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All neonates with a positive NBS require evaluation and confirmatory testing. Those with
NBS positive for a condition that may result in decompensation in the neonatal period require
emergent evaluation even if they appear to be asymptomatic.
Most neonates with a positive NBS will have a false-positive result.
Evaluation should include history and physical examination, and IEM-specific routine
laboratory tests to reveal clinical manifestation or confirm absence of findings.
Confirmatory NBS tests should be sent even if routine laboratory tests are normal.
Evaluation, management, and disposition should be in consultation with an IEM specialist.
Management should include correction of any metabolic derangements, assuring adequate
hydration and avoidance of potentially toxic substances even in asymptomatic patients.

Goals of Treatment
Treatment goal is to confirm NBS and to prevent symptoms and metabolic derangements of IEM.

Current Understanding
The Advisory Committee on Heritable Disorders in Newborns and Children, as of July 2018,
recommends that states screen for a core panel of 35 conditions, 24 of which are IEMs, and an additional
26 conditions that are considered secondary targets on the basis of more mild symptoms and/or absence
of treatment options, of which 24 are IEMs. Most, but not all states, now screen for core conditions, and
at least some of the secondary targets ( ).
For every true-positive NBS, there are 12 to 60 false positives. To minimize the number of falsenegative NBS results, cutoff values have been deliberately set low with a national goal of an overall 0.3%
false-positive rate and a 20% positive predictive value. False positives also occur because of maternal
IEM, which, in some cases is undiagnosed. Even in the asymptomatic neonate, a false positive cannot be
assumed. Evaluation should include history, physical examination, and routine laboratory tests to reveal
clinical manifestations of disease or confirm absence of manifestations. The IEMs most likely to cause
acute decompensation in neonates include certain forms of tyrosinemia, organic acidemias, urea cycle
defects, galactosemia, and, less commonly, biotinidase deficiency. Manifestations and treatment of these
conditions are detailed in the section of this chapter on known IEMs, and for congenital adrenal
hyperplasia in Chapter 89 Endocrine Emergencies . Evaluation and management of neonates with
positive NBS should be in consultation with a metabolic specialist, or endocrinologist in the case of
congenital adrenal hyperplasia, and guided by American College of Medical Genetics NBS condition

specific ACTion sheets and confirmatory algorithms, which provide an overview of the condition and
information about potential clinical manifestations, and appropriate routine and confirmatory laboratory
tests ( ).
The New England Consortium website includes descriptions of some of the diseases in their acute
illness
protocols
( />).
Descriptions of specific IEMs can also be found in texts referenced at the end of this chapter and on
various websites, including the National Center for Biotechnology Information’s “Online Mendelian
Inheritance in Man” website ( ).

Clinical Considerations
Triage
Triage should be based on symptoms. Patients with even subtle symptoms should be expedited for care.
Assessment


History should focus on details of pregnancy and delivery, including gestational age, complications,
medications, exposures, route of delivery, Apgar scores, and complications; medications; family history
of affected relatives, stillbirths, SIDS; and postnatal history, including fever, lethargy, feeding, vomiting,
diarrhea, jaundice, abnormal movements, and abnormal odors. History may be unremarkable.
Examination should take note of level of activity, vital signs, temperature, weight, height, head
circumference, dysmorphic features, skin color, fontanelle, red reflex, cataracts, heart sounds, perfusion,
respiratory distress, abdominal distention, bowel sounds, hepatomegaly, splenomegaly, ambiguous
genitalia, cryptorchidism, suck, grasp, Moro, deep tendon reflexes, tone, symmetry, and seizures.
Physical examination may be normal.
Confirmatory testing is required for all neonates with a positive screen. Laboratory evaluation should
be disease specific. Routine tests may include electrolytes, BUN, creatinine, glucose, ammonia, AST,
ALT, bilirubin, PT, PTT, CBC, differential, platelets, and blood gas. Concurrent evaluation for infection
should be guided by history and examination. Appropriate tests for confirmation of the NBS condition for

which the patient is positive should be sent, even if all routine laboratory tests are normal. In some cases,
further testing is limited, at least initially, to repeat NBS, which may include measurement of standard
NBS analytes, as well as additional analytes, while in other cases, specialized tests including enzyme
assays and/or molecular tests are indicated.
Management
Specifics of management depend not only on the condition for which the patient screened positive but
also on the likely variant(s) of that condition, the concentration of the metabolite on NBS interpreted in
the context of age at the time of screening, and other factors that could modify test results.
Cardiopulmonary abnormalities and metabolic derangements must be corrected. Dietary modification,
vitamin cofactors, and/or medication may be appropriate and, in many cases, can prevent clinical
manifestations. Consultation with a specialist is indicated. Patients with any abnormality should, in most
cases, be admitted to the hospital. For patients who are discharged, a plan for very close follow-up and
genetic counseling, even though confirmatory testing may rule out true disease, should be established.

SUMMARY
Collectively IEMs are not rare, and clinical manifestations are often nonspecific. Therefore, a high index
of suspicion is essential for diagnosis. A few routine tests will serve as an informative screen for most
IEMs. Evaluation and treatment of patients with known IEM should be disease specific. All neonates
with positive NBS, even if asymptomatic, require evaluation and confirmatory testing, and if at risk for
acute decompensation emergent initiation of treatment. Rapid initiation of appropriate treatment for
patients with suspected or known IEM or positive NBS may not only be lifesaving but is also critical for
optimizing long-term outcome.
Suggested Readings and Key References
ACMG Newborn Screening Work Group. Metabolic disorders. Newborn screening ACT sheets and
confirmatory algorithms. Available at . Accessed March 9, 2019.
Acute Illness Protocols. New England Consortium of metabolic programs at Children’s Hospital Boston.
Available at . Accessed
March 9, 2019.
Advisory Committee on Heritable Disorders in Newborns and Children. Recommended uniform
screening

panel.
Available
at
Accessed April 4, 2019.
Bahi-Buisson N, Dulac O. Epilepsy in inborn errors of metabolism. Handb Clin Neurol 2013;111:533–
541.


Blau N, Duran M, Gibson KM, et al., eds. Physicians’ Guide to the Laboratory Diagnosis of Metabolic
Diseases . 2nd ed. Heidelberg, Germany: Springer; 2002.
Cakir B, Teksam M, Kosehan D, et al. Inborn errors of metabolism presenting in childhood. J
Neuroimaging 2011;21(2):e117–e133. Review. Erratum in: J Neuroimaging 2011;21(3):306.
Ficicioglu C, An Haack K. Failure to thrive: when to suspect inborn errors of metabolism. Pediatrics
2009;124(3):972–979.
Ghaziuddin M, Al-Owain M. Autism spectrum disorders and inborn errors of metabolism: an update.
Pediatr Neurol 2013;49(4):232–236.
Hoffman GF, Nyhan WL, Zschocke J. Inherited Metabolic Diseases . Philadelphia, PA: Lippincott
Williams & Wilkins; 2010.
Krishna SH, McKinney AM, Lucato LT. Congenital genetic inborn errors of metabolism presenting as an
adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders. Semin
Ultrasound CT MR 2014;35(2):160–191.
Levy PA. Inborn errors of metabolism: part 1: overview. Pediatr Rev 2009;30(4):131–137.
Levy PA. Inborn errors of metabolism: part 2: specific disorders. Pediatr Rev 2009;30(4):e22–e28.
Mak CM, Lee HC, Chan AY, et al. Inborn errors of metabolism and expanded newborn screening: review
and update. Crit Rev Clin Lab Sci 2013;50(6):142–162.
McKusik VA. OMIM online Mendelian inheritance in man [database online]. Available at
. Accessed January 30, 2009.
National Newborn Screening and Genetics Resource Center. United States table of newborn screening
tests performed by state. What is Newborn Screening? Available at .
Accessed March 26, 2020.

Nia S. Psychiatric signs and symptoms in treatable inborn errors of metabolism. J Neurol 2014;261(Suppl
2):559–568.
Ozben T. Expanded newborn screening and confirmatory follow-up testing for inborn errors of
metabolism detected by tandem mass spectrometry. Clin Chem Lab Med 2013;51(1):157–176.
Pagon RA. Gene tests. Available at .
Accessed March 11, 2019.
Parvaneh N, Quartier P, Rostami P, et al. Inborn errors of metabolism underlying primary
immunodeficiencies. J ClinImmunol 2014;34(7):753–771.
Rahman S, Footitt EJ, Varadkar S, et al. Inborn errors of metabolism causing epilepsy. Dev Med Child
Neurol 2013;55(1):23–36.
Sahoo S, Franzson L, Jonsson JJ, et al. A compendium of inborn errors of metabolism mapped onto the
human metabolic network. Mol Biosyst 2012;8(10):2545–2558.
Saudubray JM, Van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment
. 5th ed. Heidelberg, Germany: Springer MedizinVerlag; 2012.
Sun A, Lam C, Wong DA. Expanded newborn screening for inborn errors of metabolism: overview and
outcomes. Adv Pediatr 2012;59(1):209–245.
Vockley J, Chapman KA, Arnold GL. Development of clinical guidelines for inborn errors of
metabolism: commentary. Mol Genet Metab 2013;108(4):203–205.
Weinstein DA, Butte AJ, Raymond K. High incidence of unrecognized metabolic and endocrinologic
disorders in acutely ill children with previously unrecognized hypoglycemia. Pediatr Res
2001;49:88A.
Weismiller DG. Expanded newborn screening: information and resources for the family physician. Am
Fam Physician 2017;95(11):703–709.
Wolf NI, García-Cazorla A, Hoffmann GF. Epilepsy and inborn errors of metabolism in children. J
Inherit Metab Dis 2009;32(5):609–617.
Zand DJ, Brown KM, Lichter-Konecki U, et al. Effectiveness of a clinical pathway for the emergency
treatment of patients with inborn errors of metabolism. Pediatrics 2008;122(6):1191–1195.


CHAPTER 96 ■ NEONATAL EMERGENCIES

NICKIE NIFORATOS ANDESCAVAGE, DEENA BERKOWITZ

INTRODUCTION AND INITIAL ASSESSMENT
Goals of Emergency Care
The neonate is in a fragile state of transition to extrauterine life. Newborns have
limited ability to maintain temperature and glucose and they have limited
cardiopulmonary reserves to compensate for dehydration, sepsis, or other
stressors. Newborns may exhibit apnea, rather than tachypnea, in response to
hypoxia. They are immunocompromised and are unable to communicate
subjective findings. Every clinical finding is likely to be more subtle in the
neonate than in the older infant. Therefore, the goals of emergency care are to
triage and treat neonates urgently until serious disease has been ruled out, while
maintaining body temperature and serum glucose.
KEY POINTS
Newborns have very little reserve to compensate when acute illnesses
occur.
Tachypnea may be the only presenting sign of congestive heart failure.
Hypothermia, rather than fever, may be a neonate’s response to sepsis.
Weight loss is the most sensitive sign of dehydration in the newborn. A
loss greater than 10% of birth weight during the first 10 to 14 days of
life should be thoroughly investigated.
Careful attention must be paid to maintenance of temperature and
glucose in the ED.
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