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Iron Supplementation in Pregnancy

or Infancy and Motor Development:


A Randomized Controlled Trial
Rosa M. Angulo-Barroso, PhD,a,b Ming Li, MD,c Denise C.C. Santos, PhD,b,d Yang Bian, BSN,c Julie Sturza,
MPH,b Yaping Jiang, PhD,e Niko Kaciroti, PhD,b Blair Richards, MPH,b Betsy Lozoff, MDb,f

BACKGROUND AND OBJECTIVE: Insufficient iron levels for optimal fetal and infant development is abstract
a concern during pregnancy and infancy. The goal of this study was to assess the effects of
iron supplementation in pregnancy and/or infancy on motor development at 9 months.
METHODS: The study was a randomized controlled trial (RCT) of infancy iron supplementation
linked to an RCT of pregnancy iron supplementation, conducted in Hebei, China. A total of
1482 infants were randomly assigned to receive placebo (n = 730) or supplemental iron (n =
752) from 6 weeks to 9 months. Gross motor development (assessed by using the Peabody
Developmental Motor Scale, Second Edition, instrument) was the primary outcome.
Neurologic integrity and motor quality were secondary outcomes.
RESULTS: Motor outcome was available for 1196 infants, divided into 4 supplementation
period groups: (1) placebo in pregnancy/placebo in infancy (n = 288); (2) placebo in
pregnancy/iron in infancy (n = 305); (3) iron in pregnancy/placebo in infancy (n = 298);
and (4) iron in pregnancy/iron in infancy (n = 305). Using the Peabody Developmental
Motor Scale, instrument, iron supplementation in infancy but not pregnancy improved
gross motor scores: overall, P < .001; reflexes, P = .03; stationary, P < .001; and locomotion,
P < .001. Iron supplementation in infancy improved motor scores by 0.3 SD compared
with no supplementation or supplementation during pregnancy alone. Effects of iron
supplementation in infancy alone were similar to effects with iron in both pregnancy and
infancy.
CONCLUSIONS: The RCT design supports the causal inference that iron supplementation in
infancy, with or without iron supplementation in pregnancy, improved gross motor test
scores at 9 months.
NIH

aDepartment of Kinesiology, California State University, Northridge, Northridge, California; bCenter for Human WHATS KNOWN ON THIS SUBJECT: Iron deciency in
Growth and Development, and fDepartment of Pediatrics and Communicable Diseases, University of Michigan, infancy is associated with poorer motor development.
Ann Arbor, Michigan; cDepartment of Pediatrics, and eClinical Laboratory, Peking University First Hospital, Some randomized controlled trials (RCTs) of iron
Beijing, China; and dHuman Movement Sciences Graduate Program, Methodist University of Piracicaba,
supplementation in infancy show positive effects
Piracicaba, SP, Brazil
on motor behavior, but others do not. Few RCTs of
Dr Angulo-Barroso conceptualized and designed the study, acquired data, interpreted data, iron supplementation in pregnancy reported motor
and drafted and revised the manuscript; Dr Li conceptualized and designed the study, acquired outcomes.
data, interpreted data, and critically reviewed the manuscript; Dr Santos interpreted the data
and drafted and revised the manuscript; Ms Bian coordinated and supervised data collection WHAT THIS STUDY ADDS: The study linked an infancy
and critically revised the manuscript; Ms Sturza and Mr Richards analyzed data and revised RCT to a pregnancy RCT of iron supplementation to
the statistical analysis sections critically for important intellectual content; Dr Jiang acquired support causal inferences about developmental
data and critically reviewed the laboratory assessment of iron status sections; Dr Kaciroti impacts of timing and duration. Iron supplementation
conceptualized and designed the study, analyzed data, and revised the statistical analysis in infancy, regardless of supplementation in
sections critically for important intellectual content; and Dr Lozoff conceptualized and designed pregnancy, improved gross motor development at 9
the study, interpreted data, revised the manuscript, organized funding of the study, and provided months.
To cite: Angulo-Barroso RM, Li M, Santos DC, et al. Iron Supplementation in
Pregnancy or Infancy and Motor Development: A Randomized Controlled Trial.
Pediatrics. 2016;137(4):e20153547

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PEDIATRICS Volume 137, number 4, April 2016:e20153547 ARTICLE
The acquisition of varied and outcomes were reported previously. approved by the ethics committees
successful motor skills in early Pregnancy iron supplementation of the University of Michigan and
childhood, especially gross motor reduced iron deficiency (ID) and Peking University First Hospital. The
skills such as locomotion,1 affects iron-deficiency anemia in mothers RCTs are briefly described here; full
the development of cognitive2 but had little impact on fetal details were reported previously.17,18
and socio-emotional capabilities.3 neonatal iron status17; infancy iron
Movement is considered to be a supplementation reduced ID at 9 Participants
vehicle for improving knowledge of months, with no added benefit of Participants were infants born
self and environment46 such that pregnancy iron supplementation.18 to women in the pregnancy RCT.
being active assists in learning how There were no adverse effects of The pregnancy RCT enrolled 2371
to learn.7 Many factors, including iron supplementation on infant women with uncomplicated singleton
nutrition, contribute to motor health or growth overall or among pregnancies between June 2009
development.8 Lack of sufficient iron, infants who were iron-sufficient and December 2011 who were
which is common during pregnancy at birth. We report here the effects randomized to receive iron/folate
and infancy, may have adverse effects on gross motor development, or placebo/folate. Most attrition
through irons role in muscle and neurologic integrity, and quality of was due to mothers giving birth
brain function.912 Establishing a motor behavior at 9 months. This in a nonparticipating hospital. In
causal connection between lack of assessment was more comprehensive the infancy RCT, 1482 infants were
iron and lower developmental test than previous studies, reflecting enrolled between December 2009
scores in humans largely depends on that motor development requires and June 2012 and were randomly
randomized controlled trials (RCTs) behavioral and motor control as assigned to receive placebo (n =
of iron supplementation. In a 2010 well as skill development. We 730) or supplemental iron (n = 752)
expert review that organized RCTs hypothesized that the greatest impact from 6 weeks to 9 months. Infants
of iron supplementation in infancy would be when iron supplementation with cord ferritin concentrations
according to duration and child age, coincided with the period of rapid suggesting brain ID (<35 g/L) were
13 6 of 8 pertinent RCTs reported change in motor development excluded. At 9 months, 1276 infants
benefits on motor development. (ie, during infancy). We also provided outcome data (September
The investigators considered the predicted greater benefits with iron 2010March 2013).18
evidence sufficient to conclude supplementation during pregnancy
that long-term (>2 months) iron and infancy than supplementation in Enrollment and Informed Consent
supplementation during infancy only 1 period.
Mothers were informed of the infant
improves motor development.
development study at prenatal visits.
There is little research on motor
METHODS After delivery, project staff provided
outcomes in infancy with iron
further information and obtained
supplementation during pregnancy.
Study Setting and Design signed informed consent.
A recent summary included 4 RCTs14
and found only 1 that assessed motor The study (an RCT of infancy Randomization and Masking
development in infancy.15 Maternal iron supplementation connected
iron/folate supplementation (14 to an RCT of pregnancy iron Infants were randomly assigned 1:1
weeks gestation to delivery) did supplementation) was designed to to the iron or placebo group by a
not improve infant motor scores support causal inferences regarding University of Michigan biostatistician
in the first or second year.15,16 the developmental effects of reducing (N.K.) using PROC SURVEYSELECT
Together with the RCTs of iron ID in the fetus, young infant, or in SAS (SAS Institute, Inc, Cary, NC).
supplementation in infancy, these during both periods. The design The code was broken only after study
findings suggest motor development resulted in 4 groups based on period completion. Supplements were in
benefits from iron supplementation of supplementation in pregnancy identical dark-colored bottles, and
during infancy but not pregnancy. and/or infancy: (1) placebo in participants and personnel were
pregnancy/placebo in infancy unaware of group assignment.
The present study focused on (placebo/placebo); (2) placebo in
Interventions
developmental impacts of timing and pregnancy/iron in infancy (placebo/
duration of iron supplementation iron); (3) iron in pregnancy/placebo All participating pregnant women
by linking an RCT of iron in infancy (iron/placebo); and (4) received daily folate (0.40 mg) and
supplementation in infancy to an iron in pregnancy/iron in infancy either iron (300 mg ferrous sulfate)
RCT of iron supplementation in (iron/iron). The study, conducted or placebo from enrollment to
pregnancy. Iron status and growth in rural Hebei Province, China, was birth.17 Infants received a single daily

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2 ANGULO-BARROSO et al
dose of 1 mg/kg of elemental iron customary at Peking University First Statistical Methods
as an iron protein succinylate oral Hospital. Because almost all infants
solution (Ferplex,Italfarmico, S.A., were similar in age at the 9-month The primary analytic approach
Madrid, Spain) or carrier (placebo) assessment, the PDMS-2 outcomes was based on intention to treat.
from 6 weeks to 9 months.18 are presented as raw scores, A 2 test and analysis of variance
controlling for age in days. model were used to test for overall
Study Outcomes group differences in demographic
The INFANIB assesses infant
The primary motor outcome was neurologic integrity. The total score and biologic data. An analysis of
gross motor development, assessed of overall neurologic integrity is a covariance model was used to test
by using the Peabody Developmental composite derived from 20 items for group differences for primary and
Motor Scale, Second Edition within 5 factors (spasticity/muscle secondary outcomes, controlling for
(PDMS-2), instrument.19 Secondary tone, head and trunk control, age at testing. SAS PROC GLMSELECT
outcomes were neurologic integrity, vestibular function, legs/lower limb with stepwise inclusion was used to
evaluated by using the Infant function, and French angles [shoulder determine if additional background
Neurologic International Battery and hip angles]). Items are scored 1 variables should be included in
(INFANIB),20 and motor quality, to 5 (abnormal to normal). Results the final models. Planned pairwise
assessed by using the Behavior are expressed as raw subscale and comparisons were conducted if
Rating Scale (BRS) of the Bayley total scores, controlling for age.20 the overall statistical test results
Scales of Infant Development, Second were significant. For effects of
The BRS motor quality factor is based
Edition.21 supplementation timing, key
on examiner ratings of infant motor
The PDMS-2 gross motor dimension performance. The factor is generated contrasts were: (1) iron/placebo
at 9 months provides an overall from 8 items related to muscle tone versus placebo/iron, followed by
motor quotient derived from 3 and movement control and quality. (2) iron/placebo versus placebo/
subscales (reflexes, stationary, Items are rated 1 to 5, with higher placebo and (3) placebo/iron versus
and locomotion). Reflexes reflect values indicating more consistently placebo/placebo to confirm a
automatic reactions to environmental appropriate behavior.21 Results are supplementation effect. For duration,
events (eg, righting reflex, parachute expressed as the BRS motor quality key contrasts were: (1) iron/iron
reflex). Stationary assesses postural factor total raw score, controlling for versus iron/placebo and (2) iron/
control within the center of gravity age. iron versus placebo/iron, followed
and equilibrium (eg, sitting while by (3) iron/iron versus placebo/
Developmental testing occurred in
manipulating a toy, transitioning placebo. Two different types of
dedicated rooms at the Maternity
to sit from prone). Locomotion effect size measures were used:
and Child Health Care Center.
covers moving from 1 place to partial squared (2) to express the
Infants were accompanied by a
another (eg, crawling, sitting to magnitude of the overall association
parent/guardian and given time for
crawling or standing).19 A Chinese between group and dependent
adjusting to the setting, frequent
version of the PDMS-2 instrument is variable in the analysis of variance
breaks, naps, and/or feeding. US
routinely used at Peking University
and Chinese investigators trained model (effect sizes were low [0.01],
First Hospital to track motor
Chinese supervisory personnel, who medium [0.06], and large [0.14])23
development and intervention
then jointly trained coders/testers and Cohens d to indicate the
effects in the rehabilitation clinic.
and provided ongoing supervision. difference between 2 group means in
The clinic follows the standard
Reliability was assessed before and pooled SD units (small, <0.2; medium,
definition of ceiling but also elicits
during testing; reliability levels were 0.5; and large, 0.8).24 Based on
each childs optimal performance
90%. primary findings, logistic regression
by administering a preset maximum
number of items in each subscale was used to estimate the relative
Sample Size risk (95% confidence interval) of
based on age. Passed items above
ceiling for each subscale are Gross motor outcomes were available scoring in the lowest quartile for
included.22 In our study, only a for 1196 infants. This sample size gross motor development based on
few infants (31 of 1195) passed was sufficient to detect small effect iron supplementation in infancy. In
items above ceiling, solely in the size differences of 0.16 SD between addition, multiple/logistic regression
locomotion subscale. Using scores the 2 groups in the pregnancy RCT was used to model relations
with passes above ceiling did not and 0.23 SD for any pairwise between bottles of iron received and
affect PDMS-2 outcome in the RCT. comparison among the 4 pregnancy/ outcomes. Significance was set at P
Therefore, scoring was preserved as infancy groups. < .05.

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PEDIATRICS Volume 137, number 4, April 2016 3
RESULTS pregnancy RCT,17 there was more performance, we analyzed the
maternal ID in the placebo/iron and proportion of infants in each group
Attrition in the pregnancy RCT
placebo/placebo groups than in the with subscale scores in the lowest
was largely due to women who
iron/placebo and iron/iron groups quartile according to PDMS-2
gave birth at a nonparticipating
(P < .001). However, there were no norms.19 For reflexes and stationary,
hospital.17 The main reason for the
group differences in fetal-neonatal <2% of infants had such low scores.
14% overall attrition in the infancy
iron status at birth. Neonatal iron However, 22.1% of locomotion
RCT was refusal or withdrawal (Fig
status was generally poor, as scores were below the 25th
1). There was no differential attrition
indicated by cord ferritin levels <75 percentile cutoff. The proportions
according to RCT group. Of the 1276
g/L or zinc protoporphyrin/heme were significantly lower in groups
infants assessed for iron status
ratio >118 mol/mol in >40%. In that received supplemental iron in
or growth at 9 months, 1196 had
keeping with hematology findings infancy, compared with groups that
data on gross motor development:
in the infancy RCT,18 iron status did not (P < .001): placebo/iron, 50
placebo/placebo, n = 288; placebo/
was worse in the groups that did (16%) of 305; iron/iron, 57 (19%) of
iron, n = 305; iron/placebo, n =
not receive iron supplementation in 305; placebo/placebo, 70 (24%) of
298; and iron/iron, n = 305. Of the
infancy. Nonetheless, ID remained 288; and iron/placebo, 87 (29%) of
80 infants who were assessed at 9
common: 59% in groups receiving 298. The risk of being in the lowest
months but did not provide gross
iron in infancy (placebo/iron and quartile was reduced by 36% in
motor development data, the PDMS-2
iron/iron) versus 69% in infancy placebo/iron and iron/iron groups,
tool was not administered for 67 and
placebo groups (iron/placebo and compared with the iron/placebo and
was not scorable for 13.
placebo/placebo) (P < .001). placebo/placebo groups (relative
Participant Characteristics risk, 0.64 [95% confidence interval,
Study Outcomes 0.520.80]).
The groups were similar in
Groups that received iron in infancy There were no group differences in
background characteristics at
(placebo/iron and iron/iron) overall neurologic integrity (INFANIB
birth (Table 1). Most infants were
reported significantly better PDMS-2 total score, P = .43). However, the
first-born. Both genders were
scores than those that did not groups differed in the head and trunk
included and approximately equally
(iron only during pregnancy [iron/ factor, which is most related to gross
represented. Almost all were born
placebo] or in neither time period motor development (P < .001). Scores
at term (>37 weeks gestation) and
[placebo/placebo]). The pattern were better in groups receiving
weighed 3.36 kg on average. At 9
was similar for overall gross motor iron supplementation in infancy
months, there was a suggestive
score (P < .001; p-2 = 0.02) and for compared with groups that did not.
overall difference in age at gross
the subscales: reflexes (P = .03; p-2 Motor quality (examiner BRS ratings)
motor developmental testing. The
= 0.01), stationary (P < .001; p-2 = did not show group differences (P
placebo/iron and iron/iron groups
0.03), and locomotion (P < .001; p-2 = .93). There were no statistically
averaged 1.7 days younger than
= 0.02) (Table 2). significant relations between the
the iron/placebo and placebo/
placebo groups (P = .02). Mean The timing analysis highlighted the number of bottles of iron received
infant weight-for-age z score was benefits of iron supplementation on and motor outcomes.
0.89. More than 80% of the infants gross motor development in infancy.
were breastfeeding at the time of The placebo/iron group had higher
the 9-month assessment. Mothers PDMS-2 scores than the iron/placebo DISCUSSION
averaged 25 years of age, and group (iron only during pregnancy),
The uniqueness of our study design
most completed middle school. Most and placebo/iron group scores were
(an infancy RCT built upon a
families were stressed financially; also higher than the placebo/placebo
pregnancy RCT) addresses specific
84% had incomes below the local group scores. The duration analysis
questions regarding timing and
county threshold for public housing indicated no added benefit of iron
duration of iron supplementation
assistance.25 Family support of child supplementation in either pregnancy
and supports causal inferences. We
development was similar across or infancy; the placebo/iron and
found that iron supplementation
groups. iron/iron groups did not differ from
from 6 weeks to 9 months had a
each other, and both were higher
The groups differed in iron status, as positive effect on overall gross
than the placebo/placebo group.
expected by the RCT designs (Table motor development at 9 months.
1). In keeping with the findings To further characterize the The effect was similar whether
of improved maternal iron status beneficial effect of infancy iron supplementation was provided only
with iron supplementation in the supplementation on gross motor during infancy or also to mothers

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4 ANGULO-BARROSO et al
FIGURE 1
Infancy RCT: owchart of participants.

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PEDIATRICS Volume 137, number 4, April 2016 5
TABLE 1 Infant and Family Characteristics
Characteristic PP (n = 288) PI (n = 305) IP (n = 298) II (n = 305) Pa
Infant characteristics at birth
Male sex 155/288 (54) 141/305 (46) 149/298 (50) 158/305 (52) .29
Birth weight, g 3373.3 373.3 3368.2 375.3 3329.5 370.1 3379.8 350.2 .39
Gestational age, wk 39.7 1.1 39.7 1.1 39.8 1.1 39.7 1.1 .69
First/only child 217/283 (77) 235/298 (79) 240/293 (82) 231/300 (77) .18
ID: serum ferritin <75 g/L or zinc protoporphyrin/heme 118/288 (41) 127/305 (42) 131/298 (44) 127/305 (42) .89
>118 mol/mol
Infant characteristics at 9 mo
Age at testing, mo 9.31 0.42 9.29 0.41 9.34 0.49 9.25 0.40 .06
9-mo weight-for-age z score 0.88 1.02 0.79 1.09 0.92 0.98 0.97 0.98 .15
Milk feeding patternb .50
Only breast milk 108/217 (50) 115/238 (48) 114/230 (50) 134/237 (57)
Breast milk and formula 73/217 (34) 78/238 (33) 71/230 (31) 70/237 (29)
Only formula 36/217 (17) 45/238 (19) 45/230 (20) 33/237 (14)
IDc 195/286 (68)d,e 179/298 (60)d,f 204/296 (69)e 175/300 (58)f .01
Anemia, hemoglobin <110 g/L 129/286 (45)d 101/298 (34)e 118/296 (40)d,e 119/300 (40)d,e .05
ID anemiag 108/265 (41)d 81/278 (29)e 99/277 (36)d,e 101/282 (36)d,e .04
Maternal and family characteristics
Maternal age, y 24.6 4.0) 24.8 3.5) 24.6 3.8) 25.1 4.0 .44
Maternal education, high school or higher 89/287 (31) 115/299 (38) 98/297 (33) 96/302 (32) .21
Net family income, 50 000 yuan/y 243/284 (86) 245/300(82) 236/288 (82) 255/295 (86) .27
Maternal mood total score at 9 mo (maximum = 30, 6.09 4.54 6.06 4.48) 5.60 4.37 6.38 4.35 .21
possible depression 10)h
Home Observation for Measurement of the Environment 31.5 4.0 31.8 4.0 31.3 4.0 31.5 3.9 .51
total score at 9 mo (maximum = 45)
Maternal ID: body iron <0 mg/kgi 174/284 (61.3)d 204/304 (67.1)d 119/294 (40.5)e 128/302 (42.4)e <.001
Values are n/total (%) for categorical values and mean SD for continuous variables. The n values vary due to missing data. II, iron in pregnancy/iron in infancy; IP, iron in pregnancy/
placebo in infancy; PI, placebo in pregnancy/iron in infancy; PP, placebo in pregnancy/placebo in infancy.
a Analysis of variance for continuous variables, x2 test for categorical variables.
b Feeding solid foods was generally initiated between 4 and 6 months of age. Solids were typically not iron fortied at the time.
c ID was dened as 2 abnormal iron measurements (mean corpuscular volume <74 , zinc protoporphyrin/heme >69 mol/mol heme, serum ferritin <12 g/L).
d Groups with same superscript do not differ; different letters indicate statistically signicant difference (P < .05).
e Groups with same superscript do not differ; different letters indicate statistically signicant difference (P < .05).
f Groups with same superscript do not differ; different letters indicate statistically signicant difference (P < .05).
g Anemia by cutoff dened as hemoglobin <110 g/L, and ID was dened as 2 abnormal iron measurements (mean corpuscular volume <74 , zinc protoporphyrin/heme >69 mol/mol

heme, serum ferritin <12 g/L).


h Maternal mood evaluated by using the Edinburgh Postnatal Depression Scale.26
i Body iron was calculated by using serum ferritin and soluble transferring receptor (sTfR), according to the formula of Cook et al27: body iron (mg/kg) = [log10(sTfR*1000/ferritin)

2.8229]/0.1207.

TABLE 2 Primary Outcome: Gross Motor Development Assessed According to the PDMS-2 at 9 Months
Subscale Mean (95% CI) Pa Effect Size d
Timing Duration
PP (n =288) PI (n =305) IP (n =298) II (n =305) IP Versus IP PI Versus II Versus II Versus II Versus
PI versus PP IP PI PP
PP
Reexes 14.4 (14.3 14.6 (14.514.7) 14.4 (14.3 14.7 (14.5 .03 0.16 0.00 0.16 0.18b 0.03 0.19b
14.6) 14.6) 14.8)
Stationary 33.5 (33.4 34.0 (33.834.1) 33.4 (33.3 34.0 (33.8 <.001 0.35b 0.08 0.28b 0.37b 0.01 0.29b
33.7) 33.6) 34.1)
Locomotion 39.5 (38.7 41.4 (40.742.2) 39.5 (38.8 41.3 (40.5 <.001 0.30b 0.01 0.30b 0.27b 0.03 0.28b
40.2) 40.3) 42.0)
Overall 87.5 (86.5 90.0 (89.090.9) 87.4 (86.4 89.9 (89.0 <.001 0.31b 0.01 0.30b 0.30b 0.01 0.29b
gross 88.4) 88.3) 90.8)
motor
CI, condence interval; II, iron in pregnancy/iron in infancy; IP, iron in pregnancy/placebo in infancy; PI, placebo in pregnancy/iron in infancy; PP, placebo in pregnancy/placebo in infancy.
Subscale n values vary slightly due to missing data.
a Analysis of covariance model covarying age at testing. Pairwise comparisons expressed as effect size d (difference between means divided by pooled SD).
b Signicant difference between groups, P < .05.

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6 ANGULO-BARROSO et al
during pregnancy. The benefits planning) are subserved by different factor, in contrast to our previous
were mostly related to stationary brain areas and networks. Based on results in a small observational
and locomotor skills. Furthermore, current understanding, the complex study.38 The BRS is not a direct
iron supplementation during brain areas and pathways involved assessment of motor skills
infancy reduced the proportion of in gross motor development mature and may thus be less sensitive to
children in the lowest quartile for most rapidly in the first year of the development of specific
the locomotor subscale, regardless of life, thus requiring more iron and motor skills and more influenced
whether their mothers received iron increasing vulnerability to lack of by tester expertise and experience.
supplementation during pregnancy. iron.28 Iron is specifically required
Several gross motor skills developing
for oligodendrocyte function and
These results do not seem at 9 months seemed sensitive to
attributable to other factors. The myelin formation.2932 Consequently,
iron supplementation in infancy.
groups were similar with respect to neural pathways that are involved
Our PDMS-2 locomotor findings
background characteristics at birth; in motor skill acquisition, such as
denote better crawling in infants
group differences in maternal ID the corticospinal and corticostriatal
who receive iron supplementation
were as expected based on results tracts, may be more vulnerable to
during infancy. Onset of standing
of the pregnancy RCT. The groups effects of ID in infancy than during
with lateral progression (ie, cruising)
gestation because these pathways are
were also similar in family and infant also occurs at 9 months, as does
characteristics at 9 months. It is not completely myelinated at birth.33,
34 Iron supplementation in infancy the ability to pull from sitting to
unlikely that the small difference in standing.3941 Our stationary
testing age accounted for the findings. might also improve gross motor
subscale findings imply better
Age was a covariate in all analyses development indirectly by reducing
performance in transitioning
and did not remain significant in concurrent behaviors associated
from sitting to standing with iron
any model. Furthermore, the groups with ID, such as withdrawal35 and
supplementation in infancy. A benefit
exhibiting more advanced motor lower spontaneous motor activity.36
of iron supplementation in infancy
development (placebo/iron and iron/ Better motor scores in the placebo/
on earlier onset of specific motor
iron) were the youngest, albeit only iron and iron/iron groups did not
milestones has been reported in
by a few days. seem to result from the potential
some previous RCTs.4244 Similarly,
effects on maternal behavior of
The results confirm our hypothesis an association between better
iron supplementation in pregnancy.
that the greatest impact would iron status in infancy and earlier
Although mothers in the iron/
be when iron supplementation onset of walking was reported in
placebo group had better iron
coincided with the period of rapid 2 observational studies.45,46 These
status than those in the placebo
change in motor development; that is, locomotor-related benefits of iron
/iron group and might have been
infancy. Our findings of better motor supplementation may enhance
more proactive about their
outcome with iron supplementation infant development in other
childrens development, as suggested
in infancy are in agreement with domains (eg, cognitive, social-
by Perez et al,37 their infants did not
a 2010 expert review of previous emotional).2,3,40,47
exhibit better motor development at
RCTs.13 However, the results did not 9 months. Our results may not be directly
confirm our prediction of greater comparable to previous RCTs of iron
benefits with iron supplementation Gross motor development was supplementation due to differences
during both pregnancy and assessed by using 3 different in several respects: we used a
infancy. The lack of benefit of iron measures to include aspects different motor assessment (PDMS-2
supplementation during pregnancy of neuromotor development vs Bayley or motor milestones in
on motor development is consistent (INFANIB) and motor behavior other studies), our population was
with the sole relevant RCT in a recent (BRS motor quality factor) as growing well and mainly breast-
summary.14 well as global development fed, and the prevalence of ID was
There are several possible (PDMS-2 gross motor). Although higher than in some other studies.
explanations for motor benefits of there were no group differences The hematologic response to iron
iron supplementation in infancy but in the total INFANIB score, closer supplementation was less than
not pregnancy. Brain areas mature examination of the factor most typically observed in other infant
at different times and need iron at related to gross motor development RCTs.48 The likely explanation for the
different rates.11,12 Various motor (head and trunk control) limited reduction in prevalence of ID
domains (eg, reflexes, sensory demonstrated a pattern similar was a combination of poor iron status
integration, postural control, motor to PDMS-2 results. We found no at birth, high iron needs for growth,
activity, motor coordination and differences in BRS motor quality and insufficient supplemental iron

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PEDIATRICS Volume 137, number 4, April 2016 7
intake.18 Furthermore, the magnitude CONCLUSIONS infancy RCTs and overall supervision
of the effects we observed might not The RCT design of this study of the infancy RCT; and Dr Guobin
generalize to other populations. For supports the causal inference that Xu for supervision of laboratory
instance, effects might be stronger iron supplementation in infancy, with measures of iron status. We also
in samples with a greater reduction or without iron supplementation in appreciate the dedicated efforts of the
in ID with iron supplementation. pregnancy, improved gross motor project physicians and nurses at Sanhe
Because infant complementary foods test scores at 9 months. The study Maternal and Child Health Center.
were not generally iron fortified at confirms developmental benefits
the time of our study, and delayed of routine iron supplementation in
cord clamping was not routine, the infancy, perhaps especially in settings ABBREVIATIONS
results do not contribute to the in which iron deficiency is common. BRS:Behavior Rating Scale
discussion regarding alternatives
ID:iron deficiency
to iron supplementation. In any
ACKNOWLEDGMENTS INFANIB:Infant Neurologic
case, our results regarding timing
International Battery
and duration require replication, We thank Drs Gengli Zhao and Min
PDMS-2:Peabody Developmental
and further research is needed Zhou for overall direction of the preg-
Motor Scale, Second
on the mechanisms whereby iron nancy RCT; Drs Zhixiang Zhang,
Edition
supplementation can improve infant Twila Tardif, and Xing Li for help
RCT:randomized controlled trial
motor development. coordinating the pregnancy and

overall supervision of the research group. All authors approved the nal manuscript as submitted. All authors agree to be accountable for all aspects of the work
in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
The content is solely the responsibility of the authors and does not necessarily represent the ofcial views of funding sources. The authors had full control of
primary data and did not have an agreement with the funders that limited their ability to complete the research as planned.
This trial has been registered at www.clinicaltrials.gov (identier NCT00613717).
DOI: 10.1542/peds.2015-3547
Accepted for publication Dec 21, 2015
Address correspondence to Rosa M. Angulo-Barroso, PhD, Department of Kinesiology, California State University, Redwood Hall 250, 18111 Nordhoff St, Northridge,
CA 91330-8287. E-mail: rosa.angulobarroso@csun.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Lozoff was an unpaid speaker at 2 seminars supported by Lees Pharmaceutical Holdings Limited. The topic was iron deciency and
child development (Shanghai, April 11, 2010, and Beijing, May 15, 2011). The company covered hotel accommodations and, for the 2011 seminar, internal airfare
between Hangzhou and Beijing. The other authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: A grant from the National Institutes of Health (R01 HD052069), which included funding from the Eunice Kennedy Shriver National Institute of Child
Health and Human Development and the Ofce of Dietary Supplements, provided support for the infancy study and laboratory measures of iron status
for mothers and infants (Dr Lozoff, Principal Investigator). Vifor Pharma, Ltd provided nancial support for the pregnancy study. The So Paulo Research
FoundationFAPESP/Brazil (2014/00018-0) and Methodist University of PiracicabaUNIMEP/Brazil provided nancial support for Dr Santos. Funded by the National
Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conicts of interest to disclose.

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10 ANGULO-BARROSO et al
Iron Supplementation in Pregnancy or Infancy and Motor Development: A
Randomized Controlled Trial
Rosa M. Angulo-Barroso, Ming Li, Denise C.C. Santos, Yang Bian, Julie Sturza,
Yaping Jiang, Niko Kaciroti, Blair Richards and Betsy Lozoff
Pediatrics 2016;137;; originally published online March 2, 2016;
DOI: 10.1542/peds.2015-3547
Updated Information & including high resolution figures, can be found at:
Services /content/137/4/e20153547.full.html
References This article cites 36 articles, 16 of which can be accessed free
at:
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the following collection(s):
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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
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Iron Supplementation in Pregnancy or Infancy and Motor Development: A
Randomized Controlled Trial
Rosa M. Angulo-Barroso, Ming Li, Denise C.C. Santos, Yang Bian, Julie Sturza,
Yaping Jiang, Niko Kaciroti, Blair Richards and Betsy Lozoff
Pediatrics 2016;137;; originally published online March 2, 2016;
DOI: 10.1542/peds.2015-3547

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/137/4/e20153547.full.html

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 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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