Issues in Newborn Screening

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Issues

in Newborn

Screening

Committee on Genetics

In 1982 the American Academy of Pediatrics

pub-lished recommendations on newborn screening for

phenylketonuria (PKU) and congenital

hypothyroid-ism (CH),’ and these were updated and expanded for

CH in 1987.2 This current statement reemphasizes

the important points from those statements and

con-siders further recommendations that relate to issues

in clinical practice.

Newborn screening is a preventive public health

procedure that should be available to all neonates.

There are approximately 4 000 000 births per year in

the United States and approximately 370 000 per year

in Canada. Because the numbers to be screened are

so large, even if a relatively small percentage of babies

are excluded, a significant number of individuals will

be missed. For example, if 5% of the neonatal

popu-lation in Canada and the US were not screened during

a 1-year period, there would be 14 or more children

with undetected PKU (13 in the US and 1 in Canada)

and 43 or more with undetected CH (40 in the US

and 3 in Canada).

To maximize the screening rate, the American

Academy of Pediatrics (AAP) continues to

recom-mend that all infants have a blood specimen taken

for newborn screening prior to discharge from the

nursery.’ The practitioner should be aware of the

influence of treatments, such as transfusions and

dialysis (see below), on the screening tests. The

im-portance of accurate and complete information on the

specimen collection form, and of appropriate sample

collection technique, should be recognized.3 In

addi-tion, pediatricians should be aware of those groups

of infants who are at risk of not being screened and

should obtain a specimen from those infants at their

first contact with them. The pediatrician should

in-dude in the patient record the screening status of all

children, even transfer patients, entering the practice

for comprehensive care.

The AAP notes that screening does not equate with

diagnosis. Some infants with disorders included in

the newborn screening battery will be missed, even

when properly screened, due to individual or

biolog-ical variations.”4 Other infants may be missed due to

administrative or laboratory error. Although the

pe-diatrician cannot be held responsible for these

prob-lems, he or she must recognize that any child with a

negative newborn screening test may still be affected

by one of those disorders. The pediatrician should

trust his or her clinical judgment, even in the face of

The recommendations in this publication do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual differences, may be appropriate.

a normal newborn screening report, and should carry

out appropriate diagnostic testing if indicated by

din-ical signs and symptoms.

The number of tests included in newborn screening

batteries continues to increase. The AAP recently

issued a series of “Newborn Screening Fact 6

to assist pediatricians in reviewing their current

screening panels and in developing positions on the

addition of new tests that would be appropriate to

their states and territories. The “Fact Sheets’ were

designed to inform rather than to advocate for specific

disease screening. In this statement, we address issues

related to three disorders: PKU, CH, and sickle cell

disease. All states in the US currently screen for the

former two,7 and screening for the latter has been

recommended by a National Institutes of Health

con-sensus conference.8 Issues related to screening for

other disorders were discussed in the “Fact

although no recommendations were made.

GOAL 1

The pediatrician should be recognized as a key, but

certainly not the only, component in the newborn

screening program.

Recommendations

1.1. An adequate neonatal screening program

in-volves not only the laboratory, but also

educa-tion, administration, follow-up, management,

and evaluation components.

1.2. The pediatrician should play a role in informing

the parents or caretakers of his or her patients

of abnormal results, facilitating follow-up testing

and diagnosis, and enhancing communication

between the newborn screening program and

the family.

1 .3. The responsibility for transmission of screening

test results should rest with the authority or

agency that performed the test. It is

recom-mended that the screening status be entered into

the patient’s record (eg, on a flow sheet such as

that which is used for recording immunization

status).

1 .4. When a patient enters a pediatric practice for

comprehensive care by birth or transfer, the

pediatrician should evaluate clinical signs and

symptoms, and, if indicated, carry out

appropri-ate diagnostic testing regardless of the initial

screening test results or whether or not the results

of such initial screening can be ascertained.

Commentary

Newborn screening no longer refers only to the

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elements essential for every neonate to have access

to a system that is optimal in terms of quality and

performance. A neonatal screening program includes

the following components”9: (a) education of parents

and practitioners about newborn screening and about

their participation in the activity; (b) reliable

acquisi-tion and transportation of an adequate specimen; (c)

reliable and prompt performance of the screening

test; (d) prompt retrieval and follow-up of individuals

with abnormal screening tests; (e) accurate diagnosis

of individuals with positive confirmatory tests; (f)

education, genetic counseling, and psychosocial

sup-port for families with affected infants; (g) appropriate

medical management for patients; and (h) systematic

outcome evaluation. Key elements for the pediatrician

are education of the newborns’ families and an

effi-cient and effective mechanism for transfer of

infor-mation back to the families to facilitate confirmatory

testing, diagnosis, and treatment. This concept

rec-ognizes specific responsibilities of pediatricians in this

program, many of which already may be codified in

the state or territorial laws or regulations, or

estab-lished by court decisions. However, it also limits

potential liability to only those areas of responsibility;

thus, the pediatrician is not liable for other

compo-nents of the newborn screening program outside his

or her responsibility.

The pediatrician should recognize the need for

careful documentation of newborn screening results

on each patient entering the practice for the purpose

of comprehensive care. Patients who transfer between

practices should have this documentation easily

ad-cessible in their records for the new physician.

New-born screening is a standard procedure that should

be performed on, and the status of which should be

known for, each patient in the practice. It is analogous

to immunizations and should be recorded in a similar

fashion, perhaps on the well-baby flow sheets along

with immunization status. Documentation in this

manner will assure that patients are not missed

be-cause of administrative oversights in the pediatrician’s

office.

GOAL 2

There should be total participation of all newborns

in the screening program.

Recommendations

2. 1. A blood specimen should be obtained from every

neonate before the baby is discharged or

trans-ferred from the nursery, regardless of the nature

or status of the infant’s feeding or age.

2.2. Younger siblings of children previously

diag-nosed with one of the disorders on the screening

panel have an increased risk of that disorder

and, therefore, deserve special attention so that

the appropriate diagnostic test can rapidly

deter-mine whether or not they are affected. A

speci-men should also be sent for the complete routine

screening battery since this child is at the same

risk as the general population for one of the

other screened diseases.

2.3. Any premature infant, any infant receiving

par-enteral feeding, or any neonate being treated for

illness should have a specimen obtained for

screening at or near the seventh day of age if a

specimen has not been obtained before that time,

regardless of feeding status.

2.4. The pediatrician should recognize the patients

who are at substantially increased risk of not

being screened and take particular care to

doc-ument that appropriate screening was

per-formed. If this cannot be documented, then the

pediatrician should obtain a specimen for

screen-ing, even if the patient is beyond the neonatal

period.

Commentary

Pediatricians should participate in the development

and periodic review of newborn screening protocols

for the hospitals in which they practice. These

pro-tocols should delineate the procedures for

hospital-born neonates, including education of parents and

staff, documentation of informed consent or dissent

for the test, obtaining and forwarding an adequate

specimen, and notification and assurance of

follow-up of positive and negative results. Hospital protocols

and procedures should represent realistic practices

and not an idealized approach that is unworkable.

Responsibilities should be well-defined, recognizing

that the laws or regulations of certain states and

territories specify responsibilities for specific

pro-grammatic components, and dictate whether

in-formed consent or dissent is an issue and which is

the appropriate procedure. Specimen collections

should be routine for all neonates so that no infant is

missed because a specimen is not collected.

The pediatrician should be aware of those patients

at increased risk for not being screened. Among these

groups are sick or premature neonates,’#{176} including

those on parenteral feeding, as well as other healthy

neonates, such as those undergoing adoption or

trans-ferred within or between hospitals. The homeborn

and children of transient or homeless families are also

at increased risk of not being tested, as well as those

born outside the US and Canada.”2 The absence of

a standardized neonatal screening policy or program

for dependents of the United States Uniformed

Serv-ices also places them at increased risk for failure to

be screened, particularly those born outside the US.’3

GOAL 3

An adequate specimen should be provided to the

laboratory for analysis.

Recommendations

3. 1. The specimen should be obtained as close as

possible to the time of discharge from the

nurs-ery for the full-term, well neonate, and in no

case later than 7 days of life.

3.2. Cord blood is not adequate for detection of PKU

or other disorders with metabolite accumulation

after birth.

3.3. If an infant requires transfusion or dialysis prior

to the routine time for acquisition of the newborn

screening specimen, and if the clinical status of

the neonate permits, it is optimal to obtain the

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di-alysis. If a sample cannot be obtained before

dialysis or transfusion, the pediatrician should

ensure that an adequate repeat specimen is

ob-tamed at the appropriate time when the plasma

and/or red blood cells will again reflect the

child’s own metabolic processes or phenotype.

3.4. If the initial specimen is obtained before 24 hours

of age, then a second specimen should be

ob-tamed at 1 to 2 weeks of age to decrease the

probability that PKU and other disorders with

metabolite accumulation will be missed as a

con-sequence of testing on the first day of life.

Commentary

In fetuses affected with PKU and related disorders,

plasma concentrations of phenylalanine, and similar

small molecular weight compounds pass across the

placenta and are metabolized by the mother. The

concentrations of these metabolites are essentially

normal at birth and accumulate after birth with a time

course that is typical of the individual patient’s

dis-ease.4’6 Therefore, cord blood is not a satisfactory

specimen and should not be used for the routine

newborn screening specimen. An adequate neonatal

screening specimen should be priority in the nursery,

and acquisition of this specimen should not be

super-imposed on other protocols (eg, for hypoglycemia,

hyperviscosity, etc) that would interfere with optimal

timing of the screening specimen. The optimal timing

of the specimen for the normal, healthy newborn is

as close to discharge as possible in order to permit the

maximum possible accumulation of the abnormal

compound. Because of concerns that the

concentra-tions of the metabolites may not have reached

thresh-old values for the screening tests,4’6”4’6 the AAP

continues to recommend that if the initial specimen

is taken before 24 hours of age, then another

speci-men should be obtained at 1 to 2 weeks of age. Data

also indicate that 6% to 12% of patients with CH are

normal on the initial screening test and abnormal on

a repeat test.2’6’17

A second screening test is available in certain

re-gions, where it may be voluntary, recommended, or

mandatory, and may include tests for one or more

diseases, depending on the specific jurisdiction.

How-ever, there are regions in which a second screening

test is discouraged by the health authorities, which

may limit the availability of repeat testing in those

regions. The pediatrician cannot be held responsible

for the absence of repeat screening in a region with

policies that discourage this practice. Pediatricians

should know the law and/or regulations in their areas

and should follow these regulations as they pertain

to repeat testing as well as to other aspects of newborn

screening. They should also recognize that they do

have a responsibility to perform diagnostic testing in

any symptomatic child.

The sick and/or premature newborn may undergo

transfusion or dialysis, both of which may interfere

with newborn screening tests.’#{176}”8 The addition of

foreign red cells to the patient’s circulation will

influ-ence the screening test based on red cell constituents,

such as those for galactosemia and the

hemoglobi-nopathies, if the genotype of the transfused cells

differs from the recipient’s genotype. This can lead to

a false negative test and delayed diagnosis, as has

been reported for galactosemia,’8 but could

poten-tially result in a false positive test as well, such as for

hemoglobinopathies. Considerable time may be

re-quired for clearance of the foreign cells and

clanfica-tion of the diagnosis.18 Dialysis and plasma exchange

transfusions may reduce the concentrations of

circu-lating metabolites and hormones and may result in a

false negative test if the screening specimen is drawn

shortly after the procedure. Therefore, it is best to

obtain newborn screening specimens prior to

trans-fusion or dialysis if the patient’s clinical condition

permits. If the screening specimen is obtained after

one of these procedures, caution and clinical

judg-ment should be used in its interpretation, and a repeat

specimen should be obtained subsequently at a time

appropriate for the procedure and the disorder of

concern.

GOAL 4

Systematic follow-up and management should be

a part of the comprehensive newborn screening

pro-gram.

Recommendations

4. 1. Confirmatory testing is the initial step in the

laboratory follow-up of newborn screening.

With rare exceptions (eg, galactosemia and

ma-pie syrup urine disease), patients should not be

started on treatment until a diagnostic specimen

has been obtained. Prompt physical examination

is a part of newborn screening and has priority

particularly in those potentially life-threatening

disorders such as gaiactosemia, maple syrup

urine disease, and congenital adrenal

hyperpia-sia.

4.2. All patients with hyperphenylaianinemia that

persists on confirmatory testing should be

inves-tigated to rule out disorders of tyrosine and

biopterin metabolism.

4.3. All patients with sickle cell anemia should be

started on penicillin prophylaxis as soon as the

diagnosis is confirmed.

4.4. The evaluation of the efficacy of detection,

man-agement, and treatment for these disorders

re-quires routine follow-up at regular intervals.

Pe-diatricians should assist health authorities in

ad-quisition of data necessary for systematic

program and outcome evaluation. This is also

important in order to maintain patient contact.

Commentary

Screening tests are designed to rapidly and

inex-pensively evaluate a large number of specimens,

which are usually in the form of dried blood spots, in

specifically designed filter paper blotters. These are

not diagnostic tests. Confirmatory testing should not

merely repeat the screening test, but should include

specific diagnostic testing for the disease in question.

The testing batteries of certain regions include

dis-orders that are potentially life-threatening in the

im-mediate neonatal period. Diseases in this category

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Recommendations

5.1.

congenital adrenal hyperplasia.5 Untreated patients

with galactosemia are at a markedly increased risk of

sepsis, primarily due to Escherichia coli,19 and

fre-quently show physical signs, including jaundice,

hep-atomegaly, and failure to thrive,6 which may alert the

clinician before the confirmatory laboratory results

are available. Patients with untreated classic maple

syrup urine disease will develop life-threatening

aci-dosis accompanied by deteriorating central nervous

system status.6 Physical examination and evaluation

of urinary ketones and blood acid-base balance is

much more rapid in many areas than measurement

of the plasma leucine concentration. Patients with

congenital adrenal hyperplasia of the salt-losing

va-riety frequently fail to thrive and may progress rapidly

to Addisonian crisis if not treated. Evaluation of

weight gain and general health along with serum

electrolytes and glucose may provide a clinical

diag-nosis while awaiting laboratory confirmation.

Exam-ination of the patient by the pediatrician and referral

to a regional treatment center based on clinical

judg-ment is of particular importance for patients with

positive screening tests for diseases with a potentially

life-threatening neonatal course.

All patients with confirmed elevations of circulating

phenylalanine should have follow-up laboratory

test-ing to rule out disorders of tyrosine and biopterin

metabolism.1’6 These disorders have serious clinical

consequences that will not be ameliorated by a

phen-ylalanine-restricted diet and require prompt diagnosis

and appropriate therapeutic intervention.

Patients with sickle cell anemia should be started

on penicillin prophylaxis as soon as the diagnosis is

confirmed in an effort to prevent overwhelming

seep-sis, primarily due to Streptococcus pneumoniae. .20

In patients with penicillin allergy, an appropriate

alternative antibiotic should be selected. The

pedia-trician should ensure that prophylaxis is initiated as

soon as possible. In individual cases, the pediatrician

may elect to begin prophylaxis prior to confirmation

of an abnormal newborn screening test. If the child

subsequently is determined not to have sickle cell

anemia, antibiotics can be discontinued at that later

time. The pediatrician’s role and position of trust with

the family give this physician a unique ability to

educate the family regarding the need for continuing

antibiotics in the patient with confirmed sickle cell

anemia and in monitoring compliance with the

pro-phylaxis regimen. The pediatrician should be aware

that even though the patient is on antibiotic

prophy-laxis, serious infection can still occur. The families

must be educated about these problems and the

phy-sician must remain alert to them.

GOAL 5

Maintaining contact with women of childbearing

age affected with PKU is extremely important.

The health authorities must make every attempt

to maintain, reestablish, or establish contact with

older girls or women with PKU and

hyperphen-ylalaninemia within their jurisdictions, so that

they can be referred to the appropriate treatment

centers for counseling and management. These

efforts are intended to prevent the teratogenic

effects on the fetuses of these women, referred

to as the “maternal PKU syndrome.’ This will

occur if the women are not brought into excellent

metabolic control prior to conception and

throughout pregnancy. The pediatrician should

assist such efforts by referring these patients to

treatment centers.

5.2. The data support maintaining all PKU patients,

male and female, on a phenylalanine-restricted

diet using supplemental special formulations

in-definitely for their own well-being. This is

par-ticularly important for women with PKU to

pre-vent the maternal PKU syndrome. The

pediatri-cian is in a prime position to encourage

maintenance of the restricted diet even though

it is managed by specialty treatment centers.

Commentary

The data on psychometric testing of older children

with PKU indicate that they benefit by continuation

on a diet restricted in phenylalanine. ‘ In addition,

the preliminary results of an international study show

improved outcomes for infants born to mothers with

PKU who were brought into excellent metabolic

con-trol prior to conception and maintained in control

throughout the pregnancy.22 One problem, however,

has been the number of women with PKU as well as

hyperphenylalaninemia who were not on the special

diet at the time of conception or early in the

preg-nancy. This is due to the former practice of diet

discontinuation in the latter half of the first decade

of life with loss of these patients to follow-up by the

specialty clinics. Many of these patients may not

know of the risk to their future offspring for the

maternal PKU syndrome. One component of the

Na-tional Institute of Child Health and Human

Devel-opment-funded Maternal PKU Collaborative Study is

to identify these patients and offer them enrollment

in a national registry to facifitate ongoing contact even

if they should move to a different region.

Identifica-tion of these patients will also permit them to become

involved in educational programs through the

treat-ment centers to inform them of the risks to their

offspring and to assist them in returning to the special

diet. Again, the pediatrician is in the primary position

to identify and refer these older girls and young

women to specialty clinics so that they may become

enrolled in this program.

Experience has shown that there is considerable

difficulty in reinstating the phenylalanine-restricted

diet once it is replaced with a normal diet.23 Current

recommendations are for continuation of the special

diet indefinitely in all individuals with PKU. The

pediatrician can play a key role in discussing this issue

with the patient and the family and in supporting the

need for continuation of the phenylalanine-restricted diet.

GENERAL REMARKS

Newborn screening requires an integrated program

for systematic detection and management of all

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battery. Such efforts require organization at the state

or territorial and regional levels. Although the

incH-vidual pediatrician is not responsible for all

compo-nents of the program, the pediatric community should

take an active role in state and territorial advisory

committees to ensure that pediatricians’ activities are

functionally integrated into the overall screening

pro-gram.

Newborn screening is testing that should be

per-formed on every baby. The pediatrician should

de-velop mechanisms within his or her practice to be

sure that a specimen is collected on every child, that

a report is received on every specimen, and that this

result is documented clearly and prominently in the

patient’s record.

Cooin-r ON GENETICS, 1989 to 1990

Edward R. B. McCabe, MD, PhD, Chairman

Claire 0. Leonard, MD

Frank N. Media, MD

Margretta R. Seashore, MD

Lester Weiss, MD

Liaison Representatives

Felix de la Cruz, MD, National Institute of

Child Health and Human Development

Sherman Elias, MD, American College of

Obstetricians & Gynecologists

Jane Lin-Fu, MD, Health Resources and

Services Administration, Department of

Health and Human Services

Godfrey Oakley, MD, Centers for Disease

Control

REFERENCIS

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in newborn screening for phenylketonuria and congenital hypothyroid-ism. Pediatrics. 1982;69:104

2. American Academy of Pediatrics, Committee on Genetics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pc-diatrics. 1987;80:745

3. National Committee for Clinical Laboratory Standards (NCCLS). Blood collection on filter paper for neonatal screening programs; Approved Standard. vfflova, PA: NCCLS; 1988. NCCLS publication LA4-A 4. McCabe ER, McCabe L Mosher GA, Allen RJ, Berman JL Newborn

screening for phenylketonuria: predictive validity as a function of age. Pediatrics. 1983;72:390

5. Holtzman C, Slazyk WE, Cordero JF, Harmon, WH. Descriptive epide-miology of missed cases of phenylketonuria and congenital hypothy-roidism. Pediatrics. 1986;78:553-558

6. American Academy of Pediatrics, Committee on Genetics. Newborn

screening fact sheets. Pediatrics. 1989;83:449

7. National Screening Status Report. Infant Screening. Austin, TX: Interna-tional Society for Neonatal Screening 1988;11:20

8. National Institutes of Health Consensus Development Conference State-ment on Newborn Screening for Sickle Cell Disease and Other Hemo-globinopathies. Bethesda, MD: National Institutes of Health, Office of Medical Applications of Research; April 6-8, 1987;6(9)

9, Scriver CR and Committee. In: Marois M, Bennett HS, Klingberg MS. Brent RL, Lauder J, Saxen L, ads. Population Screening: Report of a Workshop in Prevention of Physical and Mental Congenital Defects. Part B:

Epidemiology, Early Detection and Therapy, and Environmental Factors.

New York, NY: Alan R. Lisa; 1985

10. McCabe ER, McCabe, L. Screening for PKU in sick or premature neo-nates. I Pediatr. 1983;103:502

11. McCabe ER. Principles of newborn screening for metabolic disease.. Perinat Neonatol. 1982;6:63

12. Kotzer AM, McCabe ER. Newborn screening for inherited metabolic disease: principles and practice. Neonat Network. 1988;6:15

13. Tiwary CM. Proposed guidelines for screening of metabolic and endo-crine diseases of dependent neonates of the US Armed Forces. Derived from a survey of state guidelines for neonatal screening of metabolic diseases. Clin Pediatr. 1987;26:349

14. Holtzman NA, Mellits ED, Kailman CH. Neonatal screening for phen-ylketonuria. II: Age dependence of initial phenylalanine in infants with PKU. Pediatrics. 1974;53:353

15. Kirkman HN, Carroll CL Moore EG, Matheson MS. Fifteen-year expe-rience with screening for phenylketonuria with an automated fluoro-metric method. Am I Hum Genet. 1982;34:743

16. Schneider AJ. Newborn phenylalanine/tyrosine metabolism. Implica-tions for screening for phenylketonuria. AJDC. 1983;137:427

I 7. LaFranchi SH, Hanna CE, Krainz PL, et al. Screening for congenital hypothyroidism with specimen collection at two times periods: results of the Northwest Regional Screening Program. Pediatrics. 1985;76:734 18. Sokol RJ, McCabe ER, Kotzer AM, Langendoerfer SI. Pitfalls in

diagnos-ing galactosemia: false negative newborn screen following red blood cell transfusion. JPediatr Gastroenterol Nutr. 1989;8:266

19. Levy HL, Sepe SJ, Shih yE, et al. Sepsis due to Escherichia ccli in neonates with galactosemia. N Engi IMed. 1977;297:823

20. Gaston MH, Verter JI, Woods C, et al. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trail. N Engl JMed. 1986;314:1593

21. Holtzman NA, Kronmal RA, van Doominck W, et al. Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. N Engl I Med. 1986;314:593

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