Neonatal Diagnosis

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Guthrie card
Guthrie card

In the early 1950's Virginia Apgar published the research article that was the basis of a simple diagnostic test, the 10-point Apgar score, for neonatal well-being at birth that continues to be used today.

There are a number of different neonatal diagnosis or screening (newborn screening) programs in different countries testing for various "common" abnormalities and infections. In addition to the Guthrie test there are also physical tests for hip displasia and a growing number of countries testing of newborn hearing. There are also a range of simple clinical tests for postnatal neurological development.

The Neonatal period is considered the postnatal development categorised from birth to 1 month (4 weeks).

Neonatal Diagnosis Links: neonatal diagnosis | Apgar test | Guthrie test | hearing test | Electrocardiogram (ECG/EKG) | X-ray | Tandem mass spectrometry | Classification of Diseases

Diagnosis Links: Prenatal Diagnosis | pregnancy test | amniocentesis | chorionic villus sampling | ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis

Diagnosis Categories

  • Prenatal diagnosis - number of different techniques (non-invasive, invasive) for determining normal development
  • Neonatal diagnosis (Apgar test, Guthrie test (heel-prick test), hearing test)
  • Maternal diagnosis - often pregnancy will expose maternal health problems

Some Recent Findings

  • Screening for spinal muscular atrophy[1] SMA added to newborn heel prick (Guthrie test) in 'profound' change in medical screening "In an Australian first, newborn babies are now being routinely screened for the genetic condition SMA, or spinal muscular atrophy". SMA leads to a loss of motor neurons and progressive muscle wasting and has several different forms: Type 1, Type 2, and Type 3a SMA. ABC News
  • A Historical and Current Review of Newborn Screening for Neuromuscular Disorders From Around the World: Lessons for the United States[2] "We aimed to review the history of newborn screening for three neuromuscular disorders (Duchenne muscular dystrophy, Pompe disease, and spinal muscular atrophy [SMA]) to determine best practices. The history of newborn screening for Duchenne muscular dystrophy began in 1975 with the measurement of creatinine kinase on newborn male blood spots from two Midwestern hospitals in the United States. Over the next 40 years, ten programs were implemented around the globe although none currently remain. The first experimental pilot program for Pompe disease began in 2005 in Taiwan. In 2013, Missouri was the first US state to implement Pompe newborn screening before its inclusion in the Recommended Uniform Screening Panel (RUSP) in 2015 by the Advisory Committee on Heritable Disorders in Newborns and Children (United States). In 2008, SMA was reviewed and rejected for inclusion in the RUSP because no treatment existed. With the approval of nusinersen in late 2016, spinal muscular atrophy is being reconsidered for the RUSP. A condition should meet public health screening criteria to be included in the RUSP."
More recent papers  
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<pubmed limit=5>Newborn Screening</pubmed>

Apgar Test

Apgar Test

A historic neonatal test designed by Dr Virginia Apgar[3] used in nearly all maternity clinics to assess the newborn infants well being assigned scores for each of 5 indicators: Heart Rate, Respiratory Effort, Reflex Irritability, Muscle Tone, Colour Measured at one and five minutes after birth the Score values are totalled for all indicators: 7-10 is considered normal, 4-7 may require resuscitative measures, 3 and below require immediate resuscitation. In recent years there has been some controversy of the relevance and accuracy of some of the criteria used in this test, though many feel it is still an invaluable initial assessment tool particularly where medical services are limited.

  • Measured at one and five minutes after birth.
  • The Score values are totalled for all indicators
    • 7 to 10 is considered normal
    • 4 to 7 may require resuscitative measures
    • 3 and below require immediate resuscitation
Apgar Score Calculation
Indicator Score   0 Score   1 Score   2
(muscle tone)
Limp; no movement Some flexion of arms and legs Active motion
(heart rate)
No heart rate Fewer than 100 beats per minute At least 100 beats per minute
(reflex response)
No response to airways being suctioned Grimace during suctioning Grimace and pull away, cough, or sneeze during suctioning
The baby's whole body is completely bluish-gray or pale Good color in body with bluish hands or feet Good color all over
Not breathing Weak cry; may sound like whimpering, slow or irregular breathing Good, strong cry; normal rate and effort of breathing
Table data[3]

Apgar test - Measured at one and five minutes after birth, the score values are totalled for all indicators:

Total Score: 3 and below require immediate resuscitation 4 to 7 may require resuscitative measures 7 to 10 is considered normal

Links: Apgar test

Guthrie Test

Guthrie card

A blood screening test developed by Dr Robert Guthrie[4] (1916-95) at University of Buffalo. The test is carried out on neonatal (newborn) blood detecting markers for a variety of known disorders (phenylketonuria (PKU), hypothyroidism and cystic fibrosis). In NSW and Victoria, the Guthrie Cards are currently stored indefinitely.

Note - The specific type of disorders screened for by this test varies by state and country around the world.

Links: Guthrie test

Screened Disorders

  • Biotinidase Deficiency
  • Congenital Adrenal Hyperplasia (CAH)
  • Congenital Hypothyroidism (CH)
  • Congenital Toxoplasmosis
  • Cystic Fibrosis (CF)
  • Galactosemia (GAL)
  • Homocystinuria
  • Maple Syrup Urine Disease (MSUD)
  • Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

Biotinidase Deficiency

(multiple carboxylase deficiency) Defined by time of onset (early or late) and enzyme deficiency level (profound or partial).

  1. Early-onset multiple carboxylase deficiency is caused by mutation in the holocarboxylase synthetase gene.
  2. Late-onset multiple carboxylase deficiency with biotinidase deficiency is caused by mutation in the biotinidase gene.

Mean serum biotinidase enzyme activity/level compared to normal.

  • profound- less than 10% of normal
  • partial - 10% - 30% of normal

Characteristics include:

  • neurologic abnormalities - seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss
  • cutaneous abnormalities - alopecia, skin rash, candidiasis

Links: OMIM

Congenital Adrenal Hyperplasia (CAH)

Links: adrenal | adrenal abnormalities | genital abnormalities

Congenital Hypothyroidism (CH)

Links: thyroid

Congenital Toxoplasmosis

The causal agent of Toxoplasmosis is the protist Toxoplasma gondii (T. gondii). This unicellular eukaryote is a member of the phylum Apicomplexa, which includes other parasites responsible for a variety of diseases (malaria, cryptosporidiosis). The diagnosis and timing of an infection are diagnostically based on serological tests. During a period of acute maternal infection, transplacental transmission can occur, and the rate of congenital toxoplasmosis with risk for severe fetal varies from 15 to 68%, depending on gestational age. The transmission rate is highest in the later stages of pregnancy.

Congenital toxoplasmosis is characterized by a wide range of clinical manifestations; neurological, ophthalmological, and systemic involvement.

Links: Toxoplasmosis | TORCH

Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is a serious genetic disease due to abnormal chloride channel synthesis (cystic fibrosis transmembrane conductance regulator, CFTR), the impact occurs postnatally. Mucus accumulates mainly in the passages of the lungs and in the pancreas.

Links: Respiratory Abnormalities - Cystic Fibrosis

Galactosemia (GAL)


Three different types:
  1. galactose 1-phosphate uridyltransferase (GALT) deficiency OMIM
  2. galactokinase (GALK) deficiency OMIM
  3. galactose-4'-epimerase (GALE) deficiency OMIM

Links: OMIM

Maple Syrup Urine Disease (MSUD)

Clinical features of MSUD are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The urine effects are due to the presence of keto acids of the branched-chain amino acids (branched-chain keto acid dehydrogenase enzyme subunits)

Four different types:

  1. type IA - caused by mutation in the E1-alpha subunit gene
  2. type IB - caused by a mutation in the E1-beta subunit gene
  3. type II - caused by defect in the E2 subunit gene
  4. type III - caused by defect in the E3 subunit

Links: PubMed Health | OMIM

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

MCAD deficiency is the most common inherited disorder of mitochondrial fatty acid oxidation in people from northern Europe. It is characterized by an intolerance to prolonged fasting and an inability to generate energy during periods of increased energy demand. The disorder can be severe to fatal in infants.

The other disease characteristics include: recurrent episodes of hypoglycemic coma with medium-chain dicarboxylic aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels.

Gutherie test detected autosomal recessive metabolic disease affects about one in 10 000 people (UK). This mitochondrial protein is encoded by a nuclear gene on chromosome 1 (Gene map locus 1p31) and has a common mutation (985A>G) with a carrier rate of around one in 65.2.

Galactosylcerebrosidase Deficiency (GALC)

Autosomal recessive inheritance pattern

GALC deficiency (Krabbe disease, globoid cell leukodystrophy, galactosylceramidase deficiency) is a rare lysosomal disorder associated with mutation in the GALC gene (14q31) producing less galactosylceramidase. This lysosomal enzyme is required by glial cells (oligodendrocytes) in the nervous system to make myelin that insulates nerve cells. The disease has an autosomal recessive inheritance pattern. There is an even rarer infantile form caused by a mutation in the prosaposin (PSAP) gene (10q21-q22). The rarity of this disorder means that it may not be routinely tested everywhere.

There two main identified forms:

  1. An early-onset form - appears first months of life, often lethal before infant age 2 years.
  2. A late-onset form - appears in late childhood or early adolescence.

Links: Image - autosomal recessive inheritance | Neural System Development | Neural Exam Movies | Inheritance Genetics

Tandem Mass Spectrometry

Tandem mass spectrometry (MS/MS) - can screen for PKU and many other diseases simultaneously (up to 21 metabolic diseases).[5]

Nuclear Medicine Renal Scan

DTPA Renal Scan showing the absence (agenesis) of the right kidney.

DTPA Renal Scan - a test of renal function.

A radioactive compound is injected into the venous system, it then enters the renal system for excretion by the kidneys. A gamma camera can be used to track the compounds progress through the renal system.

Renal function measured:

  • nephron function and perfusion
  • ureter obstruction and trauma or damage
  • renal artery stenosis
  • hypertension


Congenital Hypothyroidism

Thyroxine (T4) molecular structure showing iodine positions (red rings).

Neonates born with congenital hypothyroidism (CH) typically have a normal appearance and no detectable physical signs. Thyroid hormone is required for normal postnatal neural (cognitive) development with newborn screening and thyroid therapy able to be begun within 2 weeks of birth.

The availability of a universal screening program for this hormonal abnormality varies from country to country.[6]

Congenital hypothyroidism can occur through either dysgenesis or agenesis of the thyroid gland development or abnormal thyroid hormone production. A false positive high thyroid stimulating hormone (TSH) can occur, due to the neonatal TSH surge that elevates TSH levels and causes T4 and T3 changes in the first 1 or 2 days after birth.

See also Iodine deficiency.

Links: thyroid | iodine deficiency


Newborn hearing test

The incidence of significant permanent hearing loss is approximately 1-3/1000 newborns. Neonatal hearing screening is carried out in the USA, UK and in Australia (2002 NSW Statewide Infant Screening Hearing Program, SWISH) There is a general guide giving a timetable for a number of simple responses that a neonate should make if hearing has developed normally (More? Neonatal Hearing Check List).

State Wide Infant Screening Hearing Program (SWISH) a newborn hearing testing program using an automated auditory response technology (AABR). Program was introduced in NSW Australia in 2002 across 17 area health service coordinators. It is thought that in NSW 86,000 births/year = 86-172 babies potentially born with significant permanent hearing loss.

Automated Auditory Brainstem Response

(AABR) uses a stimulus which is delivered through earphones and detected by scalp electrodes. The test takes between 8 to 20 minutes and has a sensitivity 96-99%. The basis of a neonatal hearing test that uses a trigger stimulus delivered through earphones and subsequent brain electrical activity then detected by scalp electrodes. Then by computer analysis, averaging all the electrical activity following the trigger, peaks emerge reflecting signal passage activity through brain stem nuclei in the hearing central neural pathway. The infant test takes between 8 to 20 minutes, has a sensitivity 96-99%, and unlike other childhood auditory testing does not require a subject response. An alternative and simple test (pass/refer) used at a later stage is otoacoustic emission testing.

Otoacoustic Emission Testing

(OAE) The basis of a simple infant hearing test of the inner ear. A small probe containing both a speaker producing "clicks" and a microphone to detect cochlea responses is placed inside the ear canal. Acoustic energy produced by vibration of the hair cells in response to the clicks is detected by the microphone within the probe. A more complex test that can be used at an earlier stage is the automated auditory brainstem response.

Neonatal Hearing Check List

The timing and types of responses listed below reflect only a rough guide for the general population. Abnormalities in neurological, visual or motor skill development can also affect responses.

  • Birth to 3 months - Reacts to loud sounds, Quiets to familiar voices or sounds, Makes cooing noises, Responds to speech by looking at speaker’s face
  • 3 to 6 months - Turns eyes or head toward sounds, Starts to make speech-like sounds, Laughs and makes noises to indicate pleasure and displeasure
  • 6 to 9 months - Babbles, ‘dada’‘ma-ma’‘baba’, Shouts/vocalises to get attention, Will often respond to ‘no’ and own name, Responds to singing and music
  • 9 to 12 months - Imitates speech sounds of others, Understands simple words, eg ‘ball’,‘dog’, ‘daddy’, Turns head to soft sounds, First words emerge
  • 12 to 18 months _ Appears to understand some new words each week, Follows simple spoken instructions, eg ‘get the ball’, Points to people, body parts or toys when asked, Continually learns new words to say although may be unclear
  • 18 to 24 months - Listens to simple stories or songs, Combines two or more words in short phrases eg ‘more juice’

Hearing check list text based upon NSW Health Pamphlet - Why does my baby need a hearing check?

Links: hearing test | hearing


WHO motor development milestones

The newborn neuromuscular system can be initially assessed by 6 quick tests (posture, square window, arm recoil, popliteal angle, scarf sign and heel to ear). Later developmental assessment includes behaviour, reflexes (primitive and postural), muscular tone, and motor (gross, fine, co-ordination).

Neural examination can be carried out in the newborn and then later at 3 months, 6 months, 12 months and at 30 months of age.

There are several primitive reflexes (rooting, sucking reflexes, Moro, grasp) that change (are repressed) with development of the central nervous system.

Newborn Reflexes

Newborn n 23.jpg
 ‎‎Moro Reflex
Page | Play
Newborn n 24.jpg
 ‎‎Galant Reflex
Page | Play
Newborn n 22.jpg
 ‎‎Reflex Suck,Root
Page | Play
Newborn n 26.jpg
 ‎‎Grasp Reflex
Page | Play
Newborn n 25.jpg
 ‎‎Stepping Reflex
Page | Play
Newborn n 20.jpg
 ‎‎Tendon Reflexes
Page | Play
Newborn n 21.jpg
 ‎‎Plantar Reflex
Page | Play

These movies were designed by PD Larsen and SS Stensaas, Utah School of Medicine.

Links: Newborn Neural Exam | Neural Exam Movies | Neural System Development

Gene Tests

A new site developed by NIH "GeneTests" provides medical genetics information resources available at no cost to all interested persons. It contains educational information, a directory of genetic testing laboratories and links to other databases such as OMIM.

Genetic Testing Registry] (GTR) provides a central location for voluntary submission of genetic test information by providers.

Links: NIH - Genetic Testing Registry | GTR Overview


  1. Sampaio H, Wilcken B & Farrar M. (2018). Screening for spinal muscular atrophy. Med. J. Aust. , 209, 147-148. PMID: 30107765
  2. Ross LF & Clarke AJ. (2017). A Historical and Current Review of Newborn Screening for Neuromuscular Disorders From Around the World: Lessons for the United States. Pediatr. Neurol. , 77, 12-22. PMID: 29079012 DOI.
  3. 3.0 3.1 APGAR V. (1953). A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg , 32, 260-7. PMID: 13083014
  5. Cipriano LE, Rupar CA & Zaric GS. (2007). The cost-effectiveness of expanding newborn screening for up to 21 inherited metabolic disorders using tandem mass spectrometry: results from a decision-analytic model. Value Health , 10, 83-97. PMID: 17391418 DOI.
  6. Rose SR, Brown RS, Foley T, Kaplowitz PB, Kaye CI, Sundararajan S & Varma SK. (2006). Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics , 117, 2290-303. PMID: 16740880 DOI.


Search PubMed: neonatal diagnosis | neonatal screening

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Cite this page: Hill, M.A. (2024, May 25) Embryology Neonatal Diagnosis. Retrieved from

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