Newborn

Screening
Prof Dr Thong Meow Keong
Consultant Clinical Geneticist

Dr Azanna Ahmad Kamar

Consultant Neonatologist

Department of Paediatrics
Faculty of Medicine
University of Malaya
 Learning
Objectives
 Concepts of screening
 Criteria for a screening test
 Newborn screening
 Benefits of newborn screening
 Expanded newborn screening
 Introducti
 on
Population screening is the testing of individuals in the
community to identify those who are at risk for a specific
condition or in the presymptomatic phase of disorders.
 Screening in paediatrics also includes screening for
chromosomal disorders (trisomy syndromes in
pregnancy), mendelian disorders (thalassaemia,
hypercholesterolaemia) and multifactorial disorders
(neural tube defects, deafness).
Introducti
on
 The purpose of screening is to enable people to make
informed decisions about their health or the health of
their children.
 A screening programme is to identify at-risk individuals
for a genetic condition; these individuals are subjected
to certain diagnostic tests to ascertain the precise
diagnosis.
 Therefore a screening test is not a diagnostic test.
 Objectives of a population
screening programme
 To identify a risk to personal health in time for treatment
or prevention.
 Example: neonatal screening (hypothyroidism, prelingual
deafness)
 To identify a reproductive risk in time to avoid it.
 Example: pre-pregnancy and antenatal screening

 To reassure people who are not at risk.

 Example: screening for familial cancers

 Cascade screening for thalassaemia

Definition of

newborn
‘a public health program designed to screen infants
shortly after birth for a list of conditions that are treatable,
screening
but not clinically evident in the newborn period.’

The UK National Screening Committee (NSC) in 2000

Criteria for newborn

screeni
Wilson JM, Jungner YG. [Principles and practice of mass screening for disease]. Bol Oficina
Sanit Panam 1968 Oct;65(4):281-393

ng
Basic statistics in a screening
programme
Suppose we screen 1000 people (and there are 40
people who are carriers for disease X, and 960 who
are not carriers).
If the test is 90% sensitive, 36 out of 40 of the carriers
will test positive, but the remaining 4 (who are also
carriers) will test negative (False negative).
If the test is 90% specific, 864 of the non-carriers will
yield negative result, but the remaining 96 (who
should also yield negative) will test positive (False
positive).
Basic statistics in a
screening programme
‘True’ result
Present Absent Total

Positive 36 (a) 96 (b) 132 (a+b)

Negative 4 (c) 864 (d) 868 (c+d)
Total 40 (a+c) 960 (b+d) 1000 (a+b+c+d)

 (a) = true positives (b) = false positives (c) = false negatives

 (d) = true negatives, a+c = prevalence
 Sensitivity = a/a+c Specificity = d/b+d

Predictive value of positive test = a/a+b = 36/132 = 27%

Predictive value of a negative test = d/c+d = 864/868 = 99.5%
Backgrou
nd1960’s

 Guthrie’s seminal paper
 Screening for phenylketonuria begins
 Other conditions screened: MSUD, histidinaemia etc
 1970’s
 T4 assay for congenital hypothyroidism
 Later, TSH as primary assay
 Other disorders considered in the ’70s included cystic fibrosis
and Duchenne muscular dystrophy
 1980’s
 Congenital adrenal hyperplasia; cystic fibrosis – a blood-spot
method; Haemoglobinopathies – controversy in USA;
neuroblastoma – later abandoned
NEWBORN
ASSESSMENT
 Routine Newborn
Assessment
st
1 Screening = Comprehensive newborn examination
 ideally, within the first 24 hours of birth (Hall & Elliman 2006)
and must be done within 72 hours.
 Purpose :
 To identify the acutely unwell newborn who may require
urgent treatment.
 Recognise common neonatal problems and provide
advice on management.
 Identify & explain problems that may not be observable
initially but could be significant a few days or weeks
later, e.g. jaundice.
 Review problems suspected from antenatal screening,
family history, or labour.
Routine Newborn
Assessment – When
?
 The first assessment must be performed within the first few
minutes of life to :
 assess for signs of successful transition to the extra-uterine
environment
 determine gender
 identify significant congenital anomalies
 reassure parents
 Repeated before discharge and between 6-8 weeks of age.
 The 6-8 week examination should be combined with the
mother’s postnatal examination and the infant’s vaccination
to provide a ‘one stop service’.
 There is no optimal time to detect all abnormalities
Newborn
– Initial
Assessment Communication with the
Parent
 Review any problems arising or suspected from antenatal
screening, family history or labour.
 Identify parents who may have major problems
 e.g. depression, domestic violence, substance abuse,
learning difficulties/ mental health problems
 Discuss essential baby matters on care of the baby
 e.g. feeding, vitamin K, hepatitis B and BCG vaccines,
reducing risk of SIDS etc.
 Explain problems that might not be observable in the
newborn but could be significant a few days/weeks later.
 Convey information about local services, e.g. `klinik
Newborn
Assessment – Systematic
Approach
 Take note of :
 Mode of birth, resuscitation at birth, medication since
birth, Vitamin K, Hep B.
 Observations since birth -ƒaxillary temperature.

 Anthropometric measurements : weight, length and

head circumference.
 Passing ofƒurine and meconium.

 Feeding since birth

 ƒtalk to
the parents about their feeding choice and provide
further information on establishment of breast feeding.
 `Head to Toe’ and `Front to Back’ examination.
Newborn
Assessm
ent
Checklist
General Appearance & Growth
Status
 Skin colour, integrity, perfusion.
 Petechiae, pallor, haemangiomas, `birth marks’.
 State of alertness.
 Activity, range of spontaneous movements.
 Posture, muscle tone.
 Chart head circumference, length, weight on centile
charts
 Micro/macrocephaly
 SGA

 Excessive weight loss.

Skin - Erythema
Toxicum
 Metopic Suture
Head, Face & Coronal Suture

1 1
Neck
Head shape, size, scalp, fontanelle,
sutures.
 Enlarged, bulging, sunken, absent
fontanelle. 4 2 2 4
 Fused sutures Sagittal Suture
 Subgaleal haemorrhage, caput
succadaneum, cephalohaematoma, Squamosal
Suture
chignon. 3
 Hazy cornea, absent red eye reflex.
Lambdoid Suture
 Non-patent nares, absent ear canal,
1- Frontal Bone
microtia, pre-auricular pit. 2- Parietal Bones 3
 Neck masses, swelling - Occipital Bones
 Fractured clavicle. 4 - Temporal Bones
Differentiating Caput vs
Cephalhaematoma vs
Subaponeurotic(Subgaleal)
Haemorrhage
 Systems
 Examination
Respiratory:
 Colour, respiratory effort (rate, retraction, grunt, nasal flare),
mediastinal shift, auscultation.
 Cardiac:
 Assessment of colour, pulses (brachial and femoral)
precordial lift, heart sounds, murmurs.
 Abdomen:
 Shape, umbilicus (including number of umbilical arteries),
organomegaly, genitalia, hypospadius or other possible
ambiguity (such as bilateral undescended testes), anus
(site, patency)
 Peripheries:
 Digits, hands, feet, legs, arms.
 Syndactyly, polydactyly
Back - Spinal
Dysraphisms
Defective neural arch.
 Meningocoele, mylemonengocoele,
lipomeningomyelocoele,
myeloschisis, rachischisis.
 Spina bifida aperta vs. Spina bifida
occulta.
 0.5 to 8 cases per 1000 live births.
 Risk factors :
 Folate deficiency
 Maternal diabetes
 Maternal exposure to
valproate/carbamezapine
Developmental Dysplasia of the
Hip

(DDH)
A spectrum of anatomical
abnormalities in which the
femoral head & the acetabulum
are in improper alignment and/or
grow abnormally.
 Risk Factors :
 Gender - Female > Male
 Family history of DDH.
 Breech intrauterine positioning at or
after 36 weeks.
 Additional in-utero postural
deformities e.g. congenital talipes
calcaneovalgus, metatarsus
adductus.
Neurology - Newborn
Reflexes
 Other
 Reflexes
Sucking Reflex
 Onset: ~28weeks GA
 Well-established: 32-34 weeks GA
 Disappears: around 12 months
 Elicited by the examiner stroking the lips of the infant; the
infant’s mouth opens and the examiner introduces their
gloved finger and sucking starts.

 Rooting Reflex
 Onset: 28 weeks GA
 Well-established: 32-34 weeks GA
 Disappears around 4 months.
 Elicited by the examiner stroking the cheek or corner of the
infant’s mouth. The infant’s head turns toward the stimulus
and opens its mouth
Pulse Oximetry
Screening
Non-invasive  Placement of saturation probe on infant’s
lower limbs (post-ductal) or both right upper limb (pre-
ductal) and lower limb.
 To detect hypoxaemia  clinical sign of critical
congenital heart disease.
 Other conditions that may also be detected via routine
pulse oximetry :
 Neonatal sepsis with circulatory dysfuction
 Persistent pulmonary hypertension of the newborn
 Congenital pneumonia
 Transient tachypnoea of the newborn
 Meconium aspiration syndrome
Newborn Hearing
Assessment
Incidence of congenital hearing loss = 1-3 per 1000 population.
 High-risk infants :
 In-utero infections  Ototoxic medications e.g.
 Family history gentamycin
 Craniofacial anomalies  Bacterial meningitis
 Very low birth weight < 1500 grams.  Poor Apgar scores
 Severe Hyperbilirubinaemia  Mechanical ventilation

 `High Risk Neonatal Hearing Screen’ versus `Universal Neonatal

Hearing Screen’ programme.
 Hearing loss prevalence in high risk patients = 2.5 -10%, but account
for only 50% children with congenital hearing loss.
 Programmes aim for early detection & intervention for children with
hearing loss.
 Newborn screening in
 Malaysia
Newborn screening (NBS) program for inborn errors of
metabolism (IEM) in Malaysia began in 1975 where glucose-6-
phosphate dehydrogenase (G6PD) deficiency screening using
cord blood was done.
 This showed an incidence similar to that in Singapore of
approximately 2%.
 Between 1991 and 1997, there were five separate pilot studies
of NBS for congenital hypothyroidism (CH) in different parts of
Malaysia. Incidence varied from 1:2400 to 1:3666, average CH
incidence of 1:3026.
 The national CH screening program began in October 1998
with 45% coverage in 2003 and this figure steadily increased to
96% by 2014. CH cases detected = 211; 94% were treated
within 14 days.
Newborn screening to prevent
mental handicap
A rapid and inexpensive test for G6PD activity in
erythrocytes - the Beutler fluorescent spot test is in
existence. The test works by visually identifying NADPH
produced by G6PD under ultraviolet light. For the
biochemical definitive diagnosis, a quantitative analysis
of G6PD activity is mandatory
Cost effective: reduction in kenicterus
Post test approach for G6PD deficient infants
Education for parents and family
Genetic counselling
Precautions and avoidance of triggers for haemolysis
Newborn screening to prevent
mental handicap
In addition, the majority of Malaysian hospitals also
screened for congenital hypothyroidism (CH) as this is the
commonest treatable cause of mental retardation.
In many countries, neonatal thyroid screening programs are
performed for early diagnosis and treatment of
hypothyroidism.
CH is usually sporadic; occurs in one in 3000-4000 infants.
Most infants with CH are normal at birth and show no signs;
emphasizing the importance of screening programs in
early detection of CH.
Cord blood sampling is attractive in regions with early
discharge after delivery.
Glucose-6-Phophate
Dehydrogenase (G6PD)Deficiency
Screening
 G6PD deficiency : An X-linked disorder, is the most
common enzymatic disorder of red blood cells.
 G6PD-deficient erythrocytes that are exposed to
oxidants (eg, drugs, infection) become depleted of
glutathione(GSH) – essential for protection of RBC
against oxidative damage; followed by oxidation of other
sulfhydryl-containing proteins  results in acute
haemolysis.
 Higher incidence of jaundice in infants with G6PD
deficiency due to decreased bilirubin elimination.
 Onset : day 2-3
 Severity varies
G6PD -
Pathophysiology
G6PD Deficiency
- Medications & Substances
to Avoid
Medicines and other substances Chemical exposures and foods likely
likely to be UNSAFE in moderate to to be UNSAFE in moderate to severe
severe G6PD deficiency G6PD deficiency
• Anti-infectives • Aniline dyes
• Dapsone • Naphthalene (mothballs, lavatory
• Nitrofurantoin and related deodorant)
• Primaquine • Fava beans
• Miscellaneous • Some prefer to avoid red wine,
• DimercaprolΔ legumes, blueberries, soya, and
• Methylene blue tonic water[4]
• Phenazopyridine • Henna compounds (black and red
• Toluidine blue (tolonium chloride) Egyptian) and related dyes used for
• Uricase (rasburicase, pegloticase) hair and tattoos
Expanded Newborn Screening
Recent developments:
 Screening of DNA samples:

 1987: DNA recovered from dried blood spots used for

haemoglobinopathy screening, and later, CF, others

 Tandem mass spectrometry (MS/MS):

 1991 - MS/MS considered – electrospray ionisation

 Mid 1990’s: MS/MS application to NBS shown to be

effective with programmes in S. Carolina, and
Pennsylvania USA.
 1998: Routine MS/MS screening started in NSW 1998

 2006: MS/MS screening widespread – “expanded

newborn screening”
 http://www.kkh.com.sg/Services/Children/NewbornScreeni ngIEMs/Pages/Home.aspx
Heel pricks are performed on newborns at 24 – 72 hours
of life and the dried blood spots are analysed for 30 inherited
metabolic diseases (tandem mass spectrometry)
Metabolic
emergencies
reduced enzyme activity
Precursor A Substrate B Product C
1. Accumulation of 3. Reduced or
2. Activation of different pathways or
toxic precursor or absent
diversion to secondary pathways
substrate products

Toxic by-products

enzyme
Substrate Y Product Z

Pathogenesis of IEM: Faults in enzyme function may lead to deficiencies in product

formation, accumulation of normal substrates to toxic levels and diversion of
normal substrates through abnormal pathways.
Spectrum of inherited metabolic
disorders in Malaysia
Individually rare but collectively account for 1: 3,000 live births
due to lack of awareness, under-reporting and inadequate diagnostic
facilities.
 In IMR, 6-year period from 1999 to 2005, a total of 13,400 samples
were received nationwide from infants and children suspected to
have IEMs based on their clinical presentation.
 Total number of 264 (2%) of those symptomatic children with
clinical suspicion for IEM have been diagnosed with IEM; the
majority of them have MSUD (44 patients), urea cycle disorders
(UCD) and methylmalonic acidemia

Thong MK, Yunus ZM. Spectrum of inherited metabolic disorders in Malaysia. Ann Acad Med Singapore.2008;37(12
Suppl):66-5.
 Inborn errors of metabolism cause
learning disability
IEMs may present as rapidly progressive conditions and
cause irreversible damage early on. Treatment can often
be effective if started early: resuscitation, prevention of
catabolism, supportive care, long term monitoring
 Lack of awareness of IEM presentation

 Low index of suspicion – only after other ‘common’ causes

are excluded
 Inappropriate delay in sending investigations for IEM –
blood and urine samples must be collected during an acute
crisis
 Delay in starting empiric treatment
Inborn errors of metabolism cause
learning disability
2. For those conditions where treatment is not effective
or available, a correct diagnosis means early genetic
counselling can be provided regarding recurrence
risks to affected families and to offer prenatal
diagnosis if available.

3. If the condition is frequent enough with treatment

options available, newborn screening programs (NBS)
may be instituted eg phenylketonuria. Expanded NBS
using newer technology such as tandem mass
spectrometry may be used to screen for 30 IEMs
using 3-4 drops of blood.
 Expanded Newborn Screening
Recent developments:
 Expanded newborn screening: Non MS/MS screening

 Universal hearing loss

 Critical congenital heart disease

 Immunodeficiency

 Others
 Screening:
advantages
 Opportunity to offer health services to those with
unmet needs
 Opportunity for the couple to receive information and
making informed decision
 Opportunity to modify the course of some diseases
 Opportunity to detect other carriers in the family
(cascade screening)
 Anxiety relieved if the screening test is negative
Screening:
limitations
Psychological costs
 Anxieties are raised pre and post testing

 Some high risk individuals may have preferred no

information
 Possibility of social stigmatisation

Financial costs
 Need to have ongoing long-term commitment

 Public awareness programmes

 Professional education is critical

Ethical issues
Discharging The
Review : Newbo
rn Breastfeeding well  Latches well, good suck, address feeding
Newborn assessment, all necessary screening tests done.



diffculties.
 Urine & stool passage.
 Newborn observations – temperature maintenance, respiratory rate.
 Vitamin K given
 Vaccines : Hepatitis B & BCG
 To watch for : jaundice, difficulty feeding, lethargy, decreased
urine & stooling, elevated temperature.
 Advise parents on importance of follow-up, vaccines &
keeping of medical health record.