Newborn screening: New opportunities and new challenges

CLINICAL PRACTICE

AbstractNewborn screening is an old

technique for early detection of

problems and health promotion. In

recent times, genetic breakthroughs

have created the possibility of testing

for many more newborn conditions.

Some states are mandating as many as

20 to 30 tests. This article will review

newborn screening, the state of the

art, and some of the ethical questions

that our technology is raising.

Copyright 2002, Elsevier Science

(USA). All rights reserved.

NewbornScreening: NewOpportunities andNew ChallengesBy Felissa R. Lashley, PhD, RN, ACRN, FACMG, FAAN

Genetic knowledge from the Human Genome Project and the develop-ment of new technologies have led to a new era in newborn screening.Newborn screening is one of the great genetic public health success

stories. Once phenylketonuria (PKU) was found to be associated with a type ofmental retardation that could be prevented if a low phenylalanine (Phe) diet wasinstituted soon after birth, a search began for a method to reliably detect PKUin newborns. Initially, tests performed on urine samples were proposed. Even-tually, Robert Guthrie developed a bacterial growth inhibition assay based onthe use of blood taken from the neonate by heel stick with a few drops placedon filter paper and dried. Testing was based on a bacterial growth inhibitionassay using the dried blood spot. This straightforward, low-cost test became theprototype for screening virtually the entire population of newborns.1 If anabnormal screening test was identified, a low-phenylalanine diet could beinstituted, further diagnostic confirmation could be initiated, and effectivetreatment could be put in place for those whose diagnosis was confirmed. In theearly 1960s, newborn screening for PKU, after some initial opposition to theconcept of government-mandated testing, rapidly became part of state maternal-child health programs and was initiated in Massachusetts in 1962.2

Other disorders were added to the repertoire of newborn screening tests overtime, with inclusion varying by state as discussed later. A relatively stablegroup of conditions comprised the core conditions in newborn screeningprograms in the United States until recently. Scientific advances in geneticknowledge, analytical techniques, and technology made possible by the HumanGenome Project and other research, along with the publicized disparities inaccess to them, have made newborn screening a “hot” topic. Newer technology,such as tandem mass spectrometry (MS/MS) and the expansion of molecularand DNA-based techniques, have identified additional mutations that fit ac-cepted reasons for genetic screening and provided a means to detect them. Thus,the number of disorders that can be detected in the newborn has vastlyincreased.

In the U.S., there is presently no national policy regarding which disordersshould be included in newborn screening programs. Each state mandates whatis screened for within their jurisdiction. There is, therefore, quite a bit ofvariation not only in what disorders are chosen for inclusion in a screeningpanel but also in regard to other aspects surrounding the administration andoperation of these programs. For example, in Ohio, a newborn is screened forhomocystinuria, whereas a newborn in Oregon is not; however, a newborn inOregon is screened for biotinidase deficiency, a disorder that is not part of

From the College of Nursing, Rutgers, TheState University of New Jersey, Newark, NJ.

Address reprint requests to Felissa R. Lashley,RN, PhD, ACRN, FACMG, FAAN, Dean andProfessor, College of Nursing, Rutgers, The StateUniversity of New Jersey, 180 University Avenue,Suite 102, Newark, NJ 07102. E-mail:[email protected]

Copyright 2002, Elsevier Science (USA).All rights reserved.

1527-3369/02/0204-0007$35.00/0doi: 10.1053/nbin.2002.35894 Newborn and Infant Nursing Reviews, Vol 2, No 4 (December), 2002: pp 228–242 228

routine newborn screening in Ohio. Newborns in Massa-chusetts are screened for a multiplicity of conditions; inDelaware, Arkansas, and Oklahoma, they are screened foronly 4 conditions.3,4 Of the approximately 4 million babiesborn in the U.S. every year, some will be screened for thefull panel of available newborn screening tests and somewill not, depending on the state in which they are born.5

This situation has been called the “crazy quilt” status ofnewborn screening in the United States and is a majorpublic health inequity—the determination of the futurehealth of an infant by their place of birth.6 Advocacy byparents attracted popular press attention to this problem.Articles in the popular press and electronic media high-lighted cases of adverse consequences of potentially de-tectable metabolic diseases in newborns that were notdetected because the state in which the parents resided didnot include those conditions in their state screening pro-grams, as well as stories in which an infant was identifiedthrough newborn screening with a rare disorder andtreated.7,8 One example that provoked activism by parentswas that of a 6-month-old South Dakota infant who de-veloped a rotavirus infection with diarrhea and vomiting.He took Pedialyte� (Ross Laboratories, Columbus, OH)and had little else, but he was not dehydrated. The infantwas found dead in his crib the next morning, and suddeninfant death syndrome was thought to be the cause. How-ever, autopsy revealed fatty accumulation in the liver.These changes, plus the history of reduced caloric intake,led to further testing, which revealed that he had medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, asdescribed below.9 A success story was that of a Pennsyl-vania couple whose son was found to have MCAD defi-ciency through newborn screening at 5 days of age. Hereceived necessary preventive education and therapy andno untoward incident has occurred.8

The major reason for newborn screening is to identifyinfants at risk through universal newborn screening pro-grams who are apparently healthy and provide early treat-ment for certain disorders as soon as possible, therebypreventing serious health consequences, especially severemental retardation. Infants with abnormal initial testingresults will usually have second screens and, depending onthe results, further testing to confirm a diagnosis. Tempo-rary treatment may be started in the interim, if believednecessary. Many of the disorders detectable by newbornscreening tests respond well to early treatment, such as bydietary restrictions. For others, treatment may be some-what less successful. In recent years, a body of literaturehas suggested that in some cases, despite early treatment,while severe retardation may be prevented, intelligencequotients (IQs) are lower than those of siblings and laterneurological effects may be seen.10,11 The reasons for thismay vary and may involve extent and duration of dietary

restriction, particular mutant genotype, adherence to ther-apy, and other parameters. Newborn screening must notonly be concerned with screening and testing but also withother components, such as education, recalls and short-term follow-up, diagnosis, referral to specialists, manage-ment, treatment, nursing, social and psychological ser-vices, and assistance in other areas such as schools,genetic counseling, setting standards, quality assurance,and evaluation that it is ideally functioning as a coordi-nated system.

Newborn screening programs typically fall under astate’s public health department, but this is not universal.Typically, states screen for a set of metabolic disordersthat have been mandated for years and that meet a set ofcriteria, as discussed below. States may also routinelyscreen newborns by blood specimen or other assessmentfor conditions of genetic or nongenetic causation, such ascongenital hearing loss, congenital hip dysplasia, humanimmunodeficiency virus (HIV) infection, congenital toxo-plasmosis, and others. There have been a variety of stan-dards and guidelines developed regarding criteria for in-clusion of a disorder within screening programs, withsome specific to universal state newborn screening.12–19

Although some of these references are older, they are stillin standard use and have included some of the followingguidelines. Issues relating to the guidelines are in italics.

● Importance of the disorder as a public health problem. This hastypically included the incidence in order to justify screeningthe entire population, and sometimes, mortality. How shouldthis now be judged; should this be as stated or also includequestions of the seriousness of the condition and the potentialprevention or modification of complications, short- and long-term morbidity, potential impact, and disability amelioration?

● Knowledge of the natural history of the disease. Questionshave been raised regarding screening and treatment of certainrare diseases, such as MCAD, where little, if any, data areavailable on long-term outlook into adulthood. In some cases,there may not be clear evidence that early detection andtreatment significantly impact the long-term outlook.

● Availability of a screening test that meets certain criteria inregard to sensitivity and specificity; one that is rapid, simple,and reproducible; one that can be automated; and one that useseasily available specimens and causes a minimum of discom-fort and thus is acceptable to most of the population to bescreened. For some disorders, not every mutation known cancurrently be screened for in a given genetic disorder due tologistical and cost considerations. States may also vary as tothe techniques used to screen for certain disorders—sometechniques may be more accurate than others.

● Facilities for diagnosis and treatment should be available. Thishas presented new challenges. An increase in the number ofdisorders included in newborn screening programs, definedbroadly, means the identification of more newborns with con-ditions requiring education, counseling, testing recalls/confir-

Newborn Screening 229

mation, further diagnostic procedures, referral to specialists,and treatment. The availability of resources, including quali-fied professionals to provide education, for laboratory proce-dures, for management, for specialty treatment, and for accu-rate genetic counseling is limited. Moreover, the need forfamily-centered community-based coordinated care systemsis increasingly recognized, as well as is the need for continuedcoordinated treatment into adulthood, activities for whichnurses are particularly well-prepared to manage.

● Whether an effective treatment is available or the naturalcourse of the disease can be altered; in other words, that adifference in prognosis can be made by early detection ratherthan later diagnosis when symptoms appear. There is disagree-ment as to what the nature of that difference might be. Forexample, does that include supportive and anticipatory man-agement, successful adaptation, education, the offering of ge-netic counseling, allowing reproductive and life planning, pre-natal diagnosis, and prevention strategies to modify risk andseverity of illness, as well as complications? An example of thelatter is the use of prophylactic treatment with penicillin andenrollment in comprehensive care to reduce the morbidity andmortality from sepsis in children with sickle cell disease.20

● Cost-benefit considerations may also drive what is included ina given program. Considered within cost is not only the initialcost of a screening test but also follow-up diagnostic costs andthe costs of medical and other treatment, medical foods, edu-cation, counseling, nursing care, and lifelong therapy andsupports. Should cost include human suffering? While fundingfor health is not inexhaustible, some argue that screeningshould be done universally for all metabolic conditions thatcan be detected because there is no cost that should be sparedto detect even 1 affected newborn.

The maximum number of metabolic conditions thathave been incorporated into regular legislation for univer-sal mandated newborn population screening in the U.S. is11 as of May, 2002.3 Others may be soon be available asroutine and universal. From time to time, states may adddisorders to pilot screening programs that may be univer-sally applied, applied for specific selected populationsdeemed to be at greatest risk, included on a limited basis,or performed only by request. For example, Californiarecently added the option of additional screening for 25more disorders but still does not include biotinidase defi-ciency or congenital adrenal hyperplasia (CAH) as routine.The Save Babies Through Screening advocacy group(http://www.savebabies.org/release1-07.02.htm) recom-mends screening newborns for 55 diseases; that wouldrequire considerable cost and personnel time, as well asseveral procedures, and might engender parental anxiety.Metabolic disorders that are mandated for newbornscreening in most states include those conditions shown inTable 1. Screening typically includes diseases of metabo-lism, such as PKU; hemoglobinopathies, such as sicklecell disease; and endocrinopathies, such as congenital hy-

pothyroidism. Presently, all states and the District of Co-lumbia (n � 51) on a permanent basis routinely screennewborns for PKU and congenital hypothyroidism. Fiftyof the states also screen for galactosemia, and the majorityof states also screen for sickle cell disease/hemoglobinop-athies and congenital adrenal hyperplasia. Others typicallyinclude maple syrup urine disease, biotinidase deficiency,homocystinuria, cystic fibrosis, and MCAD; and 1 (theDistrict of Columbia) screens for glucose-6-phosphate de-hydrogenase (G-6-PD) deficiency. States also mandatescreening for other conditions, such as congenital hearingloss, which may be genetic or nongenetic, congenitaltoxoplasmosis; and in the case of New York, humanimmunodeficiency virus infection.3,17 Other countries in-clude conditions not currently mandated for inclusion inthe United States’ newborn screening programs and vice-versa.

Changes and proposed adjustments are now being madein screening programs due to new genetic knowledge,which has made detection of a given disorder possible;new technology for detection and analysis; or the avail-ability of new or better treatment options, thus making adisorder fit the usual criteria for newborn screening. Forthis reason, ongoing assessment of which disorders toinclude or add must be an important component of thetotal program. The availability of tandem mass spectrom-etry as an analytic technique allows about 30 differentmetabolic conditions to be screened for in the neonatalperiod using the same blood specimen. The technique doesnot, however, screen presently for every disorder presentlyincluded in screening programs, such as galactosemia,biotinidase deficiency, and others.18

Table 1. State Required Genetic Diseases Included inRoutine Newborn Screening Programs

Disorder No. States

Phenylketonuria 51Congenital hypothyroidism 51Galactosemia 50Sickle cell disease/hemoglobinopathies 44Congenital adrenal hyperplasia 29Maple syrup urine disease 23Biotinidase deficiency 24Homocystinuria 15Medium-chain acyl-CoA dehydrogenase

deficiency8

Cystic fibrosis 4Tyrosinemia 2Glucose-6-phosphate dehydrogenase

deficiency1

Note: n � 51; pilot programs and screening in selected pop-ulations or by request not included.

230 Felissa R. Lashley

A mass spectrometer is a piece of equipment that sep-arates and quantifies ions based on their mass/charge ratiosthat can use routinely obtained dried blood spot speci-mens. Data are transferred to a computer for analysis. Thisprocedure is accomplished in 1 or 2 minutes. Advantagesinclude rapidity of analysis; greater accuracy than conven-tional methods, allowing screening for certain disorders tobe more specific and sensitive; ability to detect disordersformerly difficult to detect; and the ability to screen formultiple diseases in a single run, including amino acid,fatty acid oxidation, and organic acid disorders. Someconcerns about the use of MS/MS have centered aroundcost issues; the need to provide alternate means of testingor instrumentation in case of breakdown; the need forspecial personnel to be trained in this technology; and theissue of unknowns surrounding false-positives and false-negatives because of lack of experience with detection ofcertain very rare disorders. Another issue is that somedisorders can be detected at 1 or 2 days after birth by thismeans, but others are not detectable until the newborn is 5days or older. This time is usually after hospital discharge,meaning that responsibility for additional specimen col-lection from a primary health provider or public healthclinic is needed. Thus, primary care practitioners, includ-ing nurses, are responsible for ascertaining that newbornsreferred to their practices have been screened and resultshave been returned.5,18,19,21 Often, nurses are instrumentalin assuring these initial and follow-up specimens are col-lected. Some of the disorders detectable presently throughtandem mass spectrometry are listed in Table 2. In somestates, there is an option offered to parents to choose to testtheir newborn for additional disorders for an additional feethrough the same channels that administer the mandatedprogram and/or through other facilities, such as private oruniversity laboratories. Internet offerings are making thesetests available directly to the consumer. Eventually, DNA-based technology will be used routinely for newbornscreening, replacing or augmenting current technology.

As briefly mentioned earlier, state regulation of new-born screening is highly variable.22 There is no nationalpolicy that determines which disorders should be screenedfor or that establishes uniform components of newbornscreening programs, such as procedures for the communi-cation of test results, especially in cases where initialspecimens yield a “panic” result requiring immediate no-tification and action. States may vary in which tests theyuse to detect a given condition and in what results orparameters constitute an abnormal test result. One of thedifficulties we had in reviewing data during the discus-sions of the PKU consensus panel was that states maydefine an abnormal screening test result for PKU as �4,10, 12, or 15 mg/dL, for example, depending on the state,or regulations may state “as determined by metabolic

specialists.” Thus, newborn screening statutes in each statemay or may not

● Specifically name the genetic or metabolic disorders that thenewborn is to be tested for. Some screening statutes designatethe disorders covered; others allow the state health departmentor an advisory commission to define these and add additionalones as needed. Some may be pilot programs, be done incertain populations only, or require physician request.

● Specify the time after birth at which the sample must be taken.

Table 2. Additional Disorders That Can Be Screened forUsing Tandem Mass Spectrometry

Fatty acid oxidation defectsCarnitine palmitoyl transferase deficiency type I (CPT-1)Carnitine palmitoyl transferase deficiency type II (CPT-2)Carnitine/acylcarnitine translocase deficiency (CAT)Long-chain hydroxy acyl-CoA dehydrogenase deficiency

(LCHAD)Multiple acyl-CoA dehydrogenase deficiency (GA-II)Short-chain acyl-CoA dehydrogenase deficiency (SCAD)Medium-chain acyl-CoA dehydrogenase deficiency

(MCAD)Trifunctional protein deficiencyVery-long-chain acyl-CoA dehydrogenase deficiency

(VLCAD)Long-chain acyl-CoA dehydrogenase deficiency (LCAD)2,4 dienoyl-CoA reductase deficiency

Organic acidemiasGlutaric acidemia type I (GA-1)Glutaric acidemia type II (GA-2)3-hydroxy-3-methylglutaryl CoA lyase deficiency (HMG)Isobutyryl-CoA dehydrogenase deficiencyIsovaleric acidemia (IVA)Malonic aciduria3-methylcrotonyl-CoA carboxylase deficiency (3-MCC)Methylmalonic acidemia (MMA)Mitochondrial acetoacetyl-CoA thiolase deficiency (Beta-

ketothiolase)Propionic Acidemia (PA)2-methylbutyl-CoA dehydrogenase deficiency

Urea cycle disordersArgininemiaArgininosuccinate lyase deficiency (ASA)CitrullinemiaHyperammonemia, hyperornithinemia, homocitrullinuria

(HHH)Other amino acidemias

5-oxoprolinuriaHomocystinuria (CBS deficiency)PhenylketonuriaMaple syrup urine diseaseNonketotic hyperglycinemiaTyrosinemia type ITyrosinemia type II


Some may specify only “before discharge,” which may not beoptimal for some disorders, particularly in an area wheredischarge may be 24 to 48 hours after birth. Thus, there needsto be specification for later screening, if needed, through pri-mary health care providers.

● Provide for penalties to variously denoted health providers fornot complying with the statutes. These, depending on the state,may include the physician, the hospital administration, thenurse, the midwife, or the person attending the newborn.

● Provide for penalties to parents if testing is neglected.● Specify that informed consent be obtained from the parent or

guardian. This consent process varies as to what is specified forinclusion. Some hospitals hold classes for parents to explainthe screening program, while others verbally explain it, dis-tribute written material, or cover it in a blanket way. Parentsmay not readily understand the language and concepts in thesedocuments, and while medical literacy issues have receivedmore attention and are addressed in many settings, understand-ing of newborn screening can still be limited. Many parentsenter and leave the hospital without ever realizing that theirinfant has been screened unless there is an abnormal finding.19

● Allow the newborn to be exempt from the test if the parent orguardian objects. The most common objection allowed is onreligious grounds. In some states, there must be a conflict withthe religious practices and principles of an established churchof which the parent is a member. Some states require that theobjection be a written one, which is then submitted to theresponsible institution.

● Establish an advisory council or commission on hereditary andmetabolic disorders. The composition of the group may or maynot be prescribed. It varies from all physicians, to a mixture ofhealth professionals, to a combination of professionals andconsumers.

● Specify the length of time that records of test results must bekept.

● Specify requirements on storage of filter paper blood spots andother specimens.

● Specify who is to be notified and of what type of results. Statesdo not necessarily require that parents and/or physicians benotified if screening test results are negative or that parents bedirectly notified by the state if results are positive within acertain time period or even at all. Unfortunately, at times, thiscan result in late notification for diagnostic confirmation.

● Maintain a registry of affected individuals. The intent is to usethis to ensure adequate follow-up and treatment, but the estab-lishment of such a registry is controversial for ethical reasonsand for issues such as insurability.

● Specify who is to pay for the screening tests given. Some statesassume the costs, whereas others allow hospitals and otherinstitutions to charge parents for them. There is variation inwhat third party payers will contribute.

● Specify the procedure to be followed when a first abnormalscreening result is obtained.

● Specify who pays for further diagnostic testing after an abnor-mal screening result.

● Supply treatment if a disorder is detected or assume part or allof treatment-related costs.

● Establish laboratory standards with periodic review and eval-uation as part of quality assurance protocols.

● Specify testing at one central or a few regional laboratories.This helps to avoid erroneous results by instituting a greaterdegree of quality control. A laboratory will then have experi-ence in interpreting apparently positive results.

● Establish voluntary testing for research purposes. This is oneway to perfect tests and techniques, so that they can be laterused on a larger scale, if warranted. This includes pilot pro-grams.

● Mandate educational programs on genetic disorders for physi-cians, nurses, hospital staff, or the public. These may bethrough continuing education or inclusion into basic profes-sional curricula.19

In 2000, a report on newborn screening was issued bythe Task Force on Newborn Screening of the AmericanAcademy of Pediatrics at the request of the Maternal andChild Health Bureau, Health Resources and Services Ad-ministration (HRSA), Department of Health and HumanServices.12 This report did not specify which tests shouldbe included nationally. The designation of tests was left tothe states, although efforts to try to establish a minimumcore set of tests for the nation are underway through theMaternal Child Health Bureau.3 Some of the decisionmaking of states has been based on the racial and ethnicpopulation of those states and the most prevalent geneticdisorders of those ethnic groups, since certain disordersare known to be very prevalent in certain ethnic groupsand rare in others, with cost-effectiveness as a drivingforce. Some have suggested that some disorders do notneed to be universally tested for but can be targeted byethnic group, a practice that in our ethnically mixed soci-ety may be genetically as well as ethically unsound, al-though some states are at least piloting targeted newbornscreening for certain disorders. While the recommenda-tions in this report are too numerous to cover in theirentirety, some of the other major emphases in this reportwere that12

● Newborn screening is changing rapidly and that public healthdepartments may not be keeping up with changes in technol-ogy, genetic discoveries, and increased advocacy efforts, andthat there was a need for federal and state public healthagencies in partnership with health professionals and consum-ers to better define responsibilities.

● Public health agencies need to involve families, health profes-sionals, and the public in the development, operation, andoversight of newborn screening information.

● Effective newborn screening systems require an adequate pub-lic health infrastructure and must be integrated within thehealth care delivery system with children being linked to amedical home to assure appropriate care and treatment formedical, nonmedical, psychosocial, and educational needs ofthe child and family in the local community. The Consensus


Panel on Phenylketonuria emphasized this need for compre-hensive long-term care also.21

● Public health agencies ensure adequate financial mechanisms.● Cost-effectiveness may be defined in various ways.● The cost of screening has not included the needed infrastruc-

ture in most studies and some studies have looked at cost onlyin regard to the screening test but other elements, includingcost of finding and informing families and reporting results,should be accomplished.

● Design and evaluate model systems of care and support frominfancy to adulthood for infants identified with disorders innewborn screening programs.

● They suggested that national criteria need to be developed foradding disorders to state screening panels but did not specifythese or the disorder.

● Identified issues of state-to-state variance in uniformity abouttests and educational information about the process to be surethat prospective parents are aware of the process.

● Stated that parents have the right to be informed about screen-ing and the right to refuse it; have the right to confidentialityand privacy protections for newborn screening results; and beinformed about benefits as well as potential risks of tests andtreatments, use of specimens in the future, storage policies, andhow families will receive test results.

In response to this report, in 2000, the March of Dimesissued a statement which called for nationally mandatednewborn testing for the following diseases: PKU, hypo-thyroidism, galactosemia, sickle cell disease, congenitaladrenal hyperplasia, biotinidase deficiency, maple syrupurine disease, and homocystinuria. In 2001, they addedMCAD to this list.23

The March of Dimes also called for the need for

● Abandoning currently available tests for new tests if the newtest achieves a greater precision or a shorter turnaround time,regardless of the cost differential.

● Putting safeguards in place for timely reporting of test results.● Assuring uniform quality of newborn screening tests nation-

wide, including an over-arching authority to ensure this.● Ensuring that every newborn has the same core of screening

tests by mandate and that those be the best available, even ifthe test is for a rare disease if that diagnosis can make adifference in the child’s health.24

Some states have opted to allow parents to choose tohave supplemental screening tests at outside labs at amoderate extra cost, such as $25. Some of the companiesand universities offering this service advertise on the In-ternet with full instructions for parents. One of the prob-lems identified is not the cost of the $25 for testing but themoney needed to fund the infrastructure for recall andshort-term follow-up, diagnosis, treatment, management,quality assurance, and program evaluation for many moreconditions than originally planned.

Brief Description of Disorders Typically Includedin Newborn Screening Programs

Presently, every state in the U.S. includes phenylketon-uria and congenital hypothyroidism in their newborn

screening programs. These and other disorders commonlyincluded in these programs are briefly described below.Most of these disorders are inherited in an autosomalrecessive manner; that means that the parents are usuallyclinically unaffected heterozygous carriers who have a25% risk of having an affected child with each pregnancy,regardless of sex.

Phenylketonuria/Hyperphenylalaninemia

Hyperphenylalaninemia (HPA) may be due to morethan 1 disorder, the most common of which is PKU.Classical PKU results from a mutation in the gene codingfor phenylalanine hydroxylase (PAH), a large gene.25,26

More than 400 different mutations of this gene may resultin PKU. There is a great deal of interest in examining therelationship between particular genotypes and phenotypesin terms of the best treatment approaches and for predict-ing natural history of PKU, although there is wide clinicalvariability. High levels of phenylalanine (Phe) in theblood, brain, and other tissues occur and can cause dam-age. Treatment of those with blood Phe levels above 10mg/dL should be started as soon as possible, usuallybefore 7 to 10 days of age. If Phe levels of 7 to 10 mg/dLare seen to persist in newborns, most practitioners willbegin medical nutritional therapy. The incidence rangesfrom 1 in 13,500 to 1 in 19,000 newborns and is mostcommon in whites and Native Americans and less com-mon in blacks, Hispanics, and Asians.21 Early detection bynewborn screening has prevented the severe mental retar-dation that was formerly seen. Untreated PKU results alsoin developmental delay, lighter pigmentation than othersin the family, seizures, a certain cross-legged sitting posi-tion, behavioral problems, eczema, and a musty, mouse-like odor.21,26 Clinical variability depends on genetic fac-tors, such as the gene defect, but also on age atachievement of metabolic control and degree of metaboliccontrol, as well as other environmental and life-style fac-tors. Treatment is with a phenylalanine-restricted diet afterexcluding tetrahydrobiopterin deficiency. Metabolic con-trol is achieved with the use of medical foods and proteins,low-protein products, and small amounts of natural pro-tein. Blood Phe levels are monitored, as is nutritionalstatus and intake.

There is no consensus about optimal levels of bloodPhe to be maintained, and opinions vary. In the U.S., mostclinics recommend between 2 and 6 mg/dL. While for-merly this was relaxed after 12 years of age to 10 mg/dL,


the degree of ongoing control to minimize any cognitive orbehavioral deficits is not known. It is now clear thatdietary treatment must be lifelong with re-evaluation in thepreconceptual period, counseling before conception, andcareful monitoring in pregnancy to prevent consequencesto the fetus exposed to elevated Phe levels in utero ormaternal phenylketonuria.21 The U.S. Maternal Phenylke-tonuria Collaborative Study recommends maintaining Phelevels in the mother-to-be at 2 to 6 mg/dL, while Britishand German standards recommend 1 to 4 mg/dL. Effectsof Phe exposure in utero are teratogenic and can includemicrocephaly, mental retardation, congenital heart disease,and other birth defects.27 Adherence to treatment, as inother metabolic disorders requiring special diets, is diffi-cult. Other studies have shown that even with control,there can be effects on white matter and on higher cogni-tive skills, memory, executive function, and other neuro-psychological impairments in adulthood.10,21,28 Supportgroups include the National Coalition for PKU & AlliedDisorders, http://www.pku-allieddisorders.org, and theChildren’s PKU Network, http://www.pkunetwork.org.

Congenital Hypothyroidism

Congenital hypothyroidism (CH) is included in theneonatal screening programs of every state. CH has anincidence of 1 in 3,600 to 1 in 5,000 live births and thus isthe most common known preventable cause of mentalretardation. CH may be transient or nontransient and fromgenetic causes with a variety of transmission mechanismsor nongenetic causes. Nontransient causes include defectsin thyroidal or extrathyroidal function, and hypothyroid-ism can also be part of other syndromes. Other causesinclude congenital deficiency of the thyroid tissue, impair-ment of activity in 1 of the enzymes involved in thyroidhormone biosynthesis, deficiency of thyroid stimulatinghormone (TSH) secretion, tissue resistance or impairedresponse to TSH secretion, deficiency of thyrotropin re-leasing hormone (TRH), or impaired pituitary response toTRH. Treatment is with thyroxine, and current trendsfavor starting treatment as soon as possible, often with aninitial higher dose.29 Even though neonatal detection andtreatment have virtually eliminated mental retardation,long-term studies indicate that IQs may be reduced, withsubtle impairments occurring in language, visual spatialabilities, neuromotor skills, attention, memory, hearing,and auditory discrimination that are noted in adolescence.These impairments may be related to cause of the disorder,severity, adequacy and timing of treatment, as well ascompliance. They have implications for the long-termfollow-up and treatment plans.11,30,31 Infants with CH havebeen found to have an excess of certain other anomalies,especially of the heart, eyes, and nervous system.32

Galactosemia

Lactose (milk sugar) is composed of galactose andglucose. Galactose is metabolized to glucose by certainenzymes. Classic galactosemia is due to deficiency of theenzyme galactose-1-phosphate uridyltransferase. Variousmutations in the gene encoding for this enzyme may resultin galactosemia, but a few are common, especially inspecific populations, while the rest are rare.33–35 Galac-tosemia may also result from deficiency of galactose epi-merase or galactokinase deficiency. The infant usuallyappears normal before milk feeding begins. Once it does,galactose and other metabolites appear in the blood andurine. In classic galactosemia, if dietary restriction is notbegun, affected infants can present in the first few weeksof life with a life-threatening illness that may includehypotonia, lethargy, vomiting, and diarrhea, as well asmetabolic acidosis, liver dysfunction, and bleeding ten-dencies. Escherichia coli sepsis may occur. A major fea-ture may be cataracts. If untreated, mental retardation,speech abnormalities, cirrhosis, and failure to thrive maybe seen.33,35,36 A benefit of detection by newborn screen-ing is the limitation of early morbidity and mortality, butit is questionable whether long-term complications aresignificantly affected. Despite early detection, diagnosis,and therapeutic intervention, late effects frequently occurin persons with classical galactosemia. These commonlyinclude delayed growth, which eventually tends to reachnormal limits in adulthood, progressive neurologic com-plications, such as ataxia and brain imaging abnormalities;and ovarian failure manifested as delayed puberty andprimary or secondary amenorrhea. Long-term behavioralproblems, neurological impairment, visual spatial dys-function, low IQ, delayed speech, and short attention spanhave been reported despite early detection and treat-ment.33,37 It is important to exclude galactose from thediets of infants who are found to be positive on newbornscreening while awaiting the results of further diagnosticevaluations. This includes both breast milk and cow’s milkformulas. Treatment after diagnosis is the dietary exclu-sion of milk and milk products; however, Acosta andGross note that galactose is also present in most freshfruits and vegetables,38 but others do not believe that inthose forms it affects accumulation. It is present in somemedications.36 The need for dietary restriction is generallyconsidered lifelong. The incidence overall is considered tobe 1 in 60,000 to 1 in 250,000.34,39 While galactosemia isincluded in the newborn screening programs of all statesexcept 1, it has been questioned whether selective screen-ing would be an alternate approach to universal screening,based on information that there were no differences inoutcome based on whether diagnosis was made because ofneonatal screening program or clinical suspicion.37 Sup-


port groups for galactosemia include American LiverFoundation (http://www.liverfoundation.org) and Parents ofGalactosemic Children, Inc (http://www.galactosemia.org).

Sickle Cell Disease and Other Hemoglobinopathies

In addition to sickle cell (SC) disease, most states alsoscreen for Hemoglobin (Hb) SC disease, the thalassemias,sickle-thalassemia, and other hemoglobinopathies, such asHb E. There are about 750 structural hemoglobin variantsknown, most of which are not clinically significant. Sicklecell anemia (HbSS) is the most prevalent of the geneticconditions included in universal newborn screening pro-grams. It may be found overall in non-African Americaninfants from 1 in 40,000 to 1 in 60,000 newborns but in 1in 375 African American infant live births in the U.S. It isalso most commonly found in persons of African, Medi-terranean, Caribbean, South and Central American, andMiddle Eastern or East Indian ancestry.20,40,41 Some statesconduct screening in high-risk ethnic groups, while othersdo not screen for sickle cell disease at all based on theirassumptions about the ethnic mix in their states. Thehomozygous condition, HbSS, sickle cell anemia, can leadto sickling of the red blood cells, particularly under con-ditions of low oxygenation or reduced or slow blood flow.Sickle cell anemia usually becomes evident in the first orsecond year of life. Signs and symptoms include failure tothrive, repeated infections in infancy, pallor, and hemo-lytic anemia. There may be growth retardation, dactylitis,and splenomegaly, with acute exacerbations known ascrises. The sickle cell crisis is very painful. Chest syn-drome is another cause of morbidity and mortality, as isabdominal crisis resembling peritonitis. Neurologic crisesmay also occur, reflecting cerebral infarction or hemor-rhage. Chronic organ damage occurs from the repetition ofvaso-occlusive episodes. Renal and hepatic involvementare frequent, and avascular necrosis of the head of thefemur or humerus may occur. Leg ulcerations may bechronic, and priapism is a painful penile manifestation inmales. One benefit of newborn screening is to be able toinstitute preventive health care measures, such as prompttreatment of infections, prophylactic penicillin if needed,and immunization against Haemophilus pneumoniae, me-ningococcal, and pneumococcal infections.20,40,41 A num-ber of antisickling agents have been used in treatment,including hydroxyurea.41 Comprehensive sickle cell cen-ters offer expert care. In addition to homozygotes, personswho have sickle cell trait are also detected by newbornscreening, and it is important that education accompanycounseling so that families understand the differences,which are considerable, since there is little, if any, clinicaleffects from sickle cell trait under normal conditions.20

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is the term applied to agroup of disorders with an enzyme defect in adrenal cor-ticosteroid biosynthesis. The most common form (about90% to 95%) results from 21-hydroxylase (CYP-21) de-ficiency, resulting in decreased cortisol production, in-creased adrenocorticotropic hormone (ACTH) secretion,and adrenal cortex hyperplasia, as well as androgen hy-persecretion. In about 75% of cases, there is a decreasedability to synthesize aldosterone, leading to a salt wastingcrisis early in life. The incidence ranges from 1 in 10,000to 1 in 20,000 live births29 and is as common as 1 in 300newborns in Yupik Eskimos of Alaska.42,43 About 5% ofcases result from 11-beta-hydroxylase (CYP11B1) defi-ciency, which results in accumulation of 11-deoxycortisol,a mineralocorticoid. This condition results in hyperten-sion. Forms include the classic or severe form with orwithout salt loss and the mild or nonclassic forms.43 Oneof the classic neonatal presentations includes salt wasting,hyperkalemia, and hypoglycemia, and females may alsoshow virilization. It is important to achieve rapid diagnosisto prevent adrenal crisis, which may occur about the 7thday of life. It is generally considered important to proceedwith rapid, correct gender assignment in virilized fe-males,29 although not all agree.20 Later effects in womenmay include polycystic ovary syndrome and infertility.Treatment is aimed at reducing excessive corticotropinsand replacing both glucocorticoids and mineral corti-coids.43 Support groups include the Congenital AdrenalHyperplasia Support Association, 801 Country Rd #3,Wrenshall, MN 55797, and The Magic Foundation, 1327N Harlem Ave, Oak Park, IL 60302, http://www.magic-foundation.org.

Biotinidase Deficiency

Biotinidase deficiency is also known as late onset orjuvenile multiple carboxylase deficiency and results in aninability to recycle endogenous biotin and to release di-etary protein-bound biotin. This can result in the accumu-lation of lactate. Biotinidase deficiency may be profoundor partial. More than 20 mutations have been identified inthe mutated gene.44 The worldwide incidence ranges from1 in 60,000 to 1 in 137,000.29,44 Symptoms may beginanywhere from 1 week to 2 years of age but typicallybegin at about 3 to 5 months; however, children presentingat 10 years of age or later have been reported.44 Clinicalpresentation may vary and can include myoclonic seizures,hypotonia, ketoacidosis, and organic aciduria, as well asfeeding difficulties, fungal infections, vomiting, diarrhea,and coma. Other signs/symptoms can include skin rash,partial or complete alopecia, ataxia, developmental delay,


breathing problems, visual abnormalities, conjunctivitis,and hearing loss, which may be more common than orig-inally believed.44 Treatment is with free biotin in pharma-cological doses, usually ranging between 5 and 20 mg perday and less for those with partial deficiency. Supportgroups include the Biotinidase Family Support Group,http://www.geocities.com/biotinidasedeficiency/.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is a metabolicdisorder that in its classic form, consists of a defect in thebranched-chain alpha-ketoacid dehydrogenase complexthat results in elevated blood levels of 3 branched-chainketoacids—leucine, isoleucine, and valine—as well ascorresponding branched-chain alpha-ketoacids. This mul-tienzyme complex has several enzymes and loci contrib-uting to it.26,45,46 In addition to the classic forms there arevariant forms, all of which have deficient decarboxylationof the 3 branched-chain ketoacids to varying degrees. Thevariant forms may be referred to by clinical phenotype asclassic, intermediate, intermittent, thiamine-responsive,and dihydrolipoyl dehydrogenase deficiency. They mayalso be classified molecularly by affected gene loci asMSUD types Ia, Ib, II, and III. There are multiple genemutations known at each locus.46 Classic MSUD is rela-tively rare, with an incidence of about 1 in 100,000 new-borns overall, except in the Mennonite populations ofLancaster and Lebanon counties, Pennsylvania, where theincidence is about 1 in 176. In the classic form, enzymeactivity may be 0% to 2% of normal.26,46,47 Early symp-toms may include poor feeding, lethargy, hypotonia, in-creased muscle tone, ketoacidosis, and seizures, usuallyseen in the first 10 days of life. A characteristic sweetmaple syrup odor may be noticed in the urine, sweat, orcerumen. If untreated, neurological problems, mental re-tardation, and physical delays may occur.26,47 Some typesare thiamine-responsive, and thiamine supplementationmay be given to ascertain response. Prompt detection,diagnosis, and therapy are needed because only a fewinfants who receive treatment after 14 days of age are saidto achieve normal intellect. The earlier treatment begins,the better the potential outcome. Ideally, this should bebefore the 10th day of life.26,45,46

Diet therapy, first initiated in 1959, is based on abranched-chain amino acid (BCAA)-free formula, withaddition of protein-based formulas in infancy. These needto be individually adjusted as the child grows. Monitoringof plasma branched-chain amino acids may be done ininfancy, eventually shifting to urinary measurements ofbranched-chain ketoacids, if needed. The need for medicaldiet treatment is lifelong. Nonadherence to the diet orexposure to stress, such as infection, fever, illness, or

surgery can lead to metabolic decompensation that can befatal. Thus, special management is needed in connectionwith elective surgery. Despite diet treatment, it has beenreported that approximately one third of affected personsachieved IQ scores greater than 90, with one third beingbetween 70 and 90. Performance scores were lower thanverbal scores.46 A support group, the Maple Syrup UrineDisease Family Support Group, is available at http://www.msud-support.org.

Homocystinuria

The major cause of homocystinuria is cystathioninebeta-synthetase deficiency, either partial or total. This re-sults in increased methionine, increased homocysteine,increased mixed disulfide, and decreased cysteine.33,45 Ifuntreated, signs and symptoms can include developmentaldelay; mental retardation; dislocation of the lens of the eye(ectopia lentis); seizures; skeletal abnormalities, such as aMarfanoid habitus, pectus excavatum, osteoporosis, arach-nodactyly, and scoliosis; psychiatric disturbances; andblood clotting and untoward thromboembolic events.26,48

Cystathionine beta-synthetase is a vitamin B6-responsiveenzyme, and therefore some individuals (about 50%) withthis disorder are responsive to pharmacological doses ofpyridoxine (vitamin B6) and folic acid.45 Those who arepartially or nonresponsive to pyridoxine are put on amethionine-restricted diet based on a methionine-freeproduct or formula. Supplementation with cysteine is nec-essary for adequate growth and development, and betainemay also be used as a dietary supplement, if needed, sinceit stimulates the remethylation of homocysteine, reducingits levels. The overall incidence is about 1 in 150,000 to 1in 200,000 and is more prevalent in Ireland. It is rare inJapan (1 in 900,000).49,50 A support group is the NationalCoalition for PKU & Allied Disorders, http://www.pku-allieddisorders.org.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency

While MCAD deficiency is rare, the first crisis, oftenmisdiagnosed as sudden infant death syndrome, is fatal inabout 25% of cases.51,52 The crisis is manifested when aninfant goes for a long time without eating, usually due toillness. The catabolic stress can result in hypoketotic hy-poglycemia and hepatic encephalopathy. It may be mis-taken for Reye syndrome. While symptoms may be seen inthe neonatal period, episodes in the undiagnosed are mostfrequently seen between 3 months to 6 years of age andcan result in neurological damage or death. Some affectedindividuals appear to be asymptomatic throughout theirlife, but long-term effects are not yet fully known. MCADdeficiency is a disorder of mitochondrial fatty acid oxida-


tion affecting cellular energy and is especially common inthose of northern European origin.53 A single mutation(A985G) accounts for more than 90% of the mutant allelesfound in those who present clinically with MCAD defi-ciency.54 Maintaining carbohydrate intake can prevent ep-isodes. MCAD deficiency detection, as part of newbornscreening protocols, became possible with the advent ofMS/MS technology. Several states have added it to theirmandated screening protocols, while others are piloting itsinclusion. The March of Dimes has added it as an additionto their recommended core of disorders to be included ina national newborn screening protocol,23 and lay individ-uals and groups, such as Save Babies Through Screening,have lobbied for its inclusion. Some states have not insti-tuted screening because of perceived concerns about theuncertainty of natural history, clinical effectiveness, andcost.53,54

Cystic Fibrosis

As of May, 2002, only 4 states routinely screenednewborns for cystic fibrosis (CF), although it is included inother pilot programs.3 CF is caused by mutations in thegene that encodes the cystic fibrosis transmembrane con-ductance regulator (CFTR) protein, one of a family ofmembrane proteins, and is considered a membrane trans-port disorder. The most common mutation is F508, whichaccounts for about 70% of mutations in European Cauca-sian populations, but there are more than 800 mutationsknown.55 The incidence varies according to population,ranging from 1 in 1,800 in some Caucasian populations to1 in 323,000 in some Japanese populations. An overallincidence in Caucasians is typically given at 1 in 3,000.56

The constellation of clinical features includes chronic si-nopulmonary diseases, including colonization/persistentinfection with certain microbial pathogens, such asPseudomonas aeruginosa and Burkholderia cepacia;chronic productive cough with persistent chest problems,such as bronchiectasis; airway obstruction and nasal pol-yps; gastrointestinal and nutritional abnormalities that mayinclude pancreatic insufficiency and recurrent pancreatitis,biliary cirrhosis, rectal prolapse or distal intestinal obstruc-tion syndrome, chronic hepatic disease, and nutritionalproblems, including protein-calorie malnutrition, edema,failure to thrive, and hypoproteinemia; salt loss syn-dromes, including chronic metabolic alkalosis; and maleurogenital abnormalities resulting in obstructive azoosper-mia. Newborns may manifest meconium ileus. Growthreduction can be evident by 2 months of age. Particularlyfor pancreatic disease and sweat abnormalities, there aregenotype/phenotype correlations. These are less strong forthe pulmonary manifestations.55 Two states (Colorado andWisconsin) have been screening for CF in their newborn

screening programs since the mid-1980s. In 1997, theNational Institutes of Health issued a consensus develop-ment statement concluding that “Offering cystic fibrosisgenetic testing to newborn infants is not recommended.”57

The Centers for Disease Control and Prevention,58 also in1997, concluded that “. . . before recommending universalCF screening for newborns as a routine public healthintervention, policymakers will need more compellingdata about its effectiveness” (p 21). That same year, astudy was published, finding nutritional benefits to chil-dren identified as newborns and to whom adequate treat-ment was offered.59 However, flaws in methodology, suchas selection bias, have been suggested, with the conclusionby others that there was no evidence of benefit.60 Sincethat time, the original study authors have reported addi-tional subjects and responded to the methodological ques-tions. They report both statistically and clinically signifi-cant findings, especially in regard to significantly betterlong-term growth in those patients detected through neo-natal screening programs.61 Other studies indicate thatpulmonary benefits could accrue from early diagnosis andtreatment, including less morbidity.55 Because CF couldbe included in newborn screening programs using a2-tiered testing method of immunoreactive trypsinogen([IRT] followed by DNA testing for the most commonmutation, F508, and perhaps other mutations), little addi-tional cost would be added, and it is estimated that thismethod followed by diagnosis via sweat electrolyte testingwould detect more than 97% of affected infants.29 Someresearchers believe that now the burden of proof is onthose who believe CF should not be included in screeningprograms to show why that is the case.61 A support groupis the Cystic Fibrosis Foundation, http://www.cff.org.

Tyrosinemia

Tyrosinemia type I, also known as hepatorenal ty-rosinemia, is caused by fumarylacetoacetate hydrolase(FAH) deficiency, resulting in hypertyrosinemia.26 Othercauses of hypertyrosinemia include transient tyrosinemiaof the newborn, oculocutaneous tyrosinemia due to ty-rosine aminotransferase deficiency (type II), and primarydysfunction of 4-hydroxyphenylpyruvate dioxygenase(4HPPD).62 Transient tyrosinemia of the newborn im-proves spontaneously, but it can be hastened by the ad-ministration of vitamin C intake and dietary protein re-striction. It may not be entirely benign, however, althoughinfants with it are usually asymptomatic. When the infantis not detected by newborn screening, tyrosinemia type Ican manifest in a variety of ways. Symptoms can begin inthe first month of life and, if not treated, can progress,leading to death. They may include acute failure to thrive;vomiting; diarrhea; acute hepatic crisis, including ascites,


jaundice, and hepatomegaly; and renal tubular dysfunc-tion. A “boiled cabbage” odor may be noticed. In thechronic form, presentation may be between 6 months and3 years of age and include renal tubule dysfunction, hy-pophosphatemic rickets, peripheral neuropathy with pain-ful neurologic crises, and hypotonia that can result inrapidly developing respiratory insufficiency. Coagulopa-thy may be seen. Death can be caused by cirrhosis orhepatoma in childhood.29,62 Traditional management waswith dietary restriction of phenylalanine and tyrosine, butthis approach did not prevent eventual progression. Livertransplantation was also used to prevent hepatoma fromdeveloping and in cases of hepatic encephalopathy.62 Cur-rent therapy now relies on 2-(2-nitro-4-trifuoro-methyl-benzoyl)-1,3-cyclohexanedione, better known as NTBC.NTBC is a drug that inhibits 4HPPD. Long-term efficacyand adverse effects are not yet known, including whetheror not hepatic transplantation may still ultimately be nec-essary.26,62 The incidence is considered to be 1 in 100,000to 1 in 120,000 worldwide and is more frequent in parts ofQuebec, Canada, where it is estimated to be 1 in 16,786live births, and in Scandinavia.62 A support group is Chil-dren’s Liver Alliance, http://www.livertx.org.

Glucose-6-Phosphate Dehydrogenase Deficiency

The District of Columbia screens newborns for glu-cose-6-phosphate dehydrogenase deficiency. G-6-PD de-ficiency is the most common enzyme disorder known,estimated to affect 400 million worldwide. At least 400different variants are known. Most persons with this areasymptomatic, but hemolysis can occur in concomitancewith taking certain drugs, such as dapsone or primaquine,infection, eating fava beans, diabetic ketoacidosis, andhypoglycemia. In some cases, neonatal hemolysis andjaundice may occur. G-6-PD deficiency is most commonin blacks and certain Mediterranean and Asian populationsand rare in northern European populations. It is inheritedin a X-linked recessive manner, thus males are morefrequently affected.63,64

Congenital Toxoplasmosis

Toxoplasmosis results from infection with the parasite,Toxoplasma gondii. When the mother is infected duringpregnancy, the fetus may be infected via transplacentaltransmission. This occurs in 30% to 40% of women whowere initially infected in pregnancy. Transmission alsooccurs in women with chronic infection who are immu-nosuppressed. Many infants infected in utero are asymp-tomatic at birth, others are stillborn, and others exhibitfindings that tend to be predominately generalized or pre-dominately neurologic in nature. Symptoms may include

fever, hydrocephalis, hepatosplenomegaly, jaundice, sei-zures, anemia, and intracranial calcifications, with occa-sional other untoward symptoms. Infants may also sufferfrom prematurity, or growth retardation. Early treatment isessential, particularly to prevent chorioretinitis and deaf-ness and mental retardation, and if successful may de-crease severity or prevent sequelae. Treatment is usuallyfor a year or longer.65,66 Congenital toxoplasmosis is mostcommon in mothers born outside the U.S., especially insoutheast Asia.67

Congenital Hearing Screening

Moderate to profound bilateral congenital hearing lossoccurs in approximately 1 to 3 per 1,000 newborns in theUnited States. It is associated with delays in developmentof language, learning, and speech that can have lifelongconsequences.68–70 Reliance on recognition by parents orhealth care providers or relying on family history has onlyidentified, within the first year of life, a proportion of thoseaffected.68 Thus, it was proposed that screening for hear-ing loss, including unilateral and milder loss, become partof universal newborn screening. A number of states havealready included this in their program, but some have notyet done so. A much-awaited report from the U.S. Pre-ventive Services Task Force on Newborn Hearing Screen-ing70 concluded, “the evidence is insufficient to recom-mend for or against routine screening of newborns forhearing loss during the postpartum hospitalization” (p1995). Part of their rationale was based on the absence ofprospective controlled studies to demonstrate “whetherearlier treatment resulting from screening leads to clini-cally important improvement in speech or language skillsat age three years or older . . .” (p 1996) and stated thatthey could not determine whether potential benefits out-weigh the potential harm of false-positive tests. Othergroups have supported inclusion in newborn screeningprograms. The Maternal and Child Health Bureau hasfinancially supported states in implementing such pro-grams, and more than 30 states have acted to incorporatesuch screening. Congenital deafness may arise from avariety of causes, including in utero infection with cyto-megalovirus, and from a variety of genetic causes withvarying modes of transmission. Eventually, methods ofscreening will include reliable DNA-based testing forcommon genetic forms of deafness, such as connexin 26and mitochondrial deafness that is syndromic or nonsyn-dromic, and others, as at least 50% of profound hearingloss is attributable to 1 or more gene mutations.71,72 Forexample, sensorineural hearing loss occurs in about 75%of children with profound biotinidase deficiency.73 It isimportant that all newborns with congenital hearing lossbe evaluated for etiology and receive an accurate genetic


evaluation and counseling. This will not only benefit thefamily but may, depending on the etiology, indicate theinvolvement of other organs and systems requiring atten-tion and treatment.

Other Fatty Acid Oxidation Defects, OrganicAcidemias, Aminoacidemias, and Other MetabolicDefects

With the advent of MS/MS technology, a large numberof these disorders, shown in Table 2, can be detected usinga single sample. In several states, one or more of these arebeing included in pilot programs within state newbornscreening. In the New England Newborn Screening Pro-gram, there are 20 additional disorders for which testing isbeing piloted.74 Most of these disorders are individuallyrare, but when looked at collectively, they are said to havean incidence of 1 in 4,000 to 1 in 5,000.

Other Disorders Suggested for Inclusion in NewbornScreening Programs

A variety of other genetic and nongenetic disordershave been suggested for potential inclusion in newbornscreening programs. Some of these include diabetes mel-litus type 1, hyperlipidemia, familial hypercholesterol-emia, neuroblastoma, congenital cytomegalovirus disease,fragile X and other chromosome disorders, alpha-1-anti-trypsin deficiency, Duchenne muscular dystrophy, hemo-chromatosis, BRCA1 and other gene mutations predispos-ing to cancer, Tay Sachs disease, tuberous sclerosis, andHuntington disease. Arguments against inclusion of someof these have to do with 1 or more of the following: therarity of the disorder so that cost-effectiveness may becompromised; the cost of the procedure, for example, inconnection with chromosome analysis; the lack of estab-lished ranges of normal; lack of agreement as to what thepossession of a given variation or disorder means relativeto any disease process or harmful event; whether or not adisorder to which a genetic predisposition is identified willeventually become manifested, for example, in BRCA1mutations, not all with the mutation eventually developcancer; penetrance and variable expression of disorders;disagreement on the need for early or any therapeuticintervention; lack of treatment options available; in thecase of no available treatment options, the possibility ofpsychological distress for a lifetime for presymptomaticdisorders, such as Huntington disease, as well as discrim-ination as to education, jobs, and insurance; if screeningfor 1 type of chromosome disorder, such as fragile X, isdone and another finding is identified, whether to revealthe incidental finding; interference with the person’s rightnot to know (in this case, the child might not want such

information, but parents may already have obtained it);and the inability to alter or affect the natural history of thedisease.19 An important issue is whether early detectionimpacts on the disorder. For example, large studies ininfants who were being screened for neuroblastoma con-cluded that screening did not decrease associated mortalityor advanced-stage disease.

Ethical and Social Issues

Genetic testing and screening programs in generalevoke a number of ethical issues and concerns.75

Some apply more specifically to newborn screening. Theseare only considered briefly here, and the interested readermay look to references 19 and 76 and the paper by JohnTwomey in this issue for more discussion. A major issuehas to do with informed consent regarding newbornscreening and if such consents are worded in such a wayas to be understood, including items regarding ownership,storage, and disposition of samples, and the conditionsunder which parents have the right to refuse screening.75

The advocacy calls for active parental/consumer involve-ment are considered by many to be a potential 2-edgedsword. Should parental refusal be honored overall; shouldit be honored in regard to certain, selected tests; or is itunjustified? Should parents have the right to deny potentialbenefit of treatment to a child to prevent untoward out-comes if that child has a condition such as PKU or con-genital hypothyroidism when the child cannot speak forherself/himself? Another issue has to do with storage andownership of samples. Typically, the dried blood filterpaper specimens from newborn screening are stored, oftenfor confirmatory or additional testing or for future diag-nosis in case of early infant death, but often these are alsoused for research to determine prevalence of a disorder ina population, test a new technique for diagnosis, or forsome other reason. What responsibilities are there if thesesamples are tested later and found to be positive for aparticular disorder or if a future treatment becomes avail-able? Could these samples be used for forensic or otherlegal identification reasons, and do these uses violate in-dividuals’ rights to privacy? Should identifiers be discon-nected from samples after use? Should screening be con-ducted for disorders where no medical treatment iscurrently available and the major advantage would be withanticipatory management and reproductive planning, per-haps for the parents and not the actual affected person?Should we screen for every disorder we can screen for?What if we do not know the meaning or consequence ofcertain variations or mutated genes? Are cost containmentconcerns legitimate reasons for not including disorders inuniversal newborn screening? Can there be a price on such


knowledge, even given that monetary resources may befinite? If parents choose to pay extra for such testing andif a child is found to be affected, how will the necessarymanagement and infrastructure costs be managed in an eraof cost containment? What are the “set” of services thatmust be provided—do they include services that addressany difficulties in school, families, and emotional andbehavioral disorders? Will shifting cost burdens to parentscreate access issues based on socioeconomic issues? Istargeting newborn screening based on ethnic group ethicalor discriminatory, and is it genetically sound, given thatpeople may have considerable genetic diversity? Howshould issues of incidental findings, including discovery ofcarrier status rather than disease status, be handled? Whatprovisions are in place for other ethical issues, such as theuncovering of misattributed parenthood? How are issuesof confidentiality, right to privacy, and access to informa-tion handled? Can genetic discrimination result from find-ings, and can there be jeopardy based on genetic pre-existing or predisposing conditions? What are theobligations of the state to provide full services for new-borns identified with genetic conditions, and should thosevary from state to state or should there be some nationalstandards? Should core genetic newborn screening testsand standards be nationally promulgated? What proce-dures are in place for notification of blood relatives whomay need to know results because they are relevant to theirown well-being, and how do such procedures fit withprivacy and confidentiality? Can early identification ofcertain variations or disorders that may not be associatedwith a clear treatment benefit interfere with such things asinfant-parent bonding or result in psychological conse-quences, such as guilt, reduced self-worth, or altered self-concept? These are questions that are relevant now and forwhich society has no easy answers.

The Future

What does the future hold in terms of newbornscreening? It is virtually certain that there will be

an increase in the number of disorders that can be detectedthrough newborn screening; that more of these will meetcriteria for inclusion in newborn screening programs; thatwe will know more about genotype/phenotype correla-tions; that more emerging technological innovations andtherapeutic approaches in medication and medical foods/diet will be available to identify and treat an expanding listof disorders; and that there will be increased consumeradvocacy to make broader universal detection available ina timely and responsible manner. This expansion demandsthat nurses, among other health care professionals, beaware of the trends and issues surrounding newborn

screening; be informed so that they can educate and inter-pret information correctly for their clients in a culturallysensitive and educationally appropriate manner; under-stand the need for prompt case finding, recall, and fol-low-up after a positive first screening test; understand theemotional and psychological impact of results, the poten-tial impact on insurability, and so on; understand the needfor a coordinated comprehensive plan of care and man-agement; be aware of, and understand, ethical, legal, andsocial issues.

What has seemed like an established area of practicehas emerged to the forefront of current health care issuesfor some of the reasons described in this article. Effectivenewborn screening requires that there be a coordinated,comprehensive multidisciplinary integrated system for de-livery of care and that complex systems function effec-tively. This includes specimen collection; transport, track-ing, and laboratory analysis; data collection and analysis;locating and contacting families of infants with abnormalresults for further evaluation and testing; and that there isprovision for follow-up services, including diagnosis,treatment, and long-term management that includes edu-cation; psychological, nursing, and social services; geneticcounseling; medical nutrition therapy; and medical foods.To date, parents have been minimally aware that theirnewborn has been screened for genetic disorders. Asawareness of newborn screening opportunities and issuesgrows, public and professional voices will influence hownewborn screening occurs in the U.S. in the future.

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Continuing Education Questions

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Article: Newborn Screening: New Opportunities& Challenges (1.5 credit)

1. Extensive newborn screening at birth was madepossible by the development of the GuthrieA. bacterial growth inhibition assayB. counterimmunoelectrophoresis testC. tandem mass spectrometry

2. The first state to initiate government-mandatedtesting of all newborns wasA. ConnecticutB. MassachusettsC. Pennsylvania

3. The maximum number of metabolic diseases in-corporated into government-mandated newbornscreening programs in the United States isA. 7B. 11C. 15

4. All fifty states and the District of Columbia re-quire universal newborn screening for congenitalA. cystic fibrosisB. galactosemiaC. hypothyroidism

5. The only state with a mandated screening pro-gram for Human immunodeficiency virus (HIV)infection isA. CaliforniaB. FloridaC. New York

6. The recurrence risk for disorders that use an au-tosomal recessive mode of inheritance isA. 25%B. 50%C. 75%

7. The incidence of phenylketonuria (PKU) is mostcommon inA. African-AmericansB. HispanicsC. Native Americans

8. The recommended level for maintaining bloodphenylalanine in the United States isA. 2-6 mg/dLB. 7-11 mg/dLC. 12-16 mg/dL

9. The most common cause of preventable mentalretardation is congenitalA. adrenal hyperplasiaB. hypothyroidismC. maple syrup urine disease

10. Infants with congenital hypothyroidism are at in-creased risk for anomalies of theA. eyes, heart and nervous systemB. heart, liver and musclesC. nervous system, ears and skin

11. A major clinical feature of galactosemia isA. cataractsB. detached retinasC. epicanthal folds

12. Researcher disagree on the clinical impact of ga-lactose inA. fresh fruitsB. meat proteinC. saturated fats

13. The most prevalent hemoglobinopathy includedin state-mandated newborn screening programs isA. hemoglobin E diseaseB. sickle cell anemiaC. thalassemia

14. The most common type of congenital adrenalhyperplasia (CAH) is a deficiency in the enzymeA. 11-hydroxylaseB. 17-hydroxylaseC. 21-hydroxylase

15. The salt-wasting crisis of CAH is due to a de-creased ability to synthesizeA. aldosteroneB. cortisolC. testosterone

Continuing Education Questions 1

16. Significant accumulation of lactate is found inA. acyl-CoA dehydrogenase deficiencyB. biotinidase deficiencyC. homocystinuria

17. The incidence of maple sugar urine disease isespecially high in the population ofA. Mennonites of PennsylvaniaB. natives of IrelandC. Yupik Eskimos of Alaska

18. Thiamine can be used in the diagnosis and treat-ment of the following inborn error of metabolismA. maple syrup urine diseaseB. medium-chain acyl-coA dehydrogenase defi-

ciencyC. methylmalonic acidemia

19. What percentage of individuals affected with ho-mocystinuria are responsive to treatment withpryridoxine (vitamin B6) and folate?A. 30%B. 50%C. 70%D.

20. A disorder of mitochondrial fatty acid oxidation isA. argininosuccinate lyase deficiencyB. isobutyryl-coA dehydrogenase deficiencyC. medium-chain acyl-coA dehydrogenase defi-

ciency21. Individuals affected by cystic fibrosis are at in-

creased risk for chronic sinus and/or respiratoryinfections caused byA. Burkholderia cepeciaB. Eschericha coliC. Staphylococcus aureus

22. Resolution of transient tyrosinemia of the newborncan be accelerated by administration of vitaminA. AB. CC. E

23. An infant presents with failure to thrive, vomiting,diarrhea, jaundice, and renal dysfunction. A‘boiled cabbage’ odor is also noted. This infantshould be evaluated for

A. glutaric academia type IIB. propionic acidemiaC. tyrosinemia type I

24. The most common enzyme disorder worldwide isA. galactose-1-phosphate uridyltransferaseB. glucose-6-phosphate dehydrogenaseC. glutaric academia type I

25. Glucose-6-phosphate dehydrogenase deficiency ismost common inA. BlacksB. EskimosC. Hispanics

26. The incidence of profound bilateral hearing lossin the United States is _______ per 1,000 liveborn newbornsA. 1-3B. 4-6C. 7-9

27. The incidence of sensorineural hearing lossin infants with profound biotinidase deficiencyisA. 25%B. 50%C. 75%

28. In the future, the number of disorders that can bedetected through newborn screening is expectedtoA. decreaseB. increaseC. remain the same

29. The diagnostic test responsible for the increasedavailability of disorders included in newbornscreening programs isA. DNA fingerprintingB. Guthrie blood-spot testC. mass spectrometry

30. Decisions for government-mandated newbornscreening programs are usually made by theA. federal governmentB. public health departmentsC. state legislatures

2 Continuing Education Questions

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Newborn screening: New opportunities and new challenges