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Indian Pediatr 2009;46: 1045-1049 |
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Neonatal Screening Program for G6PD Deficiency
in India: Need and Feasibility |
Harish Nair
From Public Health Foundation of India, Indian Institute
of Public Health- Delhi, Sector 44, Institutional area, Gurgaon 122 002,
India.
Correspondence to: Dr Harish Nair, Assistant Professor,
Public Health Foundation of India, Indian Institute of Public Health-
Delhi, Plot No. 34, Sector 44, Institutional area, Gurgaon 122 002, India.
Email: [email protected]
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Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
is a common genetic disorder affecting approximately 400 million people
worldwide. In India, 390,000 children are born annually with this
disorder causing significant morbidity and mortality in childhood. A
National Neonatal Screening program for presumptive screening of all
neonates using modified Formazan ring test method could be introduced.
The test requires blood sample obtained using simple heel prick in the
first 48 hours of life, and can be carried out using basic laboratory
equipment and reagents. The screening program could be introduced in all
institutional deliveries at tertiary hospitals in the major metropolitan
cities and then gradually scaled up to cover institutional deliveries
over the entire country. After field trials, the program can be expanded
to cover home deliveries as well. Increased funding for the health
sector under the National Rural Health Mission can provide the required
financial support to the program.
Key words: Glucose-6-phosphate
dehydrogenase (G6PD) deficiency, India, Modified Formazan ring test,
Neonate, Screening program.
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India is currently undergoing an
epidemiological transition and congenital malformations and genetic
disorders are gradually replacing sepsis as the major cause of perinatal
and neonatal mortality. Presently, they constitute the fourth commonest
cause (9.2%) of neonatal mortality in urban areas(1). This is because
consanguineous marriages are still fairly common in many parts of India
and these disorders which were hitherto masked by infections and
malnutrition are being increasingly identified. Glucose-6-phosphate
dehydrogenase (G6PD) deficiency, a hereditary predisposition to hemolysis,
is the most common of all clinically significant enzyme defects in the
whole of human biology. It is estimated to affect approximately 400
million people worldwide(2) with the highest prevalence rates in tropical
Africa, the Middle East, tropical and subtropical Asia, some parts of the
Mediterranean and in Papua New Guinea. Several countries in Europe, South
East Asia, the Middle East and the United States of America have
successfully established a neonatal screening programme for this disorder.
Taiwan has even established the first international program for quality
assurance of G6PD screening(3). With almost 24 million children born
annually in India, it is estimated that at least 390,000 children
suffering from this disorder are born in the country every year(4).
Several agents have been identified as triggers for hemolysis, viral and
bacterial infections being the most common. Certain drugs (e.g.
aspirin, chloramphenicol, chloroquine, primaquine, sulphanilamide etc.)
and chemicals (naphthalene and henna) have been implicated as hemolytic
triggers(5-7). Hemolysis may also be triggered by ingestion of fava beans
(Vicia faba) or even inhalation of its pollen(8). Early detection
and prevention of hemolytic episodes (by avoiding the triggers) is the
only cure for this disorder. Hence, a neonatal screening program for G6PD
deficiency is warranted with the increased availability of funds for the
health sector under the National Rural Health Mission (NRHM).
The Condition
G6PD deficiency is by far the most common genetic
disorder in India(4). Though the exact incidence in India is not known,
various studies have reported an incidence ranging from 2% to 27.9% in
different communities(9). Four hundred different variants and ninety
different mutations of this disease are known globally. In India the most
common mutation is the G6PD Mediterranean (563 C->T) seen in the Vatalia
Prajapatis of North India and the Parsis(10). The other two mutations
commonly found in India are the G6PD Kerala-Kalyan mutation (949 G->A)
reported from Maharashtra, Kerala, Andhra Pradesh, Tamil Nadu and Punjab;
and the G6PD Orissa (131 C->G) found in the tribals of central, eastern
and southern India. G6PD Mediterranean is the most severe variety.
Children with G6PD deficiency usually present with prolonged neonatal
jaundice or later in life with acute hemolytic crises. The disease as such
causes significant morbidity and mortality in childhood. There are no
primary prevention interventions available for this disease and the only
way to avoid the adverse outcomes is to recognise such children early on
in life and prevent exposure to agents which can trigger hemolysis.
The Screening Program
Screening programs help us to identify those
individuals who cannot be identified by routine observation and physical
examination. Indeed, in India, only 32% of the G6PD deficient neonates had
hyperbilirubinemia(10) and 55% of the G6PD deficient newborns did not
require photo-therapy(11). This implies that without a newborn screening
program to identify the G6PD deficient newborns, these infants run a
greater risk of unexpected hemolytic anaemia if exposed to triggers. Apart
from the United States of America, many countries of South East Asia (e.g.
Malaysia, Singapore, Taiwan, Hong Kong and the Philippines) the Middle
East and Europe (where the incidence of G6PD deficiency is high) have been
successfully running a neonatal screening program for this disorder.
Singapore was one of the first countries to introduce this mass screening
program in 1965. Data from Singapore reveal that with the preventative
measures, the incidence of kernicterus has dropped dramatically, and in
the last 20 years there has been only one reported case of kernicterus in
newborns(12). Greece, where such a program is in operation since 1977, has
reported a fourfold reduction in the hospital admission of patients for
the treatment of hemolytic crisis(13).
The need for a mass screening program for G6PD
deficiency has long been perceived by the pediatric and public health
experts in the country. The newborn screening program covering a number of
genetic diseases including G6PD deficiency which was piloted in Bangalore
and Hyderabad has been well received by the health professionals and the
public(14). Introduction of the screening programme will substantially
decrease hospital admissions due to acute haemolysis, thereby reducing
number of blood transfusions and dialysis needed. The cost of introducing
the screening program can be justified by the savings in the medical care
as a whole for these patients.
The Test
Several screening tests for G6PD deficiency are now
available. The International Committee for Standardization in Hematology
has recommended the Beutler Fluorescent spot test for screening of G6PD
deficiency(15). However, this test requires an UV light source which poses
a serious limitation to its use in mass screening programs in resource
poor settings. Recently, two new screening tests have been developed which
are cheaper, easier to perform, do not require an UV light source and have
a high sensitivity and specificity. One of them is the color reduction
test involving reduction of a blue dye, dichlorophenol indophenol, to a
colourless state and is produced by Sigma Diagnostics, USA(16). The other
test is the modified Formazan ring test method(17) which uses the
principle of the MTT-Linked Spot test recommended by the World Health
Organization Scientific Group(8), with a minor modification. In
individuals with normal G6PD levels, MTT, a soluble tetrazolium compound,
is reduced to a purple insoluble formazan derivative with the diameter of
the discoloration ranging from under 6 mm to over 7.5 mm.
For the screening program in India, it may be prudent
to adopt the modified Formazan ring test method(17) as it uses the same
filter paper (Schleicher and Schuell #903C Duren, Germany) which is used
in routine newborn screening for metabolic disorders allowing easy
integration with other screening program for other inborn errors of
metabolism. The test is rapid with results available in less than 24
hours, requires only basic laboratory equipments and does not require
extensive training of personnel. Additionally, the cost of reagents for
this method is approximately $0.64 (less than Rs 30) per subject which is
affordable. A positive screen is defined as a disc with absence of bluish
discoloration or a bluish discoloration less than 5.5 mm. This cut-off
value has been recommended as it gives the best sensitivity (96%) and
specificity (90%). It is anticipated that since the test involves a simple
heel prick within the first 48 hours of life, it should be acceptable to
the population, this being not against any of the prevailing social
values.
Those neonates who will be identified as positive for
G6PD deficiency on the screening test will need to undergo a definitive,
quantitative test using a commercial kit (Sigma Diagnostics, USA)(16). An
enzyme level less than 100U/ trillion RBCs has been defined as the cut off
for classifying the neonate as G6PD deficient(10). Since the kit is
expensive and requires the use of a spectrophotometer, these tests can be
made available only at apex laboratories. However, it must be noted that
the screening test can only identify patients with enzyme deficiency and
cannot identify G6PD variants with normal enzyme activity(17) or the
female heterozygote(16).
The Plan
The program could be initially piloted in selected
tertiary level Government Hospitals in the four metros (i.e. Delhi,
Kolkata, Mumbai and Chennai). The pilot will also provide valuable data
regarding prevalence of G6PD deficiency in the community. WHO recommends
gradual scaling up of such programs in resource poor settings(18).
Subsequently, the program can be extended to cover the entire country over
a period of three to four years.
In consonance with the NRHM agenda to encourage and
incentivise institutional deli-veries(19), the screening program may first
be implemented in all institutional deliveries both in the government and
the private sector. The blood sample can be collected any time in the
first 48 hours of life and the babies should only be discharged from the
hospital after receipt of the report. In case the discharge has to be made
earlier, adequate contact information should be available with the
hospital and feedback provided by the quickest possible means. Subsequent
to successful introduction in institutional deliveries, this program may
be extended to home-based deliveries. In this case, the sample collection
may be entrusted to the Auxiliary Nurse Midwife (ANM) or the Accredited
Social Health Activist (ASHA), who can collect the sample during their
routine home visit in the first seven days of life. The ANM/ASHA can
provide the feedback and arrange for blood collection for the definitive
test in case of infants found positive for G6PD deficiency. However, field
based trials will need to be conducted prior to this extension to verify
that the cut-off value of 5.5 mm for the Formazan ring indeed holds good
beyond the 48 hour period. The existing laboratories at the primary health
centres have sufficient infrastructure for undertaking this screening prog-ram.
To handle the enhanced laboratory workload generated by this program, the
9795 presently vacant positions out of a total of 26415 required positions
of laboratory technicians at the PHCs and CHCs will need to be filled
up(20). The Quality Council of India (QCI) can be entrusted to develop the
quality assurance standards. They can also independently monitor the
quality aspects of the programme through the National Accreditation Board
for Hospitals and Healthcare Providers (NABH) and the National
Accreditation Board for Testing and Calibration Laboratories (NABL).
Though many would argue that it would not be easy to
find funds for implementing the screening program, there is scope within
NRHM budget which is committed to increase to INR 4743.9 billion by
2012(19) from the present INR 1205 billion for 2008-09(21). Additionally,
funds for the pilot project can also be sought from the Norway India
Partnership Initiative (NIPI) which has committed to provide 500 million
NOK (INR 36 billion) over 5 years i.e. till 2011 for strengthening
neonatal health programs in India(22).
Funding: None.
Competing interests: None stated.
Key Messages |
• G6PD deficiency is an important public health problem in India and
warrants introduction of a neonatal screening program.
• Modified Formazan ring test involving a simple
heel prick in the first 48 hours of life can be used in neonates.
• A positive screen is defined as a disc with
absence of bluish discoloration or a bluish discoloration less than
5.5 mm.
• The screening program can be introduced
initially in institutional deliveries in major metros and then
gradually scaled up.
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