Around 2 billion people, amounting to over 30% of the world’s population are anemic, mainly due to iron deficiency 1. Iron deficiency is the most prevalent and also the most neglected nutrient deficiency in the world, particularly among pregnant women and children, especially in developing countries 2. It is also significantly prevalent in industrialized countries. Estimates say that globally, fifty six million pregnant women (41.8% of the total) are affected with anemia, again mostly due to iron deficiency 3. In developing countries, this proportion can be as high as 80% like in South Asia 4, making pregnant mothers susceptible to increased risk of mortality and decreased work capacity. It may also lead to other perinatal complications like pre-eclampsia, low birth weight, prematurity and perinatal mortality 5. It is the poorest, most vulnerable and least educated who are disproportionately affected by iron deficiency, and it is this group that stands to gain the most by its reduction.

Anemia, as defined by low hemoglobin or hematocrit, is commonly used to assess the severity of iron deficiency in populations without high rates of malaria. The high physiological requirement for iron in pregnancy is difficult to meet with most diets. Therefore, pregnant women should routinely receive iron supplementation, especially in developing countries. Prenatal iron supplementation is not compulsory in many industrialized countries and the recommended dose is usually small (30 mg ferrous iron daily) 6. However, for developing countries, the recommendation is a daily dose of 60 mg of iron for pregnant, non-anemic women for six months and an increased dose of 120 mg of iron daily if the duration of supplementation is shorter, if iron deficiency prevalence in women of a given country is high, and if pregnant women are anemic. This supplement should include 400 µg of folic acid or lower doses if this amount is not available 7.

Earlier studies have provided sufficient evidence to show that iron supplementation with or without folic acid results in a significant reduction in the incidence of anemia during pregnancy 28. There has also been a limited impact of iron supplementation in community settings owing to lack of compliance and poor infrastructure 9. However, data regarding quality of evidence for the effectiveness of iron during pregnancy are lacking. Besides, the data on studies in developing countries have not been presented separately. This article is one of the series of papers that aim to determine efficacy of interventions for recommendations into the Lives Saved Tool (LiST), especially in developing countries and is, therefore, different from previously published systematic reviews. In LiST, increases in coverage of an intervention results in a reduction of risk factor or one or more causes of mortality. In this review, the recommendations are made based on application of adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for the quality of evidence and use of the Child Health Epidemiology Reference Group (CHERG) rules. For more details of the review methods, the adapted GRADE approach or the LiST model, see the methods paper for by CHERG group 10.

The search generated 3550 hits on PubMed and 290 in Cochrane Library that were screened and after removing duplicates, 81 abstracts were preliminarily selected. These were reviewed in detail, including full texts and finally 31 1617181920212223242526272829303132333435363738394041424344454647 studies were selected for inclusion in this paper. A detailed account of the number of abstracts and titles scanned is given as a flow chart (Figure 1). Table 1 gives the summary of the quality of evidence and the impact estimates of different interventions.

This outcome was reported by 18 studies 161719202123242729303233343738394147. Daily supplementation with iron only versus no intervention/placebo was evaluated by 14 studies 1719212324272930333437383941. There was a statistically significant 73% reduction in the incidence of anemia at term (RR = 0.27; 95% CI: 0.17 – 0.42; random model) (Figure 2). There were three studies 161721 that evaluated daily supplementation with iron and folic acid both versus no intervention/placebo and pooled data also showed a significant 73% reduction in anemia at term (RR = 0.27; 95% CI: 0.12 – 0.56; random model) (Figure 3). There was, however, no difference between intermittent iron-folic acid supplementation vs. daily iron-folate on this outcome based on three studies 203247 (RR = 1.61; 95% CI: 0.82 –3.14; random model) (Figure 4).

This outcome was reported by seven studies 23273133344345. Daily supplementation with iron alone versus no intervention/placebo had a significant 67% reduction in incidence of iron deficiency anemia at term based on six studies 232733344345 (RR = 0.33; 95% CI: 0.16 – 0.69; random model). There was one study 31 on daily iron-folic acid versus no intervention/placebo and the effect was large but non-significant (RR = 0.43; 95% CI: 0.17 – 1.09; random model)

This outcome was estimated by 13 studies 16182023273031323334354145. Daily iron supplementation versus no intervention/placebo, as seen in 8 studies 1823273033344145, had a non significant adverse impact on severe anemia at term (RR = 4.83; 95% CI: 0.23 - 99.88; random model). This result was primarily based on one study 33 as all the other studies had zero events in both groups. Three studies evaluated the impact of daily supplementation with iron and folate both on severe anemia at term 161831, but the number of events in these studies in both groups was nil. Intermittent supplementation with iron and folate vs. daily supplementation of same micronutrients also yielded no severely anemic patients in the intervention and control groups in the three studies that looked at this outcome 203235.

Severe anemia during second and third trimester was reported by 19 studies 16182223252728303132333435364042444546. Daily iron alone compared to no supplementation had no impact on severe anemia in second and third trimester based on nine studies 182223272830333445, (RR = 0.48; 95% CI: 0.01 – 34.52; random model), with only two studies 2233 having events greater than zero in the intervention and control groups. For intermittent iron alone vs. daily iron alone, there were two studies 3644 that looked at this outcome and both had zero events in the two groups. Daily iron-folic acid versus no intervention/placebo also had no effect on severe anemia at any time during second and third trimester based on four studies 16182231 (RR = 0.11; 95% CI: 0.01 – 0.83), with zero events in three of these studies in both groups, except one 22. Intermittent iron-folate vs. daily iron-folate outcome included 6 studies 253235404246 and events were nil in both groups in all these six studies.

Iron supplementation alone or in combination with folic acid has been associated with the well being of the mother and fetus. It leads to a significant reduction in anemia incidence during pregnancy and, thus, plays a vital role in reducing maternal morbidity and mortality. The results of our review were consistent with those of an earlier Cochrane review by Pena Rosas and Viteri 2 that also showed a significant reduction in incidence of anemia and iron deficiency anemia at term with daily iron supplementation and that of anemia at term due to daily iron-folate supplementation versus no intervention/placebo.

The pooled analysis of effect of daily iron supplementation vs. control had a high heterogeneity (fig 2). The most likely explanation of this substantial statistical heterogeneity (I² =73 %) is the variable effect size of the studies which in turn depend on the baseline anemia status of the study population. An important observation to make is that the direction effect in all the studies was in the same direction. We can expect that biologic effect of iron supplementation would differ based on prevalence of anemia in the study population. To further elaborate on this observation, we conducted a post hoc subgroup analysis based on baseline anemia status of the study population (data not shown). There were seven studies that included only non-anemic pregnant women based on laboratory evidence of absence of anemia (hemoglobin < 110 g/L) 21232427293339 and in other seven studies, population was that of mixed status 17193034373841. Pooled estimates for non-anemic women were less heterogeneous (I² =47%) and size of summary estimate was less prominent (RR 0.31, 95 % CI 0.19-0.52) compared to that of mixed population that had more heterogeneous (I²=83%) and more prominent results (RR 0.22, 95 % CI 0.11-0.47). This shows a strong biologic effect in favor of the intervention and also indicates that effect of Iron supplementation would depend on degree of baseline anemia in the study population.

CHERG rules were applied to the collective outcomes of anemia for recommendation of iron deficiency anemia into the LiST model. Daily supplementation with iron led to 73% reduction in incidence of anemia at term as compared to no supplementation. This intervention had a ‘moderate’ quality evidence owing to some limitations in included studies like unclear 1721243034383941 or inadequate sequence generation 19, and high loss to follow up 172327. Another limitation was that all the studies in the pooled analysis were not conducted in developing countries. In any case, based on strong biologic plausibility and consistent direction of effect across the studies, we recommend a 73 % reduction in anemia at term with iron supplementation during pregnancy, for inclusion in the LiST model. Daily supplementation with iron and folate led to 73% reduction in incidence of anemia at term when compared with no supplementation. We recommend this estimate for reduction in anemia at term for inclusion in the LiST model. The quality of evidence regarding this intervention had to be down-graded from ‘high’ to moderate due to some limitations like high loss to follow up 17 and unclear sequence generation 21 and also the fact that all the studies were not conducted in developing countries.

Our results show that there was not much difference in effect between iron alone and iron-folate combined. The effect sizes were similar for both the analyses but CIs were wider for that of iron/folate, mainly due to less number of studies in the pooled analysis. This shows that we can expect a similar biological effect when the iron is supplemented alone or in combination with folate. We did a subgroup for developing and developed countries. There were not sufficient studies from developing countries for all the analyses. An important observation to make in figure 2 is that even though there were two studies from developing countries, the results were very consistent (I²=0%). Even though there are not a lot of randomized trials conducted in developing countries but we can suggest that iron supplementation would be much effective in developing world by looking at biological plausibility of the intervention. The populations that are most at risk for iron deficiency and IDA are young children and women of reproductive age, especially during pregnancy. The global estimates on prevalence of anemia showed that more than half the pregnant women and young children are anemic in Southeast Asia, West Pacific and Africa 48. This shows that amount of effect would be substantially high in developing countries however more efficacy trials are required to determine the conduct of the intervention.

Weekly iron and folic acid supplementation (WIFS) is a relatively new phenomenon, and there is very little data at the moment comparing weekly supplementation with daily dosage. Weekly iron and folic acid supplementation, in synchrony with the turnover of mucosal cells, may be a promising substitute for daily iron supplementation and has been proposed as a more efficient preventive approach in public health programs 4950. The WHO says that WIFS should be considered a strategy for prevention of iron deficiency in population groups where the prevalence of anemia is above 20% among women of reproductive age and mass fortification programs of staple foods with iron and folic acid are unlikely to be implemented within 1-2 years. However, conclusive data regarding its efficacy as compared to the daily regimen are not yet available. Weekly dosage may have benefits of reduced side effects and increased compliance, but more field randomized controlled trials are needed to establish the efficacy of weekly supplementation compared to daily regimen.

Iron supplementation has a significant benefit in reducing anemia and iron deficiency anemia at term. Iron in combination with folic acid also has a beneficial impact on anemia at term and should be routinely used in pregnant women at least in developing countries to reduce the incidence of anemia due to increased demands during pregnancy.

We do not have any financial or non-financial competing interests for this review.

Professor Zulfiqar A Bhutta developed the parameters and scope for the review and secured support. Dr Mohammad Yawar Yakoob undertook the literature search, data extraction and wrote the manuscript along under the supervision of Professor Bhutta.