental abruption, pre-eclampsia, moderate anaemia at postpartum, maternal severe anaemia a postpartum; puerperal infection, antepartum haemorrhage and postpartum haemorrhage, constipation, nausea, heartburn, or vomiting. No trials reported on the remaining secondary outcomes.

 

(4) Supplementation with iron + folic acid versus no treatment/placebo (eight studies)

 

Infant primary outcomes

 
Low birthweight (less than 2500 g)

Two studies with 1311 participants examined this outcome (Christian 2003 (C); Taylor 1982). There was no clear evidence of significant differences between infants of women receiving daily iron + folic acid supplementation versus no supplements (RR 1.07; 95% CI 0.31 to 3.74) ( Analysis 4.1).

Data from the these trials suggest that infant birthweight were 57.73 g heavier 95% CI 7.66 to 107.79 g in comparison to no treatment/placebo ( Analysis 4.2). One trial (Christian 2003 (C)) met our criteria for high quality.

 
Premature birth (less than 37 weeks' gestation)

Three studies with 1497 participants examined this outcome (Christian 2003 (C); Lee 2005; Taylor 1982). We found no evidence of differences in the numbers experiencing preterm birth between women who received daily iron and folic acid supplements and those receiving no treatment or placebo. One these trials met criteria for high quality (Christian 2003 (C)). There were no subgroup differences; only two of these trials had estimable data for this outcome.

 
Neonatal death

Three studies with 1793 women reported on this outcome (Barton 1994; Christian 2003 (C); Taylor 1982); there was no clear evidence of any difference between groups (average RR 0.81; 95% CI 0.51 to 1.30) ( Analysis 4.8).

 
Congenital anomalies

Only one study (1652 participants) reported data on this outcome (Christian 2003 (C)) and there appears to be no differences between the groups compared (RR 0.70, 95% CI 0.35 to 1.40) ( Analysis 4.13).

No trials reported on other review primary outcomes for infants.

 

Maternal primary outcomes

 
Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more)

The data from three trials including 346 women (Barton 1994; Batu 1976; Chisholm 1966) suggest that women who routinely receive daily iron and folic acid supplementation during pregnancy are less likely to have anaemia at term than those not taking any iron and folic acid supplements at all (defined as Hb less than 110 g/L) (7.2% versus 28.2%; average RR 0.34; 95% CI 0.21 to 0.54) ( Analysis 4.14). Only one study with no estimable data met the prespecified criteria for high quality. There was no evidence of subgroup differences.

 
Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more)

Data from one trial involving 131 women (Lee 2005) suggest that women who routinely receive daily oral supplementation with iron are less likely to have iron deficiency at term than women taking placebo or not taking any iron and folic acid supplements at all although the difference between groups did not reach statistical significance (3.6% versus 15%; RR 0.24; 95% CI 0.06 to 0.99) ( Analysis 4.19).

 
Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator at 37 weeks' gestation or more)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo in the single trial contributing data to this analysis (RR 0.43, 95% CI 0.17 to 1.09) ( Analysis 4.20). The study (131 participants) contributing data did not meet prespecified criteria for high quality.

 
Side effects (any)

One trial including 456 women (Charoenlarp 1988) suggests that women routinely receiving iron and folic acid supplementation are more likely to report any side effects; none of those receiving no supplementation reported side effects, however the CI is very broad for this finding (RR 44.32; 95% CI 2.77 to 709.09) ( Analysis 4.22). This trial did not meet criteria for high methodological quality.

 
Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L)

Two trials reported estimable data for this outcome and results suggest that women were less likely to be identified with severe anaemia in the group receiving iron (RR 0.12, 95% CI 0.02 to 0.63) ( Analysis 4.23).

 
Other outcomes

One trial with 48 women reported on infection in pregnancy (Taylor 1982); there were four events in total, two in each group ( Analysis 4.25). A single study reported on maternal deaths and there were no estimable data ( Analysis 4.21). There were no data on the remaining prespecified primary outcomes.

 

Infant secondary outcomes

No evidence of significant differences was found between infants from these groups of women receiving daily iron + folic acid supplementation and those taking placebo or not taking any supplements at all in the following secondary outcomes: very low birthweight (less than 1500 g) or admission to special care unit.

 

Maternal secondary outcomes

 
Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more)

The data from three trials including 346 women (Barton 1994; Batu 1976; Chisholm 1966) suggest that women who routinely receive daily iron and folic acid supplementation during pregnancy are less likely to have anaemia at term than those not taking any iron and folic acid supplements at all (defined as Hb less than 110 g/L) (7.2% versus 28.2%; average RR 0.34; 95% CI 0.21 to 0.54) ( Analysis 4.31). Only one study with no estimable data met the prespecified criteria for high quality.

 
Maternal iron deficiency at or near term (as defined by as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)

Data from one trial involving 131 women (Lee 2005) suggest that women who routinely receive daily oral supplementation with iron are less likely to have iron deficiency at term than women taking placebo or not taking any iron and folic acid supplements at all although the difference between groups was not statistically significant (3.6% versus 15%; RR 0.24; 95% CI 0.06 to 0.99) ( Analysis 4.32).

 
Maternal iron deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicator at 34 weeks' gestation or more)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo in the single trial contributing data to this analysis ( Analysis 4.33). The study contributing data did not meet prespecified criteria for high quality.

 
Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more)

The data from three trials including 140 women (Barton 1994; Batu 1976; Taylor 1982) suggest that women who routinely receive daily iron and folic acid supplementation reach term with higher Hb concentration than women taking placebo or not taking any iron and folic acid supplement at all (MD 16.13 g/L; 95% CI 12.74 to 19.52) ( Analysis 4.34). The effect of iron-folic acid supplementation was associated with higher Hb concentrations in the single high-quality trial (MD 17.10; 95% CI 8.44 to 25.76 ) (Barton 1994).

 
Maternal high Hb concentrations at any time during second or third trimesters (defined as Hb greater than 130 g/L)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo ( Analysis 4.36).

 
Maternal high Hb concentrations at term (defined as Hb greater than 130 g/L at 37 weeks' gestation or more)

No evidence of significant differences was found between women who received daily iron and folic acid supplements and those receiving no treatment or placebo ( Analysis 4.37).

 
Maternal Hb concentration within 6 weeks postpartum in g/L

Two studies (Christian 2003 (C); Taylor 1982) involving 459 women reported this outcome. The data from these trials suggest that women receiving daily iron + folic acid supplementation achieve a higher concentration of Hb within 6 weeks postpartum than women not taking any supplements at all (MD 10.07; 95% CI 7.33 to 12.81) ( Analysis 4.35) but no firm conclusions can be made given the scarcity of the data.

 
Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more)

Three trials reported severe anaemia at term, but only one study had cases ( Analysis 4.39).

 
Maternal severe or moderate anaemia at postpartum (Hb less than 80 g/L)

There was only one trial with estimable data on women with severe or moderate anaemia in the postpartum period ( Analysis 4.38;  Analysis 4.40). The scarcity of data makes it difficult to draw any conclusions on these outcomes.

 
Other secondary maternal outcomes

No evidence of significant differences was found in the following secondary outcomes: very premature delivery, moderate anaemia at term, moderate anaemia at any time during second or third trimesters, puerperal infection, antepartum haemorrhage, postpartum haemorrhage, placental abruption and pre-eclampsia. No trials reported on the remaining maternal secondary outcomes.

 

(5) Supplementation with iron + folic acid versus folic acid alone (without iron) supplementation (five studies)

The study by Zeng 2008 (C) was a cluster-randomised trial and the sample size and event rate have been adjusted to take account of the design effect. In the results below we have used the effective sample size rather than the total number of women included in the study.

 

Infant primary outcomes

 
Low birthweight (less than 2500 g)

Three studies with an effective sample size of 4316 contributed data to this outcome, all studies met the criteria for high quality (Christian 2003 (C); Zeng 2008 (C); Ziaei 2007). There was a slight difference between groups receiving iron and folic acid versus folic acid alone (average RR 0.84; 95% CI 0.73 to 0.95) ( Analysis 5.1). These studies reported mean infant birthweight but was a difference between groups (MD 32.23; 95% CI 0.86 to 63.60) ( Analysis 5.6).

 
Premature birth (less than 37 weeks' gestation)

Three studies with an effective sample size of 4314 contributed data to this outcome; all studies met the criteria for high quality (Christian 2003 (C); Zeng 2008 (C); Ziaei 2007). There was no statistically significant difference between groups receiving iron and folic acid versus folic acid alone and no subgroup differences were apparent (average RR 0.97; 95% CI 0.78 to 1.20) ( Analysis 5.11).

 
Neonatal death

Three studies (4771 participants) (Christian 2003 (C); Zeng 2008 (C); Ziaei 2007) contributed data; there was no clear evidence of a difference between groups (average RR 0.85; 95% CI 0.63 to 1.15) ( Analysis 5.16). There were no differences between subgroups identified.

 
Congenital anomalies

One study with 1652 women reported the number of infants with congenital anomalies; and there was no clear evidence of any difference between groups (RR 0.70; 95% CI 0.35 to 1.40) ( Analysis 5.21).

No studies reported on our remaining infant primary outcomes.

 

Maternal primary outcomes

 
Maternal anaemia at term (at 37 weeks' gestation or more)

Two studies with 303 women reported on the number of women with anaemia at term (Batu 1976; Chisholm 1966). The group receiving iron and folic acid were less likely to be anaemic compared to those receiving folic acid alone (9.7% versus 30.4%; average RR 0.34; 95% CI 0.21 to 0.55) ( Analysis 5.22). The result remained significant when the study that did not meet our criteria for high quality was removed (data not shown). We did not find subgroup differences.

 
Maternal iron deficiency anaemia at term (at 37 weeks' gestation or more)

A single study (Ziaei 2007) reported on the number of women with iron deficiency anaemia at term; there were no estimable data for this outcome ( Analysis 5.28).

 
Side effects (any)

One study reported on side effects (Ziaei 2007). There were no significant differences between the compared groups ( Analysis 5.30).

 
Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L)

Three studies reported on maternal severe anaemia in pregnancy although there were estimable data for only one (Christian 2003 (C)). In this study women receiving supplements were less likely to be identified with severe anaemia (RR 0.06; 95% CI 0.01 to 0.47) ( Analysis 5.31).

 
Infection during pregnancy

This outcome was reported in a single study with 727 women. There was no evidence of significant differences between groups ( Analysis 5.33).

Studies did not provide data on our remaining maternal prespecified outcomes (maternal iron deficiency, maternal death or clinical malaria).

 

Infant secondary outcomes

There was no evidence of differences between groups for very premature birth, very low birthweight. There were no data reported on our remaining infant secondary outcomes.

 

Maternal secondary outcomes

 
Maternal anaemia at or near term (at 34 weeks' gestation or more)

Two studies with 303 women reported on the number of women with anaemia at term (Batu 1976; Chisholm 1966). The group receiving iron and folic acid were less likely to be anaemic compared to those receiving folic acid alone (9.7% versus 30.4%; average RR 0.34; 95% CI 0.21 to 0.55) ( Analysis 5.39). The result remained significant when the study that did not meet our criteria for high quality was removed (data not shown).

 
Maternal iron deficiency anaemia at or near term (at 34 weeks' gestation or more)

A single study (Ziaei 2007) reported on the number of women with iron deficiency anaemia at term; there were no estimable data for this outcome ( Analysis 5.41).

 
Maternal Hb at or near term (in g/L, at 34 weeks' gestation or more)

Two studies with 771 women contributed data to this outcome (Batu 1976; Ziaei 2007). The mean concentration of Hb was higher in the women receiving iron and folic acid as opposed to those receiving folic acid alone (MD 12.44; 95% CI 0.95 to 23.93). However, with only two studies contributing data this result should be treated with caution ( Analysis 5.42).

 
Maternal high Hb concentrations at or near term (at 37 weeks' gestation or more) and during pregnancy

Two studies with 967 reported data for the number of women with high Hb concentrations at term (Chisholm 1966; Ziaei 2007). The evidence of difference between groups was not statistically significant (average RR 1.87; 95% CI 0.32 to 10.84) ( Analysis 5.45).

Two studies with 1042 women reported on high Hb concentrations in the third trimester of pregnancy. Women receiving iron in addition to folic acid were more likely to have high Hb concentrations during pregnancy (RR 4.33; 95% CI 2.26 to 8.30) ( Analysis 5.44).

 
Other outcomes

There was no evidence of significant differences between groups for the following secondary outcomes: maternal high Hb concentrations during second or third trimester, puerperal infection, antepartum haemorrhage, postpartum haemorrhage, transfusion provided, diarrhoea, vomiting, nausea or constipation, placental abruption, premature rupture of the membranes or pre-eclampsia.

Studies did not report data on our remaining maternal secondary outcomes.

 

(6) Supplementation with iron + other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation (three studies)

We have included data from three trials (Cantlie 1971; Ouladsahebmadarek 2011; Siega-Riz 2001).

 

Infant primary outcomes

A single study with 334 women provided data for infant primary outcomes. The study met our prespecified criteria for high quality (Siega-Riz 2001)

There was no evidence of a statistically significant differences between groups for infant birthweight or premature delivery. There were no data on perinatal death or other prespecified primary outcomes.

 

Maternal primary outcomes

One study provided data on side effects and no significant differences between groups were identified ( Analysis 6.10). No studies provided information on maternal anaemia at term, maternal infection or any of our other prespecified maternal outcomes.

 

Infant secondary outcomes

There was no significant evidence that there was any difference between groups for the number of babies small-for-gestational age. There were no data reported for our remaining infant secondary outcomes.

 

Maternal secondary outcomes

Two studies with 809 women reported on mean maternal Hb levels at term and women receiving iron were more likely to have higher Hb levels compared with those without iron (average RR 10.85,; 95% CI 7.29 to 14.42) ( Analysis 6.22). Cantlie 1971 also reported on mean maternal Hb levels in the postpartum period and women receiving iron in addition to other vitamins and minerals were more likely to have higher Hb levels compared with those receiving other vitamins and minerals without iron (MD 14.00; 95% CI 3.56 to 24.44) ( Analysis 6.23).

Siega-Riz 2001 reported on side effects, there were no differences between groups in terms of the number of women suffering constipation, diarrhoea, vomiting or heartburn.

Ouladsahebmadarek 2011 reported on placental abruption, premature rupture of the membranes and pre-eclampsia for 782 women; there were no significant differences between groups for any of these outcomes ( Analysis 6.39;  Analysis 6.40;  Analysis 6.41).

No information was reported on our remaining maternal secondary outcomes.

 

(7) Daily oral iron + folic acid + other vitamins and minerals supplementation versus daily oral folic acid + same other vitamins and minerals (without iron) supplementation (no studies)

No studies compared women receiving daily oral iron + folic acid + other vitamins and minerals supplementation versus daily oral folic acid + same other vitamins and minerals (without iron) supplementation.

 

(8) Daily oral iron + folic acid + other vitamins and minerals supplementation versus daily oral same other vitamins and minerals (without iron nor folic acid) supplementation (no studies)

No studies compared women receiving daily oral iron + folic acid + other vitamins and minerals with women receiving other vitamins and minerals (without either folic acid or iron).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Summary of main results

We have set out a summary of our main findings along with an overall assessment of the quality of the evidence in additional tables ( Summary of findings for the main comparison;  Summary of findings 2).

Forty-three trials compared the effects of daily oral supplements containing iron versus no iron or placebo. The majority of them (35) compared arms receiving iron alone versus no treatment and placebo. Overall, women taking iron supplements were less likely to have low birthweight newborns (below 2500 g) compared with controls (8.4% versus 10.2%). Mean birthweight was 30.81 g greater for those infants whose mothers received iron during pregnancy. Results also suggest that babies born to mothers receiving iron were less likely to be born before 34 weeks' gestation (average risk ratio (RR) 0.51; 95% confidence interval (CI) 0.29 to 0.91). For other infant outcomes there were no clear differences between groups.

Regarding maternal outcomes, women receiving iron compared with those receiving no treatment or placebo were less likely to be anaemic at term (13.06% versus 35.71%) and were less likely to have iron-deficiency (28.50% versus 51.33%) and iron-deficiency anaemia at term (4.37% versus 13.18%). At the same time, women who received iron supplements were more likely than controls to report side effects (25.30% versus 9.91%) and had increased risk of high haemoglobin (Hb) concentrations at any time during second or third trimester (RR 2.26; 95% CI 1.40 to 3.66) and at term (RR 3.08; 95% CI 1.28 to 5.41), particularly at does higher than 60 mg of elemental iron daily. Women receiving iron were on average more likely to have higher Hb levels at term and in the postpartum period. For several outcomes where there was evidence of differences between groups, the size of the treatment effect in individual studies varied considerably, and so our results should be interpreted with caution.

Only nine trials compared the effects of daily iron + folic acid supplementation with the effects of same supplements without iron + folic acid. There were clear positive effects on maternal haematological status while the effects on infant outcomes were uncertain.

 

Overall completeness and applicability of evidence

This review included 60 randomised controlled trials carried out since 1936 in 27 countries across the globe. Trials were mostly conducted during the last 20 years. There was some equilibrium between the trials that included non-anaemic women and those focused on populations with high prevalence of anaemia as well among the trials assessing early or late gestational iron supplementation. Although it was not possible to extract data from all the trials, these numbers clearly reflect the wide applicability of this review.

We addressed the effects of the use of iron or iron + folic acid by pregnant women, either provided alone or in combination with other vitamins and minerals. The effects can be determined if the differences between the comparison groups relies only in the presence of iron or iron + folic acid, that is, we are estimating the effects of the addition of iron or iron + folic acid to the pregnant women independently of any other co-interventions given to both groups being compared.

Most of the trials focused primarily on maternal changes in Hb and on some haematological indices after a certain period of supplementation. The results consistently show that iron supplementation in pregnancy improves maternal haematological outcomes independently of the dosage. However, those women who consumed higher amounts of iron (60 mg of iron or more per day) tended to have higher Hb values at the end or near term of pregnancy. In some cases, women reached levels above the threshold of 130 g/L at sea level which may be associated with negative pregnancy outcomes, including preterm birth, low birth weight and pre-eclampsia. Although the clinical significance of high Hb concentration is still being debated, it seems sensible to provide supplements with lower iron concentrations to those populations with lower prevalence of anaemia and iron deficiency.

Side effects are also a clear drawback to most current iron compounds used as supplements, either alone or with folic acid. The results of this review show that women who consume daily supplements containing 60 mg of elemental iron or more report side effects, particularly diarrhoea, more frequently than those who consume lower doses per day. This concurs with the Institute of Medicine's approach which set 45 mg of elemental iron as the upper tolerable limit per day based on the likelihood of having side effects (IOM 2001). As a result, investigators are now testing highly bioavailable iron compounds (e.g. FeNaEDTA) that may produce fewer side effects and that can be administered at low doses, but their information is still limited.

There are two important contributions of this updated review in comparison to previous versions. First, the inclusion of new trials allowed us to observe more clearly the protective effects of iron supplements on infant outcomes such as birth weight, low birth weight and premature birth and very premature birth. Second, the recent development of statistical methods to test subgroup differences when using random-effects models allowed us to examine the possible effects of the iron dosage, iron compounds, gestational age at the start of supplementation, anaemia status at baseline or malaria endemicity. In spite of this, in some cases the interpretation of high level of heterogeneity remained a challenge.

 

Quality of the evidence

The overall quality of the evidence in this review is mixed, with many studies being at risk of bias. In more than half of the included trials the methods used to conceal allocation were not described. Blinding of women, care providers and outcome assessors was not attempted in more than a third of trials although in some studies technical staff carrying out laboratory investigations were reported to be unaware of group allocation. While for some outcomes (e.g. infant birthweight), the lack of blinding may have been unlikely to have had any impact on results, for others (e.g. maternal reports of side effects to care providers), lack of blinding may represent a potentially serious source of bias. Attrition was a problem in some studies and it was not always clear that loss was balanced across groups

The overall quality of the evidence for iron supplementation versus no iron was moderate for low birthweight, premature birth, maternal anaemia at term and maternal iron deficiency at term. The evidence was of low quality for birthweight, neonatal death, congenital anomalies, maternal death, maternal severe anaemia, and infections during pregnancy; whereas, it was of very low quality for side effects (see  Summary of findings for the main comparison).

The overall quality of the evidence for iron + folic acid supplementation versus no iron + folic acid was high for maternal anaemia at term. The evidence was of low quality for neonatal death, maternal iron deficiency at term, maternal death at term, side effects and maternal severe anaemia at any time during the 2nd or 3rd trimesters. Evidence was of very low quality for low birthweight, birthweight, premature birth and congenital anomalies (see  Summary of findings 2).

 

Potential biases in the review process

We were aware of the possibility of introducing bias at every stage of the reviewing process. In this updated review, we tried to minimise bias in a number of ways; two review authors assessed eligibility for inclusion, carried out data extraction and assessed risk of bias. Each worked independently. Nevertheless, the process of assessing risk of bias, for example, is not an exact science and includes many personal judgements. Further, the process of reviewing research studies is known to be affected by prior beliefs and attitudes. It is difficult to control for this type of bias in the reviewing process.

While we attempted to be as inclusive as possible in the search strategy, the literature identified was predominantly written in English and published in North American and European journals. Although we did attempt to assess reporting bias, constraints of time meant that this assessment largely relied on information available in the published trial reports and thus, reporting bias was not usually apparent.

In this updated version of the review we have included 'Summary of findings' tables. Assessing the quality of the evidence relating to specific outcomes is a difficult process, but we attempted to produce the tables using a transparent process. Two review authors independently assessed the evidence for each outcome for each quality domain and discussed any disagreements.

 

Agreements and disagreements with other studies or reviews

Iron supplementation to pregnant women has been a long standing public health intervention that has been subject to multiple reviews, some of which also include a meta-analysis. In general, those meta-analyses tend to report the results in a segmented manner. Most of them are focused only on maternal anaemia (Sloan 2002; Yakoob 2011) while others also include a few infant outcomes (Imdad 2012). This topic has also been studied from the social determinants perspective (Nagata 2011).

A recent overview of reviews on the prevention and treatment of maternal anaemia identified 11 systematic reviews assessing the effects of iron and folic acid supplementation during the antenatal period, but only five were deemed as high quality, using AMSTAR as the assessment tool for methodological quality (Parker 2012).

This Cochrane review is the most comprehensive assessment on the effects of daily iron supplementation on both maternal and infant outcomes. After two updates, there is consistent evidence that providing iron supplements to pregnant women as part of the antenatal care helps improve gestational outcomes and that these benefits can be observed at lower iron doses than usual, with less side effects.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

 

Implications for practice

Available data from 43 studies indicate that in comparison with receiving no iron or a placebo, women receiving daily iron supplements had:

  • lower risk of anaemia at term;
  • higher haemoglobin (Hb) concentrations at term and six weeks postpartum;
  • lower risk of delivering low birth weight babies;
  • borderline lower risk of giving birth to infants less than 34 weeks' gestation;
  • higher side effects, with a dose response pattern in which women receiving 60 mg of elemental iron or more per day reported more side effects;
  • higher risk of high Hb concentrations during the second and third trimesters of pregnancy. Women who received higher iron doses tended to have the highest Hb concentrations.

The lack of data impeded any evaluation of the effects of iron supplementation on maternal mortality.

Relatively few studies assessed the combined effects of iron and folic acid on maternal and infant outcomes. There were clear positive effects on maternal haematological status while the effects on infant outcomes were uncertain.

Supplementation with iron to pregnant women may be used as a preventive strategy to improve maternal and infant outcomes in all settings, including those where malaria is endemic. In these areas, it seems sensible to complement iron and folic acid supplementation programmes with measures to prevent, diagnose and treat malaria. In order to improve the success of this intervention in public health, it is important to encourage the establishment of logistic procedures that facilitate and improve accessibility to supplements and foster compliance.

 
Implications for research

On the basis of the results of this review, researchers could consider investigating the following points regarding the use of iron or iron + folate supplements by pregnant women.

  1. Identify the mechanisms involved in high Hb concentrations during various gestational ages and its functional consequences.
  2. The effects of providing other micronutrients than iron and folic acid on maternal and infant outcomes.
  3. The assessment of effectiveness, safety, and affordability of novel iron supplementation compounds for use in public health pre-pregnancy and prenatal preventive supplementation programmes.

A better documentation of haematological indicators pre and post intervention, congenital anomalies, and side and adverse effects, including malaria-related outcomes, is encouraged

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

We would like to thank the trial authors who have contributed additional data for this review; and Richard Riley and Simon Gates who provided statistical advice. In addition, we would like to thank the staff at the editorial office of the Cochrane Pregnancy and Childbirth Group in Liverpool for their support in the preparation of this review and, in particular, Professor Zarko Alfirevic. We are grateful to Dr Rebecca Stolsfuz for her thoughtful and critical review of this version of the review and for the helpful suggestions that were incorporated. We thank Mr Joseph Ashong for his help to classify malaria trials.

We would like to thank Rachel Harper, Simon Lewin and Claire Glenton, from the Norwegian Knowledge Centre for the Health Services, Oslo, Norway for extracting information on setting and lay health worker cadre of the interventions.

As part of the pre-publication editorial process, this review has been commented on by two peers (an editor and referee who is external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

The World Health Organization (WHO) retains copyright and all other rights in the manuscript of this review as submitted for publication, including any revisions or updates to the manuscript which WHO may make from time to time.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
Download statistical data

 
Comparison 1. Any supplements containing iron versus same supplements without iron or no treatment/placebo (no iron or placebo)

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

 1 Low birthweight (less than 2500 g) (ALL)118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    2.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
65379Risk Ratio (M-H, Random, 95% CI)0.74 [0.55, 1.00]

    2.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3665Risk Ratio (M-H, Random, 95% CI)1.05 [0.50, 2.19]

    2.3 Unspecified or mixed gestational age at the start of supplementation
22436Risk Ratio (M-H, Random, 95% CI)0.87 [0.61, 1.24]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at the start of supplementation
84710Risk Ratio (M-H, Random, 95% CI)0.75 [0.49, 1.16]

    3.3 Unspecified or mixed anaemia status
33770Risk Ratio (M-H, Random, 95% CI)0.82 [0.72, 0.94]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    4.1 Low daily dose of iron (30 mg or less of elemental iron)
41031Risk Ratio (M-H, Random, 95% CI)0.57 [0.23, 1.41]

    4.2 Medium daily dose of iron (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    4.3 Higher daily dose of iron (60 mg elemental iron or more)
66722Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.94]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting118480Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.97]

    5.1 Malarial setting
54645Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.94]

    5.2 Non-malarial setting
63835Risk Ratio (M-H, Random, 95% CI)0.70 [0.40, 1.24]

 6 Birthweight (g) (ALL)149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

    7.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
106378Mean Difference (IV, Random, 95% CI)38.63 [3.26, 73.99]

    7.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3681Mean Difference (IV, Random, 95% CI)-0.19 [-77.46, 77.08]

    7.3 Unspecified or mixed gestational age at the start of supplementation
12326Mean Difference (IV, Random, 95% CI)20.20 [-15.13, 55.53]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at the start of supplementation
105426Mean Difference (IV, Random, 95% CI)31.13 [-8.90, 71.15]

    8.3 Unspecified or mixed anaemia status
43959Mean Difference (IV, Random, 95% CI)33.02 [3.65, 62.38]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron149385Mean Difference (IV, Random, 95% CI)30.63 [7.05, 54.22]

    9.1 Low daily dose (30 mg or less of elemental iron)
61902Mean Difference (IV, Random, 95% CI)52.87 [-11.51, 117.26]

    9.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    9.3 Higher daily dose (60 mg elemental iron or more)
86756Mean Difference (IV, Random, 95% CI)27.56 [2.59, 52.54]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting149385Mean Difference (IV, Random, 95% CI)30.81 [5.94, 55.68]

    10.1 Malarial setting
65443Mean Difference (IV, Random, 95% CI)33.48 [10.58, 56.37]

    10.2 Non-malarial setting
83942Mean Difference (IV, Random, 95% CI)25.96 [-42.06, 93.97]

 11 Premature birth (less than 37 weeks of gestation) (ALL)1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

 12 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    12.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
107345Risk Ratio (M-H, Random, 95% CI)0.93 [0.80, 1.08]

    12.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
2477Risk Ratio (M-H, Random, 95% CI)0.58 [0.29, 1.13]

    12.3 Unspecified or mixed`gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.79 [0.57, 1.09]

 13 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at the start of supplementation
105699Risk Ratio (M-H, Random, 95% CI)0.74 [0.59, 0.94]

    13.3 Unspecified/ mixed anaemia status
34449Risk Ratio (M-H, Random, 95% CI)0.96 [0.81, 1.14]

 14 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    14.1 Low daily dose (30 mg or less of elemental iron)
51817Risk Ratio (M-H, Random, 95% CI)0.70 [0.50, 0.98]

    14.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    14.3 Higher daily dose (60 mg elemental iron or more)
77604Risk Ratio (M-H, Random, 95% CI)0.91 [0.78, 1.06]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting1310148Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]

    15.1 Malarial setting
76406Risk Ratio (M-H, Random, 95% CI)0.95 [0.82, 1.11]

    15.2 Non-malarial setting
63742Risk Ratio (M-H, Random, 95% CI)0.69 [0.52, 0.91]

 16 Neonatal death (within 28 days after delivery) (ALL)47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

 17 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

    17.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
34970Risk Ratio (M-H, Random, 95% CI)1.01 [0.67, 1.53]

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

    17.3 Unspecified or mixed gestational age at the start of supplementation
12495Risk Ratio (M-H, Random, 95% CI)0.81 [0.56, 1.19]

 18 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

   18.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    18.2 Non-anaemic at the start of supplementation
23421Risk Ratio (M-H, Random, 95% CI)0.94 [0.37, 2.39]

    18.3 Unspecified or mixed anaemia status
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 19 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

   19.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    19.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    19.3 Higher daily dose (60 mg elemental iron or more)
36738Risk Ratio (M-H, Random, 95% CI)0.92 [0.69, 1.23]

 20 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting47465Risk Ratio (M-H, Random, 95% CI)0.90 [0.68, 1.19]

    20.1 Malarial setting
34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    20.2 Non-malarial setting
12694Risk Ratio (M-H, Random, 95% CI)1.32 [0.58, 3.00]

 21 Congenital anomalies (ALL)32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 22 Congenital anomalies: SUBGROUP ANALYSIS by gestational age at the start of supplementation)32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

    22.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

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

   22.3 Unspecified or mixed gestational age at the start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 23 Congenital anomalies: SUBGROUP ANALYSIS by anaemia status at the start of supplementation32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

   23.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.2 Non-anaemic at the start of supplementation
1300Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.3 Unspecified or mixed anaemia status
22402Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 24 Congenital anomalies: SUBGROUP ANALYSIS by dose of iron32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

   24.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   24.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    24.3 Higher daily dose (60 mg elemental iron or more)
32702Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 25 Congenital anomalies: SUBGROUP ANALYSIS by malarial status of setting32699Risk Ratio (M-H, Random, 95% CI)0.87 [0.60, 1.26]

    25.1 Malarial setting
32699Risk Ratio (M-H, Random, 95% CI)0.87 [0.60, 1.26]

   25.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 26 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

 27 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation):142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    27.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
7749Risk Ratio (M-H, Random, 95% CI)0.28 [0.12, 0.70]

    27.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
51178Risk Ratio (M-H, Random, 95% CI)0.36 [0.22, 0.61]

    27.3 Unspecified or mixed gestational age
2272Risk Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.59]

 28 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

   28.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    28.2 Non-anaemic at the start of supplementation
81295Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]

    28.3 Unspecified or mixed anaemia status
6904Risk Ratio (M-H, Random, 95% CI)0.24 [0.12, 0.49]

 29 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    29.1 Low daily dose (30 mg or less of elemental iron)
3590Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.03]

    29.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
169Risk Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.73]

    29.3 Higher daily dose (60 mg elemental iron or more)
101540Risk Ratio (M-H, Random, 95% CI)0.25 [0.14, 0.45]

 30 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting)142199Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.46]

    30.1 Malarial setting
3530Risk Ratio (M-H, Random, 95% CI)0.61 [0.45, 0.82]

    30.2 Non-malarial setting
111669Risk Ratio (M-H, Random, 95% CI)0.18 [0.10, 0.34]

 31 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks's gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 32 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    32.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4653Risk Ratio (M-H, Random, 95% CI)0.45 [0.22, 0.93]

    32.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3603Risk Ratio (M-H, Random, 95% CI)0.36 [0.18, 0.72]

   32.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

   33.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    33.2 Non-anaemic at the start of supplementation
51092Risk Ratio (M-H, Random, 95% CI)0.56 [0.39, 0.82]

    33.3 Unspecified/ mixed anaemia status
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

 34 Maternal iron deficiency at term (as defined by as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    34.1 Low daily dose (30 mg or less of elemental iron)
3703Risk Ratio (M-H, Random, 95% CI)0.52 [0.34, 0.78]

    34.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.17]

    34.3 Higher daily dose (60 mg elemental iron or more)
3312Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.41]

 35 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    35.1 Malarial setting
2192Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.53]

    35.2 Non-malarial setting
51064Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.78]

 36 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more) (ALL)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 37 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    37.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
4660Risk Ratio (M-H, Random, 95% CI)0.39 [0.13, 1.11]

    37.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
2428Risk Ratio (M-H, Random, 95% CI)0.25 [0.11, 0.58]

   37.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 38 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

   38.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    38.2 Non-anaemic at the start of supplementation
5968Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    38.3 Unspecified or mixed anaemia status
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 39 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    39.1 Low daily dose (30 mg or less of elemental iron)
3579Risk Ratio (M-H, Random, 95% CI)0.38 [0.13, 1.11]

    39.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.34 [0.16, 0.70]

    39.3 Higher daily dose (60 mg elemental iron or more)
2268Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 40 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    40.1 Malarial setting
1148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    40.2 Non-malarial setting
5940Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 41 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 42 Side effects (any reported throughout the intervention period) (ALL)114418Risk Ratio (M-H, Random, 95% CI)2.36 [0.96, 5.82]

 43 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation:114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

    43.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
53181Risk Ratio (M-H, Random, 95% CI)2.44 [0.34, 17.39]

    43.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
51032Risk Ratio (M-H, Random, 95% CI)1.43 [0.89, 2.29]

    43.3 Unspecified or mixed gestational age
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

 44 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

   44.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    44.2 Non-anaemic at the start of supplementation
73643Risk Ratio (M-H, Random, 95% CI)1.87 [0.64, 5.45]

    44.3 Unspecified or mixed anaemia status
4775Risk Ratio (M-H, Random, 95% CI)5.16 [0.78, 34.29]

 45 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron114418Risk Ratio (M-H, Random, 95% CI)2.36 [1.06, 5.24]

    45.1 Low daily dose (30 mg or less of elemental iron)
5973Risk Ratio (M-H, Random, 95% CI)1.01 [0.84, 1.21]

    45.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
2225Risk Ratio (M-H, Random, 95% CI)2.00 [0.66, 6.02]

    45.3 Higher daily dose (60 mg elemental iron or more)
63220Risk Ratio (M-H, Random, 95% CI)6.52 [1.13, 37.69]

 46 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting114418Risk Ratio (M-H, Random, 95% CI)2.43 [1.05, 5.63]

    46.1 Malarial setting
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

    46.2 Non-malarial setting
104213Risk Ratio (M-H, Random, 95% CI)2.02 [0.88, 4.65]

 47 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

 48 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    48.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
51417Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.47]

    48.2 Late gestational age (supplementation started at 20 weeks of gestation or later)
3559Risk Ratio (M-H, Random, 95% CI)0.48 [0.00, 46.15]

    48.3 Unspecified or mixed gestational age
1149Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 49 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

   49.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    49.2 Non-anaemic at the start of supplementation
51394Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    49.3 Unspecified or mixed anaemia status
4731Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

 50 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    50.1 Low daily dose (30 mg or less of elemental iron)
3654Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    50.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    50.3 Higher daily dose (60 mg elemental iron or more)
5744Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

 51 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting92125Risk Ratio (M-H, Random, 95% CI)0.22 [0.01, 3.20]

    51.1 Malarial setting
31102Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.30]

    51.2 Non-malarial setting
61023Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

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

 53 Infection during pregnancy (including urinary tract infections) (ALL)23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

 54 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by gestational age at the start of supplementation23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

    54.1 Early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy)
23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

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

   54.3 Unspecified or mixed gestational age
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 55 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by anaemia status at the start of supplementation23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   55.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    55.2 Non-anaemic at the start of supplementation
23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   55.3 Unspecified or mixed anaemia status
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 56 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by dose of iron23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

   56.1 Low daily dose (30 mg or less of elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    56.2 Medium daily dose (more than 30 mg and less than 60 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

    56.3 Higher daily dose (60 mg elemental iron or more)
12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 57 Infection during pregnancy (including urinary tract infections): SUBGROUP ANALYSIS by malarial status of setting23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]

    57.1 Malarial setting
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

    57.2 Non-malarial setting
12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 58 Very low birthweight (less than 1500 g) (ALL)52687Risk Ratio (M-H, Random, 95% CI)0.73 [0.31, 1.74]

 59 Very premature birth (less than 34 weeks' gestation) (ALL)53743Risk Ratio (M-H, Random, 95% CI)0.51 [0.29, 0.91]

 60 Infant Hb concentration within the first 6 months (in g/L counting the last reported measure after birth within this period) (ALL)2533Mean Difference (IV, Random, 95% CI)-1.25 [-8.10, 5.59]

 61 Infant serum ferritin concentration within first 6 months (in μg/L counting the last reported measure after birth within this period) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]

 62 Admission to special care unit (ALL)22805Risk Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.23]

 63 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)154893Risk Ratio (M-H, Random, 95% CI)0.30 [0.19, 0.45]

 64 Maternal iron deficiency at or near term (as defined by as defined by trialists, based on any indicator of iron status at 34 weeks's gestation or more)) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 65 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 66 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)193704Mean Difference (IV, Random, 95% CI)8.88 [6.96, 10.80]

 67 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)7956Mean Difference (IV, Random, 95% CI)7.61 [5.50, 9.72]

 68 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)104882Risk Ratio (M-H, Random, 95% CI)2.26 [1.40, 3.66]

 69 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)94850Risk Ratio (M-H, Random, 95% CI)3.08 [1.28, 7.41]

 70 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)81819Risk Ratio (M-H, Random, 95% CI)0.47 [0.01, 44.11]

 71 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)81339Risk Ratio (M-H, Random, 95% CI)0.04 [0.01, 0.28]

 72 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3766Risk Ratio (M-H, Random, 95% CI)0.55 [0.12, 2.51]

 73 Puerperal infection (ALL)44374Risk Ratio (M-H, Random, 95% CI)0.68 [0.50, 0.92]

 74 Antepartum haemorrhage (ALL)21157Risk Ratio (M-H, Random, 95% CI)1.48 [0.51, 4.31]

 75 Postpartum haemorrhage (ALL)41488Risk Ratio (M-H, Random, 95% CI)0.93 [0.59, 1.49]

 76 Transfusion provided (ALL)33453Risk Ratio (M-H, Random, 95% CI)0.61 [0.38, 0.96]

 77 Diarrhoea (ALL)31088Risk Ratio (M-H, Random, 95% CI)0.55 [0.32, 0.93]

 78 Constipation (ALL)41495Risk Ratio (M-H, Random, 95% CI)0.95 [0.62, 1.43]

 79 Nausea (ALL)41377Risk Ratio (M-H, Random, 95% CI)1.21 [0.72, 2.03]

 80 Heartburn (ALL)31323Risk Ratio (M-H, Random, 95% CI)1.19 [0.86, 1.66]

 81 Vomiting (ALL)41392Risk Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.30]

 82 Maternal wellbeing/satisfaction (ALL)22604Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.09]

 83 Placental abruption (ALL)32951Risk Ratio (M-H, Random, 95% CI)1.41 [0.56, 3.59]

 84 Premature rupture of membranes (ALL)21509Risk Ratio (M-H, Random, 95% CI)0.95 [0.72, 1.24]

 85 Pre-eclampsia (ALL)41704Risk Ratio (M-H, Random, 95% CI)1.63 [0.87, 3.07]

 
Comparison 2. Any supplements containing iron and folic acid versus same supplements without iron nor folic acid (no iron nor folic acid or placebo)

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

 1 Low birthweight (less than 2500 g) (ALL)21311Risk Ratio (M-H, Random, 95% CI)1.07 [0.31, 3.74]

 2 Birthweight (ALL)21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]

 3 Premature birth (less than 37 weeks of gestation) (ALL)31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 4 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestation at the start of supplementation3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

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

    4.3 Unspecified or mixed gestational age at start of supplementation
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3Risk Ratio (M-H, Random, 95% CI)Subtotals only

   5.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   5.2 Non-anaemic at the start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Unspecified or mixed anaemic status at start of supplementation
31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 6 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    6.1 Low daily dose (30 mg elemental iron or less)
1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   6.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Higher daily dose (60 mg elemental iron and above)
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 7 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of settings31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    7.1 Malarial setting
21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]

    7.2 Non-malarial setting
148Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

 8 Neonatal death (within 28 days after delivery) (ALL)31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 9 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestation at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    9.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

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

   9.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   10.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

    10.3 Unspecified or mixed anaemic status at start of supplementation
21696Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

 11 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   11.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   11.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Higher daily dose (60 mg elemental iron and above)
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 12 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status at the start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    12.1 Malarial setting
11648Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

    12.2 Non-malarial setting
2145Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

 13 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 14 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 15 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestation at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    15.3 Unspecified or mixed gestational age at start of supplementation
1183Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 16 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   16.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Non-anaemic at start of supplementation
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

    16.3 Unspecified or mixed anaemic status at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

 17 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   17.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   17.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    17.3 Higher daily dose (60 mg elemental iron and above)
3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    18.1 Malarial setting
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    18.2 Non-malarial setting
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 19 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 20 Maternal iron deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 21 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Side effects (any reported throughout the intervention period) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]

 23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 24 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestation at the start of supplementation4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    24.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3456Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.83]

    24.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
150Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

   24.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 25 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status at the start of supplementation4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

   25.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Unspecified or mixed anaemic status at start of supplementation
3409Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 26 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    26.1 Low daily dose (30 mg elemental iron or less)
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   26.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    26.3 Higher daily dose (60 mg elemental iron and above)
3462Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

 27 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    27.1 Malarial setting
3409Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

    27.2 Non-malarial setting
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

 29 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]

 30 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 31 Very premature birth (less than 34 weeks' gestation) (ALL)292Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 32 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 34 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 35 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 36 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)3140Mean Difference (IV, Random, 95% CI)16.13 [12.74, 19.52]

 37 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)2459Mean Difference (IV, Random, 95% CI)10.07 [7.33, 12.81]

 38 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]

 39 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)2314Risk Ratio (M-H, Random, 95% CI)4.37 [0.58, 32.71]

 40 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.33 [0.17, 0.65]

 41 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more ) (ALL)3191Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

 42 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.76]

 43 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]

 44 Antepartum haemorrhage (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]

45 Postpartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 46 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]

 47 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.16]

 
Comparison 3. Supplementation with iron alone versus no treatment/placebo

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

 1 Low birthweight (less than 2500 g) (ALL)73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
33055Risk Ratio (M-H, Random, 95% CI)0.53 [0.22, 1.23]

    2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3665Risk Ratio (M-H, Random, 95% CI)1.05 [0.50, 2.19]

    2.3 Unspecified or mixed gestational age at the start of supplementation
1110Risk Ratio (M-H, Random, 95% CI)1.79 [0.17, 19.20]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at start of supplementation
63649Risk Ratio (M-H, Random, 95% CI)0.72 [0.39, 1.32]

    3.3 Unspecified or mixed anaemic status at start of supplementation
1181Risk Ratio (M-H, Random, 95% CI)0.57 [0.14, 2.31]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    4.1 Low daily dose (30 mg elemental iron or less)
3697Risk Ratio (M-H, Random, 95% CI)0.59 [0.12, 2.96]

   4.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Higher daily dose (60 mg elemental iron and above)
43133Risk Ratio (M-H, Random, 95% CI)0.83 [0.56, 1.23]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting73830Risk Ratio (M-H, Random, 95% CI)0.71 [0.42, 1.19]

    5.1 Malarial setting
2329Risk Ratio (M-H, Random, 95% CI)0.52 [0.20, 1.35]

    5.2 Non-malarial setting
53501Risk Ratio (M-H, Random, 95% CI)0.77 [0.38, 1.57]

 6 Birthweight (g) (ALL)93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

    7.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
53099Mean Difference (IV, Random, 95% CI)30.74 [-83.78, 145.25]

    7.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
4854Mean Difference (IV, Random, 95% CI)-8.70 [-74.71, 57.31]

   7.3 Unspecified or mixed gestational age at the start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at start of supplementation
73583Mean Difference (IV, Random, 95% CI)22.44 [-54.15, 99.03]

    8.3 Unspecified or mixed anaemic status at start of supplementation
2370Mean Difference (IV, Random, 95% CI)0.90 [-86.32, 88.12]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron93953Mean Difference (IV, Random, 95% CI)15.73 [-33.92, 65.38]

    9.1 Low daily dose (30 mg elemental iron or less)
4785Mean Difference (IV, Random, 95% CI)46.83 [-76.57, 170.22]

   9.2 Medium daily dose (31 to 59 mg elemental iron)
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    9.3 Higher daily dose (60 mg elemental iron and above)
63168Mean Difference (IV, Random, 95% CI)12.51 [-25.07, 50.10]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting93953Mean Difference (IV, Random, 95% CI)16.43 [-37.28, 70.14]

    10.1 Malarial setting
2345Mean Difference (IV, Random, 95% CI)33.74 [-61.16, 128.65]

    10.2 Non-malarial setting
73608Mean Difference (IV, Random, 95% CI)10.18 [-65.06, 85.42]

 11 Premature birth (less than 37 weeks of gestation) (ALL)74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

 12 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    12.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
53930Risk Ratio (M-H, Random, 95% CI)0.81 [0.61, 1.07]

    12.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2477Risk Ratio (M-H, Random, 95% CI)0.58 [0.29, 1.13]

   12.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 13 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at start of supplementation
63545Risk Ratio (M-H, Random, 95% CI)0.71 [0.53, 0.97]

    13.3 Unspecified or mixed anaemic status at start of supplementation
1862Risk Ratio (M-H, Random, 95% CI)0.95 [0.58, 1.57]

 14 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    14.1 Low daily dose (30 mg elemental iron or less)
3690Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.24]

   14.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    14.3 Higher daily dose (60 mg elemental iron and above)
43717Risk Ratio (M-H, Random, 95% CI)0.78 [0.57, 1.05]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting74407Risk Ratio (M-H, Random, 95% CI)0.77 [0.60, 1.00]

    15.1 Malarial setting
21010Risk Ratio (M-H, Random, 95% CI)0.87 [0.54, 1.39]

    15.2 Non-malarial setting
53397Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.99]

 16 Neonatal death (within 28 days after delivery) (ALL)12694Risk Ratio (M-H, Random, 95% CI)1.32 [0.58, 3.00]

 17 Congenital anomalies (ALL)22402Risk Ratio (M-H, Random, 95% CI)0.86 [0.55, 1.35]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)142136Risk Ratio (M-H, Random, 95% CI)0.29 [0.19, 0.47]

 19 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation144693Risk Ratio (M-H, Random, 95% CI)0.26 [0.17, 0.40]

    19.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
73243Risk Ratio (M-H, Random, 95% CI)0.24 [0.12, 0.50]

    19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
61301Risk Ratio (M-H, Random, 95% CI)0.32 [0.20, 0.53]

    19.3 Unspecified or mixed gestational age at start of supplementation
1149Risk Ratio (M-H, Random, 95% CI)0.03 [0.00, 0.18]

 20 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation144630Risk Ratio (M-H, Random, 95% CI)0.26 [0.16, 0.41]

   20.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    20.2 Non-anaemic at start of supplementation
93938Risk Ratio (M-H, Random, 95% CI)0.23 [0.13, 0.41]

    20.3 Unspecified or mixed anaemic status at start of supplementation
5692Risk Ratio (M-H, Random, 95% CI)0.34 [0.18, 0.64]

 21 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron144693Risk Ratio (M-H, Random, 95% CI)0.26 [0.17, 0.40]

    21.1 Low daily dose (30 mg elemental iron or less)
3590Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.03]

    21.2 Medium daily dose (31 to 59 mg elemental iron)
169Risk Ratio (M-H, Random, 95% CI)0.21 [0.06, 0.73]

    21.3 Higher daily dose (60 mg elemental iron and above)
104034Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.37]

 22 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting144630Risk Ratio (M-H, Random, 95% CI)0.26 [0.16, 0.41]

    22.1 Malarial setting
2267Risk Ratio (M-H, Random, 95% CI)0.58 [0.46, 0.72]

    22.2 Non-malarial setting
124363Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.34]

 23 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 24 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    24.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4653Risk Ratio (M-H, Random, 95% CI)0.45 [0.22, 0.93]

    24.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3603Risk Ratio (M-H, Random, 95% CI)0.36 [0.18, 0.72]

   24.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 25 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

   25.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.2 Non-anaemic at start of supplementation
51092Risk Ratio (M-H, Random, 95% CI)0.56 [0.39, 0.82]

    25.3 Unspecified or mixed anaemic status at start of supplementation
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

 26 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    26.1 Low daily dose (30 mg elemental iron or less)
3703Risk Ratio (M-H, Random, 95% CI)0.52 [0.34, 0.78]

    26.2 Medium daily dose (31 to 59 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.92 [0.73, 1.17]

    26.3 Higher daily dose (60 mg elemental iron and above)
3312Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.41]

 27 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

    27.1 Malarial setting
2192Risk Ratio (M-H, Random, 95% CI)0.28 [0.15, 0.53]

    27.2 Non-malarial setting
51064Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.78]

 28 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more) (ALL)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 29 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    29.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4660Risk Ratio (M-H, Random, 95% CI)0.39 [0.13, 1.11]

    29.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2428Risk Ratio (M-H, Random, 95% CI)0.25 [0.11, 0.58]

   29.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 30 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

   30.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    30.2 Non-anaemic at start of supplementation
5968Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    30.3 Unspecified or mixed anaemic status at start of supplementation
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 31 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    31.1 Daily low dose (60 mg elemental iron or less)
3579Risk Ratio (M-H, Random, 95% CI)0.38 [0.13, 1.11]

    31.2 Medium dose (31 to 59 mg elemental iron)
1241Risk Ratio (M-H, Random, 95% CI)0.34 [0.16, 0.70]

    31.3 High dose (60 mg elemental iron and above)
2268Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 32 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

    32.1 Malarial setting
1148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    32.2 Non-malarial setting
5940Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 33 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 34 Side effects (any reported throughout the intervention period) (ALL)104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

 35 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by gestational age at the start of supplementation104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

    35.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
42993Risk Ratio (M-H, Random, 95% CI)3.65 [0.40, 33.51]

    35.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
51034Risk Ratio (M-H, Random, 95% CI)1.42 [0.89, 2.28]

    35.3 Unspecified or mixed gestational age at start of supplementation
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

 36 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by anaemia status at the start of supplementation104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

   36.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    36.2 Non-anaemic at start of supplementation
63455Risk Ratio (M-H, Random, 95% CI)2.25 [0.57, 8.93]

    36.3 Unspecified or mixed anaemic status at start of supplementation
4777Risk Ratio (M-H, Random, 95% CI)5.11 [0.78, 33.60]

 37 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by dose of iron104232Risk Ratio (M-H, Random, 95% CI)2.75 [1.10, 6.89]

    37.1 Low daily dose (30 mg elemental iron or less)
4785Risk Ratio (M-H, Random, 95% CI)1.07 [0.90, 1.26]

    37.2 Medium daily dose (31 to 59 mg elemental iron)
2225Risk Ratio (M-H, Random, 95% CI)2.00 [0.66, 6.02]

    37.3 Higher daily dose (60 mg elemental iron and above)
63222Risk Ratio (M-H, Random, 95% CI)7.95 [1.38, 45.72]

 38 Side effects (any reported throughout the intervention period): SUBGROUP ANALYSIS by malarial status of setting104232Risk Ratio (M-H, Random, 95% CI)2.92 [1.10, 7.76]

    38.1 Malarial setting
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

    38.2 Non-malarial setting
94027Risk Ratio (M-H, Random, 95% CI)2.35 [0.89, 6.24]

 39 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

 40 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by gestational age at the start of supplementation71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    40.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3416Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    40.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3513Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    40.3 Unspecified or mixed gestational age at start of supplementation
1149Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 41 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by anaemia status age at the start of supplementation71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

   41.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    41.2 Non-anaemic at start of supplementation
5816Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

    41.3 Unspecified or mixed anaemic status at start of supplementation
2262Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

 42 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by dose of iron71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    42.1 Low daily dose (30 mg elemental iron or less)
3654Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

   42.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    42.3 Higher daily dose (60 mg elemental iron and above)
4424Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

 43 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L): SUBGROUP ANALYSIS by malarial status of setting71078Risk Ratio (M-H, Random, 95% CI)0.75 [0.02, 29.10]

    43.1 Malarial setting
155Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.21]

    43.2 Non-malarial setting
61023Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

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

 45 Infection during pregnancy (including urinary tract infections) (ALL)12694Risk Ratio (M-H, Random, 95% CI)1.16 [0.82, 1.65]

 46 Very low birthweight (less than 1500 g) (ALL)3697Risk Ratio (M-H, Random, 95% CI)0.55 [0.03, 9.07]

 47 Very premature birth (less than 34 weeks' gestation) (ALL)3690Risk Ratio (M-H, Random, 95% CI)0.32 [0.10, 1.09]

 48 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)2533Mean Difference (IV, Random, 95% CI)-1.25 [-8.10, 5.59]

 49 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]

 50 Admission to special care unit (ALL)22805Risk Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.23]

 51 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)144390Risk Ratio (M-H, Random, 95% CI)0.29 [0.19, 0.45]

 52 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)71256Risk Ratio (M-H, Random, 95% CI)0.43 [0.27, 0.66]

 53 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)61088Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 54 Maternal Hb concentration at or near term (in g/L, at 34 weeks' gestation or more) (ALL)161851Mean Difference (IV, Random, 95% CI)8.95 [6.37, 11.53]

 55 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)6659Mean Difference (IV, Random, 95% CI)7.26 [4.78, 9.74]

 56 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)83840Risk Ratio (M-H, Random, 95% CI)1.81 [1.21, 2.71]

 57 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)83883Risk Ratio (M-H, Random, 95% CI)3.67 [2.23, 6.04]

 58 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)3453Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 13.91]

 59 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)71046Risk Ratio (M-H, Random, 95% CI)0.74 [0.02, 27.81]

 60 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)7953Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.33]

 61 Puerperal infection (ALL)22292Risk Ratio (M-H, Random, 95% CI)0.65 [0.41, 1.03]

 62 Antepartum haemorrhage (ALL)1430Risk Ratio (M-H, Random, 95% CI)2.97 [0.12, 72.56]

 63 Postpartum haemorrhage (ALL)3761Risk Ratio (M-H, Random, 95% CI)0.82 [0.51, 1.34]

 64 Transfusion provided (ALL)22726Risk Ratio (M-H, Random, 95% CI)0.59 [0.37, 0.94]

 65 Diarrhoea (ALL)1173Risk Ratio (M-H, Random, 95% CI)0.98 [0.09, 10.61]

 66 Constipation (ALL)2580Risk Ratio (M-H, Random, 95% CI)0.88 [0.18, 4.40]

 67 Nausea (ALL)3650Risk Ratio (M-H, Random, 95% CI)2.38 [0.49, 11.52]

 68 Heartburn (ALL)1408Risk Ratio (M-H, Random, 95% CI)1.0 [0.82, 1.22]

 69 Vomiting (ALL)2477Risk Ratio (M-H, Random, 95% CI)0.88 [0.38, 2.07]

 70 Maternal wellbeing/satisfaction (ALL)22604Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.09]

 71 Placental abruption (ALL)11442Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 70.53]

72 Premature rupture of membranes (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 73 Pre-eclampsia (ALL)147Risk Ratio (M-H, Random, 95% CI)0.96 [0.06, 14.43]

 
Comparison 4. Supplementation with iron+folic acid versus no treatment/placebo

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

 1 Low birthweight (less than 2500 g) (ALL)21311Risk Ratio (M-H, Random, 95% CI)1.07 [0.31, 3.74]

 2 Birthweight (ALL)21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]

 3 Premature birth (less than 37 weeks of gestation) (ALL)31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 4 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation31410Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

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

    4.3 Unspecified or mixed gestational age at start of supplementation
144Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

   5.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   5.2 Non-anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Unspecified or mixed anaemic status at start of supplementation
31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 6 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    6.1 Low daily dose (30 mg elemental iron or less)
1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   6.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Higher daily dose (60 mg elemental iron and above)
21366Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

 7 Premature birth (less than 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]

    7.1 Malarial setting
21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]

    7.2 Non-malarial setting
148Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

 8 Neonatal death (within 28 days after delivery) (ALL)31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 9 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    9.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

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

   9.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by anaemia status at start of supplementation31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   10.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Non-anaemic at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

    10.3 Unspecified or mixed anaemic status at start of supplementation
21696Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

 11 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

   11.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   11.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    11.3 Higher daily dose (60 mg elemental iron and above)
31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

 12 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting31793Risk Ratio (M-H, Random, 95% CI)0.81 [0.51, 1.30]

    12.1 Malarial setting
11648Risk Ratio (M-H, Random, 95% CI)0.79 [0.49, 1.27]

    12.2 Non-malarial setting
2145Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

 13 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 14 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 15 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
197Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2249Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   15.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   16.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    16.2 Non-anaemic at start of supplementation
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

    16.3 Unspecified or mixed anaemic status at start of supplementation
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

 17 Maternal anaemia at term (Hb less than 110 g/Lat 37 weeks' gestation or more): SUBGROUP ANALYSIS by dose of iron3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

   17.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   17.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    17.3 Higher daily dose (60 mg elemental iron and above)
3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 18 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by malarial status of setting3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

    18.1 Malarial setting
166Risk Ratio (M-H, Random, 95% CI)0.37 [0.22, 0.62]

    18.2 Non-malarial setting
2280Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.68]

 19 Maternal iron deficiency at term (as defined by trialists, based on any indicator of iron status at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 20 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 21 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Side effects (any reported throughout the intervention period) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]

 23 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)4506Risk Ratio (M-H, Random, 95% CI)0.12 [0.02, 0.63]

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

 25 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]

 26 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 27 Very premature birth (less than 34 weeks' gestation) (ALL)292Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

28 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

29 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 30 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 31 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.54]

 32 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]

 33 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]

 34 Maternal Hb concentration at term or near term (in g/L, at 34 weeks' gestation or more) (ALL)3140Mean Difference (IV, Random, 95% CI)16.13 [12.74, 19.52]

 35 Maternal Hb concentration within 6 wk postpartum (g/L) (ALL)2459Mean Difference (IV, Random, 95% CI)10.07 [7.33, 12.81]

 36 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]

 37 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)2314Risk Ratio (M-H, Random, 95% CI)4.37 [0.58, 32.71]

 38 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)2458Risk Ratio (M-H, Random, 95% CI)0.34 [0.17, 0.69]

 39 Maternal severe anaemia at term or near (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)3191Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.63]

 40 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)3491Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.76]

 41 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]

 42 Antepartum haemorrhage (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]

43 Postpartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 44 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]

 45 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.16]

 
Comparison 5. Supplementation with iron+folic acid versus folic acid alone (without iron) supplementation

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

 1 Low birthweight (less than 2500 g) (ALL)34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

 2 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by gestational age at the start of supplementation34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21990Risk Ratio (M-H, Random, 95% CI)0.83 [0.73, 0.96]

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

    2.3 Unspecified or mixed gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.85 [0.59, 1.22]

 3 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   3.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    3.3 Unspecified or mixed anaemia status
23589Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.94]

 4 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by dose of iron34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   4.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.54]

    4.3 Higher daily dose (60 mg elemental iron and above)
23589Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.94]

 5 Low birthweight (less than 2500 g): SUBGROUP ANALYSIS by malarial status of setting34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

    5.1 Malarial setting
34316Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.95]

   5.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Birthweight (g) (ALL)34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

 7 Birthweight (g): SUBGROUP ANALYSIS by gestational age at the start of supplementation34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

    7.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21990Mean Difference (IV, Random, 95% CI)41.19 [-12.23, 94.60]

   7.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    7.3 Unspecified or mixed gestational age at the start of supplementation
12326Mean Difference (IV, Random, 95% CI)20.20 [-15.13, 55.53]

 8 Birthweight (g): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

   8.1 Anaemic at start of supplementation
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Non-anaemic at start of supplementation
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    8.3 Unspecified or mixed anaemic status at start of supplementation
23589Mean Difference (IV, Random, 95% CI)39.61 [-3.90, 83.13]

 9 Birthweight (g): SUBGROUP ANALYSIS by dose of iron34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

   9.1 Low daily dose (30 mg elemental iron or less)
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    9.2 Medium daily dose (31 to 59 mg elemental iron)
1727Mean Difference (IV, Random, 95% CI)10.0 [-51.92, 71.92]

    9.3 Higher daily dose (60 mg elemental iron and above)
23589Mean Difference (IV, Random, 95% CI)39.61 [-3.90, 83.13]

 10 Birthweight (g): SUBGROUP ANALYSIS by malarial status of setting34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

    10.1 Malarial setting
34316Mean Difference (IV, Random, 95% CI)32.23 [0.86, 63.60]

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

 11 Premature birth (less than 37 weeks of gestation) (ALL)34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

 12 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by gestational age at the start of supplementation34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

    12.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
21988Risk Ratio (M-H, Random, 95% CI)1.06 [0.87, 1.29]

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

    12.3 Unspecified or mixed gestational age at the start of supplementation
12326Risk Ratio (M-H, Random, 95% CI)0.79 [0.57, 1.09]

 13 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by anaemia status at the start of supplementation34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   13.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    13.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    13.3 Unspecified or mixed anaemic status at start of supplementation
23587Risk Ratio (M-H, Random, 95% CI)0.93 [0.71, 1.22]

 14 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by dose of iron34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   14.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    14.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)1.26 [0.62, 2.56]

    14.3 Higher daily dose (60 mg elemental iron and above)
23587Risk Ratio (M-H, Random, 95% CI)0.93 [0.71, 1.22]

 15 Premature birth (less 37 weeks of gestation): SUBGROUP ANALYSIS by malarial status of setting34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

    15.1 Malarial setting
34314Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

   15.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 16 Neonatal death (within 28 days after delivery) (ALL)34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

 17 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by gestational age at the start of supplementation34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    17.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
22276Risk Ratio (M-H, Random, 95% CI)0.92 [0.57, 1.49]

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

    17.3 Unspecified or mixed gestational age at the start of supplementation
12495Risk Ratio (M-H, Random, 95% CI)0.81 [0.56, 1.19]

 18 Neonatal death (within 28 days after delivery) : SUBGROUP ANALYSIS by anaemia status at the start of supplementation34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   18.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    18.2 Non-anaemic at start of supplementation
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    18.3 Unspecified or mixed anaemic status at start of supplementation
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 19 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by dose of iron34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   19.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    19.2 Medium daily dose (31 to 59 mg elemental iron)
1727Risk Ratio (M-H, Random, 95% CI)0.48 [0.12, 1.91]

    19.3 Higher daily dose (60 mg elemental iron and above)
24044Risk Ratio (M-H, Random, 95% CI)0.88 [0.65, 1.19]

 20 Neonatal death (within 28 days after delivery): SUBGROUP ANALYSIS by malarial status of setting34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

    20.1 Malarial setting
34771Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.15]

   20.2 Non-malarial setting
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 21 Congenital anomalies (ALL)11652Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.40]

 22 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

 23 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by gestational age at the start of supplementation2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   23.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    23.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   23.3 Unspecified or mixed gestational age at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 24 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more): SUBGROUP ANALYSIS by anaemia status at the start of supplementation2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   24.1 Anaemic at start of supplementation
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    24.2 Non-anaemic at start of supplementation
1240Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.61]

    24.3 Unspecified or mixed anaemic status at start of supplementation
163Risk Ratio (M-H, Random, 95% CI)0.39 [0.23, 0.67]

 25 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by dose of iron2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

   25.1 Low daily dose (30 mg elemental iron or less)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   25.2 Medium daily dose (31 to 59 mg elemental iron)
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Higher daily dose (60 mg elemental iron and above)
2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

 26 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more ): SUBGROUP ANALYSIS by malarial status of setting2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

    26.1 Malarial setting
163Risk Ratio (M-H, Random, 95% CI)0.39 [0.23, 0.67]

    26.2 Non-malarial setting
1240Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.61]

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

 28 Maternal iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicators at 37 weeks' gestation or more) (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

 30 Side effects (any reported throughout the intervention period) (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.10 [0.55, 2.23]

 31 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)31047Risk Ratio (M-H, Random, 95% CI)0.06 [0.01, 0.47]

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

 33 Infection during pregnancy (including urinary tract infections) (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.46]

 34 Very low birthweight (less than 1500 g) (ALL)21990Risk Ratio (M-H, Random, 95% CI)0.76 [0.28, 2.01]

 35 Very premature birth (less than 34 weeks' gestation) (ALL)23053Risk Ratio (M-H, Random, 95% CI)0.58 [0.30, 1.12]

36 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

37 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

38 Admission to special care unit (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 39 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)2303Risk Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

40 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 41 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 42 Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)2771Mean Difference (IV, Random, 95% CI)12.44 [0.95, 23.93]

 43 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)1297Mean Difference (IV, Random, 95% CI)9.20 [5.78, 12.62]

 44 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)21042Risk Ratio (M-H, Random, 95% CI)4.33 [2.26, 8.30]

 45 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)2967Risk Ratio (M-H, Random, 95% CI)1.87 [0.32, 10.84]

 46 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)1353Risk Ratio (M-H, Random, 95% CI)0.38 [0.18, 0.81]

 47 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)2773Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 48 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)2386Risk Ratio (M-H, Random, 95% CI)0.08 [0.00, 1.33]

 49 Puerperal infection (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.96 [0.20, 4.75]

 50 Antepartum haemorrhage (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.35 [0.43, 4.22]

 51 Postpartum haemorrhage (ALL)1727Risk Ratio (M-H, Random, 95% CI)3.38 [0.71, 16.15]

 52 Transfusion provided (ALL)1727Risk Ratio (M-H, Random, 95% CI)2.89 [0.12, 70.83]

 53 Diarrhoea (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.55 [0.16, 1.87]

 54 Constipation (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.10 [0.55, 2.23]

 55 Nausea (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.96 [0.47, 1.99]

 56 Heartburn (ALL)1727Risk Ratio (M-H, Random, 95% CI)1.65 [0.66, 4.15]

57 Vomiting (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

58 Maternal wellbeing/satisfaction (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 59 Placental abruption (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.96 [0.24, 3.83]

 60 Premature rupture of membranes (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.99 [0.74, 1.34]

 61 Pre-eclampsia (ALL)1727Risk Ratio (M-H, Random, 95% CI)3.22 [0.89, 11.59]

 
Comparison 6. Supplementation with iron+other vitamins and minerals supplementation versus same other vitamins and minerals (without iron) supplementation

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

 1 Low birthweight (less than 2500 g) (ALL)1334Risk Ratio (M-H, Random, 95% CI)0.51 [0.22, 1.15]

 2 Birthweight (g) (ALL)21116Mean Difference (IV, Random, 95% CI)55.70 [3.42, 107.97]

 3 Premature birth (less than 37 weeks of gestation) (ALL)21127Risk Ratio (M-H, Random, 95% CI)0.66 [0.41, 1.04]

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

5 Congenital anomalies (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

6 Maternal anaemia at term (Hb less than 110 g/L at 37 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

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

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

 10 Side effects (any reported throughout the intervention period) (ALL)1188Risk Ratio (M-H, Random, 95% CI)0.77 [0.55, 1.07]

11 Maternal severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

13 Infection during pregnancy (including urinary tract infections) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

14 Very low birthweight (less than 1500 g) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

15 Very premature birth (less than 34 weeks' gestation) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

16 Infant Hb concentration in the first 6 months (in g/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

17 Infant serum ferritin concentration in the first 6 months (in μg/L, counting the last reported measure after birth within this period) (ALL)00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

18 Admission to special care unit (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

19 Maternal anaemia at or near term (Hb less than 110 g/L at 34 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

20 Maternal iron deficiency at or near term (as defined by trialists, based on any indicator of iron status at 34 weeks' gestation or more)(ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

21 Maternal iron-deficiency anaemia at or near term (Hb less than 110 g/L and at least one additional laboratory indicators at 34 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 22 Maternal Hb concentration at or near term (in g/L at 34 weeks' gestation or more) (ALL)2809Mean Difference (IV, Random, 95% CI)10.85 [7.29, 14.42]

 23 Maternal Hb concentration within 6 wk postpartum (in g/L) (ALL)127Mean Difference (IV, Random, 95% CI)14.0 [3.56, 24.44]

24 Maternal high haemoglobin concentrations during second or third trimester (Hb more than 130 g/L) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

25 Maternal high haemoglobin concentrations at or near term (Hb more than 130 g/L at 34 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

26 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 110 g/L) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

27 Maternal severe anaemia at or near term (Hb less than 70 g/L at 34 weeks' gestation or more) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

28 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

29 Puerperal infection (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

30 Antepartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

31 Postpartum haemorrhage (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

32 Transfusion provided (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 33 Constipation (ALL)1188Risk Ratio (M-H, Random, 95% CI)0.77 [0.55, 1.07]

34 Nausea (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 35 Heartburn (ALL)1188Risk Ratio (M-H, Random, 95% CI)1.49 [0.95, 2.34]

 36 Vomiting (ALL)1188Risk Ratio (M-H, Random, 95% CI)1.13 [0.58, 2.20]

 37 Diarrhoea (ALL)1188Risk Ratio (M-H, Random, 95% CI)0.53 [0.29, 0.96]

38 Maternal wellbeing/satisfaction (ALL)00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 39 Placental abruption (ALL)1782Risk Ratio (M-H, Random, 95% CI)1.81 [0.46, 7.20]

 40 Premature rupture of membranes (ALL)1782Risk Ratio (M-H, Random, 95% CI)0.79 [0.44, 1.41]

 41 Pre-eclampsia (ALL)1782Risk Ratio (M-H, Random, 95% CI)1.45 [0.67, 3.16]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Appendix 1. Search terms used for additional author searching

Review authors searched the WHO International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned trials on 2 July 2012 using the terms "iron supplementation and pregnancy"; "iron and pregnancy"; "daily iron and pregnancy"; "iron supplements and pregnancy"; "daily supplements and pregnancy" and "anaemia and pregnancy". Duplicates were removed.

 

Feedback

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Hemminki, June 2008

 

Summary

My trial, Hemminki 1989a, is excluded from this review and it is not clear why. The comment in Characteristics of excluded studies is "Only women who were anaemic received iron in the unsupplemented group thus making any comparisons among the groups biased for the purposes of this review."

What bias is being referred to? Hemminki 1989a was in the previous version of this review. It was a randomised trial, analysed by intention to treat, having outcome data for all women randomised, and a high compliance (about 80% of women in both groups received the treatment they were allocated to). The 20% of women who received iron in the non-routine supplementation group was as expected.

There are two options for dealing with women whose haemoglobin falls below a pre-specified cut-off in the non-routine supplemented group:
1.  give them iron, as in my study where 20% of women in the non-routine treatment group had iron; or
2.  call those who take iron non-compliant and do the analysis by intention to treat, as did some of the included studies.

What is the difference between these two strategies? They seem to me to be essentially the same.

The effect of routine iron therapy on substantive health outcomes remains unclear. It is a real pity that you have excluded Hemminki 1989a, based on criteria I consider inappropriate: it had a large number of women, several health outcomes including long term follow up, and was well conducted.

A minor issue is that it is misleading to call this trial Hemminki 1989a. Although the study design was published in 1989, the main results were not published until 1991. Hence a more appropriate study identifier would be ‘Hemminki 1991’.

(Summary of feedback from Elina Hemminki, June 2008)

 

Reply

We agree that your trial was well conducted, had a large number of women and looked at several health outcomes including long term follow up.  We did review all publications on the work you have conducted on assessing the effects of routine versus selective iron supplementation during pregnancy. This systematic review aims to assess the effectiveness and safety of daily and intermittent use of iron supplements by pregnant women, either alone or in conjunction with folic acid given as a preventive universal measure. Your trial provided 100 mg of elemental iron daily with various choice of iron compounds and dosage as determined individually by the midwives to all women in the routine iron supplementation group. For women in the "selective iron supplementation group", treatment with iron supplements as slow release form for two months or until the hematocrit increased to 0.32 was provided only to those whose hematocrit was lower than 0.30 on two consecutive visits. Consequently, we have included your trial in the included studies and we thank you for the additional data you have provided us for this analysis. Your study compared the effects of routine versus selective iron supplementation, an issue that certainly deserves better understanding and that reflects current practices.   

We have changed the study identifier to Hemminki 1991 as requested.

 

Contributors

Juan Pablo Pena-Rosas, MD, PhD, MPH

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

Last assessed as up-to-date: 1 November 2012.


DateEventDescription

1 November 2012New citation required and conclusions have changedThis review updates part of Peña-Rosas 2009 to only evaluate the effects of oral daily iron supplementation regimens. The effects of intermittent iron supplementation regimens are evaluated in a separate review (Pena-Rosas 2012).

2 July 2012New search has been performedIn this split review we updated the search and used the latest Cochrane methodological guidance. We included information on the health worker cadre and malaria setting. Specific changes to the previous version are described in the section Differences between protocol and review. Two new authors have contributed to this review.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

Protocol first published: Issue 2, 2004
Review first published: Issue 3, 2006


DateEventDescription

16 June 2009New search has been performedSearch updated. Ten new trials included (Cantlie 1971; Christian 2003 (C); Hemminki 1991; Harvey 2007; Lee 2005; Meier 2003; Mukhopadhyay 2004; Siega-Riz 2001; Ziaei 2007; Ziaei 2008). One trial included is now excluded (Ortega-Soler 1998). Twenty-seven new trials excluded.

16 June 2009New citation required but conclusions have not changedIn this update, trials assessing the effect of iron or folic acid when given in combination with other micronutrients were included as long as both groups being compared in the daily regimens received the same other micronutrient interventions. This has resulted in four trials previously excluded now being included (Cantlie 1971; Christian 2003 (C); Hemminki 1991; Siega-Riz 2001).

20 October 2008Feedback has been incorporatedFeedback from Elina Hemminki added with response from author.

15 April 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

Juan Pablo Pena-Rosas and Fernando Viteri co-wrote the initial protocol and first two versions of the review. Juan Pablo Pena-Rosas abstracted the trial data and carried out the analysis with the technical support and guidance of Fernando Viteri for those early versions. For this update Luz Maria De-Regil and Therese Dowswell extracted the data from additional trials in the search and produced the GRADE evidence profiles for the critical outcomes. Therese Dowswell wrote the description of the updated results and all authors contributed to the final preparation of this version.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Juan Pablo Pena-Rosas was author of an excluded study on iron and folic acid intermittent supplementation.

Disclaimer: Juan Pablo Pena-Rosas and Luz Maria De-Regil are currently staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Internal sources

  • Children's Hospital and Oakland Research Institute (CHORI), USA.
  • Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.
  • University of Liverpool, UK.

 

External sources

  • Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.
  • TD is supported by the NIHR NHS Cochrane Collaboration Programme grant scheme award for NHS-prioritised centrally-managed, pregnancy and childbirth systematic reviews: CPGS 10/4001/02, UK.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

This review updates part of Peña-Rosas 2009 to only evaluate the effects of oral daily iron supplementation regimens. In this update we have included 60 trials; 40 of these studies were included in the previous version of the review; but 10 had been excluded because they did not report outcomes of interest or the data reported were not extractable. In this version we include trials that comply with the eligibility criteria, even if there are no data extractable or do not report the outcomes of interest. In a previous version of this review, daily and intermittent provision of iron supplements were included. This review, however, only focuses on daily iron supplementation. The effects of intermittent iron supplementation are addressed in a separate review (Pena-Rosas 2012).

Outcomes

  • Only pre-specified primary and secondary outcomes are reported. The non pre-specified outcomes that were included in previous versions were removed from this updated version and the overall number of haematological outcomes was reduced for clarity.
  • We have added a description of the lay health worker setting for each trial. We have included a timeframe for haematological variables: at or near term (34 weeks or more gestational age) in addition to at term (37 weeks or more of gestational age).
  • We have added the outcome 'congenital anomalies' instead of birth defects as this name reflects adequately a condition existing at birth and often before birth, which involves defects in or damage to a developing fetus.
  • A new search was conducted (2 July 2012) and the comparisons were changed to evaluate the effects of daily tablets containing iron (alone or with any other micronutrients) versus no iron; iron alone; iron and folic acid; as well as the additional effects of iron alone or iron and folic acid when given in addition to other micronutrients in pregnancy.

Methods

This review uses the latest Cochrane methodological guidance (Higgins 2011), particularly on:

  • the use of formal tests for subgroup analyses using random-effects models;
  • the adjustment of cluster trials;
  • the inclusion of 'Summary of findings' tables to assess the overall quality of the evidence for primary outcomes.

We included three additional subgroup analysis: by type of iron compound, iron compound release, and malaria setting.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifiqueアブストラクトAbstrak
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to ongoing studies
  24. Additional references
  25. References to other published versions of this review
Barton 1994 {published data only (unpublished sought but not used)}
  • Barton DPJ, Joy MT, Lappin TRJ, Afrasiabi M, Morel JG, O'Riordan J, et al. Maternal erythropoietin in singleton pregnancies: a randomized trial on the effect of oral hematinic supplementation. American Journal of Obstetrics and Gynecology 1994;170:896-901.
  • Murphy JF. Randomised double blind control trial of iron/placebo administration to pregnant women with high booking Hb concentrations (Hb>149/dl). Personal communication 1990.
Batu 1976 {published data only}
  • Batu AT, Toe T, Pe H, Nyunt KK. A prophylactic trial of iron and folic acid supplements in pregnant Burmese women. Israel Journal of Medical Sciences 1976;12:1410-7.
Butler 1968 {published and unpublished data}
  • Butler EB. The effect of iron and folic acid in normal pregnancy (MD thesis). Vol. 1, Cardiff: Welsh National School of Medicine, 1967.
  • Butler EB. The effect of iron and folic acid in normal pregnancy (MD thesis). Vol. 2 (Appendixes), Cardiff: Welsh National School of Medicine, Department of Obstetrics,