Introduction

In this chapter, we are going to discuss the origins of the newborn screening program in the United States. We are going to learn about the process of selection of disorders to the newborn screen program. The chapter will describe the process of evaluating a baby with an abnormal newborn screen and the next steps to take. The purpose of the chapter is to familiarize the neonatologist with the newborn screening program and disorders. The chapter includes special considerations that can affect the newborn screening results, specifically in the neonatal intensive care unit (NICU).

Background

In the United States, a program was established in the 1960s to screen all neonates for the detection of classic phenylketonuria (PKU). To this day, newborn screening is considered one of the most successful public health programs due to its ability to screen large populations, identify babies at risk of fatal illnesses, and prevent their death or severe comorbidities. It was developed by Dr. Robert Guthrie with the purpose of identifying babies who had PKU to prevent intellectual disability by starting a special diet at birth. The newborn screen started with a simple method of adding a few drops of blood to a filter card and testing it with a bacterial inhibition assay to determine the amount of phenylalanine in a baby’s blood. The filter card used was known as the PKU card, and when babies had abnormalities, it was called having an abnormal PKU test. Even though we have been screening for many more disorders since the 1990s, the name of the PKU test remains, creating confusion for parents. The author of this chapter feels strongly that healthcare providers should use the terminology “newborn screen test results” when discussing findings with parents or other healthcare providers.

Although technology changed in 1990 with the addition of tandem mass spectroscopy, we continue to use a filter card for blood collection. Nowadays, we also use gene sequencing as part of the newborn screening. The goals of the newborn screen are to prevent or minimize significant morbidity and mortality associated with various disorders.

Selection of Disorders

In 1968, Wilson and Jungner wrote a report to the World Health Organization proposing screening criteria ( Box 76.1 ). In 2006 the Maternal and Child Health Bureau commissioned the American College of Medical Genetics (ACMG) to develop a uniform screening panel and system. Their selection criteria stated that a condition should meet the following minimal criteria: it can be identified at a time (24–48 hours after birth) at which it would not ordinarily be detected clinically; a test with appropriate sensitivity and specificity is available for it; and there are demonstrated benefits of early detection, timely intervention, and efficacious treatment of the condition.

The Advisory Committee on Heritable Disorders in Newborns and Children has the purpose of evaluating disorders and making recommendations to the U.S. Department of Health and Human Services. The Recommended Uniform Screening Panel (RUSP) is the final list recommended by the U.S. Department of Health and Human Services. After a new disorder is proposed to the committee, the selection to add it to the RUSP is based on evidence-based literature. The recommendations are independent of financial support, and each state has the autonomy to decide which disorders it will screen for and how to support its program. Initially in 2006, the RUSP included 29 conditions that were mandated and an additional 25 conditions that were part of the differential diagnosis of a core panel of conditions, were clinically significant, and were revealed with the screening technology but lacked efficacious treatment or were incidental findings with potential clinical significance. Currently, the RUSP includes 37 core conditions and 26 secondary conditions (as of February 2023). The core and secondary conditions can be classified as organic acidemias, fatty acid oxidation disorders (FAOD), amino acid disorders, endocrine disorders, hemoglobinopathies, and other genetic disorders ( Fig. 76.1 ).

Recommended Uniform Screening Panel .

It is important to understand that although the United States are somewhat uniform in following the RUSP, they are not completely uniform, and some states take longer to implement new disorders into their programs. The RUSP list can be found at this website: https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html .

Description of the Process

A filter card is collected at the birth place. The nurse or midwife has to perform a heelstick and fill five full circles with blood. The sample is then sent to the state lab. Every state has a different system; however, most states have carriers to pick up the filter cards daily and send them to their state lab. There are a few states that do not have a state lab and have to send their filter cards to an adjacent state’s lab. The speed of processing is of utmost importance because there are certain disorders that will present in the first few days of life. Every state must develop their reference ranges, and these are calibrated for newborns. There is no consent needed to obtain a filter card. Parents can refuse to have a filter card done. The recommendation is to obtain the filter card after 24 hours of life. There are states that recommend having a second newborn screen in the 2-week-old checkup. NICUs have other recommendations due to the fragility of the population in those units. The recommendations for NICUs are to obtain the first newborn screen at birth in case there is an unexpected death. However, the screen must be repeated when the newborn is at least 48 to 72 hours of age. Another specimen is collected at 28 days of life and/or prior to discharge.

There are specific situations to be aware of in the NICU because some babies receive blood transfusions. Once a baby has had a red blood cell transfusion, certain disorders are not identified due to red blood cell enzymes, such as galactosemia and hemoglobinopathies. For these conditions, it is recommended to wait at least 120 days for enzyme testing. However, the physician can proceed with gene testing rather than waiting.

Another concerning reality is that there are extremely premature infants who spend more than 3 months in the NICU and have multiple newborn screens repeated. The reference ranges are meant for full-term newborns, which would result in abnormal newborn screens that are false-positive screens. Some researchers have published about the importance of using age-appropriate reference values when working with a prematurely born population.

There are two disorders that are part of the RUSP that do not require blood collection: congenital hearing loss and critical congenital heart disease.

Congenital hearing loss screening has to include a one- or two-step validated protocol. The most common protocol used is a two-step screening process that starts with otoacoustic emissions, followed by an auditory brainstem response if the first step is failed. Every baby should be screened for congenital hearing loss in the first month of life. If a baby is born at home or a birthing center, there should be a process established to refer the baby for screening in the first month of life.

Regarding critical congenital heart disease, the recommendations are to screen with pulse oximetry in a preductal and postductal position (right hand and a foot) after 24 hours of age. The baby should be off oxygen to perform the screening test. If the baby is unable to be weaned off oxygen for the test, an echocardiogram is recommended. If the screening test is positive (the baby has failed the screen), further tests are recommended. Fig. 76.2 shows the proposed algorithm ( https://www.cdc.gov/ncbddd/heartdefects/hcp.html ).

Critical Congenital Heart Defect Newborn Screen Algorithm .

Abnormal Newborn Screen Results

For blood-tested disorders, once the filter card reaches the lab, it will be processed for the respective disorders included in that state’s labs. There are certain conditions that require second-tier testing, and the results of those take longer, such as X-linked Adrenoleukodystrophy (XALD) and Mucopolysaccharidosis Type I (MPSI). Typically, the newborn screen results are available in the first 5 to 7 days of life. Every state has a process in place to manage abnormal newborn screen results. Neonatologists will encounter many abnormal newborn screens. The tables below summarize the first steps to take when encountering an abnormal newborn screen for one of the core disorders.

The ACMG prepared ACTion Sheets that provide information to the healthcare provider to give to families as well as algorithms to follow. Tables 76.1 to 76.8 presented in this chapter are a summary of the ACT sheets posted at https://www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_and_Algorithms.aspx .

Table 76.2

Organic Acidemias and Fatty Acid Oxidation Disorders That Are in the RUSP as Secondary Conditions

Metabolite/condition	Signs and symptoms	First-Line Labs	Consider	Contact
C3DC ↑ Malonic acidemia	• Marked lethargy • Vomiting • Hypotonia • Hypoglycemia, lactic acidosis, and metabolic acidosis	• Plasma acylcarnitine profile • Plasma methylmalonic acid • Urine organic acids	• If baby is ill: glucose, electrolytes, blood gas • Other symptoms include seizures and cardiomyopathy	Metabolic geneticist
C4 ↑ Short-chain acyl-CoA dehydrogenase deficiency (SCAD) Isobutyrylglycinuria	• Poor feeding or vomiting • Lethargy • Hypoketotic hypoglycemia, metabolic acidosis	• Plasma acylcarnitine profile • Urine organic acids • Urine acylglycines • Urine acylcarnitine C4	• If baby is ill: glucose, electrolytes, blood gas, ammonia • Most neonates are asymptomatic • A neonate can be extremely ill with vomiting, lethargy, and seizures	Metabolic geneticist
C4-OH ↑ Medium/short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (SCHAD)	• Poor feeding or vomiting • Lethargy • Hypoglycemia, metabolic acidosis	• Plasma acylcarnitine profile • Urine organic acids • Plasma insulin	• If baby is ill: glucose, electrolytes, blood gas, ammonia • Most neonates are asymptomatic • Severe hypoglycemia and severe hyperinsulinism may appear later • Sudden death in infancy has been reported	Metabolic geneticist
C4 ↑, C5 ↑ Glutaric acidemia type II (GAII)	• Poor feeding or vomiting • Lethargy • Odor of sweaty feet • Facial dysmorphism • Hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia	• Plasma acylcarnitine profile • Urine organic acids • Urine acylglycines	• If baby is ill: glucose, electrolytes, blood gas, ammonia • Can have renal anomalies	Metabolic geneticist
C0/C16+C18 ↑ Carnitine palmitoyl transferase 1 deficiency (CPT1)	• Lethargy • Hepatomegaly • Seizures • Hypoketotic hypoglycemia	• Plasma free and total carnitine • Plasma acylcarnitine profile	• If baby is ill: glucose, electrolytes, blood gas, ammonia, LFTs	Metabolic geneticist
C16 ↑ and/or C18:1 ↑ Carnitine palmitoyltransferase (CPT2) deficiency Carnitine acylcarnitine translocase (CACT) deficiency	• Poor feeding or vomiting • Lethargy • Dysmorphic facies • Hepatomegaly • Cardiac insufficiency • History of sudden unexpected death in a sibling	• Plasma acylcarnitine profile	• If baby is ill: glucose, electrolytes, blood gas, ammonia, LFTs, CPK • Neonatal form is associated with multiple congenital anomalies, profound illness with marked hypoglycemia, metabolic acidosis, cardiac arrhythmias, and facial dysmorphism	Metabolic geneticist

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4. Neurodevelopmental Impairment in Specific Neonatal Disorders

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