Development, prevention and treatment of iron deficiency in women

Nuhition Research. W. 18, No. 3. pp. 489-502.1998 Copyright 0 1998 Elsevia Science Inc. F’rintedin the USA. All tights reserved 0271-5317/w $19.00 + .oo

ELSEVIER

DEVELOPMENT,

PI1SO271-5317(98)00037-2

PREVENTION

AND TREATMENT

OF IRON DEFICIENCY

IN WOMEN

Amanda J Patterson, BSc. M.Nut.Diet.’ ; Wendy J Brown, PhD’ ; and DCK Roberts, PhD* 1. Research Institute for Gender and Health, The University of Newcastle, NSW, Australia 2. Nutrition and Dietetics Department, The University of Newcastle, NSW, Australia

ABSTRACT

Iron deficiency is the most common nutritional deficiency in the world. Women of childbearing age are at particular risk of developing iron deficiency due to the iron losses associated with menstruation and childbirth. Women in less developed countries are often unable to obtain adequate dietary iron for their needs due to poor food supplies and inadequate bioavailable iron. In this situation, fortification and supplementation of the diet with extra iron is a reasonable approach to the prevention and treatment of iron deficiency. In Western countries however, food supply is unlikely to be an issue in the development of iron deficiency, yet studies have shown that many women in these countries receive inadequate dietary iron. Research has shown that the form of iron and the role of enhancers and inhibitors of iron absorption may be more important than total iron intake in determining iron status. Despite this, very little research attention has been paid to the role of diet in the prevention and treatment of iron deficiency. Dietary modification would appear to be a viable option for the prevention and treatment of iron deficiency in Western women, especially if the effects of enhancers/inhibitors of absorption are considered. While dietary modification has the potential to address at least part of the cause of iron deficiency in women of childbearing age, its efficacy is yet to be 0 1998 rlsscvicr Scimcc hc. proven. KEYWORDS: iron deficiency; iron intake; treatment; women

INTRODUCTION

While the detrimental effects on health of iron deficiency anaemia have long been recognised, the effects of iron deficiency (without anaemia) on the general health and well-being of Western populations has, until recently, received little research interest. In the last three years there has however been more attention given to this issue. For example, the report of the British Nutrition Foundation Task Force provides a comprehensive review of the factors affecting iron deficiency (1). This report recognises the importance of iron deficiency for women, who are at increased risk of iron deficiency due to the iron losses associated with menstruation, increased iron needs during pregnancy, and poor dietary iron intake associated with the restrictive eating patterns of many in today’s society. There has however been little research into this issue in Australia. 489

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490

One recent Australian report has shown that 8% of Australian women have serious iron deficiency, with a serum ferritin of
FACTORS CONTRIBUTING

TO IRON DEFICIENCY

IN WOMEN

Iron deficiency results when dietary intake does not adequately meet the requirements of metabolism, menstrual losses, and needs at specific life stages, such as during pregnancy and lactation. In the absence of any other illness, iron deficiency develops slowly over time, reflecting a gradual depletion of iron stores, associated with heavy menstrual loss or consecutive pregnancies. Due to this gradual development, iron deficiency often remains unrecognised, and the subtle symptoms (which may include pallor, changes to hair, nails, mucosa etc.) may be attributed to other lifestyle or social factors. Why then, are the diets of Western societies not meeting the iron requirements of their female populations, when adequate dietary iron would appear to be available to almost all women? Inadecluate Dietan, Intake Firstly, in many Western societies, modern lifestyles and reduced activity have resulted in lowered energy intakes, placing all population groups at increased risk of micronutrient deficiencies (19). Iron is particularly sensitive to total energy intake, and women of childbearing age are particularly prone to low energy intakes. Coupled with the reduced energy intake of modern life is the fashionable desire to remain slim. Baseline data from the current Australian Longitudinal Study on Women’s Health suggest that almost one in two young and middle aged women (47.6% of IS-22 year olds and 43.2% of 4549 year olds) have tried to lose weight in the last 12 months through dieting (20). Dieting to lose weight places women at risk of iron deficiency. A recent study showed that adolescent girls who

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IN WOMEN

491

had tried to lose weight in the previous year had significantly lower haemoglobin levels when compared to their non-dieting counterparts (21). The 1989 Australian National Dietary Survey of Adults reported that up to 47% of women aged 25-64 years were receiving less than 70% of the RDI for iron (12 mg) (22). The British Dietary Nutritional Survey of Adults also found that about one third of women had dietary intakes below the Lower Reference Nutrient Intake (8mg). Inadequate dietary iron intake is thus a significant problem for Australian women and women in other Western societies. Following a vegetarian diet also places women at risk. A 1987 Australian study showed that 27% of vegetarian women were iron deficient (23), and two studies from London and New Zealand report markedly reduced ferritin levels (approximately 50%) for both ovo-lacto and vegan vegetarians when compared to omnivores (24,25). This was despite total iron intake for the vegetarians being the same or greater than for the omnivores. Iron content of The type of iron in the bioavailability of iron. animal flesh foods and

the diet is not however the only issue affecting adequate daily intake of iron. diet, and the presence of enhancers and inhibitors can significantly affect the There are two types of iron in the diet. Haem iron is derived mostly from non-haem iron is found mainly in cereals, vegetables and fruits.

The relative absorption of haem iron is greater than that of non-haem iron (1 l-22% compared to l-7%) because haem iron is taken up directly by gut mucosal cells and is thus not susceptible to inhibitory ligands which affect non-haem iron absorption (26). Because of its greater absorption rate, haem iron contributes disproportionately to bioavailable iron. In a typical U.S. diet, haem iron accounts for only 16% of total dietary iron, but represents 30% of bioavailable iron for menstruating women (27). This difference in bioavailability has been reflected in studies comparing dietary iron intake and biochemical iron status. In two studies in menstruating women, iron status was not associated with total iron intake, but did correlate with meat intake (28,29). Thus, haem iron intake is more likely to correlate with iron status, while total iron and non-haem iron appear unrelated to iron status. Inhibitors and Enhancers of Iron Absorvtion Due to the different absorption methods of haem and non-haem iron, haem iron absorption is much less influenced by other dietary factors. Meat and calcium are the only two dietary factors known to influence haem iron absorption. In contrast, non-haem iron absorption is markedly influenced by a great number of dietary factors. Those known to bear the greatest influence are inhibitors such as phytates, tannins and calcium, and enhancers such as meat and ascorbic acid. Inhibitors Phytic acid is present in cereal foods as a component of the bran. Thus, diets high in fibre, such as vegetarian diets, are also high in phytates. It is generally thought that the inhibitory effect of phytate is to bind iron in an insoluble complex, making it unavailable for absorption (27). The effect has been found to be dose related and is counteracted by the inclusion of enhancers of iron absorption, such as meat and ascorbic acid, in a meal (30,3 1). Tannins bind iron, with subsequent polymerisation into insoluble, and thus unavailable, complexes (32). Tannins therefore markedly reduce iron absorption. Like phytates, they are widely distributed in foods, but are particularly concentrated in tea. Serving tea with meals has been

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shown to reduce non-haem iron absorption by half (33,34). In a study looking at the iron status of a group of menstruating women (institutionalised with behavioural disabilities), tea intake at meals was negatively correlated with serum ferritin concentrations (35). Again, the effects are dose dependent, and counteracted by ascorbic acid and meat (3 1,36). Hallberg et al (1991) have shown that calcium inhibits non-haem iron absorption in a dose dependent manner (37). Subsequently, these researchers have shown that calcium also inhibits haem iron absorption (38). Calcium is the only dietary factor which has been shown to inhibit haem iron absorption, and the different mechanisms of haem and non-haem iron absorption suggest that inhibition is not located in the gastrointestinal lumen, but rather in the transport of iron through the mucosal cells. Gleerup found no duration effect of calcium on iron absorption, two and four hours after a calcium-containing meal (39). As calcium is found in high concentrations only in dairy foods, it is possible to separate calcium and iron in the daily meals. In summary, high dietary fibre intakes, tea drinking with meals and the inclusion of dairy foods in the main iron-containing meals are likely to lead to reduced iron status. The scope for manipulating intakes of tea and dairy foods to not coincide with the main iron-containing meals is great, and this is a practical way to enhance overall iron absorption. Phytates however, are likely to be a component of most meals. Hallberg has calculated that the inclusion of 50mg of Vitamin C with each main meal will counteract the effect on iron of phytate in a typical western diet (30). The addition of meat to the meal will also act in a synergistic fashion to further enhance iron absorption (40). Enhancers A number of dietary factors act to enhance the absorption of non-haem iron by improving the solubility of the iron compounds. The most significant of these are meat, Vitamin C and alcohol. The acid environment of the stomach also promotes solubility of iron (41). Ascorbic acid improves the solubility of non-haem iron by: promoting acid conditions in the stomach, improving the solubility of iron (42,43); reducing solubilised ferric iron (Fe3’) to ferrous iron (Fe”), making it unavailable to form insoluble ferric hydroxides which are not absorbed (27); and combining with iron to form a soluble complex, which can be maintained in the alkaline environment of the small intestine aiding transport across the mucosal membrane (41). In studies by Hallberg et al, addition of 50mg of ascorbic acid to a maize meal increased iron absorption by 3-5 times (40). In food terms, the addition of a glass of orange juice (70mg ascorbic acid) to a hamburger meal more than doubled iron absorption, while a salad containing 45mg of ascorbic acid almost doubled iron absorption from the same meal. Animal flesh foods also significantly promote the absorption of non-haem iron. Meat, fish and poultry are the only dietary factors to enhance haem iron absorption, and the effect is of about the same magnitude as for non-haem iron (44). The average effect is a 2.6 fold increase in absorption, and is thought to be dose related (45). The method by which meat promotes non-haem iron absorption is not fully understood (26). It is not a general property of animal protein, as egg and dairy proteins do not improve absorption (41,45). After reviewing the literature, Zhang proposed a hypothesis for the mechanism of meat enhancement on iron absorption, which involves several processes (46). Firstly, it is proposed that an unknown meat factor (or factors) is released which may complex with iron to maintain its solubility throughout the digestive tract. Secondly, meat stimulates secretion of gastric acid,

IRON DEFICIENCY

IN WOMEN

providing an acid pH which promotes solubility of iron. This is supported by the fact that the capacity for normal acid production is critical for the enhancement of iron absorption by beef, pork and chicken (27). Thirdly, meat stimulates a relatively large increase in serum gastrin, when compared to soy protein. It is possible that gastrin forms soluble iron-gastrin complexes which are then readily absorbed. Like ascorbic acid, alcohol ingestion stimulates gastric acid secretion, and thus improves the solubility of iron (47,48). The effect appears to occur only with oral alcohol taken with a meal, as intravenous alcohol does not increase iron absorption (49). Cook et al showed differences in iron absorption for red and white wines, the polyphenols in red wine opposing the increased absorption of iron due to the alcohol (50). The bioavailability of dietary haem and non-haem iron is a complicated subject area. One main criticism of the research in this area is that the results of single meal studies may not be appropriate to a whole diet situation. After testing diets designed to maximise and inhibit iron absorption, Cook et al have proposed that in the context of a varied Western diet, non-haem iron bioavailability is less important than single meal absorption studies would suggest (51). However Lynch et al have found that absorption from a radiolabelled single meal compared very well with the average absorption from 28 different radiolabelled meals eaten over a 14 day period (45). More work is needed to clarify the relative importance of enhancers and inhibitors of iron absorption in the context of a usual diet. Iron Losses In terms of iron losses, menstruation seems to be the most important factor contributing to iron deficiency in non-pregnant women. Median menstrual losses of iron, averaged over the month, increase daily iron requirements by about 0.45mg per day, to about 1.35mg per day (52). The distribution of menstrual blood loss however, is markedly skewed towards heavier losses (53), thus increasing iron requirements by up to 300% in some women. Contraceptive choice is the main external factor which will vary an individual woman’s menstrual blood loss. The oral contraceptive pill reduces menstrual loss by half (54) and intrauterine devices double blood losses (55). More acute periods of iron depletion accompany pregnancy and blood donation. During pregnancy, extra iron is required for the growing foetus and placenta, but also for the expanding red cell mass of the mother (see Table 1). Between 2.9 and 4.8mg of iron per day may be required during a pregnancy, depending on iron stores (41). Thus pregnancy can more than double the iron requirements of premenopausal women and low iron intake during pregnancy can severely deplete body iron stores. Subsequent pregnancies, especially if they occur over a short time period, may result in further iron deficits. Loss of iron in breast milk amounts to less than lmg/day, which is comparable to losses due to menstruation. As menstruation usually ceases during full lactation, lactation represents no extra demands on iron requirements (56). Iron losses due to lactation may be important for mothers who continue to partially breastfeed for extended periods, once menstruation has returned. Not surprisingly, blood donation can also impact on iron losses. One Australian study reported that men and women aged 15 to 32 with low haemoglobin were more likely to be blood donors (22), and a large Danish study has shown that blood donors in all age groups have lower serum ferritin than non-donors (57). The effect was greatest in pre-menopausal women, with twice the proportion who donated blood having a serum ferritin below lSug/L (31.7% in donors, 15.2% in non-donors).

A.J. PATTERSON et al.

TABLE 1 Maternal Iron Balance During Pregnancy

Iron requirements

Amount

1. Permanent iron losses Foetal requirements Placental iron Perinatal blood loss Obligatory, basal loss (0.9mg x 280 days)

250-300 150 150 252

2. Temporary requirements Enlarged red cell mass

250-500

Total additional

iron required

per pregnancy

(mg)

1050-1350

From Roeser 1990 (4 1)

PREVENTION

AND TREATMENT

Three strategies exist for the prevention and treatment of iron deficiency. Fortification Dietary fortification with iron is one approach to improving iron status. However, four major concerns have been voiced about the appropriateness of iron fortification. The first concern is that few agencies have been able to assess the success of iron fortification programs, due to inadequate knowledge about the prevalence of iron deficiency in the populations involved. Since the introduction of a flour fortification program in Sweden, the prevalence of iron deficiency anaemia among Swedish women of childbearing age has dropped from 25-30% in 1963-64 to 6-7% in 1974-75 (58). However, it has been estimated that only 25% of the improvement can be ascribed to the fortification, and that together, increased consumption of iron tablets and ascorbic acid supplements, and diminished menstrual losses due to the increased use of oral contraceptives, explain a greater proportion of the improvement (26). Secondly, bioavailability must be considered. In early fortification programs, little or no attention was paid to the bioavailability of the iron fortificant, and many of the forms used were extremely poorly absorbed (26). Good results have been seen recently with the use of NaFeEDTA as a fortificant (59,60). Iron in this form is well absorbed because it is chelated and thus protected from inhibitors (particularly phytate) present in the food (6 1,62). Another option for fortification is the use of haem iron as the fortificant. Bovine-haemoglobin-fortified cookies have been used in the Chilean School Lunch Program with good results (63). The third major concern with widespread iron fortification is the variation in individual requirements. Cereals and food from flour represent the main source of dietary inorganic iron, so

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total iron intake is closely linked with energy intake. It has been calculated that if the iron content of food for the general population is adjusted to meet the average requirements of all family members, but intake is distributed according to energy requirements, then fathers obtain twice their needs while mothers receive only slightly more than half their needs (56). If the iron content of the diet is adjusted to fully meet the mothers’ requirements, then all other family members have an excessive intake (64). Thus, fortification is one way to improve the iron status of entire iron deficient populations, such as those found in some developing countries, but it is not a means to reach specific susceptible target groups within populations (64,65). The fourth major concern with iron fortification is the associated risk of iron storage disease (64). Haemochromatosis is a genetic disorder which results in iron overload and subsequent deposition of iron in major organs and tissues. One in 300 Australians is homozygous for this disorder and therefore susceptible to iron overload (66). It is not certain whether heterozygotes (who comprise about 10% of the population) (2) are at risk of iron overload if excessive iron is available in the diet, but several researchers have used this idea to argue against widespread supplementation and fortification (64,67). For populations in which the majority of individuals are iron deficient or have poor iron stores, iron fortification would appear to be a viable option. However, this can never be the complete answer as it is not possible to target sub-groups who are particularly at risk, and concerns about iron overload persist (64,67). Supplementation Iron supplementation during pregnancy is probably the best and most established example of across-the-board supplementation of an at-risk population. However, despite many controlled clinical trials supporting the efficacy of iron supplementation during pregnancy, there is a major discrepancy between the results of these trials and those observed in large scale population supplementation programs (68). Factors such as inadequate distribution and availability of supplements, knowledge and motivation of the health care provider, misunderstanding of instructions, side effects, frustration about the frequency and number of pills being taken and the subtlety of the symptoms of iron deficiency (which make the demand for treatment low), have all been shown to decrease compliance with iron supplementation programs. The well known side effects of iron supplements include metallic taste, epigastric discomfort and constipation (69). The effects are dose-dependent (70), and reducing the dosage is. an obvious strategy for reducing side effects. Daily doses of 30-60mg of iron are effective in maintaining and improving haematological status with minimal gastrointestinal side effects (7 1). A lower dose of iron may also require a less frequent dosing schedule (65). Recent studies have shown that daily dosing results in impaired absorption. Iron administration reduces gastrointestinal iron absorption capacity for several days due to the mucosal blockage from the recent dose of iron (72). Weekly administration of 120mg of iron has been shown to be as effective as daily dosing of 60mg in preschool children and pregnant women, producing only negligible side effects (73,74). Recent research has, however, cast safety concerns over targeted supplementation programs. While three studies have found there to be no problem with daily iron supplementation of iron replete subjects (75), one study in Indonesian toddlers has reported reduced weight gain compared with a placebo group (76).

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Ferrous sulphate is the most widely used form of iron supplementation (77). Intolerance by a significant proportion of patients, however, has led to the development of several slow-release iron preparations, and a gastric delivery system (65,78). However, slow-release preparations lead to reduced absorption, and gastric delivery systems are more costly than simple ferrous sulphate preparations. Thus, understanding of the barriers to iron supplementation has resulted in the development of strategies for improving compliance, such as decreased frequency of supplementation and preparations to minimise gastrointestinal side effects. However, problems relating to knowledge, attitudes and motivation require further investigation. Dietarv Intervention A recent booklet produced by the Australian Iron Status Advisory Panel and mailed to all Medical Practitioners in Australia advocates the use of dietary intervention as the first treatment option in mild cases of iron deficiency (serum ferritin 10-151.&L) (79). Obviously dietary intervention can only be appropriate in communities where good sources of dietary iron are readily available. In Australia, counselling a patient with mild iron deficiency on strategies for increasing iron intake and improving iron absorption could well be feasible. There has however, been little research into the role dietary intervention can play in the treatment of iron deficiency. One study has shown that increasing dietary haem iron maintains iron status better than iron supplements, in previously sedentary college women who underwent a three month moderate exercise program (80). In this study, the group with increased meat intake maintained iron status better than the group taking iron supplements, despite the fact that the supplement group received higher calculated levels of bioavailable iron. Studies on the effects of enhancers and inhibitors in the maintenance/improvement of iron status are also limited. Ascorbic acid improves iron absorption from single meals but when ascorbic acid supplements are given with meals three times a day for ten weeks they have only a limited effect on serum ferritin, without impacting on other biochemical indices of iron status (81). Cook et al found that maximising enhancers of iron absorption in a diet improved iron absorption from 6.7% to 8.2% (5 l), while modifying the diet to inhibit iron absorption reduced the absorption rate to 3.1%. Both the inhibiting and enhancing effects were not as great as would be expected from studies of single meals, and the authors concluded that in the context of a varied Western diet, nonhaem iron bioavailability is less important than absorption studies with single meals would suggest (51).

CONCLUSION

Iron deficiency is still the most common nutrient deficiency in the developed world. With increased understanding of its effects on health and well-being, and resultant costs to the health care system, this condition is receiving increased research attention. In countries such as Australia, Canada and the USA, where the prevalence of the haemochromatosis gene is quite high, where not all individuals are at risk of iron deficiency, and where access to health care is relatively good, the most viable option for the treatment of iron deficiency would appear to be individual assessment and treatment (67). Currently, advice given to General Practitioners in Australia through print media such as “Australian Family Physician” and “Modem Medicine” includes biochemical assessment of iron status in those suspected to be

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deficient, and subsequent iron supplementation with an appropriate ferrous sulphate preparation, if tests are positive for iron deficiency (82,83). In Australia, iron supplements are readily available and relatively inexpensive. However, there are many disadvantages of iron supplementation, and it is unlikely to be a successful long-term approach to prevention and treatment. Dietary intervention is a feasible alternative to supplementation and may include increasing total iron intake, and particularly haem iron intake where appropriate. The effects of enhancers and inhibitors of iron absorption should also be considered, and foods combined appropriately to enhance absorption, especially for vegetarian women. Such dietary change would require General Practitioners to spend considerable time assessing dietary intake and counselling patients, or alternatively referring patients to a Dietitian. Dietary change appears to be the optimal long term strategy for the prevention and treatment of iron deficiency because it addresses one of the main causes of iron deficiency for Western women of childbearing age. It has advantages over supplementation in terms of compliance, acceptability and risk of iron overload. It also has the advantage of a beneficial effect on the iron intake of families. However, the efficacy of dietary treatment of iron deficiency is yet to be proven.

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Accepted

for

publication

October

31,

1997.

on the relation between iron and folate status

in Chinese preschool

in community control of iron-deficiency

on weight gain

of iron deficiency. Mod Med Aust