Background Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it is thought to improve other maternal and birth outcomes. Objectives To assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention in antenatal care. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 January 2015). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (26 February 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (26 February 2015) . Selection criteria Randomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy. Data collection and analysis We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. We used the GRADE approach to assess the quality of the evidence for primary outcomes.We anticipated high heterogeneity among trials and we pooled trial results using a random-effects model and were cautious in our interpretation of the pooled results: the random-effects model gives the average treatment effect. Main results We included 61 trials. Forty-four trials, involving 43,274 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo.Preventive iron supplementation reduced maternal anaemia at term by 70% (risk ratio (RR) 0.30; 95% confidence interval (CI) 0.19 to 0.46, 14 trials, 2199 women, low quality evidence), iron-deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69, six trials, 1088 women), and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women, low quality evidence). There were no clear differences between groups for severe anaemia in the second or third trimester, or maternal infection during pregnancy (RR 0.22; 95% CI 0.01 to 3.20, nine trials, 2125 women, very low quality evidence; and, RR 1.21; 95% CI 0.33 to 4.46; one trial, 727 women, low quality evidence, respectively), or maternal mortality (RR 0.33; 95% CI 0.01 to 8.19, two trials, 12,560 women, very low quality evidence), or reporting of side effects (RR 1.29; 95% CI 0.83 to 2.02, 11 trials, 2423 women, very low quality evidence). Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130 g/L during pregnancy, and at term.Compared with controls, women taking iron supplements less frequently had low birthweight newborns (8.4% versus 10.3%, average RR 0.84; 95% CI 0.69 to 1.03, 11 trials, 17,613 women, low quality evidence), and preterm babies (RR 0.93; 95% CI 0.84 to 1.03, 13 trials, 19,286 women, moderate quality evidence). They appeared to also deliver slightly heavier babies (mean difference (MD) 23.75; 95% CI -3.02 to 50.51, 15 trials, 18,590 women, moderate quality evidence). None of these results were statistically significant. There were no clear differences between groups for neonatal death (RR 0.91; 95% CI 0.71 to 1.18, four trials, 16,603 infants, low quality evidence), or congenital anomalies (RR 0.88, 95% CI 0.58 to 1.33, four trials, 14,636 infants, low quality evidence).Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these studies reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%. Authors' conclusions Supplementation reduces the risk of maternal anaemia and iron deficiency in pregnancy but the positive effect on other maternal and infant outcomes is less clear. Implementation of iron supplementation recommendations may produce heterogeneous results depending on the populations' background risk for low birthweight and anaemia, as well as the level of adherence to the intervention.

Daily oral iron supplementation during pregnancy

Nutrition and maternal mortality in the developing world

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.

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

Effectiveness and strategies of iron supplementation during pregnancy.

BACKGROUND It has been suggested that routine intake of supplements containing iron or combination of iron and folic acid during pregnancy improves maternal health and pregnancy outcomes. OBJECTIVES To assess the efficacy, effectiveness and safety of routine antenatal daily or intermittent iron supplementation with or without folic acid during pregnancy on the health of mothers and newborns. SEARCH STRATEGY We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (June 2005). Additionally, we contacted relevant organizations for the identification of ongoing and unpublished studies. SELECTION CRITERIA All randomised or quasi-randomised trials evaluating the effect of routine supplementation with iron or combination of iron and folic acid during pregnancy. DATA COLLECTION AND ANALYSIS We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion and one author extracted data. We collected information on randomisation method, allocation concealment, blinding and loss to follow up. The primary outcomes included maternal and infant clinical and laboratory outcomes. MAIN RESULTS Forty trials, involving 12706 women, were included in the review. Overall, the results showed significant heterogeneity across most prespecified outcomes. Heterogeneity could not be explained by standard sensitivity analyses including quality assessment; therefore, all results were analysed assuming random-effects. Very limited information related to clinical maternal and infant outcomes was available in the included trials. The data suggest that daily antenatal iron supplementation increases haemoglobin levels in maternal blood both antenatally and postnatally. It is difficult to quantify this increase due to significant heterogeneity between the studies. Women who receive daily antenatal iron supplementation are less likely to have iron deficiency and iron-deficiency anaemia at term as defined by current cut-off values. Side-effects and haemoconcentration are more common in women who receive daily iron supplementation. No differences were evident between daily and weekly supplementation with regards to gestational anaemia; haemoconcentration during pregnancy appears less frequent with the weekly regimen. The clinical significance of hemoconcentration defined as haemoglobin greater than 130 g/L remains uncertain. AUTHORS' CONCLUSIONS Further studies are needed to assess the effects of routine antenatal supplementation with iron or a combination of iron and folic acid on clinically important maternal and infant outcomes.

Anne Uski

Papers

Iron supplementation during pregnancy--experiences of a randomized trial relying on health service personnel.