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*
Department of Population and International Health,
Department of Epidemiology and
**
Department of Environmental Health and the Program for Population Genetics, Harvard School of Public Health, Boston, MA 02115
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • China • women • folic acid • vitamin B-12 • vitamin B-6 • iron
|
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), and similar findings have been reported for women
in developing countries (Hercberg and Galan 1992
). The
limited data that are available from China suggest that deficiencies of
iron (Li et al. 1993
, Zhou et al. 1998
),
folic acid (An and Xiu-qing 1986
) and other B
vitamins (Zhan et al. 1997
) may be relatively common
among young Chinese women.
The recognition of micronutrient deficiencies in women of reproductive
age is important not only because nutritional status affects the
woman’s health and productivity but also because deficiencies are
associated with adverse pregnancy outcomes. Poor periconceptional folic
acid status increases the risk of neural tube defects
(NTD3
) (Czeizel and Dudas 1992
, Mills et al. 1995
, Steegers-Theunissen et al. 1994
), and
other evidence indicates that vitamin B-12 status also may influence
NTD risk, independent of folate status (Kirke et al. 1993
, Steen et al. 1998
). Folate deficiency
during pregnancy has been associated with low birth weight (LBW) and
preterm delivery (Baumslaug et al. 1970
, Scholl et al. 1996
), and prenatal vitamin B-6 status may influence
birth weight as well (Kubler 1981
). Poor B vitamin
status also has been linked to hyperhomocysteinemia, which is
associated with an increased risk of NTD (Mills et al. 1995
, Molloy et al. 1998
), preeclampsia
(Leeda et al. 1998
, Rajkovic et al. 1997
)
and spontaneous abortion (Steegers-Theunissen et al. 1992
, Wouters et al. 1993
).
Iron deficiency remains the most common nutrient deficiency worldwide,
with women of childbearing age among those at the greatest risk
(DeMaeyer and Adiels-Tegman 1985
). Iron deficiency
impairs immune function (IOM 1990
) and was
associated with reduced work output among women cotton mill workers in
Beijing, China (Li et al. 1994
). Recent evidence
indicates that iron deficiency during pregnancy negatively affects
fetal growth (Singla et al. 1997
) and increases the risk
of infant iron deficiency (Kilbride et al. 1999
,
Preziosi et al. 1997
), which is associated with lower
Apgar scores (Preziosi et al. 1997
) and potentially
irreversible delays in cognitive and psychomotor development
(Lozoff et al. 1996
).
The identification of iron deficiency can be complicated by physiologic
changes that perturb typical measures of iron status. For instance,
although plasma ferritin concentration is the most sensitive indicator
of iron deficiency in healthy persons (Cook and Skikne 1989
), infections and other inflammatory processes that trigger
an acute-phase response can artificially elevate ferritin
concentrations. Previous studies indicate that the exposure of textile
workers to cotton dust initiates both acute and chronic lung
inflammation (Li et al. 1995
, Rylander 1987
), which could speciously elevate ferritin concentrations,
thereby complicating estimates of iron deficiency in textile workers.
Recently, transferrin receptor (TfR) concentration was identified as a
useful and stable measure of iron status, reflecting tissue iron
availability while remaining unaffected by infection (Ahluwalia 1998
). The determination of both ferritin and TfR may provide a
more sensitive and reliable measure of iron status in some groups,
including textile workers.
Although micronutrient deficiencies in reproductive-age women
jeopardize both their health and that of their offspring, intervention
trials indicate that supplementation improves nutritional status
(Li et al. 1994
, Ubbink et al. 1994
) and
reduces the reproductive risks associated with deficiency
(Baumslag et al. 1970
, Berry et al. 1999
,
Czeizel and Dudas 1992
, Medical Research Council Vitamin Study Research Group 1991
). In 1992, the U.S. Public
Health Service advised women who were pregnant or were capable of
becoming pregnant to consume at least 400 µg of folic acid/d
(MMWR 1992
). No data are available on the prevalence of
routine periconceptional vitamin and mineral supplementation in China.
However, cereal grains in China are not fortified with folic acid, and
a recent folic acid intervention study in China found that 40–48% of
women who had been asked to purchase and consume folate supplements in
the perinatal period did not comply (Berry et al. 1999
).
Even in large urban areas such as Beijing, where antenatal care is
widely available and prenatal supplements are routinely recommended,
supplementation most likely begins after pregnancy has been clinically
established, usually around weeks 8–10, which is too late to prevent
adverse pregnancy events that occur earlier in gestation, such as
spontaneous abortion or certain birth defects. Thus, suboptimal
micronutrient status in young Chinese women could be an important
determinant of adverse pregnancy outcomes that would be amenable to
intervention.
The present study in Chinese women of childbearing age was designed to address the following questions: 1) How prevalent and severe are deficiencies of B vitamins and iron in this population? 2) Does the prevalence of these deficiencies vary by season? 3) What is the relation between anemia and plasma concentrations of ferritin and TfR? 4) What is the relation between anemia and B vitamin deficiencies?
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The current assessment of nutritional status was conducted in
conjunction with an on-going prospective study of the effects of
rotating shift work on reproductive outcomes among female textile
workers in Anqing, China. Anqing is located 
200 km west of Shanghai.
All employees of the textile mills and their families receive health
care, including prenatal, delivery and postnatal care, in the nearby
hospital. For the present study, eligible subjects were the 563 women
enrolled in the shift work study between August 1996 and December 1998.
All women were married and between 20 and 34 y of age and had
never smoked. In addition, eligible women had obtained permission to
have a child and were attempting to become pregnant during the course
of the prospective study. Women were excluded if they were pregnant at
the initial interview, had tried unsuccessfully to get pregnant for at
least 1 y, were current or former smokers or planned to quit,
change jobs or move out of the city in the coming year. Although we
originally intended to evaluate the effects of work shift on
nutritional status, only 39 women enrolled during this period worked
nonrotating shifts, so data for all types of shifts were pooled for
analyses. The Human Investigations Review Committees at the Harvard
School of Public Health and Beijing Medical University approved all
study procedures, and informed consent was obtained from each woman.
Measurements.
At enrollment, height and body weight in light clothing were measured to the nearest 0.1 kg and 0.1 cm, respectively, with a beam weighing scale and measuring system. At that time, interviewers administered a previously validated questionnaire to the women and their husbands to collect baseline information on sociodemographic, environmental and personal attributes that might be related to shift work and reproductive outcomes. Included among these variables were education level, menstrual characteristics (cycle length and bleeding days/cycle), use of contraceptives or vitamin and/or mineral supplements and current intake of alcohol.
Preexisting nonfasting blood samples were used for this project. They were obtained from women before the initial interview via venipuncture into 10-mL, metal-free EDTA-treated tubes. A small aliquot of whole blood was used to determine hemoglobin (Hb) concentration. The remaining blood was centrifuged, and plasma was obtained and stored at -20°C until shipped on dry ice to the Harvard School of Public Health, where it was stored at -70°C before nutritional analyses. Frozen samples were transported to the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, where plasma concentrations of ferritin, TfR, folic acid and vitamins B-6 and B-12 were measured.
Hb concentration was determined in whole blood according to an
automated colorimetric procedure. Plasma folate and vitamin B-12
concentrations were determined with a radioimmunoassay method using a
commercially available kit from BioRad Diagnotics Group (Hercules, CA).
Plasma vitamin B-6 (as pyridoxal-5'-phosphate) was measured according
to the tyrosine decarboxylase apoenzyme method (Shin et al. 1983
). Vitamin measurements were completed in four batches over
an 11-mo period, with 63–282 samples in each batch. Typical
coefficients of variation for in-house control plasma samples were
4.4–7.5% for folate, 5.3–7.4% for vitamin B-12 and 3.1–5.8% for
vitamin B-6. Plasma ferritin and TfR concentrations were determined in
a subset of 499 women for whom adequate plasma samples were available
with the use of enzyme immunoassays kits from Ramco Laboratories
(Houston, TX). These measurements were made in three batches during a
13-mo period, with 100–282 samples in each batch. Mean intra-assay
and interassay variabilities were 4.2 and 6.0% for TfR and 6.7 and
7.7% for ferritin, respectively.
Statistical analysis.
We used SAS statistical software for Windows, version 6.12 (SAS Institute 1989
) for all analyses. Summary statistics were
calculated and used to describe Hb and plasma concentrations of folic
acid, vitamin B-12, vitamin B-6, ferritin and TfR. Mean (arithmetic)
plasma vitamin concentrations were compared with published reference
values to determine the proportion of women with deficiency. Below
normal Hb concentration was defined as <120 g/L, which is based on
World Health Organization recommendations (World Health Organization 1968
) for nonpregnant women. Below-normal
concentrations for other nutritional variables were defined as <12
µg/L for ferritin (DeMaeyer 1989
), >8.3 mg/L for TfR
(Yeung et al. 1998
), <6.8 nmol/L (3 ng/mL) for folic
acid (Herbert and Das 1994
), <30 nmol/L for
pyridoxal-5'-phosphate (Leklem 1994
) and <221 pmol/L
(300 pg/mL) for vitamin B-12 (Koehler et al. 1996
).
To determine whether micronutrient status was related to age, body mass
index (BMI), education, menstrual characteristics or the use of
contraceptives, we compared mean micronutrient concentrations across
categories of these variables using the General Linear Models (GLM)
procedure of SAS Institute and compared the proportion of women with
abnormal values across categories using 
2 analyses
(Selvin 1996
). To determine whether micronutrient status
was influenced by the season in which blood samples were obtained, we
defined four seasons as follows: winter (December, January, February),
spring (March, April, May), summer (June, July, August) and fall
(September, October, November). Seasons in which mean Hb or plasma
micronutrient concentrations differed significantly were identified
using the GLM procedure of SAS Institute with Tukey’s adjustment for
multiple comparisons (Kleinbaum et al. 1988
). In
addition, the proportion of women with abnormal values was determined
for each season, and significant differences among the proportions were
evaluated using 2 analyses (Selvin 1996
).
The GLM procedure was also used to determine whether mean TfR
concentration varied across strata of ferritin and whether mean
vitamin, ferritin and TfR concentrations varied across Hb strata. In
both analyses, significantly different means were identified using
Tukey’s adjustment for multiple comparisons (Kleinbaum et al. 1988
). Similarly, the proportion of women with elevated TfR was
compared across ferritin strata and the proportion of women with
abnormal nutritional parameters was compared across strata of Hb, with
significant differences among the proportions evaluated using
2 analyses and the Mantel-Haenszel 2
test for trend (Rosner 1995
). If not otherwise noted,
statistical significance refers to P 
0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Most women (90%) were between 23 and 28 y old, and 95% had a
BMI of 23 kg/m2. Because eligible women were
married, had obtained permission to become pregnant and were planning
to become pregnant in the near future, only 18% reported the current
use of any type of contraceptive. Only 2% indicated they used nutrient
supplements of any kind.
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Although mean folic acid and vitamin B-6 concentrations were within the
normal range, deficiencies of these vitamins were observed in 23 and
26% of women, respectively (Table 2
). Ten percent of women had combined deficiencies of folic acid and
vitamin B-6, and 39% were deficient in either folate or vitamin B-6.
Low plasma concentrations of vitamin B-12 were observed in 10% of
women. Overall, 44% of women were deficient in at least one B vitamin,
although <2% were deficient in all three. The mean concentration of
folic acid was significantly lower in women in the lowest BMI quintile
(18.02 kg/m2) than in those in the upper four
quintiles (8.7 ± 3.4 versus 10.0 ± 4.2 nmol/L, P
= 0.001). In addition, the prevalence of folate deficiency
decreased significantly across BMI quintiles from 30% in the lowest
quintile to 17% in the highest quintile (P for trend = 0.02). The prevalence of vitamin B-12 deficiency, however, increased
across BMI quintiles from 5% in the lowest quintile to 19% in the
highest (P for trend = 0.0002). Vitamin status was
unrelated to age, education, menstrual characteristics or contraceptive
use.
|
. As shown in the distribution of Hb
concentration (Fig. 1
), nearly 60% of women had an Hb concentration of 100–119 g/L, and
20% had <100 g/L; only 5% had <90 g/L. Plasma ferritin and TfR
concentrations were determined in a subset of 499 women for whom
adequate plasma samples were available. Of these, 17% had a ferritin
concentration of <12 µg/L, indicating iron depletion (Table 2)
, and
an additional 19% had a ferritin concentration of 12–24 µg/L,
indicative of low but not yet depleted stores; 11% of women had
elevated TfR. Overall, 22% of women had either low ferritin or
elevated TfR. Mean TfR concentration was significantly higher among
women with depleted iron stores than among women with ferritin of 
12
µg/L (Table 3
). Furthermore, 33% of women with depleted iron stores, and 24% with
ferritin of <20 µg/L had elevated TfR concentrations, indicating
functional iron deficiency. Among women with elevated TfR, 51% also
had depleted iron stores. No relation was observed between age, BMI,
education, contraceptive use, menstrual cycle length or number of
bleeding days per cycle and either mean concentrations of Hb, ferritin
and TfR (ANOVA P > 0.05) or the proportion of women
with anemia, depleted iron stores or elevated TfR
(2 P > 0.05).
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Mean folic acid and Hb concentrations were significantly lower in
summer than in the other seasons, whereas mean vitamin B-6
concentration was lower in winter and spring than in summer and fall
(Table 4
). No seasonal variations were observed in plasma concentrations of
vitamin B-12, ferritin or TfR.
|
). Folate deficiency was much more common in summer than in the other
seasons (42% versus <20%, 2 P
= 0.001), and the prevalence of moderate anemia (Hb <100 g/L)
followed the same seasonal pattern as folate deficiency, with twice as
many moderately anemic women observed in summer as in winter (31%
versus 15%, 2 P = 0.01). The
percentage of women with mild anemia (Hb 100–120 g/L) remained fairly
constant across the seasons at 60% (data not shown). Vitamin B-6
deficiency occurred in 35% of women in winter and spring compared
with only 15% of women in fall (2
P = 0.001).
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We compared nutritional status across three strata of Hb concentration:
<100, 100–119 and 120 g/L (Table 5
). Mean concentrations of all three vitamins were significantly lower
among women with Hb of <100 g/L than among nonanemic women. Moreover,
the prevalence of vitamin deficiencies decreased across Hb strata, with
the prevalence of vitamin B-6 deficiency, for instance, nearly 250%
greater among women in the lowest Hb group than among nonanemic women.
Among women with Hb of <100 g/L, 54% were deficient in one or more
vitamins compared with 31% of nonanemic women
(2 P = 0.002). Although the
prevalence of iron depletion (ferritin <12 µg/L) was 275% greater
among women in the lowest Hb group than among nonanemic women, only
18% of all anemic women and 23% of women with Hb of <100 g/L had
depleted iron stores, and only 12% of anemic women had elevated TfR.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We found strong evidence that the prevalence of moderate anemia and
deficiencies of both folate and vitamin B-6 varies according to season.
Zheng et al. (1989)
also reported seasonal variations in
folate status among subjects in Linxian, China, with lower red cell
folate observed between April and August compared with September
through March, which is consistent with our finding of lower plasma
folate during summer. To our knowledge, ours is the first report of
seasonal variation in vitamin B-6 status from China. Understanding
seasonal variations in nutritional status is particularly important in
women of childbearing age because some evidence suggests that perinatal
outcomes, including perinatal death, also vary by season (Zhang et al. 1991
).
The high prevalence of deficiencies of folic acid or vitamin B-12
(30%) among women who may be attempting to become pregnant poses
particular reproductive risks given recent findings that relate poor
periconceptional folate (Czeizel and Dudas 1992
,
Mills et al. 1995
) and vitamin B-12 (Kirke et al. 1993
, Steen et al. 1998
) status to the
occurrence of NTD and other birth defects (Shaw et al. 1995
). Reports indicate that NTD occur more frequently in rural
areas (Hu et al. 1996
, Lian et al. 1987
,
Wang et al. 1996
) and Northern provinces (Berry et al. 1999
, Moore et al. 1997
) of China than in
Western countries, and there is evidence that poor B vitamin status may
be involved. In a study of 195 urban and 216 rural women, Zhan et al. (1997)
reported a correlation between measures of folate
and vitamin B-12 status and the occurrence of NTD in rural China.
Furthermore, a recent folic acid supplementation trial among nearly
250,000 Chinese women reported that periconceptional intake of 400 µg
of folic acid/d reduced the risk of NTD by as much as 85% in Northern
areas and 40% in Southern regions (Berry et al. 1999
).
In addition to birth defects, however, which are relatively rare
events, maternal B vitamin deficiencies may contribute to more common
adverse pregnancy complications, such as spontaneous abortion
(Giles 1966, Hibbard 1964
, Wouters et al. 1993
), preeclampsia (Brophy and Siiteri 1975), preterm birth and LBW (Hibbard 1975
,
Kubler 1981
, Scholl et al. 1996
), and can
lead to elevated homocysteine concentrations, which have been linked to
preeclampsia (Rajkovic et al. 1997
) and spontaneous
abortion (Wouters et al. 1993
). The high prevalence of B
vitamin deficiencies that we observed may increase the risk of adverse
pregnancy outcomes. In 1990, the proportion of Chinese infants with LBW
was estimated at 5–9.9% (World Health Organization 1992
). Zhang et al. (1991)
reported that from
1986 to 1987, the perinatal mortality rates in Shanghai were 13 and 15
times higher among LBW and preterm infants, respectively, than among
infants of normal weight and gestational age. Correction of maternal
vitamin deficiencies through supplementation could provide an easy and
inexpensive means of reducing perinatal deaths.
In the present study, 17% of women had ferritin concentrations of <12
µg/L, and an additional 19% had ferritin concentrations of 12–24
µg/L, reflecting low but not yet depleted iron stores. Although these
findings suggest that nearly 40% of women had some degree of iron
depletion, they may actually underestimate the true prevalence of iron
deficiency. Ferritin concentration is pathologically elevated in
response to acute and chronic inflammation (Blake et al. 1981
, Kuvibidila et al. 1994
), and Li et al. (1995)
reported that exposure to cotton dust increased
airway inflammation in cotton mill workers in Beijing. Similar
increases in inflammatory markers among textile workers have been
reported by others (Keman et al. 1998
, Rylander 1987
), and it is possible that the women in our study had
artificially elevated ferritin concentrations due to an inflammatory
response related to textile work. An independent measure of
inflammation, such as C-reactive protein, would be necessary to
confirm this suspicion.
Even if we assume that only 17% of our subjects have iron deficiency,
without supplemental iron their iron status is likely to deteriorate
further, particularly because most will become pregnant over subsequent
months (IOM 1990
). In a study of 221 pregnant
women in Taipei, Taiwan, Ho et al. (1987)
found that
10% of previously nonanemic, unsupplemented women developed frank iron
deficiency anemia and that 52% developed some degree of iron
deficiency by the end of their pregnancy. Poor maternal iron status
during pregnancy is associated with reduced infant length and Apgar
scores (Preziosi et al. 1997
), lower birth weight and
mid-arm circumference (Singla et al. 1997
) and iron
deficiency during infancy (Kilbride et al. 1999
), which
is associated with long-term developmental disadvantages
(Lozoff et al. 1991
).
Assessment of TfR concentration has been advocated as a way of more
sensitively identifying iron deficiency in conditions in which ferritin
concentrations may be altered by factors other than iron stores, such
as gestation (Carmel and Skikne 1992
) or inflammation
(Ahluwalia 1998
). We found that the prevalence of
elevated TfR increased significantly as Hb and ferritin concentrations
decreased, with elevated TfR observed in a third of women with depleted
iron stores. However, of the 53 women with elevated TfR concentrations,
only 27 (51%) had a plasma ferritin concentration of <12 µg/L, and
32 (60%) had a ferritin concentration of <16 µg/L. This finding
contrasts with those of Carriaga et al. (1991)
, who
reported that 100% of their subjects with elevated TfR also had
ferritin of <16 µg/L. Our results can be interpreted in one of two
ways: either 1) ferritin is pathologically elevated due to
infection or inflammation or 2) factors other than iron
depletion are contributing to elevated TfR concentrations. Previous
studies showed that elevated TfR also occurs in conditions associated
with ineffective erythropoiesis, such as thalassemia (Ahluwalia 1998
) and megaloblastic anemia due to vitamin B-12 deficiency
(Carmel and Skikne 1992
). We have no data on the
prevalence of thalassemia in our cohort, although others have reported
that some variant of the trait may be carried by >3% of persons in
Southern China (Xu et al. 1996
), so this disorder may be
a factor in our study. Severe vitamin B-12 deficiency (<275 pmol/L)
was rare in our population, occurring in just 7 women (1.2%), whereas
severe folic acid deficiency (<4.5 nmol/L) was detected in 33 women
(6%). Without other hematologic measures, such as mean cell volume, we
cannot determine whether severe B vitamin deficiencies were associated
with megaloblastosis.
Although 80% of our study subjects met the World Health Organization (1968)
criteria for anemia (Hb <120 g/L), 75% of
these had very mild anemia (Hb of 100–119 g/L) and 20% had Hb of
<100 g/L. The high prevalence of mild anemia is consistent with data
from the Chinese Institute of Nutrition and Food Hygiene (1985)
, which reported that 21–55% of "fertile women"
were anemic. In a study of 447 nonpregnant female cotton mill workers
in Beijing, Li et al. (1993)
reported a mean Hb of 123
± 15 g/L and a 34% prevalence of anemia. In that study, 71% of
anemic women (24% of their subjects overall) had serum ferritin of
<12 µg/L, leading the authors to conclude that most of the anemia in
their population was related to iron deficiency. In our study, the
contribution of iron deficiency to anemia appears to be much smaller.
We found that only 18% of all anemic women and 22% of those with Hb
of <100 g/L had depleted iron stores, whereas 54% of our subjects
with Hb of <100 g/L were deficient in at least one B vitamin. These
findings suggest that in addition to iron deficiency, B vitamin
deficiencies are contributing to the high prevalence of anemia in our
population. This conclusion is supported by the similarity in the
seasonal patterns observed for low Hb and folate deficiency, whereas no
seasonal effects were observed for plasma ferritin. No data were
available on the folic acid, vitamin B-6 or vitamin B-12 status of
women in the Beijing study (Li et al. 1993
). However,
the mean weight and BMI of Anqing women in the present study were 49.2
kg and 19.8 kg/m2, respectively, compared with
55.6 kg and 22.1 kg/m2 in the Beijing study.
These anthropometric differences suggest that energy balance and
perhaps overall nutritional status differed between the Anqing and
Beijing textile workers, although without reliable dietary data for the
two groups, it is impossible to conclude that such differences were
necessarily related to nutrient intake. Nevertheless, it is clear from
our data that the women with low Hb concentrations were also more
likely to have micronutrient deficiencies.
Poor micronutrient status among women of childbearing age jeopardizes their health and may influence their risk of achieving a normal pregnancy and delivering a healthy infant. Although we found a high prevalence of micronutrient deficiencies in Chinese textile workers of reproductive age, most of these deficiencies could be corrected easily and inexpensively through appropriate supplementation with B vitamins and iron. Family planning and antenatal care are available to these women, and the incorporation of nutritional counseling and therapy into these services could provide a convenient means of improving both maternal and infant health.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
|---|
3 Abbreviations used: BMI, body mass index; Hb, hemoglobin; LBW, low birth weight; NTD, neural tube defects; TfR, transferrin receptor.
Manuscript received April 10, 2000. Initial review completed May 16, 2000. Revision accepted August 3, 2000.
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