Newborn Scr creening- Presen and nd Future Dr Pratibha atibha - - PowerPoint PPT Presentation
Newborn Scr creening- Presen and nd Future Dr Pratibha atibha Agarwal Senior enior Consultant, Department of of Child Development KK Womens and Chi hildrens Hospital, Singapore Outline: What is NBS and what are are
What is NBS and what are Criteria and content of NB The Statistical Square Components of NBS scree New Paradigms in NBS Current issues and Conce Future are its aims BS screening in Singapore cerns
individuals without signs or symptom pre-symptomatic or unrecognized s
performed on persons apparently in
identify an unrecognized disease in toms – can include individuals with d symptomatic disease. ewhat unique in that they are ewhat unique in that they are in good health efore it becomes a problem”
Unselective screening of new For a variety of serious tre evident on physical exam Which if undetected or un disability or death Early identification =>Earl
gram to screen newborn babies for: ewborns shortly after birth s treatable disorders which are not mination and untreated will result in disease, arly Intervention => improved infant
Most babies with metabolic
NBS helps to pick up ab features are present
Early diagnosis facilitates ea prevents unwanted conseq Individually these conditions clubbed together they are no lic disorder, congenital hypothyroidism al” at birth above conditions before any clinical
early and effective interventions and sequences of untreated disorder
not that uncommon
Disorder screened Implic sc Congenital hypothyroidism Severe me G6PD deficiency Sev Ke Seve Phenylketonuria Severe me Galactosemia Death Congenital adrenal hyperplasia lications if not screened Outcomes of screened & early intervention mental retardation Normal evere NNJ Kernicterus vere anemia Normal mental retardation Normal ath or cataract Active and normal Death Active and normal
Condition sought should be Natural history of the conditio There should be a recogniza
There should be a recogniza stage There should be an accep recognized disease Facilities for diagnosis and tr There should be an agreed p an important health problem ition should be well understood nizable latent or early symptomatic
nizable latent or early symptomatic ccepted treatment for patients with treatment should be available policy on when to treat a patient
There should be a suitable the population Balanced cost-benefit ratio Balanced cost-benefit ratio psychological, should be less Case funding should be a and for all” project Adequate health service pro clinical workload resulting fro
le test which should be acceptable to tio & the risks, both physical and tio & the risks, both physical and ess than the benefits continuing process and not a “once rovision should be made for the extra from screening
Disorder has significant prevalence Disorder is asymptomatic at birth a
Effective and early preventive treat Simple method for sample collectio Reasonably simple, reproducible results Follow-up program for diagnosis an High benefit to cost ratio ce in the population h and only symptomatic when damage has
eatment is available tion test with few false positive and false negativ and treatment available
STATE PUBLIC HEALTH DEPARTMENT CONSUMERS
MEDICAL PROVIDERS RESEARCHERS
cal geneticists
gologists.
Offer newborn screening Discuss the benefits Discuss how the test is done Discuss how the test is done required Discuss the timing Discuss the difference betw Discuss possible results Answer questions / brochure
tween screening and diagnostic test ure
Disease State
+ - +
A True Positive B False Positiv C False Negative D True Negativ Sensitivity = A/(A+C) (TP/All those with disease)
Specificity = D/(B+D) (TN/All those without disease) PPV = A/(A+B) (TP/(TP+FP) NPV = D/(C+D) (TN/(TN+FN) tive tive
False negative tests increased cost
late treatment
treatment Loss of productive member
society Emotional burden of living with preventable condition Increased False Positive with fewer false negative tests Cost of retesting
Cost of retesting Cost of unnecessary treatment
Emotional burden and anxiety
Surveys and focus groups of expec families would like to receive inform visits BENEFITS:
BENEFITS: Integrating NBS education into pre for their newborn undergoing scree Parents view their care from prena care without health care provider di HOW: Written or website information along ectant parents demonstrate that women and their
renatal care allows parents to be better prepared eening and for receiving NBS test results. natal care thru pediatric care as a continuum of distinction
First started in 1960s in retardation associated with p Expanded to developed and
Expanded to developed and In 2008 – Newborn screen (USA) – signed into law the USA to prevent mental phenylketonuria d developing countries
d developing countries ening saves lives Act of 2007
1965 •Mass newborn screening for G6PD 1981 •18-month pilot screening for cong 1990 •Nationwide screening for congeni
1990 •Nationwide screening for congeni 1998 •Pilot newborn hearing screening u 2002 •Universal newborn hearing screen 2003 •UHNS in private hospitals 2006 •Tandem mass spectrometry (TMS)
PD deficiency ngenital hypothyroidism enital hypothyroidism
enital hypothyroidism using transient evoked oto-acoustic emissions ening in (UNHS) in 3 hospitals: KKH, SGH & NUH S) for inborn errors of metabolism
Newborn physical examination Cord blood screening
Hearing screen Inborn errors of metabolism screen Oxygen saturation (SpO2) screen Timing of the screening test
G6PD Thyroid screening Hearing screening – (OAE & IEM – Tandem mass spectro SpO2- Pulse oximeter Cord bl
SpO2- Pulse oximeter
Physician Midwife Nurse Medical technologist Audiologist & ABBR)- ctrometry (TMS) blood
Cord G6PD screening - with Cord thyroid (TSH/PT4) – w Hearing screen – immediate
Hearing screen – immediate SpO2 - Immediately IEM - 7-14 days A negative screen – results a A positive screen – further te ithin 24 hours within 24 hours ately, 7-14 days
ately, 7-14 days ts are normal r testing is needed
G6PD deficiency
Congenital hypothyroidism
Blood group
Common cause of sever kernicterus in the early 195 March 1955 – 10 months 96 infants with severe ha
96 infants with severe ha No blood group incompa 26 (27%) kernicteric 81% of kernicteric babie 44% of kernicterus was seco 60% of first week deaths w
Wong HB, Neo
vere neonatal hyperbilirubinaemia and 950s haemolytic jaundice and anaemia
haemolytic jaundice and anaemia patibility bies died
Wong HB, Arch Dis Child 1957
secondary to G6PD deficiency were due to kernicterus
eonatal hyperbilirubinaemia, Bulletin of KKH 1964
RBC membrane stabiliser Hemo Kernicterus – disability or death molysis Bilirubin production and jaundice Deposition in the basal ganglia
All newborns in Singapore deficiency The objective is to identify th No informed consent
No informed consent If screened deficient co enzyme activity performed Babies were kept for 7 – 14 Parents educated on triggers re – cord blood screened for G6PD those affected within a day of birth
confirmatory quantitative estimation of days in nursery** ers and prevention of haemolysis
100 120 140 160
20 40 60 80 '54 '56 '58 '60 '62 No of patients
The Journal of the Singap
'64 '66 '68 '70 '72 '74 '76 '78 '80 '82 Year
apore Paediatric Society Vol 25 No. 1 & 2, 1983
Source: Medscape
Incidence 1 in 3000 All newborns in Singapore a blood (Normal range: 1 – 25 No informed consent
No informed consent Method: semi-automated no sensitivity and rapid turnaroun Results known prior to discha Recall rate approximately 1% are screened at birth for TSH in cord mIU/L)
non - radioisotopic assay with high und time scharge % for value of TSH >25 mIU/L
Cord TSH Free T4 & TSH
Abnormal
TSH ≥ 25 Free T4 low/normal (12-33)
H >25 mIU/L TSH on Day 3 – 4
Discharge
Normal
– Treatment started within 1 – Initial total T4 level > 4.3 p
14 days of age pmol/L
Tillotson et al. BMJ 1994 Dubuis et al. J Clin Endocr Metab 19 Ray et al. Arch Dis Child 1997
intervention implemented by
Delayed detection and intervention Abnormal speech, language an psychosocia developme
loss: 1 in 1000 births earing loss detected by 3 months and 6 months
al h, and cial ent Poor academic achievements
Started in 2002 in restructure Methods: Oto-acoustic emission (OA
Automated auditory brainst Results: ‘PASS’ or ‘REFER Goals (Joint Commission of H Universal screening by 6 w Diagnosis by 3 months Intervention by 6 months red hospitals OAE)
instem response (AABR) ER’ Hearing Institute): weeks
Oto-Acoustic Emission (OAE)
Automated Auditory Brainstem Response (AABR)
OAE
not detect neuro-sensory defects (beyond cochlear)
AABR
ry
KKH, NUH, SGH Central database and tracki Diagnosis, recall and interve
Diagnosis, recall and interve 1st test done within 24 – 48 ‘REFER’ result repeat h 2nd ‘REFER’ result repea 3rd ‘REFER’ result onwa cking system ervention
ervention 48 hours of delivery t hearing test before discharge peat 2 weeks later (OPD basis) ward referral to ENT
140 million children are born Four million are born with con 25-30% are expected to have 5-15% of all sick newborns i
rn every year. congenital problems ave Inborn errors with Metabolism in NICU are expected to have transien
The mechanism of disease following: Accumulation of an abnormal Lack of a normal product
Secondary metabolic phenom is the result of one or more of the al substrate as a result of shunting
menon
Diseases of Intoxication
Progressive accumulation of toxic metabolites secondary to lack of key enzymes Treatment available and intervention
Treatment available and intervention prior to symptoms results in improved outcome PKU Classical Galactosemia MSUD Tyrosinemia I xic ey ion
Diseases
Fatty Ac
Deficiency of MCAD/ LCAD; Enzym which convert fat into energy Most common IEM-1:10000
ion in Most common IEM-1:10000 Normal toddler after short illne presents with vomiting, Hypoglycem seizures, coma 20% mortality and 20% brain damage TMS- High levels of octanoylcarnitine Preventable M&M Minimise morbidity if fasting prevent and metabolic crisis averted
Guthrie
Robert Guthrie (1916 - 1995) T “Today over 20 million babies are scr
rie Card PKU Bacterial Inhibition As
) The "Father of Newborn Screening.“ screened using the Guthrie test each yea
About 25 – 30 IEMs can be scre technology called Tandem Mass TMS is an analytic instrume quantify or ions in a sample on
quantify or ions in a sample on Individually IEMs are rare but Singapore Newborns typically appear wel disorders may lead to developm brain damage and even death screened for from a blood spot using a novel ass Spectometry (TMS) ent that separates and determines the the basis of their mass-to-charge ratios
the basis of their mass-to-charge ratios collectively incidence 1 in 3000 births in ell at birth, but if left undiagnosed, these pmental delay, poor growth, severe illness,
A few drops of blood are collect and 72 hours when baby has est The sample is then sent to analyzed – measurement of m analyzed – measurement of m blood More than 99% of all babies wil In less than 1% of cases an abn If the screening tests indicate a confirm and identify the particul
ected from a heel prick – usually between 24 established full oral feeds the MENS lab in KKH/NUH where it is metabolites and enzyme activity in whole metabolites and enzyme activity in whole will have normal results bnormal result may be detected an abnormal result more testing done to cular problem
Amino acid disorders and urea cycle defects
disease (MSUD) Orga
acid
disease (MSUD)
acid
type
met defic
carb rganic acid disorders ropionic acidaemia ethylmalonic cidaemia Fatty acid oxidation disorders
deficiency
cidaemia
pe 1 Hydroxy-3- ethylglutaryl-CoA lyase eficiency Methylcrotonyl-CoA arboxylase deficiency
dehydrogenase (MCAD) deficiency
deficiency
palmitoyltransferase deficiency
1.Smudged: dried bood-spot
sample placed on wet surface
2.Insufficient Blood 3.Seperation: wet card
placed in plastic bag
4.Blood not soaked to other side
Front of card Back of card
Handling and storage of filter pa Volume of blood collected Absorption time for blood
paper
Critical congenital heart diseases (C congenital malformations and up to Early detection of CCHD in asympto
Current Strategies- Antenatal ultraso 25 – 30% of children with life-threate undiagnosed 5% of children with critical congenita community (CCHD) - Up to 40% of all infant deaths from to 7.5% of all infant deaths are due to CCHD ptomatic newborns poses an important challeng
asound and newborn physical examination atening congenital heart diseases leave hospita
Abu-Harb 1994, Mellander 2006, Wren 20
nital heart disease die undiagnosed in the
Wren 2008, de-Wahl Granelli 20
Pulse oximetry detects hypoxae Meta-analysis of 229,421 infant Sensitivity - 77% (70-83%)
Sensitivity - 77% (70-83%) Specificity - 93% (88-96%) If pulse oximetry s done beyon from 0.5% to 0.05% Limitations - conditions which m
aemia in the absence of clinical cyanosis. nts
yond 24 hours the false positive rates drop may still be missed are critical left heart
In addition to critical congenita identify babies unwell from other In a study, 50% of cases screene
In a study, 50% of cases screene Transient tachypnoea of new Pneumothorax Sepsis ital heart diseases, SpO2 also helps to er causes ened positive had non-cardiac problems:
ened positive had non-cardiac problems: ewborn
De-Wahl Granelli 2014
Easy to implement Midwife, trained screener or Time taken only 5 minutes
Time taken only 5 minutes Pulse oximetry is now acce detection of CCHD
ccepted as a good screening tool for ear
Saturation measurement from Good pulsatile waveform m Stable readings and free fr
must be present from artefacts
Check SpO2 in right han ≥ 95% in both RH and F AND ≤ 3% difference between RH and F
PASS
≥ 4% di
Home if otherwise fit
PASS
≥ 95% in both RH and F AND ≤ 3% difference between RH and F
PASS
≥ 4% di t hand (RH) and either foot (F) 90 – 94% in RH or F OR % difference between RH and F
RESCREEN
< 90% in RH
FAIL
Repeat in 1 hour
RESCREEN
90 – 94% in RH or F OR % difference between RH and F
FAIL
< 90% in RH or F
FAIL
Benefits
Early Identification Early Intervention
Early Intervention Decreased mortality and morbidity
Potential Harm
More tests, more false + ► Parental Anxiety
Missed diagnosis (False negative) Ambigious results- unnecessary treatment and anxiety Unanticipated Outcomes Labelling -Identification of unaffected carriers The right to “NOT KNOW”
Explosion of new treatment New technology
New technology ?New Preventive strategies
?? Susceptibility testing Use of residual spots for Use of residual spots for research Advanced Screening technolog might identify children with oth conditions not originally targete for screening Ethical Issues
Development of effective new tre Expansion of treatable disease c considered
Fragile X syndrome Lysosomal Storage Disorders
Lysosomal Storage Disorders SCID Advancing technology will enable
Modification of Tandem Mass spe extraction from newborn screen Identification of unaffected carrie treatments for hithertho untreatable disorders criteria - Additional Conditions being
ble new testing strategies to be developed
spectrometry (TMS) with DNA Analysis and ening dried blood spot riers
Cost of a successful screeni Low False positive) Treatment efficacy Risks and cost of treatment ? Appropriate time to initiate
? Appropriate time to initiate
Ethics Lack of data regarding the n Funding problems. ning strategy (High sensitivity, High PPV, te treatment in diseases with mild or late
te treatment in diseases with mild or late natural history of some of the disorders
A]Scientific Issues - Lack efficacy and natural history of B] Funding isssues- Limited
Increased resource utilisation
Increased resource utilisation
C] Health system needs
Complex multidisciplinary car Challenges in diagnosis conf Integrated system of care wit up
ted cost utility analysis
ion with false + results
ion with false + results care nfirmation and long term management with seamless screening, diagnosis and follow
D] Quality and Training Issues
Very few physicians are trained Very few people are trained to labs
Limited capacity and services quickly and accurately provide screen
E] Lack of Quality Assurance S
Limited comprehensive QA sys comparisons ned to manage children with IEM to oversee biochemical genetic testing
to de definitive diagnostics for a positive NBS
System
systems to define targets and perform interlab
Fabry disease, MPS, Krabb Fabry disease :Prevalence
Fabry disease :Prevalence 1;3000 in Italy Enzyme replacement thera are treatment options whi early in life bbe disease nce : 1 in 1250 newborns in Taiwan
nce : 1 in 1250 newborns in Taiwan erapy and bone marrow transplantation hich are particularly effective if initiated
Early identification of fragile X syndr heightened parental anxiety and dis Informed consent could overwhelm hospitals, and reduce participation in
hospitals, and reduce participation in Screening will identify some children Screening might identify children wit screening Screening could overwhelm an alrea comprehensive care Increases the likelihood of negative insurance or employment discrimina Screening will suggest risk in extend issues (because they never consent ndrome, an "untreatable" condition, could lead to disrupt bonding lm parents with information, significantly burden n in the core screening program
n in the core screening program ren who are or appear to be phenotypically norma with other conditions not originally targeted for lready limited capacity for genetic counseling and ve self-concept, societal stigmatization, and ination ended family members, raising ethical and legal ented to screening)
Two questions have persisted
developments made possible
the medical advances and th NBS programs sted throughout the history of NBS: ical standards accommodate the rapid
ical standards accommodate the rapid ssible by new technologies? systems prepared to respond to both the political forces driving expansion o
Increased collaboration between Larger role for the MOH with ove Infrastructure, funding, consisten Assurance Mandatory and uniform Screenin
Mandatory and uniform Screenin Education of public and medical Improved infrastructure to suppo and follow –up For disorders where there is not prudent to recommend pilot scre be used to adapt or even to stop en public and private sector
tent data collection, research and Quality ning strategy nationwide
ning strategy nationwide al community port testing, counselling, education, treatment
reening and to have a mechanism that can
Most newborn screening test enzyme actively in whole blo paper Hearing loss – using automat Congenital heart defects – u Congenital hypothyroidism & immunoassay Cystic fibrosis – molecular tec
ests are done by measuring metabolites and blood samples collected on specialized filter ated brain stem response using pulse oximetry m & congenital adrenal hyperplasia – technique
Start L-thyroixine 8 – 10 mcg Monitor thyroid function tests Monthly x 3
3 monthly x 3 4 monthly x 3 6 monthly x 2 Keep free T4 levels in blood TSH within normal range cg/kg/day sts (free T4 and TSH):
d in upper quartile of normal range and
NBS programs are one of the past decade (Centers for Disea Have led to the saving of lives Decreased financial burden on
Success of NBS in early pre-symptomatic identific identifiable conditions to facilitate early and timely inte with resultant avoidance or elim e pivotal public health achievements of the sease Control and Prevention, 2011) and improving quality of life
ification of a group of severe, rare & clearly ntervention limination of adverse outcome
testing, reporting of results
methods, specimen delivery, laborator lts anagement, long term follow up
for at risk fetus (eg: Trisom
symptomatic newborn
symptomatic newborn
ening – a type of primary prevention my 13, 18) ype of secondary prevention for pre-
ymptomatic newborn metabolic autopsy
Common cause of severe ne kernicterus Incidence of G6PD deficiency
1.62% of all newborns 3.15% in males and 0.11% Chinese males 3.94%, M males 0.66%
Joseph R, Southea
neonatal hyperbilirubinaemia and ncy at NUH, Singapore
11% in females Malay males 2.95%, Indian
east Asian J Trop Med Public Health 1999
In Singapore: Average age of identification o Average age for intervention:
>50% have no risk factors hearing
42 months (too late)
and 90% have parents with normal
Low WK et al, Ann Acad Med Singapore, 2005
In high risk ethnic populations, con Galactosaemia – Accumulation cataracts
cataracts Cystic fibrosis – Inherited diso provides better management an Additional tests done in other co
consider the following: ion of galactose resulting in liver damage an
isorder affecting lungs and gut. Early detectio and better quality of life countries
ficiency sia
Heel prick with a sterile lancet Wipe away the first drop of blo Allow a large blood drop touching it to the pre-printed c
touching it to the pre-printed c paper Collect 4 drops of blood Fill all circles completely and fr Dry specimen in room air in h before sending to laboratory cet lood to form before circle on the filter
circle on the filter from1 side only horizontal position
Fatty Acid Oxidation defects Organic acid disorders
**One test- One disorder Galactosemia Hypothyroid G6PD deficiency Cystic fibrosi
mino acid disorders zyme Assay/Immune assay)
rosis Biotidinase deficiency