Newborn screening was initiated in 1963 and the
year 2013 marks the celebration of its 50 years. It is indeed a
co-incidence that the Indian Academy of Pediatrics also celebrates its
golden jubilee in 2013. We take this fortunate moment to discuss newborn
screening and its evolution in India. The Health Ministry’s desire to
introduce newborn screening [1], and the recommendations of the
multicentre task force study of the Indian Council of Medical Research
(ICMR) for inborn metabolic disorders (to be released soon)[2], have
begun to catalyse the initiation of a National Newborn Screening
Program. Time is now ripe to discuss universal newborn screening and
expanded screening with their current feasibility in India. This
communiqué discusses screening for inborn metabolic disorders.
Since our last perspective published in in 2010 [3],
there has been a surge of publications [4-6] from different parts of the
country narrating their experience with newborn screening for a selected
group of disorders. It is vital to understand the terms "core" and
"expanded" panel of disorders. The term core indicates the basic minimum
set of disorders for which screening should be advocated at a national
level. Since all countries chose the set of disorders to be initiated in
their domain based on epidemiologic prevalence and resources, the panel
across the world is not uniform This distinction not only outlines the
group to be tested but also the differences in technology for the set of
disorders included in each category. The term expanded newborn screening
emerged after the introduction of tandem mass spectrometry (MS/MS) into
the newborn screening program [7]. It utilizes the same modality of
sample collection on filter paper (dried blood spot technology) as for
the core set of disorders. When introduced it was used as- ‘one drop-
phenylketonuria (PKU) and later for congenital hypothyroidism (CH). The
simultaneous screening of multiple analytes from the same drop of blood
by a technology known as MS/MS paved the way for "expanded newborn
screening".
The core or traditional newborn screening is intended
to test infants for medical conditions that might cause significant
morbidity and mortality like CH. With the availability of multi-analyte
testing in the expanded program, identification of disorders of
ambiguous medical significance like short chain acyl CoA dehydrogenase
deficiency and histidinemia along with identification of mild variants
of diseases which may decompensate in adulthood like Citrullinemia Type
1 started appearing. So overall, there was a distinct change in focus in
countries adopting expanded screening. Each country had to use available
data, resources and significant brainstorming to decide on any new
disorder that needed inclusion in the expanded panel. There was lack of
broad consensus even in developed nations at the level of National
Policy making on what to include in the core panel of disorders. Pollit
[8] compared the disease panels recommended across the United States of
America (USA) and four European countries using MS/MS. The two extremes
were represented by the United Kingdom (UK) where only phenylketonuria
and medium chain acyl co-A dehydrogenase (MCAD) deficiency were
recommended for newborn screening with MS/MS and in the USA where up to
40 disorders were tested. There was a common core panel which was
screened for in most of these nations and included CH and other
disorders depending upon respective national regulations. We now propose
to discuss the set of conditions that should be included in the core
panel for the nation using the template laid down by Wilson and Jeugner
(Table I).
TABLE I Wilson and Juegner criteria for disease screening
1.
|
The condition sought should be an important health problem. |
2.
|
There should be an accepted treatment for patients with
recognized disease. |
3.
|
Facilities for diagnosis and treatment should be available. |
4.
|
There should be a recognizable latent or early symptomatic
stage. |
5.
|
There should be a suitable test or examination. |
6.
|
The test should be acceptable to the population. |
7.
|
The natural history of the condition, including development from
latent to declared disease, should be adequately understood. |
8. |
There should be an agreed policy on whom to treat as patients. |
9.
|
The cost of case-finding (including diagnosis and treatment of
patients diagnosed) should be economically balanced in relation
to possible expenditure on medical care as a whole. |
10. |
Case-finding should be a continuing process and not a “once and
for all” project. |
Core Panel
What are the disorders with significant public health
relevance? The first criterion for inclusion of a disorder for
screening is that the disease should be of a magnitude to qualify to be
called a significant public health problem.
Congenital hypothyroidism. Data from various
parts of India for CH suggests varying incidences; from North India
(Chandigarh) 1 in 3400[4], Southern India (Kochi) 1 in 500 [9], and
Eastern part of the country 1in 600 (10). The data clearly suggests the
significant burden of CH in India. The data for congenital
hypothyroidism appears to be discrepant from various parts of the
country. One of the reasons to explain the discrepancy could be the
region from which the data originated. TSH is a marker of iodine
deficiency and in belts where this continues to be an important health
issue, a high TSH may not be due to problems inherent to neonatal
thyroid pituitary axis but as a result of iodine deficiency. Use of
thyroid stimulating hormone (TSH) levels to screen for CH could over
diagnose possible CH, especially in preterm babies due to combination of
low iodine stores achieved in utero and the immaturity of the
hypothalamic- pituitary axis [11]. Both these conditions reflect
transient CH. Delay in diagnosis in CH is evident from recent data from
an endocrine clinic in Delhi [12] wherein nearly one third of children
presenting beyond 5 years had CH. The mean age of presentation of
symptoms in the CH group was 35.2± 25.9 months (range: 12-132 months]
and the average interval between onset of symptoms and diagnosis was
nearly 51 months.
Congenital adrenal hyperplasia.(CAH). The next
disorder that deserves mention is CAH. Data from Chandigarh suggest a
prevalence of 1 in 6813. Previous data also suggest a high incidence of
CAH [13]. Recent published data from eastern part of the country by
Maiti and Chaterjee [14] suggested that the mean age at diagnosis in the
salt wasting group of CAH was 0.5 years compared to 9 years in the
simple virilizing group, majority being girls. Similar observations were
made in North India. The study had evaluated 62 patients; 50 were simple
virilizers and 12 saltwasters [15] and 90% being girls. The skewed male
to female ratio in these studies suggests that a substantial proportion
of males were being missed due to early demise and non-recognition of
the disease. Given the fact that transgenders are encountered at street
crossings, bus stops and during social events at Indian homes, it is
possible that a fair proportion of them could be simple virilizers (21-
a hydroxylase
deficient). There thus seems to emerge a need to screen for CAH.
Glucose 6- phosphate dehydrogenase deficiency (G6PD).
This is another disease that has been targeted for screening in India.
The author’s data (unpublished) suggests an incidence of 1 in 192 for
G6PD deficiency. Data from Chandigarh suggests an incidence of 1 in 112
and from eastern India [16] an incidence of 1 in 15. This disorder that
has been genotypically well mapped from different parts of the country
with G6PD Mediterranean (563 C-T) being seen commonly in North India,
G6PD Kerala- Kalyan (949 G-A) in Maharashtra, Kerala, Andhra Pradesh,
Tamil Nadu and Punjab and G6PD Orissa (131C-G) in tribals of central,
eastern and southern India. Nair also highlighted the need for a
screening program for G6PD in our country and from the existing
prevalence he extrapolated that the burden due to this disorder is
likely to be nearly 390,000 births per year [17].
Based on the information provided in the preceding
section, we suggest that in India core screening should include CH, CAH
and G6PD. Besides, multi-analyte screening is more cost effective than
screening for a single disease. Alternatively, if it is likely to impose
significant burden on the State’s health budget, screening may be
initiated for congenital hypothyroidism, and subsequently the remaining
two conditions can be added in a phased manner.
Is there an accepted treatment policy for
these conditions? The second criterion for including a disease in
the screening panel is that facilities for confirmatory diagnosis and
treatment should be available. Since dried blood spot can be easily
collected from any part of the country, couriered to enabled
laboratories, diagnosing these disorders would no longer be rate
limiting. Both ELISA based assays and assays based on time resolved
fluorimetry are reliable, though the ones using ELISA show some cross
reactivity. But both do well in the pathologic ranges. MS/MS technology
is also available in both the private and public sector, hence it would
also be possible to screen for the expanded panel of disorders when
needed. Treatment for CH, CAH and G6PD are available. CH requires
supplementation with L- thyroxine, CAH would require glucocorticoids
with/without mineralocorticoid therapy along with surgical intervention
like clitoral resection. G6PD just requires avoidance of certain drugs
and food stuffs which may initiate hemolysis.
Do these disorders have a latent recognizable
phase? The next important criterion is that there should be a latent
recognizable phase during which symptoms have not become manifest and
initiation of therapy can avoid the sequelae. For all the disorders in
the core panel such a phase exists. But for defects of urea cycle,
organic acidemias and nonketotic hyperglycinemia, there may be no window
period and these may present before the results of screening are
available early in the first week of life.
Is there a policy on whom to treat? The next
outlined criteria is that there should be an agreed upon policy on whom
to treat as patients. For the group of disorders where a biochemical
abnormality translates into a defined clinical phenotype such as CH and
CAH, there would be no debate. However for certain disorders there is no
distinguishable phenotype and an example of this is histidinemia, a
biochemical entity with non-significant clinical phenotype.
What is the likely cost of screening versus case
finding? These are important issues. Clearly for CH there is
sufficient evidence that screening and treatment is cost effective
compared to cost of case-finding and of permanent mental subnormality
with its attendant loss of productivity. Cost benefit analysis for CH in
Iran suggests a benefit of 22 times [18]. The same can be said for CAH
and G-6-PD. Presently the costs of expanded screening are probably not
cost effective for India. It is important to underscore that screening
is an on-going activity and not a one-time health screening event, if
the nation has to accrue the benefits just described.
Expanded Screening
The introduction of MS/MS technology for analysis has
led to the expansion of disorders that could be screened. However, for
most of these conditions there is no data on the disease burden in the
country. MCAD, a disorder of fatty acid metabolism is included even in
the most conservative programs of Europe. This disorder needs tandem
mass spectrometry for identification and requires frequent feeding for
its treatment. This is also a disorder of energy metabolism which may
present as SIDS[19]. There is some data for MCAD; 1case was detected of
25578 newborns screened in Goa between 2008-2011 and a single case by
screening 4946 neonates in Andhra Pradesh along with a single case from
PICU[5,20, 21,22]. Targeted or high risk screening may identify more
cases. We admit that each case diagnosed by the technology is important
for the family for subsequent genetic counselling; but here we are
discussing the feasibility of universal screening. It may be important
for regional laboratories to be set up that could cater to the needs of
selected NICU patients in whom these conditions are suspected.
MS/MS technology is now available in both the private and public sector
and hence it would be possible to screen for these conditions in the
future. Availability of confirmatory testing and treatment appear to be
the major rate limiting factor in implementing expanded screening in
India. We reiterate that all screening tests need confirmatory testing
as there is always an existent possibility of a false positive result.
Scaling up: Hurdles and Challenges
This communiqué would be incomplete without answering
the question ‘Are we ready for the leap?’ The key factors that are
critical for scale up are manpower, budget, logistics, infrastructure,
and advocacy.
Manpower: The country has a small pool of trained
pediatricians and geneticists who have been exposed to newborn screening
in India and understand its limitations and strengths. Many more
pediatricians, neonatologists, biochemists and geneticists are needed to
make this viable. It is worthwhile to reemphasize that newborn screening
is not just a test but a program and this networking is crucial for not
only for its initiation but sustainability as well.
Budget: The current budgetary allocation for
health is 0.9% of GDP and the state expenditure on the health sector is
5.5% of the budget. The central funding in the state for public health
is 15% and 70-80% is out of pocket expenditure for most of the
population residing in the states. If India increases its health budget
to 2.5% of GDP, it must make provisions then for allocating funds to a
national newborn screening program for the core panel.
Phasing out of the program: The introduction of
the program must be initially in major metropolitan cities and states
with low IMR. Even in these areas, it could be started initially in
medical colleges and district hospitals where it may be possible to
integrate it with basic newborn care interventions which are already in
place. Simultaneously operational research to evaluate feasibility of
initiating a newborn screening program in difficult to access areas,
tribal areas and states with poor infrastructure should be implemented.
Subsequently, one should aim at targeting all institutional births for
the three core panel disorders in the rest of the country.
Logistics: The major logistics include training
of health care providers such as ANMs and nurses for taking heel prick
samples on filter papers, completing required information and
transporting them to the designated laboratories for analysis and their
subsequent storage for at least 5years, but if a national cold storage
is in place one could extend it till 20 years [23]. The labs engaged in
screening have to be enrolled into a quality assurance program. An
alliance with ERNDIM (External Quality Assurance Programme for Amino
Acids, Quantitative Organic Acids, Purines and Pyrimidines, Special
Assays in Serum and Urine, Cystine in White Blood Cells and Lysosomal
Enzymes) and Center for Disease Control (CDC) could be an interim till
the country establishes a national quality assurance centre.
Advocacy and consent: A national advocacy
campaign for mass awareness on the utility of newborn screening is
important since it involves taking a blood sample (although only a few
drops) from an apparently healthy newborn. Partnering with all
stakeholders, pediatricians, obstetricians, professional medical bodies
such as the Indian Medical Association, government, and civil society
and media would help in achieving this objective. Obtaining written
consent could be challenge in our country both because of low literacy
levels and inherent suspicion of signing on formal papers. Many
countries have adopted a policy of parents ‘opting out’ and have done
away with informed consent process. This is also justifiable as it is no
longer a research module and has moved into the program phase. Probably
India for the reasons cited above should also adopt a similar process
and do away with formal consenting procedures.
Finally, the benefits translated to the population at
large. Using the SRS 2012 data which estimates the national
population to be 1220 million, and birth rate of 20.6, the estimated
number of neonates who would have CH alone would be about 17000 births
each year. Translated into preventable mental sub-normality and
productivity loss, it would amount to millions of rupees each year.
By the time policy makers take note of this plea,
more centres would have come for high risk or targeted analysis.
Screening not only needs setting up of logistics and infrastructure, but
a policy that facilitates manufacture, or easy import of therapeutic
agents at affordable prices for these inherited metabolic disorders.
This may be a small voice from a select band of professionals, but it
speaks also on behalf of the muted sufferers with preventable metabolic
disorders. We realize that introducing newborn screen is likely to be
complex in India as quoted by Miller. India is at cross roads, on the
one hand still grappling with providing equitable health care for all,
but on the other it can provide care comparable to the best elsewhere in
the world. We believe that we should move forward and contribute to
decreasing the burden of disability and ensure equitable quality of life
for all.
Acknowledgments: The authors thank ICMR for the
directions in the project. Specific thanks are due to Dr SS Aggarwal, Dr
Veena Kalra, Dr Vasantha Muthuswamy, Dr IC Verma, Dr Vijay Kumar, Dr
Roli Mathur and all the investigators of the ICMR Task force on Inborn
Metabolic disorders.
Declaration: The study is a personal perspective
and may not represent the opinion of the entire task force.
Contributors: SK conceived and drafted the
manuscript. NG and MK were involved in conception execution and critical
appraisal of the manuscript.
Funding: None; Competing interests: None
stated.
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