A Primer on Newborn Screening

Kristin Gatrell Bryant, RN, BSN, MSN; Kimberly M. Horns, RNC, NNP, PhD; Nicola Longo, MD, PhD; Julieanne Schiefelbein, MappSc, RNC, MA (Ed), RM, PNP, NNP


Adv Neonatal Care. 2004;4(5) 

In This Article

Implications for Clinical Practice

Every infant should be enrolled in a newborn screening program. The timing of screening is critical and can affect the accuracy of detecting certain metabolic disorders. Although screening is most accurate after 48 hours, certain circumstances may necessitate earlier screening For example, if a blood transfusion or antibiotic therapy is essential, obtain an initial screening sample prior to beginning therapy.[5] Collect blood specimens before discharge and no later than 72 hours of age.[5] Some infants may be hospitalized for an extended period of time. Screen all hospitalized infants on or before 7 days of life.[11]

Increasingly, repeat screens are mandated to accurately detect disorders. For example, one of the screening tests used to detect galactosemia, the Hill test, directly measures galactose levels by using a fluorimetric assay.[19] Metabolite accumulation of galactose occurs when an infant with galactosemia ingests breast milk or formula containing lactose.[5,19] If screening is performed prior to initiation of feedings, a false-negative result can occur[5]; it is optimal to repeat the screening once feedings have been established.

Compliance with repeat screening is often inconsistent. Although repeat screening is recommended by the AAP for infants screened prior to 24 hours of life, it was not obtained in 50% of infants who were discharged prior to 24 hours of life.[11] Health care providers need to ensure that the initial and repeat screening tests are ordered correctly and that they are performed on an appropriate schedule. Any transport, transfer, discharge, or change of care provider should trigger a review of this information.

Infants in the NICU have a number of unique issues and screening challenges. Premature infants have a higher than normal incidence of transient hypothyroidism.[19] Premature infants, those who received blood transfusions, and out-of-state births are also at risk for missed screening.[19] Infants with Down syndrome have higher TSH levels during the first 6 months of life and a higher than normal incidence of hypothyroidism.[31]

Infants in the NICU are often receiving therapies known to interfere with screening, such as hyperalimentation, blood transfusions, and antibiotic therapy.[5,19] If an infant is transfused prior to collecting the newborn screen, repeat screening for hemoglobinopathies will need to be done 4 months after the last transfusion.[5] To prevent a delay in diagnosis, an initial newborn screening test should be collected whenever possible, prior to initiating any of the above therapies.

The accuracy of the screen relies heavily on collection of an adequate specimen. This may be even more challenging in small, sick, or poorly perfused infants. The following guidelines will help decrease the number of invalid specimens.

Collect the blood using a consistent, careful technique to ensure an adequate sample. Avoid touching the filter paper with your hands or fingers; moisture, lotion, and body oil can interfere with absorption of the blood.[5] First, warm the heel prior to collecting the specimen. Prepare the infant for a painful procedure using techniques such as swaddling and sucrose. Next, cleanse the heel with isopropyl alcohol and then wipe dry with sterile gauze. Failure to do so may result in an unsatisfactory specimen. Use a lancet to puncture the heel, then wipe away the first drop of blood; the initial drop may contain unwanted cells or alcohol.[5] Avoid milking or squeezing the puncture site, which may cause hemolysis and render the specimen invalid.[5]

Do not use devices such as a capillary tube to apply blood to the filter paper; they can scratch the filter paper and lead to over absorption, making the specimen invalid. Only apply the blood droplets to 1 side of the filter paper.[5] The blood must be evenly distributed on the filter paper so 4 small, identical, circular punch-outs can be made from a single spot of blood (Fig 3). Allow the specimen to dry on a flat surface for 4 hours prior to mailing to the state laboratory. Transport the specimen to the state lab within 24 hours of collection.[5]

Completely fill all circular spots on the filter paper with blood. (B) Even distribution of blood is important as 4 small, identical, circular punch-outs are made from a single dried blood spot and are used in testing.

The requisition must be filled out properly and legibly to ensure appropriate processing and follow-up (Fig 4). Complete documentation is essential to ensure the testing information is retrievable and that rapid notification of the primary care provider regarding abnormal results can occur. Critical elements which must be documented correctly include: specimen date; infant's name, date of birth, sex, feeding status, transfusion (if applicable); mother's name, address, and phone number; mother's date of birth; and healthcare provider. Those who submit the form are legally responsible for ensuring accuracy and completeness of the information; failure to do so may delay follow-up testing of abnormal results.[5]

The importance of careful specimen labeling is critical as a high number of newborn screening samples are collected and processed each day. If data are missing or not appropriately filled in, delays in testing may result.

Timing is critical for follow-up of abnormal newborn screening results. It is the clinician's responsibility to ascertain results for each infant in their care.[5] The national standard for reporting of newborn screening test results is <7 days. Do not assume that screening was obtained or that results of the screen are normal. Potential medical and legal implications may result if screening and follow-up are missed.

If an infant needs transportation to another center or unit, clear written and verbal communication to the local provider or referral hospital are essential. Discuss the infant's newborn screening status, and if results are pending, list the laboratories' contact information. Identify the need for repeat testing and/or abnormal results in the discharge summary and in the verbal report.

Under the premise of the Institute of Medicine's "nothing about me without me" policy, parents deserve complete disclosure regarding any and all testing. Providers are obligated to provide clear written and verbal explanations to parents. Parents need information about what tests are included in the newborn screen, their infant's testing status and when to expect the results, the potential need for repeat testing, and ultimately whether the results are normal or abnormal. Provide parents with a copy of the test results for their personal medical record; encourage them to ask their primary care provider for written validation if results are pending at discharge.

The reduction of false-positive test results should be an important goal, increasing confidence in the testing and minimizing parental anxiety.[32] Nationally, there are approximately 50 false-positive results for every true-positive result identified through newborn screening.[28] As technological advances continue, further reduction of false-positive results is anticipated.

In addition to routine newborn screening, a high index of suspicion for metabolic disease is important. Inborn errors of metabolism often mirror other more common conditions and, as such, may be a diagnostic afterthought. When evaluating an infant with symptoms compatible with IBEM, it is important to perform a focused family history.[6] Pertinent findings may include a family history of:

  • Pregnancy losses

  • Dysmorphology or birth defects

  • Infant deaths or sudden infant death syndrome (SIDS)

  • Developmental disabilities including mental retardation, learning difficulties, special education, autism, seizure disorders, thyroid disorders, cerebral palsy, attention-deficit hyperactivity disorder, and institutionalization[6,33]

This process may identify undiagnosed family members who warrant referral for further testing.[33]

Conduct a careful review of the prenatal and perinatal history.[33] Key elements include prenatal drug and environmental exposures, pregnancy complications, and prenatal testing. Maternal illness during pregnancy may be associated with specific metabolic disorders.[6] Examine the history for specific issues such as diabetes, maternal hyperphenylalaninemia, thyroid disorders, and alcohol and/or drug exposures.

Perform a detailed physical assessment of the infant as some disorders are associated with dysmorphic features.[6] Note any unusual body or urine odors, which may be consistent with several organic acidemias.[6]

Critically analyze the infant's clinical history and course to identify symptom patterns compatible with IBEM. Consider data such as Apgar scores, delivery complications, and resuscitation measures when evaluating an infant who exhibits clinical signs or symptoms of an IBEM.

Diagnosis of metabolic disorders is challenging due to the wide range of clinical signs and symptoms usually associated with more common neonatal conditions.[13,25,26] These common clinical signs include feeding difficulty, vomiting, failure to thrive, jaundice, apnea, tachypnea, hypotonia or hypertonia, seizures, and lethargy.[6,26] The infant may present within a few hours of life to several days or longer. Catabolic insults such as infection, fasting or dehydration, and excessive protein or carbohydrate intake can exacerbate the undiagnosed disorder, and infants may become suddenly very ill or may present as an unexplained sudden death.[6] Five percent of cases initially diagnosed as SIDS have been attributed to undiagnosed IBEM.[10,34,35]

If a metabolic disorder is suspected, subspecialty medical consultations and referrals will be needed. Consultation with a metabolic specialist is usually necessary and always recommended.[6] If there is a potential hemoglobinopathy, consultation with a pediatric endocrinologist is optimal. Ultimately, consultation with a geneticist and formal genetic counseling may be necessary, as many disorders are genetically inherited.[6]

Staged diagnostic testing is useful to identify or rule out possible underlying metabolic disorders[25]; following a protocol or algorithm may be useful as it is important to take a systematic approach to testing. Initial laboratory studies should include a basic electrolyte panel, blood urea nitrogen (BUN) level, blood glucose, complete blood cell count with differential, platelet count, and a urinary analysis.[7,25] The next set of laboratory tests which may be indicated include a blood gas; urine metabolic screen; uric acid level; complete metabolic panel; and ammonia, lactate, and alanine levels.[7] Urine organic acids, cerebrospinal and plasma amino acids, and a carnitine level may also be indicated.[7,25] Finally, highly specialized tests such as an acylcarnitine profile, blood or tissue DNA mutation analysis, and a tissue biopsy for histology and biochemical analysis may be necessary.[7]

Most hospitals are not equipped to perform this specialized testing; the use of remote reference labs is common.[7,25] Results may take several weeks to months, and expert interpretation of results may not be readily available.[7,25]

Technical challenges exist in obtaining large amounts of blood from infants; anticipate the need for diagnostic studies prior to discontinuing central lines. It is important to communicate with the laboratory regarding the tests requested, as correct collection of the specimens is essential. Once the specimen is collected, collaboration with local and reference laboratories is needed to ensure proper handling and processing, and to ensure that send-outs are sent to the appropriate reference laboratory. This is imperative to avoid the need for repeat sampling and diagnostic delays.

Specific considerations exist in cases of suspected IBEM when survival of the infant is impossible.[7] Timely and systematic collection of fluid such as blood, urine, and cerebrospinal fluid is pertinent to evaluate for metabolic disorders in the dying infant.[7] Notify the laboratory prior to sending the samples as evaluation of these specimens is vital in determining the cause of death, developing a risk assessment for future pregnancies, and providing resolution to the family.[7]

An autopsy may be invaluable in making or confirming a diagnosis of an IBEM. When death is anticipated, provide parents with anticipatory guidance and counseling to evaluate the benefits of this information for future pregnancies and/ or future generations. The autopsy will likely include obtaining plasma, urine, and bile for further analysis; blood or tissue for DNA extraction; repeat filter paper testing; liver biopsy; skin samples for fibroblast cultures; and tissue biopsies from muscle, heart, brain, and liver for electron microscopy.[36] Death related to an IBEM of metabolism is considered a true emergency for perinatal pathologists; the autopsy should be performed within 4 to 6 hours of death, for best information.[36]


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