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OCR for page 272
14
Iron Nutrition During Pregnancy
IMPORTANCE OF IRON DURING PREGNANCY
Among healthy human beings, pregnant women and rapidly growing
infants are most vulnerable to iron deficiency (Bothwell et al., 19794. Both
groups have to absorb substantially more iron than is lost from the body,
and both are at a considerable risk of developing iron deficiency under
ordinary dietary circumstances. During pregnancy, more iron is needed
primarily to supply the growing fetus and placenta and to increase the
maternal red cell mass (Hallberg, 1988~.
Iron deficiency is common among pregnant women in industrialized
countries, as shown by numerous studies in which hemoglobin concen-
trations during the last half of pregnancy were found to be higher in
iron-supplemented women than in those given a placebo or no supplement
(Table 14-1) (Chanarin and Rothman, 1971; Dawson and McGanity, 1987;
Puolakka et al., 1980b; Romslo et al., 1983; Svanberg et al., 1976a; Tay-
lor et al., 1982; Wallenburg and van Eijk, 1984~. This higher hemoglobin
concentration as a result of an improved iron supply not only increases the
oxygen-carrying capacity, but it also provides a buffer against the blood loss
that will occur during delivery (Hallberg, 1988~.
Iron is essential for the production of hemoglobin, which functions in
the delivery of oxygen from the lungs to the tissues of the body, and for
the synthesis of iron enzymes, which are required to utilize oxygen for the
production of cellular energy (Bothwell et al., 1979~.
272
OCR for page 273
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OCR for page 274
274
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
Definition of Anemia and Iron Deficiency
Anemia is defined as a hemoglobin concentration that is more than 2
standard deviations below the mean for healthy individuals of the same age,
sex, and stage of pregnancy. Although iron deficiency is the most common
cause of anemia, infection, genetic factors, and many other conditions can
also lead to anemia. Iron depletion is generally described in terms of three
stages of progressively increasing severity (Bothwell et al., 1979~:
1. depletion of iron stores
2. impaired hemoglobin production (or iron deficiency without anemia)
3. iron deficiency anemia
The first stage, depletion of iron, is characterized by a low serum
ferritin level. This stage is the most difficult to define because it involves
an arbitrary decision about how low iron stores should be before they are
considered depleted. This is a particularly thorny issue with respect to
pregnancy, because storage iron, estimated from bone marrow aspirates (or
less directly by the serum ferritin), is low or absent in most women during
the third trimester, whether (Svanberg et al., 1976a) or not (Heinrich et
al., 1968; Svanberg et al., 1976a) they have received an iron supplement.
For this reason, the subcommittee considered low iron stores in late preg-
nancy to be physiologic and reserved the term iron deficiency for the second
and third stages. The second stage, impaired hemoglobin production, is
recognized by laboratory tests that indicate an insufficient supply of iron
to developing red blood cells, such as a low ratio of serum iron to total
ironbinding capacity (Fe1IBC), low mean corpuscular volume (MCV),
and/or elevated erythrocyte protoporphyrin (EP), but with a hemoglobin
concentration that remains within the normal reference range. Iron defi-
ciency anemia (the third stage) refers to an anemia (e.g., hemoglobin values
below the 5th percentile in Figure 14-1) that is associated with additional
laboratory evidence of iron deficiency, such as a low serum ferritin level,
low serum Fe~IBC, low MCV, or an elevated EP level (also see the section
Laboratory Characteristics of Impaired Hemoglobin Production).
Effects of Maternal Anemia on the Newborn
Although some epidemiologic evidence suggests that anemia during
pregnancy could be harmful to the fetus, the data are far from conclusive.
In a report of more than 54,000 pregnancies in the CardiD area of South
Wales, the risk of low birth weight, preterm birth, and perinatal mortality
was found to be higher when the hemoglobin concentration was in the
anemic range <10.4 g/dl before 24 weeks of gestation~ompared with
a midrange hemoglobin concentration of 10.4 to 13.2 g/dl (Murphy et al.,
1986~. Elevated hemoglobin values of >13.2 g/dl were also associated
OCR for page 275
IRON
14.0
13.5
13.0
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11.0
10.5
275
50th Percentile
5th Percentile
/
-
_
/
-
-
-
_
-
0 4 8 12 16 20 24 28
Week of Gestation
32 36 40
FIGURE 14-1 Normal hemoglobin values during pregnancy. Values from 12 to 40 weeks
of gestation are based on data from Svanberg et al. (1976a), Sjostedt et al. (1977), Puolakka
et al. (198Ob), and Taylor et al. (1982~. The baseline values (zero weeks) are based on
LSRO (1984), and the 4- and 8-week values are extrapolated from all these data and from
Clapp et al. (1988~. Unpublished figure from R. Yip, Centers for Disease Control, 1989,
with permission.
with an increased risk of the same poor pregnancy outcomes, perhaps
because such values are characteristic of women who develop preeclampsia
(hypertension accompanied by generalized pitting edema or proteinuria
after week 20 of gestation), who are similarly at risk. Another pertinent
study is that of Garn and coworkers (1981), which was based on more
than 50,000 pregnancies in the National Collaborative Perinatal Project of
the National Institute of Neurologic and Communicative Disorders and
Stroke. As in the South Wales study, there was a U-shaped relationship
between the maternal hemoglobin or hematocrit level during pregnancy
and the pregnancy outcome. When the lowest hemoglobin concentration
during any stage of pregnancy was below 10.0 g/dl, the likelihood of low
birth weight, preterm birth, and perinatal mortality was increased. A
hemoglobin concentration that was high during pregnancy (>13.0 g/dl) was
also associated with these poor pregnancy outcomes.
In most populations, iron deficiency is by far the most common cause
OCR for page 276
276
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
of anemia before 24 weeks of gestation (Puolakka et al., 1980c). It seems
plausible, therefore, that iron deficiency could account for the higher risk
to the fetus among the anemic pregnant women in the studies described
above. However, a cause-and-effect relationship has not been established.
Iron deficiency and anemia are more common in blacks and in those of
low socioeconomic status, those with multiple gestations, and those with
limited education (LSRO, 1984~. Any of these confounding factors could
be related to a poor pregnancy outcome independently of iron deficiency.
Additional studies indicate a link between maternal anemia at full
term and low birth weight (Klein, 1962; Lieberman et al., 1987; Macgregor,
1963), but interpretation of the results is complicated by the fact that the
hemoglobin concentration normally rises in the third trimester of pregnancy
(Figure 14-1) if sufficient iron is available (Puolakka et al., 1980b; Sjostedt
et al., 1977; Svanberg et al., 1976a; Taylor et al., 1982~. An association
between a low maternal hemoglobin concentration at delivery and low birth
weight can be expected since lower hemoglobin values are characteristic of
an earlier stage of gestation.
The infant of an iron-depleted mother has surprisingly little evidence
of anemia or depletion of iron stores. Numerous studies in which serum
ferritin was used to estimate the neonatal iron stores of infants from iron-
deficient or iron-sufficient or supplemented mothers show relatively little
difference (Agrawal et al., 1983; Fenton et al., 1977; Kaneshige, 1981;
Kelly et al., 1978; MacPhail et al., 1980; Milman et al., 1987; Puolakka
et al., 1980a) or no significant difference (Bratlid and Moe, 1980; Celada
et al., 1982; Hussain et al., 1977; Messer et al., 1980; Rios et al., 1975;
van Eijk et al., 1978~. Hemoglobin concentration in the newborn was
unaffected or minimally affected in most studies (Agrawal et al., 1983;
Murray et al., 1978; Sisson and Lund, 1958; Sturgeon, 1959~. In the study
reported by Sturgeon, hemoglobin concentrations of 6-, 12-, and 18-month-
old infants of iron-supplemented mothers were similar to those in infants
of unsupplemented mothers. Only in two studies, both from developing
countries, was it concluded that newborn infants of anemic mothers were
also anemic, although to a far lesser degree than their mothers (Nhonoli
et al., 1975; Singla et al., 1978~. However, comparable studies from similar
settings did not confirm this finding (Agrawal et al., 1983; Murray et al.,
1978), suggesting that other nutritional deficiencies and such factors as
infection (malaria) might explain the disagreement. Overall, there is little
or no laboratory evidence that infants of iron-deficient mothers are more
likely to be iron deficient, but it is possible that the risk of low birth weight,
prematurity, and perinatal mortality may- be increased.
OCR for page 277
IRON
277
PREVALENCE OF IRON DEFICIENCY
Data on the prevalence of iron deficiency among women during the
childbearing years in the United States are available mainly from the second
(1976-1980) National Health and Nutrition Examination Survey (NHANES
II) (LSRO, 1984~. Population estimates were based on a combination of
laboratory indices-EP, MCV, and Fe~IBC in a nationally representative
sample of 2,474 women aged 20 to 44 and 697 younger women aged 15 to
19. Serum ferritin assays were done on a subset of approximately 30% of
this population; it was a relatively new assay at the time. Ho few pregnant
women were included in the survey for detailed analysis.
Ho sets of laboratory criteria were used to estimate the prevalence of
impaired iron status, which was defined as two or three abnormal laboratory
test results out of a set of three tests for iron status. This approach had been
found to be more reliable in relation to anemia than the use of any single
test (Cook et al., 1976~. In the so-called MCV model, MCV, Fe/TIBC, and
EP were used for the analysis; these laboratory results were available for
most subjects. In the ferritin model, the serum ferritin concentration was
substituted for the MCV and probably represents an earlier stage of iron
deficiency. Impaired iron status in either model can be considered to be
equivalent to iron deficiency, taking into consideration that infection and
chronic disease can be confounding factors by mimicking the laboratory
abnormalities of iron deficiency.
Among nonpregnant women between the ages of 20 and 44, estimated
percentages of impaired iron status varied according to model used: 9.6
~ 1.3% (standard error of the mean [SEMI) as determined by the ferritin
model, and 5.4 ~ 0.5% as determined by the MCV model. Iron deficiency
anemia (two or three abnormal values and hemoglobin <11.9 g/dl) among
nonpregnant white women aged 20 to 44 was less than 2~o as determined
by both models.
If the prevalence of iron deficiency among pregnant women were no
higher than the 5 to 10% reported in NHANES II for nonpregnant women
of childbearing age, there would be little basis for considering routine
iron supplementation during pregnancy. However, it is generally agreed
that both iron needs and prevalence of iron deficiency increase substantially
during pregnancy (Hallberg, 1988~. In a paper on the worldwide prevalence
of anemia written for the World Health Organization, the global prevalence
of anemia was estimated at 51% among pregnant women, compared with
35% among women in general, including pregnant women (DeMaeyer and
Adiels-Tegman, 1985~. Most of the anemia was attributed to iron deficiency.
The higher prevalence for pregnant women is consistent with the estimated
high iron needs during pregnancy (Bothwell et al., 1979; Hallberg, 1988;
see also the section Iron Requirements for Pregnancy).
OCR for page 278
278
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
The most convincing evidence that pregnant women in industrial-
ized countries often cannot meet their iron needs from diet alone comes
from three careful longitudinal studies from northern European countries.
Groups of iron-supplemented an* unsupplemented pregnant women were
followed with laboratory studies from early pregnancy at 4-week intervals
(Puolakka et al., 1980b; Svanberg et al., 1976b; Taylor et al., 1982~. In all
these studies, the hemoglobin values in the unsupplemented group were
significantly lower than those in the supplemented group after 24 to 28
weeks of gestation. The mean difference was 1.0 to 1.7 g/dl between weeks
35 and 40 of gestation. In the latter two studies, the means were more
than 2 standard deviations apart during this period, indicating a high preva-
lence of impaired hemoglobin production because of a lack of iron in the
unsupplemented group. Thus, even though there are no good prevalence
data for iron deficiency during pregnancy, it is reasonable to infer that the
prevalence is high.
SPECIAL GROUPS AT RISK
Data from 1976-1980 NHANES II and 1982-1984 Hispanic HANES
(HHANES) suggest that low socioeconomic status, low level of education,
black or Hispanic background, and high parity were associated with iron
deficiency (impaired iron status) in the MCV model for nonpregnant women
(LSRO, 1984, 1989~. It is reasonable to infer that the same factors would
play a role, probably to a greater degree, when iron demands are drastically
increased during the last half of pregnancy. The following factors are
associated with an increased risk of iron deficiency:
Pregnancy (second two trimesters)
Menorrhagia (loss of more than 80 ml of blood per month)
Diets low in both meat and ascorbic acid
· Multiple gestation
Blood donation more than three times per year
Chronic use of aspirin
Socioeconomic Indicators
The prevalence of iron deficiency in NHANES II tended to be higher
among the poor; the difference was of borderline significance (p <.1) for
women aged 20 to 44 and significant (p <.05) for women aged 15 to 19.
The percentages were 5.1 it 0.5 (SEM) and 3.6 ~ 1.0, respectively, for
those above the poverty level and 7.8 ~ i.5 and 8.2 ~ 1.8%, respectively,
for those below the poverty level. Iron deficiency was also more common
among women between the ages of 20 and 44 with limited education (13.4
OCR for page 279
IRON
279
2.8%) compared with those with high school (5.4 ~ 0.6%) or college (4.2
0.8%) education.
Racial and Ethnic Backgrounds
The prevalence of iron deficiency using the MCV model among 20-
to 44-year-old Mexican-American women in HHANES was substantially
higher than that among non-Hispanic whites in NHANES II, 11.9 ~
2.0% compared with 5.4 ~ 0.5%, respectively. Average parity among
the Mexican-American women was considerably higher than that among
non-Hispanic whites, and this probably contributed to the higher preva-
lence of iron deficiency among the Mexican-American women. Impaired
iron status with increasing parity was also more prevalent in NHANES II.
Iron deficiency was present in 3.1 ~ 0.5% of women with no children, in
3.8 ~ 0.8% of those with one or two children, in 9.4 ~ 1.1% of those
with three to four children, and in 11.5 ~ 2.1% of those with five or more
children. In NHANES II, the same prevalence of iron deficiency (impaired
iron status) was found among black women, aged 20 to 44, as among whites
in the same age group (5.7 ~ 0.9 and 5.0 ~ 0.6%, respectively). Among
the small sample of teenagers, there was a difference (3.8 ~ 0.9 and 12.6
4.7, respectively) of borderline significance (p <0.1~.
Many risk factors, such as poverty, ethnic background, education,
and parity, are closely interrelated. Unfortunately, the effects of these
interrelationships have not been systematically studied. Most studies have
focused on only one factor at a time.
Adolescents
Teenagers may also have an increased risk of iron deficiency because of
the high iron requirements imposed by their recent growth spurt (Dawson
and McGanity, 1987~. In NHANES II, females aged 15 to 19 had a 4.9
it 1.1% prevalence of iron deficiency as determined by the MCV model
and 14.2 ~ 3.5% as determined by the ferritin model. The sample was
small, and the percentages did not differ significantly from those of the
corresponding group of women between the ages of 20 and 44.
IRON METABOLISM IN RELATION TO PREGNANCY
Essential and Storage Iron
The total amount of iron in the average woman's body is about 2.2 g
(Bothwell et al., 1979), which is equal to the weight of a dime. Most of this
iron can be considered essential because it functions in the transport and
OCR for page 280
280
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
utilization of oxygen for the production of cellular energy. I\vo compounds,
ferritin and hemosiderin, serve as a reserve. Iron from these compounds
can be mobilized for the production of essential compounds when the
supply of dietary iron is insufficient. The vulnerability of an individual to
iron deficiency depends on the amount of iron stored.
Iron Loss
Catabolized iron is efficiently reutilized, and very little iron is lost
from the body except through bleeding. Normal iron losses average ap-
proximately 0.9 mg/day in adult men the population that has been the
most thoroughly studied (Green et al., 1968~. The corresponding value for
women, excluding menstrual losses, is estimated to be about 0.8 mg/day.
Menstrual iron losses average about 0.5 mg/day. When this is added to the
other losses of 0.8 mg/day, the total is 1.3 mg/day.
Excessive menstrual blood loss (menorrhagia), defined as >80 mV
month, occurs in about 10% of women (Cole et al., 1971; Hallberg et
al., 1966~. This is equivalent to 1 mg of iron or more lost per day,
more than twice the average menstrual iron loss. Menstrual blood loss of
>80 mVmonth commonly results in iron deficiency (Hallberg et al., 1966~.
Consequently, some women face the increased iron demands of pregnancy
with an already established iron deficiency. Menstrual blood loss varies
markedly among women, but in any given woman, there is relatively little
variation in the amount of blood lost from one month to the next (Hallberg
et al., 1966~. Unfortunately, ~ careful history can barely distinguish groups
of women whose volume of blood loss is expected to differ on the basis of
oral contraceptive use (Frassinelli-Gunderson et al., 1985~.
Women who take oral contraceptive agents will, on average, halve their
menstrual blood loss, whereas those who use intrauterine devices (now rare
in the United States) will roughly double it (Hefnawi et al., 1974; Israel et
al., 1974~. Users of oral contraceptives have substantially higher iron stores
than do nonusers, based on serum ferritin values (Frassinelli-Gunderson
et al., 1985~. In NHANES II, 18% of women aged 20 to 44 took oral
contraceptives.
Other common reasons for increased iron losses are blood donation
and aspirin ingestion. Women who donate more than three units of blood
per year are at high risk of being iron deficient (Finch et al., 1977; Simon
et al., 1981), unless they take iron supplements regularly. Aspirin ingestion
amounting to 300 mg (one tablet) four times a day increases intestinal blood
loss from the normal average of about 0.5 ml/day to 5 mliday (Pierson et
al., 1961~. These amounts are equivalent to about 0.2 and 2.0 mg of iron
loss per day, respectively.
OCR for page 281
IRON
281
Regulation of Body Iron
The amount of iron in the body is determined mainly by the percentage
of food iron absorbed from the intestine a percentage that can vary
more than 20-fold (Charlton and Bothwell, 1983; Hallberg, 1981~. The
bioavailability of iron-that is, the proportion absorbed from food- is
determined both by the nature of the diet and by a regulatory mechanism
in the intestinal mucosa that is responsive to the abundance of storage iron.
Absorption of Nonheme and Heme Iron from Food
Leo types of iron are present in food: heme iron, which is found
principally in animal products, and nonheme iron, which is found mainly
in plant products. Most of the iron in the diet, an average of more than
88% (Raper et al., 1984), is present as nonheme iron and consists primarily
of iron salts. The absorption of nonheme iron is strongly influenced by its
solubility in the upper part of the small intestine, which in turn depends
on the composition of the meal as a whole (Charlton and Bothwell, 1983;
Hallberg, 1981~.
Iron absorption tends to be poor from meals in which whole-grain
cereals and legumes predominate. Phytates in whole-grain cereals, calcium
and phosphorus in milk, tannin in tea, and polyphenols in many vegetables
all inhibit iron absorption by decreasing the intestinal solubility of nonheme
iron from the entire meal. The addition of even relatively small amounts of
meat and ascorbic acid-containing foods substantially increases the absorp-
tion of iron from the entire meal by keeping nonheme iron more soluble.
For example, compared with water, orange juice will roughly double the ab-
sorption of nonheme iron from a meal. Tea and coffee, on the other hand,
will cut the absorption of nonheme iron by more than half when compared
with water (Hallberg, 1981; Rossander et al., 1979~. Thus, modifications in
the diet offer great scope for improving iron absorption during pregnancy.
Consumption of meals containing enhancers of iron absorption, such as
meat and ascorbic acid-rich fruits and vegetables, and avoidance of strong
inhibitors such as tea should do much to prevent iron deficiency (Monsen
et al., 1978~. However, there is little information on the effectiveness of
dietary counseling in preventing iron deficiency.
Heme iron is derived primarily from the hemoglobin and myoglobin in
meat, poultry, and fish. Although heme iron accounts for a smaller propor-
tion of iron in the diet than nonheme iron does, a much greater percentage
of heme iron is absorbed, and its absorption is relatively unaffected by
other dietary constituents (Hallberg, 1981~.
When both forms of iron in the diet are considered, the average total
OCR for page 282
282
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
dietary iron absorption by men is about 6% and by women in their child-
bearing years, 13% (Charlton and Bothwell, 1983~. The higher absorption
in women is related to their lower iron stores and helps to compensate for
the losses of iron associated with menstruation.
Intestinal Regulation
Entry of soluble nonheme iron into the body is regulated in the
mucosal cell of the small intestine (Charlton and Bothwell, 1983), but the
mechanism remains uncertain (Davidson and LOnnerdal, 1988; Huebers
and Finch, 1987; Peters et al., 1988~. If iron stores are low, the intestinal
mucosa readily takes up nonheme iron and increases the proportion that
is absorbed from the diet. During the course of pregnancy, as iron stores
decrease, the absorption of dietary nonheme iron increases (Svanberg et
al., 1976b). However, the adequacy of this homeostatic response is limited
by the amount of absorbable iron in the diet and the high iron requirements
for pregnancy.
IRON REQUIREMENTS FOR PREGNANCY
The body iron requirement for an average pregnancy is approximately
1,000 ma. Hallberg (1988) calculated that 350 mg of iron is lost to the
fetus and the placenta and 250 mg is lost in blood at delivery. In addition,
about 450 mg of iron is required for the large increase in maternal red
blood cell mass. Lastly, basal losses of iron from the body continue during
pregnancy and amount to about 240 ma. Thus, the total iron requirements
of a pregnancy (excluding blood loss at delivery) average about 1,040
ma. Permanent iron losses during pregnancy include loss to the fetus and
placenta, blood loss at delivery, and basal losses, which together total 840
ma.
The total iron needs of slightly more than 1,000 mg are concentrated in
the last two trimesters of pregnancy. This amount is equivalent to about 6
mg of iron absorbed per day in a woman who starts pregnancy with absent
or minimal storage iron. This is a large amount of iron to accumulate
over a 6-month period, especially when compared with the average total
body iron content of 2,200 mg and the 1.3 mg of iron absorbed per day by
nonpregnant women.
Although 450 mg of iron for red cell production must be supplied
during pregnancy, a large part of this can subsequently augment iron stores
after a vaginal delivery, when the red cell mass decreases. The result
is analogous to a postpartum injection of iron: serum ferritin levels will
spontaneously increase within a few months after delivery in most women
who develop mild iron deficiency during late pregnancy because of the iron
OCR for page 288
288
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
randomized to groups receiving either 100 mg of iron as a sustained-release
tablet of ferrous sulfate or a placebo twice a day with meals. In accord with
the study of Hahn and coworkers (1951), iron absorption in the placebo
group increased during the course of pregnancy from about 7% at 12 weeks
and 9% at 24 weeks to 14% at 35 weeks of gestation. This rise in absorption
was associated with and could be ascribed to a decline in storage iron, as
estimated from bone marrow aspirates. There was a smaller rise in mean
iron absorption in the iron-treated group, who had values of 6, 7, and 9%
at 12, 24, and 35 weeks of gestation, respectively.
Slow-release iron supplements of various types were developed pri-
marily to circumvent the high prevalence of side effects when large doses
of iron are used. These preparations are more expensive than ordinary,
rapidly soluble iron supplements. In three of the studies summarized in Ta-
ble 14-1, slow-release forms of ferrous sulfate at doses of 105 to 200 mg of
iron per day were effective in preventing iron deficiency during pregnancy
(Puolakka et al., 1980b; Svanberg et al., 1976a; Wallenburg and van Eijk,
1984~. Ekenved et al. (1976a) found that a slow-release preparation was
better absorbed than ordinary ferrous sulfate when given with a meal but
less well absorbed under fasting conditions. Several slow-release forms of
iron are so poorly absorbed that they are unlikely to confer substantial ben-
efit (Middleton et al., 1966~. Consequently, only a slow-release preparation
of proven effectiveness provides a reasonable alternative should gastroin-
testinal side effects develop when standard preparations of ferrous iron are
used at recommended doses.
Iron tablets (other than slow release preparations) are absorbed more
completely when given between rather than with meals (Ekenved et al.,
1976a; Hallberg et al., 1978; Layrisse et al., 1973~. In the study by Layrisse
et al. (1973), 100 mg of iron was given in the form of a ferrous sulfate
tablet either after an overnight fast or with a variety of meals characterized
by high or low food iron bioavailability. An average of 10 mg (10~) was
absorbed after the overnight fast. Irrespective of the type of meal, only an
average of 4 to 5 mg was absorbed when the tablet was administered with
the meal.
Iron absorption seems to be much greater when a supplement contains
only an iron salt than when the iron is part of certain multivitamin-mineral
supplements. Calcium carbonate and magnesium oxide appear to be par-
ticularly inhibitory to iron absorption (Babior et al., 1985; Seligman et
al., 1983~. In the 1983 study by Seligman and colleagues, iron absorption
improved markedly when calcium as calcium carbonate was decreased from
350 to 250 mg and magnesium as magnesium oxide was decreased from
100 to 25 ma. These findings demonstrate the importance of additional
research to test appropriate prenatal multinutrient supplements for in vivo
bioavailability. Rough comparisons of iron absorption from various sup
OCR for page 289
IRON
289
plements can be most easily derived from the increase in serum iron that
occurs after administration of the supplement (Ekenved et al., 1976b).
Since ascorbic acid-rich foods enhance the absorption of dietary iron,
one might anticipate that adding ascorbic acid to an iron supplement would
also increase iron absorption. However, this was not the case when 50 or
100 mg of ascorbate was given with 30 mg of iron as ferrous sulfate after an
overnight fast (Brise and Hallberg, 1962b). Only with very large doses of
200 mg or more was there an increase in iron absorption. However, such
large doses of ascorbate, when given with 60 mg of iron, commonly result
in epigastric pain as a side effect (Hallberg et al., 1967a). Even when an
iron supplement was given with a meal, the addition of 100 mg of ascorbic
acid was not effective in increasing the absorption of ferrous iron (Grebe
et al., 1975~. Thus, it appears that although ascorbic acid is effective in
enhancing absorption of dietary iron, presumably by helping to convert
insoluble ferric iron to more soluble ferrous iron, this role is probably less
important for supplemental iron given in the ferrous form.
Some commonly consumed foods, such as certain breakfast cereals,
are highly fortified to supply the equivalent of the Food and Drug Ad-
ministration's U.S. Recommended Daily Allowance (U.S. RDA) for iron
in a single serving. The extent to which fortification iron is absorbed is
likely to vary markedly according to the type of iron and the composition
of the product (INACG, 1982~. Absorption of added ferrous fumarate is
enhanced if the product is also fortified with ascorbic acid (INACG, 1982~.
This enhancement may be surprising in view of the lack of a similar effect
with ascorbic acid added to the much larger amounts of ferrous iron that
are contained in supplements. Iron absorption is decreased if the fortified
cereal product is rich in phytate (Hallberg et al., 1989~. Breakfast cereals
in the United States are not typically fortified with ferrous iron, and the
reliability of such products in preventing iron deficiency during pregnancy
is not established. It is therefore prudent not to rely on fortified products
as a substitute for an iron supplement.
Therapeutic Trials
Several longitudinal studies comparing the use of an iron supplement
with a placebo or no supplement during pregnancy are summarized in liable
14-1. All of them were performed in northern Europe or North America
and most involved middle-income women. The results indicate that 30 mg
(Chanarin and Rothman, 1971) or 65 mg (Dawson and McGanity, 1987;
Taylor et al., 1982) of elemental iron per day was as effective as any of the
higher doses. There are few therapeutic trials in which doses of iron were
less than 60 mg/day. Their results are important, however, because the
absorption studies of Hahn et al. (1951) indicate that lower doses should
OCR for page 290
290
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
be adequate and because the prevalence of intestinal side effects is related
to dose (Hallberg et al., 1967b; see also the section Compliance and Side
Effects).
Probably the most complete and authoritative of these studies was
that of Chanarin and Rothman (1971), who compared groups receiving
doses of ferrous fumarate supplying 30, 60, or 120 mg of iron per day
with a group given a placebo. An additional group was given one injection
of 1 g of iron as intravenous iron dextran, followed by a 60 mg oral
dose of iron per day. Women at 20 weeks of gestation were assigned
sequentially to the five groups and treated until term; the contents of
the prescribed tablets were not known to the investigators. Between 46
and 49 subjects per group completed the study. Figure 14-3 shows the
hemoglobin and serum iron values during the course of pregnancy in the
30-mg, 120-mg, and placebo groups. When compared at 37 weeks of
gestation, the hemoglobin and serum iron levels of the 30-mg group did
not differ significantly from those of the groups receiving higher doses of
iron. The investigators concluded that 30 mg of elemental iron per day was
effective in maintaining hemoglobin levels throughout pregnancy. More
recently, Hiss (1986) also recommended a dose of 30 midday in a review on
anemia during pregnancy. In support of this dose, he cited the results of
Scott and Pritchard (1974), who determined the hemoglobin concentration
and stainable iron in bone marrow at the beginning of the second trimester
and at delivery in 20 women who were given 30 mg of iron per day as
ferrous fumarate throughout that period. The hemoglobin concentration
rose from an initial mean of 11.2 g/dl to a final value of 12.6 g/dl, and bone
marrow iron at delivery equaled or exceeded the initial values. One study
that cast some doubt on the efficacy of low doses is that of de Leeuw and
coworkers (1966), who report that 39 mg of ferrous iron per day did not
maintain as high a hemoglobin concentration as did a dose of 78 mg/day.
Chanarin and Rothman (1971) suggested that compliance may not have
been as good as it was in their own well-monitored study.
A relatively modest dose of iron is preferable to a high dose since iron
may inhibit the absorption of other nutrients, zinc in particular. Sandstrom
and coworkers (1985) showed that when a multivitamin-mineral supplement
is taken on an empty stomach, high iron doses will inhibit the absorption of
concurrently administered zinc. It also appears that iron supplementation,
even at modest doses (38 to 65 mg/day for 1 to 4 weeks), may result in a
slight decline in serum zinc (Hambidge et al., 1987). Possible consequences
of the iron-zinc interaction for human nutrition were reviewed by Solomons
(1986).
OCR for page 291
IRON
291
70
60
r:n
40
0'
13
12
g
o
o
E
I 11 _
, 7
ol ~I , ,
a_
_ ~
~ 7
120 mg
30 mg
~ placebo
20 25
30 35 40
Week of Gestation
as/
30mg
1 20 mg
~ placebo
20 25 30 35 40
Week of Gestation
FIGURE 14-3 Serum iron and hemoglobin levels in groups of 46 to 49 randomly assigned
women receiving daily either a placebo or various doses of elemental iron as ferrous
fumarate given orally. Data from groups receiving 60-mg oral doses of iron or 1 g of
parenteral iron followed by 60-mg oral doses of iron per day are not shown but are similar
to those of the iron-supplemented groups shown in the figure. Based on data from Chanarin
and Rothman (1971~.
OCR for page 292
292
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
How Much Extra Iron Must Be Absorbed from a Supplement
in Order To Prevent Iron Deficiency?
A reasonable theoretic approach to estimating the requirement for
absorbed supplemental iron is to calculate how much iron would be needed
to prevent the hemoglobin deficits in unsupplemented women compared
with supplemented women. The amount of iron required to prevent such
a deficit can be derived most directly from the study of Taylor and Lind
(1979), which is summarized in Table 14-1, in which total red cell mass and
plasma volume were measured at 12 and 36 weeks of gestation. The final
hemoglobin concentration averaged 1.6 g/dl higher in the supplemented
than in the unsupplemented group (among the highest differences observed
in the studies summarized in Table 14-1~. Over this 24-week study period,
the red cell mass increased by an average of approximately 450 ml in
the supplemented group compared with 180 ml in the unsupplemented
women, a difference of 270 ml. Since each milliliter of packed red blood
cells contains about 1.2 mg of iron, a 270-ml difference in red cell mass
is equivalent to 325 mg of iron. Dividing 325 mg of iron by the 168 days
between 12 and 36 weeks of gestation indicates that 1.9 mg of extra iron
must be assimilated daily to prevent the deficit in red blood cell mass.
After allowing for a higher rate of iron accumulation between 36 and 40
weeks of gestation and adding 25% for greater than average needs, the
subcommittee estimated that about 3 mg of supplemental iron in addition
to dietary iron should be assimilated daily during the second and third
trimesters to prevent iron deficiency in most women. Figure 14-2 suggests
that 3 mg of iron can be readily absorbed from a 30-mg daily dose of
ferrous iron given between meals.
Duration and Dose
An appropriate time to begin iron supplementation at a dose of 30
mg/day is after about week 12 of gestation (the beginning of the second
trimester), when the iron requirements for pregnancy begin to increase.
Iron administration at a dose of 60 to 120 mg/day (preferably in divided
doses) is indicated if there is laboratory evidence of an already established
anemia at any stage of pregnancy. The dose should be decreased to 30
mg/day when the hemoglobin concentration is within the normal range for
the stage of gestation (Figure 14-1~.
OCR for page 293
IRON
293
Compliance and Side Effects
One problem with supplement use during pregnancy is uncertainty
about compliance (Bonnar et al., 1969), particularly when poverty and cer-
tain ethnic beliefs reduce the availability or acceptability of supplements.
Early in pregnancy, morning sickness probably contributes to reduced con-
sumption of nutrient supplements. Late in pregnancy, constipation and
abdominal discomfort are frequent regardless of whether supplements are
used or not. Taking high doses of iron may increase these problems and
thus discourage supplement use. Iron appears to be best tolerated when
administered at bedtime.
Potential side effects of iron administration include heartburn, nausea,
upper abdominal discomfort, constipation, and diarrhea. The most careful
studies that focused on side effects involved double-blind administration of
large therapeutic doses of iron to large groups of blood donors (Hallberg et
al., 1967b; Solvell, 1970~. At a dosage of 200 mg of iron per day as ferrous
sulfate divided into three doses per day, approximately 25% of subjects had
side effects, compared with 13% of those who received a placebo. When
the dose was doubled, side effects increased to 40%. Constipation and
diarrhea occurred with the same frequency at the two doses, but nausea
and upper abdominal pain were more common at the higher dose. The risk
of side effects is proportional to the amount of elemental iron in various
soluble ferrous iron compounds and therefore appeared to be primarily
a function of the amount of soluble iron in the small intestine. Little
information is available about side effects at doses below 200 ma, but it is
reasonable to infer that side effects are much less likely at 30 mg/day.
CLINICAL APPLICATIONS
.
~ prevent iron deficiency, the subcommittee recommends the
routine use of 30 mg of ferrous iron per day beginning at about week 12 of
gestation, in conjunction with a well-balanced diet that contains enhancers
of iron absorption (ascorbic acid, meat).
· 1b enhance absorption, it is advisable to take supplemental iron
between meals with liquids other than milk, tea, and coffee.
· Hemoglobin or hematocrit should routinely be determined at the
first prenatal visit in order to detect preexisting anemia. A hemoglobin
level below 11.0 gall during the first or third trimesters or below 10.5 g/dl
during the second trimester is defined as anemia. Anemia accompanied by
a serum ferritin concentration of <12 ,ug/dl can be presumed to be iron
deficiency anemia and requires treatment with 60 to 120 mg of ferrous iron
daily. When the hemoglobin concentration becomes normal for the stage
of gestation, the dose can be decreased to 30 mg/day.
OCR for page 294
294
DIETARY INTAKE AND NUTRIENT SUPPLEMENTS
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Representative terms from entire chapter:
iron absorption