Research

JAMA | Original Investigation

Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide

Complex on Hemoglobin Concentration in Young Children
With Nutritional Iron-Deficiency Anemia
A Randomized Clinical Trial
Jacquelyn M. Powers, MD, MS; George R. Buchanan, MD; Leah Adix; Song Zhang, PhD; Ang Gao, MS; Timothy L. McCavit, MD, MS

Supplemental content
IMPORTANCE Iron-deficiency anemia (IDA) affects millions of persons worldwide, and is
associated with impaired neurodevelopment in infants and children. Ferrous sulfate is the
most commonly prescribed oral iron despite iron polysaccharide complex possibly being
better tolerated.

OBJECTIVE To compare the effect of ferrous sulfate with iron polysaccharide complex on
hemoglobin concentration in infants and children with nutritional IDA.

DESIGN, SETTING, AND PARTICIPANTS Double-blind, superiority randomized clinical trial of

infants and children aged 9 to 48 months with nutritional IDA (assessed by history and
laboratory criteria) that was conducted in an outpatient hematology clinic at a US tertiary
care hospital from September 2013 through November 2015; 12-week follow-up ended
in January 2016.

INTERVENTIONS Three mg/kg of elemental iron once daily as either ferrous sulfate drops or
iron polysaccharide complex drops for 12 weeks.

MAIN OUTCOMES AND MEASURES Primary outcome was change in hemoglobin over 12 weeks.
Secondary outcomes included complete resolution of IDA (defined as hemoglobin
concentration >11 g/dL, mean corpuscular volume >70 fL, reticulocyte hemoglobin equivalent
>25 pg, serum ferritin level >15 ng/mL, and total iron-binding capacity <425 μg/dL at the
12-week visit), changes in serum ferritin level and total iron-binding capacity, adverse effects.

RESULTS Of 80 randomized infants and children (median age, 22 months; 55% male; 61%
Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31
[78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin
increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group),
a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P < .001) with ferrous sulfate (based
on a linear mixed model). Proportion with a complete resolution of IDA was higher in the
ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to
15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater
difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P < .001) with ferrous sulfate. Mean total
iron-binding capacity decreased from 501 to 389 μg/dL (ferrous sulfate) vs 506 to 417 μg/dL
(iron complex) (a greater difference of −50 μg/dL [95% CI, −86 to −14 μg/dL] with ferrous
sulfate; P < .001). There were more reports of diarrhea in the iron complex group than in the
ferrous sulfate group (58% vs 35%, respectively; P = .04).

CONCLUSIONS AND RELEVANCE Among infants and children aged 9 to 48 months with
nutritional iron-deficiency anemia, ferrous sulfate compared with iron polysaccharide complex
Author Affiliations: Author
resulted in a greater increase in hemoglobin concentration at 12 weeks. Once daily, low-dose affiliations are listed at the end of this
ferrous sulfate should be considered for children with nutritional iron-deficiency anemia. article.
Corresponding Author: Jacquelyn
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01904864 M. Powers, MD, MS, Baylor College of
Medicine, 6701 Fannin St, Ste 1580,
Houston, TX 77030 (jacquelyn
JAMA. 2017;317(22):2297-2304. doi:10.1001/jama.2017.6846 .powers@bcm.edu).

(Reprinted) 2297
© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023

 Research Original Investigation
I
ron-deficiency anemia (IDA) affected more than 1 billion
persons worldwide in 2010,1,2 including up to 3% of chil-
dren aged 1 to 2 years in the United States.3-5 The most com-
mon cause of IDA in infants and young children is inadequate
dietary iron intake resulting from excessive cow milk con-
sumption, prolonged breastfeeding without appropriate iron
supplementation, or both. It typically occurs in infants and
young children when rapid growth outstrips availability of di-
etary iron. Consequences include irritability, malaise, pica, and
both short- and long-term neurodevelopmental impairment.6-8
Successful treatment of IDA requires recognition and cor-
rection of the underlying etiology accompanied by iron replace-
ment therapy to normalize the hemoglobin concentration and
replenish iron stores. Treatment failure is common due to medi-
cation nonadherence, adverse effects related to excessive dos-
ing, and lack of evidence-based management guidelines.9 Few
randomized clinical trials inform the selection of iron prepara-
tion, dosage schedule, and duration of therapy, irrespective of
the underlying etiology, age, or sex of affected individuals.10,11
In infants and young children, standard dosing recommenda-
tions are 2 to 6 mg/kg/d of elemental iron given from 1 to 3 times
daily for a duration of 3 to 6 months.12 The literature on adults
suggests that lower therapeutic dosing strategies may be suffi-
cient for successful treatment.13,14
Dozens of oral iron preparations (most of them over-
the-counter supplements) are available for IDA treatment.
Ferrous sulfate, an iron salt, is the standard and most com-
monly used agent to treat nutritional IDA.15,16 Alternatively,
iron polysaccharide complex preparations containing ferric iron
may be prescribed due to their potentially improved tolerabil-
ity and better taste. Given the high prevalence of IDA in infants
and young children, this double-blind, randomized clinical trial
was designed to investigate whether an iron polysaccharide
complex agent was more efficacious than ferrous sulfate in
increasing hemoglobin concentration in infants and children
aged 9 to 48 months with nutritional IDA.
Methods
The BESTIRON study was a randomized, double-blind single-
center superiority trial designed to compare the efficacy of an
iron polysaccharide complex (NovaFerrum, Gensavis Phar-
maceuticals LLC) vs ferrous sulfate for the treatment of nutri-
tional IDA in infants and young children who were referred for
care at the Children’s Medical Center in Dallas, Texas.
The institutional review board at the University of Texas
Southwestern Medical Center approved the study. Written in-
formed consent was obtained from the parents of each partici-
pant prior to enrollment. The study was performed and ana-
lyzed in accordance with the Consolidated Standards of
Reporting Trials. The trial start date was September 3, 2013, and
it continued through November 5, 2015. The final follow-up date
was January 28, 2016. A single protocol modification regard-
ing inclusion of laboratory criteria was made prior to the en-
rollment of any patients and formal institutional review board
approval was received the day after the first patient was en-
rolled. The study protocol appears in Supplement 1.
2298 JAMA June 13, 2017 Volume 317, Number 22 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023
Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia
Key Points
Question Is iron polysaccharide complex more effective than
ferrous sulfate in improving the hemoglobin concentration in infants
and young children with nutritional iron-deficiency anemia?
Findings In this double-blind, randomized clinical trial that
included 80 patients, those who received ferrous sulfate for
12 weeks had a 1.0 g/dL greater increase in hemoglobin
concentration than those receiving iron polysaccharide complex.
Meaning Among infants and young children with nutritional
iron-deficiency anemia, ferrous sulfate compared with iron
polysaccharide complex resulted in a greater increase in
hemoglobin concentration at 12 weeks.
Eligible patients were infants and children aged 9 to 48
months with a diagnosis of nutritional IDA resulting from ex-
cessive cow milk intake of greater than 720 mL per day, breast-
feeding without iron supplementation, or both. Given that ra-
cial and ethnic minority groups are disproportionately affected
by IDA, this information was collected and reported for all pa-
tients. Data were obtained from the electronic medical rec-
ord, which contains self-reported racial and ethnic identifica-
tion based on fixed categories. Iron-deficiency anemia was
confirmed by the following hematologic indices: hemoglobin
concentration of 10 g/dL or less, mean corpuscular volume of
70 fL or less, reticulocyte hemoglobin equivalent of 25 pg or
less, and either serum ferritin level of 15 ng/mL or less or total
iron-binding capacity of 425 μg/dL or greater.
Patients were excluded from enrollment if they had clini-
cal or laboratory evidence of other causes of anemia (entire list
of eligibility criteria appears in eTable 1 in Supplement 2).
Receipt of a packed red blood cell transfusion for severe symp-
tomatic anemia at presentation did not exclude enrollment. All
patients who received a transfusion had repeat hematologic in-
dices assessed after the transfusion to ensure eligibility.
Enrolled patients were randomized with a 1:1 allocation to
receive either oral ferrous sulfate drops (15 mg/mL) or oral iron
polysaccharide complex drops (15 mg/mL). Randomization was
stratified by degree of anemia (hemoglobin concentration
≥8.0 g/dL vs <8.0 g/dL). Within each stratum, patients were
randomly assigned to either experimental group with a 1:1
allocation by a computer-generated randomization schedule
using permuted blocks of 4.
Allocation concealment occurred after each participant was
formally enrolled in the trial, and all baseline measurements
(history, physical examination, laboratory assessment) were
completed. Implementation of the sequence generation and
allocation concealment mechanism was performed by an in-
vestigational pharmacist who had no direct contact with study
patients. Trial investigators performed enrollment and all study
procedures after randomization. Except for the investiga-
tional pharmacist, the members of the study team were blinded
to treatment allocation.
Patients were prescribed a single daily dose of 3 mg/kg of
elemental iron administered via oral syringe by the parents or
caregiver at bedtime. Daily doses were rounded up to the near-
est 0.5 mL. Parents or caregivers were asked not to adminis-
ter other iron-containing preparations and instructed not to
jama.com
 Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia Original Investigation Research

mix the study medication with any food or drink and specifi-
Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients
cally to avoid milk intake within 1 hour of administering the
study medication. Nutritional counseling about the need to re-
81 Infants and children enrolled
duce cow milk intake to a maximum of 600 mL per day was
provided. A daily diary with the dosing instructions was given
1 Excluded (removed prior to
to parents or caregivers at each visit to record medication ad- randomization due to receiving a
packed red blood cell transfusion
ministration and adverse effects. resulting in a normal hemoglobin
Subsequent outpatient study visits were scheduled at weeks concentration)

4, 8, and 12 after enrollment to review between-interval his-

tory and perform laboratory testing (complete blood count, re-
ticulocyte count, reticulocyte hemoglobin equivalent, serum fer-
ritin level, serum iron level, total iron-binding capacity, and
blood lead level [the latter performed during week 4 only]).
Treatment failure was defined as a hemoglobin increment of less
than 0.5 g/dL above the baseline concentration at week 8. The
final visit at week 12 involved a comprehensive history, includ-
ing whether the study drug had been mixed with other liquids
or foods. Adverse effects were assessed every 2 weeks via tele-
phone contact and at clinic visits. At each follow-up visit, re-
turned medication bottles were submitted to the investiga-
tional pharmacy and the volume of unused study medication
was measured. Further details regarding adverse effect assess-
ment appear in the eMethods in Supplement 2.
The primary outcome was the change in hemoglobin con-
centration during the 12 weeks after initiation of oral iron
therapy. Secondary outcomes included the proportion of pa-
tients with complete resolution of IDA (defined as hemoglo-
bin concentration >11 g/dL, mean corpuscular volume >70 fL,
reticulocyte hemoglobin equivalent >25 pg, serum ferritin level
>15 ng/mL, and total iron-binding capacity <425 μg/dL at the
12-week visit), changes in other iron laboratory measures, ad-
verse effects, lost to follow-up rates, resolution of IDA signs
and symptoms, and medication adherence as measured by pa-
tient diary entries and returned medication volume.
Estimates for baseline mean hemoglobin concentration of
7.8 g/dL (SD, 1.5 g/dL) were derived from data on new pa-
tients with IDA seen at the Children’s Medical Center outpa-
tient hematology clinic during the preceding 4½-year period.9
We hypothesized that at the time of study completion there
would be a 1-g/dL between-group difference in the mean he-
moglobin concentration values (ferrous sulfate: 11 g/dL; iron
polysaccharide complex: 12 g/dL). The effect size of 1 g/dL was
chosen as a clinically significant difference based on an analy-
sis of studies evaluating IDA and neurocognitive outcomes by
the World Health Organization and work examining the rela-
tionship between serum ferritin level and hemoglobin con-
centration in young children. 17,18 We assumed a within-
patient correlation of 0.25. Using a linear mixed model and
assuming a lost to follow-up rate of 25%,9 the accrual goal was
40 patients per group (80 total) to allow for a 2-sided type I
error of .05 at 80% power.
We hypothesized that iron polysaccharide complex would
result in a greater hematologic response compared with fer-
rous sulfate as measured by change in hemoglobin concentra-
tion over 12 weeks. The primary analysis consisted of a linear
mixed regression model in an intention-to-treat population.
It included treatment and time as covariates and patient ran-
dom effects to account for correlation among longitudinal mea-
80 Randomized
40 Randomized to receive ferrous 40 Randomized to receive iron
sulfate polysaccharide complex
39 Received ferrous sulfate as 40 Received iron polysaccharide
randomized complex as randomized
1 Received iron polysaccharide
complex
7 Lost to follow-up 6 Lost to follow-up
3 Discontinued study drug and did 3 Discontinued study drug and did
not complete 12-wk visita not complete 12-wk visita
2 Withdrew from study
40 Included in primary analysis 40 Included in primary analysis
The total number of patients screened and the reasons for exclusion
are not available.
a
Considered a treatment failure (predefined in the study protocol as a
hemoglobin increment <0.5 g/dL above the baseline concentration at week 8,
which resulted in the discontinuation of the study drug by the study team).
surements from the same patients. The linear mixed model
readily accommodates missing data so imputation for miss-
ing data was not performed.19 Changes in other continuous
measures were modeled with a similar linear mixed regres-
sion method. The generalized estimation equation approach
was used to estimate model parameters, which accommo-
dates incomplete data and is robust against deviation from the
normality assumption.
The χ2 test was used to compare categorical outcomes, in-
cluding the proportion of patients with a complete response,
dropouts, adverse effects, and adherence measures. The per-
centage volume of unused study medication returned at each
visit was compared using the Wilcoxon rank sum test. All tests
were 2-sided with a significance level of .05. Adjustment for
multiple comparisons of secondary end points was not per-
formed. Inference about secondary outcomes should be in-
terpreted as exploratory. A post hoc between-group compari-
son of the proportion of patients who complained of abdominal
pain, constipation, vomiting, and diarrhea (combined gastro-
intestinal adverse effect profile) also was conducted using the
χ2 test. All analyses were performed using SAS version 9.4
(SAS Institute Inc).
Results
The trial enrolled 81 eligible study patients, of whom 80 were
randomized (40 in the ferrous sulfate group and 40 in the
iron polysaccharide complex group; Figure 1). The baseline demo-
graphic characteristics, laboratory values, and the percentage

jama.com (Reprinted) JAMA June 13, 2017 Volume 317, Number 22 2299

© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023

 Research Original Investigation Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia

Table 1. Baseline Characteristics

Ferrous Sulfate Iron Polysaccharide
Group (n = 40)a Complex Group (n = 40)a
Age at enrollment, median (range), mo 22 (10-37) 23 (11-34)
Female sex 18 (45) 18 (45)
Race/ethnicity
Hispanic white 23 (58) 26 (65)
Non-Hispanic white 4 (10) 3 (8)
Black 5 (13) 4 (10)
Asian 2 (5) 2 (5)
Native Hawaiian/Pacific Islander 0 1 (3)
>1 Race/ethnicity 6 (15) 4 (10)
Etiology of nutritional iron-deficiency anemia
Breast milk without iron supplementation 11 (27) 8 (20)
Excessive cow milk 29 (73) 32 (80)
Daily amount of cow milk, mean (SD), mL 1230 (330) 1260 (330)
Signs and symptoms of iron-deficiency anemiab
SI conversion factors: To convert
Pallor 18 (45) 18 (45)
ferritin to pmol/L, multiply by 2.247;
Decreased energy 13 (33) 16 (40) hemoglobin to g/L, multiply by 10.0;
Pica 18 (45) 21 (53) total iron-binding capacity to μmol/L,
multiply by 0.179.
Baseline values a
Data are expressed as No. (%)
Hemoglobin concentration, mean (SD), g/dL 7.9 (1.5) 7.7 (1.6) unless otherwise indicated.
Mean corpuscular volume, mean (SD), fL 60.2 (5.2) 59.7 (5.4) Percentages may not sum to 100%
Serum ferritin, median (interquartile range), ng/mL 3.0 (1.7-6.0) 2.0 (1.0-4.3) due to rounding.
b
Total iron-binding capacity, mean (SD), μg/dL 501 (100) 506 (85) Reported by parents or caregiver.
c
There were 26 infants and children
Reticulocyte hemoglobin equivalent, mean (SD), pg 16.8 (3.8)c 17.1 (3.8)c
for this variable in each group.
Receipt of a packed red blood cell transfusiond 10 (25) 8 (20) d
Occurred prior to study enrollment.

Figure 2. Hemoglobin Concentration Over Time

13
Mean Hemoglobin Concentration, g/dL

12 Ferrous sulfate

11

10

Iron polysaccharide complex

9

6 The error bars indicate 95% CIs.

0 2 4 6 8 10 12 Using a linear mixed model, there was
Time, wk a significant difference in the change
No. of patients in hemoglobin concentration over
Ferrous sulfate 40 35 31 28 time (1.0 g/dL [95% CI, 0.4-1.6 g/dL];
Iron polysaccharide complex 40 38 34 31 P < .001) between the 2 groups,
favoring ferrous sulfate.

who received a packed red blood cell transfusion prior to enroll- Primary Outcome
ment were similar for both groups (Table 1). The mean age was The mean hemoglobin concentration increased from 7.9 g/dL
23 months and 55% were male. Sixty-one percent were Hispanic to 11.9 g/dL in the ferrous sulfate group compared with an in-
white, 9% were non-Hispanic white, and 11% were black. crease from 7.7 g/dL to 11.1 g/dL in the iron polysaccharide com-
One child in the ferrous sulfate group erroneously re- plex group over 12 weeks (Figure 2). The primary outcome
ceived iron polysaccharide complex. This patient experi- (using a linear mixed model) demonstrated a significant dif-
enced treatment failure at week 8, was removed from study ference in the change in hemoglobin concentration of 1.0 g/dL
at that time, and was analyzed within the ferrous sulfate group. (95% CI, 0.4-1.6; P < .001) between the 2 groups, favoring
The other 79 patients received the intended treatment. ferrous sulfate.

2300 JAMA June 13, 2017 Volume 317, Number 22 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023

 Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia Original Investigation Research

Table 2. Secondary Outcomes

a
Unless otherwise indicated.
No./Total (%)a Between-Group b
Defined as hemoglobin
Ferrous Sulfate Iron Polysaccharide Difference, concentration greater than 11 g/dL,
Group Complex Group % (95% CI) P Value mean corpuscular volume greater
Complete resolution 8/28 (29) 2/31 (6) 22 (3 to 41) .04 than 70 fL, reticulocyte hemoglobin
of iron-deficiency anemiab equivalent greater than 25 pg,
Lost to follow-up 7/40 (18) 6/40 (15) 3 (−14 to 19) .76 serum ferritin level greater than
Signs and symptoms 15 ng/mL, and total iron-binding
of iron-deficiency anemia capacity less than 425 μg/dL at the
at 12 wk 12-week visit.
Resolution of pallor 21/28 (75) 26/31 (84) −9 (29 to 12) .39 c
Infant or child did not spit out
Increase in energy 25/28 (89) 27/31 (87) 2 (−14 to 18) >.99 medication.
d
Persistence of pica 5/27 (19) 6/31 (19) −1 (−21 to 19) .93 Measured by returned medication
volume.
Medication adherence e
Data were available for 32 in the
Successful administrationc 27/33 (82) 34/36 (94) −13 (−25 to −1) .009 ferrous sulfate group and 37 in the
Mixed medication 5/28 (18) 4/31 (13) 5 (−13 to 23) .73 iron polysaccharide complex group.
with juice or food f
Data were available for 30 in the
Doses taken, %d ferrous sulfate group and 32 in the
Wk 0-4e 93 99 −6 (−15 to 4) .25 iron polysaccharide complex group.
g
Wk 4-8f 94 100 −6 (−15 to 3) .18 Data were available for 28 in the
g ferrous sulfate group and 30 in the
Wk 8-12 93 98 −6 (−17 to 7) .37
iron polysaccharide complex group.

Table 3. Secondary Outcomes of Serum Ferritin Level and Total Iron-Binding Capacity
SI conversion factors: To convert
Ferrous Sulfate Group Iron Polysaccharide Complex Group
ferritin to pmol/L, multiply by 2.247;
No. of Patients Outcome No. of Patients Outcome total iron-binding capacity to μmol/L,
Serum Ferritin Level, Median (Interquartile Range), ng/mLa multiply by 0.179.
a
Wk 0 40 3.0 (1.7-6.0) 40 2.0 (1.0-4.3) Based on a linear mixed model,
treatment with ferrous sulfate
Wk 4 35 17.8 (9.9-24.8) 38 4.7 (3.5-12.9)
resulted in a greater difference
Wk 8 31 17.7 (12.2-25.0) 34 6.6 (3.5-12.9) of 10.2 ng/mL (95% CI, 6.2 to
Wk 12 28 15.6 (8.8-27.7) 31 7.5 (5.0-11.4) 14.1 ng/mL) over 12 weeks vs iron
polysaccharide complex (P < .001).
Total Iron-Binding Capacity, Mean (95% CI), μg/dLb
b
Based on a linear mixed model,
Wk 0 40 501 (469-533) 40 506 (479-533)
treatment with ferrous sulfate
Wk 4 35 413 (380-448) 38 473 (447-499) resulted in a greater difference
Wk 8 31 400 (375-425) 34 445 (418-473) of −50 μg/dL (95% CI, −86 to
−14 μg/dL) over 12 weeks vs iron
Wk 12 28 389 (360-418) 31 417 (391-444)
polysaccharide complex (P < .001).

Secondary Outcomes Adverse Effects and Events

The 59 patients who completed all study visits (28 in the fer-
rous sulfate group and 31 in the iron polysaccharide complex
group) were analyzed for the predefined complete resolution
of IDA (Table 2), which occurred in a larger proportion of pa-
tients receiving ferrous sulfate (29%, n = 8) compared with
those receiving iron polysaccharide complex (6%, n = 2)
(P = .04). There were no significant between-group differ-
ences in iron measurements at baseline.
The median serum ferritin level increased from 3.0 ng/mL
to 15.6 ng/mL in the ferrous sulfate group compared with an
increase from 2.0 ng/mL to 7.5 ng/mL in the iron polysaccha-
ride complex group over 12 weeks (a greater difference of 10.2
ng/mL [95% CI, 6.2 to 14.1 ng/mL] with ferrous sulfate, P < .001;
Table 3). The mean total iron-binding capacity decreased from
501 μg/dL to 389 μg/dL in the ferrous sulfate group compared
with a decrease from 506 μg/dL to 417 μg/dL in the iron poly-
saccharide complex group over 12 weeks (a greater difference
of −50 μg/dL [95% CI, −86 to −14 μg/dL] with ferrous sulfate,
P < .001; Table 3).
The adverse effect profiles demonstrated significantly more par-
ent reports of diarrhea with iron polysaccharide complex
(Table 4). More parent reports of vomiting were made in the
ferrous sulfate group; however, this difference was not statis-
tically significant. A combined post hoc gastrointestinal ad-
verse effect profile (abdominal pain, constipation, vomiting, and
diarrhea) showed no significant between-group differences.
One patient receiving ferrous sulfate experienced a transient
episode of methemoglobinemia of unknown cause during
week 4. The patient was successfully treated with methylene
blue and continued in the study without recurrence.
Lost to Follow-up Rates
Sixteen percent of patients were lost to follow-up (7 [18%] in the
ferrous sulfate group vs 6 [15%] in the iron polysaccharide com-
plex group; P = .72). There were no significant differences in
baseline characteristics (eTable 2 in Supplement 2) or adverse
effects (eTable 3 in Supplement 2) between those patients who
completed the study vs those who were lost to follow-up.

jama.com (Reprinted) JAMA June 13, 2017 Volume 317, Number 22 2301

© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023

 Research Original Investigation Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia

Table 4. Adverse Effects

No./Total (%) Reporting Adverse Effect

Ferrous Sulfate Group Iron Polysaccharide Complex Group P Value
Difficulty in Giving Medication
Ever reported 26/40 (65) 20/40 (50) .17
Wk 2 13/30 (43) 12/30 (40) .88
Wk 4 14/35 (40) 11/38 (29) .32
Wk 6 11/22 (50) 3/22 (14) .01
Wk 8 13/31 (42) 3/34 (9) .002
Wk 10 8/18 (44) 2/20 (10) .03
Wk 12 8/28 (29) 4/31 (13) .14
Abdominal Pain
Ever reported 9/40 (23) 13/40 (33) .32
Wk 2 4/30 (13) 2/30 (7) .67
Wk 4 5/35 (14) 5/38 (13) >.99
Wk 6 4/22 (18) 2/22 (9) .66
Wk 8 4/31 (13) 4/34 (12) >.99
Wk 10 1/18 (6) 2/20 (10) >.99
Wk 12 4/28 (14) 5/31 (16) >.99
Vomiting
Ever reported 23/40 (58) 18/40 (45) .26
Wk 2 10/30 (33) 5/30 (17) .14
Wk 4 12/35 (34) 7/38 (18) .13
Wk 6 6/22 (27) 2/22 (9) .24
Wk 8 8/31 (26) 2/34 (6) .04
Wk 10 3/18 (17) 1/20 (5) .33
Wk 12 3/28 (11) 5/31 (16) .71
Diarrhea
Ever reported 14/40 (35) 23/40 (58) .04
Wk 2 8/30 (27) 9/30 (30) .77
Wk 4 7/35 (20) 6/38 (16) .64
Wk 6 4/22 (18) 5/22 (23) >.99
Wk 8 4/31 (13) 5/34 (15) >.99
Wk 10 3/18 (17) 2/20 (10) .65
Wk 12 2/28 (7) 8/31 (26) .08
Gastrointestinala
Ever reported 29/40 (73) 32/40 (80) .43
Wk 2 16/30 (53) 12/30 (40) .30
Wk 4 21/35 (60) 16/38 (42) .13
Wk 6 12/22 (55) 7/22 (32) .13
Wk 8 14/31 (45) 10/34 (29) .19
Wk 10 6/18 (33) 5/20 (25) .57
a
Abdominal pain, vomiting, diarrhea,
Wk 12 10/28 (36) 13/31 (42) .62
or constipation.

Signs and Symptoms of IDA
Both groups had improvements in patient-centered out-
comes such as increased energy level, decreased pica, and reso-
lution of pallor that were not significantly different (Table 2).
None of the patients had an elevated blood lead level at the
week 4 study visit.
Medication Adherence
Parents reported more successful administration of all indi-
vidual iron doses (ie, the child not spitting out the medica-
tion) with iron polysaccharide complex (94% vs 82% in the
ferrous sulfate group; P = .009). There were no other signifi-
cant between-group measures for medication adherence.
Via patient diaries, 78% of families reported missing no doses
of iron polysaccharide complex compared with 53% of fami-
lies in the ferrous sulfate group (P = .12).
Fifty percent of parents reported difficulty with ad-
ministration of iron polysaccharide complex at any point
in the study compared with 65% in the ferrous sulfate
group (P = .17; Table 4). Returned medication volume indi-
cated no significant difference in adherence with iron poly-
saccharide complex compared with ferrous sulfate. As a
marker of difficulty with medication administration, there
was no significant difference in the proportion of parents
who reported mixing the iron preparation with juice or food
(Table 2).

2302 JAMA June 13, 2017 Volume 317, Number 22 (Reprinted) jama.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023

 Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia
Discussion
In this randomized clinical trial of infants and children aged 9
to 48 months with nutritional IDA treated at a single aca-
demic medical center, ferrous sulfate drops compared with iron
polysaccharide complex drops resulted in a greater increase
in hemoglobin concentration at 12 weeks. Studies of neuro-
cognitive outcomes in children with IDA 17 have demon-
strated the clinical importance of the between-group differ-
ence in hemoglobin concentration of 1 g/dL found in this trial.
Among the secondary outcomes, the proportion of pa-
tients with a complete resolution of IDA (ie, no further iron
therapy required) was higher in the ferrous sulfate group. Simi-
lar to the primary outcome, changes in iron indices favored the
ferrous sulfate group. More parent reports of diarrhea were
made in the iron polysaccharide complex group but no other
significant differences in adverse effects were found. Pa-
tients were more likely to ingest the iron polysaccharide com-
plex during administration compared with ferrous sulfate, but
there were otherwise no significant between-group differ-
ences in the lost to follow-up rates, resolution of IDA symp-
toms, or medication adherence.
Iron salts have long been used for the treatment of IDA,
with ferrous sulfate being the most common choice in per-
sons of all ages.16,20 Reports of poor taste and gastrointesti-
nal adverse effects often result in the recommendation of other
iron salts (eg, ferrous gluconate and fumarate) or iron poly-
saccharide complex preparations.16,21,22 In the current trial, an
iron polysaccharide complex agent developed specifically to
have improved taste and tolerability was hypothesized to pro-
mote a more effective hematologic response. Although both
preparations were effective and well-tolerated, ferrous sul-
fate resulted in a greater increase in hemoglobin concentra-
tion and improved diverse measures of iron homeostasis.
Previous radioisotope studies have demonstrated more ef-
fective use of iron when administered in the form of medici-
nal iron in contrast to iron-fortified foods.23 Small studies in
adults suggest that bivalent salts such as ferrous sulfate are
more effectively absorbed than trivalent ones.24,25 Limited data
from prior studies suggest improved absorption with ferrous
sulfate compared with iron polysaccharide complexes.24,25
A small case series by Diamond et al26 compared a palatable
iron carbohydrate complex with ferrous sulfate, and the lat-
ter resulted in a more rapid hemoglobin concentration in-
crease over 3 weeks.
Oral iron absorption tests were conducted and those pa-
tients receiving ferrous sulfate demonstrated a markedly higher
increase in serum iron, supporting the notion of more effec-
tive absorption. Therefore, this trial failed to demonstrate the
original hypothesis that iron polysaccharide complex would
be more effective than ferrous sulfate, likely due to more ef-
fective absorption of the latter.
Recommended therapeutic dosing of elemental iron in chil-
dren ranges widely from 2 to 6 mg/kg/d administered from 1
to 3 times daily.12 In this trial, a daily iron dose at the lower end
of the recommended range (3 mg/kg of elemental iron) ad-
ministered just once daily, at bedtime, and on an empty stom-
jama.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023
Original Investigation Research
ach was chosen. Two prior randomized clinical trials in
children10,11 informed this minimalist strategy aimed to en-
hance adherence and limit adverse effects. One trial10 com-
pared once daily ferrous sulfate (3 mg/kg of elemental iron) with
placebo in infants aged 12 months and demonstrated no sig-
nificant differences in adverse gastrointestinal effects. The
other trial11 conducted in rural Ghana documented similar suc-
cess rates in correcting anemia when ferrous sulfate was ad-
ministered once or 3 times daily. Recommendations based pri-
marily on expert opinion from the US Centers for Disease
Control and Prevention and the World Health Organization have
endorsed low-dose, once daily iron therapy.27,28
Studies involving adults with IDA also support the use of
low-dose oral iron treatment. In 1 trial,14 octogenarians with
anemia were randomized to 15 mg, 50 mg, or 150 mg of fer-
rous salts (gluconate or citrate) administered once daily and
had virtually identical hematologic responses, but there were
far less gastrointestinal toxic effects in the group receiving
15 mg. A study in women with iron deficiency using stable iron
isotopes demonstrated that a single dose of iron engendered
a prompt increase in serum hepcidin level that resulted in
markedly reduced absorption of subsequent iron doses 12 hours
or even 24 hours later.13 Taken together, these findings sug-
gest that once daily low-dose iron therapy might result in
greater fractional absorption of iron in lieu of multiple doses
of iron each day.13,29
Unlike nearly all prior therapeutic studies of oral iron
agents, this trial was designed as a double-blind, randomized
clinical trial. In concert with other literature,13,14 these re-
sults should help stimulate the conduct of further clinical trials
evaluating lower or less frequent dosing of oral iron. Antici-
pated outcomes might include improved patient adherence as
well as enhanced iron absorption leading to a more favorable
hematologic response.
Limitations
The trial has several limitations. First, it was conducted at a
single tertiary care children’s hospital. Second, there were a
disproportionate number of lower income and minority pa-
tients whose anemia was often severe, with approximately 23%
requiring a blood transfusion prior to enrollment. Third, the
trial had a lost to follow-up rate of 25% at the final 12-week visit.
Fourth, these results may not be generalizable to the general
pediatric population due to the strict monitoring involved in
a clinical trial compared with standard community practice.
Yet by choosing to use a simplified dosing regimen, the goal
was to create a practical treatment strategy that could im-
prove outcomes even when applied in a clinical setting.
Conclusions
Among infants and children aged 9 to 48 months with nutri-
tional iron-deficiency anemia, ferrous sulfate compared with
iron polysaccharide complex resulted in a greater increase in
hemoglobin concentration at 12 weeks. Once daily, low-dose
ferrous sulfate should be considered for children with nutri-
tional iron-deficiency anemia.
(Reprinted) JAMA June 13, 2017 Volume 317, Number 22 2303
 Research Original Investigation
ARTICLE INFORMATION
Accepted for Publication: May 15, 2017.
Author Affiliations: Division of Hematology and
Oncology, Baylor College of Medicine, Houston,
Texas (Powers); Department of Pediatrics, Baylor
College of Medicine, Houston, Texas (Powers);
Texas Children’s Hospital, Houston (Powers);
Division of Hematology and Oncology, University
of Texas Southwestern Medical Center, Dallas
(Buchanan); Department of Pediatrics, University
of Texas Southwestern Medical Center, Dallas
(Buchanan); Children’s Health, Dallas, Texas
(Buchanan, Adix); Department of Clinical Sciences,
University of Texas Southwestern Medical Center,
Dallas (Zhang, Gao); Division of Hematology and
Oncology, Cook Children’s Medical Center,
Ft Worth, Texas (McCavit); Department of
Pediatrics, Cook Children’s Medical Center,
Ft Worth, Texas (McCavit).
Author Contributions: Drs Powers and McCavit
had full access to all of the data in the study and
take responsibility for the integrity of the data
and the accuracy of the data analysis.
Concept and design: Powers, Buchanan, Adix,
Zhang, McCavit.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Powers, Buchanan,
Adix, McCavit.
Critical revision of the manuscript for important
intellectual content: Powers, Buchanan, Adix,
Zhang, McCavit.
Statistical analysis: Powers, Zhang, Gao, McCavit.
Obtained funding: Powers, Buchanan, McCavit.
Administrative, technical, or material support:
Buchanan, Adix, McCavit.
Supervision: Powers, Buchanan, McCavit.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/Support: This study was an
investigator-initiated trial with sponsorship
from Gensavis Pharmaceuticals LLC, the
manufacturer of the iron polysaccharide
complex used in this trial. The company provided
funding for both trial drugs, central organizational
costs, and salary support for Dr McCavit. This work
was additionally supported by grant KL2TR001103
from the National Center for Advancing
Translational Sciences and grant K23HL132001
from the National Heart, Lung, and Blood Institute.
Role of the Funder/Sponsor: The funders of the
study had no role in design and conduct of the
study; collection, management, analysis, and
interpretation of the data; and preparation,
2304 JAMA June 13, 2017 Volume 317, Number 22 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by Saptadi Yuliarto on 05/09/2023
Ferrous Sulfate vs Iron Polysaccharide Complex for Children With Anemia
review, or approval of the manuscript or the
decision to submit for publication.
Additional Contributions: Dr Zhang and Ms Gao
(Department of Clinical Sciences, University of
Texas Southwestern Medical Center, Dallas)
conducted and are responsible for the
data analysis.
REFERENCES
1. McLean E, Cogswell M, Egli I, et al. Worldwide
prevalence of anaemia, WHO Vitamin and Mineral
Nutrition Information System, 1993-2005. Public
Health Nutr. 2009;12(4):444-454.
2. Kassebaum NJ, Jasrasaria R, Naghavi M, et al.
A systematic analysis of global anemia burden from
1990 to 2010. Blood. 2014;123(5):615-624.
3. Brotanek JM, Gosz J, Weitzman M, Flores G.
Secular trends in the prevalence of iron deficiency
among US toddlers, 1976-2002. Arch Pediatr
Adolesc Med. 2008;162(4):374-381.
4. McDonagh MS, Blazina I, Dana T, et al. Screening
and routine supplementation for iron deficiency
anemia. Pediatrics. 2015;135(4):723-733.
5. Gupta PM, Perrine CG, Mei Z, Scanlon KS.
Iron, anemia, and iron deficiency anemia among
young children in the United States. Nutrients.
2016;8(6):E330.
6. Lozoff B, Jimenez E, Wolf AW. Long-term
developmental outcome of infants with iron
deficiency. N Engl J Med. 1991;325(10):687-694.
7. Lozoff B, Jimenez E, Hagen J, et al. Poorer
behavioral and developmental outcome more than
10 years after treatment for iron deficiency in
infancy. Pediatrics. 2000;105(4):E51.
8. Lukowski AF, Koss M, Burden MJ, et al. Iron
deficiency in infancy and neurocognitive
functioning at 19 years. Nutr Neurosci. 2010;13(2):
54-70.
9. Powers JM, Daniel CL, McCavit TL, Buchanan GR.
Deficiencies in the management of iron deficiency
anemia during childhood. Pediatr Blood Cancer. 2016;
63(4):743-745.
10. Reeves JD, Yip R. Lack of adverse side effects of
oral ferrous sulfate therapy in 1-year-old infants.
Pediatrics. 1985;75(2):352-355.
11. Zlotkin S, Arthur P, Antwi KY, Yeung G.
Randomized, controlled trial of single versus
3-times-daily ferrous sulfate drops for treatment
of anemia. Pediatrics. 2001;108(3):613-616.
12. Powers JM, Buchanan GR. Diagnosis and
management of iron deficiency anemia. Hematol
Oncol Clin North Am. 2014;28(4):729-745, vi-vii.
13. Moretti D, Goede JS, Zeder C, et al. Oral iron
supplements increase hepcidin and decrease
iron absorption from daily or twice-daily doses in
iron-depleted young women. Blood. 2015;126(17):
1981-1989.
14. Rimon E, Kagansky N, Kagansky M, et al. Are we
giving too much iron? Am J Med. 2005;118(10):
1142-1147.
15. Smith NJ. Iron as a therapeutic agent in
pediatric practice. J Pediatr. 1958;53(1):37-50.
16. Camaschella C. Iron-deficiency anemia. N Engl J
Med. 2015;372(19):1832-1843.
17. Stoltzfus RJ, Mullany L, Black RE. Iron
deficiency anemia. In: Ezzati M, Lopez AD, Rodgers
A, Murral CJL, eds. Comparative Quantification of
Health Risks. Vol 1. Geneva, Switzerland: World Health
Organization; 2004.
18. Abdullah K, Birken CS, Maguire JL, et al.
Re-evaluation of serum ferritin cut-off values for the
diagnosis of iron deficiency in children aged 12-36
months [published online April 18, 2017]. J Pediatr.
doi:10.1016/j.jpeds.2017.03.028
19. Rubin DB. Inference and missing data. Biometrika.
1976;63(3):581-592.
20. Powers JM, McCavit TL, Buchanan GR.
Management of iron deficiency anemia. Pediatr
Blood Cancer. 2015;62(5):842-846.
21. Pritchard JA. Hemoglobin regeneration in
severe iron-deficiency anemia. JAMA. 1966;195(9):
717-720.
22. Kerr DN, Davidson S. Gastrointestinal
intolerance to oral iron preparations. Lancet. 1958;2
(7045):489-492.
23. Schulz J, Smith NJ. A quantitative study of the
absorption of food iron in infants and children. AMA
J Dis Child. 1958;95(2):109-119.
24. Moore CV, Arrowsmith WR, Welch J, Minnich V.
Studies in iron transportation and metabolism, IV.
J Clin Invest. 1939;18(5):553-580.
25. Moore CV, Dubach R, Minnich V, Roberts HK.
Absorption of ferrous and ferric radioactive iron by
human subjects and by dogs. J Clin Invest. 1944;
23(5):755-767.
26. Diamond LK, Naiman JL, Allen DM, Oski FA.
The treatment of iron-deficiency anemia. Pediatrics.
1963;31:1041-1044.
27. From the Centers for Disease Control and
Prevention. Iron deficiency. JAMA. 2002;288(17):
2114-2116.
28. World Health Organization. Iron Deficiency
Anaemia: Assessment, Prevention, and Control:
A Guide for Programme Managers. Geneva,
Switzerland: World Health Organization; 2001.
29. Schrier SL. So you know how to treat iron
deficiency anemia. Blood. 2015;126(17):1971.
jama.com