Skip to main content

The influence of seasonality and manufacturer kit lot changes on 17α-hydroxyprogesterone measurements and referral rates of congenital adrenal hyperplasia in newborns

European Journal of Pediatrics volume 176, pages 121–129 (2017)Cite this article

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) is performed by measuring the concentration of 17α-hydroxyprogesterone (17-OHP) in dried blood spots. Unfortunately, the level of 17-OHP varies due to multiple factors, and therefore, the false positive rate for the test is a challenge. We analyzed screening data from 2007 to 2015 to determine the effect of seasonal changes and manufacturer kit lot changes on 17-OHP values and on numbers of infants referred. Data from screening 2.2 million infants over a 9-year period indicates that in the NYS during the colder months, daily mean 17-OHP values are higher, more retests are performed, and more infants are referred even though fewer infants are born. The practice of using fixed cutoffs for referring infants for CAH leads to more false positive results in colder months. In addition, there was an overall 10% increase in the daily mean 17-OHP values from the 2 years before and after a manufacturer kit lot change that occurred in November 2013, suggestive of a functional change in the kit at that time.

Conclusion: Newborn screening programs should be cognizant of seasonal temperature variations and (un)anticipated manufacturer kit changes because they may affect 17-OHP values and CAH referral rates.

What is Known:
• Newborn screening for congenital adrenal hyperplasia is generally performed by measuring 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots.
• 17-OHP concentrations are affected by gestational age/weight of infant when specimen is collected, specimen collection time after birth, as well as race and sex of infant.
What is New:
• Seasonal temperature variations and unanticipated manufacturer kit changes affect 17-OHP levels and consequently referral rates in programs that use fixed cutoffs.
• Daily mean 17-OHP is generally higher when the ambient temperature is lower.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

17-OHP:

17α-Hydroxyprogesterone

CAH:

Congenital adrenal hyperplasia

LBW:

Low birth weight

LOESS:

Local regression

NBS:

Newborn screening

NYC:

New York City

NYS:

New York State

PPV:

Positive predictive value

SV:

Simple virilizing

SW:

Salt wasting

References

  1. Allen DB, Hoffman GL, Fitzpatrick P, Laessig R, Maby S, Slyper A (1997) Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr 130:128–133

    CAS  Article  PubMed  Google Scholar 

  2. al-Nuaim AR, Abdullah MA, Stevens B, Zain M (1995) Effect of gender, birth weight and gestational age on serum 17-hydroxyprogesterone concentration and distribution among neonates in Saudi Arabia. Indian J Pediatr 62:605–609

    CAS  Article  PubMed  Google Scholar 

  3. Barra CB, Silva IN, Pezzuti IL, Januário JN (2012) Neonatal screening for congenital adrenal hyperplasia. Rev Assoc Med Bras 58:459–464

    Article  PubMed  Google Scholar 

  4. Chan CL, McFann K, Taylor L, Wright D, Zeitler PS, Barker JM (2013) Congenital adrenal hyperplasia and the second newborn screen. J Pediatr 163:109–113

    CAS  Article  PubMed  Google Scholar 

  5. Gidlöf S, Wedell A, Guthenberg C, von Döbeln U, Nordenström A (2014) Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr 168:567–574

    Article  PubMed  Google Scholar 

  6. González EC, Carvajal F, Frómeta A, Arteaga AL, Castells EM, Espinosa T, Coto R, Pérez PL, Tejeda Y, Del Río L, Segura MT, Almenares P, Robaina R, Fernández JL (2013) Newborn screening for congenital adrenal hyperplasia in Cuba: six years of experience. Clin Chim Acta 421:73–78

    Article  PubMed  Google Scholar 

  7. Gruñieiro-Papendieck L, Chiesa A, Mendez V, Prieto L (2008) Neonatal screening for congenital adrenal hyperplasia: experience and results in Argentina. J Clin Endocrinol Metab 21:73–78

    Google Scholar 

  8. Gruñieiro-Papendieck L, Prieto L, Chiesa A, Bengolea S, Bergada C (1998) Congenital adrenal hyperplasia and early newborn screening: 17α-hydroxyprogesterone (17α-OHP) during the first days of life. J Med Screen 5:24–26

    Article  Google Scholar 

  9. Heather NL, Seneviratne SN, Webster D, Derraik JG, Jefferies C, Carll J, Jiang Y, Cutfield WS, Hofman PL (2015) Newborn screening for congenital adrenal hyperplasia in New Zealand, 1994–2013. J Clin Endocrinol Metab 100:1002–1008

    Article  PubMed  Google Scholar 

  10. Hofman LF, Klaniecki JE, Smith EK (1985) Direct solid-phase radioimmunoassay for screening 17 alpha-hydroxyprogesterone in whole-blood samples from newborns. Clin Chem 31:1127–1130

    CAS  PubMed  Google Scholar 

  11. Kay DM, Maloney B, Hamel R, Pearce M, DeMartino L, McMahon R, McGrath E, Krein L, Vogel B, Saavedra-Matiz CA, Caggana M, Tavakoli NP (2016) Screening for cystic fibrosis in New York State: considerations for algorithm improvements. Eur J Pediatr 175:181–193

    Article  PubMed  Google Scholar 

  12. Kloosterboer M, Hoffman G, Rock M, Gershan W, Laxova A, Li Z, Farrell PM (2009) Clarification of laboratory and clinical variables that influence cystic fibrosis newborn screening with initial analysis of immunoreactive trypsinogen. Pediatrics 123:e338–e346

    Article  PubMed  Google Scholar 

  13. Lando VS, Batista MC, Nakamura IT, Mazi CR, Mendonca BB, Brito VN (2008) Effects of long-term storage of filter paper blood samples on neonatal thyroid stimulating hormone, thyroxin and 17-alpha-hydroxyprogesterone measurements. J Med Screen 15:109–111

    Article  PubMed  Google Scholar 

  14. Lange-Kubini K, Zachmann M, Kempken B, Torresani T (1996) 15 beta-hydroxylated steroids may be diagnostically misleading in confirming congenital adrenal hyperplasia suspected by a newborn screening programme. Eur J Pediatr 155:928–931

    CAS  Article  PubMed  Google Scholar 

  15. Morikawa S, Nakamura A, Fujikura K, Fukushi M, Hotsubo T, Miyata J, Ishizu K, Tajima T (2014) Results from 28 years of newborn screening for congenital adrenal hyperplasia in Sapporo. Clin Pediatr Endocrinol 23:35–43

    Article  PubMed  PubMed Central  Google Scholar 

  16. Murphy JF, Joyce BG, Dyas J, Hughes IA (1983) Plasma 17-OHP concentrations in ill newborn infants. Arch Dis Child 58:532–534

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Odenwald B, Dörr HG, Bonfig W, Schmidt H, Fingerhut R, Wildner M, Nennstiel-Ratzel U (2015) Classic congenital adrenal hyperplasia due to 21-hydroxylase-deficiency: 13 years of neonatal screening and follow-up in Bavaria. Klin Pädiatr 227:278–283

    CAS  Article  PubMed  Google Scholar 

  18. Olgemöller B, Roscher AA, Liebl B, Fingerhut R (2003) Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value. J Clin Endocrinol Metab 88:5790–5794

    Article  PubMed  Google Scholar 

  19. Pang SY, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon IC, Dobbins RH, Kling S, Fujieda K, Suwa S (1988) Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81:866–874

    CAS  PubMed  Google Scholar 

  20. Pearce M, DeMartino L, McMahon R, Hamel R, Maloney B, Stansfield D-M, McGrath MC, Occhionero A, Gearhart A, Caggana M, Tavakoli NP (2016) Newborn screening for congenital adrenal hyperplasia in New York State. Mol Genet Metab Rep 7:1–7

    Article  PubMed  PubMed Central  Google Scholar 

  21. Petsos P, Ratcliffe WA, Anderson DC (1985) Assessment of corpus luteum function by direct radioimmunoassay for progesterone in blood spotted on filter paper. Clin Chem 31:1289–1293

    CAS  PubMed  Google Scholar 

  22. Ryckman KK, Berberich SL, Shchelochkov OA, Cook DE, Murray JC (2013) Clinical and environmental influences on metabolic biomarkers collected for newborn screening. Clin Biochem 46:133–138

    CAS  Article  PubMed  Google Scholar 

  23. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society (2010) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95:4133–4160

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Therrell BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S (1998) Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101:583–590

    Article  PubMed  Google Scholar 

  25. Török D, Mühl A, Votava F, Heinze G, Sólyom J, Crone J, Stöckler-Ipsiroglu S, Waldhauser F (2002) Stability of 17alpha-hydroxyprogesterone in dried blood spots after autoclaving and prolonged storage. Clin Chem 48:370–372

    PubMed  Google Scholar 

  26. White PC (2009) Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 5:490–498

    CAS  Article  PubMed  Google Scholar 

  27. Wilson K, Hawken S, Ducharme R, Potter BK, Little J, Thébaud B, Chakraborty P (2014) Metabolomics of prematurity: analysis of patterns of amino acids, enzymes, and endocrine markers by categories of gestational age. Pediatr Res 75:367–373

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

Newborn screening is funded by the State of New York. The authors wish to thank the Photography Unit at Wadsworth Center for assistance with the figures.

Authors’ contributions

MP was involved in acquisition of data and revising the manuscript. ED and AGD performed statistical analysis and were involved in revising the manuscript. MC was involved in interpreting data and revising the manuscript. NPT was involved in design of the work, analysis, and interpreting of data and drafting and finalizing the manuscript.

Author information

Authors and Affiliations

  1. Division of Genetics, Wadsworth Center, New York State Department of Health, 120, New Scotland Ave., Albany, 12208, NY, USA

    Melissa Pearce, Michele Caggana & Norma P. Tavakoli

  2. Department of Epidemiology and Biostatistics, School of Public Health, State University of New York, Albany, NY, USA

    Erin Dauerer & A. Gregory DiRienzo

  3. Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, NY, USA

    Norma P. Tavakoli

Authors
  1. Melissa Pearce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erin Dauerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Gregory DiRienzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michele Caggana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norma P. Tavakoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norma P. Tavakoli.

Ethics declarations

The manuscript is a retrospective case report that does not require ethics committee approval at our institution (Wadsworth Center, NYSDOH). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Communicated by Beat Steinmann

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pearce, M., Dauerer, E., DiRienzo, A.G. et al. The influence of seasonality and manufacturer kit lot changes on 17α-hydroxyprogesterone measurements and referral rates of congenital adrenal hyperplasia in newborns. Eur J Pediatr 176, 121–129 (2017). https://doi.org/10.1007/s00431-016-2814-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-016-2814-7

Keywords

  • Newborn screening
  • Congenital adrenal hyperplasia
  • 17α-Hydroxyprogesterone
  • Seasonal variation
  • Positive predictive value