Structured Abstract
Please note: In 2003, the CTF updated its Grades of
Recommendations to include an "I Recommendation" for situations where
insufficient evidence exists to allow a recommendation to be made.
(Formerly, these situations were captured under a "C
Recommendation".) This change is not retroactive, and all
"C Recommendations" made prior to 2003 have not been
reevaluated in light of the new "I" recommendation grade. For a
discussion of these recommendation grades, please link to the 2003 article in
the Canadian Medical Association Journal here.
Screening for Phenylketonuria
Adapted by William Feldman, MD, FRCPC, Department of Pediatrics, University
of Toronto, from the report prepared for the US Preventive Services Task
Force by Robert Baldwin, MD and Modena E.H. Wilson, MD, MPH
These recommendations were finalized by the Task Force in October 1993
Contents
Objective
To make recommendations for screening pregnant Canadian women and their
newborn infants for phenylketonuria (PKU).
Burden
of Suffering
Phenylketonuria is an inborn error of phenylalanine metabolism that occurs
in 1 out of every 12,000 births in North America. In the absence
of treatment during infancy, most persons with this disorder develop severe,
irreversible mental retardation, and may also experience neurobehavioral
symptoms such as seizures, tremors, gait disorders, athetoid movements,
and psychotic episodes. Since the legislation of routine screening
in the mid 60s, these clinical manifestations have rarely developed in
children, resulting in a cohort of health phenylketonuric women entering
childbearing age. Unless dietary restriction of phenylalanine is
maintained during pregnancy, these women are at an increased risk of giving
birth to a child with mental retardation, microcephaly, congenital heart
disease, and low birth weight (incidence of maternal PKU is about 1 in
30,000-40,000 pregnancies).
Options
Screening options include a closed phenylalanine hydroxylase gene probe
for prenatal diagnosis and the Guthrie blood determination for infants.
Treatment options include strict adherence to a special low-protein diet
for 4 to 8 years or through adolescence or into adulthood. Material dietary
treatment may need to be started before conception for women with PKU.
Outcomes
False positive rates and sensitivity for the blood tests. Infants with
PKU may have reduced intelligence, cognitive function, and attention and
academic difficulties. Maternal hyperphenylketonuria with infants who do
not have PKU may develop mental retardation, microcephaly, intrauterine
growth retardation, and other birth defects.
Evidence
These recommendations were adapted from a report prepared for the U.S.
Preventive Services Task Force. MEDLINE was searched up to 1993 using
the keyword phenylketonuria.
Recommendations were graded as:
|
A
|
Good evidence to support the recommendation that the condition
be specifically considered in a PHE. |
|
B
|
Fair evidence to support the recommendation that the condition
be specifically considered in a PHE. |
|
C
|
Poor evidence regarding inclusion or exclusion of the condition
in a PHE, but recommendations may be made on other grounds. |
|
D
|
Fair evidence to support the recommendation that the condition
be specifically excluded from consideration in a PHE. |
|
E
|
Good evidence to support the recommendation that the condition
be specifically excluded from consideration in a PHE. |
Quality of evidence was rated according to 5 levels:
|
I
|
Evidence from at least 1 properly randomized controlled
trial (RCT). |
|
II-1
|
Evidence from well-designed controlled trials without randomization. |
|
II-2
|
Evidence from well-designed cohort or case-control analytic
studies, preferably from more than 1 centre or research group. |
|
II-3
|
Evidence from comparisons between times or places with
or without the intervention. Dramatic results in uncontrolled experiments
could also be included here. |
|
III
|
Opinions of respected authorities, based on clinical experience,
descriptive studies or reports of expert committees. |
Values
The 13-member Task Force of experts in family medicine, geriatric medicine,
pediatrics, psychiatry and epidemiology used an evidence-based method for
evaluating the effectiveness of preventive health care interventions. Recommendations
were not based on cost-effectiveness of options. Patient preferences were
not discussed.
Background papers providing critical appraisal of the evidence and tentative
recommendations prepared by the chapter author were pre-circulated to the
members. Evidence for this topic was presented and deliberated upon in
1- to 2-day meetings, 2 to 3 times per year from January 1993 to June 1993.
Consensus was reached on final recommendations.
Benefits,
Harms, and Costs
Using a cut point of 240 micromoles/L, false negative rates associated
with the Gurthrie test done on the first day of life ranged from 2% to
31%. These rates decreased on the second day to 0.6% to 2% and on the third
day to 0.3%. Flurometric assays have excellent sensitivity and lower false
negative rates. The gene probe has not been fully tested. Routine screening
of pregnant women has very low yields.
Untreated PKU causes mental retardation. One cohort study in 1953 showed
that 85% of untreated children had an intelligent quotient (IQ) < 40
and < 1% had an IQ above 70. Since dietary phenylalanine restriction
was introduced > 95% of children with PKU have normal or near-normal intelligence.
Diet treatment of at least 4 years (and up to adulthood) showed that treated
children have an IQ in the normal range although somewhat less than parents
and siblings. Some psychological deficits including perceptual motor dysfunction
and attention and academic difficulties have been found.
Maternal hyperphenylalanemia can cause teratogenic effects even in infants
without PKU; this effect is proportional to the levels of phenylalanine
in the mother. Children born to mothers with PKU may develop mental retardation
(>90%), encephalopathy (75%), intrauterine growth retardation (40% to 50%),
and other birth defects (10% to 25%). Low phenylalanine diets during pregnancy
may lead to poor fetal growth.
Recommendations
Recommendation grade [A, B, C, D, E] and level of evidence
[I, II-1, II-2, II-3, III] are indicated after each recommendation. Citations
in support of individual recommendations are identified in the guideline
text.
-
Good evidence exists to recommend screening of newborn infants with automated
capillary blood tests before discharge from the hospital [A,
I, III]. Infants tested before 24 hours of age should
be retested at 2 to 7 days of age.
-
No evidence exists to recommend for or against screening pregnant women
for undiagnosed PKU [C, III].
Validation
This report was externally peer reviewed. All Canadian provinces
have universal screening programs and U.S. states have varying regulations.
The 1989 United States Preventive Services Task Force recommended that
all newborn infants be screened before discharge. For infants discharged
before 24 hours, repeat the test at 7 to 14 days. They do not recommend
prenatal screening for maternal PKU. The American Academy of Pediatrics
(AAP) and the American Association of Family Physicians recommend universal
screening of infants using capillary blood samples taken as close to discharge
as possible. Premature infants and other treated infants should be checked
at 7 to 14 days. The AAP recommended repeat screening of infants if they
are tested before 24 hours of age. The AAP and the American College of
Obstetricians and Gynecologists do not recommend maternal screening.
Sponsors
The Canadian Task Force on Preventive Health Care
developed this guideline with funding from Health Canada.
Selected
References
Source Document
Link to Full Text of this
review
Link to Summary Table of Recommendations of this review
Link to Selected References list of this review
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