Genetic counseling and risk communication services of newborn screening programs

OBJECTIVES: Newborn screening test results labeled "positive" can have uncertain implications for parents, especially when false-positive results occur or when heterozygous infants are detected using molecular tests for sickle cell hemoglobinopathy or cystic fibrosis. This study surveyed communication services across state newborn screening programs. METHODS: We surveyed newborn screening programs to identify current communication practices and the methods used for quality assessment. Two successive survey instruments with fixed-answer and free-answer questions were distributed to screening program follow-up coordinators or similar designated officials associated with 52 states and territories. RESULTS: Replies from 46 respondents (89% response rate) revealed that regional newborn screening programs vary widely in their approaches to counseling. Of the 46 respondents, 35 (76%) answered that they "routinely" provide counseling services to families of affected infants. Depending on the disease, an average of approximately one-half that number provide counseling after false-positive results or for heterozygous infants. Most respondents advocate nondirective counseling more than direct advice. Most programs reported that counseling was usually done by subspecialist physicians or specially trained nurses and counselors. Respondents reported a perception that the "quality" of counseling by these professionals is better than counseling by primary care physicians. Few programs reported systems for assessing quality assurance of counseling. CONCLUSIONS: Newborn screening programs in the United States vary widely with regard to counseling practices, and no best practices are currently evident. Few programs provide counseling quality assurance. Further study and advocacy is needed to optimize communication services, preferably before implementation of molecular tests arising as a result of the Human Genome Project.     

State programs for universal newborn hearing screening

Published reports of several statewide and hospital-based systems for universal newborn hearing screening demonstrate that successful large-scale programs that appropriately identify infants with hearing loss in the earliest months of life can be developed. These programs are characterized by nursery-based screening rates of 95% or higher, referral rates of 6% or less, and reasonable per-infant costs. Less data are available regarding the outcome of these screening programs in ensuring confirmation of hearing loss by 3 months of age and initiation of intervention by 6 months of age. The results of the MDNC survey provide important information on the status of newborn hearing screening, audiologic assessment, and intervention services in 16 states. The survey reveals that hospitals have initiated universal newborn hearing screening programs using appropriate technology but that confirmation of hearing loss, fitting of amplification, and enrollment in early intervention are often delayed beyond the JCIH recommendations. Several factors might contribute to late confirmation of hearing loss and delayed amplification and intervention. First, as shown in the Colorado report, lack of a mandatory statewide system for tracking and reporting may delay transition of infants and families from screening to diagnosis, and diagnosis to intervention. In addition, many states lack a centralized system for reporting confirmed hearing loss. Successful statewide programs for universal newborn hearing screening, audiologic diagnosis, and early intervention depend on data-reporting strategies that facilitate transition of infants and families through a system of care. Second, lack of understanding about the urgent need for intervention in the earliest months of life may hinder referral to early intervention programs. Recent data from Colorado's universal newborn hearing screening program reveals that infants who are deaf or who have hearing losses achieve significantly better language development outcomes if intervention begins before age 6 months than infants whose intervention begins after 6 months of age. Hopefully, as these data become more widely available, the compelling need for early intervention will facilitate transition into these services. Although universal newborn hearing screening programs are increasing rapidly, states have not yet developed the coordinated systems for linking universal newborn hearing screening programs to audiologic diagnostic services and audiologic diagnostic services to early intervention programs. Key issues impeding development of these systems may be lack of tracking and reporting systems, lack of standardized guidelines for screening, diagnostic audiologic assessment, hearing aid fitting for very young infants, and lack of understanding about the compelling need for intervention in the earliest months of life. Development of complete systems of care must become a priority for universal newborn hearing screening to provide its ultimate benefit.     

Evaluation of the expanded newborn screening program in New York City

Since September 1974, New York State public health law has mandated that all newborn infants be tested for phenylketonuria, maple syrup urine disease, homocystinuria, histidinemia, galactosemia, adenosine deaminase deficiency, and sickle cell anemia in accordance with regulations of the state commissioner of health. During the period from May 1, 1975, to April 30, 1976, a total of 110,180 babies born in New York City were tested for these seven conditions. One year's experience with the screening program demonstrated a paucity of technological problems, low observed rate of both false-negatives and -positives, and the expected incidence of the conditions of highest prevalence, incidentally found during screening: i.e., sickle cell traits, AS and AC. What is equally apparent in reviewing this first year's experience is the extent to which the New York State law, its structure, and implementation have fallen short of the ultimate objective. The major reason for this failure is lack of funds and facilities in the areas of education, case retrieval, continuing medical care, and counseling. This report is presented with the hope that it will benefit all involved in genetic screening and especially those concerned with establishing similar programs.     

Newborn hypothyroid screening. The private sector

Newborn hypothyroid screening in four private hospitals was prospectively evaluated and compared with a state screening program. During 1982 the hospitals screened a total of 10,786 infants compared with 47,525 by the state. Eight cases of primary hypothyroidism were confirmed by the state, for an incidence of one in 5,941. No cases were detected by the hospital programs. The cost for all infants screened in the private hospitals was 51.5 times more than the total cost of the state program, yet the state screened 4.4 times more infants.     

NICU‐only versus universal screening for newborn hearing loss: Population audit

Aim: Targeted newborn hearing screening for infants in neonatal intensive care units (NICUs) may be considered when resources preclude universal newborn hearing screening (UNHS). However, process outcomes have not been compared between stand‐alone NICU hearing screening programs and NICU screening within a full UNHS program. Methods: Comparison of two consecutive hearing screening programs delivered under similar conditions in the four NICUs in Victoria, Australia. All NICU infants were eligible for pre‐discharge automated auditory brainstem response (AABR) hearing screening. Capture, referral and diagnostic data were collected for all NICU infants during the NICU‐only (April 2003–February 2005) and subsequent UNHS (April 2005–June 2006) programs. Results: 4704 eligible infants were admitted during the 23‐month NICU‐only period, and 3160 during the 15‐month UNHS period. Double AABR using ALGO 3i equipment was planned for both programs but, due to clinician concern about this high‐risk clinical population, the NICU‐only protocol was amended to single AABR using AccuScreen equipment. Capture rates were 71.1% (NICU‐only) vs. 95.4% (UNHS) (P < 0.001), successful follow‐up rates were 85.8% vs. 96% (P= 0.004), and mean corrected age at the first audiology appointment was 51.5 vs. 40.2 days (P= 0.05). Conclusions: NICU screening offered within a larger UNHS program outperformed the stand‐alone NICU hearing screening program on all measured parameters. Greater resourcing might address shortcomings of the stand‐alone program but would also reduce its potential savings. The high loss to follow‐up also argues against the often‐advocated approach of referring all NICU infants for diagnostic audiologic testing, bypassing hearing screening altogether.     

The newborn with hearing loss: detection in the nursery

BACKGROUND: Early detection of hearing loss coupled with appropriate early intervention is critical to speech, language, and cognitive development. These competencies serve as the foundation for later academic skills. For these reasons, many states are undertaking aggressive efforts to screen all newborns before hospital discharge. Universal detection of hearing loss in newborns is a three-stage process composed of 1) the birth admission screen, 2) follow-up and diagnosis, and 3) intervention services. Breakdown at any stage jeopardizes the entire effort. The goals of this research are to examine the birth admission screen by reviewing outcome measurements for 54 228 Texas newborns and to evaluate factors that impact outcomes positively or negatively. METHODOLOGY: All newborns were screened for hearing loss using a physiologic test of auditory function; either screening auditory brainstem responses or transient evoked otoacoustic emissions. Screening occurred in the newborn and intensive care nurseries, before hospital discharge in 9 sites as part of the nursery protocol. Patients. A total of 54 228 newborns were available for screening. OUTCOME MEASURES: Four measures were evaluated and are reported: the number of births screened, the number of newborns who passed the screen before discharge, the number of infants who returned for follow-up, and the number of infants identified with hearing loss. A Birth Screening Performance Index is also calculated. RESULTS: Results are reported for calendar years 1994, 1995, 1996, and through June 1997. A total of 54 228 newborns were available for screening; 52 508 were screened before hospital discharge during their birth admission and 50 721 passed this screen. Infants returning for follow-up screen as outpatients numbered 1224. Over this 31/2-year span, 113 infants who failed the birth admission screening had hearing loss that was sensorineural in nature. From these data, the estimated incidence of hearing loss is 3.14/1000 infants. CONCLUSIONS: Screening in the nursery with low false-positive rates can be achieved when three elements are present: audiology involvement, hospital support, and automated data and information management. Follow-up measures need improvement. Better tracking methods may help assure that at-risk newborns are connected to services.     

Delayed diagnosis in congenital adrenal hyperplasia. Need for newborn screening

Medical records of all patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency who were followed up at the University of Wisconsin Hospitals, Madison, from 1956 to 1979, were reviewed to document the ages at diagnoses. Without newborn screening, the average age at diagnosis for 32 patients was 12.6 months (7.3 months for female infants and children and 22.7 months for male infants and children). In the newborn population, ambiguity was recognized in 15 of 21 female infants and in none of the male infants. Initial-appearing symptoms in female infants and children included ambiguous genitalia in 15 of 21, precocious puberty in four, and salt-losing crises in two. In the male infants and children, the reasons for diagnoses were salt-losing crises in seven of 11 and precocious puberty in four. These results indicate that in the absence of newborn screening, diagnosis is frequently delayed.     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

Storage and use of residual dried blood spots from state newborn screening programs

OBJECTIVES: To provide current data for policy discussions and to assess future needs among newborn screening programs regarding the storage and use of residual dried blood spots (DBS) in the United States. STUDY DESIGN: An electronic questionnaire was administered to U.S. state health department laboratory directors in 2003. RESULTS: Responses were received from 49 of the 50 states. Approximately half of them stored residual DBS for more than 6 months, 57% did not have a written policy that determines how residual DBS can or cannot be used, and 16% informed parents that DBS might be retained. Residual DBS were used by 74% of respondents for evaluation of newborn screening tests, by 52% for clinical or forensic testing, and by 28% for epidemiologic studies. Use of DBS was reported more frequently by states with extended storage. When asked if they might participate in an anonymous multistate epidemiologic study by contributing unlinked DBS, 41% responded affirmatively. CONCLUSIONS: More states have used residual DBS for evaluating newborn screening tests than for epidemiologic studies. There is potential interest among states in using unlinked DBS for multistate studies and a need for written policies addressing all uses of residual DBS.     

Neonatal hearing screening with an automated auditory brainstem response screener in the infant's home

Universal neonatal hearing screening is essential if all infants with congenital or perinatally acquired hearing impairment are to begin treatment before the age of 6 months to facilitate development of speech, language, communication and academic skills. Screening cannot always take place in hospital because of the increase in very short-stay deliveries. Therefore screening in the home may be necessary to achieve a high level of screening. We describe a feasibility study with an automated auditory brainstem response (AABR) screener in the infant's home as part of the service offered by the Well Baby Clinics in the Netherlands. Of the 277 infants who completed the screening 266 had the result "pass", 7 "refer" and 4 had inconclusive results. The mean time needed per screening was 18 min. This study shows that neonatal hearing screening by nurses using an AABR infant screener in the home is feasible.     

A cost-effectiveness analysis of newborn hearing screening strategies

CONTEXT: Congenital hearing loss affects between 1 and 3 out of every 1,000 children. Screening of all neonates has been made possible by the development of portable automated devices. Universal screening is a 2-stage screening process using automated transient-evoked otoacoustic emissions, followed when indicated by automated auditory brain response testing. Targeted screening reserves the 2-stage screening process for those infants at risk for congenital hearing loss. OBJECTIVE: To compare the expected costs and benefits of targeted screening with universal screening for the detection of significant bilateral congenital hearing loss. DESIGN: Cost-effectiveness analysis from the health care system perspective. including costs directly related to screening and initial follow-up evaluation. MAIN OUTCOME MEASURES: Number of cases identified, number of false positives, and cost per case. RESULTS: For every 100,000 newborns screened, universal screening detects 86 of 110 cases of congenital hearing loss, at a cost of $11,650 per case identified. Targeted screening identifies 51 of 110 cases, at $3,120 per case identified. Universal screening produces 320 false-positive results, 304 more than targeted screening. Switching to universal screening from targeted screening would cost an additional $23, 930 for each extra case detected. CONCLUSIONS: Universal screening detects more cases of congenital hearing loss, at the expense of both greater cost and more false-positive screening results. Little is known about the negative impact of false-positive screening and about the benefits of early intervention for congenital hearing loss. Those who advocate adoption of universal screening should be aware not only of the direct costs of universal screening, but of the indirect costs and strategies to increase the benefits of screening.     

A cost-effectiveness evaluation of newborn hemoglobinopathy screening from the perspective of state health care systems

Objective: To determine the most cost-effective strategy for newborn hemoglobinopathy screening from the perspective of state health care systems. Study design: Using Alaska as an example, we used decision analysis to compare a policy of no screening to universal or targeted screening with selective follow-up only of infants who are homozygous or compound heterozygous for an abnormal hemoglobin variant and to universal or targeted screening with complete follow-up, including follow-up of infants with clinically insignificant traits. Probabilities and costs were varied over values that might be expected for other states. Results: Among the selective follow-up options, targeted screening would be the most cost-effective strategy for Alaska at a cost of $206 192 per death averted; by contrast, universal screening would prevent 50% more deaths at an incremental cost of $2 040 000 per death averted. Universal would be more cost-effective than targeted screening for several scenarios expected to occur in other states, including a high sickle cell disease prevalence, a low screening test cost, and a high cost per screen associated with racial targeting. Among the complete follow-up options, both targeted and universal screening would cost at least $200 000 per death averted over the range of all variables tested during sensitivity analysis; the incremental cost of universal versus targeted screening would be at least $600 000 per death averted. Conclusions: Our data suggest each state should determine the most cost-effective option based on state-specific values for sickle cell disease prevalence, test costs and racial targeting costs.     

Ohio's infant hearing screening and assessment program. A decade in development.

The early detection of hearing impairments in infants is essential to the initiation of medical and educational services which will enhance optimal development of communication and social skills. Ohio has successfully implemented a legislatively mandated two-tiered Infant Hearing Screening and Assessment Program. This statewide screening program is in accordance with the child find and early intervention services requirements of P.L. 99-457.     

MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency

OBJECTIVES: To determine whether asymptomatic persons with biochemical evidence of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency identified through expanded newborn screening with tandem mass spectometry have confirmed disease. STUDY DESIGN: We characterized 8 asymptomatic VLCAD-deficient individuals by enzyme and/or mutational analysis and compared them with clinically diagnosed, symptomatic patients with regard to mutations, enzyme activity, phenotype, and age of disease onset. RESULTS: VLCAD molecular analyses in 6 unrelated patients revealed the previously reported V243A mutation, associated with hepatic or myopathic phenotypes, on 7/12 alleles. All other mutations were also missense mutations. Residual VLCAD activities of 6% to 11% of normal were consistent with milder phenotypes. In these identified individuals treated prospectively with dietary modification as preventive measures, clinical symptoms did not develop during follow-up. CONCLUSIONS: MS/MS-based newborn screening correctly identifies VLCAD-deficient individuals. Based on mutational and enzymatic findings, these infants probably are at risk of future disease. Because life-threatening metabolic derangement can occur even in otherwise mild phenotypes, we advocate universal newborn screening programs for VLCAD deficiency to detect affected patients and prevent development of metabolic crises. Longer-term follow-up is essential to define outcomes, the definite risk of future disease, and appropriate treatment recommendations.     

Evidence for changing guidelines for routine screening for retinopathy of prematurity

CONTEXT: Existing guidelines recommended by the Canadian Pediatric Society (CPS) and American Academy of Pediatrics (AAP) for routine screening for retinopathy of prematurity (ROP) remain controversial. OBJECTIVE: To determine whether current guidelines for routine screening for ROP should be changed. DESIGN: We examined data that were collected as part of a larger study of 14 neonatal intensive care units (NICUs) in Canada. We examined the effect of strategies using different birth weight (BW) and gestational age (GA) criteria for routine ROP screening, and performed a cost-effectiveness analysis. SETTING: The 14 NICUs (except one) are regional tertiary level referral centres serving geographic regions of Canada, and include approximately 60% of all tertiary-level NICU beds in Canada. PATIENTS: This large cohort included all 16 424 infants admitted to 14 Canadian NICUs from January 8, 1996, to October 31, 1997. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Treatment for ROP. RESULTS: The most cost-effective strategy was to routinely screen only infants having a BW of 1200 g or less. This included all infants treated for ROP (except 1 outlier at 32 weeks GA and 1785 g BW), at a marginal cost per additional person with improved vision of $513 081 for screening patients between 28 weeks GA and 1200 g BW, compared with $1 800 039 and $2 075 874 for using the current AAP and CPS guidelines, respectively (cryotherapy outcomes). Results for laser therapy were similar, but costs were slightly lower. This strategy reduced the number of infants screened under the current CPS guidelines by 46%. CONCLUSION: Screening only infants having a BW of 1200 g or less is the most cost-effective strategy for routine ROP screening.     

Epidemiology of congenital toxoplasmosis identified by population-based newborn screening in Massachusetts.

BACKGROUND: Fourteen years of newborn screening in Massachusetts for congenital toxoplasmosis infection identified subpopulations that appeared to have higher rates of infection. Elaborating an epidemiologic profile and risk correlates might aid implementing targeted prenatal education and newborn screening strategies with the goal of early postnatal treatment to prevent morbidity. OBJECTIVE: To describe the epidemiology of congenital toxoplasmosis in Massachusetts and risk correlates of infection using birth certificate data. METHODS: A case-control study was conducted based on Massachusetts birth certificate data. Cases were all infants with congenital toxoplasmosis identified by statewide universal newborn screening from 1988 to 1999. Controls were all children born on the same day as those infants in Massachusetts. RESULTS: Factors that strongly predicted congenital toxoplasmosis infection were mother's country of birth outside the US (especially the southeast Asian refugee origin countries of Cambodia and Laos), mother's educational level and higher gravidity. CONCLUSIONS: More extensive, culturally and linguistically appropriate, prenatal education is needed for pregnant women, regardless of a mother's educational level, especially for non-US-born mothers, and not focused only on primiparous women. Other states may be able to use their state-specific birth certificate data to compare risk profiles with those of Massachusetts to guide a toxoplasmosis screening policy on the basis of population similarities and differences.     

Vitamin D in infants with cystic fibrosis diagnosed by newborn screening

Aims:   Screening enables early nutritional deficiencies to be detected in those with cystic fibrosis (CF). Although vitamin deficiency is considered unlikely in older subjects with normal vitamin E levels, few studies have determined vitamin D status at diagnosis and its relationship to other fat-soluble vitamins.
Methods:   We reviewed vitamin levels in infants diagnosed with CF by newborn screening over a 5-year period in Melbourne, Australia. Vitamin D levels were determined using the IDS gamma-B 25-OH Vitamin D radio-immunoassay (Immunodiagnostic Systems Limited, Boldon, UK). Vitamins A and E were evaluated by high-performance liquid chromatography. We assessed the association between vitamin D level and sex, month of birth, pancreatic status, and vitamin A and E levels.
Results:   Fifty-eight infants were diagnosed at a median age of 1 month (range: 0–3 months). Initial vitamin D levels were assessed between 0.2 and 3.5 months in 30 (vitamin D) and 45 (vitamins A and E) infants. The number of infants deficient with vitamins D, E and A were 11 (37%), 7 (16%) and 27 (60%), respectively. Vitamin D levels were unrelated to sex, vitamin A or E levels, month of birth or pancreatic status, whereas vitamin A and E levels were significantly lower in those who were pancreatic insufficient. With supplementation, vitamin D increased over time.
Conclusions:   Vitamin D deficiency is common in infants newly diagnosed with CF by newborn screening and is unrelated to pancreatic status or predicted low vitamin E levels. Vitamin D deficiency is less common over time following treatment.     

Regional Implementation of Newborn Screening for Critical Congenital Heart Disease Screening in Abu Dhabi

Congenital heart disease (CHD) is the most common birth defect and affects approximately 8 out of every 1,000 infants born each year. Despite antenatal screening and at least one examination before discharge infants with critical CHD (CCHD) are routinely not detected before discharge from the newborn nursery. Newborn screening for CCHD using pulse oximetry is widely endorsed however until recent efforts, CCHD screening programs had only been implemented at the individual hospital level. The purpose of this paper is to describe the implementation of CCHD screening across the entire Emirate of Abu Dhabi. The Health Authority—Abu Dhabi (HAAD), in collaboration with Children’s National Medical Center (Children’s National), successfully implemented CCHD screening at the emirate level using a “train-the-trainer,” two-tiered approach, starting with two pilot hospitals then rolling the program out to all birthing facilities. In the first year, CCHD screening was added as a mandatory test to the HAAD Newborn Screening Standard, has been implemented in most birthing facilities, and occurs for the majority of infants (86 %) in Abu Dhabi. This led to the identification of ten newborns with CCHD. Based on the successful identification and mitigation of barriers to implementation, the approach may be adapted for similar programs in other populations.