This is the current release of the guideline.

This release updates a previously published guideline: U.S. Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Baltimore (MD): Williams & Wilkins; 1996. Chapter 44, Screening for phenylketonuria. p. 495-502. [56 references].

Phenylketonuria (PKU)

Prevention
Screening

Family Practice
Medical Genetics
Nursing
Obstetrics and Gynecology
Pediatrics
Preventive Medicine

Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Nurses
Physician Assistants
Physicians

• To summarize the U.S. Preventive Services Task Force (USPSTF) recommendations and supporting scientific evidence on screening for phenylketonuria (PKU)
• To reaffirm the 1996 USPSTF recommendations on screening for PKU

All newborns

Screening for phenylketonuria using the Guthrie Bacterial Inhibition Assay (BIA), automated fluorometric assay, or tandem mass spectrometry

• Clinical effectiveness of treatments for phenylketonuria (PKU)
• Harms of screening for PKU

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Note from the National Guideline Clearinghouse (NGC): A targeted review of the literature was prepared by Agency for Healthcare Research and Quality (AHRQ) staff for use by the U.S. Preventive Services Task Force (USPSTF) (see the "Availability of Companion Documents" field).

In 1996, the USPSTF recommended screening for phenylketonuria (PKU) in all newborns prior to discharge from the nursery. In 2006, the USPSTF decided to update its recommendation statement on screening for PKU. Noting that its 1996 recommendation was made on a strong evidence base, and that it would take large, high-quality studies or evidence of substantial harms to overturn the current recommendation, the USPSTF chose to perform a reaffirmation update for this topic. The USPSTF performs reaffirmation updates for well-established, evidence-based standards of primary care practice that remain USPSTF priorities, are within the scope of the USPSTF, and for which there is compelling reason for the USPSTF to have a current recommendation statement. While the Task Force would like these recommendations to remain active and current as a part of its library of preventive services, it has determined that only a very high level of evidence would change the recommendation. For this reason and to maximize resources, a limited review of the evidence was conducted.

To assist the USPSTF in updating the 1996 recommendation on Screening for PKU, staff at AHRQ performed a literature search and consulted content experts. The databases searched were PubMed, the Cochrane Library, and the Centre for Reviews and Dissemination. The following search terms were used:  "phenylketonuria" and "screening," and the search was limited to:  newborns: birth-1 month, English, Publication Date from 01/01/1995 to 05/12/2006, and "core clinical journals." The search returned 52 titles, which were entered into an Endnote database. Twenty-four studies were excluded at the title stage; 9 studies were excluded at the abstract stage; and 17 were excluded at the full article stage. Exclusion criteria are listed in the Appendix of the Literature Review (see "Availability of Companion Documents" field in this summary). Numbers and reasons for exclusion were: 18 for "study design", 13 for "not PKU", 4 for "not newborn", 4 for "not screening", 4 for "too old", 3 for "no outcomes", 3 for "not English", and 1 for "other" (not published). Two studies met the inclusion criteria.

Two studies met the inclusion criteria.

Expert Consensus

Not applicable

Review

Not stated

Expert Consensus

The U.S. Preventive Services Task Force (USPSTF) systematically reviews the evidence concerning both the benefits and harms of widespread implementation of a preventive service. It then assesses the certainty of the evidence and the magnitude of the benefits and harms. On the basis of this assessment, the USPSTF assigns a letter grade to each preventive service signifying its recommendation about provision of the service (see Table below). An important, but often challenging, step is determining the balance between benefits and harms to estimate "net benefit" (that is, benefits minus harms).

Table 1. U.S. Preventive Services Task Force Recommendation Grid*

*A, B, C, D, and Insufficient represent the letter grades of recommendation or statement of insufficient evidence assigned by the U.S. Preventive Services Task Force after assessing certainty and magnitude of net benefit of the service (see the "Rating Scheme for the Strength of the Recommendations" field.

The overarching question that the Task Force seeks to answer for every preventive service is whether evidence suggests that provision of the service would improve health outcomes if implemented in a general primary care population. For screening topics, this standard could be met by a large randomized, controlled trial (RCT) in a representative asymptomatic population with follow-up of all members of both the group "invited for screening" and the group "not invited for screening."

Direct RCT evidence about screening is often unavailable, so when the Task Force undertakes a full systematic review, it considers indirect evidence. To guide its selection of indirect evidence, the Task Force constructs a "chain of evidence" within an analytic framework. Each arrow in the framework defines a key question, and each key question represents a link in the chain of evidence. Rectangles in the framework represent the intermediate outcomes (rounded corners) or the health outcomes (square corners); ovals represent harms. To form an unbroken chain, evidence must support each link in the chain, thereby connecting the target population (far left side of the framework) to the improved health outcome (far right side of the framework). For each key question, the body of pertinent literature is critically appraised, focusing on the following 6 questions:

1. Do the studies have the appropriate research design to answer the key question(s)?
2. To what extent are the existing studies of high quality? (i.e., what is the internal validity?)
3. To what extent are the results of the studies generalizable to the general U.S. primary care population and situation? (i.e., what is the external validity?)
4. How many studies have been conducted that address the key question(s)? How large are the studies? (i.e., what is the precision of the evidence?)
5. How consistent are the results of the studies?
6. Are there additional factors that assist us in drawing conclusions (e.g., presence or absence of dose–response effects, fit within a biologic model)?

The next step in the Task Force process is to use the evidence from the key questions to assess whether there would be net benefit if the service were implemented. In 2001, the USPSTF published an article that documented its systematic processes of evidence evaluation and recommendation development. At that time, the Task Force's overall assessment of evidence was described as good, fair, or poor. The Task Force realized that this rating seemed to apply only to how well studies were conducted and did not fully capture all of the issues that go into an overall assessment of the evidence about net benefit. To avoid confusion, the USPSTF has changed its terminology. Whereas individual study quality will continue to be characterized as good, fair, or poor, the term certainty will now be used to describe the Task Force's assessment of the overall body of evidence about net benefit of a preventive service and the likelihood that the assessment is correct. Certainty will be determined by considering all 6 questions listed above; the judgment about certainty will be described as high, moderate, or low.

In making its assessment of certainty about net benefit, the evaluation of the evidence from each key question plays a primary role. It is important to note that the Task Force makes recommendations for real-world medical practice in the United States and must determine to what extent the evidence for each key question—even evidence from screening RCTs or treatment RCTs—can be applied to the general primary care population. Frequently, studies are conducted in highly selected populations under special conditions. The Task Force must consider differences between the general primary care population and the populations studied in RCTs and make judgments about the likelihood of observing the same effect in actual practice.

It is also important to note that 1 of the key questions in the analytic framework refers to the potential harms of the preventive service. The Task Force considers the evidence about the benefits and harms of preventive services separately and equally. Data about harms are often obtained from observational studies because harms observed in RCTs may not be representative of those found in usual practice and because some harms are not completely measured and reported in RCTs.

Putting the body of evidence for all key questions together as a chain, the Task Force assesses the certainty of net benefit of a preventive service by asking the 6 major questions listed above. The Task Force would rate a body of convincing evidence about the benefits of a service that, for example, derives from several RCTs of screening in which the estimate of benefits can be generalized to the general primary care population as "high" certainty (see the "Rating Scheme for the Strength of Recommendations" field). The Task Force would rate a body of evidence that was not clearly applicable to general practice or has other defects in quality, research design, or consistency of studies as "moderate" certainty. Certainty is "low" when, for example, there are gaps in the evidence linking parts of the analytic framework, when evidence to determine the harms of treatment is unavailable, or when evidence about the benefits of treatment is insufficient. Table 4 in the methodology document listed below (see "Availability of Companion Documents" field) summarizes the current terminology used by the Task Force to describe the critical assessment of evidence at all 3 levels: individual studies, key questions, and overall certainty of net benefit of the preventive service.

Some clinical preventive services have a strong, well-established evidence base and are a routine part of clinical practice. Because it is unlikely that new evidence will change USPSTF recommendations for such services, the USPSTF reviews the evidence for them in an expedited manner by conducting literature searches that address benefits and harms and consulting experts. The reaffirmation recommendation statement on screening for PKU was developed on the basis of such an expedited literature review.

Sources

1. Sawaya GF et al., Update on the methods of the U.S. Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med. 2007;147:871-875. [5 references].
2. Guirguis-Blake J, et al. Current processes of the U.S. Preventive Services Task Force: refining evidence-based recommendation development. Ann Intern Med. 2007;147:117-122. [2 references]

What the United States Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice

USPSTF Levels of Certainty Regarding Net Benefit

Definition: The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Comparison with Guidelines from Other Groups
External Peer Review
Internal Peer Review

Peer Review. Before the U.S. Preventive Services Task Force makes its final determinations about recommendations on a given preventive service, the Evidence-Based Practice Center and the Agency for Healthcare Research and Quality send a draft evidence review to 4 to 6 external experts and to federal agencies and professional and disease-based health organizations with interests in the topic. They ask the experts to examine the review critically for accuracy and completeness and to respond to a series of specific questions about the document. After assembling these external review comments and documenting the proposed response to key comments, the topic team presents this information to the Task Force in memo form. In this way, the Task Force can consider these external comments before it votes on its recommendations about the service. Draft recommendation statements are then circulated for comment from reviewers representing professional societies, voluntary organizations and Federal agencies. These comments are discussed before the final recommendations are confirmed.

Comparison with Guidelines from Other Groups. Recommendations for screening from the following groups were discussed: the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Medical Genetics.

The U.S. Preventive Services Task Force (USPSTF) grades its recommendations (A, B, C, D, or I) and identifies the Levels of Certainty regarding Net Benefit (High, Moderate, and Low). The definitions of these grades can be found at the end of the "Major Recommendations" field.

Summary of Recommendation and Evidence

The USPSTF recommends screening for phenylketonuria (PKU) in newborns. This is a grade A recommendation.

Clinical Considerations

Patient Population

This recommendation applies to newborns.

Screening Tests

Screening for PKU is mandated in all 50 states, though methods of screening vary. There are three principal methods used for PKU screening in the United States: the Guthrie Bacterial Inhibition Assay (BIA), automated fluorometric assay, and tandem mass spectrometry. Screening tests are most accurate if performed after 24 hours of life but before the infant is 7 days old.

Treatment

It is essential that phenylalanine restrictions be instituted shortly after birth to prevent the neurodevelopmental effects of PKU.

Timing of Screening

Infants who are tested within the first 24 hours after birth should receive a repeat screening test by 2 weeks of age. Premature infants and those with illnesses should be tested at or near 7 days of age, but in all cases before newborn nursery discharge.

Definitions:

What the United States Preventive Services Task Force (USPSTF) Grades Mean and Suggestions for Practice

USPSTF Levels of Certainty Regarding Net Benefit

Definition: The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.

None provided

The type of supporting evidence is not specifically stated for each recommendation.

Benefits of Detection and Early Intervention

There is good evidence that detection by neonatal screening and early treatment of phenylketonuria (PKU) substantially improve neurodevelopmental outcomes for affected persons.

Harms of Detection and Early Treatment

False-positive tests could generate considerable parental anxiety.

• The U.S. Preventive Services Task Force (USPSTF) makes recommendations about preventive care services for patients without recognized signs or symptoms of the target condition.
• Recommendations are based on a systematic review of the evidence of the benefits and harms and an assessment of the net benefit of the service.
• The USPSTF recognizes that clinical or policy decisions involve more considerations than this body of evidence alone. Clinicians and policy-makers should understand the evidence but individualize decision making to the specific patient or situation.

Staying Healthy

Effectiveness
Patient-centeredness

Not applicable: The guideline was not adapted from another source.

1996 (revised 2008 Mar)

United States Preventive Services Task Force - Independent Expert Panel

The U.S. Preventive Services Task Force (USPSTF) is a federally-appointed panel of independent experts. Conclusions of the U.S. Preventive Services Task Force do not necessarily reflect policy of the U.S. Department of Health and Human Services (DHHS) or its agencies.

United States Government

U.S. Preventive Services Task Force

The U.S. Preventive Services Task Force has an explicit policy concerning conflict of interest. All members disclose at each meeting if they have a significant financial, professional/business, or intellectual conflict for each topic being discussed. Task Force members with conflicts may be recused from discussing or voting on recommendations about the topic in question.

This is the current release of the guideline.

This release updates a previously published guideline: U.S. Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Baltimore (MD): Williams & Wilkins; 1996. Chapter 44, Screening for phenylketonuria. p. 495-502. [56 references].

None available

This summary was completed by ECRI on June 30, 1998. The information was verified by the guideline developer on December 1, 1998. This NGC summary was updated by ECRI Institute on March 4, 2008. The updated information was verified by the guideline developer on March 11, 2008.