Abstract
Background: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGβ for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria.
Methods: This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGβ were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values.
Results: Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGβ MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates.
Conclusions: Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGβ but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.
Acknowledgments
We thank AnshLabs, Webster, TX, USA for their kind donation of the PAPP-A2 assays. Also, we thank Dr. Carsten Nickelsen, MD, DMSc. and Steen Rasmussen, Senior Advisor, M.Sc. for helping with the data collection.
Author contributions:All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership:Claus Oxvig is an inventor on patent US7083940 relating to measurement of PAPP-A2.
Honorarium: None declared.
Competing interests:The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem 2001;276:21849–53.10.1074/jbc.M102191200Search in Google Scholar PubMed
2. Macintire K, Tuohey L, Ye L, Palmer K, Gantier M, Tong S, et al. PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia. Reprod Fertil Dev 2014;26:351–7.10.1071/RD12384Search in Google Scholar PubMed
3. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996;335:1363–7.10.1056/NEJM199610313351805Search in Google Scholar PubMed
4. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990;345:78–80.10.1038/345078a0Search in Google Scholar PubMed
5. Yan X, Baxter RC, Firth SM. Involvement of pregnancy-associated plasma protein-A2 in insulin-like growth factor (IGF) binding protein-5 proteolysis during pregnancy: a potential mechanism for increasing IGF bioavailability. J Clin Endocrinol Metab 2010;95:1412–20.10.1210/jc.2009-2277Search in Google Scholar PubMed
6. Oxvig C. The role of PAPP-A in the IGF system: location, location, location. J Cell Commun Signal [Epub 2015 Jan 25.]. doi: 10.1007/s12079-015-0259-9.10.1007/s12079-015-0259-9Search in Google Scholar PubMed PubMed Central
7. Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH. Screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart rate, free beta-hCG and pregnancy-associated plasma protein-A. Hum Reprod 2008;23:1968–75.10.1093/humrep/den224Search in Google Scholar PubMed
8. Salvig JD, Kirkegaard I, Winding TN, Henriksen TB, Tørring N, Uldbjerg N. Low PAPP-A in the first trimester is associated with reduced fetal growth rate prior to gestational week 20. Prenat Diagn 2010;30:503–8.10.1002/pd.2487Search in Google Scholar PubMed
9. Cowans NJ, Spencer K. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system. Prenat Diagn 2007;27:264–71.10.1002/pd.1665Search in Google Scholar PubMed
10. Spencer K, Yu CK, Cowans NJ, Otigbah C, Nicolaides KH. Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler. Prenat Diagn 2005;25:949–53.10.1002/pd.1251Search in Google Scholar PubMed
11. Conover CA, Boldt HB, Bale LK, Clifton KB, Grell JA, Mader JR, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice. Endocrinology 2011;152:2837–44.10.1210/en.2011-0036Search in Google Scholar PubMed
12. Christians JK, de Zwaan DR, Fung SH. Pregnancy associated plasma protein A2 (PAPP-A2) affects bone size and shape and contributes to natural variation in postnatal growth in mice. PLoS One 2013;8:e56260.10.1371/journal.pone.0056260Search in Google Scholar PubMed PubMed Central
13. Whitehead CL, Walker SP, Ye L, Mendis S, Kaitu’u-Lino TJ, Lappas M, et al. Placental specific mRNA in the maternal circulation are globally dysregulated in pregnancies complicated by fetal growth restriction. J Clin Endocrinol Metab 2013;98:E429–36.10.1210/jc.2012-2468Search in Google Scholar PubMed
14. Nishizawa H, Pryor-Koishi K, Suzuki M, Kato T, Kogo H, Sekiya T, et al. Increased levels of pregnancy-associated plasma protein-A2 in the serum of pre-eclamptic patients. Mol Hum Reprod 2008;14:595–602.10.1093/molehr/gan054Search in Google Scholar PubMed
15. Winn VD, Gormley M, Paquet AC, Kjaer-Sorensen K, Kramer A, Rumer KK, et al. Severe preeclampsia-related changes in gene expression at the maternal-fetal interface include sialic acid-binding immunoglobulin-like lectin-6 and pappalysin-2. Endocrinology 2009;150:452–62.10.1210/en.2008-0990Search in Google Scholar PubMed PubMed Central
16. Crosley EJ, Durland U, Seethram K, Macrae S, Gruslin A, Christians JK. First-trimester levels of pregnancy-associated plasma protein A2 (PAPP-A2) in the maternal circulation are elevated in pregnancies that subsequently develop preeclampsia. Reprod Sci 2014;21:754–60.10.1177/1933719113512532Search in Google Scholar PubMed PubMed Central
17. Loughna P, Chitty L, Evans T, Chudleigh T. Fetal size and dating: charts recommended for clinical obstetric practice. Ultrasound 2009;17:161–7.10.1179/174313409X448543Search in Google Scholar
18. Robinson HP, Fleming JE. A critical evaluation of sonar “crown-rump length” measurements. Br J Obstet Gynaecol 1975;82:702–10.10.1111/j.1471-0528.1975.tb00710.xSearch in Google Scholar PubMed
19. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996;85:843–8.10.1111/j.1651-2227.1996.tb14164.xSearch in Google Scholar PubMed
20. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234–8.10.1056/NEJM199904223401603Search in Google Scholar PubMed
21. Ruge S, Pedersen JF, Sørensen S, Lange AP. Can pregnancy-associated plasma protein A (PAPP-A) predict the outcome of pregnancy in women with threatened abortion and confirmed fetal viability? Acta Obstet Gynecol Scand 1990;69:589–95.10.3109/00016349009028701Search in Google Scholar
22. Storring PL, Gaines-Das RE, Bangham DR. International Reference Preparation of Human Chorionic Gonadotrophin for Immunoassay: potency estimates in various bioassay and protein binding assay systems; and International Reference Preparations of the alpha and beta subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980;84:295–310.10.1677/joe.0.0840295Search in Google Scholar
23. Sørensen S, Momsen G, Sundberg K, Friis-Hansen L, Jørgensen FS. First-trimester risk calculation for trisomy 13, 18, and 21: comparison of the screening efficiency between 2 locally developed programs and commercial software. Clin Chem 2011;57:1023–31.10.1373/clinchem.2010.161299Search in Google Scholar
24. Kagan KO, Wright D, Spencer K, Molina FS, Nicolaides KH. First-trimester screening for trisomy 21 by free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of maternal and pregnancy characteristics. Ultrasound Obstet Gynecol 2008;31:493–502.10.1002/uog.5332Search in Google Scholar
25. Spencer K, Ong CY, Liao AW, Papademetriou D, Nicolaides KH. The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation. Prenat Diagn 2000;20:673–5.10.1002/1097-0223(200008)20:8<673::AID-PD880>3.0.CO;2-5Search in Google Scholar
26. Reynolds TM, Vranken G, Van NJ. Weight correction of MoM values: which method? J Clin Pathol 2006;59:753–8.10.1136/jcp.2005.034280Search in Google Scholar
27. Kirkegaard I, Henriksen TB, Uldbjerg N. Early fetal growth, PAPP-A and free beta-hCG in relation to risk of delivering a small-for-gestational age infant. Ultrasound Obstet Gynecol 2011;37:341–7.10.1002/uog.8808Search in Google Scholar
28. Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2008;31:15–9.10.1002/uog.5165Search in Google Scholar
29. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol 2004;191:1446–51.10.1016/j.ajog.2004.06.052Search in Google Scholar
30. Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab 2002;87:1762–7.10.1210/jcem.87.4.8430Search in Google Scholar
31. Pihl K, Larsen T, Krebs L, Christiansen M. First trimester maternal serum PAPP-A, beta-hCG and ADAM12 in prediction of small-for-gestational-age fetuses. Prenat Diagn 2008;28:1131–5.10.1002/pd.2141Search in Google Scholar PubMed
32. Kløverpris S, Gaidamauskas E, Rasmussen LC, Overgaard MT, Kronborg C, Knudsen UB, et al. A robust immunoassay for pregnancy-associated plasma protein-A2 based on analysis of circulating antigen: establishment of normal ranges in pregnancy. Mol Hum Reprod 2013;19:756–63.10.1093/molehr/gat047Search in Google Scholar PubMed
33. Bonno M, Oxvig C, Kephart GM, Wagner JM, Kristensen T, Sottrup-Jensen L, et al. Localization of pregnancy-associated plasma protein-A and colocalization of pregnancy-associated plasma protein-A messenger ribonucleic acid and eosinophil granule major basic protein messenger ribonucleic acid in placenta. Lab Invest 1994;71:560–6.Search in Google Scholar
©2016 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorial
- Building a bridge to safe diagnosis in health care. The role of the clinical laboratory
- Capillary electrophoresis for the screening and diagnosis of inherited hemoglobin disorders. Ready for prime time?
- Reviews
- Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis
- Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings
- Mini Review
- Clinical relevance of sST2 in cardiac diseases
- General Clinical Chemistry and Laboratory Medicine
- Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses
- Performance characteristics of the VIDAS® 25-OH Vitamin D Total assay – comparison with four immunoassays and two liquid chromatography-tandem mass spectrometry methods in a multicentric study
- Differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinase-associated lipocalin (uNGAL)
- Early postoperative C-terminal agrin fragment (CAF) serum levels predict graft loss and proteinuria in renal transplant recipients
- Homocitrulline: a new marker for differentiating acute from chronic renal failure
- Hematology and Coagulation
- Development of hemoglobin typing control materials for laboratory investigation of thalassemia and hemoglobinopathies
- Comparison of capillary electrophoresis and high performance liquid chromatography for detection and quantification of hemoglobin New York
- Prevalence of hemostatic alterations in patients with recurrent spontaneous subconjunctival hemorrhage
- Reference Values and Biological Variations
- Reference intervals for 24 laboratory parameters determined in 24-hour urine collections
- First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies
- Cancer Diagnostics
- Clinical utility of one versus two faecal immunochemical test samples in the detection of advanced colorectal neoplasia in symptomatic patients
- Cardiovascular Diseases
- Time from symptom onset influences high-sensitivity troponin T diagnostic accuracy for the diagnosis of acute myocardial infarction
- Prognostic significance of serum albumin level changes in acute ischemic stroke: the role of biological and analytical variation
- Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population
- Infectious Diseases
- Usefulness of several biomarkers in the management of septic patients: C-reactive protein, procalcitonin, presepsin and mid-regional pro-adrenomedullin
- Diabetes
- Performance of strip-based glucose meters and cassette-based blood gas analyzer for monitoring glucose levels in a surgical intensive care setting
- Accuracy and precision assessment of a new blood glucose monitoring system
- Acknowledgment
- Acknowledgment
- Letter to the Editors
- Glypican-1 as a highly sensitive and specific pancreatic cancer biomarker
- Platelet microRNAs are not modulated by systemic heparin in acute coronary syndromes
- Concomitant appearance of two false positive peaks with a true monoclonal one in a patient with plasma cell myeloma
- Anti-streptavidin interferences in Roche thyroid immunoassays: a case report
- Evaluation of the new Methotrexate CMIA assay on the Architect i2000SR
- Liposomal interference on Sysmex XN-series body fluid mode
- Development of an immunomagnetic beads-based test and its application in influenza surveillance
Articles in the same Issue
- Frontmatter
- Editorial
- Building a bridge to safe diagnosis in health care. The role of the clinical laboratory
- Capillary electrophoresis for the screening and diagnosis of inherited hemoglobin disorders. Ready for prime time?
- Reviews
- Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis
- Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings
- Mini Review
- Clinical relevance of sST2 in cardiac diseases
- General Clinical Chemistry and Laboratory Medicine
- Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses
- Performance characteristics of the VIDAS® 25-OH Vitamin D Total assay – comparison with four immunoassays and two liquid chromatography-tandem mass spectrometry methods in a multicentric study
- Differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinase-associated lipocalin (uNGAL)
- Early postoperative C-terminal agrin fragment (CAF) serum levels predict graft loss and proteinuria in renal transplant recipients
- Homocitrulline: a new marker for differentiating acute from chronic renal failure
- Hematology and Coagulation
- Development of hemoglobin typing control materials for laboratory investigation of thalassemia and hemoglobinopathies
- Comparison of capillary electrophoresis and high performance liquid chromatography for detection and quantification of hemoglobin New York
- Prevalence of hemostatic alterations in patients with recurrent spontaneous subconjunctival hemorrhage
- Reference Values and Biological Variations
- Reference intervals for 24 laboratory parameters determined in 24-hour urine collections
- First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies
- Cancer Diagnostics
- Clinical utility of one versus two faecal immunochemical test samples in the detection of advanced colorectal neoplasia in symptomatic patients
- Cardiovascular Diseases
- Time from symptom onset influences high-sensitivity troponin T diagnostic accuracy for the diagnosis of acute myocardial infarction
- Prognostic significance of serum albumin level changes in acute ischemic stroke: the role of biological and analytical variation
- Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population
- Infectious Diseases
- Usefulness of several biomarkers in the management of septic patients: C-reactive protein, procalcitonin, presepsin and mid-regional pro-adrenomedullin
- Diabetes
- Performance of strip-based glucose meters and cassette-based blood gas analyzer for monitoring glucose levels in a surgical intensive care setting
- Accuracy and precision assessment of a new blood glucose monitoring system
- Acknowledgment
- Acknowledgment
- Letter to the Editors
- Glypican-1 as a highly sensitive and specific pancreatic cancer biomarker
- Platelet microRNAs are not modulated by systemic heparin in acute coronary syndromes
- Concomitant appearance of two false positive peaks with a true monoclonal one in a patient with plasma cell myeloma
- Anti-streptavidin interferences in Roche thyroid immunoassays: a case report
- Evaluation of the new Methotrexate CMIA assay on the Architect i2000SR
- Liposomal interference on Sysmex XN-series body fluid mode
- Development of an immunomagnetic beads-based test and its application in influenza surveillance