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1 r Trace Elements With the exceptions of iron and iodine, the trace elements are the nutrients most recently identified as essential for humans. The roles of some have not been clearly defined, despite substantial progress over the past 30 years. Periodic reevaluation is needed as the boundaries of knowledge expand. The trace elements included in this chapter are those for which Recommended Dietary Allowances (RDAs) or safe and adequate daily dietary intakes have been established by the Food and Nutrition Board (NRC, 1989), with the exception of iron (see Chapter 14~. Progressive physiologic changes during gestation contribute to the difficulty of interpreting laboratory data. Although mild deficiency of one or more trace elements may be one etiologic factor in a multifactorial problem such as premature delivery or intrauterine growth retardation, a causal role would be difficult to detect. Suboptimal status, or marginal deficiency, of trace elements has been documented in human and animal models, but it is typically difficult to identify. The selection of appropriate subjects, the large number of subjects required, and the difficulties of implementing intervention studies in free-living populations are among the factors that hamper definitive research to determine whether and when increased intakes of specific trace elements may be of any value to the course of pregnancy and to the developing fetus. With respect to potential toxicity, the trace elements in general have an intermediate position between the fat-soluble vitamins and the water- soluble vitamins (see Chapters 17 and 18~. Of greater concern than overt 299
300 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS toxicity is the potential for interactions between trace elements. For ex- ample, relatively large doses of iron may interfere with the absorption of zinc in pregnant women. Zinc supplementation may compensate for this interaction but may, in turn, affect the metabolism of copper and other micronutrients. The full extent of nutrient-nutrient interactions is not yet completely known. ZINC Cell Replication and Differentiation At the molecular level, zinc is involved extensively in nucleic acid and protein metabolism and, hence, in the fundamental processes of cell differentiation and replication (see the review by Hambidge et al., 1986~. Zinc and zinc-dependent enzymes, for example, are involved in the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and ribosomes. Zinc deficiency reduces the activity of these enzymes, but disturbances of cell replication and differentiation appear to be attributable primarily to the adverse effects of zinc deficiency on gene expression (Cheaters, 1978; Crossley et al., 1982~. For example, zinc fingers (Klug and Rhodes, 1987) play a critical role in the attachment of the transcription proteins to DNA. These fingers are projections, the shape of which is dependent on a zinc atom at the base. This essential step in the initiation of the transcription process is but one example of the numerous ways in which zinc is involved in all stages of the cell cycle. Reproduction in Animals In view of the multiple physiologic roles of zinc in cell replication and differentiation, it is not surprising that an adequate supply of this micronutrient is necessary for reproduction. Animal studies have shown that all phases of reproduction in the female, from estrus to parturition and lactation, are affected adversely by zinc deficiency (Hambidge et al., 1986~. Severe zinc deficiency in rodents disrupts the estrous cycle and causes infertility (Swenerton and Hurley, 1980~. Zinc is necessary for the normal development of the preembryonic conceptus. In the immediate postfertilization period, zinc deficiency can result in abnormal development of Reimplantation eggs (Hurley and Schrader, 1975~. In the rat, maternal dietary zinc restriction during embryogenesis has profound teratogenic effects involving many organ systems, especially the skeletal and central nervous systems (Dreosti, 1982; Hurley, 1981~. The pattern of malformations depends on the precise period of zinc depriva- tion and the embryonic events that are occurring at that stage of gestation
TRACE ELEMENTS 301 (Record et al., 1985~. Zinc restriction can result in fetal growth retar- dation in male fetuses of monkeys and fetuses of both sexes of rats and sheep (Hurley et al., 1985~. Zinc deficiency in the postembryonic period has been associated with behavioral abnormalities in the offspring of rats and monkeys (Strobe! et al., 1979) and with abnormalities in the ontogeny and postnatal function of the immune system (Haynes et al., 1985~. Ma- ternal zinc deficiency also has species-dependent effects on the course of pregnancy and delivery. In rats, zinc deficiency in late pregnancy causes prolonged labor with atonic bleeding (Apgar, 1968~. Such effects appear to result from a failure of normal hormonal changes at delivery. Premature delivery may be the most likely complication of maternal zinc deficiency in the ewe and guinea pig (Apgar, 1987~. Reproduction in Humans There have been a few reported cases of severe human zinc deficiency during pregnancy that resulted from inadequately treated acrodermatitis enteropathica a hereditary condition in which zinc absorption is impaired. Among these cases, there was a high incidence of major obstetric com- plications and congenital malformations in the offspring (Hambidge et al., 1975~. The prevalence and consequences of milder zinc deficiency during human pregnancy remain poorly defined. In several studies, associations were found between low zinc levels in plasma or tissue and complications of pregnancy and delivery, such as pregnancy-induced hypertension; prolonged labor; intrapartum hemorrhage; and impaired fetal development such as congenital malformations, intrauterine growth retardation (Adeniyi, 1987; Crosby et al., 1977; Fehily et al., 1986), and prematurity (Cherry et al., 1987~. Campbell-Brown et al. (1985) reported unusually low dietary zinc levels among Hindu vegetarian women in London, England, whose off- spring had low birth weights. However, there was no correlation between the maternal serum zinc level and birth weight. In general, there has been a lack of consistency in the findings of different studies (see reviews by Hambidge, 1989, and Swanson and King, 1987~. In randomized controlled trials of groups believed to be at relatively high risk of zinc deficiency, zinc supplements have had limited and incon- sistent effects. For example, in a study of low-income women of Mex- ican descent, Hunt et al. (1984) found a significantly lower incidence of pregnancy-induced hypertension in the zinc-supplemented group than in the placebo-treated group. They speculated that zinc may reduce the incidence of pregnancy-induced hypertension by affecting prostaglandin metabolism. In a subsequent study of teenage pregnancies in the same population, this effect was not observed (Hunt et al., 1985~. Nor was a zinc supplement found to have a beneficial effect on pregnancy-induced hypertension in
302 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS black adolescent teenagers in New Orleans (Cherry et al., 1987), despite an association between low plasma zinc concentrations and pregnancy-induced hypertension in an earlier study of that population (Cherry et al., 1981~. Zinc supplementation was, however, associated with a lower incidence of premature births in that study. Sample sizes have been inadequate to assess definitively the effect of zinc supplements on intrauterine growth. Nevertheless, the results of one recent study (Mahomed et al., 1989) indicated that an effect on fetal growth is unlikely in an unselected population of pregnant women. Estimated Zinc Requirements During Pregnancy Swanson and King (1987) estimate that 100 mg of zinc is retained in maternal and fetal tissues during pregnancy and that 0.7 mg/day is accumulated during the last trimester. At most, 1 mg/day is retained during the third trimester, allowing for intra- and interindividual variation. If fractional absorption is 25% during the third trimester, a maximum of an additional 4 mg of zinc per day is needed. Corresponding increments in dietary requirements during the first and second trimesters would be approximately 0.5 and 1.5 mg of zinc per day, respectively. It is not yet known whether fractional zinc absorption increases during late gestation in humans as it does in rats (Davies and Williams, 1977~. Studies of nonpregnant adults provide information about zinc absorp- tion, utilization, and excretion that is potentially relevant to human preg- nanc~y. Wada et al. (1985) report that nonpregnant adults adapt to a wide range of zinc intakes. Because of this, results of traditional balance studies cannot be used to establish dietary requirements for this micronutrient. The effects of mild zinc deficiency are subtle and nonspecific. Thus, it is extremely difficult to determine the point at which adaptation gives way to accommodation, i.e., when the earliest adverse effects occur. Reliable esti- mates of dietary zinc requirements for nonpregnant adults therefore remain elusive. Gibson and Scythes (1982), Holden et al. (1979), and Patterson et al. (1984) have reported that zinc intakes by apparently healthy adults in North America average 8 to 10 mg daily. When these data are considered along with those of Swanson and King (1987), it appears likely that 12 to 14 mg of zinc per day is ample in the third trimester of pregnancy. Indeed, the requirement may be substantially lower than this figure, especially if there are adaptive mechanisms specifically related to pregnancy. Usual Zinc Intakes Usual daily dietary zinc intakes during pregnancy range from 8.8 ~ 3.5 to 14.4 ~ 1.5 (standard deviation) mg/day (Campbell, 1988~. Among
TRACE ELEMENTS 303 vegetarians, usual zinc intakes may be even lower. For example, Campbell- Brown et al. (1985) reported a mean intake by Hindu vegetarian women of only 7.5 mgtday. Dosage Range and Toxicity The level of zinc supplementation that is safe for pregnant women has not been clearly established. Doses used in zinc supplementation studies in pregnant women have ranged from 15 to 45 mg/day, but one unconfirmed report suggests an association between zinc supplements of 45 mg/day during pregnancy and premature delivery (Kumar, 1976~. A daily zinc intake of 50 mg is sufficient to impair copper and iron metabolism (Yadrick et al., 1989~. One report, based on the metabolic balance technique and a diet low in copper, indicates that copper absorption is slightly impaired at a dietary zinc intake of only 18.5 mg/day (Festa et al., 1985~. Criteria for Status Assessment There are no pathognomonic clinical features of zinc deficiency in hu- mans, except in cases of very severe zinc deficiency. The potential adverse effects of maternal zinc deficiency on obstetric course (e.g., pregnancy- induced hypertension) and fetal development (e.g., fetal growth retarda- tion) are also nonspecific and are not helpful in diagnosing zinc deficiency. No reliable and sensitive functional indices of zinc status have been found, including the activity of the metalloenzymes. Indicators of T-cell function have been suggested but are nonspecific. In the second trimester, mater- nal leukocyte zinc concentrations have been associated with fetal growth retardation (Meadows et al., 1981~; however, this is a complex technique that is not applicable outside the research laboratory. Moreover, there are valid reasons to doubt that zinc deficiency is resected in lower leukocyte zinc concentrations (Milne et al., 1985~. The most widely used laboratory assays for assessment of zinc status include measurements of plasma or serum zinc. Plasma measurements are potentially more accurate but technically more difficult to perform. ~ make valid comparisons among samples, it is necessary to collect them at a predetermined time relative to meals. Prebreakfast samples are least subject to day-to-day variation (Hambidge et al., 1989~. There is a well-established physiologic decline in plasma zinc through- out gestation, starting early in the first trimester (Hambidge et al., 1983~. The cause of this decline is probably multifactorial, including hormonal factors and, later in gestation, increased plasma volume. Because of this decline, normal ranges are needed for each stage of gestation; some guide- lines for this have been published (Hambidge et al., 1983~. Another putative
304 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS concern about the use of plasma or serum zinc is the lack of adequate sen- sitivity in identifying women with zinc deficiency. Other tissue zinc assays, such as hair analysis (Hambidge, 1982), have not been demonstrated to be reliable indicators of zinc status in humans. Because of the limitations of laboratory assays and functional indices, their use in assessing zinc status is not recommended as a routine part of prenatal care. Studies of response to zinc supplementation offer the most definitive approach to confirming zinc deficiency in groups, but not in individuals. Prevalence of Zinc Deficiency Without large-scale zinc supplementation studies, the prevalence of maternal zinc deficiency during pregnancy remains speculative. Effects of Other Supplements and of Nonnutritive Substances Alcohol consumption increases losses of zinc in the urine and depresses plasma zinc concentrations (Flynn et al., 1981~. Infants with fetal alcohol syndrome have been reported to have low plasma zinc levels and increased urine zinc losses (Anonymous, 1986b). It has been hypothesized, but not confirmed, that the lack of zinc plays a role in the abnormal facial appearance that is typical of fetal alcohol syndrome. Placental transport of zinc was disturbed by chronic alcohol ingestion and did not improve with maternal zinc supplementation in an animal model (Ghishan and Greene, 19834. In pregnant smokers, whose placental cadmium levels are high, the placental zinc-to-cadmium ratio is positively related to infant birth weight (Kuhnert et al., 1988~. In an animal model, administration of cadmium was teratogenic only when marginal zinc deficiency was present as well (Sato et al., 1985~; low zinc-to-cadmium ratios in the kidney were suggested as a cause of hypertension. Because of these potential interrelationships between zinc and cadmium, it may be especially important to ensure an adequate zinc intake by pregnant smokers. Interactions between iron and zinc during gastrointestinal absorption have been well documented (Hamilton et al., 1978; Solomons, 1986), but not consistently in pregnant women. However, prenatal iron supplements, especially if administered in doses >60 mg of elemental iron per day, can lower maternal plasma zinc concentrations (Dawson et al., 1989; Hambidge et al., 1987~. Administration of iron and zinc in the same multimineral supplement also impairs zinc absorption (Sandstrom et al., 1985~. Milne et al. (1984) observed that modest folate supplements may impair zinc absorption, whereas Fuller et al. (1988) reported no effect. If folate has
TRACE ELEMENTS 305 any effect on zinc absorption, it is evidently not of sufficient magnitude to be of much practical importance (Krebs et al., 1988~. Recommendations for Supplementation There is insufficient evidence on which to base a recommendation for routine zinc supplementation during pregnancy. Iron in large doses (>60 mg/day) and possibly in lower doses (Dawson et al., 1989) does appear to depress plasma zinc in pregnant women and should, therefore, be avoided. Zinc supplementation is recommended when >30 mg of supplemental iron is administered per day. COPPER Importance in Pregnancy Copper-containing enzymes such as cytochrome oxidase play key roles in many oxidative processes and, hence, in the production of most of the energy required for metabolism. Certain cuproenzymes are important in the body's defense against free radicals (e.g., superoxide dismutase in cytosol and mitochondria), in the synthesis of connective tissue (e.g., lysyl oxidase), in the transport and utilization of iron (e.g., ferroxidases, including ceruloplasmin), in the synthesis of norepinephrine (dopamine p-hydroxylase), and in other metabolic pathways (Solomons, 1985~. In animal models, maternal copper deficiency can cause infertility, abortion, and stillbirth (Davis and Mertz, 1987~. However, low-copper diets have been shown to be teratogenic only when fed in combination with chelators that bind copper and further compromise copper status (Keen et al., 1982~. When pregnant ewes graze on severely copper~eficient pastures, enzootic neonatal ataxia (swayback) occurs in their lambs (Davis and Mertz, 1987~. This necrologic disorder results from the decreased activity of cytochrome oxidase in the central nervous system. Feeding of a marginally copper-deficient diet to rats beginning 4 months prior to breeding and continuing through gestation and lactation and to the weaned offspring causes no overt problems but does result in ultrastructural abnormalities in arterial elastin that are similar to the early changes of atherosclerosis (Hunsaker et al., 1984~. Copper deficiency has not been documented in humans during preg- nancy. It is quite possible that the demonstrated teratogenic effects of the drug penicillamine, which is a copper chelator, may be mediated through copper deficiency, but copper status has not been investigated in the re- ported cases (MjOlner0d et al., 1971~. Serum copper has been reported to be lower in women who deliver prematurely (Kiiholma et al., 1984), and
306 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS weak correlations have been observed between levels of copper in maternal serum and hair and indices of fetal growth (dir et al., 1981~. Pregnancy has a major effect on maternal copper metabolism. There are marked increases in serum ceruloplasmin and in plasma copper (Ham- bidge and Mauer, 1978~. Deviations from normal pregnancy-related changes in serum copper are likely to result from an abnormal obstetric course, e.g., placental insufficiency or intrauterine death, rather than from inadequate copper intake. Estimated Requirements During Pregnancy During pregnancy, total copper retention is approximately 30 ma, in- cluding 17 mg accumulated by the fetus. Most of this copper is accumulated in late gestation, when copper retention has been calculated to average 0.28 mg/day (Campbell, 1988~. At 40% fractional absorption (~rnlund et al., 1983), these figures indicate an increased dietary copper requirement of 0.7 mg/day. Most studies of copper requirements in humans have been con- ducted in males. Requirements for nonpregnant adult females are expected to be slightly lower. Klevay et al. (1980) concluded that a copper intake of 1.3 mg/day is necessary for males to avoid negative balance. However, rnlund et al. (1989) clearly demonstrated that adults can adapt to a wide range of copper intakes with changes in copper absorption. They showed that a positive copper balance can be achieved by young men on a diet that provides only 0.8 mg of copper per day. Depending on which figures are accepted, estimated copper requirements during pregnancy would be either 1.5 or 2.0 mg/day. Usual Intakes Average copper intake by nonpregnant adults is approximately 1 mg/day (Holder et al., 1979; Pennington et al., 1989) and by pregnant women, 1.4 to 1.8 mg/day (see Table 13-2; Campbell, 1988~. Additional careful estimates of copper intake during pregnancy are needed. Dosage Range and Toxicity No studies of copper supplementation of pregnant women have been reported. Several prenatal multivitamin-mineral preparations currently marketed provide 2 mg of copper per tablet. Spitalny et al. (1984) reported chronic copper toxicity in adults who drank' water containing approximately 8 mg of copper per liter.
TRACE ELEMENTS 307 Criteria for Status Assessment Copper and ceruloplasmin concentrations are low in copper-deficient, nonpregnant adults. Pregnancy is accompanied by a progressive increase in circulating ceruloplasmin and, hence, in serum copper up to approximately twice the values in nonpregnant individuals (Hambidge and Mauer, 1978~. It is not known if and to what extent these pregnancy-related changes are affected by copper deficiency. An unusually low serum ceruloplasmin or copper concentration occurs during pregnancy if there is a failure of normal placental development, regardless of copper intake. Erythrocyte superoxide dismutase activity is a potentially valuable index of copper status (Uauy et al., 1985), but its use in pregnancy has not yet been established. Prevalence of Deficiency Nutritional copper deficiency during human pregnancy has not been documented. Effects of Other Supplements Even a moderately excessive zinc intake (e.g., 50 mg of elemental zinc per day, which is approximately three times the 1989 RDA) can interfere with copper absorption and metabolism (Yadrick et al., 1989~. A negative change in copper balance may occur if an individual takes supplements providing enough zinc to achieve a total intake of 20 to 25 midday (Festa et al., 1985~. There is a need for further substantiation of this effect, which has been reported only with very low copper intakes. Recommendations for Supplementation Although the estimated mean intake of copper is lower than the estimated copper requirements during the last trimester of pregnancy, there is no evidence that any pregnant woman is deficient in copper to the extent that normal fetal growth and development are jeopardized. Therefore, no recommendation is made for prenatal copper supplementation. If a zinc supplement is administered, however, the subcommittee recommends that a 2-mg copper supplement also be given. This relatively high dose should be at least sufficient to compensate for the relatively poor absorption that occurs when copper is administered with zinc. IODINE Iodine is an essential component of the thyroid hormones thyroxine and triiodothyronine. Maternal iodine deficiency during pregnancy is the
308 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS cause of a wide spectrum of iodine deficiency disorders in the fetus and in the offspring (Anonymous, 1983; Hetzel, 1983; Matovinovic, 1983), in- cluding stillbirth, abortions, and congenital anomalies; endemic cretinism, characterized by mental deficiency; profound deafness; spastic dysplegia; or less commonly, the myxedematous type of cretinism. Milder disorders include necrologic impairment manifested by suboptimal intellectual per- formance and motor skill development and hearing loss in children born in geographic areas where there is an endemic deficiency of iodine (Yan-You and Shu-Hua, 1985~. To avoid damage to the fetus, iodine deficiency needs to be corrected prior to conception (Hetzel and Hay, 1979~. A 50- to 70-,ug intake of iodine per day is sufficient to avoid the risk of hypothyroidism in adult women. The RDA of 150 fig for adult women is sufficient to offset the adverse effects of dietary goitrogens, and an additional 25 fig of iodine per day is recommended during pregnancy (NRC, 1989~. In the Food and Drug Administration's Total Diet Study, the mean iodine intake by women aged 25 to 30 in the United States during 1986 was 170 ,ug/day approximately half the typical intake in 1982 but still high relative to requirements (Pennington et al., 1989~. There is no evidence of residual iodine deficiency in the United States, and no iodine supple- ments are recommended. Although excess dietary iodine intake has been associated with both goiters (Mu et al., 1987) and thyrotoxicosis (Connolly, 1973), this is not a contraindication to the moderate use of iodized salt during pregnancy. In certain countries in Africa, Asia, South America, and Europe, iodine deficiency disorders continue to be a major public health problem. Strenuous international efforts are under way to eradicate this disorder by promoting the use of iodized oil or salt (Anonymous, 1986a). SELENIUM Selenium is an essential component of the enzyme glutathione peroxi- dase, which catalyzes the conversion of hydrogen peroxide to water. Thus, selenium is an important component of the body's defenses against free radical damage (Hoekstra, 1975~. In animal models, the effects of selenium deficiency are more apparent if there is a concurrent deficiency of other antioxidants, especially vitamin E. Selenium deficiency has been identified in humans living in a large area of the People's Republic of China where there is a severe geochemical de- ficiency of this micronutrient. The deficiency is manifested by a frequently fatal cardiomyopathy (Keshan disease) that occurs in young children and women of childbearing age. Although the etiology of this disease is prob- ably multifactorial, a severe dietary deficiency of selenium is the major etiologic factor (Keshan Disease Research Group, 1979a,b). There have
TRACE ELEMENTS 309 been scattered case reports of similar cardiomyopathies (Johnson et al., 1981) and of skeletal myopathies (van Rij et al., 1979) in selenium-deficient patients maintained on prolonged total parenteral nutrition without sele- nium supplements (Johnson et al., 1981~. Milder selenium deficiency in parenterally fed children has been associated with macrocytosis and hair pigment changes (Vinton et al., 1987~. Keshan disease occurs in areas where the average selenium intake by adult males is 8 ~g/day (Yang et al., 1987~. Where Keshan disease was not evident, the average selenium intake by Chinese men was 19 ~g/day. Maximal plasma glutathione peroxidase activity in Chinese men was achieved with 40 ,ug of selenium per day (Yang et al., 1988~. The average weight of a Chinese man is 60 kg, which is similar to that of women in the United States. Selenium retentions of 10 and 22 ,ug/day between weeks 10 to 20 and 30 to 40 of gestation, respectively, have been reported (Swanson et al., 1983) in women with a high selenium intake. However, since selenium homeostasis changes over a wide range of selenium intakes, the metabolic balance technique is not helpful in determining human selenium requirements (Levander and Burk, 1986~. On a factorial basis, estimates of selenium retention in the fetus have varied from as little as 1 ~g/day to an average of 14 ~g/day during the last trimester (NRC, 1989~. If fractional absorption from the mother's gastrointestinal tract is 80% (Levander, 1983), an additional 18 fig of dietary selenium would be required daily during late gestation. Thus, the estimated selenium requirement during late gestation would be approximately 60 ,ug/day. The estimated average dietary selenium intake by women aged 25 to 30 during 1985 and 1986 was about 70 ~g/day in the United States (Pennington et al., 1989~. Several cases of selenium toxicity in nonpregnant adults resulted from large intakes of selenium supplements that provided about 30 mg per tablet approximately 200 times more selenium than that advertised on the label (Helzlsouer et al., 1985~. Symptoms of selenium toxicity included nausea, vomiting, nail changes, hair loss, fatigue, and irritability. Whole blood or erythrocyte selenium levels and glutathione peroxidase activity are used to assess selenium status in nonpregnant adults (Levander, 1986~. Plasma selenium is also used, although it is subject to short-term changes. However, the value of these indices is limited by the wide range of values found in apparently healthy subjects. In the United States, plasma selenium concentrations in nonpregnant adults usually range from 100 to 200 ng/ml. Adults with evidence of mild and severe selenium deficiency have plasma levels of less than 40 and 10 ng/ml, respectively. Selenium concentrations in plasma, but not in erythrocytes, decline during gestation. There is no indication of a need to conduct laboratory tests to assess
310 DIETARY INTAKE AND NUTRIENT SUPPT FMENTS selenium status during pregnancy or to advise pregnant women to take supplemental selenium. MANGANESE Manganese is a component of two enzymes-mitochondrial superoxide dismutase, an important antioxidant, and pyruvate carboxylase. Manganese- activated enzymes include the glycosyltransferases, which are necessary for the synthesis of polysaccharides and glycoproteins. When rat dams are raised from the time of weaning on a manganese- deficient diet, the pups experience poor survival and ataxia. These abnor- malities can be prevented by correcting the manganese deficiency as late as day 14 of gestation (Hurley, 1981~. Offspring of manganese-deficient dams also have low blood glucose concentrations, which are associated with decreased activity of phosphoenolpyruvate carboxykinase a manganese en- zyme involved in gluconeogenesis (Baly et al., 1984~. Deficiency impairs mucopolysaccharide synthesis in the developing otoliths of the pig's inner ear, resulting in a lack of coordination (Hurley, 1981~. There are no adequate data on manganese accumulation in the human conceptus. Usual intake by nonpregnant women aged 25 to 30 is approx- imately 2 mg/day (Pennington et al., 1989~. Both positive and negative manganese balances were observed during late pregnancy in women whose daily manganese intake averaged 2 to 7 mg (Armstrong, 1985~. Manganese deficiency has not been observed in human adults, includ- ing pregnant women. The intestine (through absorption) and liver (through biliary excretion) provide strong homeostatic controls of body manganese. Thus, manganese supplements are not indicated during pregnancy. Some data indicate that supplemental iron can interfere with manganese absorp- tion (Davidsson et al., 1988~. This merits further research. Manganese administered orally to nonpregnant adults appears to be nontoxic in quan- tities considerably in excess of requirements (NRC, 1989~. CHROMIUM Chromium is believed to play a physiologic role as a cofactor for in- sulin, facilitating the initial attachment of the hormone to its peripheral receptors (Mertz, 1969~. However, chromium has not been found in the insulin receptor (Kahn, 1985~. There have been numerous, but uncon- firmed, reports of chromium deficiency in humans, primarily in patients maintained on prolonged parenteral nutrition (Jeejeebhoy et al., 1977~. Glucose intolerance has been the most consistently observed effect of very low chromium intake. Some reports of chromium concentrations in plasma and tissues suggest
TRACE ELEMENTS 311 that pregnancy may be associated with chromium depletion (Davidson and Burt, 1973; Hambidge and Rodgerson, 1969~. It is difficult to substantiate these results, however, because accurate analysis of chromium in human tissues is exacting and there is a lack of established laboratory indices of human chromium status. Thus, the extent to which chromium is important in human nutrition remains uncertain, and there are no data suggesting that chromium supplementation is advisable during pregnancy. MOLYBDENUM In humans, molybdenum is a component of two enzymes xanthine oxidase, which is involved in the degradation of adenosine monophosphate, and sulfite oxidase. Molybdenum deficiency has been described only in one patient who was on prolonged total parenteral nutrition. Excess molyb- denum intake interferes with copper metabolism (Mills and Davis, 1987~. Molybdenum supplementation during pregnancy is contraindicated. FLUORIDE Administration of fluoride is the most effective means to prevent dental caries. Public health measures, including fluoridation of the community or school water supplies or oral supplementation, have been directed primarily toward infants and children younger than age 16. Adults may also derive some benefit from a fluoridated water supply or a 1-mg fluoride supplement per day (American Dental Association Council on Dental Therapeutics, 1984~. The precise mechanism by which fluoride exerts its cariostatic (decay- retarding) effects is uncertain. Most fluoride accumulates in the external enamel layer. Both topical and systemic fluoride appear to provide protec- tion against dental caries most effectively in the tooth's first two posteruptive years (Stookey, 1981~. During the preeruptive phase, systemic fluoride may have some beneficial effect, but there is no unanimity of opinion on this subject (American Dental Association Council on Dental Therapeutics, 1984~. - Maternal fluoride supplementation during pregnancy has been re- ported to decrease the incidence of caries in the offspring, even when administered in an area with a fluoridated water supply (Glenn and Glenn, 1987~. The designs of the studies on which this claim is partially based have been challenged (Driscoll, 1981~. Fluoride supplementation during pregnancy has not been endorsed by the American Dental Association and has not been generally accepted as a validated procedure. Dental fluorosis, or mottled enamel, has been observed in developing
312 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS teeth in areas where water supplies contain more than twice the opti- mal fluoride concentration of 1 mg/liter. Excessive fluoride intake should therefore be avoided. The subcommittee concluded that there is insufficient evidence to warrant recommending fluoride supplementation during pregnancy as a means of benefiting the teeth of the offspring. SUMMARY Although dietary intake of zinc and copper may be considerably lower than the RDA, there is no convincing evidence that this has adverse effects on pregnancy outcome. There is also no persuasive evidence that routine antenatal supplements of any trace element other than iron are potentially beneficial for pregnant women in the United States. CLINICAL IMPLICATIONS · Laboratory tests to determine trace element status are not suffl- ciently sensitive or predictive to justify their expense in routine prenatal care. · The best means of ensuring an optimal intake of trace elements appears to be consumption of a well-balanced and adequate diet rather than use of mineral supplements. · Although vegetarian diets can provide reasonable quantities of trace elements, flesh foods frequently contribute larger amounts that are more readily absorbed and are thus potentially advantageous during pregnancy. · There is no persuasive evidence that it is potentially beneficial to routinely supplement pregnant women with any trace element other than iron in the United States. · Although zinc nutrition during pregnancy has attracted recent pro- fessional and public interest, there is insufficient evidence to support a recommendation for routine prenatal zinc supplementation. · Although the subcommittee concluded that the iodine content of the food supply in the United States is sufficiently high to make iodine supplementation unnecessary, use of iodized salt is not contraindicated. · The intake of fluoride provided by fluoridated water supplies is encouraged, but fluoride supplements that result in intake above approxi- mately 1 mg/day are not recommended.
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