Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy
Supplementary iron or iron+folic acid (provided either daily or weekly) is effective in preventing anaemia and iron deficiency at term, although there is no significant effect of supplementation on the incidence of substantive maternal and neonatal adverse clinical outcomes such as low birth weight, delayed development, preterm birth, infection, and postpartum haemorrhage.
RHL Commentary by Kaufer-Horwitz M and Gómez FE
Anaemia is a public health problem that affects rich and poor populations alike. Pregnant women are particularly vulnerable. According to the World Health Organization (WHO), the worldwide prevalence of anaemia in pregnant women is 41.8% (95% CI 39.9-43.8); there are only few exception countries in the world where anaemia is not at least a mild public health problem (1). Supplementation of diet with iron compounds during pregnancy has been recommended by international and local organizations for quite some time; intake of folic acid as a dietary supplement might have additional benefits (reduced risk of serious neural tube defects in the infant) for women of reproductive age (2). Traditionally, women have been prescribed dietary supplements during pregnancy as a daily regimen. In recently times intermittent supplementation has been suggested, since it takes advantage of the turnover time of intestinal mucosal cells favouring iron absorption regulation and is more economical and safer from the public health perspective.
This Cochrane review (3), which was updated in 2009, aims to answer three questions related to iron supplementation during pregnancy: (i) Is the provision of daily iron with or without folic acid better than receiving nothing or a placebo? (ii) Is the provision of iron with or without folic acid on an intermittent basis better than receiving nothing or a placebo? (iii) Which of these two supplementation schemes (daily or intermittent) is more effective and safer?
2. METHODS OF THE REVIEW
The authors sought only randomized or quasi-randomized trials that had evaluated the effect of supplementation with iron or iron plus folic acid during pregnancy. They searched the Cochrane Pregnancy and Childbirth Group’s Trials Register and contacted relevant organizations to identify ongoing and unpublished studies. They placed no language restrictions on their searches. Studies dealing with iron supplementation for anaemic women as a medical treatment were excluded, as were those that assessed the effects of multiple combinations of vitamins and minerals, except studies that examined the “additional effect” of iron or iron plus folic acid supplements when all arms of the study received the same co-intervention. Methodological quality of trials was assessed using the standard Cochrane criteria. Primary outcomes evaluated in women were: premature delivery; haemoglobin (Hb) concentration, anaemia (Hb <110 g/L) and haemoconcentration (Hb >130 g/L) at term; haemoconcentration in the second and third trimesters; iron deficiency (based on two or more laboratory indicators) and iron deficiency anaemia (Hb <110 g/L and at least one additional laboratory indicator) at term; and any side-effect. In infants, primary outcomes consisted of low birth weight (<2500 g) and birth weight. Secondary outcomes were numerous. For example, in the mother, they included very premature delivery, severe and moderate anaemia at term or in the second and third trimesters, infections, haemorrhage, and Hb concentration one month postpartum. Secondary outcomes in the infant were, among others, very low birth weight, perinatal mortality, and Hb and ferritin concentrations at one month post partum. Three subgroup analyses were performed on the primary outcomes to evaluate the effect of the supplementation timing, the baseline status of anaemia, and the dose of the supplement. The authors also conducted a sensitivity analysis based on the quality of the studies.
3. RESULTS OF THE REVIEW
Forty-nine trials, involving 23 200 pregnant women were included in the review. Overall, the results showed significant heterogeneity across most pre-specified outcomes and were analysed assuming random effects. The trials provided limited information related to functional maternal and infant outcomes.
Four separate comparisons could be made in the review.
i. Daily iron alone versus no intervention/placebo (36 trials, 13 high-quality)
There was no evidence of significant differences in rates of premature delivery between women who received daily iron supplementation and those who did not. Women who took daily iron supplements were less likely to have anaemia at term: 5.08% versus 14.56% [relative risk (RR) 0.27, 95% confidence interval (CI) 0.17–0.42]. When only high-quality studies were analysed, the association persisted, but it was weaker: 4.7 % versus 9.98%; RR 0.46; 95% CI 0.29–0.72. Hb concentration at term was 8.83 g/L, being higher in women who took daily iron supplements (95% CI 6.11–11.11). This increase was higher if supplementation was started after 20 weeks of gestation, but the difference was maintained with different doses of elemental iron. These results need to be interpreted with caution because heterogeneity among the treatment effects was substantial.
Haemoconcentration at term was more likely in women who took daily iron supplements (53.8% versus 38.0%; RR 2.62; 95% CI 1.21–5.67). However, the differences between the groups were not significant when only high-quality trials were included in the analysis. The risk of haemoconcentration at term was higher among women who received daily doses of more than 60 mg elemental iron.
Haemoconcentration during the second or third trimesters was higher among women who received daily iron supplements (25.1% versus 9.3%; RR 2.27; 95% CI 1.40–3.70), and the results were still significant when only high-quality trials were included (RR 2.22; 95% CI 1.28–3.85). The effect was maintained in women who started supplementation early or at higher or lower doses of elemental iron.
The prevalence of iron deficiency at term was lower in women who received daily iron supplements (30.7% versus 54.8%; RR 0.44; 95% CI 0.27–0.70); however, heterogeneity between trials was substantial and results should be interpreted with caution. Women who received daily iron supplements were less likely to have iron deficiency anaemia at term: 4.9% versus 15.5%; RR 0.33; 95% CI 0.16–0.69. They were also more likely to report side-effects of any kind (24.7% versus 4.3%; RR 3.92; 95% CI 1.21 to –12.64); however, when only high-quality trials were included in the analysis the difference between the groups was no longer significant. As expected, diarrhoea was less frequent in women who received daily iron supplements (3.9% and 5.1%; RR 0.55; 95% CI 0.32–0.93), but there was no evidence of significant differences between the groups in constipation, nausea, heartburn, and vomiting.
With regard to infant outcomes, there were no significant differences in birth weight or in the prevalence of low birth weight between infants of mothers in the two groups. However, higher infant ferritin concentration at 3 months (MD 19.0 ug/L; 95% CI 2.75-–35.25) and 6 months (MD 11.0 ug/L; 95% CI 4.37–17.63) and birth length (0.38 cm; 95% CI 0.10–0.65) was found in infants of mothers receiving daily iron supplements. No significant differences were found between the groups in very low birth weight, perinatal death, Hb at 6 months, percentage of children small for gestational age, very premature delivery, placental abruption, pre-eclampsia, severe anaemia at term or at any time during the second or third trimesters or post partum, moderate anaemia at term and post partum, puerperal infection, constipation, nausea, heartburn, vomiting, and maternal death.
ii. Intermittent iron alone versus daily iron alone (2 trials, neither of them high-quality)
No evidence of significant differences was found in the rates of premature delivery, haemoconcentration during the second or third trimesters or moderate anaemia during the second or third trimesters between women who received intermittent versus daily iron supplementation.
Neither of the two trials reported on maternal Hb concentration, anaemia, haemoconcentration, iron deficiency or iron-deficiency anaemia at term, or on side-effects of both supplementation regimens. Also, they did not report on the prevalence of low birth weight and no significant differences were found in birth weight, although only one study with 41 women provided data for this outcome.
iii. Daily iron+folic acid versus no treatment or placebo (9 trials/one high-quality)
No evidence of significant differences was found in the rates of premature delivery between women who received daily iron+folic supplementation and those receiving no treatment or placebo.
Data from four trials suggested that women who routinely received daily iron+folic supplementation reached term with higher Hb concentration (MD 12.00 g/L; 95% CI 2.93–21.07). Women who received iron+folic acid supplementation were less likely to have anaemia at term: 8.2% versus 35.5% (RR 0.27, 95% CI 0.12–0.56); these results should be interpreted with caution since the heterogeneity between treatment effects was substantial.
With regard to haemoconcentration at term or at any time during the second and third trimesters, no evidence of significant differences was found between women who received daily iron+folic acid supplementation and those who received no treatment or placebo.
Data from one trial suggested that women receiving daily iron supplementation are less likely to have iron deficiency at term than women taking placebo or no iron+folic acid (3.6% versus 15%; RR 0.24; 95% CI 0.06–0.99). Trends were the same for early or late start of supplementation. One trial suggested that women who received daily iron+folic acid supplementation were more likely to report any side-effects in comparison to none reported by those receiving no supplementation (RR 44.32; 95% CI 2.77–709.09).
With regard to infant outcomes no significant differences were found in the prevalence of low birth weight between the groups. The trials suggested that infants whose mothers received daily iron+folic acid were 57.7 g heavier (95% CI 7.66–107.79) than those born to mothers who received no treatment. One trial suggested that women receiving daily iron+folic acid supplementation were less likely to give birth to a small-for-gestational-age baby (RR 0.88; 95% CI 0.80–0.97). No evidence of significant differences was found between infants of women in the two groups with regard to very low birth weight, perinatal mortality, small size for gestational age or birth length.
iv. Intermittent iron+folic acid versus daily iron+folic acid (nine trials)
Women who took intermittent iron+folic acid were as likely to have a low-birth-weight newborn (5.6% versus 5.9%; RR 1.05; 95% CI 0.58–1.91) compared with those with those who took daily supplementation, and there were no differences in birth weight either.
No evidence of significant differences was found in premature delivery, Hb concentration, anaemia, haemoconcentration or iron-deficiency anaemia at term between the women who received intermittent versus those who received iron+folic acid supplementation. However, results from six trials suggested that women who received intermittent iron+folic acid supplementation during pregnancy were less likely to have haemoconcentration at any time during the second or third trimesters compared with those who received the daily regimen (7.7% versus 18.8%; RR 0.43; 95% CI 0.24–0.77). The difference was maintained in women who started supplementation late in pregnancy, but since heterogeneity between treatment effects was substantial, the results should be interpreted with caution. The authors found no evidence of significant differences in side-effects between the two groups.
With regard to infant outcomes, one study including 88 women suggested that infants from women receiving intermittent iron+folic acid achieved a higher ferritin concentration at six months, but no firm conclusions can be drawn given the scarcity of the data.
The authors of the review conclude that universal prenatal supplementation with iron or iron+folic acid provided either daily or weekly is effective in preventing anaemia and iron deficiency at term. However, iron or iron+folic acid supplementation does not significantly reduce the incidence of substantive maternal and neonatal adverse clinical outcomes (low birth weight, delayed development, preterm birth, infection, postpartum haemorrhage). The side-effects of iron or iron+folic acid, particularly haemoconcentration during pregnancy, possibly indicate the need for revising iron doses and schemes of supplementation during pregnancy.
4.1 Applicability of the results
The review covers a wide variety of trials involving diverse iron or iron+folic acid regimens and populations. This is valuable because the widespread problem of anaemia in pregnancy warrants different supplementation schemes due to differences in population circumstances and idiosyncrasies. At the same time, it warrants applicability of these findings.
Treatment or anaemia with iron supplements has been associated with acute exacerbations of infection, in particular, malaria (4). Although, according to projections, malaria will diminish in most regions, it will still figure as a leading cause of death in low-income countries (5, 6). This and other parasitic infections should be documented and treated for supplementation to be effective in these populations.
Even though heterogeneity between treatment effects was substantial in many comparisons, the results are consistent and coherent, and therefore widely applicable. The vast amount of information contained in this review may hamper the interpretation of the results and its translation to public health policy. Thus, when planning further updates to this Cochrane review, authors might consider separate reviews for daily and intermittent supplementation schemes. This might prove useful to researchers and decision-makers alike.
4.2 Implementation of the intervention
Iron+folic acid supplementation should start early during the reproductive years, since improving iron and folate nutrition of women of child-bearing age can improve pregnancy outcomes as well as enhance maternal and infant health (7). The intermittent approach can be effective for ensuring adequate iron status of women in communities where food-based strategies are implemented or are ineffective (7).
Knowledge of local prevalence and causes of anaemia, including iron deficiency, infectious diseases (malaria, helminth infections, HIV/AIDS and tuberculosis), as well as other nutritional deficiencies (vitamin A) is essential in planning interventions designed to optimize the benefits of iron or iron+folic acid supplementation. Interventions to control these and other causes of anaemia need to be considered in the context of devising strategies for implementation of this intervention (4, 7, 8).
The high prevalence of obesity worldwide, and its association with chronic inflammation should be taken into account when planning supplementation programmes. High pre-pregnancy body mass index increases the risk of anaemia, particularly in the postpartum period, in overweight/obese low-income women. Therefore, screening and iron supplementation of overweight and obese women may be warranted (9, 10). This is particularly important when selecting indicators to assess the iron status of women, since ferritin and serum iron can be altered in the presence of low-grade chronic inflammation (11).
Intermittent supplementation may prove useful, particularly in situations where resources to implement daily supplementation are scarce. Implementation of an intermittent regimen is feasible in community programmes where women routinely attend weekly classes or other community-level activities (7).
Successful implementation of supplementation programmes requires motivation and creation of demand from women of reproductive age, creating adequate mechanisms to sustain programmes, developing and implementing effective communication strategies, establishing methods for promoting compliance, and integrating programmes with existing delivery systems both in the private sector and through community organizations (7). The full understanding of how many of these factors vary by geography, level of development, and other social and economic factors will make it possible to design more effective and comprehensive interventions (1).
4.3 Implications for research
Limitations found in the trials included in this review should serve as an incentive for future research. Upcoming trials need to focus on evaluating, apart from the haematological indicators traditionally studied, functional outcomes for mothers and their infants. Also, haemoconcentration and its potential effect on the mother and her infant needs to be researched further.
There is some evidence to suggest that supplementation at levels recommended for children carries the risk of increased severity of infectious disease in the presence of malaria or undernutrition (4); this needs to be researched further in women of child-bearing age. Also, studies focusing on HIV and chronic infections during pregnancy are scarce and necessary.
The high prevalence of obesity worldwide and its association with chronic inflammation and anaemia is an area for future research, because anaemia of inflammation is characterised by diminished iron bioavailability and mobilization. The effect of iron or iron+folic acid supplementation has not been studied in obese women or in obese pregnant women (12, 13, 14).
Sources of support: None
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- WHO and UNICEF. Iron supplementation of young children in regions where malaria transmission is intense and infectious disease highly prevalent. Joint statement (http://www.who.int/nutrition/publications/micronutrients/WHOStatement_%20iron%20suppl.pdf).
- Bodnar LM, Siega-Riz AM, Cogswell ME. High prepregnancy BMI increases the risk of postpartum anemia. Obesity Research 2004;12:941-948.
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- Yanoff LB, Menzie CM, Denkinger B, Sebring NG, McHugh T, Remaley AT et al. Inflammation and iron deficiency in the hypoferremia of obesity. International Journal of Obstetrics 2007;31:1412-1419.
- Zimmermann MB, Zeder C, Muthayya S, Winichagoon P, Chaouki N, Aeberli I et al. Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification. International Journal of Obstetrics 2008;32:1098-1104.
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- Tussing-Humphreys LM, Nemeth E, Fantuzzi G, Freels S, Guzman G, Holterman AL, et al. Elevated systemic hepcidin and iron depletion in obese premenopausal females. Obesity 2010;18:1449-1456.
This document should be cited as: Kaufer-Horwitz M and Gómez FE. Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy: RHL commentary (last revised: 1 December 2010). The WHO Reproductive Health Library; Geneva: World Health Organization.