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OCR for page 351
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
OCR for page 353
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
OCR for page 354
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
OCR for page 355
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.
OCR for page 356
356
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OCR for page 357
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OCR for page 358
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
OCR for page 359
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,
OCR for page 361
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
OCR for page 369
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
OCR for page 370
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
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Representative terms from entire chapter:
dietary intake
