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Institute of Medicine (US) Committee on Nutritional Status During Pregnancy and Lactation. Nutrition During Pregnancy: Part I Weight Gain: Part II Nutrient Supplements. Washington (DC): National Academies Press (US); 1990.

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Nutrition During Pregnancy: Part I Weight Gain: Part II Nutrient Supplements.

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17Vitamins A, E, and K

In this chapter, the subcommittee reviews data relating to supplementation 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 functions, including vision, reproduction, immune function, and cellular growth and differentiation. Two groups of compounds are related to vitamin A: the retinoids (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 retinol, 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 A activity or certain carotenoids, such as carotene, that can be metabolized to vitamin A.

After ingestion, between 70 and 90% of preformed vitamin A is absorbed, whereas the absorption of carotenoids is less efficient and more variable, ranging from 20 to 50%. Retinyl esters are hydrolyzed, reesterified, and transported in chylomicrons to the liver. Carotenoids can be converted to retinol 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 retinol 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 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 Törmä 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 µg of all-trans retinol or 0.60 µg of all-trans β-carotene. The RE was adopted to account for the difference in the intestinal absorption of retinol and carotene. One RE is equal to 1 µg of all-trans retinol, and biologically, 1 RE is assumed to be equivalent to 6 µg of all-trans β-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.

Methods to assess deficiency include biologic measurements such as biochemical measurements of plasma retinol level or liver concentrations of vitamin A and functional tests such as correction of impaired dark adaptation.

Plasma retinol 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 retinol concentrations below 15 µg/dl (Hume and Krebs, 1949), and abnormal electroretinograms may be found at levels below 4 to 11 µg/dl (Sauberlich et al., 1974). Levels below 30 µg/dl have been associated with vitamin A-responsive anemia, and levels of 7 to 37 µg/dl, with follicular keratosis (Sauberlich et al., 1974). In Recommended Dietary Allowances (RDAs) it is recommended that nonpregnant adults maintain plasma retinol concentrations higher than 30 µg/dl in order to maintain body stores; levels less than 20 µg/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 because blood levels of RBP change with pregnancy (NRC, 1978). In research settings, liver stores of vitamin A have been used to assess vitamin A status—100 µg/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 retinol 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; Takahashi et al., 1975).

Recommended Intakes

Estimates of vitamin A intakes required to maintain desirable retinol levels have been somewhat variable, ranging from 500 to 1,200 RE/day (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; however, an excess of retinoids has also been of considerable concern, particularly regarding the possibility of teratogenicity (see review by Teratology Society, 1987). Isotretinoin, a synthetic relative of vitamin A (Accutane®, 13-cis-retinoic acid), has been reported to be teratogenic in animals and humans in the first trimester (Teratology Society, 1987). The typical phenotype 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 retinol or retinyl esters may result in a similar syndrome (Rosa et al., 1986; Stånge 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.

Usual Intake

Usual intakes of vitamin A by pregnant women are discussed in Chapter 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 A.

Recommendations for Supplementation

Since estimated dietary intake in the United States appears to be sufficient 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 countries 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 oxidation 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, manifested primarily by anemia (Oski and Barness, 1967), and in patients with prolonged, marked fat malabsorption, usually accompanied by neurologic 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.

Two classes of compounds, tocopherols and tocotrienols, include biologically active forms of vitamin E. Both classes are characterized chemically by a similar ring system, but they differ in the saturation of the side chain. The tocopherols (α-, β-, γ-, and δ-, which have a saturated side chain, are widely found in nature. α-Tocopherol is both the most active and the most prevalent biologic form.

Normal bile secretion and pancreatic function are required for intestinal 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 PUF As, with consequent damage to membranes and cells. Although vitamin E serves 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 (Horwitt 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 considerable interest in the care of newborns, particularly those born prematurely. Premature infants occasionally develop a hemolytic anemia, which is generally 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., 1987). 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 premature infants, such as bronchopulmonary 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., 1984; Wender et al., 1981; Zöberlein et al., 1982). Similarly, there is considerable 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 reviews by Karp and Robertson, 1986; Pereira and Barbosa, 1986; and Phelps, 1987). Attempts to treat diseases of preterm infants with intravenous vitamin 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., 1986).

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 (Ali 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 vitamin from balanced diets in the United States (NRC, 1989). Actual requirements have not been estimated because of methodologic difficulties. 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 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 mg. 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 absorption 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).

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 (Hamulyák 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. Vitamin 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-µg 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 phytonadione 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.

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 µg/day (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-depressing 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 retinol (preformed 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 retinol 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

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Copyright © 1990 by the National Academy of Sciences.
Bookshelf ID: NBK235251
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