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The influence of sex, gestational age, birth weight, blood transfusion, and timing of the heel prick on the pancreatitis-associated protein concentration in newborn screening for cystic fibrosis

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

Pancreatitis-associated protein (PAP) is currently discussed as a marker in newborn screening (NBS) for cystic fibrosis (CF). However, it is not known if PAP concentrations are influenced by sex, gestational age, birth weight, blood transfusion or time of collection and what this would mean for NBS for CF.

Methods

In 2008 all newborns in part of the Netherlands were screened for CF by an IRT/PAP protocol. PAP concentration was determined by the MucoPAP ELISA (DynaBio), which was modified to a Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA) method following a protocol of PerkinElmer.

Results

In healthy newborns, the median PAP concentration was 0.5 μg/l (Interquartile range (IQR 0.3-0.8) whereas this was 3.2 μg/l (IQR 2.0-12.5) in CF infants. PAP concentrations were lower in premature infants 0.94 and 0.91 times for 25 to 31 + 6 weeks GA and 32 to 36 + 6 weeks respectively. A higher PAP concentration was observed in low-birth-weight infants (<2500 gram)(p = 0.001), per 100 gram birth weight gained the PAP concentration decreased with 0.1 %. PAP levels were higher after a blood transfusion, the 95th percentile increased from 1.3 to 3.6 μg/l leading to a higher false-positive rate. The PAP concentration increased when newborn screening was performed more than 168 hours (day 7) after birth (β = 1.63), the 95th percentile increased from 1.3-1.6 μg/l to 4.0 μg/l after 168 hours (72,874 newborns were screened).

Conclusion

Sex, birth weight, and gestational age lead to small differences in PAP concentrations without consequences for the screening algorithm. However, blood transfusion as well as performance of the heel prick after 168 hours (7 days) lead to clinically significant higher PAP levels and to a higher risk on a false-positive screening test result.

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Abbreviations

PAP:

Pancreatitis-associated protein

CF:

Cystic fibrosis

IRT:

Immunoreactive trypsinogen

CFTR:

Cystic fibrosis transmembrane conductance regulator

NBS:

Newborn screening

GA:

Gestational age

BW:

Birth weight

PPV:

Positive predictive value

Se:

Sensitivity

Sp:

Specificity

DNA:

Deoxyribonucleic acid

seq:

Sequencing of the CFTR gene

MI:

Meconium Ileus

ELISA:

Enzyme-linked immuno sorbent assay

DELFIA®:

Time-resolved fluoroimmunoassay

QPIT:

Quantitative pilocarpine iontophoresis

ICM:

Intestinal current measurement

CAH:

Congenital adrenal hyperplasia

PCR:

Polymerase chain reaction

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Acknowledgements

ZonMw, The Netherlands Organization for Health Research and Development, for financing the study. CF centres participating in this study for performing all sweat tests in screen-positive newborns: Erasmus Medical Centre-Rotterdam, Maastricht University Medical Centre, University Medical Centre Utrecht, University Medical Centre Nijmegen. The Dutch CF foundation (NCFS) for their advice and participation. Albert Wong from the National Institute of Public Health and the Environment and Joris Vernooij for their statistical advice.

Details of funding

ZonMw, the Dutch Organization for Health Research Development, financed the study. ZonMw had in no way influence on the data collection, analysis or interpretation, nor did they say anything about the writing or the decision for submission.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Research and Innovation, Atrium Medical Center, PO box 4446, 6401 CX, Heerlen, The Netherlands

    Annette M. M. Vernooij-van Langen

  2. Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), PO box 1, 3720 BA, Bilthoven, The Netherlands

    Annette M. M. Vernooij-van Langen

  3. Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment, PO box 1, 3720, BA, Bilthoven, The Netherlands

    J. Gerard Loeber & Bert Elvers

  4. Clinical Chemistry Laboratory, St. Elisabeth Hospital, Hilvarenbeekseweg 60, 5022 GC, Tilburg, The Netherlands

    Ralf H. Triepels & Jos Roefs

  5. Department of Clinical Genetics, VU university medical Center, PO box 7057, 1007 MB, Amsterdam, The Netherlands

    Johan J. Gille

  6. Department of Research and Innovation, Atrium Medical Center, Henri Dunantstraat 5, PO box 4446, 6401 CX, Heerlen, The Netherlands

    Sandra Reijntjens

  7. Department of Pediatric Pulmonology, Maastricht University Medical Center, PO box 5800, 6202 AZ, Maastricht, The Netherlands

    Edward Dompeling

  8. Department of Pediatrics, Atrium Medical Center, Henri Dunantstraat 5, PO box 4446, 6401 CX, Heerlen, The Netherlands

    Jeannette E. Dankert-Roelse

Authors
  1. Annette M. M. Vernooij-van Langen
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  2. J. Gerard Loeber
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  3. Bert Elvers
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  4. Ralf H. Triepels
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  5. Jos Roefs
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  6. Johan J. Gille
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  7. Sandra Reijntjens
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  8. Edward Dompeling
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  9. Jeannette E. Dankert-Roelse
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Corresponding author

Correspondence to Annette M. M. Vernooij-van Langen.

Additional information

Communicated by: Georg Hoffmann

Data were previously presented as a poster at the 6th ISNS European Regional Meeting in Neonatal Screening, Prague, April 26-28th 2009. Vernooij-van Langen A., Dankert-Roelse J., Reijntjens S., Elvers B., Triepels R., Loeber G., Pancreatitis-associated Protein in CF screening, Abstract 69.

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Vernooij-van Langen, A.M.M., Loeber, J.G., Elvers, B. et al. The influence of sex, gestational age, birth weight, blood transfusion, and timing of the heel prick on the pancreatitis-associated protein concentration in newborn screening for cystic fibrosis. J Inherit Metab Dis 36, 147–154 (2013). https://doi.org/10.1007/s10545-012-9498-6

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  • DOI: https://doi.org/10.1007/s10545-012-9498-6

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