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Paediatrica Indonesiana

VOLUME 53 NUMBER 3 May 2O13


Original Article
150 Paediatr Indones, Vol. 53, No. 3, May 2013
Serum ferritin to detect iron deficiency in children
below five years of age
Windy Saufia Apriyanti, Sutaryo, Sri Mulatsih
Abstract
Background lron deficiencv (lD) anemia impacts the
cognitive and motor development of children until the age of
1O vears, despite receivin, iron therapv. larlv detection of lD
is recommended and serum ferritin has been proposed as an
alternative indicator for lD detection.
Objective To assess the diagnostic accuracy of serum ferritin for
detectin, lD in children below five vears of a,e.
Methods This cross-sectional, diagnostic study was conducted in
primarv health care centers in Yo,vakarta and Bantul. Hemo,lobin
(Hb), serum ferritin and soluble transferrin receptor (s1fR) levels
were performed on children a,ed 6-59 months. A s1fR level of ~
o.2 m,/l was used to define iron deficiencv. 1he best cut off point
for serum ferritin level use as a diagnostic tool was determined by
receiver operator curve.
Results 1he prevalence of lD was 32'. Mean hemo,lobin levels
in iron deficient and healthv children were 11.7 (SD O.5) ,/dl and
12.2 (SD O.7) ,/dl, respectivelv. 1he sensitivitv, specificitv, and
positive predictive value (PPV) of serum ferritin (<12 u,/l) were
17', 93', and 56', respectivelv. Usin, a cut off of <32.1 u,/l,
serum ferritin had sensitivitv of 62.1' and specificitv of 5O.o'.
Conclusions The diagnostic value of serum ferritin levels is
modestlv capable of detectin, lD. 1herefore, serum ferritin should
not be used as an alternative indicator for detectin, lD in children
below five years of age. [Paediatr Indones. 2013;53:150-4.].
Keywords: iron deficiency, serum ferritin, soluble
transferrin receptor
From the Department of Child Health, Gadjah Mada University Medical
School, Dr. Sardjito Hospital, Yo,vakarta, lndonesia
Reprint requests to: Windy Saufia Apriyanti, Department of Child
Health, Gadjah Mada University Medical School, Dr Sardjito Hospital,
Jalan Kesehatan No.1, Yo,vakarta 552o1, lndonesia. 1el 62-271-5o7333.
l-mail: wsaufia@yahoo.com
l
ron deficiencv (lD) continues to be the most
common cause of anemia worldwide.
1
ln children
below five years of age, the prevalence of iron
deficiencv anemia (lDA) was reported to be 1o.1'
in lndonesia and 3o - 73' in Yo,vakarta.
2,3
lron
deficiency anemia impairs the cognitive and motor
development of children until 1O vears of a,e, even
if iron therapy was given.
1
Therefore, detection and
treatment of iron deficiency before anemia occurs may
improve later developmental outcomes.
lron stainin, of bone marrow aspiration has
been the ,old standard for lD dia,nosis, however,
this procedure is invasive.
5
The sTfR is the best
alternative indicator to detect lD. lts sensitivitv and
specificitv are o1' and 91', respectivelv, for detectin,
lD in infants.
6
1he levels of s1fR increase when lD
occurs.
7
Nevertheless, this test, too, has limitations
as it is expensive and often unavailable in routine
settings.
o
Serum ferritin has been suggested as another
alternative indicator. lt reflects iron bodv stores.
Moreover, it is less expensive than s1fR, available in
most health care settings, and has a high specificity
for lDA dia,nosis.
5
Windy Saufia Apriyanti et al: Serum ferritin to detect iron deficiency in children below five years of age
Paediatr Indones, Vol. 53, No. 3, May 2013 151
World Health Organization recommends
usin, a serum ferritin level of <12 u,/l in combination
with a hemo,lobin level of <11 ,/l for lDA dia,nosis
in children aged 6 months to 5 years.
o,9
However, this
cut off has not been used to screen for lD. Dia,nostic
levels of serum ferritin to detect iron deficiency
in children below five years of age has not been
determined. The aim of the study was to assess serum
ferritin diagnostic levels and the best cutoff point to
detect lD in children below five vears of a,e.
Methods
We conducted a cross-sectional, diagnostic study
from November 2O1O to April 2O11 at primarv health
care centers in Yo,vakarta and Bantul. We estimated
a required sample size of 199 subjects, based on A ~
O.O5 and power ~ 9O'. 1he inclusion criteria were
healthv children a,ed 6 - 59 months whose parents
consented to participate. Children who had infection,
inflammation, anemia (Hb level <11 ,/dl), serum
ferritin level > 11O u,/l, or received iron therapv
within the prior 3 months were excluded. Patients
were classified as having infection and inflammation
when we found fever with or without a focal infection.
lron deficiencv was defined as serum ferritin <12 u,/l.
As the gold standard for detecting iron deficiency, we
measured s1fR, with a value of ~o.2 m,/l considered
to be iron-deficient.
1O
An assistant of the study interviewed parents
to collect data on every child at their first visit. Data
included a,e, sex, birth wei,ht, ,estational a,e,
diet recall, socioeconomic status, and iron therapy.
1he criteria for ,ood recalled diet were exclusive
breastfeeding, and age-appropriate diet without the
consumption of cow's milk in the first vear of life. lf
these criteria were not met, subjects were considered
to have poor recalled diet. Socio-economic status was
classified based on monthly family income as high (more
than lDR 2,OO1,OOO), middle (lDR 7O1,OOO to lDR
2,OOO,OOO), and low (less than lDR. 7OO,OOO).
11
Phvsical examinations were performed to
assess for infection and inflammation, as well as
anthropometric status by measurement of weights
(k,) and hei,hts (cm). Based on z-score, nutritional
status was classified as well-nourished (weight for
hei,ht index -2SD to 2SD) or undernourished
(wei,ht for hei,ht index -3SD to -2SD). Venous
blood samples (2.5 ml) were drawn bv laboratorv
staff to check Hb, serum ferritin and sTfR levels.
The Hb level was measured with cyanmethemoglobin
and serum ferritin level was measured with enzyme-
linked immunosorbent assav (lllSA) in the Parahita
laboratorv, Yo,vakarta. We sent eli,ible samples to the
Southeast Asian Ministry of Education Organization
(SlAMl) laboratorv in Jakarta to measure s1fR
levels usin, a sandwich lllSA technique.
Kolmogorov-Smirnov test was used for the
assessment of normality. To compare the distribution
of Hb, serum ferritin and s1fR levels between the lD
and normal groups, the T-test or Mann-Whitney test
was used. A P value of <O.O5 was considered to be
statistically significant.
Diagnostic values of serum ferritin was deter-
mined by calculating the sensitivity, specificity,
prevalence (pre-test probabilitv), positive predictive
value (PPV), ne,ative predictive value (NPV),
positive likelihood ratio, negative likelihood ratio,
pre-test odds, post-test odds, and post-test probability.
Receiver operator curve (RC) was performed to
choose the best serum ferritin concentration cut off
Figure 1. Study prole ow chart
Data analysis
n=90
sTfR level examination
n=90
Hb <11 g/dL (n=10)
Serum ferritin >140 ug/L (n=3)
Serum ferritin level examination
n=103
Hb level examination
n=103
nfection and inammation (n=0)
ron therapy (n=0)
Venous blood sample 2.5 mL
n=103
History, physical examinations,
anthropometric measurements
n=103
nformed consent
Subjects enrolled
n=103
Windy Saufia Apriyanti et al: Serum ferritin to detect iron deficiency in children below five years of age
152 Paediatr Indones, Vol. 53, No. 3, May 2013
point for lD dia,nosis. 1his studv was approved bv
the Ethics Committee of the Gadjah Mada University
Medical School, Yo,vakarta.
Results
1here were 1O3 children initiallv enrolled in this studv.
lrom these children, 13 children were excluded for
anemia (1O children) and serum ferritin level >11O
u,/l (3 children) (Figure 1).
Table 1. Baseline characteristics of subjects
Characteristics
ron decient children
(n = 29)
Normal children
(n = 61)
Age, n (%)
6 24 months
25 59 months
6
23
13 (21)
48 (79)
Sex, n (%)
Male
Female
14
15
34 (56)
27 (44)
Birth weight, n (%)
<2500 grams
2500 4000 grams
0
29
2 (3)
59 (97)
Gestational age, n (%)
<37 weeks 0 0
37 42 weeks 29 61 (100)
Nutritional status, n (%)
Well-nourished
Undernourished
13
16
42 (69)
19 (31)
Recalled diet, n (%)
Good
Poor
13
16
37 (61)
24 (39)
Socioeconomic status, n (%)
High
Middle
Low
0
13
16
2 (3)
28 (46)
31 (51)
Table 2. Hb, sTfR, and serum ferritin levels by group
Variables
ron decient children
(n = 29)
Normal children
(n = 61)
P value
Mean Hb (SD), g/dL 11.7 (0.5) 12.2 (0.7) 0.001*
Mean sTfR (SD), mg/L 9.3 (1.1) 6.2 (1.1) <0.001*
Median serum ferritin (SD), ug/L 24.3 (2.4 121.5) 33 (4.5 114.2) 0.228
#
*t-test;
#
Mann-Whitney
Table 3. Crosstabulation between serum ferritin and sTfR values
sTfR
ron decient children Normal children Total
Serum ferritin ron decient 5 4 9
Normal 24 57 81
Total 29 61 90
Sensitivity = 17%; specicity = 93%; prevalence (pre-test probability) = 32%; PPV = 56%; NPV = 70%; positive likelihood ratio =
2.63; negative likekihood ratio= 0.89; pre-test odds = 0.47; post-test odds = 1.23; post-test probability = 55%
We found that the prevalence of lD in our
subjects was 32'. 1he hi,hest prevalence was found
in the 25 - 59 months a,e ,roup (23 out of 29). All
children from the lD ,roup had normal birth wei,hts
and ,estational a,es. 1here were 11 males and 15
females detected to have lD (Table 1).
We found that iron deficient children had
significant lower Hb level and higher sTfR level
compared to normal children, but no significant
difference in median of serum ferritin levels between
the groups (Table 2).
Windy Saufia Apriyanti et al: Serum ferritin to detect iron deficiency in children below five years of age
Paediatr Indones, Vol. 53, No. 3, May 2013 153
Cross-tabulation between serum ferritin and
sTfR values are shown in Table 3. According to ROC,
the best serum ferritin level cut off point was <32.1
u,/l, increasin, its sensitivitv to 62.1' and specificitv
to 5O.o'.
Discussion
lron deficiencv usuallv occurs in the second vear of
life, due to decreased iron intake and rapid growth in
the first year of life. Normal infants need to absorb
approximatelv O.o m,/dav of dietarv iron (O.6 m, for
,rowth and O.2 m, to replace on,oin, losses). 1owards
the end of the second year of life, this swift rate of
growth begins to slow, so routine diets should include
sufficient iron-rich foods to meet demands.
5,12
ln our subjects, we found the hi,hest prevalence
of iron deficiencv to be in the third vear of life. Sixteen
of 29 children with lD were undernourished, had
poor recalled diet, and low socioeconomic status.
Poor recalled diet included children not breastfed
exclusivelv or not ,ettin, appropriate diet for their
age. No history of cows milk consumption was found
in either group. Low socioeconomic status led to
parents being unable to provide appropriate diets,
as well as appropriate developmental stimulation for
their children.
1,9
We found similar numbers of lD in males and
females. Gender differences reportedly only affect
lD in adolescents, as females are at hi,her risk due
to menstruation and rapid ,rowth. ln developin,
countries, lD has also been attributed to chronic blood
loss due to parasitic infections.
5,13
A limitation of our
studv was that we did not perform stool examinations
to detect parasitic infections.
We found that the mean Hb level in the
iron deficient group was lower than that of the
normal ,roup (P~O.O1). lven if the Hb level was
still within normal limits in iron deficient patients,
iron supplementation must be given to prevent
anemia based on the lndonesian Pediatric Societv
recommendations.
Mean sTfR level in the iron deficient group was
hi,her than that of the normal ,roup (P<O.OO1).
Levels of serum ferritin in both groups were within
normal ranges. This shows that sTfR is a more
sensitive indicator for iron deficiency than serum
ferritin. Normal values of serum ferritin for children
a,ed 6 months - 15 vears are 12 - 11O u,/l.
11
lnterpretation of serum ferritin must be looked at
closely. Ferritin is an acute-phase reactant that can
become elevated in settings of inflammation, chronic
infection, and malignancy.
5,1O,15
C-reactive protein (CRP) and A1-acid ,lvco-
protein (AOP) are common biomarkers of infection
and inflammation under field conditions. The WHO
and Centers for Disease Control (CDC) stress
the need to include CRP and AOP in iron status
assessments. CRP rises rapidlv after the onset of
infection and declines within 21-1o hours. AOP
reaches its maximum concentration 1o hours after
the onset of inflammation and remains elevated for
12O-111 hours.
16
ln order to prevent false positives
usin, serum ferritin, we excluded the children who
suffered from infection and inflammation based on
historv-takin,, and whose serum ferritin was >11O
u,/l. CRP and AOP examinations were not performed
in our study.
Both cut off and diagnostic values of serum
ferritin to detect iron deficiency in children below five
years of age have not yet been identified. The WHO
recommends usin, a serum ferritin level of <12 u,/l
in combination with a Hb level of <11 ,/dl for lDA
diagnosis in children aged 6 months to 5 years.
o,9
1herefore, we used a serum ferritin level of <12 u,/l
as an initial cut off point. However, this level resulted
in poor diagnostic values, with sensitivity, specificity
and PPV of 17', 93' and 56', respectivelv. Positive
likelihood ratio was onlv 2.63, which meant serum
ferritin was not a useful differentiator. The poor
diagnostic values may have been influenced by the
small sample size.
Several studies had similar results. Serum ferritin
levels of <15 u,/l and 12 u,/l were used to detect
lD in adult patients and also had poor dia,nostic
values.
17,1o
However, an Estonian study found serum
ferritin level <1O.9 u,/l had o3' sensitivitv and
oO' specificitv to detect lD in healthv, term infants
a,ed 9 - 12 months with normal birth wei,ht. lnfants
with increased CRP concentration (CRP >5 m,/l)
were excluded.
19
We constructed a ROC in order to choose the
best cut off point of serum ferritin concentration,
which was 32.1 u,/l. lts sensitivitv and specificitv
were 62.1' and 5O.o', respectivelv, however, this
Windy Saufia Apriyanti et al: Serum ferritin to detect iron deficiency in children below five years of age
154 Paediatr Indones, Vol. 53, No. 3, May 2013
level was still not sensitive enough to make a confident
diagnosis. A good screening tool is defined as having
a sensitivitv ~oO', despite the presence of low
specificity.
2O
ln conclusion, we recommend that serum ferritin
not be used as an alternative indicator in detectin, lD
in children below five years of age. However, further
study should be performed with a larger sample size
and with examinations of infection or inflammation
biomarkers, includin, CRP or AOP while examinin,
iron status.
Acknowledgment
We are extremelv ,rateful to lndv Parvanto MD for the special
comments during manuscript preparation, Hendro Dwi Wicaksono
as our assistant in the study. We also thank the laboratory staff
of the Parahita laboratorv in Yo,vakarta and the SlAMl
laboratorv in Jakarta.
References
1. Assessin, the iron status of populations. 2
nd
ed. Oeneva:
World Health r,anization, 2OO7. p. 1 - 112.
2. Windiastuti l. Anemia defisiensi pada bavi dan anak.
lndonesian Pediatric Societv, 2OO9 |cited 2O12 Mav 9].
Available from: http://www.idai.or.id/kesehatananak/artikel.
asp?q=20125795911
3. Sutarvo. 1ujuh puluh lima persen anak di DlY menderita
anemia defisiensi besi. Suara merdeka, 2OO7 |cited 2O12
Mav 9]. Available from: http://www.suaramerdeka.com/
cvbernews/harian/O7O5/Oo/dar3.htm
1. Soedjatmiko. Pen,aruh defisiensi besi terhadap kecerdasan
dan perilaku anak. ln: PKB lll Departemen llmu Kesehatan
Anak lakultas Kedokteran Universitas lndonesia. Pendekatan
praktis pucat. Jakarta: lndonesian Pediatric Societv, 2OO7. p.
72-o6.
5. Wu AC, Lesperance L, Bernstein H. Screening for iron
deficiencv. Pediatr Rev. 2OO2,23:171-o.
6. Vendt N, 1alvik 1, leedo S, 1omber, K, Kool P, 1illmann V,
et al. The reference limits and cut-off value for serum soluble
transferrin receptors for diagnosing iron deficiency in infants.
lnt J lab Hematol. 2OO9,31:11O-6.
7. Koulaouzidis A, Said l, Cotter R, Saeed AA. Soluble
transferrin receptors and iron deficiency, a step beyond
ferritin. A svstematic review. J Oastrointestin liver Dis.
2OO9,1o:315-52.
o. Muhammad A, Sianopar . Penentuan defisiensi besi,
anemia penyakit kronis menggunakan peran indeks
s1fR-l. lndonesian Journal Clinical Patholo,v and Medical
laboratorv. 2OO5,12:9-16.
9. Baker RD, Oreer lR, and the Committee on Nutrition
American Academv of Pediatrics. Dia,nosis and prevention
of iron deficiency and iron deficiency anemia in infants and
voun, children (O - 3 vears of a,e). Pediatrics. 2O1O,126:1O1O-
5O.
1O. lrhardt JO, lstes Jl, Pfeiffer CM, Biesalski HK, Craft Nl.
Combined measurement of ferritin, soluble transferrin
receptor, retinol binding protein, and C-reactive protein by an
inexpensive, sensitive, and simple sandwich enzvme-linked
immunosorbent assav technique. J Nutr. 2OO1, 131:3127-
32.
11. New social economv status bracket. lndonesia: Nielsen Co.,
2O1O. p. 1-1.
12. lron deficiencv anemia. Assessment, prevention, and control.
A ,uide for pro,ramme mana,ers. Oeneva: WH, 2OO1. p.
1-132.
13. Kazal l. Prevention of iron deficiencv in infant and toddlers.
Am lam Phvsicians. 2OO2,66:1217-27.
11. lanzkowskv P. lron deficiencv anemia. ln: Manual of pediatric
hematolo,v and oncolo,v. 1
th
ed. Amsterdam: llsevier
Academic Press, 2OO5. p. 31-16.
15. Badham J, zimmermann MB, Kraemer K. 1he ,uidebook
nutritional anemia. Urbana: Side and life Press. 2OO7. p.
1-52.
16. Avova MA, Spiekermann-Brouwer OM, Stoltzfus RJ, Nemeth
l, Habicht JP, Oanz 1, et al. A1-Acid ,lvcoprotein, hepcidin,
C-reactive protein, and serum ferritin are correlated in
anemic schoolchildren with Schistosoma haematobium. Am J
Clin Nutr. 2O1O,91:17o1-9O.
17. n, KH, 1an Hl, lai HC, Kuperan P. Accuracv of various
iron parameters in the prediction of iron deficiency in an
acute care hospital. Ann Acad Med Sin,apore. 2OO5,31:137-
1O.
1o. Mast Al, Blinder MA, Oronowski AM, Chumlev C, Scott
MG. Clinical utility of the soluble transferrin receptor and
comparison with serum ferritin in several populations. Clin
Chem. 199o,11:15-51.
19. Vendt N, 1alvik 1, leedo S, 1omber, K, Kool P, 1illmann V,
et al. Reference and cut-off values for serum ferritin, mean
cell volume, and hemoglobin to diagnose iron deficiency in
infants a,ed 9 to 12 months. Medicina (Kaunas). 2OO7,13:1-
5.
2O. Sastroasmoro S, lsmael S, editors. Dasar-dasar metodologi
penelitian klinis. 3
rd
ed. Jakarta: Sa,un, Seto. 2OOo.