State Newborn Screening Programs Research Articles

Parents’ interest in whole-genome sequencing of newborns

The aim of this study was to assess parents' interest in whole-genome sequencing for newborns. We conducted a survey of a nationally representative sample of 1,539 parents about their interest in whole-genome sequencing of newborns. Participants were randomly presented with one of two scenarios that differed in the venue of testing: one offered whole-genome sequencing through a state newborn screening program, whereas the other offered whole-genome sequencing in a pediatrician's office. Overall interest in having future newborns undergo whole-genome sequencing was generally high among parents. If whole-genome sequencing were offered through a state's newborn-screening program, 74% of parents were either definitely or somewhat interested in utilizing this technology. If offered in a pediatrician's office, 70% of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as "very important" in making a decision to have a newborn's whole genome sequenced. These data may help health departments and children's health-care providers anticipate parents' level of interest in genomic screening for newborns. As whole-genome sequencing is integrated into clinical and public health services, these findings may inform the development of educational strategies and outreach messages for parents.

Guidelines support the return of incidental genomic findings

Guidelines support the return of incidental genomic findings

Newborn Screening: A National Snapshot with Implications for Emergency Preparedness

To conduct a nationwide survey of the methods used in newborn screening (NBS) programs to notify birthing centers, pediatricians, and parents of the results of NBS tests in every state and territory. State and territory NBS program representatives were identified and contacted via e-mail. Each state or territory responded to a survey asking questions about their methods (eg, telephone, e-mail, surface mail) for reporting normal, borderline, and abnormal results. With 100% of states and territories responding, a broad array of reporting methods were identified with substantial variability between states for delivering NBS test results to the responsible entities. Mail, telephone, and facsimile were the predominant reporting methods. The majority of states and territories did not have Web-based reporting methods. State-to-state variability complicates NBS laboratory backup in the event of catastrophic failure and makes emergency preparedness difficult. The most common reporting methods (surface mail, telephone) do not account for likely interruption of infrastructure and the urgent need for abnormal result reporting for patients evacuating their community. Harmonization between states in their reporting methods via Web-based methods should be developed.

Does Galactocerebrosidase Activity Predict Krabbe Phenotype?

This study sought to determine whether galactocerebrosidase activity is predictive of Krabbe onset age, or of survival from onset when controlling for age at onset of signs. We analyzed data on 55 symptomatic patients from the Hunter James Kelly Research Institute's World-Wide Registry. They were tested for galactocerebrosidase activity at Jefferson Medical College (Philadelphia, PA), using survival models in a path model context. Higher galactocerebrosidase activity was predictive of later symptom onset times (P = 0.0011), but did not predict survival after symptom onset (P = 0.9064) when controlling for the logarithm of age at onset. No child with early infantile (aged 0-6 months) phenotype demonstrated galactocerebrosidase activity >0.1 nmol/hour/mg protein. Survival times within a given phenotype did not vary with galactocerebrosidase activity. Although low galactocerebrosidase activity does not predict phenotype, higher activity in the abnormal range (>0.1 nmol/hour/mg protein in this sample) was not identified in the early infantile variant. Galactocerebrosidase activity may be important to consider when predicting phenotype in the newborn screening population. Our findings provide empiric evidence that the upper end (0.15 nmol/hour/mg protein) of the high-risk galactocerebrosidase group in the New York State newborn screening program is conservatively appropriate.

Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity

Sickle cell disease is estimated to occur in 1:300-400 African-American births, with higher rates among immigrants from Africa and the Caribbean, and is less common among Hispanic births. This study determined sickle cell disease incidence among New York State newborns stratified by maternal race/ethnicity and nativity. Newborns with confirmed sickle cell disease born to New York State residents were identified by the New York State newborn screening program for the years 2000-2008 and matched to birth records to obtain birth and maternal information. Annual incidence rates were computed and bivariate analyses were conducted to examine associations with maternal race/ethnicity and nativity. From 2000 to 2008, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non-Hispanic black mothers accounted for 86% of sickle cell disease cases whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1:230 live births for non-Hispanic black mothers, 1:2,320 births for Hispanic mothers, and 1:41,647 births for non-Hispanic white mothers. Newborns of foreign-born non-Hispanic black mothers had a twofold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers (P < 0.001). This study provides the first US estimates of sickle cell disease incidence by maternal nativity. Women born outside the United States account for the majority of children with sickle cell disease born in New York State. Such findings identify at-risk populations and inform outreach activities that promote ongoing, high-quality medical management to affected children.

More states screen for severe combined immunodeficiency

More states screen for severe combined immunodeficiency

At $1,000, is genomic sequencing clinically useful in newborns?

At $1,000, is genomic sequencing clinically useful in newborns?

Developmental and Functional Outcomes in Children with a Positive Newborn Screen for Krabbe Disease: A Pilot Study of a Phone-Based Interview Surveillance Technique

To assess the utility of a telephone-based interview system in providing ongoing monitoring of the developmental and functional status of children with both positive newborn screens for Krabbe disease and low galactocerebrosidase activity on confirmatory testing, and to determine whether this approach provides improved compliance with follow-up compared with formal neuropsychological testing. Infants with low galactocerebrosidase activity (as detected by the New York State newborn screening program) were eligible for this longitudinal prospective cohort study. Consenting families were interviewed by telephone at infant ages of 4, 8, 12, 18, and 24 months. Designated instruments were the Ages and Stages Questionnaires, the Clinical Linguistic and Auditory Milestone Scale, the Gross Motor Quotient, the Warner Initial Developmental Evaluation of Adaptive and Functional Skills 50, and the WeeFIM II 0-3 instrument. Assessments with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) were scheduled at age 12 and 24 months. Seventeen patients were enrolled; 16 were assessed at age 12 and 18 months, and 15 were assessed at age 24 months. Scores were within the normal range on all tests of developmental and functional status, with the exception of expressive language. Only 7 patients completed the Bayley Scales of Infant and Toddler Development, Third Edition assessments; all their scores were in the normal range. This telephone-based technique allows close monitoring of the developmental and functional status of children with a positive newborn screen for this neurometabolic disease, with special attention to detecting plateauing or regression of developmental milestones. Compliance is improved compared with formal neuropsychological testing.

Public attitudes regarding the use of residual newborn screening specimens for research.

Many state newborn screening (NBS) programs retain residual NBS bloodspots after the completion of screening. Potential uses for residual specimens include laboratory quality assurance, biomedical research, and, rarely, forensic applications. Our objective was to evaluate public opinion about the policies and practices relevant to the retention and use of residual bloodspots for biomedical research. A total of 3855 respondents were recruited using 3 methods: focus groups (n = 157), paper or telephone surveys (n = 1418), and a Knowledge Networks panel (n = 2280). Some participants (n = 1769) viewed a 22-minute movie about the retention and use of residual specimens while other participants were provided only written information about this practice. All participants were surveyed using a 38-item questionnaire. A diverse set of participants was recruited. Respondents were very supportive of NBS in general and accepting of the use of residual bloodspots for important research activities. Respondents were evenly divided on the acceptability of NBS without parental permission, but the majority of respondents supported the use of an "opt-in" process for parental permission for residual bloodspot retention and use. Viewing the educational movie was associated with greater support for bloodspot retention and use. Our results show that the general public surveyed here was supportive of NBS and residual sample retention and research use. However, there was a clear preference for an informed permission process for parents regarding these activities. Education about NBS was associated with a higher level of support and may be important to maintain public trust in these important programs.

A qualitative secondary evaluation of statewide follow-up interviews for abnormal newborn screening results for cystic fibrosis and sickle cell hemoglobinopathy

PurposeThe purpose of this qualitative analysis was to assess parental acceptability of large-scale, telephone follow-up regarding their infants’ newborn screening (NBS) results, indicating carrier status for sickle cell hemoglobinopathy (SCH) and cystic fibrosis (CF). MethodsAnalysis of 195 interview transcripts focused on parents’ responses to two open-ended questions: “What was your reaction to being called by me?” and “What do you think of the state NBS program having follow-up people calling parents like you?” Responses were coded using conventional content analysis procedures, and nonparametric tests were performed to analyze quantitative data. ResultsMost parents reported favorable opinions about the follow-up. Favorable opinions were associated with several emotional reactions to receiving follow-up (P <0.001) and three reasons why parents found the interview beneficial (P < 0.05): it provided information, clarified NBS results, and answered questions. Seventeen parents of SCH carriers reportedly had not been told their infant’s NBS results and received them for the first time during the follow-up interview. ConclusionParents of CF and SCH carrier infants had favorable opinions and identified specific benefits to receiving follow-up contact. This analysis demonstrates an information deficit among carrier parents and illustrates the importance of NBS follow-up and need for comprehensive communication and counseling.Genet Med 2012:14(2):207–214

Expert Commentary: Practical Issues in Newborn Screening for Severe Combined Immune Deficiency (SCID)

Kate Sullivan: We asked experts in the field to comment on some of the more pressing questions in the burgeoning field of newborn screening for severe combined immune deficiency (SCID). Their valuable perspectives are provided to guide the establishment of policies as additional states consider and implement newborn screening for SCID. Jennifer Puck has been a strong advocate for newborn screening and originated the concept of T cell receptor excision circle (TREC) screening using dried blood spots; the TREC assay has been performed on all newborns in California since August 2010, and Dr. Puck is the immunology consultant for the California Genetic Disease Lab; she has instituted a centralized follow-up model, with the screening program obtaining and sending follow-up tests throughout the state to a single immunology lab. Dr. Puck and her Southern California colleague, Dr. Joseph Church, interpret all flow cytometric results from a designated laboratory with a standardized analytic panel. Dr. Jack Routes was responsible for implementing the first state newborn screening program for SCID, which started in Wisconsin in January 2008. Wisconsin is a leader in the field of newborn screening. Dr. Alexandra (Lisa) Filipovich has developed Cincinnati Children’s Hospital into one of the preeminent transplant centers. Novel protocols to limit toxicity and improve outcomes are central to the innovations at Cincinnati Children’s Hospital.

Siblings With Mitochondrial Acetoacetyl-CoA Thiolase Deficiency Not Identified by Newborn Screening

Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial acetoacetyl-coenzyme A thiolase (T2), or β-ketothiolase, deficiency is a rare autosomal recessive disorder that causes ketoacidosis and hypoglycemia/hyperglycemia. Outcomes vary from normal development to severe cognitive impairment or even death after an acute episode of ketoacidosis. The classical biochemical profile of T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of ketones, characteristic organic acids, and tiglylglycine as well as abnormal blood or plasma acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic acid, blood, and plasma acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that T2 deficiency may be underrecognized, because the incidence of T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that T2 deficiency must be considered in patients who present with ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods.

Newborn Screening for Fragile X Syndrome: Do We Care What Parents Think?

The Scottish philosopher David Hume famously observed that moral arguments cannot move directly from describing what “is” to concluding what “ought” to be done. That is, we must include assumptions or arguments between our observations of fact and our conclusions about how we should respond. In this issue of Pediatrics , Skinner et al1 describe the response of new parents to offers of newborn screening (NBS) for fragile X syndrome (FXS). They found that a majority of new parents (63%) consented to the screening of their child for this condition. An important aspect of this research is that it entailed actual choices about screening, not hypothetical scenarios, and their broader research agenda included a careful assessment of how parents and the children were affected by this information. So, although the project has provided valid information on parental choices in this screening opportunity, a larger question is whether we should care what parents think. As Skinner et al note, FXS has been under consideration for a number of years as a potential addition to the panel of conditions targeted by state NBS programs. FXS was not included on the uniform panel recommended by the American College of Medical Genetics (ACMG) in 2005.2 At that time, the condition did not meet criteria for the test, and there was uncertainty about the benefits to children from early identification. However, the ACMG noted the potential benefits … Address correspondence to Jeffrey R. Botkin, MD, MPH, Department of Pediatrics, School of Medicine, University of Utah, 50 N Medical Dr, Room 1C375, Salt Lake City, UT 84132. E-mail: jeffrey.botkin{at}hsc.utah.edu

State Laws Regarding the Retention and Use of Residual Newborn Screening Blood Samples

After newborn screening has been completed, many states retain residual newborn screening dried blood samples for various purposes, including program evaluation, quality assurance, and biomedical research. The extent to which states possess legal authority to retain residual dried blood samples (DBS) and use them for purposes unrelated to newborn screening is unclear. The purpose of this study was to evaluate state laws regarding the retention and use of DBS. State statutes and regulations related to newborn screening of all 50 states plus the District of Columbia were accessed online between November 2008 and December 2009 and reviewed by 2 independent reviewers to determine the extent to which the retention and use of DBS were addressed. The retention or use of DBS has not been addressed in 18 states. In 4 states, DBS becomes state property. Eight states require that parents be provided information regarding the retention of DBS. Parents in 5 states may request the destruction of their child's residual sample. Parental consent is required under certain circumstances to release DBS for research in 6 states. One state prohibits DBS from being used for research purposes. States have wide variability in their policies regarding the retention and use of DBS. Many states have not addressed key issues, and some states that retain DBS may be acting outside the scope of their legal authority. The lack of transparency on the part of states in retaining DBS may undermine public trust in state newborn screening programs and the research enterprise.

Parents Need Help Understanding Abnormal Newborn Screening Results

State newborn screening programs have expanded dramatically recently. A prior study reported that most states increased the average screening from 5 to 24 heritable conditions between 1995 and 2005 ( Pediatrics 2006; 118:448). In 2010, a federal advisory panel recommended newborn screening for 30 core conditions. To describe …

The Effects of Gestational Age and Birth Weight on False-Positive Newborn-Screening Rates

Newborn-screening false-positive rates (FPRs) are disproportionately increased in preterm infants. The objective of this study was to determine variation in newborn screening FPRs according to birth weight and gestational age. Our secondary objective was to examine the effect of postnatal age on FPRs in preterm infants. The Ohio State Newborn Screening Program Database was analyzed to determine the overall and birth weight-specific FPRs for 18 analytes. Data were stratified into birth weight categories (<1000 g, 1000-1499 g, 1500-2499 g, 2500-3999 g, and >4000 g). In addition, to examine the effect of postnatal age on FPRs, we examined the 2 analytes with the highest FPRs, thyrotropin with back-up thyroxine and 17-hydroxyprogesterone, in infants whose gestational age was <32 weeks, determined on the basis of postnatal age at screening. Data from 448 766 neonates were reviewed. Infants with very low birth weight (VLBW) comprised 1.9% of the study cohort, but accounted for 18% of false-positive results. For 14 of 18 analytes studied, FPRs increased with decreasing birth weight/gestational age and were significantly increased in infants with VLBW compared with infants who weighed 2500 to 3999 g (P < .001). Thyrotropin/back-up thyroxine and 17-hydroxyprogesterone accounted for 62% of total false-positive results in VLBW infants. When blood specimens were collected at a postnatal age of ≥ 48 hours in infants born at <32 weeks, a 44% relative reduction in 17-hydroxyprogesterone false-positive results was detected. False-positive newborn-screening rates are disproportionately increased in VLBW infants. FPRs may be reduced by delaying screening of <32 weeks' gestation, preterm infants until 24 to 48 hours' postnatal age.

Newborn vitamin B12 deficiency

The expansion of state newborn screening programs has led to a number of important observations, many of which do not relate directly to the detection of newborns with inherited metabolic disease. A fascinating example of this is reported in this issue of The Journal by Hinton et al from the CDC. The use of tandem mass spectrometry has made it possible to identify newborns with vitamin B12 deficiency. In a newborn, this would virtually always result from maternal deficiency. The authors queried state screening programs and identified 32 such infants over a 4-year period.

SCID suggested for uniform newborn screening panel

SCID suggested for uniform newborn screening panel

Effect of Laboratory Practices on the Incidence Rate of Congenital Hypothyroidism

Newborn screening (NBS) laboratories in the United States expanded their programs to include primary congenital hypothyroidism (CH) in the 1970s. An increase in the national CH-incidence rate since 1987 has been reported. Our goal was to analyze national data reported by state NBS programs and laboratories from 1991 to 2000 to determine the extent to which changing laboratory methods might have contributed to the reported rise in CH-incidence rate. We used generalized estimating equations to analyze the association between the rate of confirmed cases of CH per 100000 live births and the initial screening method (thyroxine [T4] or thyrotropin [TSH] assay), the T4- and TSH-assay methods, the screening-test cutoff value used to report abnormal T4- or thyrotropin-assay results, and the performance of a second screen on >or=80% of newborns in the state. We then evaluated the association of CH rate with year after adjusting for any screening methodology or parameter that was significant in the univariate analysis. During 1991-2000, laboratories that used a TSH assay for initial screening reported a 24% higher incidence rate of CH than those that used a T4 assay. The assay type also affected the incidence rate. Screening for T4 by enzyme immunometric assay (EIA) or fluoroimmunoassay (FIA) methods resulted in 38% and 24% higher incidence rates of CH, respectively, compared with the radioimmunoassay (RIA) method, whereas screening for TSH by the FIA method resulted in a 20% higher incidence rate of CH than did screening with radiochemical methods. During the decade studied, many laboratories changed their T4-assay method from RIA to either FIA or EIA; this particular change seemed to have the greatest impact on the CH-incidence rate. Although the use of different laboratory methods and screening practices by NBS laboratories affected the incidence rate of CH, after adjusting for screening methodologies and parameters, an increasing incidence rate still persisted during the decade studied. Thus, there seem to be additional unknown factors that contributed to the reported increase in incidence rate.

The Impact of Transient Hypothyroidism on the Increasing Rate of Congenital Hypothyroidism in the United States

The reported incidence rate of primary congenital hypothyroidism (CH) has been increasing in the United States over the past 2 decades. We have considered the possibility that the inclusion of cases of transient hypothyroidism has inflated the reported incidence rate of CH. Assessing the effects of cases of transient hypothyroidism on the incidence rate is problematic, because the definitions, diagnostic criteria, and differentiation from transient hyperthyrotropinemia vary widely among state newborn screening programs. Among the 4 etiologies for transient hypothyroidism (maternal thyrotropin receptor-blocking antibodies, exposure to maternal antithyroid medications, iodine deficiency, and iodine excess), there is little evidence of increases in the incidence rate from thyrotropin receptor-blocking antibodies. Exposure to antithyroid drugs could contribute significantly to the incidence rate of transient CH, given the high estimated incidence of active maternal hyperthyroidism. Iodine deficiency or excess in the United States seems unlikely to have contributed significantly to the incidence rate of CH, because the secular trend toward lower iodine intake among women of reproductive age in the 1980s and 1990s seems to have plateaued, and perinatal iodine exposure has presumably declined as a result of recommendations to discontinue using iodine-containing disinfectants. Although the female-to-male sex ratio among newborns with thyroid agenesis or dysgenesis (the most common causes of CH) is typically 2:1, analysis of the sex ratio of newborns diagnosed with presumed CH in the United States suggests that a substantial proportion might have transient hypothyroidism or hyperthyrotropinemia, because the sex ratio has been well below the expected 2:1 ratio. Combined ultrasonography and (123)I scintigraphy of the thyroid gland are effective tools for identifying cases of thyroid agenesis and dysgenesis and can help to differentiate cases of transient hypothyroidism from true CH. Imaging is also a vital component in evaluating children who, at 3 years of age, undergo a trial of discontinuation of levothyroxine treatment to test for persistence of hypothyroidism. Ultimately, thyroid gland imaging, in conjunction with long-term follow-up studies that appropriately assess and report whether there was permanence of hypothyroidism, will be necessary to address the true incidence rate of CH and any contribution to the observed rate by transient cases of hypothyroidism or hyperthyrotropinemia.