The role of ultrasound in first-trimester screening after the introduction of NIPT as a service of public health insurance – a consensus statement of the Fetal Medicine Foundation (FMF) Germany

 

 Permissions and Reprints

Abstract

Combined first-trimester screening (FTS) and noninvasive prenatal testing (NIPT) have been proven to be reliable noninvasive procedures to detect the most common chromosomal abnormalities (trisomies 21, 18, 13) in the first trimester. The aim of this paper is to demonstrate the strengths and limitations of these two procedures and to give a consensus statement of the Fetal Medicine Foundation (FMF) Germany on how to use the two techniques in the first trimester after the introduction of NIPT as a service of the statutory health insurance companies in Germany.

Zusammenfassung

Das kombinierte Ersttrimester-Screening und der nichtinvasive DNA-Test (NIPT) haben sich als verlässliche nichtinvasive Verfahren zur Diagnostik der häufigsten Chromosomen-Anomalien (Trisomie 21, 18, 13) im 1. Trimenon gezeigt. Das Ziel dieser Publikation ist es, die Stärken, wie auch die Limitierungen, beider Verfahren aufzuzeigen und ein Konsensus-Statement der Fetal Medicine Foundation (FMF) Deutschland abzugeben, wie beide Techniken im 1. Trimenon eingesetzt werden sollen, nachdem NIPT als Kassenleistung in Deutschland eingeführt wurde.

Publication History

Received: 29 January 2023

Accepted after revision: 22 May 2023

Article published online:
01 August 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Nicolaides KH, Azar G, Byrne D. et al. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 1992; 304: 867-869 DOI: 10.1136/bmj.304.6831.867. (PMID: 1392745)
  CrossrefPubMedGoogle Scholar
• 2 Nicolaides KH, Brizot ML, Snijders RJ. Fetal nuchal translucency: ultrasound screening for fetal trisomy in the first trimester of pregnancy. Br J Obstet Gynaecol 1994; 101 (09) 782-786 DOI: 10.1111/j.1471-0528.1994.tb11946.x. (PMID: 7947527)
  CrossrefPubMedGoogle Scholar
• 3 Snijders RJ, Noble P, Sebire N. et al. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998; 352: 343-346 DOI: 10.1016/s0140-6736(97)11280-6. (PMID: 9717920)
  CrossrefPubMedGoogle Scholar
• 4 Merz E, Thode C, Alkier A. et al. A new approach to calculating the risk of chromosomal abnormalities with first-trimester screening data. Ultraschall Med 2008; 29 (06) 639-645 DOI: 10.1055/s-2008-1027958.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Merz E, Thode C, Hackelöer BJ. et al. The Fetal Medicine Foundation (FMF) Germany after 20 Years – Quality Assurance of Ultrasound Examinations during First Trimester Screening. Ultraschall Med 2022; 43 (02) 115-119 DOI: 10.1055/a-1745-6879.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Lo YM, Chan KC, Sun H. et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010; 2 (61) 61ra91 DOI: 10.1126/scitranslmed.3001720. (PMID: 21148127)
  CrossrefPubMedGoogle Scholar
• 7 Bianchi DW, Parker RL, Wentworth J. et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 370 (09) 799-808 DOI: 10.1056/NEJMoa1311037. (PMID: 24571752)
  CrossrefPubMedGoogle Scholar
• 8 Taylor-Phillips S, Freeman K, Geppert J. et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open 2016; 6 (01) e010002 DOI: 10.1136/bmjopen-2015-010002. (PMID: 26781507)
  CrossrefPubMedGoogle Scholar
• 9 Borth H, Teubert A, Glaubitz R. et al. Analysis of cell-free DNA in a consecutive series of 13,607 routine cases for the detection of fetal chromosomal aneuploidies in a single center in Germany. Arch Gynecol Obstet 2021; 303 (06) 1407-1414 DOI: 10.1007/s00404-020-05856-0. (PMID: 33151425)
  CrossrefPubMedGoogle Scholar
• 10 Eiben B, Borth H, Kutur N. et al. Clinical experience with noninvasive prenatal testing in Germany: Analysis of over 500 high-risk cases for trisomy 21, 18, 13 and monosomy X. Obstet Gynecol Rep 2021; 5: 1-7 https://www.oatext.com/pdf/OGR-5–157.pdf
  CrossrefPubMedGoogle Scholar
• 11 Interactive EUROCAT prevalence charts. https://eu-rd-platform.jrc.ec.europa.eu/ eurocat/eurocat-data/prevalence_en
  PubMedGoogle Scholar
• 12 Syngelaki A, Chelemen T, Dagklis T. et al. Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11–13 weeks. Prenat Diagn 2011; 31 (01) 90-102 DOI: 10.1002/pd.2642. (PMID: 21210483)
  CrossrefPubMedGoogle Scholar
• 13 Karim JN, Roberts NW, Salomon LJ. et al. Systematic review of first-trimester ultrasound screening for detection of fetal structural anomalies and factors that affect screening performance. Ultrasound Obstet Gynecol 2017; 50 (04) 429-441 DOI: 10.1002/uog.17246.
  CrossrefPubMedGoogle Scholar
• 14 Syngelaki A, Hammami A, Bower S. et al. Diagnosis of fetal non-chromosomal abnormalities on routine ultrasound examination at 11–13 weeks’ gestation. Ultrasound Obstet Gynecol 2019; 54 (04) 468-476 DOI: 10.1002/uog.20844. (PMID: 31408229)
  CrossrefPubMedGoogle Scholar
• 15 Yoshizato T, Kozuma Y, Horinouchi T. et al. Diagnosis of Fetal Abnormalities during the First Trimester. Kurume Med J 2021; 66 (02) 85-92 DOI: 10.2739/kurumemedj.MS662002.
  CrossrefPubMedGoogle Scholar
• 16 Kenkhuis MJA, Bakker M, Bardi F. et al. Effectiveness of 12–13-week scan for early diagnosis of fetal congenital anomalies in the cell-free DNA era. Ultrasound Obstet Gynecol 2018; 51 (04) 463-469 DOI: 10.1002/uog.17487. (PMID: 28397377)
  CrossrefPubMedGoogle Scholar
• 17 Merz E, Thode C, Eiben B. et al. Prenatal Risk Calculation (PRC) 3.0: An Extended DoE-Based First-Trimester Screening Algorithm Allowing for Early Blood Sampling. Ultrasound Int Open 2016; 2 (01) E19-26 DOI: 10.1055/s-0035-1569403. (PMID: 27689162)
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Wagner P, Sonek J, Hoopmann M. et al. First-trimester screening for trisomies 18 and 13, triploidy and Turner syndrome by detailed early anomaly scan. Ultrasound Obstet Gynecol 2016; 48 (04) 446-451 DOI: 10.1002/uog.15829. (PMID: 26611869)
  CrossrefPubMedGoogle Scholar
• 19 Tørring N, Petersen OB, Becher N. et al. First trimester screening for other trisomies than trisomy 21, 18, and 13. Prenat Diagn 2015; 35 (06) 612-619 DOI: 10.1002/pd.4584.
  CrossrefPubMedGoogle Scholar
• 20 Lindquist A, Poulton A, Halliday J. et al. Prenatal diagnostic testing and atypical chromosome abnormalities following combined first-trimester screening: implications for contingent models of non-invasive prenatal testing. Ultrasound Obstet Gynecol 2018; 51 (04) 487-492 DOI: 10.1002/uog.18979. (PMID: 29226487)
  CrossrefPubMedGoogle Scholar
• 21 Vogel I, Petersen OB. Prenatal screening for atypical chromosomal abnormalities: past or future?. Ultrasound Obstet Gynecol 2018; 51 (04) 434-435 DOI: 10.1002/uog.19030. (PMID: 29634091)
  CrossrefPubMedGoogle Scholar
• 22 Chaemsaithong P, Sahota DS, Poon LC. First trimester preeclampsia screening and prediction. Am J Obstet Gynecol 2022; 226 (Suppl. 02) S1071-S1097.e2 DOI: 10.1016/j.ajog.2020.07.020. (PMID: 32682859)
  CrossrefPubMedGoogle Scholar
• 23 Mazer Zumaeta A, Wright A, Syngelaki A. et al. Screening for pre-eclampsia at 11–13 weeks’ gestation: use of pregnancy-associated plasma protein-A, placental growth factor or both. Ultrasound Obstet Gynecol 2020; 56 (03) 400-407 DOI: 10.1002/uog.22093. (PMID: 32959455)
  CrossrefPubMedGoogle Scholar
• 24 Merz E, Thode C, Eiben B. et al. Individualized correction for maternal weight in calculating the risk of chromosomal abnormalities with first-trimester screening data. Ultraschall Med 2011; 32 (01) 33-39 DOI: 10.1055/s-0029-1246001.
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Merz E, Pashaj S. Embryonic and early fetal abnormalities diagnosed with three-dimensional ultrasound in the 1^st trimester. In: Kurjak A, Chervenak F. Embryo as a person and as a patient. New Delhi – London – Panama: Jaypee Brothers Medical Publishers; 2020: 51-64
  Google Scholar
• 26 Gil MM, Accurti V, Santacruz B. et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2017; 50 (03) 302-314 DOI: 10.1002/uog.17484. (PMID: 28397325)
  CrossrefPubMedGoogle Scholar
• 27 Gross SJ, Stosic M, McDonald-McGinn DM. et al. Clinical experience with single-nucleotide polymorphism-based non-invasive prenatal screening for 22q11.2 deletion syndrome. Ultrasound Obstet Gynecol 2016; 47 (02) 177-183 DOI: 10.1002/uog.15754.
  CrossrefPubMedGoogle Scholar
• 28 Bevilacqua E, Jani JC, Chaoui R. et al. Performance of a targeted cell-free DNA prenatal test for 22q11.2 deletion in a large clinical cohort. Ultrasound Obstet Gynecol 2021; 58 (04) 597-602 DOI: 10.1002/uog.23699. (PMID: 34090308)
  CrossrefPubMedGoogle Scholar
• 29 Kagan KO, Hoopmann M, Pfaff T. et al. First Trimester Screening for Common Trisomies and Microdeletion 22q11.2 Syndrome Using Cell-Free DNA: A Prospective Clinical Study. Fetal Diagn Ther 2020; 47 (11) 841-852 DOI: 10.1159/000510069. (PMID: 32877902)
  CrossrefPubMedGoogle Scholar
• 30 Jia Y, Zhao H, Shi D. et al. Genetic effects of a 13q31.1 microdeletion detected by noninvasive prenatal testing (NIPT). Int J Clin Exp Pathol 2014; 7 (10) 7003-7011 (PMID: 25400788)
  PubMedGoogle Scholar
• 31 Bianchi DW, Wilkins-Haug L. Integration of noninvasive DNA testing for aneuploidy into prenatal care: what has happened since the rubber met the road?. Clin Chem 2014; 60 (01) 78-87 DOI: 10.1373/clinchem.2013.202663. (PMID: 24255077)
  CrossrefPubMedGoogle Scholar
• 32 Suciu I, Galeva S, Abdel Azim S. et al. First-trimester screening-biomarkers and cell-free DNA. J Matern Fetal Neonatal Med 2021; 34 (23) 3983-3989 DOI: 10.1080/14767058.2019.1698031.
  CrossrefPubMedGoogle Scholar
• 33 Van Opstal D, Srebniak MI, Polak J. et al. False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review. PLoS One 2016; 11 (01) e0146794 DOI: 10.1371/journal.pone.0146794. (PMID: 26771677)
  CrossrefPubMedGoogle Scholar
• 34 Revello R, Sarno L, Ispas A. et al. Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result. Ultrasound Obstet Gynecol 2016; 47 (06) 698-704 DOI: 10.1002/uog.15851. (PMID: 26743020)
  CrossrefPubMedGoogle Scholar
• 35 Hopkins MK, Koelper N, Caldwell S. et al. Obesity and no call results: optimal timing of cell-free DNA testing and redraw. Am J Obstet Gynecol 2021; 225 (04) 417.e1-417.e10 DOI: 10.1016/j.ajog.2021.04.212.
  CrossrefPubMedGoogle Scholar
• 36 Pergament E, Cuckle H, Zimmermann B. et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol 2014; 124: 210-218 DOI: 10.1097/AOG.0000000000000363. (PMID: 25004354)
  CrossrefPubMedGoogle Scholar
• 37 Robienski J. The new law on gene diagnostics in Germany – an overview about the main principles. Rev Derecho Genoma Hum 2010; 32: 47-68 (PMID: 21189730)
  PubMedGoogle Scholar
• 38 Oepkes D, Bartha JL, Schmid M. et al. Benefits of contingent screening vs primary screening by cell-free DNA testing: think again. Ultrasound Obstet Gynecol 2016; 47 (05) 542-545 DOI: 10.1002/uog.15758.
  CrossrefPubMedGoogle Scholar
• 39 van der Meij KRM, Sistermans EA. et al. TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands. Am J Hum Genet 2019; 105 (06) 1091-1101 DOI: 10.1016/j.ajhg.2019.10.005. (PMID: 31708118)
  CrossrefPubMedGoogle Scholar
• 40 Kagan KO, Sonek J, Kozlowski P. Antenatal screening for chromosomal abnormalities. Arch Gynecol Obstet 2022; 305 (04) 825-835 DOI: 10.1007/s00404-022-06477-5. (PMID: 35279726)
  CrossrefPubMedGoogle Scholar
• 41 Nicolaides KH. First-trimester screening for chromosomal abnormalities. Semin Perinatol 2005; 29 (04) 190-194 DOI: 10.1053/j.semperi.2005.06.001. (PMID: 27558969)
  CrossrefPubMedGoogle Scholar
• 42 Gil MM, Revello R, Poon LC. et al. Clinical implementation of routine screening for fetal trisomies in the UK NHS: cell-free DNA test contingent on results from first-trimester combined test. Ultrasound Obstet Gynecol 2016; 47 (01) 45-52 DOI: 10.1002/uog.15783.
  CrossrefPubMedGoogle Scholar
• 43 Galeva S, Konstantinidou L, Gil MM. et al. Routine first-trimester screening for fetal trisomies in twin pregnancy: cell-free DNA test contingent on results from combined test. Ultrasound Obstet Gynecol 2019; 53 (02) 208-213 DOI: 10.1002/uog.20160.
  CrossrefPubMedGoogle Scholar
• 44 Eiben B, Glaubitz R, Winkler T. et al. First-trimester screening in Germany after the introduction of NIPT as a general health insurance benefit. Ultraschall Med 2023; DOI: 10.1055/a-2028-8108. (PMID: 36746395)
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Poon LC, Shennan A, Hyett JA. et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet 2019; 145 (Suppl. 01) 1-33 DOI: 10.1002/ijgo.12802.
  CrossrefPubMedGoogle Scholar
• 46 Rolnik DL, Selvaratnam RJ, Wertaschnigg D. et al. Routine first trimester combined screening for preterm preeclampsia in Australia: A multicenter clinical implementation cohort study. Int J Gynaecol Obstet 2022; 158 (03) 634-642 DOI: 10.1002/ijgo.14049. (PMID: 34837224)
  CrossrefPubMedGoogle Scholar
• 47 Salomon LJ, Alfirevic Z, Audibert F. et al. ISUOG consensus statement on the impact of non-invasive prenatal testing (NIPT) on prenatal ultrasound practice. Z Geburtshilfe Neonatol 2014; 218 (06) 242-243 DOI: 10.1055/s-0034-1395670. (PMID: 24895295)
  Article in Thieme ConnectPubMedGoogle Scholar
• 48 Kagan KO, Hoopmann M, Hammer R. et al. Screening for chromosomal abnormalities by first trimester combined screening and noninvasive prenatal testing. Ultraschall Med 2015; 36 (01) 40-46 DOI: 10.1055/s-0034-1385059. (PMID: 25255236)
  Article in Thieme ConnectPubMedGoogle Scholar
• 49 Schmid M, Klaritsch P, Arzt W. et al. Cell-Free DNA Testing for Fetal Chromosomal Anomalies in clinical practice: Austrian-German-Swiss Recommendations for non-invasive prenatal tests (NIPT). Ultraschall Med 2015; 36 (05) 507-510 DOI: 10.1055/s-0035-1553804. (PMID: 26468773)
  Article in Thieme ConnectPubMedGoogle Scholar
• 50 Merz E. Can Prenatal Testing in the First Trimester be Performed without Ultrasound?. Ultraschall Med 2017; 38 (02) 126-128 DOI: 10.1055/s-0043-102832. (PMID: 28376536)
  Article in Thieme ConnectPubMedGoogle Scholar
• 51 Kozlowski P, Burkhardt T, Gembruch U. et al. DEGUM, ÖGUM, SGUM and FMF Germany recommendations for the implementation of first-trimester screening, detailed ultrasound, cell-free DNA screening and diagnostic procedures. Ultraschall Med 2019; 40 (02) 176-193 DOI: 10.1055/a-0631-8898. (PMID: 30001568)
  Article in Thieme ConnectPubMedGoogle Scholar
• 52 Kagan KO, Tercanli S, Hoopmann M. Ten reasons why we should not abandon a detailed first trimester anomaly scan. Ultraschall Med 2021; 42 (05) 451-459 DOI: 10.1055/a-1528-1118.
  Article in Thieme ConnectPubMedGoogle Scholar
• 53 Wapner RJ, Martin CL, Levy B. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367 (23) 2175-2184 DOI: 10.1056/NEJMoa1203382. (PMID: 23215555)
  CrossrefPubMedGoogle Scholar
• 54 Lord J, McMullan DJ, Eberhardt RY. et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 2019; 393: 747-757 DOI: 10.1016/S0140-6736(18)31940-8. (PMID: 30712880)
  CrossrefPubMedGoogle Scholar
• 55 Diderich KEM, Romijn K, Joosten M. et al. The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies. Acta Obstet Gynecol Scand 2021; 100 (06) 1106-1115 DOI: 10.1111/aogs.14053. (PMID: 33249554)
  CrossrefPubMedGoogle Scholar