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18 Water-Soluble Vitamins The subcommittee focused primarily on two water-soluble vitamins- vitamin B6 and folate, which have been associated most frequently with pregnancy complications and adverse outcomes. Furthermore, adequacy of dietary intakes of these vitamins relative to the Recommended Dietary Allowances (RDAs) by women of childbearing age is generally reported to be lower than that of other water-soluble vitamins. Thus, the subcommittee reviewed evidence regarding the importance of vitamin B6 and folate in pregnant women, the estimated need for these vitamins, and the usual dietary intakes as a basis for its recommendations on supplementation. The other water-soluble vitamins are generally considered to be consumed in adequate amounts from dietary sources and are, therefore, not an important issue with regard to routine supplementation. Thus, the literature pertaining to them is summarized only briefly. VITAMIN B6 Vitamin B6 is a collective term for six metabolically related pyridines, namely, pyridoxal, pyridoxamine, and pyridoxine and their phosphorylated derivatives (e.g., pyridoxal phosphate). These six forms of the vitamin constitute the B6 vitamers. 351

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352 DIETARY INTAKE AND NUTRIENT SUPP~F:MENTS Importance Almost 50 years ago, interest in the relationship of vitamin B6 to hu- man pregnancy originated with the empirical use of pharmacologic doses of pyridoxine in the treatment of hyperemesis gravidarum a condition of prolonged, severe nausea and vomiting during pregnancy (Willis et al., 1942~. The lack of firm scientific evidence of the efficacy of this treatment is discussed later in this chapter. Evidence has accumulated that vitamin B6 is required for protein, carbohydrate, and lipid metabolism as well as for erythrocyte, immune, and hormonal functions (see review by Lek- lem and Reynolds, 1988~. Pyridoxal phosphate (PLP), the physiologically active form of the vitamin, is a coenyme in over 100 known reactions involved primarily in amino acid metabolism. PLP-containing enzymes include aminotransferases, which are essential to the synthesis of nonessen- tial amino acids, and decarboxylases, which are needed in the formation of histamine, serotonin, dopamine, and y-aminobutyric acid. PLP is also a coenyme in the formation of aminolevulinic acid, the first step in the synthesis of heme compounds. These vitamin B6-dependent reactions are of obvious importance to the normal course and outcome of pregnancy. Estimated Requirements Even though the vitamin B6 intake and status of pregnant women have been widely studied, the requirements for this vitamin during pregnancy have not been clearly defined. It is known, however, that increased protein intake during pregnancy necessitates a modest increase in vitamin B6 intake (Table 18-1), because of the major role of the vitamin in amino acid metabolism (NRC, 1989~. Also, fetal uptake of vitamin B6, especially in late pregnancy, increases the need for the vitamin. All forms of vitamin B6, especially PLP, cross the placenta into fetal blood where concentrations are two to five times higher than those in maternal blood (Cleary et al., 1975; Contractor and Shane, 1970~. Furthermore, the normal elevation of estrogen levels during pregnancy has been reported to increase tryptophan oxygenase activity (Rose, 1978), which in turn increases the need for vitamin B6- ' A total body vitamin B6 content of approximately 60 mg and a daily turnover rate of approximately 3% have been found in healthy nonpregnant women (Shane and Contractor, 1980~. The vitamin B6 content of blood was estimated to be less than 0.5 mg of pyridoxine equivalents, i.e., the concentration of individual B6 vitamers calculated as pyridoxine. The amount of vitamin B6 in maternal and fetal tissues gained has not been determined, but presumably represents only a small part of the estimated increased need for vitamin B6 during pregnancy. The percentages of

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WATER-SOLUBLE VITAMINS TABLE 18-1 Recommended Dietary Allowances of Water-Soluble Vitamins for Nonpregnant and Pregnant Women and the Rationale for Increased Allowances During Pregnancya Recommended Dietary Allowance Nonpre~,nant Pregnant Rationale for Increased Vitamin Women Women Allowance for Pregnancy Vitamin C 60 mg 70 mg To provide for fetal needs; at term, fetal plasma levels are 50% higher than maternal levels Thiamin 1.1 mg 1.5 mg To accommodate maternal and fetal growth and increased energy allowance 353 Riboflavin 1.3 mg Niacin (NE)C 15 mg during pregnancy 1.6 mg To provide for increased maternal and fetal synthesis 17 mg Vitamin B6 1.6 mg 2.2 mg Folate Vitamin BE 2.0 ,ug l90,ug 400,ug 2.2 ,ug Based on energy increase of 300 kcal/day for pregnancy Based partially on the additional protein allowance of 10 g/day for pregnancy Based on So-so food folate absorption; to build or maintain maternal folate stores and to provide for increased folate turnover in rapidly growing tissue Fetal needs (0.1~.2 ,ug/day) based on analyses of stillborn fetuses; metabolic needs of pregnancy estimated at 0.2 ,ug/day a From NRC (1989~. b Based on highest value recommended for females between the ages of 15 and 50 years. c Niacin equivalent (NE) is equal to 1 mg of niacin or 60 mg of tryptophan. vitamin B6 absorbed and metabolized to PLP as well as the oxidation and excretion of the vitamin appear to be the same during pregnancy as they are in the nonpregnant state (Contractor and Shane, 1970~. Decreases in both blood levels of vitamin B6 and vitamin B6-dependent enzyme activity occur gradually during pregnancy. The most substantial decrease in plasma PLP levels is found between the fourth and eighth months of gestation, paralleling the period of most intensive growth of the

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354 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS fetus (Reinken and Dapunt, 1978~. The fetus appears to lack the ability to phospho~ylate pyridoxal and is dependent upon a maternal supply of PLP (Shane and Contractor, 1980~. Thus, placental transport of PLP from mother to fetus is one mechanism that clearly leads to lower levels of PLP in maternal plasma, sometimes called the biochemical deficiency of vitamin B6 of late pregnancy. Criteria for Status Assessment Overt clinical signs of vitamin B6 deficiency Cable 18-2) are rare in the United States. In the absence of established markers, assessment procedures rely almost entirely on biochemical tests, including direct mea- surements of B6 vitamers in blood or urine and indirect and functional tests to measure changes in PLP-dependent enzymes or activity coefficients (e.g., in vitro stimulation of enzyme activity by addition of PLP). Plasma PLP, which has been studied extensively, has been reported to be an indi- cator of vitamin B6 body stores, whereas pyridoxic acid has been said to reflect intake (Leklem and Reynolds, 1988; Shane and Contractor, 1980; van den Berg, 1988~. Concentrations of vitamin B6 and B6 vitamers in blood decrease with the normal increase in blood volume during mid- and late pregnancy. An important consideration is the stage of pregnancy during which the tests are administered because of changes in hormonal balance throughout gestation. Such changes can affect enzyme turnover, enzyme-coenzyme binding properties, and redistribution of the B6 vitamers in tissues. Knowl- edge about the effects of maternal homeostasis on the above-mentioned tests is limited (Shane and Contractor, 1980~. Studies of pregnant rats suggest that the pregnancy-induced changes in vitamin B6 status indicators probably reflect a higher retentive capacity and temporary deposition of vitamin B6 in tissues early in pregnancy as a result of hormone-induced changes (van den Berg and Bogaards, 1987~. There is a need to quantify the influence of these secondary effects upon the biochemical indices of vitamin B6 status in pregnant women and then to set reference standards. Studies have consistently shown that in comparison with nonpregnant controls, pregnant women have lower plasma levels of vitamin B6 and PLP (Creaky et al., 1975; Contractor and Shane, 1970; Hamfelt and ~- vemo, 1972; Lumeng et al., 1976; Reinken and Dapunt, 1978; Roepke and Kirksey, 1979a; Schuster et al., 1984), decreased e~ythrocyte alanine amino- transferase activity, and higher activity coefficients (Lumen" et al., 1976; Schuster et al., 1981), especially during late pregnancy. Other changes include decreased levels of vitamin B6 in leukocytes, eIythrocytes, and urine and increased production of tryptophan or methionine metabolites

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WATER-SOLUBLE VITAMINS 355 following a large oral test dose (2 to 5 g) of the amino acid (Sauberlich, 1978~. Abnormal results from a combination of two or more laboratory tests, e.g., decreased activity of vitamin B6-dependent enzymes coupled with high activity coefficients, are considered more indicative of vitamin B6 inadequacy than is one abnormal measurement. Usual Intakes As shown in Chapter 13, 1bble 13-2, dietary intakes of vitamin B6 by pregnant women in the United States have often been reported to be lower than the RDA (NRC, 1989~. Using 3-day diet records, Roepke and Kirksey (1979a) calculated the mean daily vitamin B6 intake of 97 middle-class U.S. women at 5 to 7 months of gestation to be 1.24 ~ 0.55 (standard deviation iSD]) ma. Reynolds et al. (1984) analyzed the dietary intakes of 36 upper- middle-class U.S. women at 37 weeks of pregnancy and found their mean vitamin B6 intake was 1.4 ~ 0.42 (SD*) mg per day. The ratio of dietary vitamin B6 to protein in these women was near the then recommended ratio for nonpregnant adults of 0.02 mg of vitamin B6 to 1 g of protein. The current recommended ratio is 0.016 mg to 1 g (NRC, 1989~. Among a group of 60 healthy pregnant Caucasian women, only three consumed 2.6 mg/day or more (dir et al., 1980~. The RDA at that time was 2.6 mg/day, compared with the current RDA of 2.2 mg/day (NRC, 1989~. No significant relationship was observed between their vitamin B6 status and the birth weights or anthropometric measurements of their neonates; however, the small sample size precluded definitive conclusions. In Florida, Schuster et al. (1981) reported that the mean daily vitamin B6 intake of disadvantaged pregnant women (mostly of black origin) was 1.4 it 1.0 (SD) ma, a level comparable to that reported for more economically advantaged women (Reynolds et al., 1984~. The mean erythrocyte alanine aminotransferase activation coefficient among the Floridian women was 1.35 (compared with a normal value of <1.25 for nonpregnant women). Many values were considered by the researchers to be suggestive of vitamin B6 inadequacy. In a subsequent study (Schuster et al., 1984) of 46 pregnant women from the same population, mean daily vitamin B6 intake was estimated to be 1.5 mg (0.019 mg/g of protein). Vitamin B6 Status and the Course and Outcome of Pregnancy Over the years, interest in the vitamin B6 status of pregnant women has been stimulated by such findings as lower PLP concentrations in the * Calculated from reported standard error of the mean.

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356 o Cal o ._ U. ._ Ct Ct Cal ._ ._ it: Cal A_ - Ct o ._ ._ Ad .s Ct .> - C~ en o U: Cal ._ - ._ au o ._ m ~ o _; ._ ~ a) C) . C) . o Cal o . . - Ct . A: - V, - e~ o . z ~0 C) . _ Ct .Q O . m .= ~ Ct . - O 5 ._ ~ C) ._ lo, ~ a O >~ =- m :' Cal Ct ~ U. ~ ._ ._ > o~ C-. ~ t '~ D con ) ct 5 C} ~ O Cal 3 ~ ~ Ct .^ Cal ') C o ~ =-o : .^ ~ E =- oc~ == o .~ ~ E o ~ ~ zo Ct > C~ ~o _ ~._ ,_, _ _ - ~ - ~X .E E .- E ~ Ct ~Ct ~V) - ~s~ .= .= .= E E C ~o ;> ~ C~ ~ ,,., o U: D c' Ct 3 - D C,: ~ X - U) ~ ~ ~ 3 s,= e~ ,) e . - ~ ^ ~ ~ ~ E C~ ^ ~ o X . ~ ~ U. ~ X Ct s~ Ct - o C~ ._ C~ o .= _ ~ C) - =: ~ C) o - ._ . - ~ ~ Ct Ct - ~ _ o Ct ~ - ,.4 ~o ~ . - c ~ct ) ~ o 'e o ~ ~ E ~ ~ ;^ ._ ._ o E_, o Ct o ~ o ~ .^ ~ ,, s ~ ~- _ C) ~ ~ ~ o ;^ Ct Ct c ._ o ._ 1 1 x . _ o D ._ .= O O ~: D ~ U) - o U: o ._ C) e~ C~ Ct ~ ._ cn - O ~ oc

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357 V: ~ ~U) i= . , _ , ~ ~ ~ ~ ~, ~ , ~ ~ ~ i> ~ -^ Ct 3 ,~ all ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ^ ~ ~ D cat ~ ~ O ~ ~ ~ O D D A, ,,,, C ~ C ~ C ~ C . ~J O ;- As - Ct C) Ct `_ Ct o o Z Ll) Z Z G ~ _ . O ~ C O ~ ~ U C - C ~ ~ 'a o ~ o ~_ ~ ~ ~ C ~ 3 ~ - ~ 3 ~ ~ ~ ~ ~ ~ 3 ~ ~ ~ ~. - ~ ~ C ~ ~o o . - ~ m m C: - ~. _ ._ ~ ~Ct Ct Ct Ct ~_ ~ z ;> ~i

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358 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS umbilical cord blood of preeclamptic mothers compared with those in women with normal pregnancies (Brophy and Siiteri, 1975~. However, Lu and colleagues (1981) failed to demonstrate any improvement in the course of toxemia following the administration of pyridoxine. Low levels of PLP in maternal plasma have been associated with low birth weight (Reinken and Dapunt, 1978), but this has not been uniformly confirmed (dir et al., 1980~. Positive associations between vitamin B6 status and the course and outcomes of pregnancy have been reported, but results of these studies are controversial, because no placebos were used and the subjects were not randomized or blinded. For example, early studies of pregnant women (Dorsey, 1949; Weinstein et al., 1944; Willis et al., 1942) in which pyri- doxine doses of 5 to 100 mg/day were claimed to be effective in treating nausea and vomiting were not controlled; therefore, a placebo effect cannot be ruled out. In a study (Hesseltine, 1946) that included a placebo but that was not randomized or blinded, both pyridoxine and placebo were found to control nausea. The American Medical Association Council on Drugs (1979) has stated that there is no scientific evidence that vitamin B6 is effective in the treatment of nausea. This viewpoint is supported by a recent review of the safety and efficacy of antiemetics in the treatment of nausea during pregnancy (Leathem, 1986~. Associations of vitamin B6 inadequacy with gestational diabetes (Spellacy et al., 1977) and with "preg- nancy depression"-described as pessimism, crying, tension without sleep, or appetite disorders (Pulkkinen et al., 1978) have also been challenged on methodologic grounds. The active transport of vitamin B6 from maternal to fetal blood against a concentration gradient in the placenta lessens the effects of maternal vitamin B6 inadequacy on the newborn, but it also could result in abnormally high levels in the fetus if pregnant women are given enough supplemental pyridoxine to increase their plasma PLP levels to those of nonpregnant women. Shane and Contractor (1975) postulated that this could adversely affect the synthesis of PLP-dependent enzymes by the fetus and might lead to a higher than normal vitamin B6 requirement by the infant. However, this hypothesis has not been confirmed or refuted experimentally. Three reports (Roepke and Kirksey, 1979a; Schuster et al., 1981, 1984) have related low vitamin B6 intakes and low plasma levels as well as low PLP levels at delivery to unsatisfactory Apgar scores of newborns. These scores are based on heart rate, respiratory effort, muscle tone, reflex irritability, and color at 1 and 5 minutes after delivery (Apgar and James, 1962; Apgar et al., 1958), all of which can be influenced by many variables. Maternal pyridoxine supplementation was associated with improved Apgar scores taken at 1 minute; however, statistically significant improvements

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WATER-SOLUBLE VITAMINS 359 TABLE 18-3 Doses of Water-Soluble Vitamins Associated with Acute or Chronic Toxicity in Otherwise Healthy Pregnant and Nonpregnant Humans Doses Associated with Toxicity Vitamin Human Pregnancy Other Human Studies Vitamin C 25~500 mg/daya >3 g/day for several mo (Hanck, 1982) Niacin NRb >3 g/day for 5-6 mo (Robie, 1967) Vitamin B6 50 mg/dayC >500 mg/day for >1 mo (Cohen and Bendich, 1986) 2 g/day for 4 mo (Schaumburg et al., 1983) Folate NRb 15 mg/day for 1 mod (Hunter et al., 1970) a Based on three isolated cases; 250 to 500 mg/day taken for 2 weeks in late pregnancy in one case (Mentzer and Collier, 1975) and 400 mg/day during pregnancy in two cases (Coch rane, 1965~. b NR = Not reported. c Based on one isolated case; dose given three to four times weekly for nausea in mid pr~e~nancy (Hunt et al., 1954~. The findings from this one uncontrolled experiment with 14 adult volunteers by Hunter et al. (1970) were later refuted in research by Hellstrom (1971~. were not observed in 5-minute scores, which may be more indicative of long-term infant health problems (Schuster et al., 1984~. Since most pregnant women in the United States now consume multivitamin-mineral preparations containing vitamin Be, it is usually not possible to conduct observational studies of relationships between dietary intake of vitamin B6 and the course and outcome of pregnancy. Toxicity There are few data on the safety of pyridoxine supplementation during human pregnancy. Oral doses of pyridoxine greater than 500 mg/day for prolonged periods can result in the development of sensory neuropathy in nonpregnant adults (Cohen and Bendich, 1986) (1bble 18-3~. In the same review of the safety of pyridoxine, no toxic effects were reported for adults given 500 mg/day or less under medical supervision for periods ranging from 6 months to 6 years. The suggestion that excessive vitamin Be intake during pregnancy produces a vitamin B6-dependengy state in the newborn is based on one isolated case (Hunt et al., 1954~. A woman treated with 50 mg of pyridoxine

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360 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS hydrochloride three or four times weekly for nausea during midpregnancy gave birth to an infant who had repeated convulsive seizures that re- sponded to pyridoxine administration. The outcome was normal in an earlier pregnancy, during which the woman had not been given large doses of pyridoxine. Although pyridoxine-responsive convulsive disorders are oc- casionally observed in newborns, no reports have confirmed an association between them and maternal pyridoxine intake. Vitamin B6 dependency appears to reflect an inborn error in metabolism rather than an acquired dependency state (Pitkin, 1982~. Recommendations for Supplementation Most clinical trials of routine pyridoxine supplementation of pregnant women have failed to demonstrate any differences in pregnancy outcome, thereby casting doubt on the benefits of vitamin B6 supplements. In a double-blind study, Schuster et al. (1984) found that a daily pyridoxine intake of 5.5 to 7.6 mg during pregnancy was required to avoid a decrease in plasma PLP levels at delivery. Without supplemental pyridoxine, mean levels decreased approximately 30% by 30 weeks of gestation and 25% at delivery over initial values. Lumeng et al. (1976) reported that pyridoxine intakes between 4 and 10 mg/day were needed to maintain plasma PLP at levels similar to those in the first trimester of pregnancy. Since physiologic changes during pregnancy may have accounted for the lower PLP levels, it is questionable whether pyridoxine supplementation should be used to produce levels similar to those in the nonpregnant state. Furthermore, the 4- to 10-mg/day doses of pyridoxine reported to maintain prepregnancy vitamin B6 status during pregnancy exceed the amount obtainable from food. For women at high risk for inadequate nutrient intake, e.g., substance abusers, pregnant adolescents, and women bearing multiple fetuses, the subcommittee recommends a daily multivitamin supplement containing 2 mg of vitamin B6. This level is slightly less than the current RDA of 2.2 mg during pregnancy (NRC, 1989~. Long-term use (>30 months) of oral contraceptives containing high levels of estrogen (e.g., 100 g of mestranol or ethinyl estradiol) was associ- ated with significantly lower maternal and umbilical cord serum vitamin B6 levels than those in women who took no oral contraceptives, and evidence indicates that their vitamin B6 reserves may be decreased in early pregnancy (Roepke and Kirksey, 1979b). Donald and Bosse (1979), Leklem (1986), and Leklem et al. (1975) concluded that oral contraceptive use, for short periods, does not significantly increase the need for vitamin B6. Concern has been expressed about women who routinely take oral contraceptives for several years to postpone their pregnancies (Miller, 1986~. However,

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WATER-SOLUBLE VITAMINS 361 no data are available regarding the vitamin Be status of women taking the currently available oral contraceptives with low doses of estrogens (20 to 35 midday). FOLATE Folate is a generic descriptor of a group of compounds with chemical structures and nutritional properties similar to those of folio acid (pteroyl- glutamic acid). Importance In India, more than 50 years ago, Wills (1931) successfully treated macrocytic anemia in pregnant women with yeast extract; the active sub- stance was later identified as folate. The etiologic role of folate deficiency in megaloblastic anemia of pregnancy and the efficacy of folate therapy in the treatment of this disease are now well established. The fundamental roles of folate in cell replication and metabolism continue to be active areas of investigation. Folates function in intermediary metabolism as coenzymes in the trans- fer of single carbon units (formyl, methyl, and formimino) from one com- pound to another. This step is vital to many metabolic processes, including the metabolism of several amino acids and the synthesis of purine and thymidylate compounds essential to nucleic acid synthesis. In light of these fundamental roles of folate, a deficiency of this vitamin in the early weeks of pregnancy might be expected to impair cell growth and replication and to result in anomalies in the fetus and placenta, leading to subsequent spontaneous abortion, fetal malformation, or small-for-gestational-age in- fants (Hibbard, 1975~. However, scientific evidence for these associations . . . IS 1nconc uslve. Folate Status and the Course and Outcomes of Pregnancy Inconsistent results have been obtained in clinical studies to determine the association of mild to moderate folate deficiencies with spontaneous abortion, preterm delivery, fetal malformations, and low birth weight. This is due in part to imprecise definitions of folate status as well as methodologic weaknesses in some of the studies in which no placebos were used and subjects were not randomized or blinded. Some investigators (Hibbard, 1975; Iyengar and Rajalakshmi, 1975) have reported a high incidence of obstetric complications such as spontaneous abortions, toxemia, preterm

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WATER-SOLUBLE VITAMINS 369 adults, megadoses of vitamin C (>3 g/day) have occasionally resulted in stomach cramps, nausea, and diarrhea, particularly when ingested under fasting conditions, and in allergic skin rash and a few isolated cases of intestinal and urinary lithiasis (Smith, 1978~. Large doses of vitamin C may also contribute to false results in some clinical tests (e.g., false-positive results for urinary glucose) and may alter the potencies of certain drugs (Briggs, 1978; Flodin, 1988; Houston and Levy, 1975; Ovesen, 1979~. The frequency of reported toxic manifestations of megadoses of vitamin C ('Ibble 18-3) is low relative to the number of persons who routinely ingest large amounts of the vitamin (Rivers, 1987~. Because the vitamin is actively transported from placental to fetal blood, megadoses taken during pregnancy could lead to markedly elevated ascorbate levels in the fetus and a potential for adverse effects. Vitamin C dependency is purported to result from megadoses of vi- tamin C consumed over time, but has not been confirmed experimentally (Hornig and Moser, 1981~. This condition has been described (Alhadeff et al., 1984; Rhead and Schrauzer, 1971) as occurring in individuals who become adapted over time to megadoses of vitamin C by an increased rate of metabolism and excretion; then, following an abrupt lowering of vitamin C intake, they develop signs of deficiency. Concern that fetal vitamin C dependency can be induced in utero by excessive intakes of the vitamin during pregnancy is based on only one anecdotal report (Cochrane, 1965~. Two infants, whose mothers were reported to be supplemented with 400 mg of ascorbic acid daily during pregnancy, developed scurvy during the first few weeks postnatally. However, this was observed in a region of Canada where infantile scurvy was relatively frequent. There is no clear evidence that the scorbutic findings were related to excessive maternal intake of vitamin C. Other Considerations Some subpopulations follow practices that increase their need for, or result in low dietary intake of, vitamin C. These include users of street drugs and cigarettes (see Chapter 20), heavy users of alcohol, long-term users of oral contraceptives (Irwin and Hutchins, 1976), and regular users of aspirin and salicylates (Flodin, 1988~. Women bearing more than one fetus (e.g., twins or triplets) may also require somewhat higher amounts of vitamin C. For women at risk of deficiency, an ascorbic acid supplement of 50 mg/day is recommended if increased consumption of fruits and vegetables is unlikely. Heavy smokers (>20 cigarettes/day) need perhaps twice as much vita- min C as nonsmokers to maintain a similar body pool of vitamin C (Kallner et al., 1981~. Smokers have decreased plasma ascorbate levels, which are

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370 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS associated with an increased rate of vitamin C metabolism rather than with changes in absorption or urinary excretion. Thiamin, Riboflavin, and Niacin Importance and Estimated Requirements Among the B-complex vitamins, thiamin, riboflavin, and niacin func- tion primarily in the release of energy in cells. Thiamin as thiamin py- rophosphate is essential to key reactions in energy metabolism, especially carbohydrate metabolism. Riboflavin functions primarily as a component of flavin mononucleotide and flavin adenine dinucleotide, both of which cat- alyze oxidation-reduction reactions. Niacin is a collective term for nicotinic acid, nicotinamide, and niacinamide. Nicotinamide functions as a compo- nent of two important coenzymes, nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Niacin is present in all cells and participates in several metabolic processes, including glycolysis, fatty acid metabolism, and tissue respiration. Because of this involvement of thiamin, riboflavin, and niacin in energy metabolism, these vitamins are needed during pregnancy in amounts proportional to the increased en- ergy requirements (Table 18-1~. Niacin intake is usually reported in niacin equivalents, since some of the amino acid tryptophan is converted to niacin in vivo. A niacin equivalent is equal to 1 mg of niacin or 60 mg of trypto- phan. Pregnant women have been reported to have an enhanced capacity to convert tryptophan to niacin (Wertz et al., 1958), which could lessen the need for increased dietary niacin during pregnancy. In animal experiments, severe deficiencies of thiamin, riboflavin, or niacin result in fetal death, low birth weight, and congenital defects. However, no analogous findings in humans have been demonstrated. Assessment Methodology Laboratory indicators of thiamin, riboflavin, and niacin status are given in Table 18-2 (see the review by Sauberlich, 19784. The most widely used procedures for assessing thiamin nutritional status are measurements of uri- nary thiamin levels, of erythrocyte transketolase activity and its stimulation by thiamin pyrophosphate added in vitro, and of erythrocyte glutathione reductase activity. The latter measurement is simple and reproducible and requires only a small sample of blood. Measurement of two major metabo- lites of niacin in urine, Ni-methylaicotinamide and Ni-methyl-2-pyridone- 5-carboxylamide (2-pyridone), has been the usual means of assessing niacin status. Although the ratio of 2-pyridone to Ni-methylnicotinamide appears to be the most practical index of niacin status, its reliability and usefulness in pregnant women is not fully established (Sauberlich, 1978~.

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WATER-SOLUBLE VITAMINS 371 There is a steady decrease in urinary riboflavin excretion during preg- nancy and a progressive increase to 20% in the activation of erythropyte glutathione reductase following in vitro incubation with the vitamin (Heller et al., 1974~. When compared with nonpregnant norms, these findings indicate riboflavin inadequacy. However, the findings were not associated with adverse effects on the course or outcomes of pregnancy. Usual Intake CSFII (USDA, 1987) showed that adult women consumed 116% of the 1.2-mg RDA for riboflavin (NRC, 1989~. In the same survey, preformed niacin in diets consumed by women aged 19 to 50 averaged 16 mg/day and calculated niacin equivalents (NE) were 27 mg/day, both of which exceeded the 1980 RDA of 13 NE (NRC, 1980~. The 1989 RDA is 15 NE (NRC, 1989~. Enriched and fortified grains, cereals, and bakery products contribute substantial amounts of thiamin, riboflavin, and niacin to the U.S. diet (Cook and Welsh, 1987~. The data in Chapter 13, Table 13-2, also suggest that the usual intake of these nutrients is adequate. Dosage Range and Toxicity In nonpregnant humans, no toxic effects have been reported for thi- amin, riboflavin, and niacin following long-term high-dose (100 to 200 mg/day) oral supplements of the vitamins, except for some gastric upset. No cases of riboflavin toxicity in humans have been reported, perhaps be- cause the gastrointestinal tract has a limited capacity to absorb riboflavin (McCormick, 1988~. Nicotinic acid is not toxic at physiologic levels, but pharmacologic doses of 3 to 9 "'day result in vasodilation (flushing), various metabolic effects, and gastrointestinal problems (Hankes, 1984~. Nicotin- amide is generally well tolerated (Flodin, 1988~. Vitamin BE Vitamin BE is a group of cobalamins, i.e., cobalt-containing corrinoids with a tetrapyrrole structure resembling that of iron porphyrins. The pre- dominant forms of the vitamin in plasma and tissues are methylcobalamin, adenosylcobalamin, and hydroxycobalamin. Cyanocobalamin is present in very small amounts in the body. Since it is the most stable form, it is used in vitamin supplements. Both cobalamin and folate function in the transport of single carbon atoms in reactions that are necessary for the synthesis of nucleic acids and the metabolism of certain amino acids. Thus, normal cell division and protein synthesis during pregnancy are dependent upon an adequacy of both vitamins.

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372 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Vitamin B12 is supplied by animal protein foods, including meat, fish, eggs, and milk. The needs of pregnancy can be easily met by body stores or by diets that provide modest amounts of animal protein foods. Vegetarian diets that include eggs, milk, and cheese provide adequate vitamin BY for pregnancy needs (Immerman, 1981~. Since a healthy fetus is estimated to contain about 50 fig of vitamin Bit, compared with maternal stores of approximately 3,000 fig, the drain on maternal stores for vitamin B,2 is usually slight (Immerman, 1981~. The 1989 RDA of 2.2 Friday during pregnancy (Bible 18-1) is based on estimates of fetal needs of 0.1 to 0.2 ,ug/day and increased metabolism during pregnancy (NRC, 1989~. An effective enterohepatic circulation recycles vitamin B:2 from bile and other intestinal secretions, accounting for its long biologic half-life. Clinical deficiency of vitamin BY is usually secondary to abnormalities of gastrointestinal function. Deficiency caused by diet is very rare but is occasionally observed in adult vegans- complete vegetarians who have followed an egg- and milk-free vegetarian diet for many years. If these individuals had previously consumed animal foods, their accumulated liver stores could protect them for several years (Immerman, 1981~. In a few isolated cases, infants born to mothers who were complete vegetarians have manifested signs of vitamin B:2 deficiency during the first few months of life (Higginbottom et al., 1978; Sklar, 1986~. In view of these findings, the subcommittee recommends a daily vitamin B:2 supplement of 2.0 ,ug for complete vegetarians. Neither oral nor injectable cyanocobalamin has been found to be toxic to nonpregnant adults when administered in quantities several thousand times the daily requirement (LSRO, 1978), but the effects of excessive vitamin B:2 intake on the fetus have not been investigated. Pantothenic Acid Pantothenic acid is present in all living cells, mostly in the form of coen- zyme A an essential cofactor in the transfer of acetyl groups. A second active form of the vitamin is acyl carrier protein a component of fatty acid synthetase complex. The vitamin is widely distributed in foods, especially in meats, whole-grain cereals, nuts, and legumes. Synthesis of pantothenic acid by intestinal bacteria possibly supplements the dietary intake of this vitamin. Spontaneous deficiency of pantothenic acid has not been observed in humans, except in cases of extreme malnutrition. Experimentally induced deficiency symptoms are intermittent diarrhea, insomnia, leg cramps, and paresthesias. Song et al. (1985) suggest that pregnant women need greater amounts of pantothenate than do nonpregnant women to maintain plasma levels and that such amounts are obtainable from food. Pantothenic acid toxicity in humans has not been reported. Occasional diarrhea is the only

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WATER-SOLUBLE VITAMINS 373 side effect reported to result from daily calcium pantothenate doses of 10 to 20 mg (Fox, 1984~. Biotin Biotin is a sulfur-containing vitamin and a coenzyme for several impor- tant carbo~ylation reactions. Because it is synthesized by intestinal bacteria, spontaneous deficient y has not been observed in humans. A deficiency was produced experimentally in nonpregnant humans by feeding them large amounts of raw egg whites, which contain avidin a biotin-binding protein. Symptoms of deficiency include seborrheic dermatitis, anorexia, muscle pain, and alopecia. Since biotin is widely distributed in food, needs are easily met by diet. Microflora synthesis also contributes to the biotin re- quirement. Blood levels of biotin fall progressively during pregnancy, but this has not been associated with adverse outcomes (Bonjour, 1984~. No toxic effects of biotin were observed in nonpregnant humans following oral doses as high as 10 to 40 mg/day in the treatment of carbo2ylase deficiencies (Packman et al., 1981, 1985), but studies of toxicity during pregnancy have not been reported. CLINICAL IMPLICATIONS Data do not provide a firm basis for recommending routine sup- plementation of the general U.S. population of pregnant women with water-soluble vitamins. Laboratory tests for assessment of water-soluble vitamin status are not sufficiently precise or practical to be recommended for routine prenatal care. When dietary sources are inadequate, daily supplementation with 300 fig of folate, 2 mg of vitamin Be, and 50 mg of vitamin C is recom- mended. For complete vegetarians, a daily vitamin B:2 supplement of 2.0 fig is recommended. Special attention should be given to improving the diet of and administering supplements to pregnant adolescents, women bearing more than one fetus, users of cigarettes or street drugs, heavy users of alcohol, and pregnant women at nutritional risk because of poor nutritional knowledge or insufficient financial resources to purchase adequate food. Supplemental water-soluble vitamins exceeding the RDA should be avoided during pregnancy, since evidence of their therapeutic efficacy is inconclusive and there is a potential risk for detrimental nutrient-nutrient interactions and for toxicity, especially to the fetus.

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374 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS REFERENCES Alhadeff, L, C.T. Gualtieri, and M. Lipton. 1984. Toxic effects of water-soluble vitamins. Nutr. Rev. 42:3340. American Medical Association Council on Drugs. 1979. American Medical Association Drug Evaluations, 4th ed. Publishing Sciences, Littleton, Mass. 417 pp. Anderson, S.A., and J.M. Talbot. 1981. IV. Folate status in the North American population. Pp. 11-25 in A Review of Folate Intake, Methodology, and Status. Life Sciences Research Office, Federation of American Societies for Experimental Biology, Rockville, Md. Apgar, V., and L.S. James. 1962. Further observations on the newborn scoring system. Am. J. Dis. Child. 104:419-428. Apgar, V., D.A. Holaday, L.S. James, I.M. Weisbrot, and C. Berrien. 1958. Evaluation of the newborn infant second report. J. Am. Med. Assoc. 168:1985-1988. Bailey, LB., C.S. Mahan, and D. Dimperio. 1980. Folacin and iron status in low-income pregnant adolescents and mature women. Am. J. Clin. Nutr. 33:1997-2001. Barnes, MJ. 1975. Function of ascorbic acid in collagen metabolism. Ann. N.Y. Acad. Sci. 258:264-277. Bates, As., NJ. Fuller, and A.M. Prentice. 1986. Folate status during pregnancy and lactation in a West African rural community. Hum. Nutr.: Clin. Nutr. 40C:3-13. Baumslag, N., T. Edelstein, and J. Metz. 1970. Reduction of incidence of prematurity by folic acid supplementation in pregnancy. Br. Med. J. 1:16-17. Bonjour, J.P. 1984. Biotin. Pp. 403-435 in L^J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects. Marcel Dekker, New York. Bnggs, M.H. 1978. Effect of specific nutrient toxicities in animals and man: vitamin C. Pp. 65-70 in M. Rechcigl, Jr., ed. CRC Handbook Series in Nutrition and Food. Section E: Nutritional Disorders, Vol. I. Effect of Nutrient Excesses and Toxicities in Animals and Man. CRC Press, West Palm Beach, Fla. Briggs, M. 1984. Vitamin C and infectious disease: a review of the literature and the results of a randomized, double-blind, prospective study over 8 years. Pp. 39-81 in M.H. Briggs, ed. Recent Vitamin Research. CRC Press, Boca Raton, Fla. Brophy, M.H., and P.K. Siiteri. 1975. Pyridoxal phosphate and hypertensive disorders of pregnan~. Am. J. Obstet. Gynecol. 121:1075-1079. Bruinse, H.W., H. van den Berg, and A.A. Haspels. 1985. Maternal serum folacin levels during and after normal pregnancy. Eur. J. Obstet., Gynecol. Reprod. Biol. 20:153-158. Butterworth, C E., Jr., R. Santini, Jr., and W.B. Frommeyer, Jr. 1963. The pteroylglutamate components of American diets as determined ~y chromatographic fractionation. J. Clin. Invest. 42:1929-1939. Chanarin, I. 1979. Distribution of folate deficiency. Pp. 7-10 in M.I. Botez and E.H. Reynolds, eds. Folic Acid in Neurology, Psychiatry, and Internal Medicine. Raven Press, New York. Chanarin, I. 1985. Folate and cobalamin. Clin. Haematol. 14:629-641. Chanarin, I., and J. Per~y. 1977. Mechanisms in the production of megaloblastic anemia. Pp. 15~168 in Folic Acid: Biochemist~ and Physiology in Relation to the Human Nutrition Requirement. Proceedings of a Workshop on Human Folate Requirements. Report of the Food and Nutrition Board. National Academy of Sciences, Washington, D.C. Chandler, C.J., T.T.Y. Wang, and C.H. Halsted. 1986. Pteroylpolyglutamate hydrolase from human jejunal brush borders. J. Biol. Chem. 261:928-933. Clea~, R.E., L~ Lumeng, and T.K Li. 1975. Maternal and fetal plasma levels of pyridoxal phosphate at term: adequacy of vitamin B6 supplementation during pregnancy. Am. J. Obstet. Gynecol. 121:25-28. Cochrane, W.A. 1965. Overnutrition in prenatal and neonatal life: a problem? Can. Med. Assoc. J. 93:893-899. Cohen, M. and ~ Bendich. 1986. Safety of pyridoxine a review of human and animal studies. Toxicol. Lett. 34:129-139.

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WATER-SOLUBLE VITAMINS 375 Colman, N., J.V. Larsen, M. Barker, E.A. Barker, R. Green, and J. Metz. 1975. Prevention of folate deficiency by food fortification. III. Effect in pregnant subjects of varying amounts of added folic acid. Am. J. Clin. Nutr. 28:465-470. Contractor, S.F., and B. Shane. 1970. Blood and urine levels of vitamin B6 in the mother and fetus before and after loading of mother with vitamin B6. Am. J. Obstet. Gynecol. 107:635-640. Cook, J.D., and E.R. Monsen. 1977. Vitamin C, the common cold, and iron absorption. Am. J. Clin. Nutr. 30:235-241. Cook, D.A., and S.O. Welsh. 1987. The effect of enriched and fortified grain products on nutrient intake. Cereal Foods World 32:191-196. Donald, E.A., and T.R. Bosse. 1979. The vitamin B6 requirement in oral contraceptive users. II. Assessment by tryptophan metabolites, vitamin B6, and pyridoxic acid levels in urine. Am. J. Clin. Nutr. 32:1024-1032. Dorsey, C.W. 1949. The use of pyridoxine and suprarenal cortex combined in the treatment of the nausea and vomiting of pregnancy. Am. J. Obstet. Gynecol. 58:1073-1078. Ek, J. 1980. Plasma and red cell folate values in newborn infants and their mothers in relation to gestational age. J. Pediatr. 97:288-292. Fleming, A.F. 1972. Urinary excretion of folate in pregnancy. J. Obstet. Gynaecol. Br. Commonw. 79.916-920. Flodin, N.W. 1988. Pharmacology of Micronutrients. Current Topics in Nutrition and Disease, Vol. 20. Alan R. Liss, New York. 340 pp. Fox, H.M. 1984. Pantothenic acid. Pp. 437~57 in L.J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical, and Clinical Aspects. Marcel Dekker, New York. Gailani, S.D., R.W. Carey, J.F. Holland, and J.A. O'Malley. 1970. Studies of folate deficiency in patients with neoplastic diseases. Cancer Res. 30:327-333. Ghishan, F.K, H.M. Said, P.C. W~lson, J.E. Murrell, and H.L. Greene. 1986. Intestinal transport of zinc and folic acid: a mutual inhibitory effect. Am. J. Clin. Nutr. 43:258-262. Giles, C. 1966. An account of 335 cases of megaloblastic anaemia of pregnancy and the puerperium. J. Clin. Pathol. 19:1-11. Giles, C., and E.M. Shuttleworth. 1958. Megaloblastic anaemia of pregnancy and the puerperium. Lancet 2 1341-1347. Goetsch, ~ 1962. An evaluation of aminopterin as an abortifacient. Am. J. Obstet. Gynecol. 83:1474-1477. Halsted, CH. 1979. The intestinal absorption of folates. Am. J. Clin. Nutr. 32:846-855. Halsted, C.H., W.H. Beer, CJ. Chandler, K. Ross, B.M. Wolfe, ~ Bailey, and JJ. Cerda. 1986. Clinical studies of intestinal folate conjugates. J. Lab. Clin. Med. 107:228-232. Hamfelt, A., and T. Il~vemo. 1972. Pyridoxal phosphate and folic acid concentration in blood and erythrocyte aspartate aminotransferase activity during pregnancy. Clin. Chim. Acta 41:287-298. Hanck, A. 1982. Tolerance and effects of high doses of ascorbic acid. Dosis facit venenum. Int. J. Vit. Nutr. Res., Suppl. 23:221-238. Hankes, L^V. 1984. Nicotinic acid and nicotinamide. Pp. 329-377 in L.J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical, and Clinical Aspects. Marcel Dekker, New York. Hansen, H., and G. Rybo. 1967. Folic acid dosage in profylactic treatment during pregnancy. Acta Obstet. Gynecol. Scand., Suppl. 7:107-112. Heller, S., R.M. Salkeld, and W.F. Korner. 1974. Riboflavin status in pregnancy. Am. J. Clin. Nutr. 27:1225-1230. Hellstrom, L~ 1971. Lack of toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1:59-61. Herbert, V. 1962. Experimental nutritional folate deficiency in man. Trans. Assoc. Am. Physicians 75:307-320. Herbert, V., N. Colman, M. Spivack, E. Ocasio, V. Ghanta, K Kimmel, L~ Brenner, J. Freundlich, and J. Scott. 1975. Folic acid deficiency in the United States: folate assays in a prenatal clinic. Am. J. Obstet. Gynecol. 123:175-179.

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376 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Hesseltine, H.C 1946. Pyridox~ne failure in nausea and vomiting of pregnancy. Am. J. Obstet. Gynecol. 51:82-86. Hibbard, B.M. 1975. Folates and the fetus. S. Afr. Med. J. 49:1223-1226. Higginbottom, M.C., L. Sweetman, and W.L Nyhan. 1978. A syndrome of methylmalonic aeiduria, homooystinuria, megaloblastic anemia and necrologic abnormalities in a vitamin B:2-defieient breast-fed infant of a strict vegetarian. N. Engl. J. Med. 299:317-323. Hoppner, K., and B. Lampi. 1980. Folate levels in human liver from autopsies in Canada. Am. J. Clin. Nutr. 33:862-864. Hornig, D.H., and U. Moser. 1981. The safety of high vitamin C intakes in man. Pp. 225-248 in J.N. Counsell and D.H. Hornig, eds. Vitamin C (Ascorbic Acid). Applied Science Publishers, London. Houston, J.B., and G. Levy. 1975. Modification of drug biotransformation by vitamin C in man. Nature 255:78-79. Huber, A.M., LL. Wallins, and P. DeRusso. 1988. Folate nutriture in pregnancy. J. Am. Diet. Assoe. 88:791-795. Hunt, A.D., Jr., J. Stokes, Jr., W.W. MeCrory, and H.H. Stroud. 1954. Pyridoxine dependency: report of a ease of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 13:140-145. Hunter, R., J. Barnes, H.F. Oakeley, and D.M. Matthews. 1970. Toxicity of folio acid given in pharmacological doses to healthy volunteers. Laneet 1:61-63. Immerman, A.M. 1981. Vitamin B12 status on a vegetarian diet. World Rev. Nutr. Diet. 37:38-54. Irwin, M.I., and B.K Hutchins. 1976. A conspectus of research on vitamin C requirements of man. J. Nutr. 106:821-880. Iyengar, L., and S. Babu. 1975. Folie acid absorption in pregnancy. Br. J. Obstet. Gynaeeol. 82:20-23. Iyengar, L., and K Rajalakshmi. 1975. Effect of folio acid supplement on birth weights of infants. Am. J. Obstet. Gyneeol. 122:332-336. Jacob, R.A., J.H. Skala, and S.T. Omaye. 1987. Biochemical indices of human vitamin C status. Am. J. Clin. Nutr. 46:818-826. Jaffe, G.M. 1984. Vitamin C. Pp. 199-244 in LJ. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical, and Clinical Aspects. Marcel Dekker, New York. Kallner, A.B., D. Hartmann, and D.H. Hornig. 1981. On the requirements of ascorbic acid in man: steady-state turnover and body pool in smokers. Am. J. Clin. Nutr. 34:1347-1355. Khattab, AK., S.^ Al Nagdy, K.A H. Mourad, and H.I. El Azghal. 1970. Foetal maternal ascorbic acid gradient in normal Egyptian subjects. J. Trop. Pediatr. 16:112-115. Landon, M.J., and F.E. Hytten. 1971. The excretion of folate in pregnancy. Br. J. Obstet. Gynaeeol. Br. Commonw. 78:769-775. Leathem, A.M. 1986. Safety and efficacy of antiemetics used to treat nausea and vomiting in pregnancy. Clin. Pharmacol. 5:660-668. Leklem, J.E. 1986. Vitamin Be requirement and oral contraceptive use a concern? J. Nutr. 116:475-477. Leklem, J.E., and R.D. Reynolds. 1988. Challenges and directions in the search for clinical applications of vitamin B6. Pp. 437-454 in J.E. Leklem and R.D. Reynolds, eds. Current Topics in Nutrition and Disease, Vol. 19. Clinical and Physiological Applications of Vitamin Be. Alan R. Liss, New York. Leklem, J.E., R.R. Brown, D.P. Rose, H. Linkswiler, and R.A. Arend. 1975. Metabolism of tryptophan and niacin in oral contraceptive users receiving controlled intakes of vitamin B6. Am. J. Clin. Nutr. 28:146-156. Letsky, E.A. 1985. Folie acid in pregnancy. Farm. Terap. 2:147-152. LSRO (Life Sciences Research Offiee). 1978. Evaluation of the Health Aspects of Vitamin B12 as a Food Ingredient. Federation of American Societies for Experimental Biology, Bethesda, Md. 26 pp.

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WATER-SOLUBLE VITAMINS 377 LSRO (Life Sciences Research Office). 1984. Assessment of the Folate Nutritional Status of the U.S. Population Based on Data Collected in the Second National Health and Nutrition Examination Survey, 1976-1980. Federation of American Societies for Experimental Biology, Bethesda, Md. 96 pp. Lu, J.Y., D.L. Cook, J.B. Javia, Z.A. Kirmani, C.C. Liu, D.N. Makadia, TA. Makadam, O.B. Omasayie, D.P. Patel, V.J. Reddy, B.W. Walker, C.S. Williams, and R.A. Chung. 1981. Intakes of vitamins and minerals by pregnant women with selected clinical symptoms. J. Am. Diet. Assoc. 78:477-482. Lumeng, L., R.E. Cleary, R. Wagner, P.L. Yu, and T.K. Li. 1976. Adequapy of vitamin B6 supplementation during pregnancy: a prospective study. Am. J. Clin. Nutr. 29:1376-1383. McCormick, D.B. 1988. Riboflavin. Pp. 362-369 in M.E. Shils and V.R. Young, eds. Modern Nutntion in Health and Disease, 7th ed. Lea & Febiger, Philadelphia. McDowell, A., ~ Engel, J.T. Massey, and K. Maurer. 1981. Plan and Operation of __ 7 _ _, the Second National Health and Nutrition Examination Survey, 1976-80. Vital and Health Statistics, Series 1, No. 15. DHHS Publ. No. (PHS) 81-1317. National Center for Health Statistics, Public Health Service, U.S. Department of Health and Human SeIvices, Hyattsville, Md. 144 pp. Mentzer, W.C., Jr., and E. Collier. 1975. Hydrops fetalis associated with erythrocyte G-6-PD deficiengy and maternal ingestion of fava beans and ascorbic acid. J. Pediatr. 86:565-567. Miller, L.T. 1986. Do oral contraceptive agents affect nutrient requirements-vitamin B6? J. Nutr. 116:1344-1345. NRC (National Research Council). 1980. Recommended Dietary Allowances, 9th ed. Report of the Committee on Dietary Allowances, Food and Nutrition Board, Division of Biological Sciences, Assembly of Life Sciences. National Academy Press, Washington, D.C. 185 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 Olson, J.A., and R.E. Hodges. 1987. Recommended dietary intakes (RDI) of vitamin C in humans. Am. J. Clin. Nutr. 45:693-703. Ovesen, L~ 1979. Drugs and vitamin deficiengy. Drugs 18:278-298. Packman, S., L. Sweetman, H. Baker, and S. Wall. 1981. The neonatal form of biotin- responsive multiple carboxylase deficiency. J. Pediatr. 99:418-420. Packman, S., M.S. Golbus, M.J. Cowan, L. Sweetman, W. Nyhan, B.J. Burri, and H. Baker. 1985. Prenatal treatment of biotin-responsive multiple carboxylase deficiency. Ann. N.Y. Acad. Sci. 447:414-416. Pitkin, R.M. 1982. Megadose nutrients during pregnancy. Pp. 203-211 in Alternative Dietary Practices and Nutritional Abuses in Pregnancy: Proceedings of a Workshop. Report of the Committee on Nutrition of the Mother and Preschool Child, Food and Nutrition Board, Commission on Life Sciences. National Academy Press, Washington, D.C. Pritchard, J.A., D.E. Scott, and P.J. Whalley. 1969. Folic acid requirements in pregnancy- induced megaloblastic anemia. J. Am. Med. Assoc. 208:1163-1167. Pulkkinen, M.O., J. Salminen, and S. Virtanen. 1978. Serum vitamin B6 in pure pregnangy depression. Acta Obstet. Gynecol. Scand. 57:471-472. Reinken, L^, and O. Dapunt. 1978. Vitamin B6 nutriture during pregnancy. Int. J. Vitam. Nutr. Res. 48:341-347. Reisenauer, A M., and CH. Halsted. 1987. Human folate requirements. J. Nutr. 117:600- 602. Reynolds, R.D., M. Polansk,v, and P.B. Moser. 1984. Analyzed vitamin B6 intakes of pregnant and postpartum lactating and nonlactating women. J. Am. Diet. Assoc. 84:1339-1344. Rhead, W.J., and G.N. Schrauzer. 1971. Risks of long term ascorbic acid overdose. Nutr. Rev. 29:262-263.

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378 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Rivers, J.M. 1987. Safety of high-level vitamin C ingestion. Ann. N.Y. Acad. Sci. 498:445- 454. Rivers, J.M., and M.M. Devine. 1975. Relationships of ascorbic acid to pregnancy and oral contraceptive steroids. Ann. N.Y. Acad. Sci. 258:465-482. Robie, T.R. 1967. pyproheptadine: an excellent antidote for niacin-induced hyperthermia. J. Schizophr. 1:13~139. Roepke, J.LB., and A. Kirksey. 1979a. Vitamin B6 nutriture during pregnancy and lactation. I. Vitamin B6 intake, levels of the vitamin in biological fluids, and condition of the infant at birth. Am. J. Clin. Nutr. 32:2249-2256. Roepke, J.LB., and A. Kirksey. 1979b. Vitamin B6 nutriture during pregnancy and lactation. II. The effect of long-term use of oral contraceptives. Am. J. Clin. Nutr. 32:2257-2264. Rose, D.P. 1978. The interactions between vitamin B6 and hormones. Pp. 53-99 in P.L. Munson, E. Di~:falusy, J. Glover, and R.E. Olson, eds. Vitamins and Hormones: Advances in Research and Applications, Vol. 36. Academic Press, New York. Sauberlich, H.E. 1978. Vitamin indices. Pp. 109-156 in Laboratory Indices of Nutri- tional 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. Sauberlich, H.E. , M.J. Kretsch, J.H. Skala, H.L Johnson, and P. C. Taylor. 1987. Folate requirement and metabolism in nonpregnant women. Am. J. Clin. Nutr. 46:1016-1028. Schaumburg, H., J. Kaplan, A. Windebank, N. Vick, S. Rasmus, D. Pleasure, and MJ. Brown. Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N. Engl. J. Med. 309:445-448. Schrauzer, G.N. 1979. Vitamin C: conservative human requirements and aspects of overdosage. Int. Rev. Biochem. 27:167-188. Schuster, K., LB. Bailey, and C.S. Mahan. 1981. Vitamin B6 status of low-income adolescent and adult pregnant women and the condition of their infants at birth. Am. J. Clin. Nutr. 34:1731-1735. Schuster, K., LB. Bailey, and C.S. Mahan. 1984. Effect of maternal pyridoxine-HC1 supplementation on the vitamin B6 status of mother and infant and on pregnancy outcome. J. Nutr. 114:977-988. Scott, KE., and R. Usher. 1966. Fetal malnutrition: its incidence, causes, and effects. Am. J. Obstet. Gynecol. 94:951-963. Shane, B., and S.F. Contractor. 1975. Assessment of vitamin B6 status. Studies on pregnant women and oral contraceptive users. Am. J. Clin. Nutr. 28:739-747. Shane, B., and S.F. Contractor. 1980. Vitamin B6 status and metabolism in pregnancy. Pp. 137-171 in G.P. llyfiates, ed. Vitamin B6 Metabolism and Role in Growth. Foods & Nutrition Press, Westport, Conn. Simmer, K., C James, and R.P.H. Thompson. 1987. Are iron-folate supplements harmful? Am. J. Clin. Nutr. 45:122-125. Sklar, R. 1986. Nutritional vitamin B12 deficiency in a breast-fed infant of a vegan-diet mother. Clin. Pediatr. 25:219-221. Smith, LH. 1978. Risk of oxalate stones from large doses of vitmain C. N. Engl. J. Med. 298:856. Song, W.O., B.W. Wyse, and R.G. Hansen. 1985. Pantothenic acid status of pregnant and lactating women. J. Am. Diet. Assoc. 85:192-198. Spellacy, W.N., W.C Buhi, and S.A. Birk. 1977. Vitamin B6 treatment of gestational diabetes mellitus: studies of blood glucose and plasma insulin. Am. J. Obstet. Gynecol. 127:599 602. Subar, AF., G. Block, and LD. James. 1989. Folate intake and food sources in the US population. Am. J. Clin. Nutr. 50:508-516. Tamura, T., and E.LR. Stokstad. 1973. The availability of food folate in man. Br. J. Haematol. 25:513-532.

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WATER-SOLUBLE VITAMINS 379 Thiersch, J.B. 195Z Therapeutic abortions with a folio acid antagonist, 4-aminopteroylglu- tamic acid (4-amino P.G.~) administered by the oral route. Am. J. Obstet. Gynecol. 63:1298-1304. Thiersch, J.B. 1960. Teratogenic effects of pteroylglutamic acid deficiency in the rat: discussion. Pp. 152-154 in G.E.W. Wolstenholme and C.M. O'Connor, eds. Ciba Foundation Symposium on Congenital Malformations. Little, Brown, Boston. USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes by Individuals. Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1986. Report No. 86-1. Nutrition Monitoring Division, Human Nutrition Information Service, U.S. Department of Agriculture, Hyattsville, Md. 98 pp. van den Berg, H. 1988. Vitamin and mineral status in healthy pregnant women. Pp. 93-108 in H. Berger, ed. Vitamins and Minerals in Pregnancy and Lactation. Vevey/Raven Press, New York. van den Berg, H., and J.J. Bogaards. 1987. Vitamin B6 metabolism in the pregnant rat: effect of progesterone on the (nondistribution in maternal vitamin B6 stores. J. Nutr. 117:1866-1874. Vir, S.C., AH. Love, and W. Thompson. 1980. Vitamin B6 status during pregnancy. Int. J. Vitam. Nutr. Res 50:403-411. Vobecky, J.S., J. Vobecly, D. Shapcott, and L. Munan. 1974. Vitamin C and outcome of pregnancy. Lancet 1:630. Weinstein, B.B., Z Wohl, GJ. Mitchell, and G.F. Sustendal. 1944. Oral administration of pyridoxine hydrochloride in the treatment of nausea and vomiting of pregnancy. Am. J. Obstet. Gynecol. 47:389-394. Wertz, A.W., M.E. Lojkin, B.S. Bouchard, and M.B. Derby. 1958. Tryptophan-niacin relationships in pregnancy. J. Nutr. 64:339-353. Willis, R.S., W.W. Quinn, A.T. Morns, AA. Newsom, and WE. Massey. 1942. Clinical observations in treatment of nausea and vomiting in pregnancy with vitamins By and B6. Am. J. Obstet. Gynecol. 44:265-271. Wills, ~ 1931. Treatment of "pernicious anaemia of pregnancy" and "tropical anaemia," with special reference to yeast extract as a curative agent. Br. Med. J. 1:1059-1064. Zamorano, OF., F. Arnalich, E.S. Casas, A. Sicilia, C. Solis, J.J. Vazquez, and R. Gasalla. 1985. Levels of iron, vitamin B12, folio acid, and their binding proteins during pregnancy. Acta Haematol. 74:92-96.