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Implementation of Thalassemia Screening
in Daily Practice

Nur Melani Sari, MD, Pediatrician

Dr. Hasan Sadikin General Hospital Faculty of Medicine
Universitas Padjadjaran Bandung Indonesia
3
 Genetic Screening Program

➢ reduce the burden of these disorders on individuals by identifying those at increased risk,
thereby enabling individuals to receive information about their personal health, future
health and/or potential health of their offspring
➢ to identify asymptomatic carriers of recessive conditions, so that they are informed and
understand their reproductive risks and options
Genetic Screening: Ethical Issues. London: Nuffield Council on Bioethics, 1993. 3 Proposed International Guidelines on Ethical Issues in Medical Genetics and Genetic Services, 4
World Health Organization, 1998. 4 Raffle AE: Information about screening- is it to achieve high uptake or to ensure informed choice? Health Expect 2001; 4: 92–98.
 Thalassemia Carrier

Thalassemia Carrier in Indonesia

No epidemiological study yet to elaborate the validated population data.
Mostly data came come from sporadic and unpublished data. Carriers of
the beta-thalassemia gene range from 3-5% and may even reach 10% in
some areas 5
• Thalassemia :China, SEA, Africa, Middle East, Mediteranian thalassemia:
Mediteranian , Middle east, India, Pakistan, Africa, SEA
• Thalassemia are now common worldwide due to migration spreading to much of
Europe, the Americas and Australia

6
Thalassemia Burden in West Java

Thalassemia: significant health burden in Indonesia

especially in West Java

`Register ed Case

carriers
3-5% Unregister ed Case:
prevention of the birthCarrier
Thalassemia of an affected child

1/5 of Indonesian Population with the birth rate of 2.4 %.

MoH Control Thalasemia Guideline, 2017
Thalassemia Major registered in 2016 : 3300/9240 (estimation)
IPA, 2016
National Statistic 2017
Models, 2001
Maharani, 2016, MJI
7
 Projections of the Cost of Treating β-Thalassemia in Selected
Countries

Alwan A, Modell B. Recommendations for introducing genetics services in developing countries. Nature 8
Review Genetics 2003; 4: 1-7
 • Programmes offering screening for b-thalassaemia heterozygotes (carrier
screening) have been available for many years.
• The majority of b-thalassaemia carriers have reduced mean corpuscular
volume and mean corpuscular haemoglobin levels in the standard full
blood examination
• A person’s carrier status can be confirmed by haemoglobin
electrophoresis and/or high-performance liquid chromatography.

Nicole E Cousens, Clara L Gaff, Sylvia A Metcalfe and Martin B Delatycki. European Journal of Human
Genetics (2010) 18, 1077–1083 9
 Objectives:
Voluntary To assess the effectiveness of systematic preconception
genet ic risk assessment to improve reproductive
• Italia outcomes in women and their partners who are identified
as carriers of thalassaemia,
• India
Mandatory
• Iran
• Saudi Arabia
• Palestina
• Cyprus

Conclusion no randomised controlled trials of preconception genetic

Amato et,. Al. J Community Genet (2014) 5:265–268.Carrier screening for
inherited haemoglobin disorders among secondary school students and young
adults in Latium, Italy
Hessin N , Weng, Cochrane library
risk assessment for thalassaemia, current policy recommendations is
limited to non-randomised studies. Information from well-designed,
adequately powered, rando mised trials is desirable in order to make
more robust recommedations for practice. However, such trials must
also consider the legal, ethical, and cultural barriers to implementation
of preconception genetic risk
10
The cost-benefit analyses of thalassemia screening vs cost of
treatment at Chiangmai University

▪ Period of screening test: 8 years

▪ 21,975 pregnant women has been screened
▪ The program prevent birth of 80 severe thalassemia cases ▪
Total cost of screening (husband and wife) and PND =
3,091,000 Thai Baht (US$ 93,667)
▪ The cost of treatment of thalassemia patients = 222,961,250
Thai Baht (US$ 6,756,401)

Benefit to conduct screening was 1: 72

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The Role of Pediatrician in Thalassemia Screening

• Screening in high risk population, who??

• Approach diagnostic in mild anemia

13
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How to start thalassemia screening in daily
practice

• “What screening method is

suitable to be applied in a country
with population with a high risk of
Thalassemia?”

Evidence Based Medicine Approach

Critical Appraisal

Level of Evidence IIa

 CLINICAL APPLICATION

Retrospective Prospective
Tracing the family members of thalassemia major
patients
Screening to identify thalassemia careers in specific
populations

Approach in prevention of
thalassemia

The approach used is:

Giving education about thalassemia, screening of high risk populations, screening cascade (family),
genetic conseling for premarital and prenatal diagnosis.
Information
Some researches
have proved:
The preventive program Society who is well-
Genetic
for thalassemia educated, will have
Conseling
better awareness
about the disease and
its danger.
Screening
Campaign
 Because of the huge population size of about
160 million people and a major section of the
community living in remote rural areas of
Population Screening
Pakiastan,it is not practical to screen the
whole population with the limited national
resources
Population Screening

3823
Family Screening
Family Screening
 VS
➢ Appropriate for rare prevalence
➢ Appropriate for small population
➢ Potentially increase detection rate for
cascade screening
➢ High difficulty.
• Cost-effective
• Appropriate for huge population
• Identified more Thalassemia carriers
than population-based screening
• Appropriate for region with lack of
health service infrastructure to
support large-scaled screening.
• Family members of Thalassemia
patients tend to be more afraid of
Thalassemia, so it would be easier to
conduct screening
• Family-based Screening
✓ A total of 13 of the 19 people who were willing to do a blood test had a Mean Corpuscular
Volume (MCV) <75 fl and Mean Corpuscular Hemoglobin (MCH) <25 pg and hemoglobin
electrophoresis was performed. Hemoglobin electrophoresis was examined in 4 family
members who met the MCV and MCH criteria. The results of the 4 family members
examined were consistent with minor thalassemia. This shows that family screening of
Thalassemia major patients can be used as a basis to detect careers.
26
Which guideline do you use? To determined
thalassemia minor

27
Establishing Diagnosis Thalasemia Trait/Minor
Gambar 2. Alur Skrining The Thalassemia International Federation
Sumber: Gallanelo
Gambar 3. Alur Skrining Thalassemia di Iran
Sumber: Karimi M
Gambar 1. Alur Skrining Thalassemia di Sardinia, Italia
Sumber: Cao A
 Thalassemia Controlled Guideline by MOH 2017

[Three alternatives of screening]

Registered Cases School Medical Unit
(UKS)

through
Pre Marital
Screening

Unregistered Cases
Carier Thalassemia Ante Natal Screening

MoH Controlled Thalasemia, 2017 32

Amatoet, al.J Community Genet (2014) 5:265–268
Thalassemia Controlled Guideline by MOH 2017
Family history of
thalassemia +/-

Hemoglobin
normal (Hb) Low Level

Reffer for lab examination Refer for lab examination

Blood smear morphology Blood smear morphology
MCV, MCH MCV, MCH

Microcytic Hypochrome MCV & MCH

normal Hipokrom Mikrositer
(MCV <80 fl, MCH <27 pg) normal
(MCV <80 fl, MCH <27 pg)
stop Probable Thalassemia 1) If in history taking and physiscal Other
diagnostic in line with thalasemia anemia
diagnositic→refer investigation
2) If not: iron supplementation for 2 weeks

Hemoglobin Analysis
Pediatric
Persisten Low Hb Increasing Hb ~ 1 gr/dL Consultation

Probability of IDA
Probable Thalassemia
Continue Iron Supplementation for +
12 weeks

Lakukan
Refer for
pemeriksaan
Hemoglobin
jenis Hb level
Thalassemianya
Analysis
Hb normal, MCV Hb normal, MCV <80 fl
normal Probable Thalassemia
Thalassemia Screening Alghoritm for First Grader Elementary High School Refer for Hemoglobin
stop Analysis
Thalassemia Controlled Guideline by MOH 2017
MCV<80fl or Pre Marital Thalassemia Screening Alghoritm
MCH<27pg

Normal Low Hb
Hb Clinically unremarkable

Iron Supplementation

Low Hb
Hb Increase
Persisted
Foetal Early
Detection
Hb Analysis

Bride Bride
Normal
Both carrier
Carrier
Genetic
Consultation
Pregnant Sick

Married Married
Cancelation
Abstinance of Abortion
Pregnant
 Diagnostic Approach of Mild Anemia
Coexistence [lowerinitialhemoglobinlevels]
[HbA2 lower]

▪ ferritin levels
<15ng/mL
Iron Deficiency Thalassemia
Anemia Carrier/Trait/Minor

Compare with
Most children with mild anemia have no signs or Youden Index
symptoms many discrimination indices (ppropriate measure
Replace transferrin saturation have been reported using red blood cell indices of validity [sensitivitiy
obtained by And specificity]
Ferritin automated blood count.
HbA2 level
35
American Family Physician June 15, 2010 ◆ Volume 81, Number 12
 Indices
▪ Mentzer Index (MI): MCV/RBC
▪ Shine and Lal Index (S & L): MCV2 × MCH × 0.01
▪ England and Fraser (E & F): MCV – RBC – (5 × Hb) – k,5
k is calculated to be 5.19 in our counter as described in the
published report
▪ Srivastava Index (S): MCH/RBC
▪ Green and King Index (G & K): MCV2 × RDW/100 × Hb
▪ RDW Index (RDWI): MCV × RDW/RBC
Mentzer WC. Differentiation of iron deficiency from thalassaemia trait. Lancet 1973; 1: 882.
Shine I, Lal S. A strategy to detect beta-thalassaemia minor.Lancet 1977; 1: 692–4.
Srivastava PC, Bevington JM. Iron deficiency and-or thalassaemia trait. Lancet 1973; 1: 832.
Green R, King R. A new red blood cell discriminant incorporating volume dispersion for differentiating iron deficiencyanemia from thalassemia minor. Blood
Cells 1989; 15:481–95.
Jayabose S, Giavanelli J, Levendoglu-Tugal O, Sandoval C, Özkaynak F, Visintainer P. Differentiating iron deficiencyanemia from Thalassemia minor by 36
using an RDW-basedindex. J. Pediatr. Hematol. 1999; 21: 314.
37
38
RDW/RBC≥3 may be an additional test to
differentiate between IDA and thalassemia carrier
in Thai population

39
 Coexistence Thalasemia Trait (TT) with IDA
Pittfall
HbA2 lower Diagnosis Screening
Difficulties Program

Iron
suplementation

Hemoglobinlevels of our patients improved

significantly (𝑃 < 0.001) after iron replacement
therapy. Similarly, red cell indices, namely,
MCV, MCH, MCHC, and RDW-CV

Coexisting Iron Deficiency Anemia and Beta Thalassemia Trait: Effect of Iron Therapy on Red Cell Parameters and Hemoglobin Subtypes. Hindawi Journal. 2014
40
41
Conclusion

1 2 3 4
Thalassemia The role of primary Consider to choose one of The expertise to
Screening : to prevent care/pediatrician guidelines which suitable differentiated etiology
new thalassemia case extremely important to with hospital setting
of mild anemia
To make future plan start extended family
for thalassemia patient screening program or
population screening
 Thank You

Preparation for program: Permission

fro health authorities in Tempuran
Municipality

Giving Guideline Book to Head of

Primary Health Care in Tempuran 43
Municipality
 Full Term (6-24 months)
Iron Supplementation Recommendation/Guidelines

WHO, 2016 IDA Working Group

o Started at 6 month In accordance with maturity o Started at 4

of iron absorption
o 10–12.5 mg month
o 3 moths each year In accordance with o Duration daily-2
o Setting: high exclusive breast feeding years
prevalence (40%) recomendation
o Dose: 2
mg/kg/day
o Setting: high
prevalence
(40%)
(strong recommendation, moderate quality of evidence).

Systematic review from 33 studies (4-23 months).

Lower risk of Stunting

Iron Deficiency Iron Deficiency Side Effect
anemia Wasting
RR: 0,3 Anemia RR: 0,14 RR: 1,1
RR: 0,61 P>0.01