Effect of Iron Deficiency Anemia in Pregnancy on Child Mental Development in

Rural China
Suying Chang, Lingxia Zeng, Inge D. Brouwer, Frans J. Kok and Hong Yan
Pediatrics 2013;131;e755; originally published online February 11, 2013;
DOI: 10.1542/peds.2011-3513

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Effect of Iron Deficiency Anemia in Pregnancy on Child Mental Development in

Rural China
Suying Chang, Lingxia Zeng, Inge D. Brouwer, Frans J. Kok and Hong Yan
Pediatrics 2013;131;e755; originally published online February 11, 2013;
DOI: 10.1542/peds.2011-3513
Updated Information &
Services

including high resolution figures, can be found at:

http://pediatrics.aappublications.org/content/131/3/e755.full.h
tml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2013 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Effect of Iron Deciency Anemia in Pregnancy on Child

Mental Development in Rural China
AUTHORS: Suying Chang, PhD,a,b Lingxia Zeng, PhD,c Inge
D. Brouwer, PhD,b Frans J. Kok, PhD,b and Hong Yan, PhDc
aUnited

Nations Childrens Fund Ofce for China, Beijing, China;

of Human Nutrition, Wageningen University,
Wageningen, Netherlands; and cSchool of Public Health, Xian
Jiaotong University College of Medicine, Shaanxi, China
bDivision

KEY WORDS
follow-up, iron deciency anemia in pregnancy, child
development
ABBREVIATIONS
BSIDBayley scale of infant development
CIcondence interval
GLMgeneral linear model
Hbhemoglobin
IDiron deciency
IDAiron deciency anemia
MDmental development crude score
MDImental development index
MMNmultiple micronutrient supplementation
PDpsychomotor development crude score
PDIpsychomotor development index
Drs Chang and Zeng contributed equally to this work.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-3513
doi:10.1542/peds.2011-3513
Accepted for publication Nov 14, 2012
Address correspondence to Hong Yan, PhD, Xian Jiaotong
University College of Medicine, Shaanxi Province 710061,
P. R. China. E-mail: hongyan57@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING: The eld work was supported by Program for New
Century Excellent Talents in University (grant NCET-11-0417), the
National Natural Science Foundation of China (grant 30300287),
and United Nations Childrens Fund (UNICEF). This work was
supported by the Ellison Medical Foundation-International
Nutrition Foundation.

WHATS KNOWN ON THIS SUBJECT: In humans, the brain growth

spurt begins in the last trimester of pregnancy and extends
through the rst 2 years of life. Studies show poor cognitive and
motor development among children who have iron deciency
anemia in infancy.
WHAT THIS STUDY ADDS: Prenatal iron deciency anemia in the
third trimester affects child mental development. Prenatal
micronutrient supplementation with sufcient iron protects child
mental development even when the womans iron deciency
anemia is not properly corrected during pregnancy.

abstract
OBJECTIVE: To determine the impact of iron deciency anemia (IDA) in
pregnancy on young child development.
METHODS: A 2-year follow-up of 850 children born to women who
participated in a double-blind cluster randomized controlled trial of
prenatal micronutrient supplementation in western rural China.
These women were randomly assigned to receive either daily folic
acid, iron/folic acid (60 mg iron), or multiple micronutrients (with
30 mg iron) during pregnancy. Children were categorized into the
prenatal-IDA and prenatalnon-IDA groups based on the mothers
hemoglobin in the third trimester. Each group contained 3
subgroups based on mothers treatment: folic acid, iron/folic acid,
and multiple micronutrients. Bayley scales of infant development
were administered to the children to assess their development at
3, 6, 12, 18, and 24 months of age.
RESULTS: Compared with the prenatalnon-IDA group, the prenatal-IDA
group showed a signicantly lower mental development index at 12,
18, and 24 months of age. The adjusted mean difference was 5.8 (95%
condence interval [CI], 1.110.5), 5.1 (95% CI, 1.29.0), and 5.3 (95%
CI, 0.99.7), respectively. Further analysis showed that the mental
development indexes in the prenatal-IDA group and prenatalnonIDA group were similar with supplementation of iron/folic acid but
were signicantly lower in the prenatal-IDA group with supplementation
of folic acid or multiple micronutrients.
CONCLUSIONS: Prenatal IDA in the third trimester is associated with
mental development of the child. However, prenatal supplementation
with sufcient iron protects child development even when the womans
IDA was not properly corrected in pregnancy. Pediatrics 2013;131:
e755e763

PEDIATRICS Volume 131, Number 3, March 2013

e755

Young children and women of reproductive age, especially during pregnancy,

have increased iron requirements,
placing them at increased risk of
deciency and related adverse consequences.1 Iron is essential for neurotransmission, energy metabolism,
and myelination in the developing
brain.2 In humans, the brain growth
spurt begins in the last trimester of
pregnancy and extends through the
rst 2 years of life.3 Numerous studies
showed lower cognitive and motor test
scores in infants with iron deciency
anemia (IDA) that persist being low
even though they received iron treatment as infants.2 There is direct evidence of biochemical abnormalities in
brains of iron-decient infants, which
demonstrated a slowed nerve conduction velocity in iron-decient infants at
6 months of age.4,5
Brain iron deciency(ID) in the fetus or
neonate could be more detrimental than
postnatal ID because of the rapidity of
brain growth during pregnancy.6 Animal
studies demonstrated that proper iron
nutrition during perinatal development
is critical not only for obtaining adequate levels of brain iron, but also for
normal behavioral and motor development in the offspring.4,7 During
pregnancy, the iron requirements of
pregnant women are increased threefold to cover needs of expansion of maternal red cell mass and growth of the
fetal placenta. Maternal anemia develops
unless these needs are met.8 Epidemiologic studies suggest that maternal
ID contributes to reduced fetal iron
stores,915 and infants born to anemic
mothers have low iron stores and are
more likely to develop anemia.911,16,17
However, knowledge on the impact of
prenatal ID and IDA on mental and motor development of children is limited.
Study results on prenatal supplementation (with iron) and child development
are inconclusive. A study in Nepal found
that prenatal supplementation with iron
e756

CHANG et al

and folic acid was positively associated

with general intellectual ability, some
aspects of executive function, and motor
function in offspring at 7 to 9 years
of age.18 A study in Indonesia did not
nd an impact of prenatal supplementation of iron on functional development
of infants.19 Li et al reported a followup of a randomized trial on prenatal
supplementation in rural China and
demonstrated a benet of multiple
micronutrient supplementation (MMN)
on the mental development of children
at 12 months of age,20,21 but this positive
impact of MMN was not shown at 18and 24-month follow-up assessments
(Li q, Yan H, Zeng L, Cheng Y, Dang S,
Duan S and Tsuji I, unpublished data,
2013). Apparently, the anemia prevalence of women in these studies was still
high at the end of pregnancy even after
iron supplementation,19,20,22 which may
have compromised the impact of iron
supplementation on child development.
The current study is a follow-up of the
same randomized trial used in Li et al.21
We followed children until 24 months of
age and explored the relation between
iron status in pregnancy and child development. We predict that IDA in
pregnancy is associated with the development of the child and that iron
supplementation in pregnancy is benecial to child development.

METHODS
This study focused on the follow-up
assessments of mental and psychomotor development of children at 3, 6, 12, 18,
and 24 months of age. These children
were born to women involved in a
double-blind cluster randomized controlled trial of prenatal micronutrient
supplementation. The aim of the original
project was to evaluate the impact of
prenatal supplementation on birth weight,
duration of pregnancy, and perinatal
mortality in rural western China from
2002 to 2006. The details of the trial are
described elsewhere.20 Briey, the trial

was conducted in 2 poor rural counties.

Villages were randomly assigned to 3
treatments: MMN, iron/folic acid, or folic
acid supplementation before recruitment of subjects. The MMNs were formulated to approximately contain
the World Health Organization/United
Nations Childrens Fund recommended
dietary allowances for each of 15 minerals or vitamins as follows: 30 mg iron,
400 mg folate, 15 mg zinc, 2.0 mg copper,
65.0 mg selenium, 150.0 mg iodine, 800
mg vitamin A, 1.4 mg vitamin B1, 1.4 mg
vitamin B2, 1.9 mg vitamin B6, 2.6 mg
vitamin B12, 5 mg vitamin D, 70 mg vitamin C, 10 mg vitamin E, and 18 mg niacin. The iron/folic acid supplementation
contained 60 mg iron and 400 mg folic
acid. The folic acid supplementation
contained 400 mg folic acid.
Figure 1 summarizes the recruitment,
randomization, and participation of
subjects in the trial. All women resident
in the project sites who became pregnant during the study period, fullled
trial selection, and lled out the consent form for this trial were recruited
by village doctors. Newly identied
pregnant women received an initial
prenatal care check-up for baseline
information. Altogether, 5828 eligible
women were recruited in the trial.
Among them, 16.7% did not attend the
hemoglobin (Hb) check because of lack
of follow-up, withdrawing from the trial, or fetal losses before the third trimester, and another 28.3% missed the
prenatal care check in the third trimester. Approximately 55% (3233) of
the women attended the Hb check in
the third trimester.
During 2004 to 2006, a follow-up study
was conducted to assess the development of these children. A total of
1286 women with a singleton full term
live birth attended the study. The current study focused on women whose Hb
had been tested at the third trimester
and who attended the follow-up study:
850 women and their children met this

ARTICLE

FIGURE 1

Participant owchart.

inclusion criterion. Among them, 95

(11%) young children missed their rst
development assessment, 61 (7%)
missed the second assessment, and 84
(10%), 96 (11%), and 96 (11%) missed
their third to fth assessment, respectively. In total, 600 (71%) children
were assessed on all 5 occasions
(Fig 1). The women and their children
were categorized into prenatal-IDA and
prenatalnon-IDA groups based on Hb
in the third trimester. Each group contained 3 subgroups based on mothers
treatment: MMN, iron/folic acid, and
folic acid subgroup.
Data Collection
Previously published papers regarding
this trial described data collection
during pregnancy and delivery20 and
data collection of the follow-up study.21
PEDIATRICS Volume 131, Number 3, March 2013

Bayley scales of infant development

(BSID) were used as a measure of each
childs development. The mental scale,
psychomotor scale, and infant behavior record are the 3 parts of the BSID.23
The BSID was translated into Chinese
and locally standardized to become
culturally appropriate.24
The BSID was administered at the village clinic or the childs own home in
a standardized manner. Both examiners and participating women were
blinded with respect to the supplementation group. The childs development and its feeding practices
were proposed to be assessed at 3, 6,
12, 18, and 24 months of age; however,
because of logistical problems, this
schedule could not always be followed.
If the child was sick, was unavailable,
or could not cooperate, assessment

was arranged for a later date within 1

month. The mental development crude
score (MD) and psychomotor development crude score (PD) signify the
items that a child passes on the mental
scale and psychomotor scale of the
BSID, respectively. The mental development index (MDI) and psychomotor development index (PDI) are
nonlinear transformations of the MD
and PD, which were transformed by
using standard procedures that are
based on data for Chinese children.25,26
We did not report the infant behavior
record in this paper.
Iron status was determined on the basis
of Hb at the third trimester by HemoCue
portablespectrophotometers(ngelholm,
Sweden). They were calibrated daily, and
all measurements were made within
the temperature operating range of this
e757

device (1530C) by research team

members. The cutoff for anemia in
pregnancy women was Hb , 110 g/L.27
Data Analysis
All data were checked manually for
completeness and were double-entered
into a data management system. We
conducted range, extremum and logical
checks for accuracy. We compared
baseline characteristics between women who were and who were not involved in the current study and between
the prenatal-IDA and prenatalnon-IDA
groups by using analysis of variance or
x2 tests.
The missing values of MD and PD in each
assessment were estimated by linear
regression between age of children
with MD and PD. A general linear model
(GLM) repeated measurements was
used to compare the overall MDI and PDI
of the 5 assessments and the MDI and
PDI per assessment. The mean differences for the MDI and PDI between the 2
groups were adjusted for treatment
and for interaction term between
treatment and Hb in the third trimester.21 We considered baseline
characteristics that differed between
the 2 groups as potential confounders
in the GLM repeated measurement
adjusted model: low birth weight,
mothers age at enrollment, gestation
weeks when Hb was checked, parity of
pregnant women, gestation weeks at
birth, and childs age at assessment.

and their children in the current study.

The socioeconomic characteristics,
womens education, womens BMI at
enrollment, mean gestation weeks at
enrollment, and BMI at enrollment
were comparable between the 2
groups. Pregnant women in the
prenatal-IDA group were signicantly
older (P = .024), reported greater
parity (P = .025) at enrollment, and
had a smaller number of gestation
weeks when Hb was checked (P =
.006). Child birth weight, gestation
weeks at birth, gender distribution,
breastfeeding rate, formula introduction, prevalence of stunting and
underweight of children and age at
each assessment were comparable
between the 2 groups except child age
at the 18-month assessment (P = .001),
breastfeeding rate at 3 months (P =
.013), and formula introduction at 24
months (P = .025).
Impact of Prenatal Iron Status on
Mental Development of Young
Children
Table 2 summarizes study ndings related to the MDI of children during the
rst 24 months of life. Overall analysis
showed signicantly lower MDI (P =
.036) in the prenatal-IDA group by using
the GLM repeated measurement
adjusted model. Assessed at individual
time points, the prenatal-IDA group
showed signicantly lower MDI at 12,
18, and 24 months of age. The adjusted
mean MDI difference was 5.8 (95%
condence interval [CI], 1.110.5), 5.1
(95% CI, 1.29.0), and 5.3 (95% CI, 0.9
9.7), respectively.

Modifying Effect of Maternal

Supplementations in Pregnancy on
the Response of Prenatal Iron
Status on Child Development
We initially hypothesized that iron
supplementation in pregnancy would
be benecial to child development. Accordingly, a subgroup analysis was
conducted to explore the modifying
effect of maternal supplementations on
the response of prenatal iron status on
child development.
Table 4 summarizes MDI and PDI by
prenatal iron status and treatment
groups. Children in the prenatal-IDA
group whose mother received folic
acid or MMN had a lower MDI compared with their peers in the prenatal
non-IDA group (P = .046 in folic acid; P =
.034 in MMN), with signicant lower
MDIs at 3-, 18-, and 24-month assessments for folic acid subgroups and at
12-, 18-, and 24-month assessments for
MMN subgroups. Children in the
prenatal-IDA group whose mother received iron/folic acid (with 60 mg iron)
supplementation had a comparable
MDI in all 5 assessments (P = .641).
We did not nd signicant differences in
PDI between the prenatal-IDA and the
prenatalnon-IDA groups, regardless
of treatment.

DISCUSSION

RESULTS

Impact of Prenatal Iron Status on

Psychomotor Development of
Young Children

Our ndings show that IDA in pregnancy

is associated with the mental development of young children. Further
analysis on subgroups showed that the
differences in the MDI between the 2
groups (prenatal-IDA and prenatal
non-IDA) were only present in the folic
acid and MMN subgroups but not in the
iron/folic acid subgroup that received
60 mg iron daily.

Baseline characteristics of the women

who were and who were not involved in
this study are comparable (data not
shown). Table 1 shows the baseline
characteristics of the pregnant women

Table 3 describes PDI of children at the

5 assessments points. No signicant
differences in PDI were found between
the 2 groups by using the GLM repeated
measurementadjusted model.

This study used a longitudinal observation approach based on data from

a previous randomized trial and explored the impact of prenatal IDA on
child development. There is no sample

All analyses were conducted with Stata

version 9.2 (Stata/SE 9.2; StataCorp,
College Station, TX). All reported P values
were 2-tailed, and values ,0.05 were
considered statistically signicant.

e758

CHANG et al

ARTICLE

TABLE 1 Comparison of Baseline Characteristics of the Women and Children in the Prenatal IDA
Group and Non-IDA Group by Iron Status in the Third Trimester, Shaanxi Province, China,
2004 to 2006
Characteristics

Iron Status in Third Trimester

Prenatal-IDA (N = 384) PrenatalNon-IDA (N = 466)

Pregnant women
Age at enrollment, years [mean (SD)]a
BMI at enrollment [mean (SD)]
Gestation at enrollment, wk [mean (SD)]
Gestation Hb checked, wk [mean (SD)]a
Education
,3 y
Primary
Secondary
High school+
Household wealth
Poor
Middle
Wealthy
Parity at enrollmenta
0
1
.2
Child
Birth weight [mean (SD)]
Gestation at birth [mean (SD)]
Gender
Boy
Girl
Age of the 5 assessments, mo[mean (SD)]
3
6
12
18
24
Breastfeeding, mo
3
6
Formula introduction, mo
3
6
12
18
24
Underweight, mo
3
6
12
18
24
Stunting, mo
3
6
12
18
24

24.9 (4.5)
20.8 (2.2)
13.7 (5.7)
32.1 (2.3)

24.1 (4.5)
20.8 (2.3)
13.5 (5.5)
32.6 (2.5)

0.024
0.946
0.604
0.006
0.213

20 (5.2)
103 (26.8)
204 (53.1)
57 (14.8)

19 (4.1)
102 (21.9)
280 (60.2)
64 (13.8)

91 (23.7)
155 (40.4)
138 (35.9)

112 (24.0)
178 (38.2)
176 (37.8)

237 (61.7)
122 (31.8)
25 (6.5)

321 (68.9)
123 (26.4)
22 (4.7)

3228 (388)
40.1 (1.3)

3182 (402)
40.1 (1.4)

244 (64)
140 (36)

273 (59)
193 (41)

3.2 (0.2)
6.2 (0.3)
12.3 (0.5)
18.4 (0.5)
24.5 (0.5)

3.2 (0.2)
6.2 (0.3)
12.3 (0.4)
18.3 (0.4)
24.4 (0.5)

0.495
0.632
0.941
0.021
0.180

324 (87)
292 (80)

421 (92)
362 (81)

0.013
0.567

46 (12)
58 (15)
77 (20)
108 (28)
100 (26)

47 (10)
65 (14)
93 (20)
117 (25)
89 (19)

0.344
0.748
0.887
0.423
0.025

15 (4)
8 (2)
15 (4)
8 (2)
8 (2)

14 (3)
14 (3)
14 (3)
9 (2)
9 (2)

0.599
0.157
0.308
0.951
0.850

46 (12)
69 (18)
42 (11)
54 (14)
54 (14)

47 (10)
75 (16)
47 (10)
65 (14)
61 (13)

0.289
0.346
0.442
0.872
0.897

0.751

0.025

0.097
0.767
0.141

Values are number (percentage) unless otherwise noted.

a P , 0.05.

selection bias between this study and

the randomized trial. To our knowledge,
this is the rst longitudinal observation
on prenatal iron status and child
PEDIATRICS Volume 131, Number 3, March 2013

development. We had consistent results

for all 5 assessments in children 3 to 24
months of age. Our study was in a socioeconomically disadvantaged area,

with no child iron supplementation

after birth. This allowed us to observe
the impact of prenatal iron status and
iron supplementation on child development.
The study was limited with respect to
measurement of iron status. IDA was
estimated by Hb in this study. Hb generally overestimates the prevalence of
IDA, because it also accounts for anemia
caused by other nutritional deciencies,
infections, hemoglobinopathies, or ethnic differences in normal hemoglobin distribution.28 From results of the
baseline survey that showed a prevalence of anemia among children ,2
years of age, reproductive-aged women,
and adult men of 33.2%, 37.6%, and
8.8%, respectively (Zeng L, Dang S, Yan H,
unpublished data, 2003), we can infer
that ID was the main cause of anemia in
our study area.29 Furthermore, for
women with adequate iron, Hb starts to
decline during the early part of the rst
trimester, reaches its nadir near the
end of the second trimester because
of a physiologic response, including
plasma volume expansion, and then
gradually rises during the third trimester.30 Studies among Chinese pregnant women showed Hb did not improve
from the second to third trimester,
providing evidence that pregnant womens iron stores were not sufcient to
continue the expansion of red cell mass
in the third trimester.3133 Hence, the
high prevalence of anemia in the third
trimester is mainly caused by ID in
China.
We cannot eliminate the possibility that
the altered behavior of the prenatal-IDA
group in this study was caused by some
relevant but unmeasured factor(s),
such as maternal depression or other
environmental disadvantages, which
could account for a lack of stimulation
(leading to altered behavior and development).
Another limitation of this work was the
low power to detect changes in the MDI
e759

TABLE 2 Comparison of Mean, SD, and 95% CIs of Adjusted Difference of the MDI of Children Born
to Mothers Enrolled in the Prenatal Supplementation Trial by Prenatal Iron Status in the
Third Trimester, Shaanxi Province, China, 2004 to 2006
Age, mo
3
6
12
18
24

Group
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA
PrenatalIDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA

Number

Mean (SD)

384
466
384
466
384
466
384
466
384
466

118.6 (21.4)
118.3 (20.0)
98.7 (17.0)
99.6 (17.4)
103.1 (19.0)
105.0 (18.8)
98.0 (15.3)
100.2 (15.7)
87.9 (18.2)
90.9 (16.8)

Adjusted Difference (95% CI)a

Pa

23.2 (28.3 to 1.9)

0.224

1.8 (22.6 to 6.1)

0.42

5.8 (1.1 to 10.5)

0.016

5.1 (1.2 to 9.0)

0.010

5.3 (0.9 to 9.7)

0.017

Adjusted by treatment, interaction between treatment and gestation Hb, low birth weight, mother age at enrollment,
gestation week when Hb was checked, parity, gestation week at delivery, and age of children at assessment.

and PDI because the ndings presented

are based on post hoc analysis. We had
a 64% power to detect a 5-score change
in MDI and 73% power to detect a 4score change in PDI, with a = 0.05. Our
results require replication using larger
sample sizes.
The shown impact on child development
in the prenatal-IDA group could have
occurred during the period of fetal brain
development or during the young
childrens development. Developing rats
subjected to prenatal ID have demonstrated neurometabolic, structural,
electrophysiological, and behavioral
alterations.3436 The postnatal consumption of iron-adequate diets among
marginal iron offspring will not fully
reverse all of the observed biochemical
disturbances.37 In humans, when maternal iron status is poor, the number
of placental transferrin receptors

increases so that more iron is taken up

by the placenta. Evidence is accumulating that the capacity of this system
may be inadequate to maintain iron
transfer to the fetus when the mother
is iron decient.38 Maternal Hb is signicantly correlated with cord blood
erythrocyte count, Hb, and hematocrit
values, and these were signicantly
lower when maternal Hb was ,110 g/L
at 32 to 35 weeks of gestation.39 Newborn infants with low cord blood Hb
and iron have altered temperament
during the rst week of life.40 In our
study, prenatal IDA appears to have
impacted fetus brain iron, having adverse effects on neurodevelopment.
Publications have suggested that prenatal IDA is related to reduced fetal iron
stores. Infants of mothers with mild or
moderate IDA during pregnancy are at
risk for ID,9,16 and infants with IDA

TABLE 3 Comparison of Mean, SD, and 95% CIs of Adjusted Difference of PDI Scores of Children
Born to Mothers Enrolled in the Prenatal Supplementation Trial by Gestation Iron Status
in the Third Trimester, Shaanxi Province, China, 2004 to 2006
Age, mo
3
6
12
18
24

Group
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA
Prenatal-IDA
Prenatalnon-IDA

Number

Mean (SD)

384
466
384
466
384
466
384
466
384
466

133.0 (17.0)
133.2 (16.7)
110.0 (23.7)
111.5 (24.3)
98.3 (16.2)
100.5 (15.9)
106.0 (21.9)
107.8 (21.0)
103.9 (12.8)
103.9 (12.4)

Adjusted Difference (95% CI)a

Pa

21.7 (25.9 to 2.5)

0.429

3.4 (22.6 to 9.5)

0.262

2.5 (21.5 to 6.5)

0.226

3.3 (22.1 to 8.6)

0.229

3.8 (0.6 to 6.9)

0.019

Adjusted by treatment, interaction between treatment and gestation Hb, low birth weight, mother age at enrollment,
gestation week when Hb was checked, parity, gestation week at delivery, and age of children at assessment.

e760

CHANG et al

show poorer cognitive, motor, socialemotional, and neurophysiologic functioning than those without.3,23,4143 In
our population, children were not
provided iron supplementation after
birth. Children in the 2 groups have no
differences in terms of feeding practices, growth, and other related background characteristics. Probably, more
children in the prenatal-IDA group suffered IDA because of low fetal iron
stores, which can explain delayed
mental development of children in this
group. We did not test childrens Hb in
our follow-up assessments because of
ethical considerations.
Our nding that the impacted child development was not present in the iron/
folic acid group (with 60 mg iron),
even when the mothers IDA was not
corrected, demonstrated the benet of
sufcient iron supplementation during
pregnancy. Most fetal iron uptake
occurs after week 30, and fetal and
placental iron needs are presumably
met by increased efciency of maternal
iron absorption.39 Iron supplementation
in pregnancy improves maternal iron
status39 and can reduce the extent of
iron depletion in the third trimester.44
However, for women who enter pregnancy with low iron stores, iron supplements fails to prevent ID.39 In our
randomized trial, the prenatal anemia
prevalence in the third trimester was
still high, being 43.1%, 45.1%, and 61%
among the MMN, iron/folic acid, and
folic acid groups, respectively.20 This
showed that a high percentage of
pregnant women had exhausted their
iron stores. Prenatal iron supplementation studies in other poverty-stricken
areas also showed a high prevalence of
prenatal anemia at the end of pregnancy.11,45 The compliance and timing of
supplementation may explain part of
the high anemia prevalence, but in our
study, the rates of adherence were 93%,
92%, and 93% among the folic, iron/ folic
acid, and MMN groups, respectively, and

ARTICLE

TABLE 4 MDI and PDI by Prenatal Iron Status in Third Trimester and Treatment Groups
Index and Age, mo

Group

Folic Acid

Iron/Folic Acid

P (Stratied by Treatment)a

MMN

Mean (SD)

Mean (SD)

Mean (SD)

Prenatal-IDA
Prenatalnon-IDA

165
148

116.2 (20.2)
121.4 (21.9)

115
168

120.4 (21.2)
117.3 (18.8)

104
150

120.3 (23.2)
116.4 (18.9)

Prenatal-IDA
Prenatalnon-IDA

165
148

98.1 (16.4)
99.3 (16.0)

115
168

99.0 (17.1)
99.0 (17.4)

104
150

99.3 (18.1)
100.4 (18.9)

Prenatal-IDA
Prenatalnon-IDA

165
148

103.2 (18.2)
103.9 (18.8)

115
168

103.6 (18.4)
103.4 (20.0)

104
150

102.6 (21.0)
108.0 (17.2)

Prenatal-IDA
Prenatalnon-IDA

165
148

97.1 (16.5)
100.2 (15.7)

115
168

100.3 (12.6)
98.9 (14.9)

104
150

96.7 (15.7)
101.7 (16.6)

Prenatal-IDA
Prenatalnon-IDA

165
148

86.7 (17.4)
91.1 (17.1)

115
168

90.9 (15.7)
89.9 (16.4)

104
150

86.6 (21.6)
91.8 (17.1)

Prenatal-IDA
Prenatalnon-IDA

165
148

131.2 (16.7)
134.3 (18.6)

115
168

134.2 (18.0)
132.6 (17.0)

104
150

134.7 (16.5)
132.7 (14.1)

Prenatal-IDA
Prenatalnon-IDA

165
148

109.8 (22.4)
112.0 (23.2)

115
168

110.1 (24.2)
110.1 (24.6)

104
150

110.1 (25.2)
112.7 (25.1)

Prenatal-IDA
Prenatalnon-IDA

165
148

98.3 (17.8)
100.8 (18.1)

115
168

98.6 (15.4)
100.2 (15.4)

104
150

98.1 (14.4)
100.4 (14.0)

Prenatal-IDA
Prenatalnon-IDA

165
148

103.8 (22.6)
109.8 (21.1)

115
168

110.7 (19.6)
106.3 (22.0)

104
150

104.5 (22.7)
107.6 (19.6)

Prenatal-IDA
Prenatalnon-IDA

165
148

104.5 (13.4)
103.2 (12.2)

115
168

105.6 (11.2)
103.7 (12.2)

104
150

101.0 (13.2)
104.6 (12.8)

Folic Acid

Iron/Folic Acid

MMN

0.057

0.763

0.483

0.487

0.807

0.772

0.796

0.917

0.030

0.049

0.341

0.036

0.042

0.676

0.026

0.140

0.930

0.832

0.449

0.757

0.361

0.322

0.167

0.470

0.063

0.069

0.435

0.711

0.240

0.063

MDI
3

12

18

24

PDI
3

12

18

24

a Stratied by treatment and adjusted low birth weight, mother age at enrollment, gestation

the mean number of supplementations

consumed was 165, 166, and 165, respectively.46 In this respect, it seems
many women were iron decient when
entering pregnancy, and supplemental
iron was not sufcient to cover the
needs during pregnancy. Study results
of others indicate that IDA in pregnancy
compromised fetal iron reserves39,47
and that iron needs of the fetus take
priority over maternal requirements,48
supporting our result on the benet
of prenatal iron supplementation. A

week when Hb was checked, parity, gestation week at delivery, and age of children at assessment.

previous study21 followed the same

randomized trial20 and showed a benet
of prenatal MMN on mental development at 12 months of age. The inconsistent conclusion with the present
study is probably because the prenatal
iron status was not considered in previous analyses.

supplementation during pregnancy is

benecial to the mental development
of children in areas with poor iron
intake. Our results support the practice of routine iron supplementation
during pregnancy in poor rural areas
of China.

In summary, prenatal IDA impacts child

mental development. Sufcient iron

ACKNOWLEDGMENTS
We thank the women and their children
for continued participation. We especially appreciate the efforts of the
Shannxi study team.

2. Lozoff B, Beard J, Connor J, Barbara F,

Georgieff M, Schallert T. Long-lasting neural
and behavioral effects of iron deciency in
infancy. Nutr Rev 2006;64(5 Pt 2):S34S43

3. McCann JC, Ames BN. An overview of

evidence for a causal relation between
iron deciency during development and
decits in cognitive or behavioral

CONCLUSIONS

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