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1. Comparison of Different Iron Preparations
in the Prophylaxis of Iron-deficiency
Anemia
Presented by: Clara Parannuan
Pembimbing :
Dr. dr. Nadirah Rasyid Ridha, M.Kes., Sp.A(K)
dr. Purnamasari Natsir Putri, Sp. A

2. Summary: We compared the efficacy of ferrous sulfate (divalent) and ferric polymaltose (trivalent) compounds for the
prophylaxis of irondeficiency anemia (IDA). Study infants included exclusively breast milk-fed term infants. Subjects
were divided randomly into 2 groups at 4 months of age and group 1 (n=56) received divalent and group 2 (n=56)
received trivalent iron (Fe) preparation at a dose of 2 mg/ kg/d for 5 months. At 9 months of age, after a 5-month
prophylaxis, a significant increase was observed in hemoglobin (Hb), hematocrit, serum Fe levels, and transferrin
saturation in both groups. However, group 1 had significantly higher Hb, hematocrit, mean corpuscular volume, Fe,
and transferrin saturation than group 2 (11.7 ± 0.6 g/dL, 34.6% ± 1.7%, 76.2 ± 2.9 fL, 55.5 ± 1.8 mcg, 20.8 ± 3.9 g/L,
respectively in group 1 vs. 11.3 ± 0.5 g/dL, 33.5% ± 1.5%, 74.7 ± 3.2 fL, 42.5 ± 1.8 mcg, 14.1 ± 7.5 g/L, respectively in
group 2). No significant difference was found in ferritin values between the groups. Fe deficiency was found in 17
(30.3%) of the subjects in group 1, and 23 (41%) of subjects in group 2 whereas 5 (8.9%) subjects had IDA in group 1
and 12 (12%) in group 2 which were insignificant between groups. No significant difference was found with regard to
side effects between 2 Fe preparations. Although divalent Fe therapy led to a higher Hb and serum Fe level, both
ferrous and ferric Fe preparations were effective for prophylactic use in the prevention of Fe deficiency and IDA with
comparable side effects.

3. Secondary to an imbalance between
iron (Fe) needs and available Fe
The most common nutritional
disorder & common cause of anemia
in children aged 4 to 23 months
Iron-deficiency Anemia
(IDA)
Global Prevalence:
• 2 billion people (30% of the
world’s population)
ID & IDA effects:
• Irreversible neurodevelopmental
• Behavioral effects
• Impaired immunity
Young infants depend on Fe from 2 sources
Birth Fe stores Breast milk
Adequate to meet
infants’ Fe
requirements as
long as the infants
are born with
sufficient birth Fe
stores
Infants reach 4 to 6 months of age
Fe needs start to exceed the Fe
intake & Fe stores begin to be
depleted
ID & IDA
Factors contributing to lower Fe
intake and absorption
• Consuming complementary
foods low in Fe
• Lower socioeconomic status
• Cow milk intake
• Exclusive breastfeeding without
additional iron supplementation

4. WHO Recommendation
• Universal IS for children ⇢ prevalence
of anemia >40%
AAP Recommendation
• Exclusively breastfed term infants
receive an IS of 1 mg/kg/d
• Starting at 4 months of age
• Continued until appropriate Fe-
containing complementary foods
have been introduced
WHO & UNICEF Recommendation
• Both ferrous sulfate & ferric
polymaltose complex for prophylaxis or
treatment of IDA in infants & children
“Iron-like Turkey Project”
AIMS of THE STUDY
To compare the efficacy of the divalent &
trivalent Fe preparations in the
prophylaxis for prevention of ID or IDA
• Commenced in Turkey in the year 2004
• Recommends IS to all children under 1 year of age
starting from 4 months of age & continuing for at least 5
months
Anemia prevalence before “Iron-like Turkey Project”
• 21% - 35%
Anemia prevalence after second year of “Iron-like Turkey
Project” in healthy infants aged 12 to 23
• 7.3%
“Iron-like Turkey Project” had a substantial effect on
prevention of IDA

5. • MATERIALS & METHODS
• STATISTICAL ANALYSIS
• RESULTS
• DISCUSSIONS

6. Inclusion Criteria
Healthy term infants (150)
Birth weight >2500 gram
Exclusively breastfed until 4 months
of age & given complementary foods
afterwards
Exclusion Criteria
Lost to follow-up
Fed formula in addition to breast milk
Had nutritional & health problems
Developed IDA defined as a Hb
value <9.5 g/dL (at age of 4 months)
150 infants
Followed by the well child outpatient clinics of Istanbul
University (July 2009 – July 2010)
• Anthropometric parameters
• Feeding practices
• Hematologic parameters (RBC, Hb, Hct, MCV, MCH,
Fe, total Fe-binding capacity, TS)
At the end of 4 months of age
Re-evaluated
112 infants
• Lost to follow up (8 infants)
• Fed formula in addition to breast milk (7 infants)
• Had nutritional & health problems (5 infants)
• Developed IDA: Hb <9.5 g/dL (18 infants)
Excluded

7. 112 infants
Simple randomization
Group 2 (56 infants)
Group 1 (56 infants)
Given ferrous sulfate (Fe+2) 2 mg/kg/d Given ferric polymaltose (Fe+3) 2 mg/kg/d
Visits schedule: Every 30-day intervals until 9 months of age
Each monthly visit
• Weights rechecked
• Dose of the medications
adjusted accordingly
• Patients’ parents/caregivers
enquired about side effects &
compliance to the Fe (yes/no)
At the end of 9 months of age ⇢ Re-evaluate
• Anthropometric parameters
• Feeding practices
• Drug side effects
• Hematologic parameters
• Fe status
Diagnosed ID
• Hgb was ≥11g/dL
• TS <16%
Diagnosed IDA
• Hgb was <11g/dL
• TS <16%
Informed consent
• Taken from
parents
Study protocol approval
• Ethical Committee of Istanbul
University

8. • MATERIALS & METHODS
• STATISTICAL ANALYSIS
• RESULTS
• DISCUSSIONS

9. Public Health
Department of Cerrahpasa
Medical Faculty
LOCATION Analysis Program • SPSS 16.0
x2 Test • Categorical data
t Test • Comparison of continuous
variables between the groups
Paired t Test • Comparison data between 4
and 9 months of age in each
groups
Data expressed • Mean ± SD
P < 0.05 • Significant

10. • MATERIALS & METHODS
• STATISTICAL ANALYSIS
• RESULTS
• DISCUSSIONS

11. At age 4 & 9 months,
demographic features
compared to anthropometric
parameters
⇣
No statistical difference
between the groups

12. Complementary foods that
fed by their caregivers
⇣
No statistical difference
between the groups
Hb, RBC, Hct, MCV, MCH,
mean corpuscular Hb
concentration & RDW
⇣
No statistical difference
between the groups
Serum Fe levels and
transferrin saturation (TS)
⇣
Significantly lower in
group 2
Groups 1 Groups 2
Erythrocyte indices & Fe status
⇣
Before prophylaxis (4 months
of age) compared after
prophylaxis (9 months of age)
Significant increase in RBC,
Hb, Hct, serum Fe
levels & TS
Decrease in RDW
Erythrocyte indices & Fe status
⇣
Before prophylaxis (4 months of age)
compared after prophylaxis (9 months
of age)
Significant increase in RBC, Hb, Hct,
mean corpuscular Hb concentration,
serum Fe levels & TS
Decrease in RDW
Serum Fe levels and transferrin saturation (TS) at 9 months of age
⇣
Hb, Hct, MCV, Fe, and TS values
⇣
Significantly higher in group 1 than group 2

14. At the age of 9 months
⇣
40 patients have ID & 17
patients have IDA
⇣
No significant difference
between the groups
Power of the study for detecting
IDA:
• 45.3% (after post hoc analysis)
Most common side effects:
• Diarrhea
• Constipation
• Vomiting
No significant difference
between the groups
All enrolled patients were reported to be compliant to both Fe
preparations
To achieve a statistically
significant difference
between groups with regard to
IDA
120 patients should enrolled in
each group
Prevalence of adverse
effects:
• 34.8% (39 patients)

16. • MATERIALS & METHODS
• STATISTICAL ANALYSIS
• RESULTS
• DISCUSSIONS

17. Prophylactic Fe therapy & Fe fortified
supplementary foods ⇢ preventing ID & IDA
[Arvas, et al.]
- Divalent Fe therapy superior for treatment
of IDA & correct total oxidative status
[Yasa & Sozmen]
- Ferrous & ferric Fe preparations (oral Fe
replacement therapy) in pediatric patients
with IDA are comparable with regard to
improvement in hematologic parameters
[Jaber, et al.]
- Infants given ferrous Fe ⇢ significantly
higher Hb mean level
- Serum Fe, ferritin, transferrin, MCV,
MCH, RDW, Hct ⇢ similar in ferrous &
ferric Fe prophylaxis groups
- Ferrous Fe more effective than ferric Fe
- Higher number of infants refusing to take
the medication ⇢ ferrous Fe less
tolerable
Both ferrous & ferric Fe prophylaxis groups showed
significant improvement in the erythrocyte indices &
Fe status after a 5-month prophylaxis
Prevalence of ID & IDA
• At the end of 9 months of age
• Infants with ID & IDA (Fe+3 group > Fe+2 group)
• No statistical difference
Hb, Hct, MCV, Fe & TS levels
• Significantly higher in ferrous Fe prophylaxis group
Higher levels of Fe & TS in Fe+2 group
• Initial higher levels at 4 months of age at the onset
of prophylaxis
Fe & TS at 9 months of age after prophylaxis
• No statistical difference
This Study
Both divalent & trivalent Fe preparations are
efficacious in the prevention of IDA

18. [Yalcin, et al.]
• “Iron-like Turkey Project” (ferrous vs. ferric) for
prophylaxis ⇢ not significantly affect the occurrence
of anemia
• Overall prevalence of IDA was found to be 7.3%
Prevalence of IDA
• Ferrous: 8.9%
• Ferric Fe: 21.4%
Total prevalence of IDA
• 15.1%
This Study
[Jaber, et al.]
• Prevalence of IDA
• Fe+2: 5.8%
• Fe+3: 19.2%
• Total prevalence of IDA: 12.4%
Higher prevalence of IDA
• Earlier blood sampling ⇢ performed at 9
months of age rather than at 12 months
Lower prevalence of IDA
• Could achieved if we had prolonged the
duration of prophylaxis until 1 year of
age
[Yalcin, et al.]
• The lower the age of the infants ⇢ the higher the
prevalence of anemia
• 1 mg/kg of prophylactic Fe started at 4 months of age
• Prevalence of IDA is 26% at 7 months of age
• After a 3-month duration prophylaxis

19. [Jaber, et al.]
• Ferrous Fe is associated with a higher overall
incidence of adverse effects Adverse effects
• Seen in 34.8% of the infants
• Without any statistical difference between the
groups
• Type of adverse effects
• Diarrhea (Fe+2 group > Fe+3 group)
• Vomiting (Fe+2 group > Fe+3 group)
• Constipation
• Tooth staining
This Study
[Yalcin, et al.]
• 72.3% of parents notified side effects
• Constipation (10%)
• Diarrhea (10%)
• Vomiting (8.8%)
• Tooth discoloration (29.7%)
• Unpleasant taste (25.8%)
[Pasricha, et al.]
• No effect from IS on constipation & diarrhea
• Risk of vomiting was increased
Children
Comparative data
between bivalent &
trivalent Fe preparations
with regard to side
effects are sparse
Adult
Confirmed a lower
incidence of GI
symptoms with
ferric versus ferrous
Fe therapy

20. LIMITATIONS
• No control group that no Fe therapy was given
• “Iron-like Turkey Program” ⇢ every infant at 4
months of age is given prophylactic Fe therapy ⇢
unethical to have a control group without Fe therapy
• The study was not a double-blind study
• The study relied on verbal histories of the
parents/caregivers about the compliance to the
medication
• Assumed that all the enrolled patients were
compliant as all of the caregivers said that they
were compliant with the medication
• Power of the study to detect IDA is 45.3%
• An ↑ in the sample size ⇢ ↑ the power of the study
• All eligible patients during the study period were
already enrolled ⇢ could not be able to ↑ the
sample size
SUMMARY
Both ferrous & ferric Fe preparations were effective for
prophylactic use in the prevention of ID and IDA with
comparable side effects
A longer duration of prophylaxis until 1 year of age
could be recommended since at the end of a 5-month
prophylaxis
IS concomitant with encouragement of feeding with Fe-
rich supplementary foods is an effective way of
preventing ID and IDA among breastfed infants

21. TELAAH KRITIS JURNAL
I. UMUM
NO HAL YANG DINILAI CHECK LIST PENILAIAN
YA TIDAK
1 JudulMakalah a. Tidak terlalu panjang atau tidak terlalu pendek
b. Menggambarkan isi utama penelitian
c. Cukup menarik
d. Tanpa singkatan, selain yang baku
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2 Abstrak a. Abstrak terstruktur
b. Mencakup komponen IMRAC (Introduction, methods, Results, Conclussion)
c. Secara keseluruhan abstrak informatif
d. Tanpa singkatan, selain yang baku
e. Kurang dari 250 kata
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3 Pendahuluan a. Ringkas terdiri dari 2 – 3 paragraf
b. Paragraf pertama mengemukakan alasan dilakukannya penelitian
c. Paragraf berikut menyatakan hipotesis atau tujuan penelitian
d. Didukung oleh pustaka yang kuat & relevan
e. Kurang dari 1 halaman
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4 Metode a. Disebutkan design, tempat dan waktu penelitian
b. Disebutkan populasi sumber (populasi terjangkau)
c. Dijelaskan kriteria pemilihan subyek (inklus i& eksklusi)
d. Disebutkan cara pemilihan subjek (teknik sampling)
e. Disebutkan perkiraan besar sampel & alasannya
f. Perkiraan besar sampel dihitung dengan rumus yang sesuai
g. Observasi, pengukuran serta intervensi dirinci sehingga orang lain dapat mengulanginya
h. Ditulis rujukan bila teknik pengukuran tidak dirinci
i. Pengkuran dilakukan secara tersamar
j. Definisi iistilah & variable penting dikemukakan
k. Ethical clearance diperoleh
l. Disebutkan rencana analisis, batas kemaknaan & power penelitian
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22. NO HAL YANG DINILAI CHECK LIST PENILAIAN YA TIDAK
5. Hasil a. Disertakan tabel karakteristik subjek penelitian
b. Karakteristik subjek yang penting (data awal) dibandingkan kesetaraannya
c. Dilakukan uji hipotesis(statistik) untuk kesetaraannya
d. Disebutkan jumlah subjek yang diteliti
e. Dijelaskan subyek yang dropout dengan alasannya
f. Ketepatan numerik dinyatakan dengan benar
g. Penulisan tabel dilakukan dengan tepat
h. Semua hasil di dalam tabel disebutkan dalam naskah
i. Semua outcome yang penting disebutkan dalam hasil
j. Subyek yang drop out diikutkan dalam analisis
k. Analisis dilakukan dengan uji statistik yang sesuai
l. Ditulis hasil ujistatistik, derajat kebebasan (degree of freedom), dan nilai p
m. Disertakan interval kepercayaan
n. Dalam hasil disertakan komentar & pendapat
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6. Diskusi a. Semua hal yang relevan dibahas
b. Tidak sering diulang hal yang dikemukakan pada hasil
c. Dibahas keterbatasan penelitian, dan dampaknya terhadap hasil
d. Disebutkan penyimpangan protokol, dan dampaknya terhadap hasil
e. Diskusi dihubungkan dengan pertanyaan penelitian
f. Dibahas hubungan hasil dengan teori/hasil penelitian terdahulu
g. Dibahas hubungan hasil dengan praktek klinis
h. Efek samping dikemukakan dan dibahas
i. Disebutkan hasil tambahan selama diobservasi
j. Disertakan simpulan utama penelitian
k. Simpulan didasarkan pada data penelitian
l. Disebutkan generalisasi hasil penelitian
m. Disertakan saran penelitian selanjutnya
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23. Il. KHUSUS
VIA (Validity, Important, Aplicability)
1. Apakah dilakukan randomisasi ? Ya dilakukan randomisasi pada penelitian ini
2. Apakah kelompok yang diperbandingkan setara pada awal studi? Tidak setara

24. 3. Apakah dilakukan penyamaran (masking)? Tidak dilakukan penyamaran
4. Bila tidak dilakukan penyamaran, apakah kelompok kelompok diperlakukan sama kecuali untuk
terapi yang diteliti? Ya semua kelompok diperlakukan sama
5. Apakah ada faktor-faktor yang mempengaruhi hasil luaran ?
6. Apakah semua pasien yang dirandomisasi diperhitungkan dalam simpulan akhir dan dianalisis sesuai
dengan alokasi awalnya? Ya
7. Uraikan unsur PICO

25. PICO
P Patient, Population, Problem
Pada bayi usia 4 bulan sampai 9 bulan dengan BBL 2500 gr dan mendapatkan Asi
I Intervention,
Pasien yang mendapat asi dan diikuti dipoli klinik rawat jalan. Intepretasi dilakukan oleh dokter yang bertugas
diklinik rawat jalan dan dilanjutkan dengan pemberian terapi besi dan pemeriksaan darah pada usia 4 bulan
dan usia 9 bulan
C Comparison
Membandingkan antara intepretasi pemberian preparate besi bivalen dan trivalen
O Outcome
membandingkan parameter ematologic antara pemberian besi bivalen dan trivalen

26. 2. PENILAIAN PENTINGNYA HASIL UJI KLINIS
1. Apakah outcome / hasil dipaparkan secara jelas (hasil uji statistik dengan
hasil nilai p)? Ya, dipaparkan untuk nilai setelah pemberian profilaksis pada usia 9 bulan yaitu pada
kelompok 1 P: 0.574 dan pada kelompok 2 P: 0,284
2. Seberapa besarkah pengaruh terapi tersebut ?( dengan menghitung ARR
& NNT serta NNH? ). Pengaruh terapi tidak dapat dihitung karena tidak disebutkan jumlah
pasien yang menjadi control dalam penelitian ini
3. Hitung interval kepercayaan dari nilai NTT? Tidak bisa dilakukan penilaian interval kepercayaan

27. THANK
YOU