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17 Vitamins A, E, and K In this chapter, the subcommittee reviews data relating to supplemen- tation of the fat-soluble vitamins A, E, and K during pregnancy. Vitamin D, another fat-soluble vitamin, is reviewed in conjunction with calcium in Chapter 16, because calcium metabolism is dependent on that vitamin. The fat-soluble vitamins are often considered together since their absorption, transport, and excretion are influenced by their very limited solubility in water. VITAMIN A The term vitamin A includes a number of closely related compounds with similar biologic activities. This group of compounds is important throughout life because of their participation in a variety of biologic func- tions, including vision, reproduction, immune function, and cellular growth and differentiation. Two groups of compounds are related to vitamin A: the rei'noids (called preformed vitamin A if they possess vitamin A activity) and the carotenoids (called precursors of vitamin A or provitamin A if they can be metabolized to an active form of the vitamin). The naturally occurring forms of retinoids include retinal, retinaldehyde, and retinoic acid. The primary form of preformed vitamin A is retinyl ester, which is found in foods of animal origin such as liver, fish liver oils, milk, eggs, and butter. Provitamin A carotenoids are mainly of vegetable origin; carrots and dark- green leafy vegetables are especially rich sources. Nutritional needs for vitamin A can be met by ingesting either preformed retinoids with vitamin 336
VITAMIN A, E' ID K 337 A activity or certain carotenoids, such as carotene, that can be metabolized to vitamin ~ After ingestion, between 70 and 90% of preformed vitamin A is ab- sorbed, whereas the absorption of carotenoids is less efficient and more variable, ranging from 20 to 50%. Retinyl esters are hydrolyzed, reester- ified, and transported in chylomicrons to the liver. Carotenoids can be converted to retinal and retinyl esters in the intestinal mucosa, and both carotenoids and the retinyl esters derived from them are transported via the chylomicrons to the liver. The major storage site is the liver, which normally contains more than 90% of the total body stores of vitamin A in well-nourished people. Adipose tissue and the kidney are minor storage sites. The liver releases a complex of retinal and retinol-binding protein (RBP). This complex combines with transthyretin in the blood, is circulated, and may be either extracted by tissues or remetabolized by the liver and excreted in bile. Importance From a public health standpoint, vitamin A is of greatest importance in maintaining visual function. Worldwide, vitamin A deficiency results in approximately 250,000 to 500,000 cases of visual impairment per year, primarily in children in developing countries (FAO, 1988; Sommer, 1982~. Thus, vitamin A deficiency appears to be a major public health problem in many parts of the world (Araujo et al., 1986, 1987; Sklan, 1987; Stanton et al., 1986; Villard and Bates, 1987) but is not common in the United States. The most widely recognized effect of vitamin A is in the retina, where it is involved in photochemical reactions with rhodopsin (Wald, 1968~. It also functions throughout the body in aiding glycoprotein synthesis and promoting cellular growth and differentiation. Vitamin A During Pregnancy There is only limited information regarding the effect of pregnancy on the metabolism and physiology of vitamin A. Some evidence suggests that the retinol-RBP complex may be different In pregnant women than in nonpregnant controls (Sklan et al., 1985~. Data from studies of pregnant sheep support the possibility that binding proteins in the fetus may be different from those in the adult (Donoghue et al., 1982~. Quantitation of the rates at which vitamin A is transferred from mother to fetus is difficult and has largely been limited to animals. The rate at which retinoic acid is transferred to the fetal rat may be lower than that of retinyl ester (Shukla et al., 1986~. Studies in vitamin A-sufficient pregnant
338 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS sheep suggest that transport of vitamin A to the fetus increases but that efficiency of transfer decreases when high levels of vitamin A are provided to the ewe (Donoghue et al., 1985), suggesting that there may be some placental regulation of transport. Several mechanisms proposed for the transfer of retinol to the fetus are based primarily on animal data. One possibility is the direct transfer of the retinol-RBP complex. Alternatively, placental uptake of retinol, transient esterification in the placental tissues, and release of retinol into the fetal circulation may be involved; this was observed in sheep by Donoghue et al. (1982) and in rats by Torma and Vahlquist (1986~. Data on both sheep and rats suggest that a dynamic equilibrium exists between mother and fetus and that there is substantial transfer in both directions (Donoghue et al., 1982, 1985; Ismadi and Olson, 1982~. Once transferred into the fetus, some retinol is stored in the fetal liver. Wallingford and Underwood (1986) reported that maternal vitamin A supplementation did not increase fetal hepatic retinol levels in rats. In human fetuses, such hepatic concentrations are consistently much lower than those in adults (Montreewasuwat and Olson, 1979; Shah et al., 1987; Wallingford and Underwood, 1986) and correlate with maternal serum retinol levels (Shah et al., 1987~. An intercountry comparison of fetal liver tissue showed a significant increase in hepatic vitamin A levels in Swedish but not Ethiopian fetuses during the second and third trimesters compared with first-trimester levels (Gebre-Medhin and Vahlquist, 1984~. Units of Measurement Chemical and pharmacologic diversity among the compounds with vitamin A activity has led to the use of different units to express vitamin A activity international units (IUs) and retinol equivalents (REs). An IU is defined in terms of the growth-promoting activity of 0.30 ,ug of all-`rans retinol or 0.60 ,ug of all-trans p-carotene. The RE was adopted to account for the difference in the intestinal absorption of retinol and carotene. One RE is equal to 1 fig of all-trans retinol, and biologically, 1 RE is assumed to be equivalent to 6 fig of all-1rans ,~?-carotene (NRC, 1989~. At present, the RE is preferred, although IUs have been widely used in the past and are still reported. Because of ambiguities in converting from one system to another, the use of IUs is retained in this chapter if that was the unit of measurement used in the report that is referenced. Criteria for Deficiency Assessment of vitamin A status is complicated by the chemical and pharmacologic diversity among the compounds with vitamin A activity.
VITAMIN A, E, AND K 339 Methods to assess deficiency include biologic measurements such as bio- chemical measurements of plasma retinal level or liver concentrations of vitamin A and functional tests such as correction of impaired dark adapta- tion. Plasma retinal concentrations can be widely used as a basis for clinical determination of vitamin A status. In normal nonpregnant adults, impaired dark adaptation may result at retinal concentrations below 15 ~g/dl (Hume and Krebs, 1949), and abnormal electroretinograms may be found at levels below 4 to 11 ~g/dl (Sauberlich et al., 1974~. Levels below 30 ,ug/dl have been associated with vitamin A-responsive anemia, and levels of 7 to 37 ,ug/dl, with follicular keratosis (Sauberlich et al., 1974~. In Recommended Dietary Allowances (RDAs) it is recommended that nonpregnant adults maintain plasma retinal concentrations higher than 30 ~g/dl in order to maintain body stores; levels less than 20 ~g/dl are associated with increased risk for development of clinical signs and symptoms of vitamin A deficiency (NRC, 1989~. Pregnancy complicates the interpretation of these values, in part be- cause blood levels of REP change with pregnancy (NRC, 1978~. In re- search settings, liver stores of vitamin A have been used to assess vitamin A status-100 ,ug/g is typical of well-nourished, nonpregnant adults. Measurement of dark adaptation has also been used for screening vitamin A deficiency (Hume and Krebs, 1949~. A more recent method of measuring dark adaptation has been reported as a practical and reliable method requiring only limited technology (Villard and Bates, 1986~. From a public health standpoint, this type of assessment may be of considerable value. Vitamin A appears to be important for fetal growth. In a study of mother-infant pairs in an undernourished population, poor maternal vitamin A status was associated with preterm birth, intrauterine growth retardation, and decreased birth weight (Shah and Rajalakshmi, 1984~. In a human autopsy series, maternal serum retinal correlated positively with fetal weight (Shah and Rajalakshmi, 1984; Shah et al., 1987~. Chytil (1985) provided evidence that vitamin A may be important for lung growth in human fetuses. Similarly, studies in several animal species, including rats and domestic farm animals, suggest positive correlations of vitamin A with fetal growth. In rats, maternal vitamin A deficiency was correlated with decreased fetal body and organ size (Khanna and Reddy, 1983; Reddy and Khanna, 1983; Sharma and Misra, 1986; ~kahashi et al., 1975~. Recommended Intakes Estimates of vitamin A intakes required to maintain desirable retinal levels have been somewhat variable, ranging from 500 to 1,200 RE/day
340 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS (FAO 1988; NRC, 1989; Sauberlich et al., 1974). The RDA for vitamin A is 800 RE for nonpregnant women in the childbearing years and is not increased during pregnancy (NRC, 1989). Vitamin A deficiency is rare in the United States, and evidence suggests that U.S. women have adequate liver stores of the vitamin. Fetal vitamin A requirements are very low until the third trimester, and even then they are estimated to increase maternal vitamin A requirements by only 9% (NRC, 1989). There is no persuasive evidence that the dietary requirement for vitamin A is increased during pregnancy. Teratogenicity and Toxicity It is apparent that vitamin A deficiency affects the human fetus; how- ever, an excess of retinoids has also been of considerable concern, partic- ularly regarding the possibility of teratogenicity (see review by Teratology Society, 1987~. Isotretinoin, a synthetic relative of vitamin A (Accutane(~, 13~s-retinoic acid), has been reported to be teratogenic in animals and humans in the first trimester (Teratology Society, 1987~. The typical pheno- type includes such central nervous system abnormalities as hydrocephalus or microcephaly, cardiovascular abnormalities, facial anomalies (e.g., of the ear and palate), and altered growth. A high incidence of spontaneous abortion has also been reported. Large doses of retinal or retinyl esters may result in a similar syndrome (Rosa et al., 1986; Stange et al., 1978; Teratology Society, 1987; Woollam, 1985~. Retinoic acid also appears to be teratogenic (Lammer et al., 1985~. The minimum teratogenic dose is not known. A wide range of maternal vitamin A intakes has been reported in these studies. Of particular concern is the association of a first-trimester 2,000-IU vitamin A supplement with phenotypic isotretinoin syndrome (Lungarotti et al., 1987~. However, most other observers suggest that an intake of at least 20,000 to 50,000 IU is required for teratogenicity. Whether or not lower doses produce a less evident clinical syndrome is not known. Ingestion of excessive amounts of preformed vitamin A produces a well-defined syndrome, including headache, vomiting, diplopia, alopecia, liver damage, and skin abnormalities (Bauernfeind, 1980~. These toxic reactions appear to require a sustained total dietary intake of preformed vitamin A in excess of 15,000 RE in adults. It is not known whether pregnancy alters the maternal clinical syndrome of vitamin A toxicity. In contrast, limited data on humans suggest that high intakes of carotenoids are not teratogenic or toxic to either mother or fetus. In nonpregnant adults, very large intakes of carotenoids do not appear to be harmful, primarily because large doses are inefficiently absorbed and converted to vitamin A.
VITAMIN A, E, AND K 341 Usual Intake Usual intakes of vitamin A by pregnant women are discussed in Chap- ter 13. As mentioned above, the average vitamin A intake in the United States appears to exceed the RDA for both pregnant and nonpregnant women. Rush et al. (1988) showed that the average vitamin A intake of low- income women in the United States exceeds the RDA' even before the women enter the Supplemental Food Program for Women, Infants, and Children. Finley et al. (1985) reported that the average dietary intake of vitamin A by complete vegetarians appears to be somewhat higher than that of the average U.S. population. However, since there is also a wide range of individual intakes, it may be important to assess vitamin A intakes, particularly in women with unusual diets or who habitually avoid dietary sources of vitamin ~ Recommendations for Supplementation Since estimated dietary intake in the United States appears to be suf- ficient to meet the needs of most pregnant women throughout gestation, routine supplementation during pregnancy is not recommended. Carefully supervised supplementation may be desirable for some groups of pregnant women in the United States, for example, for recent emigrants from coun- tries in which vitamin A deficiency is endemic. Information and opinion on the teratogenic risk of various forms of vitamin A are rapidly evolving, and supplementation of vitamin A should be approached with caution until the risk is clarified. VITAMIN E Vitamin E is required by most animal species, although the recognition of its importance in humans is relatively recent. This vitamin is biologically important as an antioxidant; i.e., it traps free radicals and prevents oxi- dation of unsaturated fatty acids. Manifestations of its deficiency include anemia, neuromuscular abnormalities, and reproductive failure. In humans, vitamin E deficiency has been demonstrated in premature infants, mani- fested primarily by anemia (Oski and Barness, 1967), and in patients with prolonged, marked fat malabsorption, usually accompanied by necrologic abnormalities (Kelleher et al., 1987; Muller, 1986; Sokol et al., 1985~. Many other functions have been attributed to vitamin E, both in the medical and lay literature, but these effects remain unproven and controversial. I\vo classes of compounds, tocopherols and tocotrienols, include bio- logically active forms of vitamin E. Both classes are characterized chemically
342 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS by a similar ring system, but they differ in the saturation of the side chain. The tocopherols act-, ,0-, by-, and b-), which have a saturated side chain, are widely found in nature. c~-ldcopherol is both the most active and the most prevalent biologic form. Normal bile secretion and pancreatic function are required for intesti- nal absorption of vitamin E. After absorption, vitamin E is carried in the blood in the lipoproteins, primarily in high-density lipoproteins in women but in low-density lipoproteins in men (Behrens et al., 1982~. As a fat- soluble compound, tocopherol is widely distributed in the fatty component of tissues. Its concentration is similar in most tissues if expressed relative to their fat content. Vitamin E is widely distributed in the polyunsaturated fatty acids (PUFAs) of cell membranes. Deficiency of vitamin E permits oxidation of PUFAs, with consequent damage to membranes and cells. Although vitamin E selves as the primary antioxidant system, ascorbic acid and selenium also serve this purpose. Importance Blood tocopherol levels increase during pregnancy, paralleling a rise in total lipid levels (Ho~witt et al., 1972; NRC, 1978~. Vitamin E deficiency is not known to be of special concern for pregnant women or their fetuses. Although vitamin E has not been a major issue in obstetrics and is not believed to be related to the risk of preterm birth, it has attracted consider- able interest in the care of newborns, particularly those born prematurely. Premature infants occasionally develop a hemolytic anemia, which is gen- erally believed to be due to vitamin E deficiency. Thus, the vitamin is given to premature infants routinely to meet their special needs (AAP/ACOG, 1988~. The limited evidence that macrocytic anemia results from vitamin E deficiency is based primarily on hemolysis after an in vitro peroxide stress. This anemia seldom occurs in full-term neonates or infants (Cruz et al., 1983; Hassan et al., 1966; Linderkamp, 1987; Oski and Barness, 1967; Vanderpas and Vertongen, 1985~. However, although the clinical syndrome of anemia is well known, more recent studies have questioned whether this anemia results from vitamin E deficiency (Zipursky et al., 19874. Linderkamp (1987) has pointed out, quite correctly, that many features are unique to the red cells of newborn infants a factor that complicates interpretation of study results. Vitamin E may be involved in several other serious problems of prema- ture infants, such as bronchopulmona~y dysplasia, a common form of lung disease. Early enthusiasm for treating this disorder with therapeutic doses of vitamin E has waned (Ehrenkranz et al., 1979, 1982; McCarthy et al.,
VITAMIN A, E, AND K 343 1984; Wender et al., 1981; Zoberlein et al., 1982). Similarly, there is con- siderable controversy regarding a role for therapeutic doses of vitamin E in reducing retinopathy of prematurity (retrolental fibroplasia), an infrequent but serious condition leading to substantial visual impairment (Bremer et al., 1986; Hittner et al., 1984; Kretzer et al., 1985; Phelps et al., 1987; Rosenbaum et al., 1985~. Evidence has also been presented that vitamin E may be protective in reducing intraventricular hemorrhage in newborn infants (Chiswick et al., 1983; Speer et al., 1984) and microcephaly in rats (Tanaka et al., 1986~. Studies of the use of vitamin E in the treatment of these clinical problems have produced inconsistent results, and vitamin E supplementation of preterm infants remains highly controversial (see re- views by Karp and Robertson, 1986; Pereira and Barbosa, 1986; and Phelps, 1987~. Attempts to treat diseases of preterm infants with intravenous vi- tamin E have resulted in major morbidity and mortality (Martone et al., 1986~. However, this is now attributed to a stabilizer in the preparation, rather than to the vitamin itself (Alade et al., 19864. There is no evidence that maternal vitamin E supplementation would reduce the incidence of health problems in premature infants. However, if the fetus acquires vitamin E while it is accumulating fat (during the last 8 to 10 weeks of gestation), the premature infant may be especially low in vitamin E. The full-term infant may therefore have larger vitamin E stores than preterm infants, but the stores are still low compared with those of adults (Gross and Melhorn, 1972~. Vitamin E status is difficult to interpret in human fetuses and newborns, in part because both serum lipids and serum levels of vitamin E are low (All et al., 1986; Desai et al., 1984; Huijbers et al., 1986; Ostrea et al., 1986; Schulz et al., 1986~. Criteria for Deficiency In clinical assessment, blood concentrations of tocopherol in normal adults range from 0.5 to 1.2 mg/dl. The tocopherol concentration relates directly to the concentration of total plasma lipids and should be expressed in relation to total lipids. Recommended and Usual Intakes The RDA for vitamin E is based on estimates of customary intakes of the vitamin from balanced diets in the United States (NRC, 1989~. Actual requirements have not been estimated because of methodologic di~culties. There is significant variation in the tocopherol content of foods. Vegetable oils are the richest source of vitamin E in the U.S. diet. Margarine, shortening, wheat germ, whole grains, and nuts contain large amounts
344 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS of vitamin E. Substantial loss of tocopherol may occur with processing, storage, and food preparation. Vitamin E appears to be safe over a wide range of intakes, and no chemical or clinical evidence of toxicity has been observed with oral vitamin E in dosages to 800 mg/day in nonpregnant adults (Farrell and Bieri, 1975~. Intake varies widely within and among diets, but appears to average 5 to 11 mg/day for adults eating a typical mixed diet. As noted in Chapter 13, the dietary intake of vitamin E may be difficult to assess because of methodologic and reporting problems. The estimated mean intake by pregnant women in the United States ranges from 3 to 9 mg/day, which is below the pregnancy RDA of 10 ma. The vitamin E intake of well- nourished pregnant and lactating women in England has also been reported to be below the RDA, but without evident clinical signs or symptoms (Black et al., 1986~. Recommendations for Supplementation In pregnant women, there have been no definable deficiency syndromes for vitamin E, and intakes below the RDA have not been accompanied by an obvious clinical morbidity. Thus, supplementation of healthy pregnant women appears to be unnecessary. Special Considerations Given the low vitamin E levels and the clinical syndrome of anemia believed to result from vitamin E deficiency, it is routine to give premature infants supplements of vitamin E. VITAMIN K Vitamin K is a fat-soluble vitamin that is required for the synthesis of prothrombin and clotting factors VII, IX, and X. Additional vitamin K- dependent proteins are found in bone, kidney, and other tissues. Natural forms include phylloquinone of plant origin and a group of menaquinones of bacterial origin. Menadione is a fat-soluble synthetic compound with vitamin K activity; several water-soluble derivatives of menadione are also available. Vitamin K can be absorbed from the small intestine. Efficient absorp- tion occurs in the presence of normal biliary and pancreatic function. The vitamin is widely distributed among tissues; the highest concentration is found in the liver. The body pool of vitamin K is small, and its turnover is rapid (Bjornsson et al., 1980~.
~IIAMIN A, E, AND K 345 Vitamin K is contained in a variety of foods, especially leafy vegetables, dairy products, meat, and eggs. Bacterial flora of the small intestine are another source of vitamin K activity. Analyses of liver compounds with vitamin K activity indicate that food and bacteria provide the normal adult with roughly equal amounts of vitamin K (Rietz et al., 1970~. Importance The specific importance of vitamin K during pregnancy is largely undetermined. It is known that vitamin K levels and the levels of vitamin K-dependent clotting factors are low in the human fetus (Pietersma-de Bruyn and van Haard, 1985~. Transport of vitamin K from mother to fetus has received little attention, but it appears to be limited (Hamulyak et al., 1987, Hiraike et al., 1988~. The process of fetal and neonatal clotting is very complicated, and specific clinical problems with bleeding in the fetus are rare. The existence of vitamin K deficiency in the fetus is uncertain (Israels et al., 1987~. By contrast, there is considerable evidence that the newborn infant is functionally vitamin K-deficient, as judged both by vitamin K levels and by abnormal clotting (Lane and Hathaway, 1985; Muntean, 1983; Pietersma- de Bruyn and van Haard, 1985; Prentice, 1985~. Accordingly, pediatric and obstetric professional groups recommend that all newborns receive parenteral vitamin K immediately after birth (AAP/ACOG, 1988), whether maternal dietary intake is high or low. Criteria for Deficiency Data on plasma vitamin K levels are not systematically available. Vita- min K status is traditionally assessed by blood clotting time. Prolongation of clotting resulting from deficiency of vitamin K-dependent factors is considered to be presumptive evidence of vitamin K deficiency. Recommended and Usual Intake The requirement for vitamin K is difficult to estimate, partly because of technical problems. Although a 65-,ug RDA for vitamin K has been established for adults, a different recommendation has not been made for vitamin K intake during pregnancy (NRC, 1989~. Normal newborns are routinely given 0.5 to 1.0 mg of vitamin K as phy- tonadione in a single dose immediately following birth. Hemolytic anemia, hyperbilirubinemia, and kernicterus have been reported in newborns who were given menadione (Owen, 1971~. These complications are uncommon today, however, since other forms of vitamin K are in current use.
346 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Vitamin K intake has not been investigated in nationwide studies of nutrient intake. Estimates for usual intake from a mixed diet in the United States range from 300 to 500 Friday (Olson, 1987~. Recommendations for Supplementation No vitamin K supplement is indicated in the routine care of pregnant women. No general public health problems have been associated with vitamin K deficiency, which is limited to individuals with disorders that cause substantial degrees of malabsorption or alterations of gut flora. There does not appear to be a need to supplement normal pregnant women with vitamin K, but treatment with vitamin K may be advisable as a part of the medical therapy for pregnant women with malabsorption or those who are undergoing treatment with antibiotics. Vitamin K status should be carefully assessed in patients taking prothrombin~epressing anticoagulants, such as coumarin. Vitamin K may also be of special importance in newborns born to women taking anticonvulsant drugs (Yerby, 1987~. CLINICAL IMPLICATIONS · Routine supplementation with vitamin A, either as retinal (pre- formed vitamin A) or carotene (its precursor), appears to be unnecessary in the United States, because the usual dietary intake is adequate to meet the needs of most pregnant women. · Because of uncertainties about the teratogenicity of preformed vitamin A, use of supplemental retool is discouraged during the first trimester of pregnancy unless there Is evidence of deficiency. . Although it is routine to supplement premature infants with vitamin E, evidence does not support routine supplementation of pregnant women with this vitamin. · Although it Is advisable that all newborns receive vitamin K at birth, evidence does not indicate that pregnant women should be provided with supplemental vitamin K. REFERENCES AAP/ACOG (American Academy of Pediatrics/American College of Obstetricians and Gynecologists). 1988. Guidelines for Perinatal Care, 2nd ed. American Academy of Pediatrics, Elk Grove, Ill. 356 pp. Alade, S.L., R.E. Brown, and A. Paquet, Jr. 1986. Polysorbate 80 and E-Ferol toxicity. Pediatrics 77:593-597. All, J., H.A. Kader, K Hassan, and H. Arshat. 1986. Changes in human milk vitamin E and total lipids during the fimt twelve days of lactation. Am. J. Clin. Nutr. 43:925-930. Araujo, R.L., M.B.D.G. Araujo, R.O. Sieior, R.D.P. Machado, and B.V Leite. 1986. Diagnostico da situac~ao da hipovitaminose a e da anemia nutricional na populaces do vale do Jequitinhonha, Minas Gerais, Brasil. Arch. Latinoam. Nutr. 36:642-653.
VITAMIN A, E, AND K 347 Araujo, R.L., M.B.D.G. Araujo, R.D.P. Machado, A.N Braga, B.V. Leite, and J.R. Oliveira. 1987. Evaluation of a program to overcome vitamin A and iron deficiencies in areas of poverty in Minas Gerais, Brazil. Arch. Latinoam. Nutr. 37:9-22. Bauernfeind, J.C. 1980. The Safe Use of Vitamin A. A Report of the International Vitamin A Consultative Group (IVACG). We Nutrition Foundation, Washington, D.C. 44 pp. Behrens, WA., J.N. Thompson, and R. Madere. 1982. Distribution of ct-tocopherol in human plasma lipoproteins. Am. J. Clin. Nutr. 35:691-696. Bjornsson, T.D., P.J. Meffin, S.E. Swezey, and T.F. Blaschke. 1980. Disposition and turnover of vitamin K1 in man. Pp. 328-332 in J.W. Suttie, ed. Vitamin K Metabolism and Vitamin K-Dependent Proteins. University Park Press, Baltimore. Black, A.E., S.J. Wiles, and A.A. Paul. 1986. The nutrient intakes of pregnant and lactating mothers of good soc~o-economic status in Cambridge, UK: some implications for recommended daily allowances of minor nutrients. Br. J. Nutr. 56:59-72. Bremer, D.L~, G.L~ Rogers, H. Bell, and R. Lytle. 1986. The efficacy of vitamin E in retinopathy of prematurity. J. Pediatr. Ophthalmol. Strab. 23:132-136. Chiswick, M.L^, M. Johnson, C. Woodhall, M. Gowland, J. Davies, N. Toner, and D. Sims. 1983. Protective effect of vitamin E on intraventricular haemorrhage in the newborn. Ciba Found. Symp. 101:186-200. Chytil, F. 1985. Vitamin A and lung development. Pediatr. Pulmonol. l:S115-S117. Cruz, C.S.D., P.D. W~mberley, K Johansen, and B. Friis-Hansen. 1983. The effect of vitamin E on erythrocyte hemolysis and lipid peroxidation in newborn premature infants. Acta Paediatr. Scand. 72:823-826. Desai, I.D., F.E. Martinez, J.E. Dos Santos, and J.E. Dutra de Oliveria. 1984. Transient lipoprotein deficiency at birth: a cause of low levels of vitamin E in the newborn. Acta Vitaminol. Enzymol. 6:71-76. Donoghue, S., D.W. Richardson, D. Sklan, and D.S. Kronfeld. 1982. Placental transport of retinol in sheep. J. Nutr. 112:2197-2203. Donoghue, S., D.W. Richardson, D. Sklan, and D.S. Kronfeld. 1985. Placental transport of retinol in ewes fed high intakes of vitamin A. J. Nutr. 115:1562-1571. Ehrenkranz, R.A., R. C. Ablow, and J.B. Warshaw. 1979. Prevention of bronchopulmonary dysplasia with vitamin E administration during the acute stages of respiratory distress syndrome. J. Pediatr. 95:873-878. Ehrenkranz, R.A., R.C. Ablow, and J.B. Warshaw. 1982. Effect of vitamin E on the development of oxygen-induced lung injury in neonates. Ann. N.Y. Acad. Sci. 393:452 466. FAO (Food and Agriculture Organization). 1988. Requirements of Vitamin A, Iron, Folate, and Vitamin B12- Report of a Joint FAD/WHO Expert Consultation. FAO Food and Nutrition Series No. 23. Food and Agriculture Organization, Rome. 107 pp. Farrell, P.M., and J.G. Bieri. 1975. Megavitamin E supplementation in man. Am. J. Clin. Nutr. 28:1381-1386. Finley, D.A., K.G. Dewey, B. Lonnerdal, and L^E. Grivetti. 1985. Food choices of vegetarians and nonvegetarians during pregnancy and lactation. J. Am. Diet. Assoc. 85:678-685. Gebre-Medhin, M., and A. Vahlquist. 1984. Vitamin A nutrition in the human foetus: a comparison of Sweden and Ethiopia. Acta Paediatr. Scand. 73:333-340. Gross, S., and D.K Melhorn. 1972. Vitamin E, red cell lipids and red cell stability in prematurity. Ann. N.Y. Acad. Sci. 203:141-162. Hamulyak, K., M.A. de Boer-van den Berg, H.H. Thijssen, H.C. Hemker, and C. Vermeer. 1987. The placental transport of [3H]vitamin K1 in rats. Br. J. Haematol. 65:335-338. Hassan, H., S.A. Hashim, T.B. Van Itallie, and W.H. Sebrell. 1966. Syndrome in premature infants associated with low plasma vitamin E levels and high polyunsaturated fatty acid diet. Am. J. Clin. Nutr. 19:147-157. Hiraike, H., M. Kimura, and Y. Itokawa. 1988. Distribution of K vitamins (phylloquinone and menaquinones) in human placenta and maternal and umbilical cord plasma. Am. J. Obstet. Gynecol. 158:564-569.
348 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Hittner, H.M., AJ. Rudolph, and F.L~ Kretzer. 1984. Suppression of severe retinopathy of prematurity with vitamin E supplementation: ultrastructural mechanism of clinical efficacy. Opthalmology 91:1512-1523. Horwitt, M.K, C.C. Harvey, C.H. Dahm, Jr., and M.T. Searcy. 1972. Relationship between tocopherol and serum lipid levels for determination of nutritional adequacy. Ann. N.Y. Acad. Sci. 203:223-236. Huijbers, WA., J. Schrijver, AJ. Speek, B.A. Deelstra, and A. Okken. 1986. Persistent low plasma vitamin E levels in premature infants surviving respiratory distress syndrome. Eur. J. Pediatr. 145:17~171. Hume, E.M., and H.A. Krebs. 1949. Vitamin A Requirement of Human Adults. Report of the Vitamin A Subcommittee, Accessory Food Factors Committee, Medical Research Council. Special Report Series No. 264. Her Majesty's Stationery Office, London. 145 pp. Ismadi, S.D., and J.A Olson. 1982. Dynamics of the fetal distribution and transfer of Vitamin A between rat fetuses and their mother. Int. J. Vitam. Nutr. Res. 52:112-119. Israels, L.G., E. Friesen, A H. Jansen, and E.D. Israels. 1987. Vitamin K1 increases sister chromatic exchange in vitro in human leukocytes and in viva in fetal sheep cells: a possible role for "vitamin K deficiency" in the fetus. Pediatr. Res. 22:405 408. Karp, W.B., and A.F. Robertson. 1986. Vitamin E in neonatology. Adv. Pediatr. 33:127-147. Kelleher, J., M.G. Miller, J.M. Littlewood, A.M. McDonald, and M.S. Losowsky. 1987. The clinical effect of correction of vitamin E depletion in cystic fibrosis. Int. J. Vitam. Nutr. Res. 57:253-259. Khanna, A., and T.S. Reddy. 1983. Effect of undernutrition and vitamin A deficiency on the phospholipid composition of rat tissues at 21 days of age. I. Liver, spleen, and kidney. Int. J. Vitam. Nutr. Res. 53:3-8. Kretzer, F.L^, AR. McPherson, A.J. Rudolph, and H.M. Hittner. 1985. Pathogenic mechanism of retinopathy of prematurity: a controversial explanation for the efficacy of oral and intramuscular vitamin E supplementation and cryotherapy. Bull. N.Y. Acad. Med. 61:883-900. Lammer, E.J., D.T. Chen, R.M. Hoar, N.D. Agnish, P.J. Benke, J.T. Braun, CJ. Curry, P.M. Fernhoff, JEW. Grix, Jr., I.T. Lott, J.M. Richard, and S.C. Sun. 1985. Retinoic acid embryopathy. N. Engl. J. Med. 313:837-841. Lane, P.A., and WE. Hathaway. 19&~. Vitamin K in infancy. J. Pediatr. 106:351-359. Linderkamp, O. 1987. Blood rheology in the newborn infant. Baill. Clin. Haematol. 1:801-825. Lungarotti, M.S., D. Marinelli, T. Mariani, and A. Calabro. 1987. Multiple congenital anomalies associated with apparently normal maternal intake of vitamin A: a phenocopy of the isotretinoin syndrome? Am. J. Med. Genet. 27:245-248. Martone, W.J., W.W. Williams, M.L Mortensen, R.P. Gaynes, J.W. White, V. Lorch, M.D. Murphy, S. N. S inha, DJ. Frank, N. Kosmetatos, CJ. Bodenstein, and R.J. Roberts. 1986. Illness with fatalities in premature infants: association with an intravenous vitamin E preparation, E-Ferol. Pediatrics 78:591-600. McCarthy, K., M. Bhogal, M. Nardi, and D. Hart. 1984. Pathogenic factors in bronchopul- monary dysplasia. Pediatr. Res. 18:483-488. Montreewasuwat, N., and J.A. Olson. 1979. Serum and liver concentrations of vitamin A in Thai fetuses as a function of gestational age. Am. J. Clin. Nutr. 32:601-606. Muller, D.P.R. 1986. Vitamin E its role in nellrr)lo~i~] Fining P~ar~1 M-A 62:107-112. Muntean, W. 1983. Vitamin-K-Mangel bet Neugeborenen. Wien. Klin. Wochenschr. 95:1-5. NRC (National Research Council). 1978. Laboratory Indices of Nutritional Status in Pregnancy. Report of the Committee on Nutrition of the Mother and Preschool Child, Food and Nutrition Board. National Academy of Sciences, Washington, D.C. 195 pp. NRC (National Research Council). 1989. Recommended Dietary Allowances, 10th ed. Report of the Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences. National Academy Press, Washington, D.C. 284 PP
VITAMIN A, E, AND K 349 Olson, J.A. 1987. Recommended dietary intakes (RDI) of vitamin K in humans. Am. J. Clin. Nutr. 45:687-692. Oski, F.A., and L~A. Barness. 1967. Vitamin E deficiency: a previously unrecognized cause of hemolytic anemia in the premature infant. J. Pediatr. 70:211-220. Ostrea, E.M., Jr., J.E. Balun, R. Winkler, and T. Porter. 1986. Influence of breast-feeding on the restoration of the low serum concentration of vitamin E and ,3-carotene in the newborn infant. Am. J. Obstet. Gynecol. 154:1014-1017. Owen, C.A., Jr. 1971. Vitamin K group. XI. Pharmacology and toxicology. Pp. 492-509 in W.H. Sebrell, Jr. and R.S. Harris, eds. The Vitamins: Chemistry, Physiology, Methods, 2nd ea., Vol. III. Academic Press, New York. Pereira, G.R., and N.M.N. Barbosa. 1986. Controversies in neonatal nutrition. Pediatr. Clin. North Am. 33:65-89. Phelps, D.L~ 1987. Current perspectives on vitamin E in infant nutrition. Am. J. Clin. Nutr. 46:187-191. Phelps, D.L^, A.L. Rosenbaum, S.J. Isenberg, R.D. Leake, and FJ. Dorey. 1987. Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized, controlled, double-masked trial. Pediatrics 79:489-500. Pietersma-de Brayn, A I~J.M., and P.M.M. van Haard. 1985. Vitamin K1 in the newborn. Clin. Chim. Acta 150:95-101. Prentice, C.R. 1985. Acquired coagulation disorders. Clin. Haematol. 14:413-442. Reddy, T.S., and A. Khanna. 1983. Effect of undernutrition and vitamin A deficiency on the phospholipid composition of rat tissues at 21 days of age.-II. Lung, heart, and testes. Int. J. Vitam. Nutr. Res. 53:9-12. Rietz, P., U. Gloor, and O. W~ss. 1970. Menachinone aus menschlicher Leber und Faulschlamm. Int. Z. Vitaminforsch. 40:351-362. Rosa, F.W., AL~ W~lk, and F.O. Kelsey. 1986. Teratogen update: vitamin A congeners. Teratology 33:355-364. Rosenbaum, AL., D.L Phelps, S.J. Isenberg, R.D. Leake, and F. Dorey. 1985. Retinal hemorrhage in retinopathy of prematurity associated with tocopherol treatment. Opthalmology 92:1012-1014. Rush, D., N.L~ Sloan, J. Leighton, J.~. Alvir, D.G. Horvitz, W.B. Seaver, G.G Garbowski, S.S. Johnson, R.A. Kulka, M. Holt, J.W. Devore, J.T Lynch, M.B. Woodside, and D.S. Shanklin. 198%. The National WIC Evaluation: evaluation of the Special Supplemental Food Program for Women, Infants, and Children. V. Longitudinal study of pregnant women. Am. J. Clin. Nutr. 48:439-483. Sauberlich, H.E., R.E. Hodges, D.L~ Wallace, H. Kolder, J.E. Canham, J. Hood, N. Raica, Jr., and L^K Low~y. 1974. Vitamin A metabolism and requirements in the human studied with the use of labeled retinol. Vitam. Horm. (N.Y.) 32:251-275. Schulz, H., K. Schroeder, and W. Feldheim. 1986. Studies on the tocopherol status in blood serum of premature babies and infants. Z. Ernaehrungswiss. 25:1-8. Shah, R.S., and R. Rajalakshmi. 1984. Vitamin A status of the newborn in relation to gestational age, body weight, and maternal nutritional status. Am. J. Clin. Nutr. 40:794-800. Shah, R.S., R. Rajalakshmi, R.V. Bhatt, M.N. Hazra, B.C Patel, N.B. Swamy, and 1:V. Patel. 1987. Liver stores of vitamin A in human fetuses in relation to gestational age, fetal size and maternal nutritional status. Br. J. Nutr. 58:181-189. Sharma, H.S., and U.K Misra. 1986. Postnatal distribution of vitamin A in liver, lung, heart, and brain of the rat in relation to maternal vitamin A status. Biol. Neonate 50:345-350. Shukla, R.R., V. Kumar, R. Banerjee, and U.K. hIisra. 1986. Placental transfer and fetal distribution of 3H-retinoic acid in rats. Int. J. Vitam. Nutr. Res. 56:29-33. Sklan, D. 1987. Vitamin A in human nutrition. Prog. Food Nutr. Sci. 11:39-55. Sklan, D., I. Shalit, N. Lasebnik, Z. Spirer, and Y. Weisman. 1985. Retinol transport proteins and concentrations in human amniotic fluid, placenta, and fetal and maternal sera. Br. J. Nutr. 54:577-583.
350 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Sokol, R.J., M.A. Guggenheim, J.E. Heubi, S.T. Iannaccone, N. Butler-Simon, V. Jackson, C. Miller, M. Cheney, W.F. Balistreri, and A. Silverman. 1985. Frequency and clinical progression of the vitamin E deficiency necrologic disorder in children with prolonged neonatal cholestasis. Am. J. Dis. Child. 139:1211-1215. Sommer, A. 1982. Nutritional Blindness: Xerophthalmia and Keratomalacia. Oxford University Press, New York. 282 pp. Speer, M.E., C. Blifeld, ~J. Rudolph, P. Chadda, M.E.B. Holbein, and H.M. Hittner. 1984. Intraventricular hemorrhage and vitamin E in the very low-birth-weight intent: evidence for efficacy of early intramuscular vitamin E administration. Pediatrics 74:1107-1112. Strange, L^, K Carlstrom, and M. Eriksson. 1978. Hypervitaminosis A in early human pregnancy and malformations of the central nervous system. Acta Obstet. Gynecol. Scand. 57:289-291. Stanton, B.F., J.D. Clemens, B. Wojtyniak, and T. Khair. 1986. Risk factors for developing mild nutritional blindness in urban Bangladesh. Am. J. Dis. Child. 140:584-588. Takahashi, Y.I., J.E. Smith, M. Winick, and D.S. Goodman. 1975. Vitamin A deficiency and fetal growth and development in the rat. J. Nutr. 105:1299-1310. Tanaka, H., S. Iwasaki, K. Inomata, F. Nasu, and S. Nishimura. 1986. The protective effects of vitamin E on microcephaly in rats X-irradiated in utero: DNA, lipid peroxide and confronting cisternae. Dev. Brain Res. 27:11-17. Teratology Society. 1987. Teratology Society position paper recommendations for vitamin A use during pregnancy. Teratology 35:267-275. Torma, H., and A. Vahlquist. 1986. Uptake of vitamin A and retinol-binding protein by human placenta in vitro. Placenta 7:295-305. Vanderpas, J., and F. Vertongen. 1985. Erythrocyte vitamin E is oxidized at a lower peroxide concentration in neonates than in adults. Blood 66:1272-1277. Villard, L., and C.J. Bates. 1986. Dark adaptation in pregnant and lactating Gambian women: feasibility of measurement and relation to vitamin A status. Hum. Nutr.: Clin. Nutr. 40C:349-357. Villard, L., and CJ. Bates. 1987. Effect of vitamin A supplementation on plasma and breast milk vitamin A levels in poorly nourished Gambian women. Hum. Nutr.: Clin. Nutr. 41C:47-58. Wald, G. 1968. The molecular basis of visual excitation. Nature 219:800-807. Wallingford, J.C., and B.^ Underwood. 1986. Vitamin A deficiency in pregnancy, lactation, and the nursing child. Pp. 101-152 in J.C. Bauernfeind, ed. Vitamin A Deficiency and its Control. Academic Press, Orlando, Fla. Wender, D.F., G.E. Thulin, G3.W. Smith, and J.B. Warshaw. 1981. Vitamin E affects lung biochemical and morphologic response to hyperoxia in the newborn rabbit. Pediatr. Res. 15:262-268. Woollam, D.H.M. 1985. Basic principles of teratology. Pp. 8S-116 in R. MacDonald, ed. Scientific Basis of Obstetrics and Gynaecology, 3rd ed. Churchill Livingston, Edinburgh. Yerby, M.S. 1987. Problems and management of the pregnant woman with epilepsy. Epilepsia 28, Suppl. 3:S29-S36. Zipurs}y, A., EJ. Brown, J. Watts, R. Milner, C. Rand, V.S. Blanchette, E.F. Bell, B. Paes, and E. Ling. 1987. Oral vitamin E supplementation for the prevention of anemia in premature infants: a controlled trial. Pediatrics 79:61-68. Zoberlein, H. G., V. Freudenberg, and H. Wehinger. 1982. Bronchopulmonale Dysplasie: prospektiv radomisierte Studie zur prophylaktischen Wirkung von Vitamin E. Monatss- chr. Kinderheilkd. 130:706-709.
