Iron supplementation during pregnancy

European Journal of Obstetrics & Gynecology and Reproductive Biology 61 (1995) 65-71

1 id S 1: \ I E R

Iron supplementation during pregnancy Annet J.C. RoodenburgaTb ‘Departmenr bDeparlmenr

of Human

of Laboratory Animal Science. Nutrition. Wageningen Agricultural

Stale Un~rersiry L~niversiry P 0.

Urrechr, Utrrchi, Box 8129. 6700

The Netherlands EV Wageningen,

The Netherlands

Abstract There is world-wide concern that women of childbearing age cannot meet the increased iron needs during pregnancy. In the industrial world however, iron supplementation during pregnancy is a controversial issue. On the one hand, selective iron supplementation after iron status assessment has been recommended because not all women need iron, and compliance is likely to be better when an individual’s need is recognized. On the other hand, routine iron supplementation to all women in the second half of pregnancy has been advocated in order to reach all women without the difficulties associated with assessment of iron status. Pregnant women could possibly meet their iron needs by increasing iron absorption efficiency. Although in that case, dietary counselling may prevent anaemia during pregnancy, supplementation with iron will be necessary to cure iron-deficiency anaemia. Keywords: Pregnancy; Iron supplementation;

Iron absorption;

Iron

Anaemia refers to a condition where blood haemoglobin concentration falls below a certain cut-off value. Cut-off values of 7.5 mmolil (12 g/dl) are generally used for non-pregnant women and 6.8 mmolil (11 gidl) for pregnant women. Although iron-deficiency is the most common cause of anaemia, infection, genetic factors, other dietary deficiencies such as those of vitamin A. vitamin B12and folate can also lead to anaemia. In the development of iron-deficiency anaemia, different stages can be distinguished. A first Stageof depleted iron stores is defined by low serum ferritin levels and no iron in bone marrow aspirates, but this stage is difficult to define in pregnancy. Most women have low or no iron storesduring pregnancy, when measuredas serum ferritin [1,2]. Therefore, it has been suggestedto distinguish only the two later stagesin iron-deficiency during pregnancy [3]; the first of these is defective haemoglobin production (with normal haemoglobin values), which can be recognized by an insufficient supply of iron to the red blood cell-forming tissues.This can be measured by a low transferrin saturation percentage, or elevated erythrocyte protoporphyrin in non-pregnant subjects.

2. Iron in pregnancy

Total iron requirements during normal pregnancy are about 840 mg (Table 1). This includes the iron needed for the fetus, placenta, increase of maternal red cell mass,and basaliron lossesby the mother. The iron content of a non-pregnant woman (60 kg) is about 2.1 g, of which about 70% percent is functional and 30% storage iron [7]. Thus the iron needs of pregnancy, about 40% of total body iron in the non-pregnant woman, should be met by increased dietary iron absorption, the cessa-

* Corresponding author. Tel.: +31 8370 &X4298/3758;Fax: +31 8370 83342; E-mail: [email protected].

SSDI

0028-2243(95)02155-L

0 1995 Elsevier Science Ireland

Ltd.

All

rights

parameters

The last stage of iron-deficiency is when haemoglobin levels are also decreased. This is defined as irondeficiency anaemia [3,4]. Anaemia is related to reduced work productivity [5] and impairs the ability to adapt to low temperatures [6,7]. Another consequenceof iron-deficiency anaemia is increased heavy metal absorption, such as lead [8]. Anaemia in infants and young children has been shown to delay cognitive development [9-l 11. The effects of iron-deficiency anaemia during pregnancy will be discussedlater. Most of the effects of iron-deficiency anaemia are reversible and can be treated by iron supplementation. Iron supplementation during pregnancy, however, is a controversial issue in the industrialized world, as discussedbelow.

1. Introduction

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Table 1 Iron requirement

during

Roodenburg

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Journal

and immediate Requirement individual

of Obstetrics

postpartum

cumulative

300 50 450 240

1040

Maternal

250

1290

450

840

loss at delivery

Contraction of maternal red cell mass immediate postpartum (based on Hallberg

[15])

tion of menstrual blood loss, and also maternal iron stores(Table 1). When the iron needscannot be met by the diet and the iron stores are insufficient, irondeficiency anaemia develops. 2. I. Prevalence women

ofanaemia

in pregnant

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pregnant women aged 20-49 years are iron-deficient (serum ferritin < 10 ,ng/l) [17].

(mg)

During pregnancy Foetus Placenta Expansion of red cell mass Basal iron losses blood

& Gynecology

and non-pregnant

Most of the available data on prevalence rates are basedon blood haemoglobin concentrations of lessthan 6.8 mmol/l (11 gidl). Estimates by the World Health Organization, based on data published between 1960 and 1985,showed that 4-290/uof European pregnant women were anaemic [12]. Data collected around 1988 indicated an overall anaemia prevalence rate in pregnant women in Europe and North America of 17% (2-450/u) [13]. In the Netherlands, the estimated prevalence of anaemiaduring pregnancy rangesfrom 6 to 28% [ 13,141. Thus, it can be concluded that prevalence rates still reach levels of public health significance (above 10%) in industrialized countries. The worldwide prevalence of anaemia in pregnant women is about 51%. Whether women are likely to become anaemic when they are pregnant dependsupon their iron status. It has been suggested that dietary habits, together with a sedentary life style in industrialized countries, makes it impossiblefor women to cover their iron needs by diet [IS]. This could be confirmed by estimates of the anaemia prevalence rate among non-pregnant women, which is 35% worldwide, In Europe and North America, 10%of the women of childbearing age are anaemic (haemoglobin < 7.5 mmol/l or 12 g/dl) [13]. Of Dutch women between 20 and 30 years of age, 2.5% were anaemic, according to figures published in 1977 [16]. A recently published study shows that 4”/u of the nonpregnant Dutch women (20-49 years) are anaemic [171. The prevalence of iron-deficiency without anaemia for women of childbearing age (serum ferritin < 12 &I) in North Europe is 16-40% [15] and in the United States 3-14% [18]. In the Netherlands, 16% of the non-

2.2. Assessment

of iron status in pregnancy

Diagnosis of iron-deficiency anaemia during pregnancy is not without difficulty. This is, in part, due to a considerable intra-individual day-to-day variation of someparameters [ 191.Moreover, plasmavolume expansion during pregnancy also causes a physiological anaemia and increases the variability among these concentration-dependent parameters;during pregnancy, the decline in haemoglobin levels reaches its lowest point at week 16 of gestation and starts to recover during the third trimester, from week 24 (Fig. 1). This decline in haemoglobin is a consequenceof haemodilution; plasmavolume expansion exceedsthe expansion of the red cell mass.Red cell massstarts to expand later, in the second half of pregnancy. When haemoglobin levels increase towards the end of pregnancy, this is indicative of sufficient iron being available. When haemoglobin failed to rise, maternal iron balance is believed to be negative [20]. The Institute of Medicine [3] has stated that if a pregnant woman is anaemic according to the cut-off values proposed by the Centres for DiseaseControl, i.e. 6.8,6.6 and 6.8 mmol/l (11, 10.5and 11 g/dl) for the first, second and third trimester [2 11,and a serumferritin of below 12 &l, she can be presumed to have iron-deficiency anaemia(Fig. 1). The cut-off values for haemoglobin are basedon pooled data of studieswith iron-supplemented pregnant women [ 1,22-241. It is relevant to add serum ferritin measurement to assessa woman’s iron status, and to distinguish between iron-deficiency anaemia and anaemia of other causes[25].

0

6 8

12

16

20 Time

24 of gestation

28

32

36

40

44

(weeks)

Fig. I. Cut-off values and concentrations of blood haemoglobin (0) and serum ferritin (A) during pregnancy in women who are sup plemented with iron. Based on data from Fenton, et al. [261 for ferritin and Centers for Disease Control [21] for haemoglobin.

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Although serum ferritin is considered to be a valid estimate of a woman’s iron stores [l-3], it needs careful consideration. During pregnancy, there is a high iron demand, and even in women with a positive iron balance, most iron will be mobilized to meet the high requirements. Ferritin levels fall during pregnancy, but gradually rise towards the end of pregnancy in women with adequate iron status [1,2,20,26] (Fig. 1). However, ferritin is an acute phase reactant, and is increased with inflammation [27]. This might mask depleted iron stores. Thus it might be important to measure inflammatory states. Also, the validity of ferritin in pregnancy is unclear [28]. The quantitive relationship, 1 pg/l ferritin = 1 mg of storage iron, is established for non-pregnant persons, but this might very well be different in the anabolic pregnant state [28]. Additional to this, plasma volume expansion and thus haemodilution will also influence ferritin concentrations. Another parameter to assess iron status is transferrin saturation, which also changes during the course of pregnancy. From observational and intervention studies, it was shown that serum transferrin or total ironbinding capacity increases during pregnancy. Serum iron concentrations decrease during the first and second trimester, followed by an increase in the third trimester. This resulted in a decrease in transferrin saturation (serum iron: total iron-binding capacity) during the first and second trimester and a rise or plateau in the third trimester [2,22,29,30]. Erythrocyte protoporphyrin concentrations remain relatively stable during pregnancy and might thus be useful [31]. Another parameter for the assessment of iron status is erythropoietin, a renal hormone stimulating red blood cell synthesis. Erythropoietin is produced by the kidney in response to hypoxia, however, in the first trimester of pregnancy this response is blunted [32]. The erythropoietin concentrations normalize in late pregnancy and then negatively correlate with haemoglobin levels in the third trimester [29,33]. These changes in pregnancy are likely to explain the late response in red cell mass expansion after the initial plasma volume expansion. Most iron parameters are subject to considerable changes in pregnancy and therefore perhaps not very useful for assessment of an individuals’ iron status. Transferrin receptor concentration is, possibly, a useful alternative (341. It is not influenced by pregnancy per se, and might thus be a valuable index of iron-deficiency in combination with serum ferritin assessment. Another advantage of transferrin receptor levels is that they are not sensitive to chronic disease or acute infection [35]. 3. Consequences pregnancy

of iron-deficiency

anaemia

during

Iron-deficiency anaemia during pregnancy is postulated to have negative consequences such as poor

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pregnancy outcome, low birth weight and complications during pregnancy. Data on these effects are, however, far from conclusive. 3.1. Complications during pregnancy Anaemia due to iron-deficiency causes increased fatigue, decreased work performance, cardiovascular stress,reduced resistanceto cold, and poor tolerance to heavy blood lossin pregnant women [7]. Many of these symptoms are expected to be causedby reduced circulating haemoglobin levels. In pregnancy, iron-deficiency increases risks of urinary tract infections and pyelonephritis [36]. HOWever, the relationship between infection and irondeficiency is complicated. One of the reasonsfor this is that anaemia protects the body against the invading diseaseagent [37]. 3.2. Anaemia and pregnanc,v outcome Anaemia during pregnancy is postulated to impair haemoglobin transport of oxygen to the uterus, placenta and also the developing fetus, thus compromising on pregnancy outcome. Indeed there is epidemiological evidence that low haemoglobin concentrations are associated with perinatal death, pre-term delivery and low birth weight [38-401. However, somestudieshave failed to find this relationship [14,41]. The evidence has to be considered critically becausethe results might be confounded by other variables associatedwith adverse pregnancy outcomes, such as smoking and low social class. In a recently published prospective study with over 800 pregnant women, it was shown that besidesethnicity and smoking, many other factors such as maternal age, parity and pre-pregnant body massindex were associated with the outcome variables of low birth weight and pre-term delivery. This study also distinguished between anaemia due to iron-deficiency, as measured by low serum ferritin (< 12 &l), and anaemia due to other causes.After correction for the confounding variables, iron-deficiency anaemiawas associatedwith an increased risk of low birth weight and pre-term delivery. However, anaemia, due to other causes, was not associated with poor pregnancy outcomes [25]. This suggeststhat it might be important to consider the causes of anaemia in pregnant women when evaluating the effects of anaemiaon the pregnancy outcome. Another analysis of thesedata showed that anaemia diagnosed at the beginning of pregnancy is associatedwith pre-term delivery, while anaemia during the third trimester is not. The authors confirmed this phenomenon when evaluating other epidemiological studies [42]. When haematocrit or haemoglobin was determined at the end of the third trimester; at delivery, as in the study of Lieberman [40], the relationship between anaemia and pre-term birth might very well be artificial. This was also suggestedby Klebanoff and others [43] who found the risks for pre-

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term birth decreasing during the third trimester. Klebanoff [43] stated that because haematocrits rise in the third trimester, studies comparing haematocrit or haemoglobin obtained from women, in either term or pre-term labour, are likely to find an artificial positive association between anaemia and pre-term delivery. Not only low, but also high haemoglobin concentrations were associated with increased risks of adverse pregnancy outcomes [14,38,39,41]. These high odds, with high haemoglobin levels, might be caused by a smaller expansion of plasma volume and related to hypertension and pre-eclampsia. However, according to one of these studies, pregnancy-induced hypertension cannot fully explain the positive relationship between haemoglobin and adverse pregnancy outcome [ 141. 3.3. Anaemia of newborn Because it has been shown that iron-deficiency anaemia in children affects cognitive function and development [9- 111,there is obvious concern whether iron-deficiency anaemic mothers are more likely to give birth to infants with iron-deficiency or anaemia. Although there are studiesthat show that maternal iron status is at least one of the determining factors for fetal iron status [26,44], most evidence suggeststhat irondeficient pregnant women have no more chance to give birth to an iron-deficient child than women who have adequate iron status [45-471. Thus, high priority is given to making iron available to the infant, while supplementing the mother with iron is more likely to benefit her than her child.

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4.1. Iron supplementation:yes or no? The first issue to agree upon is whether pregnant women can increaseiron absorption sufficiently to meet the increasedneeds.In a recently published study, iron absorption was measuredduring pregnancy with stable isotopes. Non-haem iron absorption from a breakfast of ‘intermediate non-haem iron bioavailability’ increased from 7% in the first trimester to 36% and 66% in the second and third trimesters, respectively. The authors suggestedthat sufficient iron can be taken up from the diet and thus, the increased demandsfor pregnancy will be balanced [51]. The efficiency of iron absorption is important in regulating iron balance, and is determined by a number of factors. Perhaps the most important of these is iron status, although the mechanismof this regulation is not known. The absorption of haem iron, which is by a receptor-mediated mechanism [55], is more efficient (16-26%) than that of non-haem iron ( < l-l 5%). The absorption of non-haem iron is determined by dietary factors such as the amount of iron in food and supplements [3,56]. The higher the iron dose, the larger the amount, but the lower the percentage absorbed (Fig. 2).

701

E

,

6.2mg

60,

4. Iron supplementation Whether or not to promote oral iron supplementation to pregnant women in the industrialized world is still a controversial issue[48]. Although iron supplementation during pregnancy has not been clearly shown to affect pregnancy outcome [47,48], it improves maternal iron status parameters [33,45,49,50]. The effectiveness dependsupon the dosage [50] and the form in which it is administered [49]. Concern about the iron status of women of childbearing age in general, and of pregnant women in particular [13], and the supposedinability to meet the iron needs of pregnancy with dietary iron by women living a sedentary life [ 151,supports the need of iron supplementation during pregnancy. However, not all agree upon the inability to regulate iron status during pregnancy [51]. Those in favour of iron supplementation are split into two camps.Some recommendroutine iron supplementation of all women during the second half of their pregnancy, when the iron needs are increased [3,52], while others prefer supplementation after assessmentof iron status has establisheda deficit of iron [53,54].

*

Hahn

Time

1951

_ Svanberg

1975b

Svanberg

1975a

Whittaker

1991

l

v Barret

(weeks)

1994

Fig 2. Non-haem iron absorption during pregnancy and after delivery in women who are not supplemented with iron. Comparison of results from five different studies. Iron dosage is indicated in the figure. In two studies, iron absorption was measured as part of a meal (- - -) ( 0 Svanberg et al. [SS], V Barret et al. [51]). In the other studies aqueous iron () was used (A Hahn et al. [Xi] as published by the lnstitute of Medicine [3], 0 Svanberg et al. (221, V Whittaker et al. [57]).

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Other dietary components can inhibit (calcium, phytates, polyphenols) or promote (vitamin C, animal protein) iron absorption [55]. Most studies that have observed an increased iron absorption during pregnancy have used aqueous iron [22,56,57] (Fig. 2). Svanberg and colleagues 158) have also measured absorption of iron from a meal during pregnancy. However, they concluded that the IO-fold increase in iron absorption, to 15% in the third trimester, was not sufficient to meet the increased demands. The discrepancy between this conclusion and the conclusions of Barret et al. [51] are largely explained by the availability of iron in the meal. Thus, whether pregnant women can compensate their increased iron demands by increasing absorption from dietary sources depends on iron availability, which depends in part on the composition of the diet. Therefore, dietary advice, concerning not only iron content, but also factors which enhance or inhibit iron absorption, can play an important role in preventing iron-deficiency during pregnancy (Table 2). Dietary advice will probably be most effective when given before or at the beginning of pregnancy. However, when anaemia is diagnosed, dietary iron is unlikely to be sufficient to overcome the iron deficit. Thus, iron supplements will need to be prescribed. 4.2. Iron supplementation:

selective

or routine?

The second controversial issue is whether to supplement pregnant women selectively or routinely with iron. Because it is difftcult, time consuming and costly to determine iron-deficiency in pregnancy, it has been suggested to supplement all pregnant women routinely with iron 13,521. Routine iron supplementation will result in treatment for those at risk of becoming anaemic, while iron overload is unlikely to be a problem in women of childbearing age. Since gastrointestinal side effects are dose-dependent, they can be reduced by adjusting the dose [23,52]. Another reason for routine supplementation is the fact that measurement of serum ferritin concentrations show depleted iron stores at the end of pregnancy in most women who have not taken iron supplements [2,24,26]. From these studies, it was concluded that most pregnant women are iron-deficient. However, Table 2 Dietary advices

to optimize

dietary

iron absorption

General advice: Drink orange juice or water together with a meal Drink milk, tea or coffee, not simultaneously with in between meals Eat lean meat with the meal.

et al. (551)

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serum ferritin determination during pregnancy has its limitations, as is discussed above. There is also some uncertainty about whether the mobilization of iron stores during pregnancy is a physiological phenomenon of pregnancy, and that after delivery and the contraction of red cell mass, the iron stores return. It has been shown that after delivery, serum ferritin concentrations return to levels above the cut-off value of 12 ~g/l [ 1,24,45]. Poor compliance is a serious problem in iron supplementation to pregnant women. Schultink et al. [59] reported actual compliance, as measured by iron in stool samples, was lower (25%) than self-reported compliance (64%). Those in favour of selective iron supplementation for pregnant women after assessment of iron status argue that compliance might very well improve when individual needs are recognized. One of the reasons for not supplementing routinely is the side effect of gastrointestinal complaints [23]. In fact, supplements might complicate existing gastrointestinal disorders [47]. High oral doses of iron may reduce absorption of copper [60] and zinc [61], and thus, possibly impair the status of these minerals in pregnant women. However, Arnaud et al. [62] did not find any effect of iron supplementation during pregnancy on maternal serum concentrations of copper, zinc and selenium after delivery and during lactation. Concerning the effects on pregnancy per se, a large randomized comparison of routine versus selective iron supplementation to more than 2900 pregnant women could not support either way of iron supplementation, while evaluating the effects on fetal growth, infection and pregnancy outcome. The authors advised against routine iron supplementation as a new practice, because of lack of evidence for its effectiveness [54]. In conclusion, because not all women need additional iron during pregnancy, as they increase their efficiency to absorb iron [22,51,56-581, and because of the adverse effects mentioned above, it is suggested not to supplement iron routinely to all pregnant women. However, when anaemia is diagnosed, iron supplements will need to be prescribed in order to cure the iron deficit. A promising new issue in the combat against iron-deficiency is, that twice weekly, oral iron supplements have been shown to be as effective as daily doses [63], and are likely to have less negative effects. 5. Diet and prevention of anaemia in the Netherlands

a meal,

but

Foods from which iron is highly available are: meat, poultry, lish. fruits such as lemon, orange, pineapple, tomato, vegetables such as broccoli, cabbage, cauliflower. (based on Bothwell

& Gynecology

Iron status determines iron absorption efficiency from dietary sources. Healthy persons absorb S-10% of dietary iron and those who are iron-deficient, lo-20%. Iron in the food is presented either as haem or non-haem iron. Haem iron is absorbed relatively efficiently, but absorption efficiency can be reduced by calcium [64]. The absorption of non-haem iron is profoundly in-

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fluenced by the interaction of enhancing factors such as animal protein, vitamin C, and other organic acids and inhibiting factors such as polyphenols, phytates and calcium [7,55]. In The Netherlands, it is recommended that young women consume 15-16 mg of iron per day. For pregnant women, the recommended daily intakes are 11, 15 and 19 mg for the first, second and third trimester. For the determination of these recommendations, it was assumed that absorption efficiency increases in second and third trimesters from 12 to 16% [65]. According to the most recent Dutch food consumption data which were collected in 1992, young nonpregnant women consume about 11 mg iron per day and pregnant women consume about 12.5 mg per day [66]. Thus, iron intakes are well below the Dutch recommendations. For pregnant women, bread is the most important iron source (22%) followed by non-alcoholic drinks (14.6%) and meat and poultry (14.5%). Because two of the most important iron sources contain non-haem iron, dietary factors will influence absorption efficiency considerably. Thus, dietary advices aimed at optimizing iron absorption might have some impact in preventing iron-deficiency anaemia in pregnant women. For example, it is known that non-haem iron absorption is enhanced by vitamin C from fruits and vegetables and inhibited by polyphenols in tea (tannins) and coffee, and by calcium from milk and milk products. Animal protein contains haem iron, which is relatively easy to absorb and animal protein promotes non-haem iron absorption. Therefore, our recommendation could be to drink orange juice with meals instead of tea or milk, and to consume lean meat (Table 2). In short, iron supplementation during pregnancy is a controversial issue. Although it was stressed that iron absorption could be enhanced by improving the diet, it is inevitable to supplement pregnant women with iron when they are anaemic as measured by low haemoglobin values. However, the assessment of iron status during pregnancy is difficult. Acknowledgements The author thanks Dr. Ir. M. Van Dusseldorp, Drs. S. De Pee and Prof. Dr. C.E. West for their advices. References [II

Puolakka J. Jlnne 0. Pakarinen A, Jirvinen PA, Vihko R. Serum ferritin as a measure of iron stores during and after normal pregnancy with and without iron supplements. Acta Obstet Gynecol Stand Suppl 1980; 95: 43-51. 121 Romslo I, Haram K. Sagen N. Augensen K. Iron requirement in normal pregnancy as assessed by serum ferritin, serum transferrin saturation and erythrocyte protoporphyrin determinations. Br J Obstet Gynaecol 1983; 90: 101-107. 131 Intitute of Medicine. Iron nutrition during pregnancy. In: Nutrition during pregnancy. Washington, DC: National Academy Press, 1990; 212-298.

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Nutritional Anemia Consultative Group 141 International (INACG). Measurements of iron status. Washington, D.C.: Nutrition Foundation Inc.. 1985. MS, Karyadi D, Scrimshaw NS. Iron defiI51 Basta SS, Soekirman ciency anemia and the productivity of adult males in Indonesia. Am J Clin Nutr 1979; 32: 916-925. 161 Beard J, Finch CA, Green WL. Interactions of iron deficiency, anaemiaand thyroid hormone levels of rats in response to cold exponsure. Life Sci 1982; 30: 691-697. 171 Banks VF, Beutler E. Iron. In: Shills ME, Young VR, eds. Modern nutrition in health and disease, 7th ed. Philadelphia: Lea and Febiger, 1988; 193-226. of infants with iron deficiency 181 Petrone LR. Development

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P, Pollitt E. Reversal of developmental delays in iron-deficient anaemic infants treated with iron. Lancet 1993: 341: l-4. 1111Shrestha RM, West CE, Bleichrodt N, Van de Vijver FJR, Hautvast JGAJ. Supplementation with iodine and iron improves mental development in Malawian children. (Submitted for publication). M. The prevalence of anaemia in 1121DeMaeyer E, Adiels-Tegman the world. World Health Stat Q 1985; 38: 302-316. Programme - Nutri[I31 Maternal Health and Safe Motherhood tion Programme. The prevalence of anaemia in women: a tabulation of available information. Geneva: World Health Organization, 1992. JA, Delgado LR, Knipschild PC, Essed GGM, 1141 Knottnerus Smits F. Haematologic parameters and pregnancy outcome: a prospective cohort study in the third trimester. J Clin Epidemiol 1990; 43: 461-466. 1151 Hallberg L. Iron balance in pregnancy. In: Berger H, ed. Vitamins and minerals in pregnancy and lactation. NestlC Nutrition Workshop Series, New York: Raven Press, 1988. parameters van de [I61 Wijn de JF, Luyken R. Biochemische voedingstoestand van geselecteerde groepen adolescenten en jonge volwassenen in 1968-1975. Den Haag: Voedingsraad. 1977. 1171Brussaard JH, Brandts HAM, Bouman M, Lebbink WJ. IJzerinnemingen ijzerstatus van 20-79 jarige vrouwen en mannenin Nederland. TNO-rapport V94.336. Zeist: TNO, 1994. [I81 Expert Scientific Working Group. Summary of a report on assessment of the iron nutritional status of the United States population. Am J Clin Nutr 1985; 42: 1318-1330. variation in 1191Bore1 MJ, Smith SM, Derr J, Beard JL. Day-to-day iron status indices in healthy men and women. Am J Clin Nutr 1991; 54: 729-135. [201 Yip R. Changes in iron metabolism with age. In: Brock J, Pippard M, Halliday J, Powell L, eds. Iron metabolism in health and disease. London: WB Sauders, 1994: 427-448. 1211CDC (Centers for Disease Control). CDC criteria for anemia in children and child-bearing-aged women. Morbid Mortal Week Rep 1989; 38: 400-404. B, Norrby A, Rybo G, SBlveIl L. I221 Svanberg B, Arvidsson Absorption of supplemental iron during pregnancy-a longitudinal study with repeated bone-marrow studies and absorption measurements. Acta Obstet Gynecol Stand Suppl 1975; 48: 87-108. 1231 SjBstedt JE, Manner S, Nummi S, Ekenved G. Oral prophylaxis during pregnancy - a comparative study on different dosage regimens. Acta Obstet Gynecol Stand Suppl 1977; 60: 309. N, Lind T. Effect of sup[241 Taylor DJ, Mallen C, McDougall plementation on serum ferritin levels during and after pregnancy. Br J Obstet Gynaecol 1982; 89: IO1 I-1017. [251 Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs

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