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Evidence-Based Strategies for Common Clinical Questions

May 2021

Newborn Screening: A Review and Call to ACTion


Author: Elise Loughman, MD | Pediatrics Resident

Co-authors: Christopher Nitkin, MD (Neonatology); Jotishna Sharma, MD, DCH, MEd (Neonatology); Jennifer Gannon, MD (Genetics) 


Column Editor: Kathleen Berg, MD | Co-Director, Office of Evidence-Based Practice | Pediatric Hospitalist, Division of Pediatric Hospital Medicine | Clinical Assistant Professor of Pediatrics, UMKC School of Medicine 


Newborn screening (NBS) programs across the United States strive to identify infants born with conditions that cause significant morbidity and mortality if left untreated to enable early interventions to stop the progression of disease.1 Robert Guthrie, whose niece had phenylketonuria (PKU), was motivated to identify infants with PKU at birth; in 1963, he developed an assay to screen for PKU by identifying elevated levels of phenylalanine in dried blood spots. That same year, Massachusetts became the first state to adopt this assay for universal PKU screening.1

By 2006, the Federal Advisory Committee on Heritable Disorders in Newborns and Children found discrepancies in the number of conditions on state newborn screening panels, with most states screening for six disorders, while others screened for dozens more.2 To address these disparities, the Advisory Committee commissioned a panel of experts to create the Recommended Uniform Screening Panel (RUSP), which details a core panel of 29 conditions and a secondary panel, as guidance for state newborn screening laboratories.3,4 While all states screen for the 29 core conditions, there are regional differences in screening panels; Kansas currently screens for 34 conditions while Missouri screens for 74.5

In 2006, the American Academy of Pediatrics issued a five-part system for newborn screening.6 First is mandated testing with implied consent, meaning separate informed consent is not necessary. Second, infants with abnormal results are identified and families are provided education and referrals. Third, diagnostic testing with specialized labs and interpretation in conjunction with a metabolic geneticist is imperative. Fourth involves disease management, including a pediatrician with knowledge of the disorder in conjunction with specialists. Finally, evaluations of all parts of the screening system must be performed.6

Dried blood spot specimens obtained from infants, undergo testing using a variety of technologies that are best suited to screen for the conditions on the newborn screening panel. Fluorimetric assays measure enzyme activity in dried blood spots and screen for galactosemia, biotinidase deficiency and lysosomal storage disorders.1 Also utilized is tandem mass spectrometry (MS/MS), a technique that screens for organic acidemias, fatty acid oxidation disorders, amino acid disorders and urea cycle defects.7 Key markers and abnormal thresholds are identified for each condition.

These assays, and thus screening results, can be affected by intensive care interventions. Administration of aminoglycosides can interfere with results of fluorimetric assays.7 Blood products can invalidate results of screens for hemoglobinopathies, biotinidase deficiency and galactosemia.1 Total parenteral nutrition (TPN) or enteral feeds can cause elevations of amino acids; holding TPN or feeds for two to three hours prior to obtaining the screen can minimize false positives.7,8

So, what if your patient has a positive NBS? The American College of Medical Genetics and Genomics (ACMG) ACT Sheets and their algorithms are evidence-based resources to help inform clinical decision-making.6 These can be found at: For each disorder, there is an ACT sheet that describes the immediate actions a health professional should follow in communicating with the family, and then determine the timely steps in the follow-up of the infant who has screened positive. An algorithm is provided presenting an overview of the basic steps and tests involved in determining the final diagnosis.

While the ACMG ACT Sheets provide disease-specific recommendations for evaluation of the healthy infant with an abnormal newborn screen, symptomatic infants require immediate comprehensive evaluation and treatment. Pediatric providers must be familiar with metabolic crises, a typical presentation of inborn errors of metabolism. In a survey of pediatric residents at tertiary pediatric centers, less than 15% were knowledgeable about the acute management of a new onset metabolic crisis.9 This highlights the significant need for education in acute stabilization of affected children. Children in crisis can decompensate rapidly with nonspecific symptoms such as vomiting, poor feeding, lethargy or irritability. Initial recommended labs are shown in Figure 1. Breast milk or formula, which may contain nutrients that precipitate crises, should be held while administering isotonic fluids at a high glucose infusion rate. Infants suspected of having an inborn error of metabolism should be transferred to a center with a metabolic specialist and metabolic dietitian, as the management of these infants is highly complex.

Figure 1 



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