Strategies to prevent iron deficiency and improve reproductive health nure_436
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Jacques Berger, Frank T Wieringa, Annie Lacroux, and Marjoleine A Dijkhuizen Anemia and iron deficiency affect billions of people worldwide, especially women of reproductive age, pregnant women, and young children. Many countries have iron and folic acid supplementation programs for pregnant women. However, the impact of these programs is uncertain. Multiple-micronutrient supplementation during pregnancy has been advocated; however, it is unclear whether this has additional advantages. Overall, programs have shown only modest impact on increasing birth weight. This review discusses the present state of knowledge on interventions to improve iron status during pregnancy and reproductive health, and investigates other possibilities such as supplementation prior to conception to improve maternal and child health. © 2011 International Life Sciences Institute
INTRODUCTION More people are affected by anemia and iron deficiency (ID) than by any other micronutrient deficiency, with an estimated 1.6 billion people worldwide being anemic and even more people currently having insufficient iron stores.1,2 If untreated, iron deficiency will eventually lead to iron-deficiency anemia (IDA). Indeed, the World Health Organization (WHO) estimates that roughly twice as many people are affected by ID than by IDA.3,4 However, before anemia occurs, ID is already affecting other functions, such as the immune system and the nervous system, leading to reduced immunocompetence, decreased physical activity, and cognitive impairment.5–7 Consequently, it is estimated that ID contributes to >20,000 deaths per year in children under 5 years of age and to approximately one-fifth of the maternal mortality burden.8,9 Given these serious effects, it is not surprising that prevention and treatment of ID is considered a top priority by many national and international organizations.10 However, despite many decennia of efforts, very little impact has been made.4,11 The present review focuses on strategies to prevent ID and IDA in women of
reproductive age (WRA) and during pregnancy in order to improve maternal as well as neonatal health. The presently available evidence is discussed and the challenges and opportunities for interventions are highlighted.
SCOPE OF THE PROBLEM Physiologically, ID occurs when the body’s requirements for iron exceed the amount of iron absorbed from the diet. Requirements are raised by rapid increases in body mass (such as in pregnant women and young children) or by high losses of iron (as through menstruation or hookworm infection). Iron absorption is low (~5%) from plant-based diets (which are common in developing countries) because of factors that inhibit iron uptake (such as phytates and polyphenols), and iron absorption is higher (~15%) from diets containing more meat and fish (which are more common in developed countries).3 In populations, ID is related to factors such as socioeconomic status, food insecurity and food quality, genetic background, and infectious disease burden. Data from prevalence studies on anemia or ID are useful for
Affiliations: J Berger, F Wieringa, and A Lacroux are with the Institut de Recherche pour le Développement (IRD), Montpellier, France. M Dijkhuizen is with Paediatric and International Nutrition, Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark. Correspondence: J Berger, Institut de Recherche pour le Développement (IRD), BP 64501, 34394 Montpellier Cedex 5, France. E-mail:
[email protected], Tel:+33-4-67-41-61-66, Fax: +33-4-67-41-61-57. Key words: anemia, iron deficiency, iron supplementation, pre-conception supplementation, pregnancy S78
doi:10.1111/j.1753-4887.2011.00436.x Nutrition Reviews® Vol. 69(Suppl. 1):S78–S86
assessing the extent of the problem and can provide valuable information on risk factors, associated conditions, and relative risks of vulnerable population groups. Determination of the underlying risk factors is useful for identifying opportunities and developing strategies to address ID. An important limitation is that developing countries often only report anemia data, not indicators of iron status. Although more people are affected by ID than by IDA, many cases of anemia are not due to ID; rather, they are due to other causes such as nutritional deficiencies other than iron (vitamin B12, folic acid, vitamin A, selenium), genetic traits (hemoglobinopathies such as sicklecell or thalassemia), renal insufficiency, or chronic inflammation. Therefore, anemia is not a good indicator of iron status, especially in some populations, e.g., with endemic malaria or high prevalence of hemoglobinopathies. Reporting only anemia data hampers the identification of risk factors for ID and the assessment of interventions. Based on currently available prevalence data, the highest burdens of anemia and ID are found in Africa, the Middle East, Asia, and the Western Pacific.1 In Africa, the prevalence of anemia in WRA is estimated to be approximately 47%, and in pregnant women it is around 57%,1 although prevalence rates differ widely from country to country.12 Fortunately, several studies have recorded prevalence rates for both anemia and ID, making the data much more informative. In Mali, for example, anemia is present in 47% of pregnant women (hemoglobin [Hb] < 110 g/L), while only 13% of the women have ID (serum ferritin 52,000 pregnancies. However, data on over half of these pregnancies was provided by one study from Indonesia (SUMMIT trial). This metaanalysis shows a small but significant increase in birth weight (+22.4 g, CI 8.3–36.4) and an 11% decrease in the prevalence of low-birth-weight infants (RR 0.89, CI 0.81– 0.97). However, subgroup analyses show that this effect occurs especially in women with a body mass index score of >20 kg/m2, with no effect in women with a lower score. Moreover, the meta-analysis shows no beneficial effects on early or late neonatal death (RR 1.23 and CI 0.95–1.59 versus RR 0.94 and CI 0.73–1.23, respectively).40 This latter finding is surprising, as the largest trial included in the analysis (the SUMMIT trial, performed in Lombok, Indonesia), shows a significant, beneficial effect on early infant survival (RR 0.82, CI 0.70–0.95) and post-neonatal mortality (RR 0.70, CI 0.55–0.89).41 In contrast, in the meta-analysis, there was a significant increase in the prevalence of large-for-gestational age babies (RR 1.13, CI 1.00–1.28), raising the question as to whether this could increase the number of obstructed deliveries.42 An introductory article in a recent supplement of the Food and Nutrition Bulletin reporting the findings of the MMSS Group meta-analysis states “. . . The World Health Organization will hopefully make a global recommendation that governments provide multiple micronutrient supplements instead of iron–folic acid . . . ”.43 But how strong is the evidence for such a recommendation at the moment? Given the large sample size of this metaanalysis and the use of raw pooled data, it comes as no surprise that the effect on birth size was statistically significant, even though the effect was only a meager 22 g. Of course, it is possible that tail-effects result in a much more pronounced effect on the prevalence of low-birth-weight than on average-birth-weight deliveries. Indeed, some studies suggest that different combinations of micronutrients have different effects on the birth weight distribution curve, with some combinations (iron and folic acid) especially affecting the low end of the distribution curve, whereas other combinations (multiple micronutrients) shift the whole distribution curve.44 Indeed, in the metaanalysis by the MMSS group, the effect of multiplemicronutrient supplementation during pregnancy appears to shift the whole birth weight distribution curve upwards, rather than having distinct tail effects.42 ComS81
pliance in these 12 studies was high, and most studies (8 of 12) started providing supplements before month 4 of pregnancy. In a study from China, the effects of micronutrient supplementation during pregnancy on outcomes such as birth weight were only significant when supplementation started before week 12 of gestation.45 Neither iron + folic acid nor multiple-micronutrient supplementation had an effect on birth weight when it began later than gestational week 12. Other studies confirm that Hb concentrations early in pregnancy are related to low birth weight in a U-shaped curve. Women between weeks 4 and 8 of pregnancy, with Hb concentrations between 90 and 99 g/L had a 3.27 (CI 1.09–9.77) higher risk for a low-birthweight baby than the reference category (110–119 g/L), whereas risks for low-birth-weight and preterm birth also increased with Hb concentrations >130 g/L.46 Anemia early in pregnancy appears to be much more strongly related to low birth weight than anemia in the third trimester.47 It is unlikely that these conditions (high compliance, early start of supplementation) can be met by standard national programs in which women are more likely to report to the health system for the first time at around week 16 of pregnancy. Based on the above observations, it can be expected that the effects of supplementation programs for pregnant women, whether providing iron, iron + folic acid, or multiple micronutrients, will be disappointingly small or absent. So, if women cannot be reached in time during pregnancy to start providing much-needed micronutrients, why not start before pregnancy? Surprisingly, only a few studies have investigated the effects of pre-conception supplementation with iron or multiple micronutrients on maternal or neonatal health. As for pregnant women, deficiencies of more than one micronutrient are also likely in women of reproductive age.48 To meet iron needs during pregnancy, women need an iron reserve of at least 300–500 mg prior to conception,47,49 so as not to become iron deficient after the first trimester. As iron stores are directly related to ferritin concentrations, and presuming that 1 mg/L serum ferritin reflects 140 mg/kg body weight of stored iron, a woman weighing 40–50 kg should have a serum ferritin concentration above approximately 50 mg/ L.50 Many women in developing countries will have ferritin concentrations (and hence iron reserves) below this level, and will thus be at risk of becoming iron deficient during pregnancy. Indeed, even in industrialized countries many women fail to enter pregnancy with adequate iron stores. Based on serum transferrin receptor/serum ferritin ratios, 56% of non-pregnant women in the United States (according to the NHANES III survey) had iron stores below 300 mg,47 and 500 mg) iron stores before pregnancy.49 Hence, a S82
promising approach could be to improve the iron and folic acid status of women before they become pregnant – first, because it gives a much larger time window for intervention; second, because improving micronutrient status seems to have the greatest effect early in pregnancy; and third, because nutritional status around the time of conception is important. Especially for folic acid, preconceptual increases in status have been shown to have a strong effect on the reduction of neural tube defects, with possibly >70% of neural tube defects being prevented by adequate intakes of folic acid.51 For other micronutrients such as iron, the effect of pre-conception status on maternal and child health is less clear, mainly due to a lack of studies in humans.52 A multi-country trial in Southeast Asia is one of the few examples of research investigating the effects of supplementing women of reproductive age with iron and folic acid, and following the women through pregnancy and delivery.53 Earlier studies had shown that weekly supplementation with iron and folic acid improved iron status in adolescent Malaysian54 and Indonesian girls.55 Therefore, with support of the WHO, effectiveness trials were conducted with unsupervised weekly iron + folic acid supplementation for women of reproductive age in Cambodia, Vietnam, and the Philippines. The supplements provided 3.5 mg of folic acid and 60 mg of elemental iron for non-pregnant women and 120 mg of iron + 3.5 mg folic acid for pregnant women. Supplements were free of charge for pregnant women, but sold to non-pregnant women through a social marketing program. In the non-pregnant women, iron status improved significantly over the intervention period. In Vietnam, anemia prevalence decreased from 45% at baseline to
