Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy

  • Review
  • Intervention

Authors

  • Juan Pablo Peña-Rosas,

    Corresponding author
    1. World Health Organization, Reduction of Micronutrient Malnutrition Unit, Department of Nutrition for Health and Development, Geneva 27, Switzerland
    • Juan Pablo Peña-Rosas, Reduction of Micronutrient Malnutrition Unit, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva 27, 1211, Switzerland. penarosasj@who.int.

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  • Fernando E Viteri

    1. Children's Hospital and Oakland Research Institute, Oakland, CA, USA
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Abstract

Background

Intake of supplements containing iron or a combination of iron and folic acid by pregnant women may improve maternal health and pregnancy outcomes. Recently, intermittent supplementation regimens have been proposed as alternatives to daily regimens.

Objectives

To assess the effectiveness and safety of daily and intermittent use of iron or iron+folic acid supplements by pregnant women.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2009) and contacted relevant organisations for the identification of ongoing and unpublished studies.

Selection criteria

All randomised or quasi-randomised trials evaluating the effect of supplementation with iron or iron+folic acid during pregnancy.

Data collection and analysis

We assessed the methodological quality of trials using the standard Cochrane criteria. Two authors independently assessed which trials to include in the review and one author extracted data.

Main results

We included 49 trials, involving 23,200 pregnant women. Overall, the results showed significant heterogeneity across most prespecified outcomes and were analysed assuming random-effects. The trials provided limited information related to clinical maternal and infant outcomes.

Overall, daily iron supplementation was associated with increased haemoglobin levels in maternal blood both before and after birth and reduced risk of anaemia at term. These effects did not differ significantly between women receiving intermittent or daily iron or iron+folic acid supplementation. Women who received daily prenatal iron supplementation with or without folic acid were less likely to have iron deficiency at term as defined by current cut-off values than those who received no treatment or placebo. Side effects and haemoconcentration (a haemoglobin level greater than 130 g/L) were more common among women who received daily iron or iron+folic acid supplementation than among those who received no treatment or placebo. The risk of haemoconcentration during the second and third trimester was higher among those on a daily regimen of iron supplementation. The clinical significance of haemoconcentration remains uncertain.

Authors' conclusions

Universal prenatal supplementation with iron or iron+folic acid provided either daily or weekly is effective to prevent anaemia and iron deficiency at term. We found no evidence, however, of the significant reduction in substantive maternal and neonatal adverse clinical outcomes (low birthweight, delayed development, preterm birth, infection, postpartum haemorrhage). Associated side effects and particularly haemoconcentration during pregnancy may suggest the need for revising iron doses and schemes of supplementation during pregnancy and adjust preventive iron supplementation recommendations.

摘要

背景

預防性口服鐵質或鐵質加葉酸補充品對孕婦的效果與安全性

孕婦服用含鐵質或鐵質加葉酸的補充品,或許可以改善母體健康和懷孕預後。最近,有人提出以間歇性補充來替代每日補充。

目標

評估孕婦每天和間歇性使用鐵質或鐵質加葉酸的效果與安全性。

搜尋策略

我們搜尋Cochrane Pregnancy和Childbirth Group's Trials Register (2009年3月)以及聯絡相關機構,以區別進行中的和未發表的研究。

選擇標準

評估懷孕期間補充鐵質或鐵質加葉酸的所有隨機或半隨機試驗。

資料收集與分析

我們使用Cochrane之標準規範來評估試驗的方法品質,2位作者獨立評估哪些試驗可納入回顧,1位作者摘錄資料。

主要結論

共納入49篇試驗、23,200名孕婦。整體而言,結果顯示在多數預先定義的預後之間有明顯的異質性,因此採用隨機效果模式來進行分析。試驗提供有關臨床母嬰預後的資訊有限。整體而言,每天補充鐵質和增加母親產前與產後血紅素值有關,且減少生產時之貧血風險。在間歇性或每日服用鐵質或鐵質加葉酸的婦女之間,這些效果並無顯著差異。相較於沒有接受治療或使用安慰劑者,產前每天服用鐵質補充品的婦女,不論有無加葉酸,都比較不會在生產時缺鐵(根據現有的數值定義)。相較於沒有接受治療或使用安慰劑者,副作用和血液濃稠(血紅素值大於130 g/L)在每日服用鐵或鐵加葉酸組比較常見。每天服用鐵質補充品的婦女,第2和第3懷孕期的血液濃稠之風險較高。但血液濃稠所扮演的臨床意義還不清楚。

作者結論

產前普遍在使用的鐵質或鐵質加葉酸之補充品,不論是每天或每週服用,都可有效預防生產時之貧血和缺鐵。不過,我們發現,並無證據顯示可顯著減少後續母親及嬰兒的不良臨床預後(低出生體重、發育延遲、早產、感染、產後出血)。相關的副作用,特別是懷孕期間引起血液濃稠,可能代表需調整懷孕期間鐵劑劑量以及給藥時間,而且可能代表需要修正預防性鐵質補充之建議。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

懷孕期間預防性口服鐵質或鐵質加葉酸的安全性與效果。 孕婦預防性服用鐵質或鐵質加葉酸,不論是間歇性或每日服用,都可減少孕婦的貧血和缺鐵。證據顯示,間歇性或每日服用鐵質或鐵質加葉酸,對於減少母親生產時之貧血和改善血紅素值的效果相當。每日服用鐵質或鐵質加葉酸與副作用有關。 懷孕期間,婦女需要鐵質和葉酸來滿足自己和胎兒的需求。因此後有此擔心,孕婦可能會缺乏這些物質,而無法提供足夠的量給胎兒。婦女低鐵和低葉酸會引起貧血,受孕前後時之低葉酸會增加神經管缺陷(neural tube defects (NTD))之風險。貧血會造成孕婦感到疲倦、虛弱,且會增加感染風險。鐵和葉酸的缺乏會影響婦女和懷孕,也會影響胎兒。本次回顧49篇試驗、23,200名孕婦,我們發現,使用鐵質或鐵質加葉酸之補充品可減少懷孕時之貧血和缺鐵,另外每天補充鐵質和生產時之血液濃稠風險增加有關。不論是每天或每週服用,鐵質或鐵質加葉酸減少生產時之貧血和缺鐵性貧血的效果相似。需要更多研究探討鐵質劑量和給藥時間的安全性和效果,以提供孕婦有關功能性預後的預防性補充計畫,特別是低收入國家。

Plain language summary

Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy

Preventive daily or intermittent iron or iron+folic acid supplementation taken by women during pregnancy reduces anaemia and iron deficiency in mothers. There is evidence that taking iron or iron and folic acid daily or intermittently has a similar effect in reducing anaemia at term and improving haemoglobin concentrations in the mother. Daily iron or iron and folic acid is associated with adverse side effects.

During pregnancy, women need iron and folate to meet their own needs and those of their developing fetus. There is concern that pregnant women may become deficient in these nutrients and unable to supply them in sufficient quantities to their fetus. Low iron and folate levels in women can cause anaemia, and low folate periconceptionally increases the risk of neural tube defects (NTD). Anaemia can make women tired, faint, and at increased risk for infection. Iron and folate deficiencies could impact the mother and her pregnancy, and the baby. In this review of 49 trials, involving 23,200 pregnant women, we found data to conclude that the use of iron or iron+folic acid supplements was associated with a reduced risk of anaemia and iron deficiency in pregnancy and that daily iron supplementation was associated with increased risk of haemoconcentration at term. The effects of iron or iron+folic acid on reducing anaemia and iron deficiency anaemia at term were similar whether the supplements were taken daily or weekly. More research is needed on the safe and effective amounts of iron and schemes to provide in preventive supplementation programs for pregnant women on functional outcomes, particularly in low-income countries.

Background

Iron-deficiency anaemia, the late manifestation of chronic 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 (Viteri 1998) and its main causes are a diet poor in absorbable iron, an increased requirement for iron (e.g. during pregnancy), a loss of iron due to parasitic infections, particularly hookworm, and other blood losses (Crompton 2002; INACG 2002a).

Although haemoglobin and haematocrit tests are commonly used to screen for iron deficiency, low haemoglobin or haematocrit values are not specific to iron deficiency. 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 may be independent or superimposed causal factors (WHO 2001). According to the most recent estimate, the global prevalence of anaemia among pregnant women is 41.8% (McLean 2007). According to criteria of U.S. Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO), anaemia during pregnancy should be diagnosed if a woman's haemoglobin (Hb) concentration is lower than 110 g/L during the first or third trimester, or lower than 105 g/L during the second trimester. Iron-deficiency anaemia is defined as anaemia accompanied by depleted iron stores and signs of a compromised supply of iron to the tissues (WHO 2001).

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 and under some conditions, particularly among pregnant women and where different infections (e.g. malaria, HIV/AIDS, vaginosis) are prevalent. Furthermore, the results of those tests do not correlate closely with one another because each reflects a different aspect of iron metabolism. 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 12 µg/L in adults is accepted as an indication of depleted iron stores, even among pregnant women. 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). Other indicators of iron status are also distorted during pregnancy, even among women who are administered supplements containing 200 mg of iron daily (Puolakka 1980). Recently it has been suggested that the ratio of serum transferrin receptors to serum ferritin, a seemingly good estimator of iron nutrition among non-pregnant adults, could also be used to estimate the iron nutritional status of pregnant women. However, this ratio does not seem to differentiate clearly between an iron-deficient and an iron-sufficient population of pregnant women (Cook 2003). An important consistent finding in all the studies referenced above is that pregnant women who received iron supplementation had differences in indicators of iron nutritional status during pregnancy in comparison with those who did not (i.e. their Hb, iron, transferrin saturation and ferritin levels declined less, and low serum transferrin and erythrocyte protoporphyrins among them increased less). There is a need to better define the distribution of serum transferrin receptors during pregnancy in populations that are not iron deficient (Nair 2004), as has been done in some populations from better environments (Milman 2007).

Recently, a WHO and 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 differing studies on pregnant women were included, and only one of them demonstrated changes with iron supplementation. The use of multiple indicators (Hb, ferritin and serum transferrin receptors) is useful for population-based assessments of iron-deficiency anaemia, when this is feasible. However, further studies will be needed to determine how levels of iron nutrition and its indicators among women change during pregnancy under different circumstances, and the extent to which the iron nutritional status of pregnant women influences maternal health and pregnancy outcomes in different populations.

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). 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). 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 (Steer 2000; Murphy 1986) 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 little doubt 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. Favourable pregnancy outcomes occur 30% to 45% less often in anaemic mothers, and probably 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 delayed cord clamping has been shown to provide significant iron reserves to infants (Chaparro 2006; Chaparro 2007; Mercer 2001; van Rheenen 2004). Iron deficiency adversely affects the cognitive performance and development and physical growth of infants (WHO 2001) even in the long term (Lozoff 2006), and moderate or severe iron deficiency during infancy has been shown to have irreversible cognitive effects (Gleason 2007). 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 haemoglobin 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 haemoglobin 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 prospective study in Mexico has shown associations between prenatal daily iron supplement intake at recommended doses to be associated with high haemoglobin concentrations and the risk for both low birthweight and premature delivery (Casanueva 2003a). Ziaei 2007 also showed that women whose haemoglobin concentration at gestational weeks 32 to 36 was >132 g/L had more low birth weight babies and also higher blood pressure than women with lower haemoglobin concentrations. Unfortunately any woman 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 haemoglobin 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 an association between 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).

Interventions to control iron deficiency and iron-deficiency anaemia include iron supplementation and iron fortification, health and nutrition education, control of parasitic infections, and improvement of sanitation (INACG 1977). Delayed clamping of the umbilical cord has also been shown to be effective in preventing iron deficiency among infants and young children (Chaparro 2007; Mercer 2001; van Rheenen 2004).

The results of some studies suggest that the amount of iron that can be absorbed from diet alone is insufficient to cover women's increased iron requirements during pregnancy except when women can draw enough iron from pre-pregnancy iron reserves. The Institute of Medicine recommends that women consume 27 mg/day of iron during pregnancy (IOM 2001). Because most women would need additional iron as well as sufficient iron stores to prevent iron deficiency (Bothwell 2000), 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 micronutrients for which deficiencies are documented may justify their addition to the supplementation formula.

Several studies have shown that iron supplementation, with or without folic acid during pregnancy, results in a substantial reduction in women's risk of having haemoglobin levels less than 100 g/L 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 this issue adequately. The effectiveness of iron supplementation for pregnant women has been evaluated mostly in terms of improvement in haemoglobin 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 antenatal iron and iron with folic acid supplementation during pregnancy.

International organisations have been advocating routine iron and folic acid supplementation for every pregnant woman in areas of high anaemia prevalence (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 iron and 400 ug of folic acid for six months or, if six months of treatment cannot be achieved during pregnancy, either continued supplementation during the postpartum period or increased dosage to 120 mg iron daily during pregnancy (WHO 2006), or if iron deficiency prevalence in the country is high or the pregnant women are anaemic (INACG 1998). Gastrointestinal side effects have been selected as the critical adverse effect on which to base the tolerable upper intake level for iron, as gastrointestinal distress is observed commonly in women consuming high levels of supplemental iron on an empty stomach. 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 based on gastrointestinal side effects as 45 mg/day of iron, a daily dose much lower than international recommendations (IOM 2001). In most industrialised countries, the decision to prescribe or recommend antenatal iron with folic acid supplementation to women during pregnancy is left to the health care 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 higher doses, up to 120 mg daily are recommended in the presence of anaemia (CDC 1998).

Less frequent regimens of iron supplementation, such as once weekly or twice weekly with iron alone or in conjunction with folic acid, have been evaluated in the last decade as a promising innovative regimen. The weekly iron administration is based on two lines of evidence: (1) daily iron supplementation, by maintaining an iron-rich environment in the gut lumen and in the intestinal mucosal cells, produces oxidative stress, reduces the long-term iron-absorption efficacy and is prone to increasing the severity and frequency of undesirable side effects (Srigirihar 1998; Srigiridhar 2001; Viteri 1997; Viteri 1999a); (2) the concept that exposing intestinal cells to supplemental iron less frequently, every week based on the rate of mucosal turnover that occurs every five to six days in the human, may improve the efficiency of iron utilisation. Recently, the mucosal block phenomenon of iron absorption has been demonstrated when enterocytes have high iron levels, as occurs with daily iron intake (Anderson 2005; Frazer 2003a; Frazer 2003b). Additionally, compliance could increase due to fewer side effects and the costs of supplementation may be favourable if provided outside of the medical context (Viteri 1995; Viteri 1999b). However, some authors have questioned this belief, indicating that the main reason for the poor compliance with programs is the unavailability of iron supplements for the targeted women (Galloway 1994). Recently, lower birthweight and premature delivery have been associated with excess iron intake (which may cause cell damage from the production of reactive oxygen species) and with higher levels of haemoglobin concentrations late during the second trimester and early into the third trimester but not at term (Casanueva 2003b).

This review combines and updates the three currently published Cochrane Reviews on iron and iron+folic acid supplementation (Mahomed 2000a; Mahomed 1998a; Pena-Rosas 2006) that have clearly shown improvements on biochemical and haematological parameters, and evaluates the issues related to periodicity as well as the potential benefits and hazards of these interventions.

Objectives

To assess the effectiveness and safety of preventive daily and intermittent use of iron supplements by pregnant women, either alone or in conjunction with folic acid.

The effectiveness of different treatments for iron-deficiency anaemia among pregnant women (Reveiz 2007) and the effects of supplementation with iron and vitamin A during pregnancy (Van den Broek 2002) are covered in other Cochrane Reviews. The effectiveness of vitamin C supplementation in pregnancy is covered in another Cochrane Review (Rumbold 2005). The effects of supplementation with folic acid alone (Mahomed 1998a), the effectiveness of periconceptional use of folic acid on the prevalence of neural tube defects (Lumley 2003) and the effects of multiple vitamin and mineral supplements during pregnancy have also been reviewed elsewhere (Haider 2006).

Methods

Criteria for considering studies for this review

Types of studies

We reviewed randomised and quasi-randomised trials comparing the effects of daily prenatal oral iron or iron+folic acid supplements among pregnant women with the effects of no treatment/placebo or intermittent supplementation regimens. 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 when all arms of the study group 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 alone here. We also excluded studies dealing with iron supplementation for anaemic women as a medical treatment.

Types of participants

Pregnant women of any gestational age, parity, and number of fetuses.

Types of interventions

  1. Daily universal oral supplementation with iron or iron+folic acid compared with no iron or iron+folic acid supplementation/placebo.

  2. Daily universal oral supplementation with iron or iron+folic acid compared with universal intermittent (weekly or twice weekly) regimens.

  3. Intermittent oral iron or iron+folic acid supplementation compared with no iron+folic acid supplementation/placebo.

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 (g)

Maternal
  1. Premature delivery (less than 37 weeks' gestation)

  2. Hb concentration at term in g/L

  3. Anaemia at term (Hb less than 110 g/L)

  4. Haemoconcentration at term (defined as Hb greater than 130 g/L)

  5. Haemoconcentration at any time during second or third trimesters (defined as Hb greater than 130 g/L)

  6. Iron deficiency at term (based on two or more laboratory indicators)

  7. Iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator)

  8. Side effects (any)

Secondary
Infant
  1. Very low birthweight (less than 1500 g)

  2. Perinatal mortality

  3. Hb concentration at 1 month in g/L

  4. Ferritin concentration at 1 month in ug/L

  5. Hb concentration at 3 months in g/L

  6. Ferritin concentration at 3 months in ug/L

  7. Hb concentration at 6 months in g/L

  8. Ferritin concentration at 6 months in ug/L

  9. Long-term infant developmental (as defined by trial authors)

  10. Admission to special care unit

Maternal
  1. Very premature delivery (less than 34 weeks' gestation)

  2. Severe anaemia at term (Hb less than 70 g/L)

  3. Moderate anaemia at term (Hb greater than 70 g/L and less than 110 g/L)

  4. Severe anaemia at any time during second or third trimesters (Hb less than 70 g/L)

  5. Moderate anaemia at any time during second or third trimesters (Hb greater than 70 g/L and less than 110 g/L)

  6. Infection during pregnancy (including urinary tract infections and others as specified by trial authors)

  7. Puerperal infection (as defined by trial authors)

  8. Antepartum haemorrhage (as defined by trial authors)

  9. Postpartum haemorrhage (intrapartum and postnatal, as defined by trial authors)

  10. Transfusion given (as defined by trial authors)

  11. Hb concentration within 1 month postpartum in g/L

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

  13. Moderate anaemia at postpartum (Hb greater than 80 g/L and less than 100 g/L)

  14. Diarrhoea

  15. Constipation

  16. Nausea

  17. Heartburn

  18. Vomiting

  19. Maternal death (any known)

  20. Maternal well being/satisfaction (as defined by trial authors)

  21. Placental abruption (as defined by trial authors)

  22. Premature rupture of membranes (as defined by trial authors)

  23. Pre-eclampsia (as defined by trial authors)

We recorded other relevant outcomes reported by trial authors and labelled them as 'not prespecified'.

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 (March 2009).

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

  1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. hand searches of 30 journals and the proceedings of major conferences;

  4. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE, the list of 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. 

We did not apply any language restrictions.

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) and the U.S. Centers for Disease Control and Prevention (CDC).

Data collection and analysis

We assessed trials for methodological quality using the criteria in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) for adequate, unclear and inadequate allocation concealment. We also collected information on blinding of outcome assessment and loss to follow up and incorporated them in the additional table of methodological quality. We classified blinding as "adequate" if both the trial participants and care providers/assessors were blind to the treatment, as "unclear" if either the participants or care providers/assessors were blind to the treatment and as "inadequate" if the blinding status of a trial was unclear or the trial was open. We considered follow up to be adequate if more than 80% of participants initially randomised in a trial were included in the analysis, 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.

Two authors independently assessed the eligibility of identified studies. The contact authors extracted data from the reports. We then assessed the number of losses to follow up and post-randomisation exclusions systematically for each trial. We included quasi-randomised studies and conducted a sensitivity analysis. We also included cluster-randomised studies and adjusted their samples sizes (Higgins 2008) if sufficient information was available to allow for this. If possible, we estimated the intra-cluster correlation coefficients for each outcome from original data provided by the authors and contacted authors of the original reports for additional data as required.

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 entered data onto Review Manager software (RevMan 2008). We resolved any disagreements among the authors of this review concerning what studies to include or exclude studies or concerning data extraction by discussion, and, if necessary, sought clarification from the authors of the original reports. We analysed dichotomous data in terms of risk ratio (RR) and we analysed continuous data in terms of mean difference (MD), unless the trials used in a particular analysis reported outcomes on different scales that could not be converted to a common scale, in which case, we used the standard mean difference.

We described the proportion of variability in the data due to between-study heterogeneity using the I2 statistic test available in RevMan 2008. Because of the high heterogeneity among trials, we pooled trial results using a random-effects model and were cautious in our interpretation of the pooled results.

Sensitivity analysis

We considered substantial heterogeneity when the I2 statistic was greater than 50% among trials used in a particular meta-analysis. This statistic quantifies inconsistency and describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). 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. We conducted an available case analysis and reinstated previously excluded cases when possible.

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.

We defined iron and iron+folic acid supplementation regimens as either daily (a dose taken every day either as a single or repeated dose) or intermittent (any dose taken less frequently than daily such as alternate days, twice a week or weekly).

Our original goal in this review was to compare the effects of eight pairs of supplementation regimens: (1) any iron alone compared to no intervention/placebo; (2) daily iron alone compared with no intervention/placebo; (3) intermittent iron alone compared with no intervention/placebo; (4) intermittent iron alone compared with daily iron alone; (5) any iron+folic acid compared with no intervention/placebo; (6) daily iron+folic acid compared with no intervention/placebo; (7) intermittent iron+folic acid compared with no intervention/placebo; and (8) intermittent iron+folic acid compared to daily iron+folic acid. However, to avoid presenting repetitive data and because we found no studies for some of the comparisons, we limited our review to the effects of (1) daily iron alone compared with no intervention/placebo; (2) intermittent iron alone compared with daily iron alone; (3) daily iron+folic acid compared with no intervention/placebo;and (4) intermittent iron+folic acid compared with daily iron+folic acid.

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) early gestational age (supplementation started before 20 weeks' gestation or prior to pregnancy);
(2) late gestational age (supplementation started at 20 weeks of gestation or later);
(3) unspecified gestational age or mixed gestational ages at the start of supplementation;
(4) anaemic (Hb below 110 g/L during first and third trimesters or below 105 g/L in second trimester) at start of supplementation;
(5) non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation;
(6) unspecified/mixed anaemia status at start of supplementation;
(7) low daily dose of iron(60 mg elemental iron or less);
(8) higher daily dose of iron (more than 60 mg elemental iron).

Results

Description of studies

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

We identified 209 references corresponding to 145 trials. Of these, we included 49 trials, excluded 92 trials, classified two trials as 'awaiting assessment' and confirmed that two trials are still ongoing. We treated a trial in Guatemala that included two sub-studies as two separate trials: one with supervised intake (Chew 1996a) and one with unsupervised intake (Chew 1996b). We also treated another 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). One trial in China (Liu 1996) involved three comparison groups: one receiving weekly doses of iron, one receiving daily doses of iron and a control group. However, since the allocation of the control group was not randomised, we included this study only in our comparisons of the effects of intermittent versus daily iron supplementation.

Thirty-six trials compared the effects of daily iron supplementation with the effects of no iron or placebo (Batu 1976; Butler 1968; Buytaert 1983; Cantlie 1971; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Christian 2003; Cogswell 2003; De Benaze 1989; Eskeland 1997; Hankin 1963; Harvey 2007;Hemminki 1991 Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Meier 2003; Menendez 1994; Milman 1991; Paintin 1966; Pita Martin 1999; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Siega-Riz 2001; Svanberg 1975; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947; Ziaei 2007; Ziaei 2008). Of these, 13 trials were of high quality according to our pre-established criteria (Buytaert 1983; Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Makrides 2003; Preziosi 1997; Siega-Riz 2001;Tura 1989; Wallenburg 1983; Ziaei 2007; Ziaei 2008).

Two studies compared the effects of intermittent supplementation with iron alone with the effects of daily supplementation with iron alone (Pita Martin 1999; Yu 1998). However, neither of these met our criteria for high quality. No study compared the effects of intermittent supplementation with iron alone or iron+folic acid with the effects of no treatment or placebo.

Nine trials compared the effects of daily iron+folic acid supplementation with the effects of no treatment (Barton 1994; Batu 1976; Butler 1968; Charoenlarp 1988; Chisholm 1966; Lee 2005; Liu 1996; Taylor 1982; Willoughby 1967). Only one of them (Barton 1994) met the criteria for high quality.

Nine trials compared the effects of intermittent iron+folic acid supplementation with the effects of daily iron+folic acid supplementation (Chew 1996a; Chew 1996b; Ekstrom 2002; Liu 1996; Mukhopadhyay 2004; Ridwan 1996; Robinson 1998; Winichagoon 2003; Young 2000).

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

Risk of bias in included studies

Twenty-five trials adequately randomised the participants to the treatment groups (Barton 1994; Butler 1968; Buytaert 1983; Charoenlarp 1988; Chew 1996a; Chew 1996b; Christian 2003; Cogswell 2003; Ekstrom 2002; Eskeland 1997; Harvey 2007; Hemminki 1991; Kerr 1958; Lee 2005; Makrides 2003; Meier 2003; Mukhopadhyay 2004; Preziosi 1997; Ridwan 1996; Siega-Riz 2001; Tura 1989; Wallenburg 1983; Young 2000; Ziaei 2007; Ziaei 2008). Eighteen trials did not report or did not state clearly the randomisation method used (Batu 1976; Cantlie 1971; Chisholm 1966; De Benaze 1989; Holly 1955; Hood 1960; Liu 1996; Menendez 1994; Milman 1991; Paintin 1966; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982;Van Eijk 1978; Willoughby 1967; Winichagoon 2003). Six trials were quasi-randomised using alternate or sequence allocation (Chanarin 1971; Hankin 1963; Pita Martin 1999; Robinson 1998; Wills 1947; Yu 1998). Six trials used cluster randomisation (Christian 2003; Ekstrom 2002; Makrides 2003; Mukhopadhyay 2004; Ridwan 1996; Winichagoon 2003).

Twenty-one trials reported using sealed envelopes or coded or opaque bottles when allocating women to treatment groups (Barton 1994; Butler 1968; Buytaert 1983; Chew 1996a; Chew 1996b; Chisholm 1966; Christian 2003; Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hemminki 1991; Liu 1996; Makrides 2003; Paintin 1966; Preziosi 1997; Siega-Riz 2001; Tura 1989; Wallenburg 1983; Ziaei 2007; Ziaei 2008). The method of concealing allocation used in 17 trials was unclear (Batu 1976; Cantlie 1971; Charoenlarp 1988; Holly 1955; Hood 1960; Kerr 1958; Lee 2005; Meier 2003; Milman 1991; Pritchard 1958; Puolakka 1980; Robinson 1998; Romslo 1983; Svanberg 1975; Taylor 1982; Willoughby 1967; Young 2000). Some trials used an inadequate method or did not use any allocation concealment at all (Chanarin 1971; Ekstrom 2002; Hankin 1963; Mukhopadhyay 2004; Menendez 1994;Pita Martin 1999; Ridwan 1996; Van Eijk 1978; Wills 1947; Winichagoon 2003; Yu 1998). Clearly, studies comparing the effects of intermittent supplementation regimens with the effects of daily supplementation regimens would have had difficulty keeping participants blinded as to what treatment they were receiving without obscuring participants' adherence to any intermittent supplementation regimen, given that doing so would require participants on an intermittent regimen to receive placebo for some days.

See the table of "Methodological quality assessment of included trials" (Table 1) for a summary of the trials' quality.

Table 1. Methodological quality assessment of included trials
TrialRandomisationAllocationBlindingCompleteness of dataQuality rating
Barton 1994AdequateAdequateParticipants and care provider blindedAdequate. Less than 5% lost to follow upHIGH
Batu 1976Unclear methodUnclearUnclear. Participants blinded. Care provider and outcome assessor not clearInadequate. 28% of women lost to follow up 
Butler 1968AdequateAdequateInadequate. Participant and provider were blinded for treatment for groups 1 and 2.Inadequate. More than 20% lost to follow up 
Buytaert 1983AdequateAdequateInadequate. OpenUnclearHIGH
Cantlie 1971Unclear. Method not stated.UnclearUnclearUnclear. Not reported 
Chanarin 1971Inadequate. Quasi randomised by sequence assignmentInadequateParticipants and care provider blindedAdequate. Less than 20% lost to follow up 
Charoenlarp 1988AdequateUnclearUnclear. Participants and outcome assessor blinded. Care provider unclearAdequate 
Chew 1996aAdequateAdequate by sealed envelopesInadequate. Participants, care provider and outcome assessor not blindedAdequate. Less than 20% lost to follow up 
Chew 1996bAdequateAdequate by sealed envelopesAdequate. Participants and care provider not blinded. Outcome assessor blindedInadequate. More than 20% lost to follow up 
Chisholm 1966Unclear methodAdequateParticipants and care provider blindedAdequate. Less than 20% lost to follow up 
Christian 2003Adequate. Cluster randomisationAdequate. Coded assignmentAdequate. Participants, care providers and outcome assessors blindedInadequate. More than 20% lost to follow upHIGH
Cogswell 2003AdequateAdequateAdequate. Participants, care provider and outcome assessor blindedInadequate. More than 20% lost to follow upHIGH
De Benaze 1989Unclear methodAdequateAdequate. Participants and care provider blindedAdequate. Less than 20% lost to follow up 
Ekstrom 2002Adequate by clusterInadequate. Not usedInadequate. Participants and care provider not blinded. Outcome assessor unclearInadequate. More than 20% lost to follow up 
Eskeland 1997AdequateAdequateAdequate. Participants, care provider and outcome assessor blindedInadequate. More than 20% lost to follow upHIGH
Hankin 1963Inadequate. Quasi randomised by alternate assignment by day of the weekInadequateInadequate. OpenAdequate. Less than 5% excluded 
Harvey 2007AdequateAdequate. Coded opaque bottlesInadequate. Participants blinded. Care provider and outcome assessor not blindedAdequate. No losses to follow up.HIGH
Hemminki 1989AdequateAdequate. Sealed numbered envelopes.Inadequate. Open to participants and care providers. Outcome assessor blind.Adequate.HIGH
Holly 1955Unclear methodUnclearInadequate. Participants and care provider not blinded. Outcome assessor unclearUnclear 
Hood 1960Unclear methodUnclearInadequate. Participants and care provider not blinded. Outcome assessor unclearAdequate. Less than 20% lost to follow up 
Kerr 1958AdequateUnclearInadequate. Participants blinded. Care provider not blinded. Outcome assessor unclearInadequate. More than 20% lost to follow up 
Lee 2005Adequate. Method unclearUnclearUnclear.Adequate. Less than 20% lost to follow up 
Liu 1996Unclear methodAdequate by sealed envelopesInadequate. Participants and care provider not blinded. Outcome assessor blindedAdequate. Less than 20% lost to follow up 
Makrides 2003AdequateAdequateAdequate. Participants and care provider blindedAdequate. Less than 20% lost to follow upHIGH
Meier 2003Adequate. Stratified by age groupUnclearAdequate. Participants and care provider blinded. Outcome assessor unclearInadequate. More than 20% lost to follow up 
Menendez 1994Unclear methodInadequateInadequate. Participants and care provider not blinded. Outcome assessor blindedInadequate. More than 20% lost to follow up 
Milman 1991Unclear methodUnclearAdequate. Participants and care provider blinded. Outcome assessor unclearAdequate. Less than 20% lost to follow up 
Mukhopadhyay 2004Adequate. Block randomisationInadequate. Not usedInadequate. Open to participants, and care providers. Outcome assessor unclearInadequate. More than 20% lost to follow up 
Paintin 1966Unclear methodAdequate by sequential numbersAdequate. Participants and care provider blindedAdequate. Less than 5% lost to follow up 
Pita Martin 1999Inadequate. Quasi randomisedInadequate. Not usedInadequate. OpenInadequate. More than 20% lost to follow up 
Preziosi 1997AdequateAdequateAdequate. Participant and care provider blinded. Outcome assessor blindedUnclearHIGH
Pritchard 1958Unclear methodUnclearInadequate. OpenUnclear 
Puolakka 1980Unclear methodUnclearInadequate. OpenAdequate. Less than 20% lost to follow up 
Ridwan 1996AdequateInadequate. Not usedInadequate. Participants and care provider not blinded. Outcome assessor blindedInadequate. More than 20% lost to follow up 
Robinson 1998Quasi randomised by alternate numbersUnclearInadequate. Participants and care provider not blindedInadequate. More than 20% lost to follow up 
Romslo 1983Unclear methodUnclearInadequate. Participants blinded. Care provider and outcome assessor not blindedAdequate. Less than 20% lost to follow up 
Siega-Riz 2001Adequate. Random number generatorAdequateAdequate. Participants, care provider and outcome assessor blindedInadequate. More than 20% lost to follow upHIGH
Svanberg 1975Unclear methodUnclearAdequate. Participants, care provider, and outcome assessor blindedAdequate. Less than 20% lost to follow up 
Taylor 1982Unclear methodUnclearInadequate. OpenAdequate. less than 20% lost to follow up 
Tura 1989AdequateAdequateInadequate. OpenAdequate. Less than 20% lost to follow upHIGH
Van Eijk 1978Unclear. Not statedInadequate. Not usedInadequate.OpenAdequate. Less than 20% loss to follow up 
Wallenburg 1983AdequateAdequateInadequate.OpenAdequate. Less than 20% lost to follow upHIGH
Willoughby 1967Unclear methodUnclearUnclearA. Adequate. Less than 20% lost to follow up 
Wills 1947Inadequate. Quasi randomised by alternate allocationInadequate. Not usedAdequate. Participants and care provider blinded. Outcome assessor blindedInadequate. More than 20% lost to follow up 
Winichagoon 2003Unclear method of cluster randomisationInadequate. Not usedInadequate.OpenInadequate. more than 20% lost to follow up 
Young 2000AdequateUnclearInadequate. Participants and care provider not blinded. Outcome assessor unclearInadequate. More than 20% lost to follow up 
Yu 1998Inadequate. Quasi randomisedInadequateInadequate.OpenInadequate. More than 20% lost to follow up 
Ziaei 2008Adequate. Random numbers tableAdequate. Coded assignmentsAdequate. Participants and care provider blinded. Outcome assessor unclearAdequate. Less than 5% lost to follow upHIGH
Ziaei 2007Adequate. Table of random numbersAdequate. Coded bottlesAdequate. participants and care providers blinded. Outcome assessor unclearAdequate. Less than 5% lost to follow up.HIGH

Effects of interventions

We have included 49 trials, involving 23,200 women, in this review. We have organised the summary 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. Because all the results showed significant heterogeneity that could not be explained by standard sensitivity analyses including quality assessment, we used a random-effects model to analyse the results.

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

(1) Daily iron alone compared with no intervention/placebo

Infant outcomes
Low birthweight (less than 2500 g)

Overall, we found no significant difference in the prevalence of low birthweight (less than 2500 g) between newborns of mothers in these two groups (Analysis 1.1). Among 6275 women in nine trials (Christian 2003; Cogswell 2003; Eskeland 1997; Makrides 2003; Meier 2003; Menendez 1994; Siega-Riz 2001; Ziaei 2007; Hemminki 1991), 9.6% of those who took daily iron supplementation during pregnancy had a baby with birthweight below 2500 grams versus 11.9% of those who received no iron or placebo (risk ratio (RR) 0.79; 95% CI 0.61 to 1.03) (Analysis 1.1). When we limited our analysis to high-quality studies (Christian 2003; Cogswell 2003; Eskeland 1997; Makrides 2003; Menendez 1994; Siega-Riz 2001; Ziaei 2007), the difference in the percentage of mothers with low birthweight babies remained non-significant. Results from the three trials where 1823 women had unspecified/mixed anaemic status at start of supplementation suggest that women who received iron supplements had a lower risk of having a low birthweight baby in comparison to those who did not receive the iron supplements (risk ratio (RR) 0.82; 95% CI 0.71 to 0.94).

Birthweight (g)

We found no significant difference in birthweight (Analysis 1.3) in children from mothers of the two groups. Among infants born to 5956 participants in ten trials (Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Makrides 2003; Preziosi 1997; Puolakka 1980; Siega-Riz 2001; Ziaei 2007) the mean difference (MD) in birthweight between those whose mothers had taken iron supplements and those whose mothers had not was 36.05 g and was not statistically significant (95% CI -4.84 to 76.95) (Analysis 1.3). Results from the three trials where 1577 women had unspecified/mixed anaemic status at start of supplementation suggest that women who received iron supplements had a lower risk of having a heavier baby in comparison to those who did not receive the iron supplements (MD 52.33 g; 95% CI 10.16 to 94.51).

We did find evidence of significant differences between treatment groups in the following infant secondary outcomes:

Infant ferritin concentration at 3 months in ug/L

The MD was 19.0; 95% confidence interval (CI) 2.75 to 35.25 (one trial involving 197 women) (Preziosi 1997) (Analysis 1.25).

Infant ferritin concentration at 6 months in ug/L

The MD was 11.0 ug/L; 95% CI 4.37 to 17.63 ug/L (one trial involving 197 women) (Preziosi 1997)(Analysis 1.27). However, the results of another study that evaluated infant serum ferritin concentration at six months (Makrides 2003) showed that the geometric mean of concentrations among infants from mothers who had received 20 mg elemental iron during pregnancy did not differ significantly from that of infants whose mothers had received placebo (32.5 +/- 2.0 and 30.8 +/- 2.0 ug/L respectively). The Makrides study was conducted among women from a well-nourished industrialised population (Makrides 2003), whereas the Preziosi study was conducted among women in a developing country (Preziosi 1997).

Birth length in cm (not pre-specified)

We found significant difference in birth length (Analysis 1.94) in children from mothers of the two groups. Among infants born to 2140 participants in five trials (Christian 2003; Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997), the MD in birth length between those whose mothers had taken iron supplements and those whose mothers had not was 0.38 cm (95% CI 0.10 to 0.65) (Analysis 1.94).

We found no evidence of significant difference by treatment group in the following secondary outcomes:
very low birthweight (less than 1500 g) (Analysis 1.20); perinatal death (Analysis 1.21); infant Hb concentration at 3 months in g/L (Analysis 1.24); infant haemoglobin concentration at six months (Analysis 1.26); admission to special care unit (Analysis 1.29); percentage of infants who were small for gestational age (Analysis 1.91).

No trials reported on the remaining infant outcomes.

Maternal outcomes
Premature delivery (less than 37 weeks' gestation)

We found no evidence of significant difference in rates of premature delivery between women who received daily iron supplementation and those who received no iron supplementation (Analysis 1.5).

Maternal haemoglobin concentration at term in g/L

Among 2463 women who participated in 17 trials (Batu 1976; Butler 1968; Buytaert 1983; Cantlie 1971; Chanarin 1971; Cogswell 2003; De Benaze 1989; Eskeland 1997; Makrides 2003; Milman 1991;Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983; Ziaei 2007; Ziaei 2008), those who took iron supplements had a mean haemoglobin concentration 8.83 g/L higher at term in comparison to those who took no iron supplements at all (MD 8.83; 95% CI 6.55 to 11.11 g/dL) (Analysis 1.7). However, because the heterogeneity among the treatment effects found in individual studies was substantial (I2 greater than 50%), our results have to be interpreted with caution. The difference in haemoglobin concentration was slightly higher among those starting supplementation after 20 weeks of gestation (Analysis 1.8) and the difference was maintained among those who received different doses of elemental iron. The MD did not change significantly when we included only high-quality trials (Buytaert 1983; Cogswell 2003; Eskeland 1997; Makrides 2003; Tura 1989; Wallenburg 1983; Ziaei 2007; Ziaei 2008) (MD 6.00; 95% CI 2.75 to 9.25) and heterogeneity remained high. A forest plot showed no asymmetry, suggesting that there may not be publication bias (Figure 1).

Figure 1.

Funnel plot of comparison: 1 Daily iron alone versus no intervention/placebo, outcome: 1.7 Maternal Hb concentration at term (g/L) (ALL).

Anaemia at term (Hb less than 110 g/L)

Among 4390 women in 14 trials (Batu 1976; Chanarin 1971;Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Hemminki 1991; Holly 1955; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983), 5.08% of those who received daily iron supplements during pregnancy and 14.6% who did not had anaemia at term (RR 0.27; 95% CI 0.17 to 0.42 (Analysis 1.9)). However, because the heterogeneity in study results was substantial (I2 greater than 50%), our results have to be interpreted with caution. The results of a sensitivity analysis of data from the four high-quality studies involving a total of 787 women (Cogswell 2003; Eskeland 1997; Hemminki 1991; Makrides 2003; Preziosi 1997) showed a slightly weaker association between use of iron supplements and anaemia status at term (4.7% versus 9.98%; RR 0.46; 95% CI 0.29 to 0.72), although the heterogeneity I2 value increased. A forest plot showed certain asymmetry, suggesting that there may be some publication bias (Figure 2).

Figure 2.

Funnel plot of comparison: 1 Daily iron alone versus no intervention/placebo, outcome: 1.9 Anaemia at term (Hb less than 110 g/L).

Haemoconcentration at term (defined as Hb greater than 130 g/L)

Data from 10 trials involving 4643 women (Butler 1968; Chisholm 1966; Cogswell 2003; Eskeland 1997; Hemminki 1991; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958; Ziaei 2007) indicated that 53.8% of women who took daily iron supplementation during pregnancy and 38.0% of those who did not had haemoconcentration at term (RR 2.62; 95% CI 1.21 to 5.67) (Analysis 1.10). The heterogeneity between the treatment effects was substantial (I² greater than 90%) and the results have to be interpreted with caution (Analysis 1.10). When we limited the analysis to the five high-quality trials involving a total of 1317 women (Cogswell 2003; Eskeland 1997; Hemminki 1991; Makrides 2003; Ziaei 2007) the difference in haemoconcentration prevalence was no longer significant (62.9% versus 51.9%; RR 1.73; 95% CI 0.64 to 4.66) and the heterogeneity in study increased (I² = 97%) (not shown). The risk of haemoconcentration at term was higher among women who received daily higher doses of more than 60 mg elemental iron (Analysis 1.11)

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

Ten trials involving 4841 women evaluated the effects of oral routine supplementation with iron alone and haemoconcentration at any time during the second or third trimesters (Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958; Ziaei 2007). Among women who received daily iron supplements, 25.1% were found to have haemoconcentration at some time during their second or third trimesters, compared with 9.3% of those who received no iron supplements (RR 2.27; 95% CI 1.40 to 3.70) (Analysis 1.12). However, because the heterogeneity in study results was substantial (I² = 89%), the results have to be interpreted with caution (Analysis 1.12). When we limited our analysis to the seven trials of high quality (Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007;Hemminki 1991; Makrides 2003; Ziaei 2007), the association between use of iron supplements and risk for haemoconcentration was still significant (RR 2.22; 95% CI 1.28 to 3.85), and the heterogeneity remained high (91%). The effect was maintained in women who started the supplementation at an early gestational age (less than 20 weeks) and among women who were non-anaemic at the start of the intervention. The effects were also similar in the women who received higher or lower doses of elemental iron as defined in this review (Analysis 1.13).

Iron deficiency at term (based on two or more laboratory indicators)

Data from six trials involving 1108 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989) showed that 30.7% of women who received daily iron supplements had iron-deficiency anaemia at term, compared with 54.8% of those who received no iron supplements (RR 0.44; 95% CI 0.27 to 0.70) (Analysis 1.14). The heterogeneity between the treatment effects is substantial (I² greater than 50%) and the results have to be interpreted with caution (Analysis 1.14). Five of the trials were of high quality.

Iron-deficiency anaemia at term (Hb below 110 g/L and at least one additional laboratory indicator)

Data from six trials involving 1667 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Milman 1991; Tura 1989; Ziaei 2007) showed that 4.9% of women who received daily iron supplements and 15.5% of those who did not had iron-deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69) (Analysis 1.16). The heterogeneity between the treatment effects was small (I² less than 50%) (Analysis 1.16). These results were similar for the different subgroups, including those who start supplementation early in the gestation and those who are non-anaemic at start of the study, and in any iron dose. The effect was similar (3.1% versus 7.9%); when only five trials of high quality involving 1547 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Tura 1989; Ziaei 2007) were compared: RR 0.39; 95% CI 0.20 to 0.74 and a test of heterogeneity (I² = 40.4%) (not shown).

Side effects (any)

Data from eight trials involving 3667 women (Charoenlarp 1988; Cogswell 2003; De Benaze 1989; Eskeland 1997; Harvey 2007; Hemminki 1991; Hood 1960; Kerr 1958) 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 (24.7% versus 4.3%; RR 3.92; 95% CI 1.21 to 12.64) (Analysis 1.18). However, the heterogeneity between the treatment effects is substantial (I² greater than 50%) and the results have to be interpreted with caution (Analysis 1.18). When only the four high-quality trials involving 2897 women were included (Cogswell 2003; Eskeland 1997; Harvey 2007; Hemminki 1991), the effect is no longer significant (24.5% versus 3.4%; RR 3.27; 95% CI 0.39 to 27.31 (data not shown)) with high heterogeneity (I² = 98%). The effect was significantly consistent in women who received daily higher doses of elemental iron (more than 60 mg).

There was evidence of significant differences found in the following secondary outcomes:

Moderate anaemia (defined as Hb > 70/L and < 90 g/L)at any time during the second or third trimester

Data from 10 trials involving 2266 women (Butler 1968; Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007; Holly 1955; Makrides 2003; Milman 1991; Paintin 1966; Ziaei 2007) suggest that women who routinely receive daily iron supplementation are less likely to have moderate anaemia at any time during the second or third trimesters than women receiving no iron or placebo (2.1% versus 3.3%; RR 0.42; 95% CI 0.19 to 0.92). The heterogeneity between treatment effects was small (I² less than 50%) (Analysis 1.34). When only the six high-quality trials involving 1668 women were included (Christian 2003; Cogswell 2003; Eskeland 1997; Harvey 2007; Makrides 2003; Ziaei 2007) the effect remained significant (2.1% versus 3.3%; RR 0.23; 95% CI 0.08 to 0.66 (data not shown)) with no heterogeneity (I² = 0%) as only two trials had cases.

Transfusion provided

The data from three trials involving 3453 women (Hemminki 1991; Puolakka 1980; Ziaei 2007) 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 (1.6% versus 2.7%); RR 0.61; 95% CI 0.38 to 0.96).

Maternal haemoglobin concentration within one month postpartum in g/L

The data from six trials involving 904 women (Cantlie 1971; Hankin 1963; Lee 2005; Menendez 1994; Milman 1991; Wills 1947) suggest that women that routinely receive daily iron supplementation have a higher concentration of haemoglobin after one month postpartum than those taking placebo or not taking any iron supplements at all (WMD 7.08 g/L; 95% CI 4.70 to 9.47 g/L). The I² statistic shows that heterogeneity of the results is less than 50% (Analysis 1.40). None of the trials met the criteria for high quality.

Diarrhoea

Data from three trials involving 1088 women (Paintin 1966; Siega-Riz 2001; Ziaei 2007) showed that 3.9% of women who received daily iron supplements and 5.1% of those who did not presented with diarrhoea (RR 0.55; 95% CI 0.32 to 0.93) with no heterogeneity in individual study results (I² = 0%). In our analysis of data from only the two high-quality trials involving 915 women (Siega-Riz 2001; Ziaei 2007) the association between supplement use and risk for diarrhoea remained significant (4.4% versus 5.5%; RR 0.53; 95% CI 0.31 to 0.91; data not shown), and there was no heterogeneity in study results (I² = 0%) (Analysis 1.43).

There was no evidence of significant difference between women receiving daily iron supplementation and women receiving placebo or not taking any iron supplements at all, in the following secondary outcomes:
very premature delivery (less than 34 weeks' gestation), placental abruption, pre-eclampsia, severe anaemia at term, at any time during second or third trimesters or postpartum, moderate anaemia at term; and in the postpartum, puerperal infection, antepartum haemorrhage and postpartum haemorrhage, transfusion given, constipation, nausea, heartburn, vomiting, maternal death, maternal Hb concentration at four to eight weeks postpartum in g/L (not pre-specified).

Maternal wellbeing/satisfaction

A maternal index of wellbeing was measured in one trial (Makrides 2003) through the use of a self-administered questionnaire at 36 weeks gestation and at six weeks and six months postpartum. There were not 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 wellbeing at 28 and 36 weeks' gestation, and found no differences between the iron supplemented mothers or those receiving placebo (Analysis 1.49).

No trials reported on the remaining secondary outcomes.

(2) Intermittent iron alone compared to daily iron alone

Infant outcomes
Low birthweight (less than 2500 g)

No trials reported on this outcome.

Birthweight (g)

No evidence of significant differences was found between these groups of infants in birthweight. Only one study (Pita Martin 1999) with 41 women provided data for this outcome.

No trials reported on the remaining secondary outcomes.

Maternal outcomes
Premature delivery (less than 37 weeks' gestation)

No evidence of significant differences was found between these groups of women.

Hb concentration at term in g/L

No trials reported on this outcome.

Anaemia at term (Hb less than 110 g/L) (not prespecified)

No trials reported on this outcome.

Haemoconcentration at term (defined as Hb greater than 130 g/L)

No trials reported on this outcome.

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

No evidence of significant differences was found between these groups of women.

Iron deficiency at term (based on two or more laboratory indicators)

No trials reported on this outcome.

Iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator)

No trials reported on this outcome.

Side effects (any)

No trials reported on this outcome.

No evidence of significant differences was found between these groups of women for this secondary outcome: moderate anaemia at any time during the second or third trimesters. The effect of the intervention on severe anaemia at any time during second or third trimesters could not be estimated (Analysis 2.33).

No trials reported on the remaining secondary outcomes.

(3) Daily iron-folic acid compared to no intervention/placebo

Infant outcomes
Low birthweight (less than 2500 g)

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.

Birthweight (g)

Data from two trials involving 1365 women (Christian 2003; Taylor 1982) suggest that infants whose mothers received daily iron+folic acid are 57.7 g heavier than infants born from mothers who received no iron+folic acid in pregnancy MD 57.73 (95% CI 7.66 to 107.79) (Analysis 3.3).

Small for gestational age (less than 10th percentile weight at birth for gestational age)

One trial including 1318 women (Christian 2003) suggested that women routinely receiving iron and folic acid supplementation are less likely to give birth to a small for gestational age baby, in comparison to those receiving no iron and folic acid supplementation (RR 0.88; 95% CI 0.80 to 0.97) (Analysis 3.91).

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), perinatal mortality, admission to special care unit, small for gestational age (less than 10th percentile weight for gestational age) or birth length.

No trials reported on the remaining secondary outcomes.

Maternal outcomes
Premature delivery (less than 37 weeks' gestation)

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

Haemoglobin concentration at term in g/L

The data from four trials including 179 women (Barton 1994; Batu 1976; Butler 1968; 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 12.00 g/L; 95% CI 2.93 to 21.07). However, the heterogeneity between the treatment effects is substantial (I2 greater than 50%) and the results have to be interpreted with caution (Analysis 3.7). The effect of iron-folic acid supplementation did not change significantly after including only the one high-quality trial (MD 17.10; 95% CI 8.44 to 25.76 ) (data not shown). The subgroup analysis provided similar trends (Analysis 3.8).

Anaemia at term (Hb less than 110 g/L) (not prespecified)

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) (8.2% versus 35.5%; RR 0.27; 95% CI 0.12 to 0.56) (Analysis 3.9). However, the heterogeneity between the treatment effects is substantial (I² greater than 50%) and the results have to be interpreted with caution. No studies met the prespecified criteria for high quality.

Haemoconcentration 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.

Haemoconcentration 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.

Iron deficiency at term (based on two or more laboratory indicators)

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 (3.6% versus 15%; RR 0.24; 95% CI 0.06 to 0.99) (Analysis 3.14). The effect was not significant in the trial. and arms were presented separately in the subgroup analysis for early or late start of supplementation, although the trends followed the same direction (Analysis 3.15).

Iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator)

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

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 in comparison to none from those receiving no supplementation (RR 44.32; 95% CI 2.77 to 709.09) (Analysis 3.18).

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

The data from four trials involving 523 women (Barton 1994; Butler 1968; Christian 2003; Lee 2005) suggest that women who receive iron+folic acid supplements during pregnancy have lower risk of severe anaemia at any time during second or third trimester, in comparison to those receiving no iron and folic acid (RR 0.11; 95% CI 0.01 to 0.83) (Analysis 3.33).

Haemoglobin concentration within one month postpartum in g/L

One study (Taylor 1982) involving 45 women reported this outcome. The data from this trial suggest that women receiving daily iron+folic acid supplementation achieve a higher concentration of haemoglobin at one month postpartum than women not taking any supplements at all (MD 10.40; 95% CI 4.03 to 16.77) (Analysis 3.40) but no firm conclusions can be made given the scarcity of the data.

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

The data from three trials including 525 women suggest that women who received iron+folic acid supplementation during pregnancy were less likely to present moderate anaemia at postpartum RR 0.05; 95% CI 0.00 to 0.76 (Analysis 3.41). The scarcity of data makes it difficult to draw any conclusion.

Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L)

The data from three trials including 525 women suggest that women who received iron+folic acid supplementation during pregnancy were less likely to present moderate anaemia at postpartum (3.5% versus 12.9%; RR 0.34; 95% CI 0.17 to 0.69) (Analysis 3.42). The scarcity of data makes it difficult to draw any conclusion.

No evidence of significant differences was found in the following secondary outcomes:
very premature delivery, severe anaemia at term, moderate anaemia at term, severe anaemia at any time during second or third trimesters, moderate anaemia at any time during second or third trimesters, infection during pregnancy, puerperal infection, antepartum haemorrhage, postpartum haemorrhage, maternal death, placental abruption, pre-eclampsia, haemoglobin concentration at four to eight weeks postpartum.

No trials reported on the remaining secondary outcomes.

(4) Intermittent iron-folic acid compared to daily iron-folic acid

Infant outcomes
Low birthweight (less than 2500 g)

The data from four trials (Chew 1996a; Chew 1996b; Mukhopadhyay 2004; Winichagoon 2003) involving 730 women suggest that women who take intermittent iron+folic acid supplementation during pregnancy are as likely to have a baby with birthweight below 2500 grams (5.6% versus 5.9%; RR 1.05; 95% CI 0.58 to 1.91) (Analysis 4.1).

Birthweight (g)

The data from four trials (Chew 1996a; Chew 1996b; Mukhopadhyay 2004; Winichagoon 2003) involving 730 women suggest that there is no significant effect in birthweight of newborns born from women who had taken daily supplementation with iron+folic acid during pregnancy or from those being supplemented intermittently (MD -7.10; 95% CI -67.20 to 53.01 g) (Analysis 4.3).

Infant ferritin concentration at six months in ug/L

One study (Winichagoon 2003) including 88 women reported this outcome (Analysis 4.27). The data from this trial suggest that the infants from women receiving intermittent iron+folic acid supplementation achieve a higher concentration of serum ferritin at six months (MD 0.09; 95% CI 0.05 to 0.13 ug/L) (Analysis 4.27) but no firm conclusions can be made given the scarcity of the data.

No evidence of significant differences was found in the following secondary outcomes:
very low birthweight (less than 1500 g) was not estimable.

No trials reported on the remaining secondary outcomes.

Maternal outcomes
Premature delivery (less than 37 weeks' gestation)

No evidence of significant differences was found between these groups of women.

Hb concentration at term in g/L

No evidence of significant differences was found between these groups of women.

Anaemia at term (Hb less than 110 g/L) (not prespecified)

No evidence of significant differences was found between these groups of women.

Haemoconcentration at term (defined as Hb greater than 130 g/L)

No evidence of significant differences was found between these groups of women.

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

Six trials involving 1111 women (Ekstrom 2002; Liu 1996; Mukhopadhyay 2004; Ridwan 1996; Robinson 1998; Winichagoon 2003) suggest that women who routinely receive intermittent iron+folic acid supplementation during pregnancy are less likely to have haemoconcentration at any time during the second or third trimesters than those receiving the daily regimen (7.7% versus 18.8 %; RR 0.43; 95% CI 0.24 to 0.77) (Analysis 4.12). None of the trials met the criteria for high quality. The difference trend was maintained in women who started supplementation late in pregnancy. However, the heterogeneity between the treatment effects is substantial (I² greater than 50%) and the results have to be interpreted with caution.

Iron deficiency at term (based on two or more laboratory indicators)

No trials reported on this outcome.

Iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator)

No evidence of significant differences was found between these groups of women.

Side effects (any)

No evidence of significant differences was found between these groups of women.

There was no evidence of significant difference in the following secondary outcomes:
severe anaemia at term, moderate anaemia at term, severe anaemia at any time during 2nd or 3rd trimesters, moderate anaemia at any time during 2nd or 3rd trimesters, antepartum haemorrhage, anaemia at postpartum, moderate anaemia at postpartum, diarrhoea, constipation, nausea, heartburn, vomiting, placental abruption, premature rupture of membranes.

No trials reported on the remaining secondary outcomes.

Discussion

In 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 micronutrients. 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 interventions given to both groups being compared. The effects of the use of multiple micronutrient supplementation by pregnant women were addressed by another Cochrane Review (Haider 2006).

Unfortunately, most of the studies we reviewed provided very limited information about the clinical outcomes for women or their babies. Instead, most focused primarily on maternal changes in haemoglobin and on some haematological indices after a certain period of supplementation. In addition, few studies provided much outcome data at term or postpartum except for maternal haematology and on the longer term effects of the supplementation.

The interpretation of data from studies with a high level of heterogeneity remains a challenge. Simply pooling the results from multiple studies may not be a good way to understand the effects of a particular intervention if the conditions of the studies involved are too dissimilar. For example, in a U.S study we reviewed (Cogswell 2003), women received either 30 mg of iron daily or a placebo from week 20 to week 28 of gestation, after which both groups were given iron supplements in accordance with Institute of Medicine guidelines. In an Australia study we reviewed (Makrides 2003), however, women received either 20 mg/d of iron or a placebo from week 20 until delivery. Therefore, although both studies were designed to assess the effects of low doses of iron supplements among pregnant women, both the precise iron doses given to women in the treatment groups and the length of time that they were given differed, making it difficult to analyse pooled data from the two studies.

Women who received iron alone or iron+folic acid had higher haemoglobin concentration at term, and had lower risk of having anaemia or iron deficiency at term than women who did not. There were no effects of iron or iron+folic acid in risk of low birth weight of the newborns. However, neonates born from mothers who had received iron+folic acid during pregnancy were heavier than those who had not received these micronutrients. In most studies we reviewed, the iron dosages given to women in treatment groups were high. None of them assessed the effects of low-dose iron supplements in combination with folic acid.

There were no differences in the effects of iron alone or iron+folic acid supplements for the risk of low birthweight or prematurity. Women who received the doses daily or intermittently had similar risk of developing anaemia at term and their Hb concentrations did not differ at term. None of the studies we reviewed compared the effects of intermittent iron supplementation with the effects of no iron supplementation because all the studies involving intermittent supplementation were carried out in developing countries whose legislatures require all pregnant women to be given iron supplements. In addition, few studies compared the effects of intermittent iron alone with the effects of daily iron alone because most developing countries routinely include folic acid in iron supplements for pregnant women.

Adverse effects

Side effects are a clear drawback to most current iron compounds used as supplements, either alone or with folic acid. The results of this review confirm that daily iron or iron+folic acid doses are associated with a higher risk for side effects, as has been recognised for many years. As a result, investigators are searching for highly bioavailable iron compounds that produce fewer side effects and that can be administered at low doses or intermittently (please see below). Most daily iron supplementation regimens for pregnant women involve doses of more than 45 mg/day, the upper tolerable limit suggested by the Institute of Medicine (IOM 2001). There is no stated upper limit for intermittent iron supplementation.

There is a debate on the benefits of routine daily iron supplementation during pregnancy at the currently high levels recommended by various agencies. It appears that small daily doses as recommended by the US Food and Nutrition Board, the U.S. Centers for Disease Control and Prevention and the Institute of Medicine (Anderson 1991; CDC 1998; IOM 1993), as well as weekly dosing, are essentially as efficacious as daily iron at current doses in preventing significant anaemia and iron deficiency anaemia at term, defined as that having health and functional consequences.

Although we found that the overall risk for haemoconcentration in the second and/or third trimester was lower among women who received intermittent iron+folic acid supplementation than those who received daily supplementation, these findings were confounded by the fact that in some studies low iron doses were administered from the start to nonanaemic women and high iron doses were administered to women with undefined anaemia.

This review suggests that haemoconcentration at term as well as in/or during both the second and third trimester of pregnancy is associated with daily iron supplementation, particularly when doses are high and started early in pregnancy. Haemoconcentration secondary to excessive erythropoiesis during pregnancy in association with iron supplementation has been previously suggested by researchers in Newcastle and others (Hytten 1971; Hytten 1985; Lund 1961; Letsky 1991; Mahomed 1989). Low haemoglobin levels but also high haemoglobin levels have been associated with low birthweight (Garn 1981; Huisman 1986; Koller 1979; Murphy 1986; Scanlon 2000; Steer 1995; Zhou 1998). Further associations were reported between preterm birth and low haemoglobin during the first and second trimesters, and low birthweight due to intrauterine growth retardation and high haemoglobin concentrations also during the first two trimesters (Scanlon 2000). Only haemoglobin levels during the third trimester had erratic consequences regarding birthweight. Importantly, the odds ratios for small-for-gestational-age babies were lower when haemoglobin concentrations were low-normal or low (Z scores less than -1 and greater than -2, and less than -2 and greater than -3 for haemoglobin, respectively) during the second and third trimesters than among women whose haemoglobin concentrations were above 130 g/L. These data emphasise the fact that the iron nutritional and haematological status in the first (Scholl 1992) and second trimesters are the ones that have an influence in the outcome of pregnancy, rather than the status at term or at the third trimester.

It would appear that the normal haemodilution reaching a nadir during the second and early third trimester of pregnancy favours the uneventful course of pregnancy and fetal growth and well being, resulting in normal newborns. In many instances antenatal iron supplementation, at doses currently recommended for developing nations (60 mg to 300 mg of iron/day) and commonly prescribed by obstetricians in industrial societies, may annul the normal haemodilution and even produce abnormally elevated haemoglobin levels in pregnancy (Ziaei 2007). In addition to exploring the possible association between high-dose iron supplementation and the risk for haemoconcentration, researchers also need to examine other possible adverse consequences of high iron supplementation doses, including poor placental perfusion and oxidative stress, as suggested by different studies (Casanueva 2003b). The relationship between iron supplementation and abnormally high haemoglobin levels also merits research because numerous studies have shown that haemoconcentration among pregnant women is associated with an increased risk of their child having a low birth weight.

High haemoglobin levels during pregnancy have also been associated with plasma volume depletion, pre-eclampsia, eclampsia, pregnancy complications, and low birthweight (Gallery 1979; Goodlin 1981; Koller 1979; Silver 1998) and low plasma volume appears to precede late pregnancy hypertension and low birthweight (Gallery 1979; Huisman 1986). A recent trial that studied both volumes of plasma and red blood cells simultaneously showed that both plasma and red cell volumes were reduced, plasma volume reduction averaging 16% was present only in pre-eclampsia (hypertension with albuminuria) but not in non-albuminuric gestational hypertension and was associated with a greater risk of small-for-gestational-age babies (Silver 1998). Other studies involving low birthweight babies where maternal plasma volume was measured failed to demonstrate a level of haemoconcentration that resulted in haemoglobin levels greater than or equal to 135 g/L (Gallery 1979; Hytten 1971; Hytten 1985; Koller 1979; Letsky 1991; Poulsen 1990). These results may suggest that, in otherwise normal pregnant women, haemoconcentration defined as haemoglobin greater than 135 g/L cannot be wholly explained by reduction in maternal plasma volume.

Can haemoconcentration of the levels reported in the studies included in this review result in hyperviscosity, poor placental perfusion and placento/fetal hypoxia? This seems possible based on the data presented by some authors (Erslev 2001; LeVeen 1980). On the one hand, blood viscosity increases essentially in a linear form by about 45% (from 3.2 to 4.3 units relative to H2O) between a hematocrit of 30% and 47% (corresponding to haemoglobin concentrations of 89 and 140 g/L), but oxygen transport declines only by about 4% between the optimum at hematocrit of 30% to that of 45% (corresponding to haemoglobin concentration of 134 g/L) (LeVeen 1980).

Authors' conclusions

Implications for practice

Daily or intermittent supplementation with iron or with iron+folic acid by pregnant women clearly results in a substantial reduction in the prevalence of maternal anaemia at term and increased maternal Hb concentrations at term. However, the current sparse data fail to demonstrate that supplementation with iron alone or in combination with folic acid among women without anaemia or with mild or moderate anaemia by current cut-off criteria is significantly associated with any other substantial beneficial or adverse effects on maternal health, fetal health, or pregnancy outcomes. Available data also indicate that weekly supplementation is as effective as daily supplementation in preventing low haemoglobin levels associated with negative outcome consequences and that the use of either daily or weekly iron supplements (with or without folic acid) may be beneficial where iron deficiency and anaemia are prevalent pre-gestationally or in early pregnancy. Starting supplementation early in pregnancy must be stressed, together with interventions to improve pregnancy iron and folate status prior to conception. The evidence suggests that iron supplementation schemes providing more iron than women need may not be desirable, and doses and formulations that can reduce side effects should be encouraged. However, current preventive antenatal iron supplementation doses recommended for populations in developing countries, based on therapeutic doses, appear to be excessive even where moderate/mild anaemia is found. Consequently, current recommended iron and folic acid supplementation schemes during pregnancy should be reviewed to adjust iron doses to levels that are effective and safe for the mothers and newborns and that can assure compliance. Current preventive antenatal iron supplementation doses recommended for populations in developing countries appear to be excessive. Starting supplementation early in pregnancy must be stressed, together with interventions to improve pregnancy iron and folate status prior to conception. The evidence suggests that iron supplementation schemes providing more iron than women need may not be desirable, and doses and formulations that can reduce side effects should be encouraged. Intermittent supplementation with iron could be considered in anaemia prevention strategies not only prior to but also during pregnancy.

Implications for research

On the basis of the results of this review, we recommend that researchers investigating the use of iron or iron+folate supplements by pregnant women attempt to undertake the following.

  1. Establish a solid basis for defining ranges of iron and folate nutrition and haematological conditions among pregnant woman that are associated with safe and desirable pregnancy outcomes of clinical relevance.

  2. Identify the mechanisms involved in haemoconcentration during various gestational ages and its functional consequences.

  3. Establish effective and safe doses of supplemental iron with folic acid and possibly other nutrients for pregnant women using either daily or intermittent preventive supplementation; established doses may need to vary with the early nutritional and haematological status of the mothers and with the particular setting in which supplements are used (e.g. recommended doses may need to be initially higher where iron deficiency and anaemia early in pregnancy are highly prevalent.

  4. Find effective, safe, and affordable iron compounds with fewer side effects than current iron supplements for use in public health pre-pregnancy and prenatal preventive supplementation programs..

  5. Conduct large multicenter studies to define effective and safe prenatal supplementation strategies and modalities according to the health and nutritional conditions of women of fertile age, with emphasis on maternal health and pregnancy outcomes. This research should explore supplementation strategies involving different iron doses, different supplementation starting times relative to conception, and both daily and less frequent administration of supplements. These studies could also be used to assess the influence of altitude on pregnant women and newborns' health under different iron or iron+folate supplementation regimens.

  6. Ideally, given the benefits of women entering pregnancy with iron reserves, a large prospective multicenter study exploring the same independent variables and pregnancy outcomes as in point (5) should be undertaken, including women supplemented in preventive schemes with iron, folic acid and if necessary, with other micronutrients prior to and during pregnancy.

Acknowledgements

We would like to thank the trial authors who have contributed additional data for this review; and Richard Riley 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.

As part of the pre-publication editorial process, this update has been commented on by three peers (an editor, and two referees who are external to the editorial team) and the Group's Statistical Adviser.

Data and analyses

Download statistical data

Comparison 1. Daily iron alone versus no intervention/placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Low birthweight (less than 2500 g) (ALL)96275Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.03]
2 Low birthweight (less than 2500 g) (BY SUBGROUPS)9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation75771Risk Ratio (M-H, Random, 95% CI)0.81 [0.61, 1.08]
2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation2504Risk Ratio (M-H, Random, 95% CI)0.55 [0.22, 1.38]
2.5 Non-anaemic at start of supplementation64452Risk Ratio (M-H, Random, 95% CI)0.76 [0.46, 1.25]
2.6 Unspecified/mixed anaemic status at start of supplementation31823Risk Ratio (M-H, Random, 95% CI)0.82 [0.71, 0.94]
2.7 Daily lower dose (60 mg elemental iron or less)73247Risk Ratio (M-H, Random, 95% CI)0.79 [0.53, 1.18]
2.8 Daily higher dose (more than 60 mg elemental iron)23028Risk Ratio (M-H, Random, 95% CI)0.75 [0.45, 1.26]
3 Birthweight (g) (ALL)105956Mean Difference (IV, Random, 95% CI)36.05 [-4.84, 76.95]
4 Birthweight (g) (BY SUBGROUPS)11 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation95822Mean Difference (IV, Random, 95% CI)30.89 [-13.87, 75.65]
4.2 Late gestational age (20 weeks or more of gestation) at start of supplementation2251Mean Difference (IV, Random, 95% CI)39.72 [-67.69, 147.12]
4.5 Non-anaemic at start of supplementation84496Mean Difference (IV, Random, 95% CI)29.32 [-27.08, 85.71]
4.6 Unspecified/mixed anaemic status at start of supplementation31577Mean Difference (IV, Random, 95% CI)52.33 [10.16, 94.51]
4.7 Daily low dose (60 mg elemental iron or less)62804Mean Difference (IV, Random, 95% CI)37.22 [-17.82, 92.27]
4.8 Daily higher dose (more than 60 mg elemental iron)63382Mean Difference (IV, Random, 95% CI)17.99 [-41.28, 77.26]
5 Premature delivery (less than 37 weeks of gestation) (ALL)85730Risk Ratio (M-H, Random, 95% CI)0.85 [0.67, 1.09]
6 Premature delivery (less 37 weeks of gestation) (BY SUBGROUPS)8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation62989Risk Ratio (M-H, Random, 95% CI)0.89 [0.66, 1.20]
6.2 Late gestational age (20 weeks or more of gestation) at start of supplementation147Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.48]
6.5 Non-anaemic at start of supplementation61775Risk Ratio (M-H, Random, 95% CI)0.78 [0.54, 1.12]
6.6 Unspecified/mixed anaemic status at start of supplementation11261Risk Ratio (M-H, Random, 95% CI)1.04 [0.85, 1.28]
6.7 Daily lower dose (60 mg elemental iron or less)63023Risk Ratio (M-H, Random, 95% CI)0.89 [0.68, 1.18]
6.8 Daily higher dose (more than 60 mg elemental iron)22707Risk Ratio (M-H, Random, 95% CI)0.71 [0.48, 1.06]
7 Maternal Hb concentration at term (g/L) (ALL)172463Mean Difference (IV, Random, 95% CI)8.83 [6.55, 11.11]
8 Maternal Hb concentration at term (g/L) (BY SUBGROUPS)17 Mean Difference (IV, Random, 95% CI)Subtotals only
8.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation132306Mean Difference (IV, Random, 95% CI)8.14 [5.61, 10.67]
8.2 Late gestational age (20 weeks or more of gestation) at start of supplementation3130Mean Difference (IV, Random, 95% CI)10.24 [2.45, 18.04]
8.3 Unspecified/mixed gestational age at start of supplementation127Mean Difference (IV, Random, 95% CI)14.0 [8.07, 19.93]
8.5 Non-anaemic at start of supplementation112002Mean Difference (IV, Random, 95% CI)7.77 [4.86, 10.69]
8.6 Unspecified/mixed anaemic status at start of supplementation6461Mean Difference (IV, Random, 95% CI)11.03 [7.51, 14.56]
8.7 Daily low dose (60 mg elemental iron or less)81956Mean Difference (IV, Random, 95% CI)7.16 [4.14, 10.17]
8.8 Daily higher dose (more than 60 mg elemental iron)9507Mean Difference (IV, Random, 95% CI)10.94 [7.06, 14.82]
9 Anaemia at term (Hb less than 110 g/L) (ALL)144390Risk Ratio (M-H, Random, 95% CI)0.27 [0.17, 0.42]
10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)104643Risk Ratio (M-H, Random, 95% CI)2.62 [1.21, 5.67]
11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)10 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation54173Risk Ratio (M-H, Random, 95% CI)1.99 [0.72, 5.45]
11.2 Late gestational age (20 weeks or more of gestation) at start of supplementation3198Risk Ratio (M-H, Random, 95% CI)3.94 [0.31, 50.47]
11.3 Unspecified/mixed gestational age at start of supplementation2272Risk Ratio (M-H, Random, 95% CI)4.67 [2.53, 8.60]
11.5 Non-anaemic at start of supplementation54011Risk Ratio (M-H, Random, 95% CI)1.73 [0.64, 4.66]
11.6 Unspecified/mixed anaemic status at start of supplementation5632Risk Ratio (M-H, Random, 95% CI)4.03 [1.39, 11.72]
11.7 Daily low dose (60 mg elemental iron or less)41317Risk Ratio (M-H, Random, 95% CI)1.44 [0.54, 3.86]
11.8 Daily higher dose (more than 60 mg elemental iron)63326Risk Ratio (M-H, Random, 95% CI)3.55 [1.89, 6.66]
12 Haemoconcentration during second or third trimester (ALL)104841Risk Ratio (M-H, Random, 95% CI)2.27 [1.40, 3.70]
13 Haemoconcentration during second or third trimester (BY SUBGROUPS)10 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation74522Risk Ratio (M-H, Random, 95% CI)2.62 [1.49, 4.60]
13.2 Late gestational age (20 weeks or more of gestation) at start of supplementation147Risk Ratio (M-H, Random, 95% CI)1.44 [0.72, 2.86]
13.3 Unspecified/mixed gestational age at start of supplementation2272Risk Ratio (M-H, Random, 95% CI)1.94 [0.30, 12.29]
13.5 Non-anaemic at start of supplementation64088Risk Ratio (M-H, Random, 95% CI)2.10 [1.13, 3.90]
13.6 Unspecified/mixed anaemic status at start of supplementation4753Risk Ratio (M-H, Random, 95% CI)2.67 [0.99, 7.17]
13.7 Daily low dose (60 mg elemental iron or less)51655Risk Ratio (M-H, Random, 95% CI)2.35 [1.21, 4.57]
13.8 Daily higher dose (more than 60 mg elemental iron)53186Risk Ratio (M-H, Random, 95% CI)2.14 [1.05, 4.37]
14 Iron deficiency at term (as defined by two or more indicators) (ALL)61108Risk Ratio (M-H, Random, 95% CI)0.44 [0.27, 0.70]
15 Iron deficiency at term (as defined by two or more indicators) (BY SUBGROUPS)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation4867Risk Ratio (M-H, Random, 95% CI)0.56 [0.35, 0.90]
15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation2241Risk Ratio (M-H, Random, 95% CI)0.28 [0.17, 0.44]
15.5 Non-anaemic at start of supplementation4944Risk Ratio (M-H, Random, 95% CI)0.60 [0.41, 0.90]
15.6 Unspecified/mixed anaemic status at start of supplementation2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]
15.7 Daily low dose (60 mg elemental iron or less)4944Risk Ratio (M-H, Random, 95% CI)0.60 [0.41, 0.90]
15.8 Daily higher dose (more than 60 mg elemental iron)2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]
16 Iron deficiency anaemia at term (ALL)61667Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]
17 Iron deficiency anaemia at term (BY SUBGROUPS)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation51622Risk Ratio (M-H, Random, 95% CI)0.37 [0.18, 0.76]
17.2 Late gestational age (20 weeks or more of gestation) at start of supplementation145Risk Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.13]
17.5 Non-anaemic at start of supplementation51547Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]
17.6 Unspecified/mixed anaemic status at start of supplementation1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]
17.7 Daily low dose (60 mg elemental iron or less)51547Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]
17.8 Daily higher dose (more than 60 mg elemental iron)1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]
18 Side-effects (Any) (ALL)83667Risk Ratio (M-H, Random, 95% CI)3.92 [1.21, 12.64]
19 Side-effects (Any) (BY SUBGROUPS)8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
19.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation43034Risk Ratio (M-H, Random, 95% CI)3.69 [0.42, 32.71]
19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation3428Risk Ratio (M-H, Random, 95% CI)1.75 [0.99, 3.08]
19.3 Unspecified/mixed gestational age at start of supplementation1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]
19.5 Non-anaemic at start of supplementation42897Risk Ratio (M-H, Random, 95% CI)3.27 [0.39, 27.31]
19.6 Unspecified/mixed anaemic status at start of supplementation4770Risk Ratio (M-H, Random, 95% CI)3.94 [1.09, 14.28]
19.7 Daily low dose (60 mg elemental iron or less)4566Risk Ratio (M-H, Random, 95% CI)1.36 [0.99, 1.87]
19.8 Daily higher dose (more than 60 mg elemental iron)53148Risk Ratio (M-H, Random, 95% CI)12.12 [1.76, 83.43]
20 Very low birthweight (less than 1500 g) (ALL)52687Risk Ratio (M-H, Random, 95% CI)0.73 [0.31, 1.74]
21 Perinatal death (ALL)35036Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.29]
24 Infant Hb concentration at 3 months (g/L) (ALL)1197Mean Difference (IV, Random, 95% CI)Not estimable
25 Infant serum ferritin concentration at 3 months (ug/L) (ALL)1197Mean Difference (IV, Random, 95% CI)19.0 [2.75, 35.25]
26 Infant Hb concentration at 6 months (g/L) (ALL)2533Mean Difference (IV, Random, 95% CI)-1.25 [-8.10, 5.59]
27 Infant serum ferritin concentration at 6 months (ug/L) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]
29 Admission to special care unit (ALL)22805Risk Ratio (M-H, Random, 95% CI)0.95 [0.73, 1.23]
30 Very premature delivery (less than 34 weeks' gestation) (ALL)41417Risk Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.24]
31 Severe anaemia at term (Hb less than 70 g/L) (ALL)81751Risk Ratio (M-H, Random, 95% CI)4.83 [0.23, 99.88]
32 Moderate anaemia at term (Hb more than 70 g/L and less than 90 g/L) (ALL)91868Risk Ratio (M-H, Random, 95% CI)0.94 [0.55, 1.62]
33 Severe anaemia at any time during second and third trimester (ALL)92089Risk Ratio (M-H, Random, 95% CI)0.48 [0.01, 34.52]
34 Moderate anaemia at any time during second or third trimester (ALL)102266Risk Ratio (M-H, Random, 95% CI)0.42 [0.19, 0.92]
35 Infection during pregnancy (including urinary tract infections) (ALL)23421Risk Ratio (M-H, Random, 95% CI)1.16 [0.83, 1.63]
36 Puerperal infection (ALL)22169Risk Ratio (M-H, Random, 95% CI)0.72 [0.25, 2.10]
37 Antepartum haemorraghe (ALL)21157Risk Ratio (M-H, Random, 95% CI)1.48 [0.51, 4.31]
38 Postpartum haemorraghe (ALL)51554Risk Ratio (M-H, Random, 95% CI)0.95 [0.51, 1.78]
39 Transfusion provided (ALL)33453Risk Ratio (M-H, Random, 95% CI)0.61 [0.38, 0.96]
40 Haemoglobin concentration within one month postpartum (ALL)6904Mean Difference (IV, Random, 95% CI)7.08 [4.70, 9.47]
41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)71094Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 1.05]
42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)4831Risk Ratio (M-H, Random, 95% CI)0.55 [0.12, 2.51]
43 Diarrhoea (ALL)31088Risk Ratio (M-H, Random, 95% CI)0.55 [0.32, 0.93]
44 Constipation (ALL)41495Risk Ratio (M-H, Random, 95% CI)0.95 [0.62, 1.43]
45 Nausea (ALL)41377Risk Ratio (M-H, Random, 95% CI)1.21 [0.72, 2.03]
46 Heartburn (ALL)31323Risk Ratio (M-H, Random, 95% CI)1.19 [0.86, 1.66]
47 Vomiting (ALL)41392Risk Ratio (M-H, Random, 95% CI)0.88 [0.59, 1.30]
48 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)Not estimable
49 Maternal wellbeing/satisfaction (ALL)22604Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.09]
50 Placental abruption (ALL)22169Risk Ratio (M-H, Random, 95% CI)1.14 [0.32, 4.06]
51 Premature rupture of membranes (ALL)1727Risk Ratio (M-H, Random, 95% CI)0.99 [0.74, 1.34]
52 Pre-eclampsia (ALL)2774Risk Ratio (M-H, Random, 95% CI)2.58 [0.81, 8.22]
91 Small for gestational age (less than 10th percentile weight at birth for gestational age) (not pre-specified)42511Risk Ratio (M-H, Random, 95% CI)0.87 [0.58, 1.30]
93 Cesarean delivery (not pre-specified)74283Risk Ratio (M-H, Random, 95% CI)0.94 [0.78, 1.13]
94 Birth length in cm (not pre-specified)52140Mean Difference (IV, Random, 95% CI)0.38 [0.10, 0.65]
95 Forceps or vacuum delivery (not pre-specified)2477Risk Ratio (M-H, Random, 95% CI)1.50 [0.94, 2.40]
96 Breastfeeding at least 4 months (not pre-specified)148Risk Ratio (M-H, Random, 95% CI)1.00 [0.89, 1.13]
97 Haemoglobin concentration at 4-8 weeks' postpartum (g/L) (not pre-specified)101188Mean Difference (IV, Random, 95% CI)5.13 [0.24, 10.02]
98 Apgar score < 7 at 5 minutes (not pre-specified)2475Risk Ratio (M-H, Random, 95% CI)0.74 [0.17, 3.28]
99 Apgar Score at 5 min (not pre-specified)2228Mean Difference (IV, Random, 95% CI)0.27 [-0.07, 0.62]
Analysis 1.1.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 1 Low birthweight (less than 2500 g) (ALL).

Analysis 1.2.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 2 Low birthweight (less than 2500 g) (BY SUBGROUPS).

Analysis 1.3.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 3 Birthweight (g) (ALL).

Analysis 1.4.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 4 Birthweight (g) (BY SUBGROUPS).

Analysis 1.5.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 5 Premature delivery (less than 37 weeks of gestation) (ALL).

Analysis 1.6.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 6 Premature delivery (less 37 weeks of gestation) (BY SUBGROUPS).

Analysis 1.7.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 7 Maternal Hb concentration at term (g/L) (ALL).

Analysis 1.8.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 8 Maternal Hb concentration at term (g/L) (BY SUBGROUPS).

Analysis 1.9.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 9 Anaemia at term (Hb less than 110 g/L) (ALL).

Analysis 1.10.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL).

Analysis 1.11.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS).

Analysis 1.12.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 12 Haemoconcentration during second or third trimester (ALL).

Analysis 1.13.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 13 Haemoconcentration during second or third trimester (BY SUBGROUPS).

Analysis 1.14.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 14 Iron deficiency at term (as defined by two or more indicators) (ALL).

Analysis 1.15.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 15 Iron deficiency at term (as defined by two or more indicators) (BY SUBGROUPS).

Analysis 1.16.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 16 Iron deficiency anaemia at term (ALL).

Analysis 1.17.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 17 Iron deficiency anaemia at term (BY SUBGROUPS).

Analysis 1.18.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 18 Side-effects (Any) (ALL).

Analysis 1.19.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 19 Side-effects (Any) (BY SUBGROUPS).

Analysis 1.20.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 20 Very low birthweight (less than 1500 g) (ALL).

Analysis 1.21.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 21 Perinatal death (ALL).

Analysis 1.24.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 24 Infant Hb concentration at 3 months (g/L) (ALL).

Analysis 1.25.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 25 Infant serum ferritin concentration at 3 months (ug/L) (ALL).

Analysis 1.26.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 26 Infant Hb concentration at 6 months (g/L) (ALL).

Analysis 1.27.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 27 Infant serum ferritin concentration at 6 months (ug/L) (ALL).

Analysis 1.29.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 29 Admission to special care unit (ALL).

Analysis 1.30.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 30 Very premature delivery (less than 34 weeks' gestation) (ALL).

Analysis 1.31.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 31 Severe anaemia at term (Hb less than 70 g/L) (ALL).

Analysis 1.32.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 32 Moderate anaemia at term (Hb more than 70 g/L and less than 90 g/L) (ALL).

Analysis 1.33.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 33 Severe anaemia at any time during second and third trimester (ALL).

Analysis 1.34.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 34 Moderate anaemia at any time during second or third trimester (ALL).

Analysis 1.35.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 35 Infection during pregnancy (including urinary tract infections) (ALL).

Analysis 1.36.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 36 Puerperal infection (ALL).

Analysis 1.37.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 37 Antepartum haemorraghe (ALL).

Analysis 1.38.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 38 Postpartum haemorraghe (ALL).

Analysis 1.39.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 39 Transfusion provided (ALL).

Analysis 1.40.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 40 Haemoglobin concentration within one month postpartum (ALL).

Analysis 1.41.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL).

Analysis 1.42.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL).

Analysis 1.43.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 43 Diarrhoea (ALL).

Analysis 1.44.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 44 Constipation (ALL).

Analysis 1.45.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 45 Nausea (ALL).

Analysis 1.46.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 46 Heartburn (ALL).

Analysis 1.47.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 47 Vomiting (ALL).

Analysis 1.48.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 48 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).

Analysis 1.49.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 49 Maternal wellbeing/satisfaction (ALL).

Analysis 1.50.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 50 Placental abruption (ALL).

Analysis 1.51.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 51 Premature rupture of membranes (ALL).

Analysis 1.52.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 52 Pre-eclampsia (ALL).

Analysis 1.91.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 91 Small for gestational age (less than 10th percentile weight at birth for gestational age) (not pre-specified).

Analysis 1.93.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 93 Cesarean delivery (not pre-specified).

Analysis 1.94.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 94 Birth length in cm (not pre-specified).

Analysis 1.95.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 95 Forceps or vacuum delivery (not pre-specified).

Analysis 1.96.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 96 Breastfeeding at least 4 months (not pre-specified).

Analysis 1.97.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 97 Haemoglobin concentration at 4-8 weeks' postpartum (g/L) (not pre-specified).

Analysis 1.98.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 98 Apgar score < 7 at 5 minutes (not pre-specified).

Analysis 1.99.

Comparison 1 Daily iron alone versus no intervention/placebo, Outcome 99 Apgar Score at 5 min (not pre-specified).

Comparison 2. Intermittent iron alone versus daily iron alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3 Birthweight (ALL)141Mean Difference (IV, Random, 95% CI)-68.0 [-398.33, 262.33]
5 Premature delivery (less than 37 weeks of gestation) (ALL)141Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 8.96]
12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL)264Risk Ratio (M-H, Random, 95% CI)0.54 [0.18, 1.58]
33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)264Risk Ratio (M-H, Random, 95% CI)Not estimable
34 Moderate anaemia at any time during second or third trimester (ALL)264Risk Ratio (M-H, Random, 95% CI)2.42 [0.16, 35.56]
Analysis 2.3.

Comparison 2 Intermittent iron alone versus daily iron alone, Outcome 3 Birthweight (ALL).

Analysis 2.5.

Comparison 2 Intermittent iron alone versus daily iron alone, Outcome 5 Premature delivery (less than 37 weeks of gestation) (ALL).

Analysis 2.12.

Comparison 2 Intermittent iron alone versus daily iron alone, Outcome 12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL).

Analysis 2.33.

Comparison 2 Intermittent iron alone versus daily iron alone, Outcome 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL).

Analysis 2.34.

Comparison 2 Intermittent iron alone versus daily iron alone, Outcome 34 Moderate anaemia at any time during second or third trimester (ALL).

Comparison 3. Daily iron-folic acid versus no intervention/placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Low birthweight (less than 2500 g) (ALL)21368Risk Ratio (M-H, Random, 95% CI)1.06 [0.28, 4.02]
2 Low birthweight (less than 2500 g) (BY SUBGROUPS)2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation21368Risk Ratio (M-H, Random, 95% CI)1.06 [0.28, 4.02]
2.6 Unspecified/mixed anaemic status at start of supplementation21368Risk Ratio (M-H, Random, 95% CI)1.06 [0.28, 4.02]
2.7 Daily low dose (60 mg elemental iron or less)11320Risk Ratio (M-H, Random, 95% CI)0.79 [0.69, 0.91]
2.8 Daily higher dose (more than 60 mg elemental iron)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]
3 Birthweight (ALL)21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]
4 Birthweight (BY SUBGROUPS)2 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]
4.6 Unspecified/mixed anaemic status at start of supplementation21365Mean Difference (IV, Random, 95% CI)57.73 [7.66, 107.79]
4.7 Daily low dose (60 mg elemental iron or less)11320Mean Difference (IV, Random, 95% CI)65.0 [17.46, 112.54]
4.8 Daily higher dose (more than 60 mg elemental iron)145Mean Difference (IV, Random, 95% CI)-32.0 [-213.62, 149.62]
5 Premature delivery (less than 37 weeks of gestation) (ALL)31497Risk Ratio (M-H, Random, 95% CI)1.55 [0.40, 6.00]
6 Premature delivery (less than 37 weeks of gestation) (BY SUB GROUPS)2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation21362Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]
6.2 Late gestational age (20 weeks or more of gestation) at start of supplementation00Risk Ratio (M-H, Random, 95% CI)Not estimable
6.6 Unspecified/mixed anaemic status at start of supplementation21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]
6.7 Daily low dose (60 mg elemental iron or less)21449Risk Ratio (M-H, Random, 95% CI)1.13 [0.92, 1.39]
7 Haemoglobin concentration at term (ALL)4179Mean Difference (IV, Random, 95% CI)12.00 [2.93, 21.07]
8 Haemoglobin concentration at term (BY SUBGROUPS)4 Mean Difference (IV, Random, 95% CI)Subtotals only
8.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation293Mean Difference (IV, Random, 95% CI)15.65 [11.84, 19.46]
8.2 Late gestational age (20 weeks or more of gestation) at start of supplementation286Mean Difference (IV, Random, 95% CI)7.92 [-11.68, 27.52]
8.5 Non-anaemic at start of supplementation148Mean Difference (IV, Random, 95% CI)17.10 [8.44, 25.76]
8.6 Unspecified/mixed anaemic status at start of supplementation3131Mean Difference (IV, Random, 95% CI)10.47 [-1.07, 22.00]
8.7 Daily low dose (60 mg elemental iron or less)00Mean Difference (IV, Random, 95% CI)Not estimable
8.8 Daily higher dose (more than 60 mg elemental iron)4179Mean Difference (IV, Random, 95% CI)12.00 [2.93, 21.07]
9 Anaemia at term (Hb less than 110 g/L) (ALL)3346Risk Ratio (M-H, Random, 95% CI)0.27 [0.12, 0.56]
10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)3353Risk Ratio (M-H, Random, 95% CI)1.74 [0.34, 8.94]
11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation175Risk Ratio (M-H, Random, 95% CI)3.37 [0.19, 60.03]
11.2 Late gestational age (20 weeks or more of gestation) at start of supplementation3298Risk Ratio (M-H, Random, 95% CI)1.97 [0.32, 12.08]
11.6 Unspecified/mixed anaemic status at start of supplementation1131Risk Ratio (M-H, Random, 95% CI)4.31 [0.26, 70.41]
11.7 Daily low dose (60 mg elemental iron or less)1131Risk Ratio (M-H, Random, 95% CI)4.31 [0.26, 70.41]
11.8 Daily higher dose (more than 60 mg elemental iron)2222Risk Ratio (M-H, Random, 95% CI)1.28 [0.24, 6.78]
12 Haemoconcentration during second or third trimester (ALL)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]
13 Haemoconcentration during second or third trimester (BY SUBGROUPS)2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation2390Risk Ratio (M-H, Random, 95% CI)1.45 [0.33, 6.32]
13.2 Late gestational age (20 weeks or more of gestation) at start of supplementation176Risk Ratio (M-H, Random, 95% CI)1.34 [0.50, 3.56]
13.3 Unspecified/mixed gestational age at start of supplementation00Risk Ratio (M-H, Random, 95% CI)Not estimable
13.5 Non-anaemic at start of supplementation00Risk Ratio (M-H, Random, 95% CI)Not estimable
13.6 Unspecified/mixed anaemic status at start of supplementation2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]
13.7 Daily low dose (60 mg elemental iron or less)2446Risk Ratio (M-H, Random, 95% CI)1.78 [0.63, 5.04]
13.8 Daily higher dose (more than 60 mg elemental iron)00Risk Ratio (M-H, Random, 95% CI)Not estimable
14 Iron deficiency at term (as defined by two or more indicators) (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]
15 Iron deficiency at term (as defined by two or more indicators) (BY SUBGROUPS)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation175Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 1.10]
15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation176Risk Ratio (M-H, Random, 95% CI)0.36 [0.08, 1.63]
15.5 Non-anaemic at start of supplementation00Risk Ratio (M-H, Random, 95% CI)Not estimable
15.6 Unspecified/mixed anaemic status at start of supplementation1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]
15.7 Daily low dose (60 mg elemental iron or less)1131Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.99]
15.8 Daily higher dose (more than 60 mg elemental iron)00Risk Ratio (M-H, Random, 95% CI)Not estimable
16 Iron deficiency anaemia at term (ALL)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]
17 Iron deficiency anaemia at term (BY SUBGROUPS)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation175Risk Ratio (M-H, Random, 95% CI)0.36 [0.12, 1.12]
17.2 Late gestational age (20 weeks or more of gestation) at start of supplementation176Risk Ratio (M-H, Random, 95% CI)0.5 [0.18, 1.40]
17.5 Non-anaemic at start of supplementation00Risk Ratio (M-H, Random, 95% CI)Not estimable
17.6 Unspecified/mixed anaemic status at start of supplementation1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]
17.7 Daily low dose (60 mg elemental iron or less)1131Risk Ratio (M-H, Random, 95% CI)0.43 [0.17, 1.09]
17.8 Daily higher dose (more than 60 mg elemental iron)00Risk Ratio (M-H, Random, 95% CI)Not estimable
18 Side effects (Any) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]
20 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]
21 Perinatal death (ALL)31862Risk Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.17]
29 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)Not estimable
30 Very premature delivery (less than 34 weeks' gestation) (ALL)292Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]
31 Severe anaemia at term (Hb less than 70 g/L) (ALL)3180Risk Ratio (M-H, Random, 95% CI)Not estimable
32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL)3180Risk Ratio (M-H, Random, 95% CI)Not estimable
33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)4523Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.83]
34 Moderate anaemia at any time during second or third trimester (ALL)4523Risk Ratio (M-H, Random, 95% CI)0.34 [0.11, 1.04]
35 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]
36 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]
37 Antepartum haemorrhage (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]
38 Postpartum haemorrhage (ALL)168Risk Ratio (M-H, Random, 95% CI)0.12 [0.00, 2.71]
40 Haemoglobin concentration within one month postpartum (ALL)145Mean Difference (IV, Random, 95% CI)10.40 [4.03, 16.77]
41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)3525Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.76]
42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)3525Risk Ratio (M-H, Random, 95% CI)0.34 [0.17, 0.69]
48 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)1131Risk Ratio (M-H, Random, 95% CI)Not estimable
50 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]
52 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.00 [0.13, 70.16]
91 Small for gestational age (less than 10th percentile weight at birth for gestational age) (not pre-specified)11318Risk Ratio (M-H, Random, 95% CI)0.88 [0.80, 0.97]
92 Oedema during pregnancy (not pre-specified)167Risk Ratio (M-H, Random, 95% CI)2.82 [0.99, 8.09]
93 Caesarean delivery (not pre-specified)197Risk Ratio (M-H, Random, 95% CI)0.83 [0.22, 3.13]
94 Birth length in cm (not pre-specified)11320Mean Difference (IV, Random, 95% CI)0.20 [-0.06, 0.46]
97 Haemoglobin concentration at 4-8 weeks postpartum (not prespecified)3526Mean Difference (IV, Random, 95% CI)4.88 [-0.85, 10.62]
Analysis 3.1.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 1 Low birthweight (less than 2500 g) (ALL).

Analysis 3.2.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 2 Low birthweight (less than 2500 g) (BY SUBGROUPS).

Analysis 3.3.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 3 Birthweight (ALL).

Analysis 3.4.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 4 Birthweight (BY SUBGROUPS).

Analysis 3.5.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 5 Premature delivery (less than 37 weeks of gestation) (ALL).

Analysis 3.6.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 6 Premature delivery (less than 37 weeks of gestation) (BY SUB GROUPS).

Analysis 3.7.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 7 Haemoglobin concentration at term (ALL).

Analysis 3.8.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 8 Haemoglobin concentration at term (BY SUBGROUPS).

Analysis 3.9.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 9 Anaemia at term (Hb less than 110 g/L) (ALL).

Analysis 3.10.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL).

Analysis 3.11.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS).

Analysis 3.12.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 12 Haemoconcentration during second or third trimester (ALL).

Analysis 3.13.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 13 Haemoconcentration during second or third trimester (BY SUBGROUPS).

Analysis 3.14.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 14 Iron deficiency at term (as defined by two or more indicators) (ALL).

Analysis 3.15.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 15 Iron deficiency at term (as defined by two or more indicators) (BY SUBGROUPS).

Analysis 3.16.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 16 Iron deficiency anaemia at term (ALL).

Analysis 3.17.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 17 Iron deficiency anaemia at term (BY SUBGROUPS).

Analysis 3.18.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 18 Side effects (Any) (ALL).

Analysis 3.20.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 20 Very low birthweight (less than 1500 g) (ALL).

Analysis 3.21.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 21 Perinatal death (ALL).

Analysis 3.29.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 29 Admission to special care unit (ALL).

Analysis 3.30.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 30 Very premature delivery (less than 34 weeks' gestation) (ALL).

Analysis 3.31.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 31 Severe anaemia at term (Hb less than 70 g/L) (ALL).

Analysis 3.32.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL).

Analysis 3.33.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL).

Analysis 3.34.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 34 Moderate anaemia at any time during second or third trimester (ALL).

Analysis 3.35.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 35 Infection during pregnancy (including urinary tract infections) (ALL).

Analysis 3.36.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 36 Puerperal infection (ALL).

Analysis 3.37.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 37 Antepartum haemorrhage (ALL).

Analysis 3.38.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 38 Postpartum haemorrhage (ALL).

Analysis 3.40.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 40 Haemoglobin concentration within one month postpartum (ALL).

Analysis 3.41.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL).

Analysis 3.42.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL).

Analysis 3.48.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 48 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL).

Analysis 3.50.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 50 Placental abruption (ALL).

Analysis 3.52.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 52 Pre-eclampsia (ALL).

Analysis 3.91.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 91 Small for gestational age (less than 10th percentile weight at birth for gestational age) (not pre-specified).

Analysis 3.92.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 92 Oedema during pregnancy (not pre-specified).

Analysis 3.93.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 93 Caesarean delivery (not pre-specified).

Analysis 3.94.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 94 Birth length in cm (not pre-specified).

Analysis 3.97.

Comparison 3 Daily iron-folic acid versus no intervention/placebo, Outcome 97 Haemoglobin concentration at 4-8 weeks postpartum (not prespecified).

Comparison 4. Intermittent iron-folic acid versus daily iron-folic acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Low birthweight (less than 2500 g) (ALL)4730Risk Ratio (M-H, Random, 95% CI)1.05 [0.58, 1.91]
2 Low birthweight (less than 2500 g) (BY SUBGROUPS)4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation2455Risk Ratio (M-H, Random, 95% CI)1.29 [0.55, 3.01]
2.3 Unspecified/mixed gestational age at start of supplementation2275Risk Ratio (M-H, Random, 95% CI)0.85 [0.36, 1.99]
2.5 Non-anaemic at start of supplementation180Risk Ratio (M-H, Random, 95% CI)1.25 [0.36, 4.32]
2.7 Daily low dose (60 mg elemental iron or less)3650Risk Ratio (M-H, Random, 95% CI)0.99 [0.50, 1.97]
2.8 Daily higher dose (more than 60 mg elemental iron)180Risk Ratio (M-H, Random, 95% CI)1.25 [0.36, 4.32]
3 Birthweight (ALL)4730Mean Difference (IV, Random, 95% CI)-7.10 [-67.20, 53.01]
4 Birthweight (BY SUBGROUPS)4 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation2455Mean Difference (IV, Random, 95% CI)1.19 [-70.50, 72.87]
4.3 Unspecified/mixed gestational age at start of supplementation2275Mean Difference (IV, Random, 95% CI)-26.71 [-137.00, 83.58]
4.5 Non-anaemic at start of supplementation180Mean Difference (IV, Random, 95% CI)Not estimable
4.7 Daily low dose (60 mg elemental iron or less)3650Mean Difference (IV, Random, 95% CI)-8.36 [-73.56, 56.85]
4.8 Daily higher dose (more than 60 mg elemental iron)180Mean Difference (IV, Random, 95% CI)Not estimable
5 Premature delivery (less than 37 weeks of gestation) (ALL)180Risk Ratio (M-H, Random, 95% CI)2.0 [0.39, 10.31]
7 Haemoglobin concentration at term (ALL)3475Mean Difference (IV, Random, 95% CI)-0.83 [-4.74, 3.08]
8 Haemoglobin concentration at term (BY SUBGROUPS)3 Mean Difference (IV, Random, 95% CI)Subtotals only
8.3 Unspecified/mixed gestational age at start of supplementation2301Mean Difference (IV, Random, 95% CI)-2.19 [-6.85, 2.47]
8.7 Daily low dose (60 mg elemental iron or less)3422Mean Difference (IV, Random, 95% CI)-0.10 [-5.15, 4.95]
8.8 Daily higher dose (more than 60 mg elemental iron)1109Mean Difference (IV, Random, 95% CI)-0.82 [-4.99, 3.35]
9 Anaemia at term (Hb < 110 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]
10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)0.93 [0.47, 1.82]
11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.7 Daily low dose (60 mg elemental iron or less)3422Risk Ratio (M-H, Random, 95% CI)1.24 [0.42, 3.66]
11.8 Daily higher dose (more than 60 mg elemental iron)1109Risk Ratio (M-H, Random, 95% CI)0.63 [0.19, 2.11]
12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL)61111Risk Ratio (M-H, Random, 95% CI)0.43 [0.24, 0.77]
13 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (BY SUBGROUPS)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation2250Risk Ratio (M-H, Random, 95% CI)0.52 [0.26, 1.01]
13.2 Late gestational age (20 weeks or more of gestation) at start of supplementation1166Risk Ratio (M-H, Random, 95% CI)0.24 [0.10, 0.55]
13.3 Unspecified/mixed gestational age at start of supplementation3695Risk Ratio (M-H, Random, 95% CI)0.46 [0.13, 1.65]
13.4 Anaemic at start of supplementation (Hb <110 g/L if in first or <105 g/L if in second trimester)147Risk Ratio (M-H, Random, 95% CI)Not estimable
13.5 Non-anaemic at start of supplementation180Risk Ratio (M-H, Random, 95% CI)0.6 [0.15, 2.34]
13.6 Unspecified/mixed anaemic status at start of supplementation4966Risk Ratio (M-H, Random, 95% CI)0.41 [0.21, 0.80]
13.7 Daily low dose (60 mg elemental iron or less)5953Risk Ratio (M-H, Random, 95% CI)0.41 [0.20, 0.82]
13.8 Daily higher dose (more than 60 mg elemental iron)2247Risk Ratio (M-H, Random, 95% CI)0.74 [0.42, 1.31]
16 Iron deficiency anaemia at term (based on two or more indicators) (ALL)1156Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.63]
18 Side effects (any) (ALL)71307Risk Ratio (M-H, Random, 95% CI)0.69 [0.45, 1.04]
19 Side effects (any) (BY SUBGROUPS)7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
19.1 Early gestational age (less than 20 weeks or pre-pregnancy) at start of supplementation180Risk Ratio (M-H, Random, 95% CI)0.2 [0.08, 0.53]
19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation1172Risk Ratio (M-H, Random, 95% CI)1.0 [0.79, 1.27]
19.3 Unspecified/mixed gestational age at start of supplementation51055Risk Ratio (M-H, Random, 95% CI)0.72 [0.42, 1.26]
19.4 Non-anaemic at start of supplementation180Risk Ratio (M-H, Random, 95% CI)0.2 [0.08, 0.53]
19.7 Daily low dose (60 mg elemental iron or less)61171Risk Ratio (M-H, Random, 95% CI)0.92 [0.71, 1.19]
19.8 Daily higher dose (more than 60 mg elemental iron)2253Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.25]
20 Very low birthweight (less than 1500 g) (ALL)4737Risk Ratio (M-H, Random, 95% CI)Not estimable
21 Perinatal death (ALL)180Risk Ratio (M-H, Random, 95% CI)Not estimable
27 Infant ferritin concentration at 6 months (ug/L) (ALL)188Mean Difference (IV, Random, 95% CI)0.09 [0.05, 0.13]
30 Very premature delivery (less than 34 weeks of gestation) (ALL)1111Risk Ratio (M-H, Random, 95% CI)0.98 [0.06, 15.31]
31 Severe anaemia at term (Hb less than 70 g/L) (ALL)4555Risk Ratio (M-H, Random, 95% CI)Not estimable
32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)1.03 [0.07, 16.23]
33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)61240Risk Ratio (M-H, Random, 95% CI)Not estimable
34 Moderate anaemia at any time during second or third trimester (ALL)61111Risk Ratio (M-H, Random, 95% CI)2.54 [0.63, 10.17]
37 Antepartum haemorraghe (ALL)1110Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.59]
41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)0.43 [0.04, 4.64]
42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)1.14 [0.26, 4.95]
43 Diarrhoea (ALL)4553Risk Ratio (M-H, Random, 95% CI)0.94 [0.38, 2.34]
44 Constipation (ALL)4553Risk Ratio (M-H, Random, 95% CI)0.99 [0.48, 2.06]
45 Nausea (ALL)5854Risk Ratio (M-H, Random, 95% CI)0.59 [0.30, 1.16]
46 Heartburn (ALL)3473Risk Ratio (M-H, Random, 95% CI)0.78 [0.29, 2.06]
47 Vomiting (ALL)5854Risk Ratio (M-H, Random, 95% CI)1.44 [0.82, 2.53]
50 Placental abruption (ALL)1110Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]
51 Premature rupture of membranes (ALL)180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]
68 Ln (serum ferritin concentration) 4-8 wk postpartum (not pre-specified)1160Mean Difference (IV, Random, 95% CI)-0.13 [-0.42, 0.16]
70 Low serum ferritin concentration at postpartum (4-8 wk) (not pre-specified)1146Risk Ratio (M-H, Random, 95% CI)1.19 [0.40, 3.57]
71 High serum transferrin receptors at 6 weeks postpartum (not pre-specified)1146Risk Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.33]
93 Caesarean delivery (not pre-specified)180Risk Ratio (M-H, Random, 95% CI)0.89 [0.38, 2.07]
97 Haemoglobin concentration at 4-8 weeks postpartum (not pre-specified)1146Mean Difference (IV, Random, 95% CI)2.0 [-3.86, 7.86]
Analysis 4.1.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 1 Low birthweight (less than 2500 g) (ALL).

Analysis 4.2.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 2 Low birthweight (less than 2500 g) (BY SUBGROUPS).

Analysis 4.3.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 3 Birthweight (ALL).

Analysis 4.4.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 4 Birthweight (BY SUBGROUPS).

Analysis 4.5.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 5 Premature delivery (less than 37 weeks of gestation) (ALL).

Analysis 4.7.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 7 Haemoglobin concentration at term (ALL).

Analysis 4.8.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 8 Haemoglobin concentration at term (BY SUBGROUPS).

Analysis 4.9.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 9 Anaemia at term (Hb < 110 g/L) (ALL).

Analysis 4.10.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL).

Analysis 4.11.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS).

Analysis 4.12.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL).

Analysis 4.13.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 13 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (BY SUBGROUPS).

Analysis 4.16.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 16 Iron deficiency anaemia at term (based on two or more indicators) (ALL).

Analysis 4.18.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 18 Side effects (any) (ALL).

Analysis 4.19.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 19 Side effects (any) (BY SUBGROUPS).

Analysis 4.20.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 20 Very low birthweight (less than 1500 g) (ALL).

Analysis 4.21.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 21 Perinatal death (ALL).

Analysis 4.27.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 27 Infant ferritin concentration at 6 months (ug/L) (ALL).

Analysis 4.30.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 30 Very premature delivery (less than 34 weeks of gestation) (ALL).

Analysis 4.31.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 31 Severe anaemia at term (Hb less than 70 g/L) (ALL).

Analysis 4.32.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL).

Analysis 4.33.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL).

Analysis 4.34.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 34 Moderate anaemia at any time during second or third trimester (ALL).

Analysis 4.37.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 37 Antepartum haemorraghe (ALL).

Analysis 4.41.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL).

Analysis 4.42.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL).

Analysis 4.43.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 43 Diarrhoea (ALL).

Analysis 4.44.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 44 Constipation (ALL).

Analysis 4.45.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 45 Nausea (ALL).

Analysis 4.46.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 46 Heartburn (ALL).

Analysis 4.47.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 47 Vomiting (ALL).

Analysis 4.50.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 50 Placental abruption (ALL).

Analysis 4.51.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 51 Premature rupture of membranes (ALL).

Analysis 4.68.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 68 Ln (serum ferritin concentration) 4-8 wk postpartum (not pre-specified).

Analysis 4.70.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 70 Low serum ferritin concentration at postpartum (4-8 wk) (not pre-specified).

Analysis 4.71.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 71 High serum transferrin receptors at 6 weeks postpartum (not pre-specified).

Analysis 4.93.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 93 Caesarean delivery (not pre-specified).

Analysis 4.97.

Comparison 4 Intermittent iron-folic acid versus daily iron-folic acid, Outcome 97 Haemoglobin concentration at 4-8 weeks postpartum (not pre-specified).

Feedback

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

Last assessed as up-to-date: 24 June 2009.

DateEventDescription
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; Hemminki 1991; Siega-Riz 2001).
16 June 2009New search has been performedSearch updated. Ten new trials included (Cantlie 1971; Christian 2003; 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.
20 October 2008Feedback has been incorporatedFeedback from Elina Hemminki added with response from author.

History

Protocol first published: Issue 2, 2004
Review first published: Issue 3, 2006

DateEventDescription
15 April 2008AmendedConverted to new review format.

Contributions of authors

Juan Pablo Pena-Rosas and Fernando Viteri co-wrote the protocol, the review and the update. Juan Pablo Pena-Rosas abstracted the trial data and carried out the analysis with the technical support and guidance of Fernando Viteri. Both took primary responsibility in producing the final manuscript.

Disclaimer: Juan Pablo Pena-Rosas is currently a staff member 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.

Declarations of interest

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).

Fernando Viteri was involved in some included studies with intermittent iron supplementation. Juan Pablo Pena-Rosas was author of an excluded study on iron and folic acid intermittent supplementation.

Sources of support

Internal sources

  • Children's Hospital and Oakland Research Institute (CHORI), USA.

  • International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt) - U.S. Centers for Disease Control and Prevention (CDC), USA.

External sources

  • Department of Reproductive Health and Research, World Health Organization (WHO), Switzerland.

Differences between protocol and review

This review aims to evaluate the effectiveness of supplementation with iron alone or in combination with folic acid on functional outcomes in the mother and the infant rather than just haematological indicators. It also evaluates the regimen schedules by comparing intermittent (less frequent than daily) supplement intake with the standard daily regimens and the effects of these interventions on side-effects and haemoconcentration. Unlike the previous version of this review, in this updated version, 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, which has led to some previously excluded studies now being included.

The comparisons in this review were reduced to four instead of eight as stated in the original protocol. The subgroup analyses were considered only for the primary outcomes.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barton 1994

MethodsRandomisation: adequate by means of computer-generated numbers. Allocation concealment: adequate. Blinding: adequate. Participant and care provider blinded. Loss to follow up: adequate. Less than 5%.
Participants97 healthy women attending prenatal care at National Maternity Hospital, Dublin, Ireland with singleton pregnancy, during their first trimester of pregnancy, and with haemoglobin equal or higher than 140 g/L were assigned to the groups. Women were excluded if they had a recent blood transfusion, chronic respiratory disease, chronic hypertension, renal disease, diabetes mellitus, history of haematologic disorder and alcohol dependence.
InterventionsWomen were randomly assigned to one of two groups: group 1: received iron and folic acid tablets, one tablet to be taken by mouth twice daily (each tablet contained 0.5 mg of folic acid and 60 mg elemental iron); group 2: placebo tablets also to be taken by mouth twice daily.
Supplementation started at 12 wks until delivery. No postpartum supplementation.
OutcomesMaternal: haemoglobin, hematocrit, serum erythropoietin concentrations at baseline and at 24, 28, 32, 36 and 40 wk; serum ferritin at baseline and at 36 wk; number of hypertensive disorders, antepartum haemorrhage, cesarean delivery.
Infant: perinatal death, birthweight below 10th percentile, Apgar score, need for neonatal resuscitation and admission to neonatal intensive care unit data recorded but not reported in paper. Cord blood values of haemoglobin, hematocrit, serum ferritin, and erythropoietin concentrations.
NotesUnsupervised.
No participants were withdrawn because of anaemia.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by means of computer-generated numbers.
Allocation concealment?YesAdequate.
Blinding?
All outcomes
YesAdequate.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 5% lost to follow up.

Batu 1976

MethodsRandomisation: unclear - method not stated. Allocation concealment: unclear. Blinding: unclear - participant blinded. Provider/assessor not stated or clear. Loss to follow up: inadequate - 37 women (28%) were excluded for analysis.
Participants133 women referred to investigators from a population of women attending an antenatal clinic for the fist time in Yangoon (also known as Rangoon), Myanmar (Burma). Women with severe anaemia were excluded from the trial during the intervention for treatment.
InterventionsWomen were randomly assigned to one of four groups starting at 22-25 wks: group 1: one ferrous sulphate tablet containing 60 mg of elemental iron, and one placebo tablets twice daily; group 2: one tablet containing 60 mg of elemental iron as ferrous sulphate, and one tablet containing 0.5 mg of folic acid twice daily; group 3: two placebo tablets twice daily; group 4: one placebo tablet and one tablet containing 0.5 mg of folic acid twice daily. Administration of the treatments was carefully supervised. Supplementation started at 22-25 wks until term.
OutcomesMaternal: haemoglobin concentrations at baseline, at term (38-40th wk) and 4-7 wk postpartum, serum iron, serum and red cell folate activity and hypersegmented polimorph count at baseline, at 38-40th wk and postpartum.
NotesSupervised. 32 women who had taken other supplements or whose Hb level at full term was not available were excluded from the analysis. Three women from group 3 and two from group 4 developed severe anaemia and were also withdrawn from analysis.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear - method not stated.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
UnclearUnclear - participant blinded. Provider/assessor not stated or clear.
Incomplete outcome data addressed?
All outcomes
NoInadequate - 37 women (28%) were excluded for analysis.

Butler 1968

MethodsRandomisation: adequate by means of a randomised list stratified by age, parity and initial haemoglobin level. Allocation concealment: adequate. Numbered bottles of tablets and code was broken after study completed for group 1 and 2. Blinding: inadequate. Participant and provider were blinded to treatment for groups 1 and 2. The control group did not get a placebo. Loss to follow up: inadequate - more than 20% were lost to follow up to the postnatal visit.
Participants200 women before 20th week of gestation and Hb above 100 g/L attending antenatal clinic at the Maternity Hospital in Glossop Terrace, Cardiff, England, United Kingdom were studied. Exclusion criteria included urinary infection and threatened miscarriage, confusion over therapy, intercurrent illness and difficult veins, intolerant to the iron form, premature labor.
InterventionsWomen were randomly allocated to three groups: group 1: received 122 mg of elemental iron as ferrous sulphate daily; group 2: received 122 mg of elemental iron as ferrous sulphate plus 3.4 mg of folic acid daily; group 3: no treatment. A group 4 was formed as some subjects (n = 38) from group 3 received iron supplements for treatment of anaemia in the course of the intervention. They are excluded for analysis. Women were supplemented from week 20 to week 40 of gestation.
OutcomesMaternal: haemoglobin concentrations, blood and plasma volume, haematocrit (not reported), red cell volume, albumin and globulin fractions, oedema, intrapartum haemorrhage.
NotesUnsupervised.
154 women were followed through to the postnatal visit. Only 16 women (30%) in the no treatment group remained untreated.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by means of a randomised list stratified by age, parity and initial haemoglobin level.
Allocation concealment?YesAdequate.
Blinding?
All outcomes
NoInadequate. Participant and provider were blinded to treatment for groups 1 and 2. The control group did not get a placebo.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% were lost to follow up to the postnatal visit.

Buytaert 1983

MethodsRandomisation: adequate by random table numbers. Allocation concealment: adequate by means of sealed envelopes. Blinding: inadequate. Participant nor provider blinded. No placebo used. Loss to follow-up: adequate - less than 20% lost to follow up.
Participants45 non-anaemic women with singleton pregnancy and no major illnesses attending the University Hospital Obstetric and Gynaecologic Clinic in Antwerp, Belgium.
InterventionsWomen were randomly assigned to one of two groups:
group 1: received 105 mg of elemental iron as ferrous sulphate daily in a sustained release preparation and group 2: received no iron supplement.
Supplementation started at 14-16th week of gestation and continued until delivery.
OutcomesMaternal: haemoglobin, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 wks, delivery and 6 wks postpartum.
NotesUnsupervised. The randomisation was made for each clinic in Antwerp, and the results are presented separately by clinic. Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate - by random table numbers.
Allocation concealment?YesAdequate, by means of sealed envelopes.
Blinding?
All outcomes
NoInadequate. Participant nor provider blinded. No placebo used.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up

Cantlie 1971

MethodsRandomisation: unclear. method not stated. Allocation concealment: unclear. Blinding: unclear. Not specified. Loss to follow up: unclear. Not reported.
Participants27 apparently healthy non-anaemic pregnant women 17-35 years of age from 4 participating obstetricians' private practice clinics from Montreal, Canada in their 1-5th month of pregnancy with Hb 12 g/dL or higher in first trimester and 11 g/dL or higher in second trimester. Women with history of pathological blood loss or gross dietary imbalance were excluded.
InterventionsWomen were randomly assigned to two groups: group 1 received 39 mg elemental iron to be taken twice daily with meals (total daily 78 mg elemental iron) or group 2 who received no iron tablets. Both groups received one tablet of multivitamin supplement daily containing: copper citrate 2 mg, magnesium stearate 6 mg, manganese carbonate 0.3 mg, vitamin A 1000 IU, vitamin D 500 IU, bone flour 130 mg, vitamin B1 1 mg, vitamin B2 1 mg, brewer yeast concentrate 50 mg, niacinamide 5 mg, vitamin C 25 mg, sodium iodide 0.2 mg and folate 0.049 ug (naturally occurring). Duration of supplementation unclear.
OutcomesMaternal: Hb concentration, packed cell volume, reticulocyte count, sedimentation rate, total white blood cell and differential counts, serum iron, unsaturated and total iron binding capacity, serum B12, serum and RBC folate at baseline and at 32, 36, 39th wks and 7 days postpartum.
NotesSupervision unclear.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear - method not stated.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
UnclearUnclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate - not reported.

Chanarin 1971

MethodsRandomisation: inadequate - quasi-randomised study, assignment by sequence. Allocation concealment: inadequate. Blinding: adequate. Participant and provider blinded. Loss to follow up: adequate - less than 20%.
Participants251 women attending antenatal clinic at St Mary's Hospital, London, England, United Kingdom before 20th week of gestation.
InterventionsWomen were allocated by sequence to one of five groups: group 1: oral dose of 30 mg of elemental iron daily; group 2: oral dose of 60 mg of elemental iron daily; group 3: oral dose of 120 mg of elemental iron daily; group 4: placebo; group 5: 1 g of iron (Imferon, 4 x 250 mg) intravenously before week 20, and thereafter oral 60 mg of elemental iron as ferrous fumarate daily (not included in this review). Oral elemental iron provided as ferrous fumarate.
Supplementation started at 20th week until 37th week. Only the data related to comparisons of group 1: oral dose of 30 mg of elemental iron daily with group 4: placebo are used in this review given that no data for the other groups could be desegregated.
OutcomesMaternal: full blood count, serum iron at 20, 25, 30 and 37th week. Sternal marrow aspiration at 37 wks; antepartum haemorrhage, threatened abortion, urinary tract infection, fetal abnormalities, pregnancy hypertension, premature delivery and puerperal infection measured but not reported by groups.
Infant: birthweight (not reported by groups).
NotesCompliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi-randomised study, assignment by sequence.
Allocation concealment?NoInadequate.
Blinding?
All outcomes
YesAdequate. Participant and provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20%.

Charoenlarp 1988

MethodsRandomisation: adequate, using a set of random tables. Allocation concealment: unclear. Blinding: unclear - participant and outcome assessor blinded. Provider blinding unclear. Loss to follow up: adequate. Ranged from 10%-15%.
Participants325 pregnant women with Hb (AA) and 232 pregnant women with Hb (AE) attending midwife centres in 80 villages from the Varin Chamrab district of Ubon Province, Thailand. Chronic illness, complicated pregnancy, severe anaemia (Hb < 80 g/L), haemoglobinopathies Hb (EE) and (EF), and unwillingness to cooperate were reason for exclusion. Individuals with Hb (AA) have normal hemoglobin genes. Individuals with Hb (AE) have a heterozygous Hb E trait with normal Hb gene (A-adults) and an abnormal Hb gene (E). This is usually a clinically insignificant condition.
InterventionsWomen were divided into two groups according to Hb (AA) and Hb (AE) and studied separately. Women from each group were randomly assigned to one of the following interventions: group 1: placebo, supervised; group 2, 120 mg of elemental iron and 5 mg folic acid daily supervised; group 3, 240 mg of elemental iron daily supervised; group 4: 240 mg of elemental iron daily supervised; group 5: 120 mg elemental iron and 5 mg of folic acid, motivated but unsupervised; and group 6: 240 mg of elemental iron and 5 mg of folic acid daily, motivated but unsupervised. For the Hb (AE) group, women were randomly assigned to one of the following groups: group 7: placebo, supervised; group 8: 240 mg elemental iron and 5 mg of folic acid daily, supervised; group 9: 240 mg of elemental iron daily, supervised; group 10: 120 mg of elemental iron and 5 mg of folic acid daily, motivated but unsupervised, and group 11: 240 mg of elemental iron and 5 mg of folic acid daily, motivated but unsupervised. Elemental iron was given as ferrous sulphate.
Starting and ending time of supplementation not stated.
OutcomesMaternal: haemoglobin, serum ferritin after 10 and 15 wks of supplementation, and side effects.
NotesGroups 1, 2, 3, 4, 7, 8, 9 supervised. Groups 5, 6, 10 and 11 motivated but unsupervised. For purposes of analysis, the groups were merged by iron alone or iron-folic acid, and included as daily higher doses in both cases.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate, using a set of random tables.
Allocation concealment?UnclearUnclear
Blinding?
All outcomes
YesUnclear - participant and outcome assessor blinded. Provider blinding unclear.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Ranged from 10%-15%.

Chew 1996a

MethodsRandomisation: adequate - by computerised random numbers. Allocation concealment: adequate by sealed envelopes. Blinding: inadequate - participant, care provider and outcome assessor not blinded. Loss to follow up: inadequate - more than 20% lost to follow up.
Participants256 clinically healthy pregnant women from low socio-economic status attending one antenatal care clinic in Guatemala City, Guatemala and Hb > 80 g/L were recruited. City of Guatemala is at 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb.
InterventionsWomen were randomly assigned to one of two groups: group 1: daily supervised intake of 60 mg elemental iron and 500 ug folic acid; group 2: weekly supervised intake of 180 mg of elemental iron and 3.5 mg of folic acid in one intake once a week. Iron given as ferrous sulphate.
Supplementation started at different gestational age for each participant. Average gestational age at start was 20.5 wks until 38th wk.
OutcomesMaternal: haemoglobin concentration at baseline and at term (38th week of gestation); side effects and total iron intake.
Infant: birthweight.
NotesSupervised.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate - by computerised random numbers.
Allocation concealment?YesAdequate, by sealed envelopes.
Blinding?
All outcomes
NoInadequate -participant, care provider and outcome assessor not blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% lost to follow up.

Chew 1996b

MethodsRandomisation: adequate by computerised random numbers. Allocation concealment: adequate by sealed envelopes. Blinding: inadequate. Participant and provider not blinded. Outcome assessor for laboratory blinded to groups. Loss to follow up: inadequate.
Participants120 clinically healthy pregnant women attending one antenatal care clinic in Guatemala City, Guatemala with Hb >80 g/L were recruited. Women were from low SES. City of Guatemala is 1500 m above sea level, so values were adjusted by altitude subtracting 5 g/L in Hb.
InterventionsWomen from low SES were randomly assigned to one of two groups: group 3: daily unsupervised intake of 60 mg elemental iron as ferrous sulphate and 500 ug folic acid; or group 4: weekly unsupervised intake of 180 mg of elemental iron as ferrous sulphate and 3.5 mg of folic acid in one intake once a week.
Supplementation started at an average of 20.5 wks of gestation until 38th wk.
OutcomesMaternal: haemoglobin concentration at baseline and at term (38th week of gestation); side effects and total iron intake.
Infant: birthweight.
NotesUnsupervised.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate, by computerised random numbers.
Allocation concealment?YesAdequate, by sealed envelopes.
Blinding?
All outcomes
NoInadequate. Participant and provider not blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate

Chisholm 1966

MethodsRandomisation: method unclear. Allocation concealment: adequate. Bottles containing the tablets had been numbered by random selection at source and the code was unknown during trial. Blinding: adequate. participant and provider blinded. Loss to follow up: adequate. No losses to follow up.
Participants360 non-anaemic women attending antenatal clinic at Ridcliffe Infirmary, Oxford, England United Kingdom before 28th week of gestation, who had not taken iron supplements in the preceding 8 wks and with Hb >= 102 g/L or a normal serum iron reading. Exclusion criteria: Hb < 110 g/L and serum iron less than 60 ug/L.
InterventionsWomen were randomly assigned to one of various combinations of elemental iron as ferrous gluconate and folic acid, as follows:
group 1: 900 mg elemental iron alone daily; group 2: 900 mg elemental iron and 500 ug folic acid daily; group 3: 900 mg elemental iron and 5 mg folic acid daily; group 4: placebo; group 5: 500 ug folic acid daily; group 6: 5 mg of folic acid daily. Iron and folic acid placebos were used.
Supplementation started at 28th week until 40th week.
OutcomesMaternal: haemoglobin, haematocrit, serum iron, serum folic acid activity, serum vitamin B12 estimation at 28 wks of gestation and predelivery.
NotesUnsupervised.
For purposes of this review, placebo group was the group who received neither iron nor folic acid. Groups 2 and 3 were merged for iron-folic acid comparisons.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?YesAdequate. Bottles containing the tablets had been numbered by random selection at source and the code was unknown during trial.
Blinding?
All outcomes
YesAdequate. Participant and provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate. No losses to follow up.

Christian 2003

MethodsRandomisation: adequate. Cluster randomisation. Allocation concealment: adequate. Coded. Blinding: adequate. Participant, provider and outcome assessors blinded. Loss to follow up: inadequate. More than 20% losses to follow up.
Participants4998 married pregnant women (with positive pregnancy test) living in the south eastern plains district of Sarlahi, Nepal. Widows were excluded.
InterventionsWomen were randomly assigned to one of five groups: group 1 received 1000 ug retinol equivalents vitamin A (control) daily; group 2 received 1000 ug retinol equivalents vitamin A and 400 ug folic acid daily; group 3 received 1000 ug retinol equivalents vitamin A, 400 ug folic acid and 60 mg elemental iron as ferrous fumarate daily; group 4 received 1000 ug retinol equivalents vitamin A, 400 ug folic acid, 60 mg of elemental iron as ferrous fumarate and 30 mg of zinc sulphate daily; and group 5 received 1000 ug retinol equivalents vitamin A, 400 ug folic acid, 60 mg elemental iron as ferrous fumarate, 30 mg of zinc, 10 ug vitamin D, 10 mg vitamin E, 1.6 mg thiamine, 1.8 mg riboflavin, 20 mg niacin, 2.2 mg vitamin B6, 2.6 ug vitamin B12, 100 mg vitamin C, 65 ug vitamin K, 2 mg cooper, and 100 mg magnesium daily. Only groups 1 and three are considered in this review. Supplementation started at recruitment and continued until 3 month post-partum in the case of live births of 5 wks or more after a miscarriage or stillbirth. All participating women were offered deworming treatment (albendazole 400 mg single dose) in the second and third trimester.
Supplementation lasted 257.5 days in group 1 (control) and 251.7 days in the group 3 receiving vitamin A, iron and folic acid.
Comparisons: group 3 vs group 1: effect of iron supplementation with folic acid; group 3 vs group 2: effect of iron supplementation alone.
OutcomesMaternal: premature delivery, Hb and iron status at baseline in the third trimester and Hb at 6 wk postpartum, prevalence of anemia in third trimester and at 6 wk postpartum, severe anemia postpartum, moderate anaemia during third trimester, moderate anaemia postpartum, moderate haemoconcentration during third trimester
Infant: birth weight, prevalence of low birth weight, perinatal mortality, neonatal mortality, infant deaths, small for gestational age.
NotesUnsupervised but trial personnel visited women twice each week to monitor supplement intake.
Compliance during pregnancy measured by pill count was high (median 88%) and did not vary by groups.
98% of the women accepted the albendazole treatment at both times (second and third trimesters)
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate. Cluster randomisation.
Allocation concealment?YesAdequate. Coded.
Blinding?
All outcomes
YesAdequate - participant, provider and outcome assessors blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% losses to follow up.

Cogswell 2003

MethodsRandomisation: adequate by computerised random numbers. Allocation concealment: adequate. Blinding: adequate - participant and care provider blinded. Outcome assessor unclear. Loss to follow up: inadequate - more than 20% lost to follow up.
Participants275 legally competent, non-imprisoned, non-anaemic, low-income pregnant women at < 20 wks of gestation with ferritin levels above 20 ug/L enrolled at the Cuyahoga County, MetroHealth Center, Supplemental Nutrition Program for Women, Infants and Children in Cleveland, Ohio, USA.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 1 gelatin capsule containing 30 mg of elemental iron as ferrous sulphate daily; group 2 received 1 placebo soft gelatin capsule daily for 119 days.
Supplementation started at an average of 11 wks of gestation until delivery.
OutcomesMaternal: prevalence of anaemia at 28 and 38 wks, side effects, compliance to treatment, maternal weight gain, iron status (mean cell volume, haemoglobin concentration, serum ferritin, erythrocyte protoporphyrin concentrations at 28 and 38 wks.
Infant: birthweight, birth length, proportion of low birthweight, low birthweight and premature, small-for-gestational age.
NotesUnsupervised. Women were re-evaluated at 28 wks of gestation, and according to haemoglobin concentrations at that time were prescribed treatment following the Institute of Medicine guidelines for iron supplementation during pregnancy.
Compliance was 63.4% and 65.2% in groups 1 and 2 respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate, by computerised random numbers.
Allocation concealment?YesAdequate
Blinding?
All outcomes
YesAdequate - participant and care provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% lost to follow up.

De Benaze 1989

MethodsRandomisation: unclear - randomised but method used unclear. Allocation concealment: adequate. Blinding: adequate. Participant and provider blinded. Loss to follow up: adequate - less than 20%.
Participants191 non-anaemic pregnant women with 12-18 wks of gestation attending antenatal care clinic at the Maternity at Poissy Hospital, Paris, France. Exclusion criteria included women who had taken iron or folate supplements in the prior 6 months and those with language barriers for proper communication.
Supplementation started at 12-18 wks until delivery.
InterventionsWomen were randomly allocated to one of 2 groups: group 1: daily intake of 45 mg of elemental iron as ferrous betainate hydrochloride (15 mg elemental iron per tablet) and group 2: placebo tablets.
OutcomesMaternal: haemoglobin, MCV, serum iron, total iron binding capacity, transferrin saturation, serum ferritin at baseline, at 5 months, at 7 months, at delivery and 2 months postpartum.
NotesUnsupervised.
Serum ferritin values presented as arithmetic and geometric means. No standard deviation in transformed ferritin values is presented. Women in the placebo group were prescribed treatment after delivery thus not allowing comparisons at 2 months postpartum among the groups.
Compliance reported as good.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear - randomised but method used unclear.
Allocation concealment?YesAdequate.
Blinding?
All outcomes
YesAdequate. Participant and provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate, less than 20%.

Ekstrom 2002

MethodsRandomisation: adequate by cluster. Allocation concealment: inadequate - not used. Blinding: inadequate - neither participant nor provider blinded. Outcome assessor unclear. Loss to follow up: inadequate - more than 20% loss to follow up.
Participants209 apparently healthy women attending antenatal care clinics in rural areas of Mymemsingh thana, Bangladesh, with fundal height of 14-22 cm (18-24 wks of gestation), who had not used iron supplements prior to the study. Exclusion criteria: women with haemoglobin concentrations < 80 g/L.
InterventionsEach clinic was randomly assigned to one of two interventions: 60 mg of elemental iron as ferrous sulphate and 250 ug folic acid given in one tablet daily, or 120 mg of elemental iron as ferrous sulphate and 500 ug folic acid once a week (given in two tablets one day of the week). Supplementation continued until 6 wks postpartum.
Supplementation started at baseline for 12 wks.
OutcomesMaternal: haemoglobin concentration at baseline and after 12 wks of supplementation. Compliance, side-effects, serum ferritin and serum transferrin receptors at 6 wks postpartum.
NotesUnsupervised.
Cluster randomisation used among 52 antenatal clinics: n = 25 to daily supplementation and n = 25 to weekly supplementation. Two antenatal care units ceased operation during the trial period.
Compliance was 104% and 68% for weekly and daily groups respectively. The compliance above 100% for the weekly means that more tablets that were indicated to be taken were ingested in the period of time.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by cluster.
Allocation concealment?NoNot used.
Blinding?
All outcomes
NoInadequate - neither participant nor provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% loss to follow up.

Eskeland 1997

MethodsRandomisation: adequate - computer generated. Allocation concealment: adequate - central allocation at trials office, sequentially numbered. Blinding: adequate - participant and care provider blinded. Loss to follow up: inadequate. 23% and 21% in groups included.
Participants90 healthy non-anaemic pregnant women with singleton pregnancy of less than 13 wks, attending an inner city maternity centre in Bergen, Norway and willing to participate. Exclusion criteria: uncertain gestational age according to menstrual history, haemoglobin concentration < 110 g/L, chronic disease or pregnancy complications (hypertension, diabetes, bleeding), multiple pregnancy, liver enzymes out of normal range and logistic difficulties foreseen at baseline (moving out of area).
InterventionsWomen were randomly allocated to one of the following: group 1: three tablets containing 1.2 mg heme iron from porcine blood and 9 mg of elemental iron as ferrous fumarate (Hemofer®) and one placebo tablet (total 27 mg elemental iron a day); group 2: one tablet containing 27 mg elemental iron as iron fumarate with 100 mg vitamin C (Collet®) and three placebo tablets; or group 3: four placebo tablets.
Supplementation started at 20th week until 38-40th week.
OutcomesMaternal: haemoglobin, erythrocytes count, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, reticulocytes, serum iron, total iron binding capacity, serum transferrin, erythrocyte protoporphyrin at baseline and at 20, 28, 38 wks, 8 wks postpartum, and 6 months postpartum; pregnancy complications: hypertension, pre-eclampsia, forceps, postpartum haemorrhage, maternal wellbeing and breastfeeding duration.
Infant: birthweight and length.
NotesUnsupervised.
Only groups 1 and 3 (placebo) were included in this review.
Compliance was 81% and 82% in groups 1 and 3 respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate, computer generated.
Allocation concealment?YesAdequate
Blinding?
All outcomes
YesAdequate - participant and care provider blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate. 23% and 21% in groups included.

Hankin 1963

MethodsRandomisation: inadequate - alternate by day of the week. Allocation concealment: inadequate. Blinding: inadequate. Open. Loss to follow up: adequate. Less than 5% excluded.
Participants174 primigravidae or secundigravidae at their first visit at the antenatal Clinic of Queen Elizabeth Hospital in Woodville, Australia with ability to write and speak English.
InterventionsWomen were divided into a supplemented group receiving a daily dose of 100 mg of elemental iron as ferrous gluconate or a control group that was unsupplemented.
Supplementation started during 2nd trimester and ending time is unclear.
OutcomesMaternal: haemoglobin and haematocrit at 20-30 wk, 30-40 wk, at 5 days, at 6 wk and at 3 months postpartum.
Infant: haemoglobin from umbilical cord, at 6 wk, at 3 months and at 6 months of age (not reported).
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi-randomised, alternate by day of the week.
Allocation concealment?NoInadequate.
Blinding?
All outcomes
NoInadequate. Open.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 5% excluded.

Harvey 2007

MethodsRandomisation: adequate. Allocation concealment: adequate - supplied in coded opaque bottles. Blinding: inadequate - participant blinded. Care provider and outcome assessor unblinded. Loss to follow up: adequate. No losses to follow up.
Participants13 apparently healthy non-anemic non-smokers pregnant women aged 18-40 years and < 14 wks of gestation with singleton pregnancy recruited through local medical practitioners and the Maternity Department of the Norfolk and Norwich University Hospital, England, United Kingdom.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 100 mg elemental iron as ferrous gluconate daily after food and group 2 received a placebo. Supplementation started at 16th week of gestation until delivery.
OutcomesMaternal: haemoglobin, serum ferritin, transferrin receptor, plasma zinc, exchangeable zinc pool, zinc excretion and zinc absorption at 16, 24 and 34 wks of gestation.
Infant: birth weight (not reported).
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate.
Allocation concealment?YesAdequate, supplied in coded opaque bottles.
Blinding?
All outcomes
NoInadequate - participant blinded. Care provider and outcome assessor unblinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - no losses to follow up.

Hemminki 1991

MethodsRandomisation: adequate. Random codes created by computer in blocks of ten by maternity centre. Allocation concealment: adequate. Sealed numbered envelopes stored in containers from which midwives were asked to take them in order. Blinding: inadequate - neither participants nor provider blinded. Outcome assessor blinded. Loss to follow up: adequate - less than 5% lost to follow up.
Participants2994 pregnant women with less than 16 wks of gestation attending 15 communal maternity centres and 12 centres in five neighbouring communities in Tampere, Finland who consented to participate. Exclusion criteria included: chronic illness, anemia (hematocrit under 0.32 or Hb <110 g/L), late arrival, likelihood of moving away from the area before child birth, or twin pregnancies.
InterventionsWomen were randomly assigned to one of two policy groups: group 1 (routine) were recommended to take 100 mg elemental iron alone (iron compounds and dosage varied as per midwife recommendation) daily after the 16th week gestation; or group 2 (selective) who received no iron supplements. Women in the selective group who had a haematocrit of < 0.30 (Hb < 100 g/L) on two consecutive visits were provided 100 mg elemental iron (as ferrous sulphate) to be taken one tablet (50 mg) twice a day for two months or until haematocrit increased to 0.31 (Hb 100 g/L)
Outcomes

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

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

Notes

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

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

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

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

Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate. Random codes created by computer in blocks of ten by maternity centre.
Allocation concealment?YesAdequate - sealed numbered envelopes stored in containers from which midwives were asked to take them in order.
Blinding?
All outcomes
NoInadequate - neither participants nor provider blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 5% lost to follow up.
Free of selective reporting?Yes 

Holly 1955

MethodsRandomisation: unclear. Allocation concealment: unclear. Blinding: inadequate - neither participants nor provider blinded. Outcome assessor unclear. Loss to follow up: unclear.
Participants207 pregnant women with less than 26 wks of gestation and Hb > 100 g/L attending antenatal care clinic in Nebraska, USA.
InterventionsWomen were randomly assigned to one of 3 groups: group 1 received 1 g of an iron salt daily; group 2 received 0.8-1.2 g of ferrous sulphate and 60-90 mg of cobalt chloride daily, and group 3 received no treatment.
Supplementation started at various times before 26th week of gestation for each of the subjects until delivery.
OutcomesMaternal: haemoglobin, haematocrit, serum iron, erythrocyte protoporphyrin at 3-6 months and pre-delivery.
NotesUnsupervised.
Three iron salts (n = 94) were used: ferrous gluconate (n = 40), ferrous sulphate (n = 32) and Mol-Iron® (n = 22). The iron treated groups with different iron salts were merged together by the author as iron treated group since the results were comparable. The iron and cobalt treatment group is not included in this review.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - neither participants nor provider blinded.
Incomplete outcome data addressed?
All outcomes
UnclearUnclear.

Hood 1960

MethodsRandomisation: unclear. Allocation concealment: unclear. Blinding: inadequate - neither participant nor provider blinded. Outcome assessor unclear. Loss to follow up: adequate. Less than 20%.
Participants75 consecutive apparently healthy pregnant women with 32-34 wks of gestation attending the maternity clinic at St Anthony's Hospital, Oklahoma City, Oklahoma, USA.
InterventionsWomen were randomly divided in three groups: group 1 served as control and received no treatment; group 2 received 220 mg elemental iron as ferrous sulphate daily; and group 3 received 55 mg elemental iron as sustained release ferrous sulphate daily.
Supplementation started at 32-34 week of gestation until delivery.
OutcomesMaternal: haemoglobin, haematocrit, incidence and severity of side effects on a weekly basis until delivery.
NotesUnsupervised.
Group 2 is recorded as higher daily dose and group 3 as low daily dose. For any iron versus no treatment comparison groups were merged.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - neither participant nor provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 20% losses to follow up.

Kerr 1958

MethodsRandomisation: adequate by cards shuffle. Allocation concealment: unclear. Blinding: inadequate - participant blinded. Provider blinded to treatments but not to controls. Outcome assessor unclear. Loss to follow up: inadequate. 23% of participants were lost to follow up.
Participants430 apparently healthy women with 24-25 wks of singleton pregnancy and Hb equal or above 104 g/L attending antenatal clinic at Simpson Memorial Maternity Pavillion, Edinburgh, Scotland, United Kingdom.
InterventionsWomen were randomly allocated to one of 4 groups: group 1 received 35 mg of elemental iron as ferrous sulphate three times a day; group 2 received 35 mg of elemental iron as ferrous gluconate three times a day; group 3 received 35 mg of elemental iron as ferrous gluconate with 25 mg of ascorbic acid, three times a day; group 4 received placebo.
Supplementation started at 24-25th week of gestation until term.
OutcomesMaternal: haemoglobin, red cell count, haematocrit at baseline and at 37th week.
NotesUnsupervised.
Groups 1 and 2 were merged for analysis. Group 3 was not used in this review.
Compliance not measured.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by cards shuffle.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - participant blinded. Provider blinded to treatments but not to controls. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate. 23% of participants were lost to follow up.

Lee 2005

MethodsRandomisation: adequate. Allocation concealment: unclear. Blinding: inadequate: subject, provider and outcome assessor unclear. Loss to follow up: adequate: more than 80% of participants were included in the analysis. 16.2% of participants were lost to follow up.
Participants154 apparently healthy pregnant women seeking prenatal care in Gwangju, South Korea during first trimester of pregnancy who did not receive other supplements or medications throughout pregnancy and who were willing to participate.
InterventionsWomen were randomly allocated to one of 5 groups: group 1 received 30 mg elemental iron and 175 ug folic acid daily from first trimester until delivery; group 2 received 60 mg of elemental iron with 350 ug of folic acid from first trimester until delivery; group 3 received 30 mg elemental iron and 175 ug of folic acid from 20th week of gestation until delivery; group 4 received 60 mg elemental iron and 350 ug of folic acid from 20th week of gestation until delivery; or control group with no supplement. Elemental iron was given as ferrous sulphate.
OutcomesMaternal: haemoglobin, haematocrit, serum ferritin, serum soluble transferrin receptor concentrations at baseline and during first, second, third trimester of pregnancy and at delivery.
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoUnclear: subject, provider and outcome assessor blinding unclear.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up.

Liu 1996

MethodsRandomisation: method unclear. Non-supplemented group was self-selected.
Allocation concealment: adequate by sealed closed envelopes. Blinding: inadequate. Neither participant nor provider blinded. Outcome assessor blinded. Follow up: adequate - less than 20% lost to follow up.
Participants395 healthy, anaemic and non anaemic, pregnant women attending prenatal care at 2 outpatient clinics at Changji Hospital and Shihezi Maternal and Child Health Station in Xianjiang, China. Women with Hb < 80 g/L were excluded. Maternal age was 25.15 ± 2.28 years.
InterventionsWomen were randomly assigned to one of 3 groups: group 1: 60 mg elemental iron as ferrous sulphate and 0.25 mg of folic acid daily; group 2: 120 mg of elemental iron as ferrous sulphate and 0.5 mg of folic acid daily; group 3: 120 mg elemental iron as ferrous sulphate and 0.5 mg of folic acid once weekly. A control group that received no iron was composed of women who did not want to participate in the study and did not receive any iron supplements.
OutcomesMaternal: haemoglobin concentration at 3, 5, 8 months and at term; serum ferritin concentrations at 3 months and at term in a subgroup; side effects.
Weight at entry and at term (not used in the review).
NotesUnsupervised.
Iron supplementation is not mandatory for women in China, if they have a Hb concentration > 80 g/L.
Compliance for group 1 (daily 60 mg Fe), group 2 (daily 120 mg Fe) and group 3 (weekly 20 mg Fe) were 77%, 75% and 86% respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoMethod unclear. Non-supplemented group was self-selected.
Allocation concealment?YesAdequate by sealed closed envelopes.
Blinding?
All outcomes
NoInadequate. Neither participant nor provider blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up.

Makrides 2003

MethodsRandomisation: adequate by means of computer generated with balanced blocks and stratified for parity. Allocation concealment:adequate - opaque bottles marked with sequential numerical code prepared by the Pharmacy Department of Women's & Children's Hospital. Blinding: adequate - participant and care provider blinded. Loss to follow up: adequate. Less than 20% lost to follow up.
Participants430 non-anaemic pregnant women attending antenatal clinics at Women's and Children's Hospital in Adelaide, Australia with singleton or twin pregnancies and informed consent. Exclusion criteria: diagnosis of thalassaemia, history of drug or alcohol abuse and history of vitamin and mineral preparations containing iron prior to enrolment in study.
InterventionsWomen were randomly assigned to receive one tablet containing 20 mg of elemental iron daily between meals from week 20 until delivery or a placebo tablet.
OutcomesMaternal: haemoglobin concentration at 28 wk, at delivery, and at 6 months postpartum; ferritin concentration at delivery and at 6 months postpartum; maternal gastrointestinal side effects at 24 and 36 wk of gestation; serum zinc at delivery and at 6 month postpartum; maternal well being at 36 wk of gestation, at 6 wk and at 6 months postpartum; pregnancy outcomes: type of birth, blood loss at delivery, gestational age. At 4 years postpartum: general health of mothers using the SF-36, a self administered questionnaire that assesses 8 concepts of health.
Infant: birthweight, birth length, birth head circumference, Apgar scores, and level of nursery care. Follow up at 4 years: intelligence quotient (IQ) using Stanford-Binet Intelligence Scale, child behaviour using Strength and Difficulties Questionnaire parent report form.
NotesUnsupervised but monthly phone calls to encourage compliance.
If anaemia was detected in the routine 28 wk blood sample or if the clinician considered her Hb too low the woman was advised to purchase and take a high-dose iron supplement (containing > 80 mg elemental iron per tablet) until the end of pregnancy.
Compliance was 86% and 85% in the iron and placebo groups respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by means of computer generated with balanced blocks and stratified for parity.
Allocation concealment?YesAadequate, opaque bottles marked with sequential numerical code prepared by the Pharmacy Department of Women's & Children's Hospital.
Blinding?
All outcomes
YesAdequate - participant and care provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 20% lost to follow up.

Meier 2003

MethodsRandomisation: adequate stratified by age group. Allocation concealment: unclear. Blinding: adequate. Participant and provider blinded. Outcome assessor unclear. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants144 non-iron deficient adolescents 15-18 years old in their first pregnancy and adult women 19 or older in their first or greater pregnancy attending prenatal care at Marshfield Clinic, Wisconsin, USA.
InterventionsWomen were randomly assigned to receive once daily 60 mg of elemental iron as ferrous sulphate or a placebo. All women received 1 mg of folic acid daily.
OutcomesMaternal: prevalence of iron deficiency anaemia, compliance to treatment, side effects, vomiting, nausea, constipation, diarrhoea, C-section, serum ferritin and haemoglobin concentrations at 24-28 wk gestation and at 36-40 wk gestation.
infant: perinatal morbidity and mortality, birth weight, birth length, Apgar scores at 1 and 5 minutes, admission to neonatal unit, prevalence of birthweight.
NotesUnsupervised.
All adolescents and adult pregnant women who developed iron deficiency anaemia at 24-28 wk gestation were offered 60 mg elemental iron three times a day.
Compliance was assessed through pill counts and ranged from 32% to 124% (median 95.5% in iron supplemented group and 87.4% in placebo group.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate stratified by age group.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
YesAdequate. Participant and provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% lost to follow up.

Menendez 1994

MethodsRandomisation: unclear - randomised but method unclear. Allocation concealment: inadequate. Blinding: inadequate. Participant and provider not blinded. Outcome assessor blinded. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants550 multi gravidae pregnant women with less than 34 wks of gestation attending antenatal care clinics in 18 villages near the town of Farafenni, in North Bank Division, Gambia where malaria is endemic with high transmission during 4-5 months a year.
InterventionsWomen were allocated randomly by compound of residence to receive 60 mg of elemental iron as ferrous sulphate or placebo. All pregnant women received a weekly tablet of 5 mg of folic acid but no antimalarial chemoprophylaxis.
Supplementation started at 23-24 wks until delivery.
OutcomesMaternal: haemoglobin concentrations at baseline, 4-6 wks before delivery and one week postpartum; plasma iron, total iron binding capacity, transferrin saturation, deposition of malaria pigment in placenta.
Infant: birthweight within 7 days of delivery.
NotesUnsupervised.
Malaria prophylaxis is provided to primigravidae in The Gambia. Thirty women with PCV less than 25% after enrolment (17 in iron group and 13 in placebo) were treated and withdrawn from study and analysis. Additionally 29 women (7 in iron and 22 in placebo group) had PCV below 25% at the second visit and were also withdrawn from study.
Compliance: estimated tablet consumption was 81.1 and 81.7 tablets in the iron and placebo groups respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear - randomised but method unclear.
Allocation concealment?NoInadequate.
Blinding?
All outcomes
NoInadequate. Participant and provider not blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% lost to follow up.

Milman 1991

MethodsRandomisation: method unclear. Allocation concealment: unclear. Blinding: adequate. Participant and provider blinded. Outcome assessor unclear. Loss to follow up: adequate. Less than 20% lost to follow up.
Participants248 healthy Caucasian Danish women attending Birth Clinic in Copenhagen, Denmark within 9-18 wks of gestation and normal pregnancy. Exclusion criteria: complicated delivery, excessive smoking (> 9 cigarettes/day).
InterventionsWomen were randomly assigned to receive 66 mg of elemental iron as ferrous fumarate daily (n = 121) or placebo (n = 127) until delivery.
Supplementation started at 8-9th week until delivery.
OutcomesMaternal: haemoglobin, haematocrit, erythrocyte indices, iron status, serum ferritin, serum transferrin saturation, serum erythropoietin at baseline and every 4th week until delivery, and 1-8 wks after delivery in sub sample; pregnancy complications.
Infant: birthweight, serum ferritin, transferrin saturation and serum erythropoietin in umbilical cord.
NotesUnsupervised.
Of the 248 women, 20 placebo and 21 iron treated were excluded by the authors in some of the analysis for the following reasons: withdrawn consent, 10; uterine bleeding episodes, 5; placental insufficiency, placenta praevia and abruptio placentae, 7; pre-eclampsia, 3; partus prematurus, 5; excessive smoking, 3. Sample size has been adjusted for intention to treat ITT.
Compliance: number of tablets consumed was 159 +/- 38 and 93 +/-43 tablets in the iron treated and placebo groups respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
YesAdequate. Participant and provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 20% lost to follow up.

Mukhopadhyay 2004

MethodsRandomisation: adequate. computer generated random numbers. Block randomisation (block size = 10). Allocation concealment: inadequate - not used. Blinding: inadequate. Open to participants, care providers and outcome assessor. Loss to follow up: inadequate. More than 20% excluded.
Participants111 apparently healthy pregnant women with less than 20 wks and no prior intake of iron supplements during this pregnancy with Hb equal or higher than 100 g/L and singleton pregnancy in New Delhi, India. Women who were taking anti-epileptics or anti-thyroid medications, had history of menorrhagia, bleeding disorders, chronic peptic ulcers, bleeding piles, thalassaemia or other haemoglobinopathies, or history of haemorrhage in present or past pregnancies were excluded.
InterventionsWomen were randomly assigned to one of two groups: group 1 received two tablets of 100 mg elemental iron and 500 ug folic acid each (total 200 mg iron and 1000 ug folic acid), to be taken only once a week, one tablet before lunch and another tablet before dinner; group 2 received one tablet of 100 mg elemental iron and 500 ug folic acid daily. Women were advised to take the supplements 30 minutes before the meals and not with tea, coffee or milk. Also, women were advised to take calcium supplements after meals (500 mg elemental calcium twice daily). Iron supplementation started between 14 and 20 wks until delivery. Deworming, if required, was carried out with Mebendazole 100 mg twice a day for 3 days in the second trimester.
OutcomesMaternal: Hb, serum ferritin concentrations at baseline and at 32-34 wks, prevalence of anaemia, compliance to treatment, presence of intestinal parasites.
Infant: birth weight.
NotesUnsupervised.
Compliance measured by pill count and interview. compliance was 85% in group 1 (intermittent) and 40% in group 2 (daily).
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate. computer generated random numbers. Block randomisation (block size=10).
Allocation concealment?NoNot used.
Blinding?
All outcomes
NoInadequate - open to participants, care providers and outcome assessor.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% excluded.

Paintin 1966

MethodsRandomisation: method unclear. Allocation concealment: adequate - sequentially numbered. Blinding: adequate - participant and provider blinded. Loss to follow up: adequate - less than 5%.
Participants180 primigravidae women with less than 20 wk gestation and Hb > 100 g/L attending antenatal clinic in Aberdeen Maternity Hospital, Scotland, United Kingdom.
InterventionsWomen were randomly assigned to one of three groups: group 1 received 3 tablets containing 4 mg elemental iron each (total 12 mg daily); group 2 received 3 tablets containing 35 mg elemental iron (total 105 mg elemental iron daily) and group 3 received placebo. Intervention was from week 20 to week 36 of gestation.
OutcomesMaternal: haemoglobin, haematocrit at baseline, and at wks 20, 30, 36 of gestation and 7-13 days postpartum; plasma volume at 30 wks, total red cell volume, serum iron and total iron binding capacity at 30 wks, subjective health and side effects at 30 wks.
NotesUnsupervised.
Compliance estimated by measuring tablets returned. Authors report good compliance.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?YesAdequate, sequentially numbered.
Blinding?
All outcomes
YesAdequate - participant and provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 5%.

Pita Martin 1999

MethodsRandomisation: inadequate - quasi randomised. Allocation concealment: not used. Blinding: inadequate - neither participant nor provider blinded. Outcome assessor blinded. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants203 healthy pregnant women with normal blood pressure at first visit, attending antenatal care clinic at Diego Paroissien Hospital in the Province of Buenos Aires, Argentina.
InterventionsWomen were assigned to one of three groups: group 1 received 60 mg of elemental iron as ferrous fumarate daily; group 2 received 60 mg elemental iron every three days; and group 3 received no treatment. Supplementation started at 8-28 wks until 34-37 wks of gestation.
OutcomesMaternal: Hb, haematocrit, erythroporphyrin, serum ferritin concentration at baseline and at 34-37wk gestation, premature delivery.
Infant: birthweight.
NotesUnsupervised.
Women from control group (group 3) were not assigned randomly. These women were recruited but due to delays in the acquisition of the iron tablets and the progression of their pregnancies without supplementation they were left as controls in the study.
This study is used only for comparison between intermittent and daily iron supplementation (group 2 vs group 1).
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi randomised.
Allocation concealment?NoNot used
Blinding?
All outcomes
NoInadequate - neither participant nor provider blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% lost to follow up.
Free of selective reporting?No 
Free of other bias?No 

Preziosi 1997

MethodsRandomisation: adequate - by random numbers. Allocation concealment: adequate - packages of tablets numbered by manufacturer. Blinding: adequate - participant and provider blinded. Outcome assessor blinded. Loss to follow up: unclear.
Participants197 healthy pregnant women 17-40 years of age, with 28 +/- 3 wks of gestation attending antenatal care clinic in a Mother-Child Health Center in Niamey, Niger.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 100 mg of elemental iron as ferrous betainate daily; group 2 received placebo.
Supplementation was from 28 +/- 3 wks of gestation until delivery.
OutcomesMaternal: haemoglobin concentration, mean corpuscular volume, haematocrit, erythrocyte protoporphyrin, serum iron, transferrin, total iron binding capacity, serum ferritin concentrations, at baseline and at the first stage of labor and at 3 and 6 months postpartum, prevalence of iron deficiency and iron deficiency anaemia.
Infant: birthweight and length, haemoglobin concentration, mean corpuscular volume, erythrocyte protoporphyrin, serum iron, transferrin saturation, serum ferritin concentrations at birth and at 3 and 6 months; Apgar scores.
NotesSupervised by physicians who recorded tablet consumption.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate - by random numbers.
Allocation concealment?YesAdequate, packages of tablets numbered by manufacturer.
Blinding?
All outcomes
YesAdequate - participant and provider blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
UnclearUnclear.

Pritchard 1958

MethodsRandomisation: method unclear. Allocation concealment: unclear. Blinding: inadequate. Neither participant nor provider blinded. Outcome assessor not blinded. Loss to follow up: unclear.
Participants172 pregnant women believed to be in the second trimester of pregnancy by date of last menstrual period attending antenatal care clinic in Parland Memorial Hospital, Dallas, Texas, USA.
InterventionsWomen were randomly assigned to one of three interventions: group 1 received 1000 mg of iron intramuscularly as iron-dextran; group 2 received 112 mg of elemental iron as ferrous gluconate daily in 3 tablets; group 3 received placebo tablets.
Supplementation started during 2nd trimester until delivery.
OutcomesMaternal: haemoglobin concentration at baseline and at delivery.
NotesUnsupervised.
Only groups 2 (oral iron) and 3 (placebo) were included in this review.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate. Neither participant no provider blinded. Outcome assessor not blinded.
Incomplete outcome data addressed?
All outcomes
UnclearUnclear.
Free of other bias?No 

Puolakka 1980

MethodsRandomisation: method unclear. Allocation concealment: unclear. Blinding: inadequate - open. Loss to follow up: adequate - less than 20% lost to follow up.
Participants32 healthy non-anaemic pregnant women attending antenatal care at maternity centres of Oulu University Central Hospital, Finland with uncomplicated pregnancy of less than 16 wks, and no earlier haematological problems.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 200 mg of elemental iron as ferrous sulphate daily; group 2 received no treatment.
Supplementation started at 16th week of gestation until one month postpartum.
OutcomesMaternal: haemoglobin, haematocrit, red cell count, leucocyte count, reticulocytes, mean corpuscular volume, mean corpuscular haemoglobin concentration, mean corpuscular haemoglobin, serum iron, total iron binding capacity, transferrin, vitamin B12, whole folate, and serum ferritin concentration at baseline, and at wks, 16, 20, 24, 28, 32, 36, 40 and 5 days, 1, 2, and 6 months postpartum. Bone marrow aspirates at 16th and 32nd week and at 2 months postpartum.
Infant: birthweight, Apgar scores at 5 minutes.
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - open.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up.

Ridwan 1996

MethodsRandomisation: adequate - block randomised by randomised numbers table. Allocation concealment: not used. Blinding: inadequate - participant and care provider not blinded. Outcome assessor blinded. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants176 pregnant women with 8-24 wks of gestation attending antenatal care at six health centres in West Java, Indonesia.
InterventionsHealth centres were randomised to one of two interventions: weekly regimen, where women received 120 mg of elemental iron as ferrous sulphate with 0.50 mg of folic acid; or daily regimen where women received 60 mg of elemental iron as ferrous sulphate with 0.25 mg of folic acid daily until week 28-32 of gestation.
Supplementation started at 8-24 wks until 28-32 wks of gestation.
OutcomesMaternal: haemoglobin concentration, serum ferritin, weight at baseline and at 28-32 wks of gestation; compliance to treatment and prevalence of parasitic infections.
NotesUnsupervised but frequent contact with participants.
Randomisation was made by health centres.
Compliance measured by stool tests was 54.3% in the daily group and 62.2% in the weekly group.
Adjustment by intra class correlation coefficient to show effective sample size taking into account cluster randomisation and unit of analysis.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate - block randomised by randomised numbers table.
Allocation concealment?NoNot used.
Blinding?
All outcomes
NoInadequate - participant and care provider not blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% lost to follow up.

Robinson 1998

MethodsRandomisation: inadequate - by alternating numbers. Allocation concealment: unclear. Blinding: inadequate - participant and provider not blinded. Outcome assessor blinded. Loss to follow up: inadequate - more than 20% lost to follow up.
Participants680 pregnant women served by 11 health centres from five sub districts on or near the western end of the island of Seram in the Province of Maluku, Indonesia.
InterventionsWomen were assigned to one of two interventions: group 1 received 60 mg of elemental iron as ferrous sulphate with 0.25 mg of folic acid daily by a traditional birth attendant; group 2 received 120 mg of elemental iron as ferrous sulphate with 0.5 mg of folic acid once a week by the traditional home visiting birth attendants. A control group was formed by participants receiving traditional iron supplements (60 mg elemental iron) with folic acid from health centres, self administered without incentive.
OutcomesMaternal: haemoglobin concentration at baseline and after 12 and 20 wks of supplementation; serum ferritin at baseline and after 12 wks of supplementation; compliance.
NotesDaily group and control unsupervised. Weekly group supervised.
Each group was further assigned alternatively by registration number to receive 500 mg of mebendazole or a placebo at the second trimester of pregnancy.
Only groups 1 and 2 are used in this analysis. Compliance was 69.6%, 96.2% and 46.9% for groups 1, 2 and control respectively. The study area is endemic to malaria.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi-randomised, by alternating numbers.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - participant and provider not blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% lost to follow up.

Romslo 1983

MethodsRandomisation: method unclear. Allocation concealment: unclear. Blinding: inadequate - participant blinded. Provider and outcome assessor unclear. Loss to follow up: adequate - less than 20%.
Participants52 healthy pregnant women attending outpatient Women's clinic at Haukeland Hospital, Bergen, Norway within first 10 wks of a normal singleton pregnancy with uncomplicated delivery at 37-42 wks.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 200 mg of elemental iron as ferrous sulphate daily; group 2 received placebo.
Supplementation started at 10 wks of gestation.
OutcomesMaternal: haemoglobin, haematocrit, plasma cell volume, erythrocyte count, leucocyte count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, serum iron, iron binding capacity, erythrocyte protoporphyrin, serum ferritin at baseline and every month during 2nd trimester and every 2 wks until delivery.
Infant: birthweight and Apgar scores.
NotesUnsupervised.
Compliance measured by tablet count was 55% in the iron-treated group.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear
Blinding?
All outcomes
NoInadequate - participant blinded. Provider and outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20%.

Siega-Riz 2001

MethodsRandomisation: adequate - by using random number generator. Allocation concealment: adequate. Blinding: adequate - participant, provider and outcome assessor blinded to treatment. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants429 non anaemic iron replete women with less than 20 wks of gestation attending who had not taken supplements containing iron in the last month, with a singleton pregnancy attending the prenatal clinic at the Wake County Human services in Raleigh, North Carolina, USA.
InterventionsWomen were randomly assigned to one of two groups: group 1 received multivitamin/mineral supplements containing 30 mg of iron as ferrous sulphate daily or group 2 received multivitamin/mineral supplements containing 0 mg of iron (no iron) until 29 wks of gestation. Supplementation started on average at 12 wks. The multivitamin/mineral supplement contained the following: vitamin A 4000 IU; vitamin D 400 IU; vitamin C 70 mg; folic acid 0.5 mg; thiamine 1.5 mg; riboflavin 1.6 mg; niacin 17 mg; vitamin B6 2.6 mg; vitamin B12 2.5 ?g; calcium 200 mg; magnesium 100 mg; copper 1.5 mg; zinc 15 mg. Folic acid supplements were prescribed for all women who had received the positive pregnancy test until the first prenatal visit.
OutcomesMaternal: prevalence of anaemia, iron repletion andiron deficiency anaemia at 26-29 wks, side effects, compliance to treatment, iron status (haemoglobin concentration, serum ferritin at 26-29 wks, preterm delivery.
Infant: birthweight, proportion of low birthweight, small-for-gestational age.
NotesUnsupervised.
Compliance measured by pill counts and a questionnaire and was 66% in the iron group and 63% in the control group. Compliance was also measured by the Medication Event Monitoring System (MEMS) in a sub sample of 100 women.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate, by using random number generator.
Allocation concealment?YesAdequate.
Blinding?
All outcomes
YesAdequate - participant, provider and outcome assessor blinded to treatment.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 20% lost to follow up.

Svanberg 1975

MethodsRandomisation: unclear. Allocation concealment: unclear. Blinding: adequate. Participants blind, care provider blind and outcome assessor blinded. Loss to follow up: adequate - less than 20% lost to follow up.
Participants60 healthy primiparous women attending antenatal care clinic in Goteborg, Sweden with uncomplicated pregnancy and less than 14 wks of gestation and with Hb concentrations above 120 g/L who had not received iron supplements in the previous 6 months or parenteral iron at any previous time. Women whose Hb concentration fell below 100 g/L during the study period were excluded and received immediate therapy.
InterventionsWomen were randomly allocated to receive 200 mg of elemental iron as a sustained release preparation of ferrous sulphate daily or placebo from 12 wks of gestation until 9 wks postdelivery.
OutcomesMaternal: iron absorption measurements; haemoglobin concentration, haematocrit, bone marrow haemosiderin, mean corpuscular haemoglobin concentration, total iron binding capacity, transferrin saturation at baseline, and at wks 16, 20, 24, 28, 32, and 35; and 8-10 wks after delivery.
NotesUnsupervised.
Compliance measured by remaining pills count was 86 +/- 3%.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
YesAdequate. Participants blind, care provider blind and outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up.

Taylor 1982

MethodsRandomisation: randomised but method unclear. Allocation concealment: unclear. Blinding: inadequate - open. Loss to follow up: adequate - less than 20% lost to follow up.
Participants48 healthy pregnant women with no adverse medical or obstetric history attending antenatal care clinic in Newcastle, England, United Kingdom before 12 wks of gestation.
InterventionsWomen were randomly allocated to one of two groups: group 1 receive 325 mg of ferrous sulphate (about 65 mg elemental iron) and 350 ug of folic acid daily from 12 wks until delivery and group 2 received no supplements.
OutcomesMaternal: haemoglobin concentration, serum ferritin, mean cell volume at 12 wks and every 4 wks until delivery, and at 6 days, 6 wks and 6 months after delivery; plasma volume at 12 and 36 wks of gestation.
Infant: birthweight, infant death, admission to special care unit.
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - open.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% lost to follow up.

Tura 1989

MethodsRandomisation: adequate by random number lists. Allocation concealment: adequate, sealed envelopes progressively numerated. Blinding: inadequate - open. Loss to follow up: adequate - less than 20%.
Participants254 non-anaemic non-iron deficient healthy pregnant women from multiple centres in Italy. Exclusion criteria: acquired or congenital anaemia, haemoglobinopathies, thalassaemia, medically or surgically treated cardiopathy, abortion, hypertension, gastric resection, metabolic or endocrine disorder, hepatic or renal disease, epilepsy or another neurological disease, previously treated for cancer, alcohol or substance dependence.
InterventionsWomen were randomly assigned to receive 40 mg of elemental iron containing 250 g of ferritin in a microgranulated gastric resistant capsule daily or no treatment from 12-16 wks of gestation until the end of puerperium.
OutcomesMaternal: haemoglobin concentration, red cell count, mean corpuscular volume, serum iron, total transferrin, transferrin saturation, serum ferritin at 12-16 wks, two times during pregnancy, at 38-42 wks, and at puerperium 48-52 wks.
NotesUnsupervised.
The study included another sample of women who were iron deficient and received two forms of iron preparation. This sample is not used in this review.
Compliance reported as higher than 98.5%.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by random number lists
Allocation concealment?YesAdequate, sealed envelopes progressively numerated.
Blinding?
All outcomes
NoInadequate - open
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% losses to follow up.

Van Eijk 1978

MethodsRandomisation: method unclear. Allocation concealment: not used. Blinding: inadequate - open. Loss to follow up: adequate - less than 20%.
Participants30 pregnant women with uncomplicated pregnancies and deliveries attending antenatal care clinic at the University Hospital Obstetric Unit in Rotterdam, Netherlands.
InterventionsWomen received 100 mg of elemental iron as ferrous sulphate daily or no treatment from the third month of gestation until delivery. Follow up was until 12 wks after delivery.
OutcomesMaternal: haemoglobin concentration, serum iron, serum ferritin, transferrin concentration at baseline and every 3-4 wks until delivery, and three months after delivery.
Infant: haemoglobin concentration, transferrin, serum iron, serum ferritin in cord blood at term.
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?NoNot used.
Blinding?
All outcomes
NoInadequate - open.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% losses to follow up.

Wallenburg 1983

MethodsRandomisation: adequate - by random table numbers. Allocation concealment: adequate by means of sealed envelopes. Blinding: inadequate. Participant nor provider blinded. No placebo used. Loss to follow up: adequate - less than 20%.
Participants44 non-anaemic Caucasian women with singleton pregnancy and no major illnesses attending the University Hospital Obstetrical Clinic of the Erasmus University in Rotterdam who had not received iron supplementation during their first visit.
InterventionsWomen were randomly assigned to one of two groups:
group 1: received 105 mg of elemental iron as ferrous sulphate daily in a sustained release preparation and group 2: received no iron supplement.
Supplementation started at 14-16th week of gestation until delivery.
OutcomesMaternal: haemoglobin, serum iron, serum transferrin and serum ferritin concentrations at 16, 28, 36 wks, delivery, 6 and 12 wks postpartum.
NotesUnsupervised.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate - by random table numbers.
Allocation concealment?YesAdequate, by means of sealed envelopes.
Blinding?
All outcomes
NoInadequate. Participant nor provider blinded. No placebo used.
Incomplete outcome data addressed?
All outcomes
YesAdequate - less than 20% losses to follow up.

Willoughby 1967

MethodsRandomisation: method unclear. Allocation concealment: unclear. Blinding: unclear. Loss to follow up: adequate - less than 20%.
Participants3599 pregnant women with Hb above 100 g/L at their antenatal care clinic visit at Queen's Mother's Hospital in Glasgow, Scotland, United Kingdom. Women who reported not taken the tablets regularly ere excluded as well as those diagnosed with anaemia during the study.
InterventionsWomen were randomly allocated to one of five interventions: group 1 received no prophylactic supplements; group 2 received 105 mg of elemental iron daily as chelated iron aminoates; group 3 received 105 mg of elemental iron with 100 ug of folic acid; group 4 received 105 mg of elemental iron daily with 300 ug of folic acid; and group 5 received 105 mg elemental iron daily with 450 ug of folic acid.
Starting and ending time of supplementation variable.
OutcomesMaternal: haemoglobin concentration at baseline and in every visit, at early puerperium and during postnatal visit; incidence of obstetric complications. incidence of megaloblastic anaemia.
Infant: Hb and whole blood folate levels a 6 wks of age. Incidence of neonatal complications.
NotesUnsupervised.
Groups 3-5 were merged for the purposes of this review.
Women were excluded from the trial and the analysis if they were diagnosed as anaemic.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearMethod unclear.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
UnclearUnclear.
Incomplete outcome data addressed?
All outcomes
UnclearAdequate - less than 20% losses to follow up. However, women were excluded from the trial and the analysis if they were diagnosed as anaemic.
Free of selective reporting?No 

Wills 1947

MethodsRandomisation: inadequate - alternate. Allocation concealment: not used. Blinding: adequate - participant and care provider blinded. Outcome assessor blinded. Loss to follow up: inadequate. More than 20% lost to follow up.
Participants500 pregnant women attending antenatal care clinic at the Royal Free Hospital in London, England, United Kingdom during wartime, with ages between 18-43 years. Women with severe anaemic or rheumatoid arthritis were excluded.
InterventionsWomen were alternatively allocated to receive 580 mg of elemental iron as ferrous gluconate daily or placebo from their first visit.
Supplementation starting variable and ending time unclear.
OutcomesMaternal: haemoglobin concentration using the Haldane method at baseline and every 4 wks until delivery, then 1 day, 2-4 days, 5-16 days and 6 wks postpartum; serum protein and pregnancy complications (not reported by group).
Infant: birthweight (not reported).
NotesUnsupervised.
The study was conducted during wartime and a bomb incident interrupted the work allowing only a small portion of original sample studied and reported. Women were receiving special food rations.
Compliance not reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi randomised, alternate.
Allocation concealment?NoNot used.
Blinding?
All outcomes
YesAdequate - participant and care provider blinded. Outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
UnclearInadequate. More than 20% lost to follow up.

Winichagoon 2003

MethodsRandomisation: cluster randomisation but method unclear. Allocation concealment: not used. Blinding: inadequate - open. Loss to follow up: inadequate - more than 20% lost to follow up.
Participants484 apparently healthy pregnant women with 13-17 wks of gestation who had not received iron supplements before enrolling in the study, and who had a haemoglobin concentration > 80 g/L attending antenatal care clinics at the district hospital and 7 health centres from 54 villages in the Province of Khon-Kaen in northeast Thailand.
InterventionsThe villages were grouped according to size and then randomised in 4 clusters to one of three interventions: group 1 received a daily regimen providing 60 mg of elemental iron as ferrous sulphate with 0.25 mg of folic acid daily; group 2 received 120 mg of elemental iron with 3.5 mg of folic acid once a week; and group 3 received 180 mg of elemental iron as ferrous sulphate with 3.5 mg of folic acid once a week.
Supplementation started at 15 +/- 2 wks until delivery.
OutcomesMaternal: haemoglobin concentration, serum ferritin, free erythrocyte protoporphyrin at baseline and at 35 +/- 2 wks of gestation, and 4-6 months postpartum; haematocrit prior to delivery; weight at baseline and at 35 wks of gestation; compliance, haemoglobin type, and hookworm prevalence.
Infant: birthweight, haemoglobin concentration and serum ferritin at 4-6 months.
NotesUnsupervised.
Compliance not reported.
Values adjusted to reflect effective sample size for cluster randomisation.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear - cluster randomisation but method unclear.
Allocation concealment?NoNot used.
Blinding?
All outcomes
NoInadequate - open.
Incomplete outcome data addressed?
All outcomes
NoInadequate - more than 20% lost to follow up.
Free of other bias?No 

Young 2000

MethodsRandomisation: adequate by computer-generated random number table. Allocation concealment: unclear. Blinding: inadequate - neither participant nor provider blinded. Outcome assessor unclear. Loss to follow up: inadequate. More than 47% lost to follow up.
Participants413 healthy non-severely anaemic pregnant women attending antenatal care at Ekwendeni Hospital or its mobile clinics in northern Malawi with less than 30 wks of gestation at their first visit, stratified by initial haemoglobin concentration before randomisation.
Supplementation starting time variable (22.2 +/- 4.8 wks) and ending time variable (32.2 +/- 4.4 wks of gestation).
InterventionsWomen were randomly assigned within each anaemia grade category to one of two interventions: group 1 received 120 mg of elemental iron as ferrous sulphate with 0.5 mg of folic acid once a week; group 2 received 60 mg of elemental iron as ferrous sulphate with 0.25 mg of folic acid daily.
OutcomesMaternal: haemoglobin concentration at baseline and after 8 wks of supplementation; compliance, presence of side effects, and prevalence of anaemia.
NotesUnsupervised.
Average gestational age at start was 22.2 +/- 4.8 wk and 32.2 +/- 4.4 wk at the end of study.
Compliance estimated by self reporting was 76% and 60% in the weekly and daily groups respectively.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate by computer-generated random number table.
Allocation concealment?UnclearUnclear.
Blinding?
All outcomes
NoInadequate - neither participant nor provider blinded. Outcome assessor unclear.
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 47% lost to follow up.
Free of selective reporting?NoCompliance estimated by self reporting was 76% and 60% in the weekly and daily groups respectively.
Free of other bias?No 

Yu 1998

MethodsRandomisation: inadequate - quasi randomised. Allocation concealment: inadequate. Blinding: inadequate. Participant and care provider not blinded. Outcome assessor blinded. Loss to follow up: inadequate. More than 54% lost to follow up.
Participants51 healthy pregnant women with 18-22 wks of gestation who had not taken supplements or medication in the previous six months attending public health centre in Ulsan, South Korea.
InterventionsWomen were randomly assigned to one of two treatments: group 1 received 160 mg of elemental iron in one intake once a week; group 2 received 80 mg of elemental iron daily. Elemental iron was given in the form of ferrous sulphate. Women with low Hb were assigned by the trialists to daily regimen.
Supplementation started at 20.1 wks and 20.2 wks of gestation for groups 1 and 2 respectively.
OutcomesMaternal: haemoglobin concentration, serum ferritin, red blood cell count, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, serum iron, total iron binding capacity, transferrin saturation at baseline and after treatment; zinc status before and after treatment, weight gain, nutrient intake before and after treatment.
Infant: birthweight.
NotesUnsupervised.
No compliance reported for all the groups. Analysis reported on high compliers only.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?NoInadequate - quasi randomised.
Allocation concealment?NoInadequate
Blinding?
All outcomes
NoInadequate. Participant and care provider not blinded. Outcome assessor blinded
Incomplete outcome data addressed?
All outcomes
NoInadequate. More than 54% lost to follow up.
Free of selective reporting?NoNo compliance reported for all the groups. Analysis reported on high compliers only.

Ziaei 2007

MethodsRandomisation: adequate with table of random numbers. Allocation concealment: adequate. Coded bottles. Blinding: adequate - participants and care provider and outcome assessor blinded. Loss to follow up: adequate. Less than 5% lost to follow up.
Participants750 apparently healthy non-smoking non-anaemic (with Hb higher or equal to 132 g/L) pregnant women in early stage of second trimester, BMI 19.8-26 kg/m2 and age 17-35 years with singleton pregnancy attending prenatal care in Tehran, Iran. Women with history of threatened abortion in the present pregnancy or diseases related with polycythaemia such as asthma and chronic hypertension were not included.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 50 mg of elemental iron as ferrous sulphate with 1 mg folic acid daily and group 2 received placebo and 1 mg of folic acid daily.
Outcomes

Maternal: haemoglobin at 24-28 wk, 32-36 wk, premature delivery, weight gain, C-sections, hypertensive disorders, severe anaemia, haemoconcentration, iron deficiency, iron deficiency anaemia, mean corpuscular volume, mean corpuscular haemoglobin and Hb concentrations at term, severe anaemia and haemoconcentration at any time during 2-3 trimesters, symptomatic tract infection, puerperal infection, antepartum and postpartum haemorrhage, transfusion provided, side effects (any), diarrhoea, constipation, nausea, heartburn, vomiting, placental abruption, premature rupture of membranes.

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

NotesUnsupervised.
Supplementation started 13.07 ± 2.02 wks gestation for group 1 and 13.66 ± 3.45 wks gestation for the placebo group and lasted until after delivery.
No compliance reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate with table of random numbers.
Allocation concealment?YesAdequate. Coded bottles.
Blinding?
All outcomes
YesAdequate - participants and care provider and outcome assessor blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 5% lost to follow up.

Ziaei 2008

  1. a

    Fe: iron
    Hb: haemoglobin
    ITT: intention to treat
    MCV: mean corpuscular volume
    PCV: plasma cell volume
    SES: socioeconomic status
    vs: versus
    wk(s): week(s)

MethodsRandomisation: adequate with table of random numbers. Allocation concealment: adequate. Coded bottles. Blinding: adequate - participants and care provider blinded. Loss to follow up: adequate. Less than 5% lost to follow up.
Participants244 pregnant women 17-35 years of age attending prenatal care in Tehran, Iran, with BMI between 19.8-26 kg/m2, and 13-18 wks of gestation, with singleton pregnancy and non-anaemic (Hb 132 g/L or higher) and normal serum ferritin (15 ug/L or higher). Women who smoked, had history of diseases such as polycythaemia, asthma, or chronic hypertension, or a history or threatened abortion in the present pregnancy were excluded.
InterventionsWomen were randomly assigned to one of two groups: group 1 received 50 mg of elemental iron as ferrous sulphate daily and group 2 received placebo from 20th week of gestation until delivery. All women received 50 mg elemental iron as ferrous sulphate after delivery for 6 wks.
OutcomesMaternal: haemoglobin, haematocrit, serum ferritin at baseline, at time of delivery, one week post-partum and six wks post-partum, postpartum haemorrhage, C-sections.
NotesUnsupervised.
No compliance reported.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesAdequate with table of random numbers.
Allocation concealment?YesAdequate. Coded bottles.
Blinding?
All outcomes
YesAdequate - participants and care provider blinded.
Incomplete outcome data addressed?
All outcomes
YesAdequate. Less than 5% lost to follow up.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    IU: international units
    Hb: Haemoglobin

    wk(s): week(s)

Aaseth 200167 non-anaemic pregnant women attending prenatal care clinics in Kingsvinger Hospital, in Kingsvinger, Norway were allocated to a daily regimen of either 100 mg Fe or 15 mg Fe. Both groups received iron at different doses. No comparisons allowed within the scope of this review.
Abel 2000Community based study in Vellore district, India using a pre-post experimental design measuring the impact of an iron supplementation program, helminthic treatment and education intervention in the prevalence of anaemia in the different trimesters of pregnancy. The same pregnant women were not followed.
Afifi 1978260 pregnant women from Cairo, United Arab Republic were randomly allocated to two forms of iron: a slow release ferrous sulphate preparation and ferrous sulphate in addition to folic acid. Both groups received iron supplementation in different preparations. No comparisons allowed within the scope of this review.
Ahn 2006209 pregnant women between 18 and 45 years of age, attending outpatient obstetric clinics at North York General Hospital and the Hospital for Sick Children in Toronto, Canada were randomly assigned to receive multiple micronutrient supplements containing 60 mg of iron as ferrous fumarate (Materna) or another supplement (PregVit) to be taken twice daily with the morning dose containing 35 mg of iron and the evening dose containing 300 mg calcium, among other vitamins and minerals. Both groups received iron in different doses as well as other vitamins and minerals. No comparisons allowed within the scope of this review.
Angeles-Agdeppa 2003744 apparently healthy pregnant (with less than 20 wks) and non-pregnant women of reproductive age (15-49 years) from the municipalities of Calasiao, Binmaley and Santa Barbara, Philippines who were pregnant or most likely to become pregnant within the 12-month duration of the study, and who volunteered to participate in the study were provided two preparations of iron-folic acid supplements. Women with severe anaemia or history of malaria were excluded. Non-pregnant women were prescribed four capsules monthly each containing 60 mg of elemental iron and 3.5 mg folic acid to be taken once weekly before bedtime (to be purchased by the women in local drugstores). Pregnant women received free of cost four capsules monthly each containing 120 mg of elemental iron and 3.5 mg of folic acid to be taken once a week before bedtime until delivery and for 3 months thereafter. Pregnant women seen at the health centres with 20 wks or more of gestation were advised to take their usual daily dose of iron-folic acid tablets containing 60 mg of elemental iron and 0.5 mg of folic acid. Women were followed for 12 months. Haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin concentration, serum ferritin, transferrin receptors, prevalence of iron deficiency and anaemia, compliance were assessed at baseline, 4.5, 9 and 12 months. There was not randomisation and the control group was not appropriate for comparisons.
Babior 1985Fifteen healthy pregnant women 22-32 years old, in the first trimester of pregnancy from Boston, Massachusetts, USA were randomly assigned to three different multiple micronutrient preparations to assess absorption of iron.
Bencaiova 2007260 women with singleton pregnancy in Zurich, Germany, were randomised at 21-24 wks of gestation to receive either intravenous iron group (further divided into two doses of 200 mg iron saccharate or three doses of 200 mg iron) or 80 mg elemental iron as ferrous sulphate daily. Both groups received iron in different routes of administration. No comparisons allowed within the scope of this review.
Berger 2003864 apparently healthy married pregnant and non-pregnant nulliparous women of reproductive age planning to have a child soon from 19 rural communes of the Thanh Mien district in Hai Duong province, Vietnam were invited to participate and assigned to one of the following interventions according to their pregnancy status at baseline: women who were pregnant received free of charge UNICEF tablets containing 60 mg of elemental iron and 0.25 mg of folic acid to be taken daily and women who were non-pregnant were prescribed pink packs of tablets containing 60 mg of elemental iron and 3.5 mg of folic acid that they could buy at their village from the Women's Union, to be taken once weekly. If these women became pregnant, women received red packs of tablets containing 120 mg of elemental iron and 3.5 mg of folic acid free of charge to be taken once weekly. After delivery women were given tablets containing 60 mg of iron and 0.5 mg of folic acid free of charge for 3 months to be taken weekly. Haemoglobin concentration, serum ferritin, and serum ferritin receptors, prevalence of anaemia and iron deficiency and compliance were measured at baseline, at 4.5, 9 and 12 months. This is not a randomised study and no comparisons can be made for the aims of this review.
Bergsjo 1987Planned study registered at the Oxford Database of Perinatal Trials. Author contacted and informed the project was not completed.
Blot 1980203 pregnant women attending prenatal care clinics during their 6th month visit were randomly allocated to either 105 mg of elemental iron with 500 mg of ascorbic acid or a placebo. Both groups received iron.
Brown 1972109 pregnant women attending prenatal care clinics in Manchester, England were randomly allocated to one of three groups: group A: one tablet daily given in 'reminder packs', group B: one tablet daily given in loose forms, or group C two tablets daily given in loose form. Tablets contained 50 mg of elemental iron as slow release ferrous sulphate and 400 ug of folic acid. All groups received iron. No comparisons allowed within the scope of this review.
Burslem 1968472 pregnant women attending the booking clinic were alternatively allocated to two forms of iron: a slow release ferrous sulphate preparation and folic acid or combined conventional ferrous sulphate/folic acid. Both groups received iron supplementation in different preparations. No comparisons allowed within the scope of this review.
Buss 198118 pregnant women were randomly assigned to receive either a tablet containing 80 mg of elemental iron with a new mucous membrane vaccine (Tardyferon® or a tablet containing 80 mg elemental iron with 0.35 mg folic acid (Tardyferon-Fol®) for a period of 3 months. All women received iron. No comparisons allowed within the scope of this review.
Carrasco 1962Two liquid preparations were used in this study: one with D-sorbitol and the other without. Both preparations contained vitamin B12, vitamin B6, ferric pyrophosphate and folic acid.
Casanueva 2003a120 singleton pregnant women attending the Instituto Nacional de Perinatologia in Mexico City, Mexico with haemoglobin concentrations higher than 115 g/L at 20 wks of gestation (equivalent to 105 g/L at sea level) were randomly assigned to one of two groups, group 1: one tablet containing 60 mg of elemental iron, 200 ug folic acid and 1 ug vitamin B12 given daily, and group 2: two tablets (total 120 mg of elemental iron, 400 ug folic acid, and 2 ug vitamin B12) to be taken once weekly. Haemoglobin and serum ferritin concentrations were measured every 4 wks from wks 20 until 36, side effects, compliance, birth weight, gestational age at birth, anaemia, iron deficiency. The addition of vitamin B12 to the formulation makes this study ineligible to the inclusion criteria. No comparisons allowed within the scope of this review.
Chanarin 1965190 pregnant women attending antenatal clinic in St Mary's Hospital in London, England were randomly assigned to one of three groups: ferrous fumarate, ferrous fumarate and folic acid, or placebo. The outcomes measured include full blood count at 20th, 30th, 35th and 39th week of gestation and 6th day after delivery. The paper does not report standard deviations in the variables measured and no data can be extracted.
Chawla 199581 pregnant women with 20 +/- wks of gestation from Ludhiana City, India were divided to one of three groups: group 1, 60 mg of elemental iron ad 500 ug of folic acid daily; group 2, 60 mg of elemental iron and 2,000,000 IU of vitamin A, or group 3, who did not receive any supplements. Supplementation was for a period of 15 wks. Outcomes measured included haemoglobin, red blood cell count, total iron binding capacity, transferrin saturation, serum iron, serum vitamin A at baseline and at 36 +/- 2 wks of gestation. Poor methodological quality. None of the outcomes pre-specified in our protocol were recorded due to the varied time of final measurements.
Coelho 2000100 pregnant women with 20-34 wks of gestation attending the antenatal clinic at The Bandra Holy Family Hospital, Bandra, Mumbai India were randomly assigned to receive 30 mg elemental iron + other essential micronutrients daily or 116 mg elemental iron, folic acid, zinc and vitamin C daily. Outcomes included haemoglobin concentration, maternal weight gain, infant birth weight and maternal compliance and side effects Both groups received iron supplementation. No comparisons allowed within the scope of this review.
Cook 1990200 women were randomly assigned to receive 50 mg iron daily given either as Gastric Delivery System (GDS) or conventional ferrous sulphate. Gastrointestinal side effects were evaluated. The participants were non-pregnant women.
Dawson 198742 healthy women with less than 16 wks of pregnancy were randomly assigned to receive either a multiple micronutrient supplement containing 65 mg of elemental iron or one multiple micronutrient supplement with no iron, calcium, zinc and copper and pantothenic acid. Both groups received different multivitamin/multi mineral supplement formulations. No comparisons allowed within the scope of this review.
Dijkhuizen 2004170 pregnant women with less than 20 wk gestation from 13 adjacent villages in a rural area in Bogor District, West Java, Indonesia were randomly assigned to receive daily supplementation with B-carotene (4.5 mg), zinc (30 mg), both, or placebo containing iron (30 mg) and folic acid (0.4 mg). Both groups received iron and folic acid. No comparisons allowed within the scope of this review.
Dommisse 1983146 pregnant women with less than 20 wks of gestation were randomly allocated to receive either a multivitamin tablet twice a day or a multivitamin tablet in conjunction with a standard ferrous sulphate tablet twice a day providing a total of 120 mg of elemental iron daily. Both groups received a multivitamin supplement. No data can be extracted from the published article.
Edgar 1956179 pregnant women with Hb levels below 105 g/L and more than 16 wks of gestation volunteered for this study and were divided into four supplementation groups according to the stage of pregnancy: 16th week, 20th week, 24th week, and non-supplemented controls. 37% of these women were lost to follow up and were excluded from the final analysis. Data are presented without standard deviation. No data can be extracted from the publication for this review.
Ekstrom 1996176 pregnant women attending Ilula Lutheran Health Center's antenatal service in Iringa region, Tanzania with 21-26 wks of gestational age and haemoglobin > 80 g/L were randomly assigned to receive 120 mg elemental iron as ferrous sulphate in conventional form or 50 mg elemental iron as gastric delivery system (GDS). Both groups received iron supplementation in different preparations. No comparisons allowed within the scope of this review.
Fenton 1977154 pregnant women with less than 14 wks of gestation, and who had not received or were receiving treatment for a blood disorder were divided into 2 groups according to the day in which they attended the clinic in Cardiff: group 1 received 60 mg of ferrous sulphate and group 2 received placebo. Haemoglobin concentration, mean corpuscular volume (MCV), serum ferritin, serum iron and total iron binding capacity were measured at 10-14 wk and at term. The data in the paper are presented with no standard deviation values. No data can be extracted from the publication for this review.
Fleming 1974146 consecutive pregnant women attending a public antenatal clinic in Western Australia before the 20th week of gestation who had not received iron supplements and were willing to participate were randomly assigned in sequences of 50 to one of the 5 interventions groups: group 1 received placebo; group 2 received 60 mg of elemental iron as ferrous sulphate; group 3 received 0.5 mg of folic acid; group 4 received 60 mg of elemental iron as ferrous sulphate and 0.5 mg of folic acid; and group 5 received 60 mg of elemental iron as ferrous sulphate and 5 mg of folic acid. Supplementation with iron was from 20th week of gestation until delivery. All women had received 50 mg of ascorbic acid daily from the first visit until week 20th. More than 20% of the women were lost to follow up. No data can be extracted from the publication for this review.
Fleming 1986200 apparently healthy primigravidae Hausa women living in Zaria, Nigeria and planning to deliver in Zaria, with less than 24 wks of gestation, who had not taken any antimalarial treatment or iron supplements in current pregnancy were randomly assigned to one of five groups: group 1: received no active treatment; group 2: received chloroquine 600 mg base once, followed by proguanil 100 mg per day; group 3 received in addition to chloroquine and proguanil, 60 mg elemental iron daily; group 4 received in addition to chloroquine and proguanil, 1 mg of folic acid daily, and group 5: in addition to chloroquine and proguanil received 60 mg of elemental iron and 1 mg of folic acid daily. Eighty-nine out of 200 women delivered in the hospital and no other complete clear data can be extracted for the outcomes of interest in this review.
Fletcher 1971643 pregnant women attending antenatal clinic in London were randomly assigned to one of two groups: group 1 received 200 mg of ferrous sulphate daily; group 2 received 200 mg of ferrous sulphate with 5 mg of folic acid daily. Both groups received iron. No comparisons allowed within the scope of this review.
Foulkes 1982568 apparently healthy pregnant women with less than 20 wks of pregnancy and no prior iron supplementation were allocated alternatively to receive 100 mg of elemental iron and 350 ug of folic acid daily or no treatment. Ferritin and haemoglobin concentrations were measured at baseline and at 28 and 36 wks of gestation and 2 days postpartum. Mean corpuscular volume and mean corpuscular haemoglobin were measured at 2 days postpartum. Only means and median are presented. No standard deviation is shown and for ferritin concentrations no ln-transformed data are presented. No data were extractable from the paper and subsequent communication with author.
Freire 1989412 non-black pregnant women with 26 ± 2 wks of gestation, who had not received iron supplements in the previous 6 months, from low SES using the prenatal unit of Quito's public obstetric hospital, Ecuador were randomly assigned to receive two tablets containing 78 mg of elemental iron as ferrous sulphate daily or placebo during a period of 2 months. Overall loss to follow up rate was 41.7%. Haemoglobin, PCV, red cell indices, serum ferritin, total iron binding capacity, serum folate, serum vitamin B12 at baseline and after 2 months. Prevalence of iron deficiency was estimated by response to therapy. No prespecified outcomes from this review are presented in the paper. No further data were available.
Gomber 200240 apparently healthy women with singleton pregnancy in their second trimester (between 16-24 wks of gestation), living in urban slums, from low socio-economic status attending Guru Teg Bahadur Hospital, Delhi, India were randomly assigned to receive one tablet containing 100 mg of elemental iron as ferrous sulphate with 500 ug of folic acid daily or once a week. Weekly intake was supervised. Duration of supplementation was 100 days. Haemoglobin and haematocrit concentrations at baseline, at 4 wks, 8 wks and 14 wks of supplementation, serum ferritin concentration, at baseline, at 14 wks of supplementation and at delivery.
No prespecified outcomes in this review are reported. Serum ferritin values is reported as log transformed values but no standard deviations are presented.
Goonewardene 200192 pregnant women from 14-24 wks of gestation attending the university antenatal clinic, in Galle, Sri Lanka were randomly assigned to one of three regimens: group 1 (n = 26) received a tablet containing 100 mg of elemental iron as ferrous fumarate, with additional micronutrients once a week; group 2 (n = 35) received the same tablet but three times a week; and group 3 (n = 31) received the same supplement in a daily fashion. All groups were receiving multiple micronutrients. No comparisons allowed within the scope of this review.
Gopalan 2004900 pregnant women of poor socio-economic status females attending government antenatal care clinics were grouped in three groups: group 1 (n = 300) received routine antenatal care; group 2 (n = 300) received 100 mg of elemental iron and 500 ug folic acid daily from the 20th week of gestation and group 3 (n = 300) received 100 mg of elemental iron and 500 ug folic acid daily from the 20th week of gestation and additionally 900 mg of alpha linolenic acid from the 22nd week of gestation. Outcomes assessed included birth weight, low birth weigh, premature delivery. The study is not reported as randomised and is excluded in the first screening for eligibility.  
Gringras 198240 pregnant women attending antenatal care clinic were given a tablet containing 47 mg of elemental iron, as ferrous sulphate and 0.5 mg of folic acid daily or a tablet containing 100 mg of elemental iron as ferrous glycine sulphate daily. Both groups received iron. No comparisons allowed within the scope of this review.
Groner 198640 pregnant women attending antenatal care at the Adolescent Pregnancy Clinic and Obstetrics Clinics at the John Hopkins and Sinai Hospital in Baltimore, Maryland, USA at or before 16 wks of pregnancy with haematocrit equal or above 31% were randomly assigned to one of two groups: group 1 (n = 16) received 60 mg of elemental iron as ferrous fumarate and prenatal vitamins daily; or group 2 (n = 9) received only the prenatal vitamins with no iron. Two women objected to the randomisation and 13 dropped out of the study. Both groups received multiple micronutrients. Supplementation lasted a month. Psychometric tests (arithmetic, total digit span, digit symbol, vocabulary and others) were performed and hematologic status was measured at baseline and after a month. Hematologic outcomes cannot be extracted from the paper. None of the other outcomes were sought.
Guldholt 1991192 pregnant women were consecutively randomised to receive one of two treatments: group 1: received a daily vitamin-mineral tablet containing 15 mg of elemental iron or group 2: received a daily vitamin-mineral tablet containing 100 mg of elemental iron. Both groups received iron in different doses. No comparisons allowed within the scope of this review.
Hampel 197465 untreated and 54 treated pregnant women in West Berlin, Germany were assessed during pregnancy for haemoglobin concentrations, iron an folate levels, total iron binding capacity, and red cell count. No data are presented for outcomes prespecified in the review. Women were of different gestational age. No outcomes can be extracted from the paper.
Hawkins 1987No report available of the study results.
Hermsdorf 1986120 unselected pregnant women were given 114 mg of elemental iron daily from week 15 until delivery, or not treatment. Only an abstract with insufficient data available.
Hoa 2005202 apparently healthy pregnant women 20-32 years of age attending health clinics from 12 communes in Dong HungDistrict, Thai Binh Province, Vietnam with 14-18 wks of gestation who agreed to participate in the study were selected to participate. Women were assigned through block randomly assigned to one of 4 interventions: group 1 (n = 44) received 400 ml fortified milk with iron (ferrous fumarate), vitamin C and folic acid daily; group 2 (n = 41) received 400 ml of milk fortified with vitamin C and folic acid but no iron daily; group 3 (n = 40) received one tablet containing 60 mg of elemental iron (as ferrous sulphate) and 250 ug of folic acid daily and group 4 (n = 43) received one placebo tablet daily. For purposes of this review groups 3 and 4 comparing iron and folic acid supplements to placebo could be included. However, no data on outcomes of interest could be extracted from the published report.
Horgan 196642 apparently healthy pregnant women attending two antenatal care clinics in London, England were assigned to one of three interventions: group 1 received 200 mg ferrous sulphate with 5 mg of folic acid three times a day; group 2 received 350 mg of ferrous aminoate with 50 ug of folic acid three times a day; and group 3 received 200 mg of ferrous sulphate with 500 ug of folic acid once a day. Intervention period was 3 wks. All groups received iron and folic acid. No comparisons allowed within the scope of this review.
Hosokawa 198984 anaemic women seeking antenatal care in the Department of Obstetrics and Gynaecology of the Fukui School of Medicine Hospital, Japan were randomly assigned to receive 100 mg of elemental iron as ferrous sulphate daily after the evening meal, or the same dose + vitamin C for 4 wks. Both groups received iron. No comparisons allowed within the scope of this review.
Iyengar 1970800 pregnant women with less than 24 wks of gestation and Hb > 85 g/L in India were assigned by rotation to one of four groups: group 1 received placebo tablets; group 2 received 30 mg of elemental iron as ferrous fumarate in a single tablet daily; group 3 received 30 mg of elemental iron as ferrous fumarate with 500 ug of folic acid in a single tablet; and group 4 received in addition to iron and folic acid, 2 ug of vitamin B12 in a single tablet. Loss to follow up was 65%. None of the pre-specified outcomes in the protocol was reported and no data were extractable from the paper.
Kaestel 20052100 pregnant women (22 +/- 7 wk gestation at entry) attending antenatal clinics in Bissau, Guinea-Bissau or who were identified by The Bandim Health project were randomly assigned to receive daily multi micronutrient tablet containing one Recommended Dietary Allowance (RDA) of 15 micronutrients, or daily multi micronutrients containing two times the RDA except for iron that was maintained at one RDA or a conventional prenatal daily iron (60 mg) and folic acid (400 ug) supplement. All groups receive iron and folic acid daily. No comparisons allowed within the scope of this review.
Kann 198836 healthy non-anaemic pregnant women in second or third trimesters of gestation were randomly assigned to receive one of four prenatal commercial multivitamin/multi mineral preparations daily: Stuartnatal 1+1; Stuart Prenatal; Materna; and Natalins Rx. All participants received multiple micronutrients. No comparisons allowed within the scope of this review.
Kumar 2005220 pregnant women with a singleton pregnancy and Hb between 80-110 g/L at 16-24 wk gestation from New Delhi, India were randomly allocated to receive daily oral iron therapy of 100 mg elemental iron as ferrous sulphate with 500 ug folic acid or 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4-6 wks. This trial compares the effects of daily oral iron with two injections of high dose parenteral iron. No comparisons allowed within the scope of this review.
Madan 1999109 apparently healthy pregnant women with 16-24 wks of gestation who had not received iron supplements were randomly assigned to one of three groups: group 1 received 60 mg of elemental iron + 0.5 mg of folic acid once daily; group 2 received 120 mg of elemental iron + 0.5 mg of folic acid once daily; group 3 received 120 mg of elemental iron twice daily + 0.5 mg of folic acid. Duration of supplementation was 12-14 wks. All participants received iron and folic acid daily. No comparisons are allowed within the scope of this review.
Mbaye 20061035 pregnant women attending mother and child health clinics near the town of Farafenni, The Gambia were randomised to receive either folic acid (500-1500 ug/day) together with oral iron (47 mg of ferrous sulphate per tablet) or oral iron alone (60 mg of ferrous sulphate per tablet) daily for 14 days. All women received treatment with three tablets of SP (25 mg of pyrimethamine and 500 mg of sulfadoxine). Both groups received iron daily. No comparisons allowed within the scope of this review.
McKenna 2002102 healthy pregnant women attending antenatal clinics at the Royal Jubilee Maternity Hospital in Belfast, Ireland with a singleton pregnancy and haemoglobin > 104 g/L and known gestational age of less than 20 wks who were non-compliers with routine prescription of 200 mg of ferrous sulphate daily, were randomly assigned to receive 2 sachets of 24 ml each of Spatone® water containing 10 mg of elemental iron or placebo. Participants were instructed to take the two sachets daily half an hour before breakfast diluting it in orange juice. Primary outcomes were compliance and side effects. Duration of intervention was from week 22 to week 28 of gestation.
Menon 1962273 healthy pregnant women with 16-24 wks of gestation and haemoglobin concentrations at or above 105 g/L attending antenatal care clinics were divided in order in which they were registered in three groups: group 1 was given 5 g of ferrous sulphate daily; group 2 received 5 mg of folic acid daily; and group 3 received 5 g of ferrous sulphate and 5 mg of folic acid daily. All participants were given 3 multivitamin tablets daily containing vitamin A, vitamin B, C and D. The study was not randomised.
Milman 2005427 healthy Danish pregnant women living in the northeastern part of Copenhagen County, Denmark were randomly allocated to receive iron (as ferrous fumarate) in daily doses of 20 mg (n = 105), 40 mg (n = 108), 60 mg (n = 106), and 80 mg (n = 108) from 18 wks of gestation. Hemoglobin (Hb), serum ferritin, and serum soluble transferrin receptor concentrations were measured at 18 wks (inclusion), 32 wks, and 39 wks of gestation and 8 wks postpartum. All women received iron daily. No comparisons allowed within the scope of this review.
Morgan 1961356 pregnant women attending two different antenatal care clinics at the King Edward Memorial Hospital for Women in Subiaco, Australia received according to the clinic they visited, either no treatment or 100 mg of elemental iron as ferrous gluconate daily. No systematic allocation was used in this open trial.
Morrison 1977105 pregnant women attending the University Unit, Mater Misericordiae Mothers' Hospital, South Brisbane, Australia, with normal height, weight and nutrition for the Australian population and with no previous adverse medical, surgical or obstetrical history were allotted by random selection to one of four types of supplements: group 1 received 50 mg of elemental iron as dried ferrous sulphate daily; group 2 received 80 mg elemental iron as dried ferrous sulphate with 300 ug of folic acid daily; group 3 received 105 mg elemental iron as ferrous sulphate and group 4 received 105 mg of elemental iron as ferrous sulphate with 300 ug of folic acid. All groups received iron daily. No comparisons allowed within the scope of this review.
Mumtaz 2000191 anaemic pregnant women between the ages of 17-35 years of age, and uneventful obstetric history attending the Maternity wing of the Federal Government Services Hospital in Islamabad and the Maternal & Child Health Clinic at the Christian Mission Hospital in Taxila, Pakistan were randomly assigned to one of two interventions: group 1 received 200 mg of ferrous sulphate (40 mg elemental iron) with 1 mg of folic acid once daily; and group 2 received 200 mg of ferrous sulphate with 1 mg of folic acid on two days of the week and placebo the rest of the days. Subjects and care providers were blinded to the treatments. Outcomes measured included haemoglobin concentration and serum ferritin at baseline and during the three following consecutive visits as well as compliance and weight. Change in haemoglobin Z-scores after supplementation was the main outcome variable, in women from different gestational ages and duration of intervention, thus not allowing outcomes prespecified in this review.
Nguyen 2008167 pregnant women with less than 20 wks of gestation who called either Motherisk General Information line or the Motherisk Nausea and Vomiting of Pregnancy (NVP) Helpline (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were randomly assigned to one of two groups: group 1 were provided, PregVit®  (a small-size, containing 35 mg elemental iron as ferrous fumarate and multivitamins; or group 2 who received Orifer F®  (high iron content, small size) containing 60 mg elemental iron as ferrous sulphate and multivitamins. Follow-up interviews documented pill intake and adverse events. Participants from both groups received iron in different amounts and compounds.
Nogueira 200274 low-income pregnant adolescents ranging from 13-18 years of age attending antenatal care at the Evangelina Rosa Maternity Hospital in Teresina, Piaui State, Brazil were distributed into five groups: group 1 received 120 mg elemental iron as ferrous sulphate and 250 ug of folic acid daily; group 2 received 80 mg elemental iron as ferrous sulphate and 250 ug folic acid daily; group 3 received 120 mg of elemental iron, with 5 mg of zinc sulphate and 250 ug of folic acid daily; and group 4 received 80 mg of elemental iron as ferrous sulphate, with 5 mg of zinc sulphate and 250 ug of folic acid daily. All groups received iron and two groups received zinc in addition to iron and folic acid. No comparisons allowed within the scope of this review.
Ogunbode 198480 apparently healthy non-anaemic pregnant women attending University College Hospital and Inalende Maternity Hospital in Ibadan, Nigeria during the first and second trimesters of pregnancy were randomly allocated to one of two groups: group 1 (n = 39) received one tablet Ferrograd Folic 500 Plus® daily, a sustained-released formulation containing ferrous sulphate and folic acid (composition is not available); or group 2 (n = 41) received a capsule containing 200 mg ferrous sulphate and 5 mg of folic acid. All patients were also provided 25 mg weekly of pyrimethamine throughout pregnancy as an anti-malarial agent. Patients who became anaemic during pregnancy were excluded of the study and analysis. Outcomes measured included reticulocyte count, haematocrit, anaemia, side effects. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.
Ogunbode 1992315 apparently healthy pregnant women attending four prenatal care clinics in 4 geographical areas of Nigeria with mild to moderate anaemia (as defined by haematocrit between 26%-34%) and 18-28 wks of gestation, single pregnancies, no complications and who consented to participate in the study were randomly allocated to one of two groups: group 1 (n = 159) received one daily capsule of a multiple micronutrient supplement Chemiron® containing 300 mg of ferrous fumarate, 5 mg folic acid, 10 ug vitamin B12, 25 mg of vitamin C, 0.3 mg magnesium sulphate and 0.3 mg of zinc sulphate; group 2 (n = 156) received a capsule containing 200 mg ferrous sulphate and 5 mg of folic acid. All patients were also provided 600 mg of cloroquine to be taken under supervision and 25 mg weekly of pyrimethamine throughout pregnancy. Patients who became anaemic during pregnancy were excluded of the study and analysis. Outcomes measured included blood haemoglobin, anaemia, haematocrit, serum ferritin levels, side effects. A second published study followed these same women and their infants. Both groups received iron and folic acid supplements, thus making the comparisons not suitable for this review.
Ortega-Soler 199841 healthy pregnant women, attending prenatal care clinics at Hospital Diego Paroissien in La Matanza, Province of Buenos Aires, Argentina with serum ferritin below 50 mg/mL. Women were assigned to one of two groups: group 1 received 100 mg of elemental iron daily as ferric maltosate, and group 2 received no treatment.
Supplementation started at 21 +/- 7 wks of gestation until birth. Maternal outcomes measured included: haemoglobin, erythrocyte protoporphyrin, serum ferritin at baseline and term, dietary intake. The iron intake was unsupervised and compliance was not reported. The trial is not randomised nor quasi randomised so it does not fill the inclusion criteria for this review.
Osrin 20051200 healthy pregnant women with a singleton pregnancy and less than 20 wk gestation attending an antenatal clinic at Janakpur zonal hospital in Nepal, were randomly assigned to receive routine daily iron (60 mg) and folic acid (400 ug) supplements or a multiple micronutrient supplement containing 15 vitamins and minerals including iron (30 mg) and folic acid (400 ug). Both groups received iron and folic acid. No comparisons allowed within the scope of this review.
Payne 1968200 pregnant women attending antenatal clinics in Glasgow, Scotland with less than 20 wk gestation, whose antenatal care was undertaken wholly by the hospital antenatal clinic and who subsequently had a normal delivery, were randomly allocated to receive 200 mg of ferrous sulphate daily or 200 mg of ferrous sulphate with 1.7 mg of folic acid daily throughout pregnancy. Both groups received iron. No comparisons allowed within the scope of this review.
Pena-Rosas 2003116 pregnant women of 10-30 wk of gestational age attended antenatal care clinics in Trujillo, Venezuela were randomly allocated to receive a 120 mg oral dose of iron as ferrous sulphate and 0.5 mg of folic acid weekly (n = 52) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly (n = 44). Haemoglobin, hematocrit, serum ferritin and transferrin saturation were estimated at baseline and at 36-39 wk of gestation. All groups received iron and folic acid in two intermittent regimens with no control group. No comparisons allowed within the scope of this review.
Picha 1975In a randomised double-blind study the new effervescent iron tablet Loesferron® was tested in 57 postpartum women. The participants were not pregnant women.
Quintero 2004107 healthy pregnant women with 6-20 wks of gestation who had not received iron supplements during the current pregnancy attending 19 health units in the State of Morelos, Mexico were randomly assigned by block pairs to receive either 120 mg of elemental iron as ferrous sulphate in a single dose daily or once weekly. Haemoglobin concentration, prevalence of anaemia and nutrient consumption at baseline and after 10 wks of supplementation were measured. None of the prespecified outcomes of this review were available. Gestational ages were variable among the participants.
Ramakrishnan 2003873 pregnant women living near Cuernavaca, Morelos, Mexico with less than 13 wks of gestation who did not use micronutrient supplements were randomly assigned to receive a daily multiple micronutrient supplement or a daily iron-only supplement. Both supplements contained 60 mg of elemental iron as ferrous sulphate. Supplement intake was supervised by trained workers from registration until delivery by home visits 6 days a week. No comparison allowed within the scope of this review.
Rayado 1997394 healthy non-anaemic adult pregnant women with 24-32 wks of gestation and singleton pregnancy from Fuentalabra, Spain were randomly assigned to one of two groups: group 1 received 40 mg of elemental iron as iron mannitol albumin daily; and group 2 received 40 mg elemental iron as iron protein succinylate daily. Both groups received iron daily. No comparisons allowed within the scope of this review.
Reddaiah 1989110 pregnant women attending the antenatal clinic at Comprehensive Rura Health Services Project Hospital, Ballabgarh, India, with 16-24 wks of gestation were randomly assigned to one of three groups: group 1 received 60 mg elemental iron and 0.5 mg of folic acid daily; group 2 received 120 mg elemental iron with 0.5 mg of folic acid daily; and group 3 received 240 mg elemental iron and 0.5 mg of folic acid daily. Elemental iron was given as ferrous sulphate. All groups received iron daily. No comparisons allowed within the scope of this review.
Roztocil 199484 non-anaemic pregnant women at Mazarik University Brno in Czech Republic were treated from 20-24 wks with one capsule of Actiferrin Compositum®, and from 36 wks to delivery with 2 capsules. The group was compared with 57 non-anaemic pregnant women who received no supplements. The supplement contained 34.5 mg of elemental iron as ferrous sulphate, 0.5 mg of folic acid, and 0.3 mg of cyanocobalamin. No comparisons allowed within the scope of this review.
Rybo 1971117 pregnant women between 20-29 wks of gestation were alternatively assigned during three consecutive two wks periods to receive daily tablets containing 200 mg of elemental iron as ferrous sulphate, 200 mg of elemental iron as a sustained released iron or placebo. After each 2-wks treatment period women were questioned about possible side effects. No side effects are reported by group assigned. No comparisons are allowed within the scope of this review.
Sandstad 2003233 pregnant women attending their second antenatal care visit at the University Health Services of Oslo, Norway with serum ferritin concentration < 60 ug/L were randomised to two different iron preparations, group 1 received one tablet containing 60 mg of elemental iron as ferrous sulphate daily; group 2 received three tablets each containing 1.2 mg of heme iron from porcine blood plus 8 mg of elemental iron as ferrous fumarate per tablet (total 3.6 heme iron and 24 mg elemental iron) daily. A third group (n = 93) of pregnant women who had been given advice to take or not the iron supplements according to the centre recommendations were enrolled in the trial at 6 wks postpartum and served as control. The study groups were not randomised to the interventions and no comparisons can be made within the scope of this review.
Seck 2008221 apparently healthy pregnant women, had not used iron supplements prior to enrolment, who were 12 to 16 wks were recruited from six health centres in Dakar, Senegal during their first prenatal visit, and randomly assigned to receive either a prescription to purchase iron/folic acid tablets to be taken daily, according to official policy, or to receive free tablets. Compliance was assessed 20 wks after enrolment through interviews and pill count. All women received iron. No comparisons allowed within the scope of this review.
Shatrugna 1999115 healthy pregnant women with 20-28 wks of gestation attending the antenatal clinic of the National Institute of Nutrition, Government Maternity Hospital, India were randomly assigned to one of 11 different formulations and doses of iron and then undergo iron tolerance tests. They received ferrous sulphate tablets containing 60 mg, 12 mg, and 180 mg of elemental iron; formulations containing 60 mg of elemental iron as pure ferrous sulphate salt, ferrous fumarate tablets, ferrous fumarate syrup, excipients added to pure ferrous sulphate salts; powdered ferrous sulphate tablets, iron tablets distributed by the National Nutritional Anaemia Prophylaxis Programme and pure ferrous salt in gelatin capsules.
Simmons 1993376 pregnant women with ages between 16-35 y, with mild anaemia (Hb concentrations between 80-110 g/L) attending eight maternal and child health centres in Kingston, St. Andrews and Spanish Town, Jamaica, with gestational age between 14-22 wks were randomly assigned to one of three groups: group 1 received one placebo tablet daily; group 2 received 100 mg of elemental iron as ferrous sulphate daily; group 3 received gastric delivery system capsule containing 50 mg of elemental iron daily. All women received 400 mg of folic acid. Outcomes measure included haemoglobin, haematocrit, MCV, white cell count, serum iron, total iron binding capacity, serum ferritin, serum transferrin receptor, at baseline, at 6 wks and at 12 wks after start of supplementation as well as side effects. No prespecified outcomes are presented at the paper as gestational ages differed in the participants.
Sjostedt 1977300 pregnant women attending the Maternity Welfare Center, in Oulu, Finland before the 5th month of pregnancy were randomly assigned to one of three interventions: group 1 received 100 mg of elemental iron daily as sustained-release tablets daily; group 2 received 200 mg of elemental iron daily as sustained-release tablets and group 3 received 200 mg of elemental iron daily as rapidly disintegrating ferrous sulphate tablets. All groups received iron in different doses and formulations.
Sood 1979151 healthy pregnant women with Hb > 50 g/L who had not received iron supplements during the last 6 months from Delhi and Vellore, India were divided in one of three strata according to Hb concentration (50-79 g/L; 80-109 g/L;110 g/L and above) and within each strata were allocated randomly to one of five interventions: group 1 received 120 mg of elemental iron as ferrous sulphate 6 days a week; group 2 received 100 mg of elemental iron as iron dextran complex intramuscular twice per week; group 3 received iron as group 1 + pteroylmonoglutamic acid 5 mg/d 6 days a week + cyanocobalamin 100 ug intramuscular once per 14 d; group 4 received 100 mg of elemental iron intramuscular + pteroylmonoglutamic acid + cyanocobalamin 100 ug intramuscular; and group 5 received iron dextran complex intramuscular in a single total dose infusion + 5 mg/d pteroylmonoglutamic acid + 100 ug intramuscular cyanocobalamin once per 14 days. All groups received iron at different doses and routes. No comparisons allowed within the scope of this review.
Steer 1992Trial abandoned. No data available.
Stone 1975248 healthy pregnant women attending hospital antenatal clinic in London, England, were allocated randomly to receive a slow-release dose of 105 mg of elemental iron as ferrous sulphate and 350 ug of folic acid daily or 80 mg of elemental iron as ferrous fumarate and 400 ug of folic acid daily in a standard preparation. Both groups received iron in different doses and preparations. No comparisons allowed within the scope of this review.
Suharno 1993251 pregnant women aged 17-35 years, parity 0-4 and haemoglobin concentrations between 80 and 109 g/L were randomly allocated to one of four groups: group 1 received 2.4 mg of retinol and one placebo iron tablet daily; group 2 received 60 mg of elemental iron as ferrous sulphate and a placebo vitamin A tablet daily; group 3 received 2.4 mg of retinol and 60 mg of elemental iron; and group 4 received two placebos for 8 wks. Outcomes measured include: haemoglobin, haematocrit, serum ferritin, serum iron, total iron binding capacity, serum retinol, transferrin saturation, at baseline and after 8 wks of supplementation. None of the pre-specified outcomes in this review can be extracted from this paper.
Tampakoudis 199682 pregnant women with haemoglobin concentrations 140 g/L or above attending clinic in Thessaloniki, Greece were randomised to receive 80 mg iron protein succinylate daily or a placebo. Serial haemoglobin, haematocrit and serum erythropoietin were measured from maternal blood and cord blood on delivery; serum ferritin measured in frequent intervals. Abstract only available. Insufficient information to assess characteristics of the trial.
Tan 1995285 healthy middle-class pregnant women with haemoglobin concentration above 100 g/L attending antenatal clinic at the University Hospital at Kuala Lumpur, Malaysia were assigned to receive daily iron supplements or no treatment. Abstract only available. No additional information was available, including doses, regimens and other characteristics of the trial.
Tange 1993128 anaemic and non-anaemic pregnant females aged 10-19 years old, with an average gestation of 16 wks, were grouped for three levels of iron supplementation: group 1 (n = 42 non-anaemic participants) received placebo (no iron); group 2 (n = 41 anaemic and non-anaemic participants) received 22 mg of elemental iron daily and group 3 (n = 45 anaemic and non-anaemic participants) received 55 mg elemental iron daily. Women were supplemented from 16 wks until delivery. Outcomes assessed included Hb, haematocrit, red cell count, mean corpuscular volume, serum iron, serum transferring and serum, ferritin measured every four wks. The study is not reported as randomised and is excluded in the first screening for eligibility.  
Thane-Toe 1982135 healthy pregnant women between 22-28 wks of gestation attending antenatal clinic in Burma, were randomly assigned to receive a daily dose of 60 mg, 120 mg or 240 mg of elemental iron as ferrous sulphate. A control group was composed by 47 apparently healthy adults (17 males and 30 single women). Control groups are not appropriate. No comparisons allowed within the scope of this review.
Tholin 199383 healthy nulliparous non vegetarian, non-anaemic pregnant women with serum ferritin concentrations above 10 ug/L were randomly assigned to one of three groups: group 1 received 100 mg of elemental iron as ferrous sulphate daily; group 2 received placebo, and group 3 received dietary advice only. Blood haemoglobin, serum ferritin and blood manganese were determined at baseline before 15th week of gestation, between 25-28 wks, and between 35-40 wks of gestation. Median and ranges are presented. No outcomes were extractable from this report for this review.
Thomsen 199352 healthy non-anaemic nulliparous women with normal singleton pregnancy and serum ferritin levels above 15 mg/L at 16th week in Herlev, Denmark were randomly assigned to receive either a daily tablet containing 18 mg or a daily tablet containing 100 mg of elemental iron from 16 wks until delivery. All women received 0.3 mg of folic acid daily. All women received iron in different doses. No comparisons allowed within the scope of this review.
Vogel 1963191 consecutive pregnant when attending antenatal care clinics and at 32 wks of gestation were divided in two groups by alternate allocation by clinic: group 1 received 140 mg of elemental iron daily as ferrous gluconate in four tablets; group 2 received 150 mg elemental iron daily as ferrous glutamate in 3 tablets. All women received iron in different dose and number of tablets. No comparisons allowed within the scope of this review.
Wali 200260 iron deficiency anaemic pregnant women with the gestational age of 12-34 wks were randomly assigned to one of 3 groups: Group A (n = 15) received intravenous 500 mg of iron sucrose for storage; group B (n = 20) received intravenous iron sucrose according to deficit calculated as per formula with 200 mg of iron was given for storage and group C received intra muscular iron Sorbitol in the dose used as practice. All groups received iron intravenous or intramuscular.
Willoughby 1966350 consecutive pregnant women attending antenatal care clinic were allocated to one of five groups: group 1 received no hematinic supplements; group 2 received 105 mg of elemental iron daily as iron chelate aminoates; group 3 received 105 mg of elemental iron daily with 100 ug of folic acid; group 4 received 105 mg of elemental iron daily with 300 ug of folic acid; and group 5 received 105 mg of elemental iron daily th 450 ug of folic acid. All women received a multivitamin preparation (Vivatel) free of folic acid.
Willoughby 196868 pregnant women attending antenatal care clinic in Queen Mother's Hospital in Scotland, were randomly allocated to receive 195 mg of elemental iron alone daily or 195 mg of elemental iron in conjunction with 300 ug of folic acid daily.
Wu 1998369 pregnant women attending antenatal care at Beijing Hospital, China were divided into two groups according to their initial haemoglobin concentrations. Women with Hb 110 g/L or above were randomly assigned to one of two groups: group 1 (n = 96) received one daily tablet of maternal supplement containing 60 mg of elemental iron in addition to other micronutrients including calcium and magnesium ; group 2 (n = 95) served as control and received no supplements. Another group of women with Hb < 110 g/L (treatment group) were randomly assigned to one of three groups: group 1 received 1 tablet of maternal supplement daily; group 2 received 0.9 g of ferrous sulphate daily; and group 3 received one tablet of Ferroids, a sustained released preparation daily. In the preventive group, women entered the study from 20-24 gestational wks. In the treatment groups, women less than 36 gestational wks were accepted. No comparisons allowed due to the addition of other micronutrients in the treatment.
Zhou 2007180 anaemic women (Hb < 110 g/L) attending antenatal care at the Children, Youth and Women's Health Service, Adelaide, Australia with 24-32 wks of gestation and a singleton pregnancy. Women were excluded if they were taking iron or vitamin and mineral supplements, had presumptive diagnosis of non iron deficiency related anaemia, history of thalassaemia, drug or alcohol abuse and/or diabetes requiring insulin or a known fetal abnormality. Women were randomly assigned to receive a daily dose of 20, 40 or 80 mg of elemental iron as ferrous sulphate for 8 wks or until birth. The primary outcomes measured were Hb levels, anaemia at the end of the intervention and gastrointestinal side effects during treatment. All women received iron at different doses. No comparisons allowed within the scope of this review.
Zittoun 1983203 pregnant women attending antenatal clinic in Paris, France, with 28 +/- 2 wks of gestation were studied. Women with Hb below 110 g/L (n = 48) were provided 105 mg of elemental iron and 500 mg of ascorbic acid daily. Women with Hb concentration above 110 g/L were randomly assigned to receive 105 mg of elemental iron and 500 mg of ascorbic acid daily until delivery or placebo. Iron was provided in conjunction with vitamin C. No comparisons allowed within the scope of this review.
Zutshi 2004200 apparently pregnant women with 24-26 wks of gestation, with singleton pregnancy with moderate anaemia (Hb > 80 g/L and < 110 g/L) were randomly assigned to receive injectable iron-sorbitol-citrate in three intramuscular doses of 150 mg each at 4 wks intervals or 100 mg of elemental iron daily. Haemoglobin concentrations were measured at baseline, every 4 wks and at delivery. The study compares two routes of iron administration. Both groups receive iron. No comparisons allowed within the scope of this review.

Characteristics of studies awaiting assessment [ordered by study ID]

Bhatla 2009

MethodsRandomisation: adequate. Computer-generated random numbers. Allocation concealment: inadequate - not used. Blinding: inadequate. Open to participants, care providers and outcome assessor. Loss to follow up: adequate. Less than 20% were lost to follow up.
Participants109 pregnant non-anaemic women between 14 and 18 wks with no prior intake of iron supplements in the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences in New Delhi, India were invited to participate in the study. Exclusion criteria were: haemoglobin < 110 g/L, packed cell volume (PCV) < 30; cigarette smoking; preexisting hypertension or diabetes; history of chronic illness, e.g. liver or renal disease, tuberculosis, heart disease, malaria; history of bleeding disorders, bleeding piles, chronic peptic ulcer; thalassaemia or other haemoglobinopathies; intake of drugs such as antiepileptics, non-steroidal anti-inflammatory drugs (NSAIDs), antithyroid medication, vitamins, antioxidants; multiple pregnancy; and prior history of blood transfusion.
InterventionsParticipants were randomly allocated into one of three different groups: group 1 (n = 37) received the standard Government of India supply of Irofol®  tablets containing 100 mg of elemental iron as ferrous sulphate and 500 ug folic acid (Nestor Pharmaceuticals Ltd., Faridabad, Haryana, India) to be taken once weekly; group 2 (n = 36) received the standard Government of India supply of Irofol® tablets containing 100 mg of elemental iron as ferrous sulphate and 500 ug folic acid and were instructed to take two tablets on any one day of the week ? one before lunch and the other before dinner (total 200 mg elemental iron and 1000 ug folic acid a week) with no tablets were taken during the rest of the week; group 3 (n = 36) received Ferium® tablets iron (III)-hydroxide polymaltose complex tablets daily containing Iron (III) Hydroxide Polymaltose containing 100 mg elemental iron and 350 ug folic acid  to be taken one tablet daily (Emcure Pharmaceuticals Ltd., Pune). All groups received health education regarding the importance of diet in pregnancy, iron-rich foods and appropriate dietary practices and were instructed to take the tablets 30 min before meals and not with tea, coffee or milk. They were also advised to take calcium supplements after meals.
Outcomes

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

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

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

Zeng 2008

MethodsRandomisation: (A) adequate. Cluster randomised. Allocation concealment: (A) adequate. A treatment colour code was assigned to each village based on the treatment allocation schedule and opened only once all data had been collected and blinded analysis completed. Blinding: (A) adequate. Participant and care provider blinded. Loss to follow up: (A) adequate. Less than 20% loss to follow up.
Participants5828 eligible pregnant women with less than 28 wks and residents in two poor rural counties in Shaanxi Province of north west China participated in the study. Their villages were randomly assigned for women to receive one of three groups.
InterventionsTheir villages were randomly assigned for women to receive one of three groups: group 1, daily antenatal multiple micronutrients containing 30 mg iron, 400 µg folic acid and 15 mg zinc, 2 mg copper, 65 µg selenium, 150 µg iodine, 800 µg vitamin A, 1.4 mg vitamin B-1 (thiamine), 1.4 mg vitamin B-2 (riboflavin), 1.9 mg vitamin B-6, 2.6 µg vitamin B-12, 5 µg vitamin D, 70 mg vitamin C, 10 mg vitamin E, and 18 mg niacin; group 2 who received a tablet containing 60 mg iron and 400 ug of folic acid; and group 3 received a tablet containing 400 ug of folic acid alone (control).
OutcomesBirth weight within one hour of delivery, low birth weight, birth length, gestational age at birth, preterm delivery, small for gestational age babies, maternal haemoglobin concentration in the third trimester (gestation 28-32 wks), anaemia in the third trimester, fetal losses during pregnancy, birth outcome, delivery information, neonatal and maternal deaths; neonatal survival at the six wks, perinatal deaths, neonatal deaths, stillbirths.
Notes 

Characteristics of ongoing studies [ordered by study ID]

Cogswell 2006

Trial name or titleImpact of iron/folic acid versus multimicronutrient versus folic acid supplements during pregnancy on mortality, morbidity, and complications during pregnancy, labor, and delivery: a randomised controlled trial in China.
Methods 
ParticipantsPregnant women 20 years or older who live in one of the study counties (Laoting, Mancheng, Fengrun, Xianghe, Yuanshi), who can follow instructions and can swallow pills.
InterventionsDaily prenatal supplements that contain 400 ug folic acid alone, or daily supplements that contain 30 mg iron and 400 ug folic acid.
Daily supplements that contain 30 mg iron and 400 ug folic acid or daily supplement containing 30 mg iron, 400ug folic acid and other vitamins and minerals (UNICEF formulation).
OutcomesPerinatal mortality, i.e., the number of stillbirths (fetal deaths of 28 wks or more of gestation) and the number of deaths within the first 0-6 days of life per 1000 births (live births and stillbirths); Gastrointestinal side effects at monthly visits.
Starting dateMay 2006; expected completion: December 2010.
Contact informationMary E Cogswell, DrPH, RN 770-488-6053 MCogswell@cdc.gov
Mei Zuguo, MD, MPH 770-488-5864 ZMei@cdc.gov
Notes 

Hemminki 2008

Trial name or titleRoutine Iron Prophylaxis During Pregnancy (PROFEG)
MethodsA pragmatic randomised controlled trial with non-blind design. Total intended sample size is 4000 women. Hypothesis: group 2 will have better health outcomes. Study site: Mozambique, Maputo City.
ParticipantsPregnant women 18 years of age or older attending prenatal care in two health centres, one in Maputo city and one in Maputo province. The women are followed in prenatal visits and until delivery.
InterventionsWomen will be randomised individually and allocated into two different groups: group 1, women in the routine iron prophylaxis will receive 65 mg ferrous sulphate and 400 ug of folic acid daily; group 2, women will be screened in the antenatal visits with measurements of Hb. If Hb is lower than 90 g/L women will receive a monthly supply of 130 mg of iron to be taken daily and folic acid. If Hb is 90 g/L or higher then women receive 1 tablet containing 1 mg of folic acid.
OutcomesPrimary outcomes: preterm delivery, low birth weight, malaria reactivation during pregnancy (mother) [Time Frame: Until birth]. Secondary Outcome Measures: perinatal mortality, complications during pregnancy and birth [Time Frame: pregnancy and neonatal period].
Starting dateThe project consists of three interlinked phases: the preparatory phase, pilot study and trial as such. The research project started in April 2005 with the preparatory phase, the pilot study of the second phase tested the data collection methods and procedures in the study protocol. The third phase is currently ongoing.
Contact information

Principal Investigator:Elina Hemminki;

Study Director: Baltazar Chilundo

Elina Hemminki, Research Professor
THL (National Institute for Health and Welfare)
P.O.Box 30, 00271 Helsinki, Finland
E-mail: elina.hemminki@thl.fi
Phone: +358-20-6107307
fax  +358-20 6107227
http://groups.stakes.fi/thp/en       

Baltazar Chilundo, MD, PhD

Universidade Eduardo Mondlande,

Faculty of Medicine, Department of Community Health  

Phone: +258 84 3158350    

E-mail: chilubal@yahoo.com

Notes