Paradigms of NBS Testing

There are 2 methods of screening for disorders on the RUSP: dried bloodspot screening and point of care screening, both of which are generally performed prior to discharge at the hospital where the infant was born.12

Dried Bloodspot Screening

With the original RUSP in 2005, 28 conditions on the list were screened by bloodspot. Since then, 5 additional disorders have been added, bringing the total number of conditions screened by bloodspot to 33 as of July 2018.4 The most recent conditions and the year each was added include glycogen storage disease type II, also known as Pompe disease, (2013); severe combined immunodeficiencies (2010); mucopolysaccharidosis type 1 (2015); x-linked adrenoleukodystrophy (2015); and spinal muscular atrophy (2018).4


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Ideally, the blood test is performed at 24 to 48 hours of age.13 However, timing and frequency for bloodspot collection vary to some degree by state.14 For example, some states require a second screen for all infants15 and some require a second screen during neonatal intensive care unit (NICU) hospitalization when the infant received a blood transfusion.16 Screens performed at less than 24 hours of age are not recommended and may not detect all disorders. If the NBS was done earlier than 24 hours of age, a repeat NBS is recommended by 2 weeks of age.13

The standardized procedure for bloodspot collection and handling is as follows17:

  1. Check the expiration date and complete the information on the NBS form/card, taking care not to contaminate the filter paper circles.
  2. After warming the infant’s heel for 3 to 5 minutes, cleanse and puncture a safe area of the heal (ie, medial or lateral aspect of the plantar surface), wipe away the first blood drop, and allow another drop to form. 
  3. Lightly apply the filter paper card to a large drop of blood to completely fill the circle (only on one side of the form/card) and repeat for the remaining circles. A total of 4 to 5 drops of blood is usually sufficient.14
  4. Allow the bloodspots to dry on a clean, flat surface for at least 4 hours before sending the form to either the hospital laboratory or the appropriate state-affiliated laboratory for analysis. It is critical that the NBS form be sent to the centralized testing laboratory within 24 hours of collection.13,14

Once received at the centralized laboratory performing the analysis, a standardized amount of the blood specimen is punched out of the filter paper card, and metabolites of interest are extracted from the punch and chemically modified for tandem mass spectrometry (MS/MS) analysis. A large number of disorders belonging to a particular disease category can be screened for with each sample. 11

Point of Care Screening

While the NBS primarily detects genetic disorders assessed by laboratory analysis of dried bloodspot specimens, 2 of the most common conditions included in the RUSP are assessed by point of care screening: congenital hearing loss and critical congenital heart disease (CCHD). Screening for congenital hearing loss has been recommended in the NBS since the original RUSP was developed and critical congenital heart disease (CCHD) was added to the RUSP in 2011 12

Congenital Hearing Screen

 The frequency of congenital hearing loss is 1.3 per 1000 live births.4 Universal newborn hearing screening identifies congenital bilateral or unilateral hearing loss and deafness. Timely identification of hearing loss is critical because early intervention maximizes speech, language, and cognition development. While both automated auditory brainstem response (AABR) and otoacoustic emissions (OAE) are both appropriate methods for screening hearing, AABR may have a lower referral rate compared to OAE and has the benefit of assessing more of the auditory system, including detection of neurologic involvement.18 Newborns who fail one or both types of screening prior to hospital discharge should be referred for follow-up testing within a month.17,18

False positives are sometimes secondary to ambient noise or the presence of amniotic fluid, vernix, or mucus in the ear.18 Challenges associated with hearing screens include the lack of availability of audiology staff when infants are discharged after business hours, keeping infants quiet during the screening, and ensuring patients are not lost to follow-up.14,18

Critical Congenital Heart Disease

Heart disease affects 1 in 550 infants.4 The 7 defects classified as CCHD are hypoplastic left heart syndrome, pulmonary atresia, tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, and truncus arteriosus. Symptoms of CCHD may not be apparent until days or weeks after birth, but infants can present with circulatory collapse and require emergency care when discharged home with an undetected ductal-dependent congenital heart defect.17 Testing for CCHD is noninvasive and is performed using pulse oximetry, which can detect even mild hypoxemia. 19

Typically, CCHD screening is done at 24 to 48 hours of age or as close to hospital discharge as possible if the infant’s stay is less than 24 hours.19 While a negative screen does not ensure the absence of a heart defect, a positive screen indicates lower than normal oxygenation or a significant gradient in saturation readings between the right hand and foot, necessitating follow-up testing by diagnostic echocardiogram unless a reversible cause of hypoxemia has been identified.19 The Centers for Disease Control and Prevention (CDC) algorithm for CCHD is not a substitute for a thorough physical examination and complete family and pregnancy history.19

Heart screening challenges include poor perfusion, probe detachment, hemoglobin pathologies, and occurrence of false positives.14 False positives may be lower when the infant is alert and when the screen is performed at least 24 hours of age.19 Proper training is needed for staff to perform CCHD screens.

Ethical Considerations

Consent

Screening programs are operated at the state level; therefore, there is no national uniform policy for obtaining content for NBS or providing educational materials to parents. There are varying models for obtaining consent for screening, described as implied consent20 and standard of care,21 while opt-in approaches are often described as informed choice, consent, or dissent.22 Currently, consent is usually included in the forms for standard medical newborn care that is required after birth6; however, such models assume parents have knowledge of the NBS policies. Some states require parents to sign an informed dissent document or a test refusal form releasing the health care provider from liability and thereby placing responsibility with the parent if a serious illness or permanent damage to the child occurs as a result of not screening the infant.6 If NBS information is provided prenatally and parents have an opportunity to learn about NBS prior to the birth of the newborn, the current system of informed dissent may be adequate.

Storage of Specimens after Testing 

Dried blood samples (DBS) have long-term stability, providing the opportunity for reanalysis.13 Each state has its own policy regarding residual blood spot storage and use. Some states store DBS for a few weeks and then destroy them, while others store them indefinitely.6 States retain the specimen as a part of a quality control program while work is done to improve existing testing methods or develop new screening tests. Residual DBS are a valuable resource for researchers who aim to further understand diseases in children.6,23 The use of residual specimens beyond routine NBS screening purposes is strictly controlled, although oversight is state mandated. The Newborn Screening Saves Lives Reauthorization Act of 2014 authorized grant programs and other initiatives to promote expanded screening of newborns for genetic disorders.24 The law requires that all research funded pursuant to the Public Health Service Act using DBS be considered human subjects research regardless of whether the specimens are identifiable. There are privacy protections and patient confidentiality rules to ensure that DBS cannot be accessed by a third party, including insurers and law enforcement.6

Timely Follow-Up of NBS Results

Most conditions included in the RUSP can cause serious health issues if not detected and treated early; therefore, timely analysis of specimens, reporting of results, and follow-up of all NBS results is critical. Challenges with NBS that nurses may face include insufficient knowledge related to adequate specimen collection and the NBS process, confusion related to differences in the timing of specimen collection between states, time demands required for parental support, and lack of a dedicated quality assurance team to monitor the NBS process.13,14 In addition, infants in the NICU pose additional challenges because of prematurity, illness, metabolic instability, prolonged parenteral nutrition, need for repeat specimens, variations in state protocols for specimen collection post-transfusion, and increased rates of false-positive results.13,14,16

Most states use a computerized follow-up system to send NBS results. Health care providers must register and create a profile within the state’s system to request permission to access NBS results. For states who do not use a computerized system to report NBS results, a copy of the results may be faxed or mailed to the infant’s hospital of birth and to the infant’s primary care provider on record. State NBS programs rely on information submitted with the DBS to identify the newborn’s physician or medical home. However, many newborns lack an identified child health professional at the time of hospital discharge and the submitted specimen may list the nursery physician or the on-call physician as the physician of record.

Screening results should be expected in the timeframe of 2 to 3 weeks from specimen collection. If results have not been received by 3 weeks, the infant’s pediatrician should request the results.6 Reporting procedures and protocols vary by state. Some states are developing systems that allow information integration and program linkage to improve tracking of screening results and patient outcomes, but again this is not yet standardized on the national level.

Most NBS programs have follow-up protocols in the event of a positive result. A state coordinator will notify the health care provider on record and allow the health professional to perform repeat testing or refer to a specialist. Some programs notify both the child health care provider and the family.25 Education is one of the most important aspects when discussing a positive screen result, including a discussion of a potential false positive. It is important to inform parents about a positive result in person to explain what the initial and follow-up results mean even if the diagnosis is unconfirmed.3

Conclusion

Newborn screening is the largest and one of the most successful public health programs in the United States.13 Dried bloodspot screening and point of care testing for specific disorders reduce morbidity and mortality. Although there is some variation between states, most screen for the disorders listed on the RUSP. Timely collection, processing, reporting, and follow-up are critical for prompt disease management even when newborns are often asymptomatic. Parental education before screening or with an explanation of positive results may help increase follow-up and decrease anxiety. Click here for NBS information by state.

Sharron Forest, DNP, APRN, NNP-BC, has 30 years of experience in neonatal critical care nursing, 25 of which are as a neonatal nurse practitioner. She is an associate professor and DNP program director at the University of Texas Medical Branch. Her research and grant activities focus on maternal tobacco prevention and breastfeeding initiatives.

Jennifer Barnett, DNP, FNP-BC, is an assistant professor at University of Texas Medical Branch in the School of Nursing. She is a family practice nurse practitioner with over 20 years’ experience in the clinical setting. Dr Barnett’s clinical experiences include labor and delivery, medical–surgical, and primary care in the community including pediatric and home assessment care.

Ariana Komaroff, DNP, FNP-BC, is a family nurse practitioner and board-certified lactation consultant (IBCLC). She works in a pediatric practice in southern Connecticut with a focus on newborn care and breastfeeding medicine. She is an assistant professor of nursing at Columbia University School of Nursing, New York City.

References

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2. Woolf LI, Adams J. The early history of PKU. Int J Neonatal Screen. 2020;6(3):59. doi:10.3390/ijns6030059

3. Weismiller DG. Expanded newborn screening: information and resources for the family physician. Am Fam Physician. 2017;95(11):703-709.

4. Federal Advisor Committees. Advisory Committee on Heritable Disorders in Newborns and Children. Health Resources & Services Administration. Accessed March 16 2022. https://www.hrsa.gov/advisory-committees/heritable-disorders/index.html

5. Texas Department of State Health Services. Texas newborn screening — frequently asked questions. Texas Department of State Health Services. Published 2019. Accessed March 16, 2022. https://dshs.texas.gov/newborn/faqs_expansion_professionals.aspx?terms=secondary+conditions

6. Baby’s First Test. What is newborn screening? Baby Health. Published 2020. Accessed March 16, 2022. https://babysfirsttest.org/

7. Blackburn S. Endocrine disorders. In: Verklan MT, Walden M, Forest S, eds. Core Curriculum for Neonatal Intensive Care Nursing. 6th ed. Elsevier; 2021:543-567.

8. Lubber L. Congenital anomalies. In: Verklan MT, Walden M, Forest S, eds. Core Curriculum for Neonatal Intensive Care Nursing. 6th ed. Elsevier; 2021:654-677.

9. Chuang J, Gutmark-Little I. Thyroid disorders in the neonate. In: Martin R, Fanaroff A, Walsh M, eds, Fanaroff & Martin’s Neonatal-Perinatal Medicine Diseases of the Fetus and Newborn.11th ed. Elsevier; 2020:1642-1664.

10. Larson-Nath C, Gurram B, Chelimsy G. Disorders of digestion in the neonate. In: Martin R, Fanaroff A, Walsh M, eds. Fanaroff & Martin’s Neonatal-Perinatal Medicine Diseases of the Fetus and Newborn. 11th ed. Elsevier; 2020:1522-1540.

11. Konczal L, Zinn A. Inborn errors of metabolism. In: Martin R, Fanaroff A, Walsh M, eds. Fanaroff & Martin’s Neonatal-Perinatal Medicine Diseases of the Fetus and Newborn. 11th ed. Elsevier; 2020:1706-1795.

12. Centers for Disease Control and Prevention. Newborn Screening Portal. Published November 29, 2021. Accessed March 16, 2022. https://www.cdc.gov/newbornscreening/index.html

13. Kronn D. Navigating newborn screening in the NICU: a user’s guide. NeoReviews. 2019;20(5):e280-e291. doi:10.1542/neo.20-5-e280

14. Joseph RA. Expanded newborn screening. Adv Neonatal Care. 2017;17(3):151-161. doi:10.1097/anc.0000000000000381

15. McCandless SE, Wright EJ. Mandatory newborn screening in the United States: history, current status, and existential challenges. Birth Defects Res. 2020;112(4):350-366. doi:10.1002/bdr2.1653

16. Fabie NA, Pappas KB, Feldman GL. The current state of newborn screening in the United States. Pediatr Clin North Am. 2019;66(2):369-386. doi:10.1016/j.pcl.2018.12.007

17. Riley C, Spencer B, Prater L. Normal Term Newborn. In: Kenner C, Altimeier L, Boykova M, eds. Comprehensive Neonatal Nursing Care.6th ed. Springer; 2020:105-126.

18. Wroblewska-Seniuk KE, Dabrowski P, Szyfter W, Mazela J. Universal newborn hearing screening: methods and results, obstacles, and benefits. Pediatric Research.2016;81(3):415-422. doi:10.1038/pr.2016.250d

19. Centers for Disease Control and Prevention. Congenital heart defects information for healthcare providers. Published November 17, 2020. Accessed March 16, 2022. https://www.cdc.gov/ncbddd/heartdefects/hcp.html

20. Miller FA, Hayeems RZ, Carroll JC, et al. Consent for newborn screening: the attitudes of health care providers. Public Health Genomics. 2010;13(3):181-190. doi:10.1159/000240966

21. Araia MH, Wilson BJ, Chakraborty P, et al. Factors associated with knowledge of and satisfaction with newborn screening education: a survey of mothers. Genet Med.. 2012;14(12):963-970. doi:10.1038/gim.2012.87

22. Hargreaves K, Stewart R, Oliver S. Informed choice and public health screening for children: the case of blood spot screening. Health Expect. 2005;8(2):161-171. doi: 10.1111/j.1369-7625.2005.00324.x

23. New York State Department of Health, Wadsworth Center. Specimen usage, retention and security policies. Published October 11, 2019. Accessed March 16, 2022. https://www.wadsworth.org/programs/newborn/screening/families/specimen-usage

24. Lewis MH, Botkin JR. Newborn screening in the United States: ethical issues. In: Mastroianni AC, Kahn JP, Kass NE, eds. The Oxford Handbook of Public Health Ethics. Oxford University Press; 2019:652-663. doi:10.1093/oxfordhb/9780190245191.013.59

25. Percenti L, Vickery G. Newborn screening follow-up. N C Med J. 2019;80(1):37-41. doi:10.18043/ncm.80.1.37