Abstract
Objectives
Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free β-human chorionic gonadotropin (free β-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency.
Methods
Singleton pregnancies recruited at 11–14 weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates.
Results
Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72–97%) of the cases at a false-positive rate of 13% (95% CI: 12–15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82–99%) at a false-positive rate of 4% (95% CI: 4–5%) using a 1:300 cut-off and to 100% (95% CI: 89–100%) at a false-positive rate of 6% (95% CI: 5–8%) using a 1:500 cut-off.
Conclusions
First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.
Funding source: Jeanne et J.-Louis Lévesque Perinatal Research Chair
Acknowledgments
We thank the members of the Department of Obstetrics & Gynecology and the Department of Family Medicine of the Centre Hospitalier Universitaire de Québec, Québec, QC, Canada for the recruitment of women in this study. ThermoFisher/BRAHMS provided the kits, equipment and reagents that were used to measure the biochemical markers.
-
Research funding: This study was funded by the Jeanne-et-Jean-Louis-Lévesque Perinatal Research Chair at Université Laval. Dr. Bujold holds a Clinician-Scientist Award from the Fonds de recherche du Québec–Santé (FRQ-S).
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The study was approved by the CHU de Québec-Université Laval Research Ethics Board.
References
1. Nicolaides, KH. First-trimester screening for chromosomal abnormalities. Semin Perinatol 2005;29:190–4. https://doi.org/10.1053/j.semperi.2005.06.001.Search in Google Scholar PubMed
2. Nicolaides, KH, Spencer, K, Avgidou, K, Faiola, S, Falcon, O. Multicenter study of first-trimester screening for trisomy 21 in 75, 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221–6. https://doi.org/10.1002/uog.1860.Search in Google Scholar PubMed
3. Rink, BD, Norton, ME. Screening for fetal aneuploidy. Semin Perinatol 2016;40:35–43. https://doi.org/10.1053/j.semperi.2015.11.006.Search in Google Scholar PubMed
4. Boutin, A, Demers, S, Gasse, C, Giguère, Y, Tétu, A, Laforest, G, et al.. First trimester screening for fetal aneuploidies using placental growth factor: the Great Obstetrical Syndrome (GOS) Study. J Obstet Gynaecol Can 2018;40:1044–9. https://doi.org/10.1016/j.jogc.2017.11.032.Search in Google Scholar PubMed
5. Badeghiesh, A, Volodarsky-Perel, A, Lasry, A, Hemmings, R, Gil, Y, Balayla, J. Use of placental growth factor for trisomy 21 screening in pregnancy: a systematic review. Am J Perinatol Rep 2020;10:e234–40. https://doi.org/10.1055/s-0040-1713785.Search in Google Scholar PubMed PubMed Central
6. Bredaki, FE, Wright, D, Matos, P, Syngelaki, A, Nicolaides, KH. First-trimester screening for trisomy 21 using alpha-fetoprotein. Fetal Diagn Ther 2011;30:215–8. https://doi.org/10.1159/000330198.Search in Google Scholar PubMed
7. Yamamoto, R, Ohkouchi, T, Tabata, K, Ebina, Y, Watari, H, Kudo, M, et al.. A study of oligosaccharide variants of alpha-fetoproteins produced by normal fetuses and fetuses with trisomy 21. Acta Obstet Gynecol Scand 2005;84:1145–9. https://doi.org/10.1111/j.0001-6349.2005.00815.x.Search in Google Scholar PubMed
8. Suresh, S, Cuckle, HS, Jagadeesh, S, Ghosh, K, Vemavarapu, G, Taval, T, et al.. Down’s syndrome screening in the first trimester with additional serum markers: Indian parameters. J Obstet Gynaecol India 2020;70:12–7. https://doi.org/10.1007/s13224-018-1198-1.Search in Google Scholar PubMed PubMed Central
9. Donalson, K, Turner, S, Morrison, L, Liitti, P, Nilsson, C, Cuckle, H. Maternal serum placental growth factor and α-fetoprotein testing in first trimester screening for Down syndrome. Prenat Diagn 2013;33:457–61. https://doi.org/10.1002/pd.4087.Search in Google Scholar PubMed
10. Johnson, J, Pastuck, M, Metcalfe, A, Connors, G, Krause, R, Wilson, D, et al.. First-trimester Down syndrome screening using additional serum markers with and without nuchal translucency and cell-free DNA. Prenat Diagn 2013;33:1044–9. https://doi.org/10.1002/pd.4194.Search in Google Scholar PubMed
11. Wright, D, Syngelaki, A, Bradbury, I, Akolekar, R, Nicolaides, KH. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal Diagn Ther 2014;35:118–26. https://doi.org/10.1159/000357430.Search in Google Scholar PubMed
12. Huang, T, Dennis, A, Meschino, WS, Rashid, S, Mak-Tam, E, Cuckle, H. First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy-associated plasma protein A, free-β human chorionic gonadotrophin, placental growth factor, and α-fetoprotein. Prenat Diagn 2015;35:709–16. https://doi.org/10.1002/pd.4597.Search in Google Scholar PubMed
13. Palomaki, GE, Eklund, EE, Neveux, LM, Lambert Messerlian, GM. Evaluating first trimester maternal serum screening combinations for Down syndrome suitable for use with reflexive secondary screening via sequencing of cell free DNA: high detection with low rates of invasive procedures. Prenat Diagn 2015;35:789–96. https://doi.org/10.1002/pd.4609.Search in Google Scholar PubMed
14. Carmichael, JB, Liu, HP, Janik, D, Hallahan, TW, Nicolaides, KH, Krantz, DA. Expanded conventional first trimester screening. Prenat Diagn 2017;37:802–7. https://doi.org/10.1002/pd.5090.Search in Google Scholar PubMed PubMed Central
15. Boutin, A, Demers, S, Gasse, C, Giguere, Y, Tetu, A, Laforest, G, et al.. First-trimester placental growth factor for the prediction of preeclampsia in nulliparous women: the Great Obstetrical Syndromes Cohort Study. Fetal Diagn Ther 2019;45:69–75. https://doi.org/10.1159/000487301.Search in Google Scholar PubMed
16. Boutin, A, Gasse, C, Demers, S, Blanchet, G, Giguère, Y, Bujold, E. Does low PAPP-A predict adverse placenta-mediated outcomes in a low-risk nulliparous population? The Great Obstetrical Syndromes (GOS) Study. J Obstet Gynaecol Can 2018;40:663–8. https://doi.org/10.1016/j.jogc.2017.08.047.Search in Google Scholar PubMed
17. Boutin, A, Gasse, C, Guerby, P, Giguere, Y, Tetu, A, Bujold, E. First-trimester preterm preeclampsia screening in nulliparous women: the Great Obstetrical Syndrome (GOS) Study. J Obstet Gynaecol Can 2021;43:43–9. https://doi.org/10.1016/j.jogc.2020.06.011.Search in Google Scholar PubMed
18. Boutin, A, Guerby, P, Gasse, C, Tapp, S, Bujold, E. Pregnancy outcomes in nulliparous women with positive first-trimester preterm preeclampsia screening test: the Great Obstetrical Syndromes Cohort Study. Am J Obstet Gynecol 2021;224:204 e1–7. https://doi.org/10.1016/j.ajog.2020.08.008.Search in Google Scholar PubMed
19. Wang, L, Xu, J, Niu, W, Hu, L, Zhang, Y, Sun, Y. Genetic testing on products of conception and its relationship with body mass index. J Assist Reprod Genet 2020;37:1853–60. https://doi.org/10.1007/s10815-020-01849-9.Search in Google Scholar PubMed PubMed Central
20. Mazer Zumaeta, A, Wright, A, Syngelaki, A, Maritsa, VA, Bardani, E, Nicolaides, KH. Screening for trisomy at 11–13 weeks’ gestation: use of pregnancy-associated plasma protein-A, placental growth factor or both. Ultrasound Obstet Gynecol 2020;56:408–15. https://doi.org/10.1002/uog.22140.Search in Google Scholar PubMed
21. Huang, T, Dennis, A, Meschino, WS, Rashid, S, Mak-Tam, E, Cuckle, H. First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy-associated plasma protein A, free-beta human chorionic gonadotrophin, placental growth factor, and alpha-fetoprotein. Prenat Diagn 2015;35:709–16. https://doi.org/10.1002/pd.4597.Search in Google Scholar PubMed
22. Gareau-Leonard, A, Fillion, A, Labine, L, Gasse, C, Demers, S, Bujold, E. Evolution of Down syndrome prenatal screening clinical practices in Quebec. J Obstet Gynaecol Can 2020;42:439–45. https://doi.org/10.1016/j.jogc.2019.09.025.Search in Google Scholar PubMed
23. Davies, V, Gledhill, J, McFadyen, A, Whitlow, B, Economides, D. Psychological outcome in women undergoing termination of pregnancy for ultrasound-detected fetal anomaly in the first and second trimesters: a pilot study. Ultrasound Obstet Gynecol 2005;25:389–92. https://doi.org/10.1002/uog.1854.Search in Google Scholar PubMed
24. Bujold, E, Roberge, S, Lacasse, Y, Bureau, M, Audibert, F, Marcoux, S, et al.. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010;116:402–14. https://doi.org/10.1097/aog.0b013e3181e9322a.Search in Google Scholar PubMed
25. Roberge, S, Bujold, E, Nicolaides, KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol 2018;218:287–93 e1. https://doi.org/10.1016/j.ajog.2017.11.561.Search in Google Scholar PubMed
26. Roberge, S, Nicolaides, K, Demers, S, Hyett, J, Chaillet, N, Bujold, E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017;216:110–20 e6. https://doi.org/10.1016/j.ajog.2016.09.076.Search in Google Scholar PubMed
27. Roberge, S, Nicolaides, KH, Demers, S, Villa, P, Bujold, E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol 2013;41:491–9. https://doi.org/10.1002/uog.12421.Search in Google Scholar PubMed
28. Rolnik, DL, Wright, D, Poon, LC, O’Gorman, N, Syngelaki, A, de Paco Matallana, C, et al.. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613–22. https://doi.org/10.1056/nejmoa1704559.Search in Google Scholar
29. Rolnik, DL, Nicolaides, KH, Poon, LC. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol 2022;226:S1108–19. https://doi.org/10.1016/j.ajog.2020.08.045.Search in Google Scholar PubMed
30. Spencer, K, Heath, V, Flack, N, Ong, C, Nicolaides, KH. First trimester maternal serum AFP and total hCG in aneuploidies other than trisomy 21. Prenat Diagn 2000;20:635–9. https://doi.org/10.1002/1097-0223(200008)20:8<635::aid-pd868>3.0.co;2-u.10.1002/1097-0223(200008)20:8<635::AID-PD868>3.0.CO;2-USearch in Google Scholar
© 2023 Walter de Gruyter GmbH, Berlin/Boston
