Annals of Hematology

, Volume 85, Issue 12, pp 821–828

Iron prophylaxis in pregnancy—general or individual and in which dose?

Authors

    • Department of Medicine B 2142University of Copenhagen
Review Article

DOI: 10.1007/s00277-006-0145-x

Cite this article as:
Milman, N. Ann Hematol (2006) 85: 821. doi:10.1007/s00277-006-0145-x
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Abstract

Iron is mandatory for normal fetal development, including the brain. Iron deficiency may have deleterious effects for intelligence and behavioral development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in the pregnant woman. Iron deficiency anemia during pregnancy is a risk factor for preterm delivery and low birth weight. In the Western countries there is no consensus on iron prophylaxis to pregnant women. An adequate iron balance during pregnancy implies body iron reserves of ≥500 mg at conception. The physiologic iron requirements in the second half of gestation cannot be fulfilled solely through dietary iron. Iron supplements during gestation consistently increase serum ferritin and hemoglobin and reduce the prevalence of iron deficiency anemia. Iron has a negative influence on absorption of other divalent metals and increases oxidative stress in pregnancy, for which reason minimum effective iron dose should be advised. From a physiologic point of view, individual iron prophylaxis according to serum ferritin concentration should be preferred to general prophylaxis. Suggested guidelines are (1) ferritin >70 μg/l: no iron supplements; (2) ferritin 30–70 μg/l: 40 mg ferrous iron daily; and (3) ferritin <30 μg/l: 80–100 mg ferrous iron daily. In controlled studies, there are no documented side effects of iron supplements below 100 mg/day. Iron supplements should be taken at bedtime or between meals to ensure optimum absorption.

Keywords

AnemiaIron deficiencyFerritinFetusHemoglobinsIronNewbornPregnancyProphylaxis

Introduction

Iron is an essential element both to the pregnant woman and to the growing fetus. The majority of pregnant women who do not take iron supplements become iron depleted and a substantial fraction develops iron deficiency anemia. However, the debate concerning prophylactic iron supplementation to pregnant women is still controversial and there exists no consensus or common guidelines on this important issue. This review shall focus on iron prophylaxis in pregnancy and postpartum in the affluent Western countries and will give a critical reappraisal of the indications for iron supplementation.

Iron is essential to the fetus

In the growing fetus, iron is mandatory for normal development and function of the organs. Therefore, it appears important to prevent iron deficiency in the fetus, including the early phase of fetal life. The natural way to obtain this goal is by ensuring an adequate iron status in pregnant women.

In the fetus, the largest amount of iron is used in the synthesis of hemoglobin. However, the importance of iron for other organ systems should not be underestimated [1]. Iron plays a pivotal role in the development of the central nervous system because iron-containing enzymes are involved in many pathways of brain metabolism [2, 3]. The brain has a high growth rate and needs a regulated supply of iron across the blood-brain barrier to maintain brain iron homeostasis [4]. If the brain’s demands for iron are not fulfilled due to iron deficiency in fetal life, the consequences may be permanent damage to the central nervous system, affecting intelligence and behavioral development in childhood.

Fetal iron supplies

In the pregnant woman iron is transferred from one body compartment to another in the plasma iron pool, bound to the iron transporting protein transferrin. Reaching placenta, iron is transported across the placental barrier by an active process involving the specific transporter of divalent metal ions (DMT1) [5]. The woman’s transferrin-bound iron is then coupled to transferrin receptors in placenta. Subsequently, iron is transported through the maternal–fetal barrier into the fetal circulation [68]. By the high efficiency of this transport system, nature signals how essential iron is for normal fetal development. The transport system ensures that fetal supply of iron is widely independent of the woman’s iron status. Consequently, clinically overt fetal iron deficiency occurs only by marked iron deficiency in the woman and is rarely recognized in uncomplicated pregnancies in Caucasians in the Western societies.

Iron status in the newborn

The newborn’s iron status is, among other factors, dependent on the woman’s iron status in pregnancy [911]. Children of mothers who have taken iron supplements during gestation have higher cord blood serum ferritin and therefore most likely have higher body iron than children of mothers who have taken placebo [10, 12, 13]. This implies that children of iron-supplemented mothers have a lower risk for getting iron deficiency during infancy and early childhood [10, 14, 15]. Another important factor influencing the newborn’s iron reserves is the amount of blood being transferred from the placenta before the clamping of the umbilical cord [16]. From a hematinic point of view, the newborn should, immediately after birth, be placed below placental level and the umbilical cord should not be clamped before pulsation in the blood vessels could no longer be recognized. Following this procedure, the newborn’s blood volume can be increased by ∼32% and an extra 30–50 mg of iron is transferred, thereby reducing the risk for iron deficiency in infancy.

Iron status in pregnancy and the newborn’s birth weight

Accumulating evidence suggests that iron deficiency anemia in the pregnant women is a risk factor for preterm delivery and low birth weight [11, 17]. Experiences from undeveloped countries where iron deficiency anemia is prevalent in pregnancy show that anemia is associated with preterm delivery and low birth weight [10, 18]. A placebo-controlled study from Nepal with a high prevalence of iron deficiency demonstrated that a supplement of 60 mg of ferrous iron and 0.4 mg of folic acid daily from 11 weeks gestation significantly increased the birth weight [19]. In New Jersey, iron deficiency anemia in pregnancy doubled the risk for preterm delivery before 37 weeks of gestation and tripled the risk for having a child with a birth weight of <2,500 g [20]. Another study in the same area showed that women taking a supplement of 65 mg of ferrous iron daily had a significantly lower frequency of preterm delivery and low birth weight [21]. A placebo-controlled study from Cleveland demonstrated that 30 mg of ferrous iron daily in pregnancy, started before 20 weeks gestation, gave a significantly higher birth weight compared with the placebo group [22]. The results of these studies suggest that to obtain a maximum effect on birth weight, iron supplements should be started in early pregnancy [17, 19, 22]. However, the design of these studies was not quite optimal, so we need additional studies to address the association between iron deficiency and birth weight [17, 23, 24].

Iron prophylaxis—an ongoing debate

The attitude toward iron prophylaxis differs in many Western countries and within a single country there are often discrepancies between the recommendations from different health institutions.

Food and Agriculture Organization of the United Nations concludes: “Iron requirements in the second and third trimesters cannot be satisfied by dietary iron alone, even if it is of high bioavailability and, unless stores of about 500 mg are believed to exist before pregnancy, administration of iron supplements may be indicated if impairment of the expected increase in haemoglobin mass in the mother is to be avoided” [25]. Department of Health in United Kingdom states: “Ideally all women of childbearing age should have sufficient stores to cope with the metabolic demands made by pregnancy which can be met without further increase because of cessation of menstrual losses and by mobilisation of maternal iron stores and increased intestinal absorption. However, when iron stores are inappropriately low at the start of pregnancy, supplementation with iron may be necessary” [26]. The European Union states: “The physiologic solution for covering the high iron requirements in pregnancy is to use iron from stores. The problem, however, is that very few women, if any, have iron stores of this magnitude. Therefore, daily iron supplements are recommended in the latter half of pregnancy” [27]. The Nordic Nutrition Recommendations states: “An adequate iron balance during pregnancy implies iron reserves of at least 500 mg. The physiologic iron requirements in the second half of gestation cannot be fulfilled solely through dietary iron” [28].

Prophylactic iron in pregnancy—which dose is appropriate?

All placebo-controlled studies of iron supplements during gestation showed that women taking placebo have lower iron status, i.e., lower serum ferritin and hemoglobin compared with women taking iron supplements (Table 1) [12, 13, 2939]. The differences in iron status persist for many months after delivery [12, 2934, 37]. The studies furthermore demonstrate that a significant fraction of women taking placebo develop iron deficiency and iron deficiency anemia.
Table 1

Placebo-controlled studies of iron prophylaxis during pregnancy in Europe and Australia and two Danish dose–response studies

 

Treatment

Women (n)

Ferrous iron (mg/day)

Study period

Results of lowest recorded values in study period

Fleming et al. 1974 [31]

Placebo

21

 

20 weeks to term

48% Hb <100 g/l

Iron

17

60

12% Hb <100 g/l

Svanberg 1975 [29]

Placebo

26

 

12 weeks to term

Hb mean 114 g/l

Iron

24

200

Hb mean 120 g/l

Puolakka et al. 1980 [32]

Placebo

16

 

16 weeks to term

SF median 21 μg/l; Hb mean 109 g/l (38% <110 g/l)

Iron

16

200

SF median 63 μg/l; Hb mean 115 g/l (0% <110 g/l)

Foulkes and Goldie 1982 [33]

Placebo

250

 

12 weeks to term

Low SF; 18% Hb <105 g/l

Iron

251

100

Higher SF; 5% Hb <105 g/l

Taylor et al. 1982 [34]

Placebo

24

 

12 weeks to term

SF median 5 μg/l; Hb mean 111 g/l

Iron

21

65

SF median 15 μg/l; Hb mean 119 g/l

Romslo et al. 1983 [13]

Placebo

23

 

12 weeks to term

SF mean 5 μg/l (83% <10 μg/l) 30% Hb <110 g/l

Iron

22

200

SF mean 15 μg/l (5% <10 μg/l) 9% Hb <110 g/l

Galan et al. 1990 [35]

Placebo

84

 

12 weeks to term

SF median 10 μg/l (65% <13 μg/l) Hb mean 117 g/l 26% Hb <110 g/l

Iron

81

40

SF median 19 μg/l (30% <13 μg/l) Hb mean 121 g/l 4% Hb <110 g/l

Milman et al. 1991 [12]

Placebo

108

 

9–14 weeks to term

SF median 12 μg/l (28% <10 μg/l) Hb mean 114 g/l (34% <110 g/l) 12% IDAa

Iron

99

66

SF median 21 μg/l (3% <10 μg/l)Hb mean 118 g/l (17% <110 g/l) 0% IDA

Thomsen et al. 1993 [36]

Iron

21

18

16 weeks to term

SF median 12 μg/l (72% <15 μg/l)

Iron

22

100

SF median 30 μg/l (5% <15 μg/l)

Eskeland et al. 1997 [37]

Placebo

23

 

20 weeks to term

17% IDAb

Iron

48

27

0% IDAb

Makrides et al. 2003 [38]

Placebo

214

 

20 weeks to term

58% IDc 11% IDAd

Iron

216

20

35% ID 3% IDA

Milman et al. 2005 [43]

Iron

76

20

18 weeks to term

50% IDc 10.0% IDAd

 

Iron

78

40

 

26% ID 4.5% IDA

 

Iron

78

60

 

17% ID 0% IDA

 

Iron

78

80

 

13% ID 1.5% IDA

The lowest recorded, corresponding concentrations of hemoglobin and serum ferritin are shown

Hb Hemoglobin, SF serum ferritin, ID iron deficiency, and IDA iron deficiency anemia

aSF <12 μg/l and Hb <110 g/l

bSF <15 μg/l and Hb <100 g/l

cSF <12 μg/l

dSF <12 μg/l and Hb <110 g/l

Previously, there was a tradition to recommend high doses of iron supplements of 100–200 mg of ferrous iron daily in pregnancy [9, 13, 29, 32, 33, 40]. A daily dose of 100 mg of ferrous iron induces a maximum rise in the hemoglobin concentration [40] and a dose of 200 mg of ferrous iron increases serum ferritin and hemoglobin at term to the same or even higher level as in nonpregnant women [9, 40].

It is known that 2–4% of apparently healthy fertile nonpregnant Scandinavian women have iron deficiency anemia [41, 42]. Therefore, we consider that iron supplements should be adequate to prevent iron deficiency anemia in at least 95% of pregnant women. In a placebo-controlled study started between 14 and 18 weeks of gestation, 50% of women taking placebo developed iron deficiency and 21% iron deficiency anemia in the third trimester [12, 30]. Among women taking 66 mg of ferrous iron daily, 10% developed iron deficiency and none had anemia (Table 1).

English and Danish studies have both shown that a supplement of 66 mg of ferrous iron daily from 18 weeks gestation can prevent iron deficiency in 80–90% and iron deficiency anemia in all pregnant women [12, 34]. A French study found that 40 mg of ferrous iron daily was adequate to prevent iron deficiency [35]. Even a daily dose of 27 mg of ferrous iron has a favorable influence on iron status in pregnant Norwegian women [37]. In Australia a placebo-controlled study demonstrated that a daily dose of 20 mg of ferrous iron from 20 weeks of gestation reduced the frequency of iron deficiency at delivery from 58% in the placebo group to 35% in the iron group and the frequency of iron deficiency anemia from 11 to 3%, respectively [38]. Therefore, a low dose of iron supplement is better than no supplement at all. However, a daily dose of 18 mg of ferrous iron contained in a multivitamin-mineral tablet taken from 16 weeks of gestation is inadequate to prevent iron deficiency in 72% of the women [36].

A recent placebo-controlled study assessed the effect of various doses of iron supplements ranging from 20, 40, 60, to 80 mg of ferrous iron daily from 18 weeks of gestation to 8 weeks postpartum [43]. There were no significant differences in the serum ferritin concentrations in women taking 40, 60, or 80 mg of ferrous iron daily (Table 2).
Table 2

Serum ferritin during pregnancy and postpartum (pp) in relation to various doses of prophylactic iron from 18 weeks gestation to 8 weeks postpartum (based on [43])

 

Gestation week

Ferrous iron (mg/day)

P value

20

40

60

80

Serum ferritin (μg/l)a

18

29 (15–85)

29 (14–73)

32 (15–74)

34 (12–83)

NS

 

32

13 (8–28)

17 (10–36)

18 (10–28)

21 (12–42)

<0.0001*

 

39

16 (9–28)

21 (13–38)

23 (13–45)

24 (15–56)

<0.0001*

 

8 pp

32 (17–83)

55 (25–142)

50 (24–102)

50 (29–93)

<0.01*

*Significant difference between 20 mg and 40, 60, and 80 mg; no significant difference between 40, 60, and 80 mg

aMedian, 10–90 percentile

The results show that a daily dose of 20 mg of ferrous iron is inadequate to prevent iron deficiency in 50% and iron deficiency anemia in 10% of the women. However, a daily dose of 40 mg of ferrous iron appears to be adequate to prevent iron deficiency anemia in more than 95% of the women (Fig. 1 and Table 3). Dietary components such as calcium, polyphenols, and phytate may inhibit the absorption of iron supplements [44], especially at low iron doses. For example, the absorption of 30–90 mg of ferrous iron is, on the average, 40% lower when the iron is taken with a meal instead of between meals [45]. Iron supplements should therefore be taken at bedtime or between meals to ensure that conditions for absorption are at their optimum [43].
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0145-x/MediaObjects/277_2006_145_Fig1_HTML.gif
Fig. 1

Serum ferritin (geometric mean±SEM) in pregnant women taking iron supplements in various doses from 18 weeks of gestation to 8 weeks postpartum (reproduced with permission from [43])

Table 3

Frequency of iron deficiency and iron deficiency anemia during pregnancy and postpartum (pp) in relation to various doses of prophylactic iron from 18 weeks gestation to 8 weeks postpartum (based on [43, 68])

 

Iron deficiency

Iron deficiency anemia

Gestation week

18

32

39

8 pp

18

32

39

8 pp

n=

427 (%)

310 (%)

269 (%)

173 (%)

427 (%)

310 (%)

269 (%)

173 (%)

Ferrous iron (mg/day)

        

20

6.1

50.0

28.8

6.7

0

1.3

10.0

0

40

9.0

26.0

11.1

2.9

1.9

1.3

4.5

0

60

6.9

16.9

10.0

2.1

0

0

0

2.1

80

10.8

13.2

9.0

0

0

0

1.5

0

P value*

 

<0.0001

<0.01

   

0.02

 

*Significant values are shown

Drawbacks of iron supplements

Iron absorption is mediated via the divalent metal ion transporter DMT1 [4]. Different divalent metal ions may therefore compete about the absorption capacity. In iron deficiency, the DMT1 absorption capacity is upregulated. Through this mechanism, iron deficiency may cause an increased, but also undesirable absorption of toxic metal ions, e.g., lead and cadmium [46, 47].

Furthermore, the common absorption mechanism implies that iron has a potential inhibitory influence on the absorption of other essential divalent metal ions, e.g., zinc, copper, chromium, molybdenum, manganese, and magnesium [44, 4851]. In pregnant women a daily supplement of 60 mg of ferrous iron induces a significant fall in the absorption of zinc and in serum zinc levels [49]. On the other hand, a supplement of 15 mg of zinc does not affect the absorption of a supplement of 60 mg of ferrous iron [52].

During pregnancy, there is a gradual increase in the body’s oxidative stress, which reaches maximum in the second trimester [53]. Iron supplements tend to augment the oxidative stress. Also, iron tablets induce a high concentration of free radicals in the intestinal milieu, which may damage the intestinal epithelium [54]. Knowing these drawbacks, it is essential that a prophylactic iron dose should be as low as possible in consideration of the prevention of iron deficiency.

Side effects of iron supplements—myth or reality?

It is generally believed that iron supplements inevitably cause gastrointestinal discomfort. Kerr and Davidson’s [55] statement from 1958: “It will take a long time to dispel the popular belief that iron pills inevitably cause unpleasant side-effects,” is still relevant. However, gastrointestinal side-effects are dose-related and first of all prevalent at high iron doses above 180 mg [56]. In placebo-controlled studies, the frequency of gastrointestinal symptoms is not significantly different among women taking placebo compared with women taking 20 or 105 mg of ferrous iron daily [38, 55, 57]. The Danish dose–response study could not demonstrate any significant difference in gastrointestinal symptoms in women taking 20, 40, 60, or 80 mg of ferrous iron daily in pregnancy [58]. The study concludes that a supplement of 80 mg of ferrous iron or less does not have documented side effects. Therefore, postulated side effects cannot be used as an argument against iron prophylaxis to pregnant women [58].

Pro et con iron prophylaxis

The discussion of iron supplements to pregnant women contains both teleological views and pragmatic attitudes. One of the major points in the debate has addressed the issue whether routine iron supplements might have a negative influence on the outcome of gestation.

As a consequence of the inverse relationship between the pregnant woman’s hemoglobin concentration and the newborn’s birth weight [59], many obstetricians hold the opinion that iron depletion and anemia are normal physiologic adaptations in pregnancy and consider iron prophylaxis to be unnecessary or even harmful [6063]. If this argument were true, one would expect that iron supplements would increase the prevalence of birth complications and the number of newborns with low birth weight. However, no evidence points in this direction [23, 24]. Placebo-controlled studies in Western countries where pregnant women have a high iron status compared with women in developing countries have not shown any harmful effect of iron supplements [12, 13, 29, 3235, 38]. On the other hand, a placebo-controlled study from Niger where nearly all pregnant women have iron deficiency demonstrated that iron supplements caused a marked decrease in the prevalence of iron deficiency anemia in pregnancy and postpartum [10]. Newborns to mothers who took iron supplements had higher birth length and higher Apgar score than children to mothers taking placebo [10].

In a study from Finland with the initial purpose of proving harmful effects of iron supplements, pregnant women were randomized in two groups. One took a routine supplement of 100 mg of ferrous iron daily; the other had selective supplementation with the same iron dose if their hematocrit dropped below 0.31 corresponding to a hemoglobin below 100 g/l [64]. There was a beneficial effect of routine iron supplement, i.e., a lower frequency of cesarean section and of blood transfusions and a longer length of gestation in routinely supplemented compared with selectively supplemented women. Postpartum hemoglobin was higher in routinely supplemented compared with selectively supplemented women [64].

If one agrees that iron supplementation has no deleterious effect, the next question to ask is whether iron has any beneficial influence on the course of pregnancies in women in the Western countries. If the effect parameters consist of “hard” endpoints such as: (1) complications during gestation, (2) complications at delivery, (3) newborns’ birth weight, and (4) Apgar score, there appears to be none or only a marginal effect of routine iron prophylaxis in the affluent Western societies where malnutrition seldom occurs.

On the other hand, there appears to be positive effects of iron supplements if the effect parameters are composed of “soft” endpoints such as: (1) in the pregnant women: no iron deficiency anemia, i.e., higher hemoglobin concentration, thereby increasing physical and cognitive performance and well-being; (2) in the early postpartum period: higher hemoglobin and larger body iron reserves to cope with blood losses at delivery; (3) in the lactation period: lower frequency of iron deficiency and iron deficiency anemia improving physical performance and well-being; (4) in the fetus: the importance of iron for the development of the brain; and (5) in the newborn: the possible influence of iron on birth weight and larger iron reserves, thereby reducing the prevalence of iron deficiency in early childhood.

General or individual iron prophylaxis?

General iron prophylaxis implies that all pregnant women are advised to take iron supplements regardless of their iron status. Individual prophylaxis implies that iron supplements are adjusted to the women’s iron status, i.e., only women at risk for iron deficiency should be advised to take iron supplements.

From a physiologic and nutritional point of view, individual iron prophylaxis should be preferred. As mentioned above, iron has a negative influence on the absorption of other essential divalent metals [4951] and causes an increase in the oxidative stress [53, 54].

In the planning of individual iron prophylaxis, serum ferritin should be analyzed either before conception or in early pregnancy, before 15 weeks gestation. By analyzing serum ferritin we can identify women with marginal iron status being at risk for iron deficiency. Likewise, it is possible to avoid unnecessary iron loading of women with adequate iron status, i.e., iron reserves of ≥500 mg. It is especially important to avoid treating women with genetic predisposition to iron overload disorders (hereditary hemochromatosis) due to an inappropriately high absorption of dietary iron [65]. In Scandinavia the most prevalent type of disorder, comprising more than 95% of the hemochromatosis cases, is due to mutations of the HFE gene (C282Y, H63D). This type of hemochromatosis is inherited as an autosomal recessive trait. It is most prevalent in the populations in Northwestern Europe where 0.4–0.7% are C282Y homozygous and 10–15% are heterozygous [66, 67]. In Southern Europe and the Mediterranean, mutations in other hemochromatosis genes are more prevalent [65].

Suggested guidelines for iron prophylaxis

General prophylaxis

The lowest dose of ferrous iron supplement protecting against iron deficiency anemia is 40 mg daily [43]. Therefore, the recommended daily dose in general iron prophylaxis dose is 40 mg of ferrous iron.

Individual prophylaxis

Serum ferritin should be measured before conception or in early pregnancy as a biomarker for iron status. In general, women should be advised to take a daily multivitamin-mineral tablet, which in Denmark contain 14 to 27 mg of ferrous iron besides folic acid, vitamin B12, and vitamin B6.
  1. (1)

    Serum ferritin >70 μg/l: iron supplements are not indicated [68]. If ferritin is >100–150 μg/l one should consider screening for hemochromatosis and recommend multivitamin-mineral tablets without iron.

     
  2. (2)

    Serum ferritin 30–70 μg/l: supplement of 40 mg of ferrous iron daily [69].

     
  3. (3)

    Serum ferritin <30 μg/l: supplement of 80–100 mg of ferrous iron daily [69].

     

When should iron prophylaxis begin?

Most official guidelines recommend that iron supplements should be started at the latest at 20 weeks gestation. This point was chosen because there is a marked increase in iron absorption, which, however, in part is caused by iron depletion [59]. Considering that iron is essential for the development of the central nervous system [2, 3, 70] and has implications for the birth weight [1921], iron prophylaxis should probably be started around the time of conception or in early pregnancy.

Should iron supplements be advised postpartum?

So far no placebo-controlled studies have examined whether it would be an advantage to give iron supplements to mothers in the lactation period. If blood losses at delivery are greater than “normal” it appears logical to recommend iron supplements for 2–3 months. In general, mothers should be advised to continue taking a daily multivitamin-mineral tablet with iron during lactation.

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