DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

Abstract

First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening – cell-free DNA screening – diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

Key words

cell-free dna - detailed early ultrasound - diagnostic procedures - chromosomal anomalies - first-trimester screening

• Literatur

• 1 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 in der Medizin (Stuttgart, Germany: 1980) 2015; 36: 507-510
• 2 Advani HV, Barrett AN, Evans MI. et al. Challenges in non-invasive prenatal screening for sub-chromosomal copy number variations using cell-free DNA. Prenatal diagnosis 2017; 37: 1067-1075
• 3 Nicolaides KH. Turning the pyramid of prenatal care. Fetal diagnosis and therapy 2011; 29: 183-196
• 4 Sonek JD, Kagan KO, Nicolaides KH. Inverted Pyramid of Care. Clinics in laboratory medicine 2016; 36: 305-317
• 5 Kagan KO, Sroka F, Sonek J. et al. First trimester screening based on ultrasound and cfDNA vs. first-trimester combined screening – a randomized controlled study. Ultrasound Obstet Gynecol 2017;
• 6 [Anonym]. http://www.gesetze-im-internet.de/gendg/ doi:
• 7 [Anonym]. doi: http://www.patienten-rechte-gesetz.de
• 8 [Anonym]. http://www.rki.de/DE/Content/Kommissionen/GendiagnostikKommission/Mitteilungen/GEKO_Mitteilungen_08.html doi:
• 9 Salomon LJ, Alfirevic Z, Bilardo CM. et al. ISUOG practice guidelines: performance of first-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2013; 41: 102-113
• 10 von Kaisenberg C, Chaoui R, Hausler M. et al. Quality Requirements for the early Fetal Ultrasound Assessment at 11–13+6 Weeks of Gestation (DEGUM Levels II and III). Ultraschall in der Medizin (Stuttgart, Germany: 1980) 2016; 37: 297-302
• 11 Syngelaki A, Chelemen T, Dagklis T. et al. Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11–13 weeks. Prenatal diagnosis 2011; 31: 90-102
• 12 Becker R, Wegner RD. Detailed screening for fetal anomalies and cardiac defects at the 11–13-week scan. Ultrasound Obstet Gynecol 2006; 27: 613-618
• 13 Becker R, Schmitz L, Kilavuz S. et al. “Normal” nuchal translucency: a justification to refrain from detailed scan? Analysis of 6858 cases with special reference to ethical aspects. Prenatal diagnosis 2012; 32: 550-556
• 14 Rossi AC, Prefumo F. Accuracy of ultrasonography at 11–14 weeks of gestation for detection of fetal structural anomalies: a systematic review. Obstetrics and gynecology 2013; 122: 1160-1167
• 15 Chaoui R, Benoit B, Mitkowska-Wozniak H. et al. Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11–13-week scan. Ultrasound Obstet Gynecol 2009; 34: 249-252
• 16 Lachmann R, Chaoui R, Moratalla J. et al. Posterior brain in fetuses with open spina bifida at 11 to 13 weeks. Prenatal diagnosis 2011; 31: 103-106
• 17 Maruotti GM, Saccone G, D’Antonio F. et al. Diagnostic accuracy of intracranial translucency in detecting spina bifida: a systematic review and meta-analysis. Prenatal diagnosis 2016; 36: 991-996
• 18 Kagan KO, Hoopmann M, Hammer R. et al. Screening for chromosomal abnormalities by first trimester combined screening and noninvasive prenatal testing. Ultraschall in der Medizin (Stuttgart, Germany: 1980) 2015; 36: 40-46
• 19 Gasiorek-Wiens A, Tercanli S, Kozlowski P. et al. Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in Germany, Austria and Switzerland. Ultrasound Obstet Gynecol 2001; 18: 645-648
• 20 von Kaisenberg CS, Gasiorek-Wiens A, Bielicki M. et al. Screening for trisomy 21 by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11–14 weeks: a German multicenter study. The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2002; 12: 89-94
• 21 Souka AP, Von Kaisenberg CS, Hyett JA. et al. Increased nuchal translucency with normal karyotype. American journal of obstetrics and gynecology 2005; 192: 1005-1021
• 22 Hyett JA, Perdu M, Sharland GK. et al. Increased nuchal translucency at 10–14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol 1997; 10: 242-246
• 23 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: 446-451
• 24 Jelliffe-Pawlowski LL, Norton ME, Shaw GM. et al. Risk of critical congenital heart defects by nuchal translucency norms. American journal of obstetrics and gynecology 2015; 212: 518.e511-510
• 25 Chelemen T, Syngelaki A, Maiz N. et al. Contribution of ductus venosus Doppler in first-trimester screening for major cardiac defects. Fetal diagnosis and therapy 2011; 29: 127-134
• 26 Pereira S, Ganapathy R, Syngelaki A. et al. Contribution of fetal tricuspid regurgitation in first-trimester screening for major cardiac defects. Obstetrics and gynecology 2011; 117: 1384-1391
• 27 Khalil A, Nicolaides KH. Fetal heart defects: potential and pitfalls of first-trimester detection. Seminars in fetal & neonatal medicine 2013; 18: 251-260
• 28 Geipel A, Gembruch U. Screening performance of first trimester nuchal translucency, ductus venosus blood flow and tricuspid regurgitation for cardiac defects. Zeitschrift fur Geburtshilfe und Neonatologie 2012; 216: 157-161
• 29 De Robertis V, Rembouskos G, Fanelli T. et al. The three-vessel and trachea view (3VTV) in the first trimester of pregnancy: an additional tool in screening for congenital heart defects (CHD) in an unselected population. Prenatal diagnosis 2017; 37: 693-698
• 30 Quarello E, Lafouge A, Fries N. et al. Basic heart examination: feasibility study of first-trimester systematic simplified fetal echocardiography. Ultrasound Obstet Gynecol 2017; 49: 224-230
• 31 Stagnati V, Zanardini C, Fichera A. et al. Early prediction of twin-to-twin transfusion syndrome: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017; 49: 573-582
• 32 Khalil A, Rodgers M, Baschat A. et al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. Ultrasound Obstet Gynecol 2016; 47: 247-263
• 33 Souka AP, Krampl E, Bakalis S. et al. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001; 18: 9-17
• 34 Commission on Genetic Testing (GEKO). Guideline on Requirements for Qualification in and Content of Genetic Counseling according to § 23 Genetic Diagnostics Act. Bundesgesundheitsbl 2011; 54: 1248-1256 doi:10.1007/s00103-011-1357-3
• 35 Commission on Genetic Testing (GEKO). Guideline on Quality Requirements in Prenatal Risk Assessment and Necessary Measures for Quality Assurance according to § 23 Genetic Diagnostics Act. Bundesgesundheitsbl 2013; 56: 1023-1027 doi:10.1007/s00103-013-1782-6
• 36 Kagan KO, Schmid M, Hoopmann M. et al. Screening Performance and Costs of Different Strategies in Prenatal Screening for Trisomy 21. Geburtshilfe und Frauenheilkunde 2015; 75: 244-250
• 37 Wright D, Syngelaki A, Bradbury I. et al. First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing. Fetal diagnosis and therapy 2014; 35: 118-126
• 38 Kagan KO, Wright D, Baker A. et al. Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2008; 31: 618-624
• 39 Santorum M, Wright D, Syngelaki A. et al. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound Obstet Gynecol 2017; 49: 714-720
• 40 Ashoor G, Syngelaki A, Wagner M. et al. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. American journal of obstetrics and gynecology 2012; 206: 322.e321-325
• 41 Bianchi DW, Platt LD, Goldberg JD. et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstetrics and gynecology 2012; 119: 890-901
• 42 Norton ME, Brar H, Weiss J. et al. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. American journal of obstetrics and gynecology 2012; 207: 137.e131-138
• 43 Palomaki GE, Deciu C, Kloza EM. et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genetics in medicine: official journal of the American College of Medical Genetics 2012; 14: 296-305
• 44 Sparks AB, Struble CA, Wang ET. et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. American journal of obstetrics and gynecology 2012; 206: 319.e1-9
• 45 Stumm M, Entezami M, Trunk N. et al. Noninvasive prenatal detection of chromosomal aneuploidies using different next generation sequencing strategies and algorithms. Prenatal diagnosis 2012; 32: 569-577
• 46 Zimmermann B, Hill M, Gemelos G. et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenatal diagnosis 2012; 32: 1233-1241
• 47 Norton ME, Wapner RJ. Cell-free DNA Analysis for Noninvasive Examination of Trisomy. The New England journal of medicine 2015; 373: 2582
• 48 Pergament E, Cuckle H, Zimmermann B. et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstetrics and gynecology 2014; 124: 210-218
• 49 Quezada MS, Gil MM, Francisco C. et al. Screening for trisomies 21, 18 and 13 by cell-free DNA analysis of maternal blood at 10–11 weeks’ gestation and the combined test at 11–13 weeks. Ultrasound Obstet Gynecol 2015; 45: 36-41
• 50 Stokowski R, Wang E, White K. et al. Clinical performance of non-invasive prenatal testing (NIPT) using targeted cell-free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies. Prenatal diagnosis 2015; 35: 1243-1246
• 51 McLennan A, Palma-Dias R, da Silva Costa F. et al. Noninvasive prenatal testing in routine clinical practice--an audit of NIPT and combined first-trimester screening in an unselected Australian population. The Australian & New Zealand journal of obstetrics & gynaecology 2016; 56: 22-28
• 52 Iwarsson E, Jacobsson B, Dagerhamn J. et al. Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population – a systematic review and meta-analysis. Acta obstetricia et gynecologica Scandinavica 2017; 96: 7-18
• 53 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: 302-314
• 54 Gil MM, Quezada MS, Revello R. et al. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2015; 45: 249-266
• 55 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: e010002
• 56 Wax JR, Chard R, Litton C. et al. Prenatal aneuploidy screening using cell-free DNA. American journal of obstetrics and gynecology 2015; 213: 879-880
• 57 Mackie FL, Hemming K, Allen S. et al. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG: an international journal of obstetrics and gynaecology 2017; 124: 32-46
• 58 Grati FR, Bajaj K, Malvestiti F. et al. The type of feto-placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure. Prenatal diagnosis 2015; 35: 994-998
• 59 Taneja PA, Snyder HL, de Feo E. et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 cases. Prenatal diagnosis 2016; 36: 237-243
• 60 Zhang H, Gao Y, Jiang F. et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol 2015; 45: 530-538
• 61 Dar P, Gross SJ, Benn P. Positive predictive values and false-positive results in noninvasive prenatal screening. American journal of obstetrics and gynecology 2015; 213: 595-596
• 62 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: 698-704
• 63 Scott FP, Menezes M, Palma-Dias R. et al. Factors affecting cell-free DNA fetal fraction and the consequences for test accuracy. The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2017; , doi:10.1080/14767058.2017.1330881 1-8
• 64 Livergood MC, LeChien KA, Trudell AS. Obesity and cell-free DNA “no calls”: is there an optimal gestational age at time of sampling?. American journal of obstetrics and gynecology 2017; 216: 413.e411-413.e419
• 65 Ma GC, Wu WJ, Lee MH. et al. Low-molecular-weight heparin associated with reduced fetal fraction and subsequent false-negative cell-free DNA test result for trisomy 21. Ultrasound Obstet Gynecol 2018; 51: 276-277
• 66 Grati FR, Kagan KO. Rate of no result in cell-free DNA testing and its influence on test performance metrics. Ultrasound Obstet Gynecol 2017; 50: 134-137
• 67 Cirigliano V, Ordonez E, Rueda L. et al. Performance of the neoBona test: a new paired-end massively parallel shotgun sequencing approach for cell-free DNA-based aneuploidy screening. Ultrasound Obstet Gynecol 2017; 49: 460-464
• 68 Sarno L, Revello R, Hanson E. et al. Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. Ultrasound Obstet Gynecol 2016; 47: 705-711
• 69 Huang X, Zheng J, Chen M. et al. Noninvasive prenatal testing of trisomies 21 and 18 by massively parallel sequencing of maternal plasma DNA in twin pregnancies. Prenatal diagnosis 2014; 34: 335-340
• 70 Le ConteG, Letourneau A, Jani J. et al. Cell-free fetal DNA analysis in maternal plasma as a screening test for trisomy 21, 18 and 13 in twin pregnancies. Ultrasound Obstet Gynecol 2017;
• 71 Lau TK, Jiang F, Chan MK. et al. Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies. The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet 2013; 26: 434-437
• 72 Tan Y, Gao Y, Lin G. et al. Noninvasive prenatal testing (NIPT) in twin pregnancies with treatment of assisted reproductive techniques (ART) in a single center. Prenatal diagnosis 2016; 36: 672-679
• 73 Bevilacqua E, Gil MM, Nicolaides KH. et al. Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies. Ultrasound Obstet Gynecol 2015; 45: 61-66
• 74 Gromminger S, Yagmur E, Erkan S. et al. Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins. Journal of clinical medicine 2014; 3: 679-692
• 75 Oneda B, Baldinger R, Reissmann R. et al. High-resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power. Prenatal diagnosis 2014; 34: 525-533
• 76 Beulen L, Faas BHW, Feenstra I. et al. Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies. Ultrasound Obstet Gynecol 2017; 49: 721-728
• 77 Wapner RJ, Martin CL, Levy B. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. The New England journal of medicine 2012; 367: 2175-2184
• 78 Shaffer LG, Rosenfeld JA, Dabell MP. et al. Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound. Prenatal diagnosis 2012; 32: 986-995
• 79 Grande M, Jansen FA, Blumenfeld YJ. et al. Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015; 46: 650-658
• 80 Vogel I, Petersen OB, Christensen R. et al. Chromosomal microarray as a primary diagnostic genomic tool for pregnancies defined as being at increased risk within a population based combined first-trimester screening program. Ultrasound Obstet Gynecol 2017;
• 81 Drury S, Williams H, Trump N. et al. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenatal diagnosis 2015; 35: 1010-1017
• 82 Hillman SC, Willams D, Carss KJ. et al. Prenatal exome sequencing for fetuses with structural abnormalities: the next step. Ultrasound Obstet Gynecol 2015; 45: 4-9
• 83 Best S, Wou K, Vora N. et al. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenatal diagnosis 2018; 38: 10-19
• 84 Oneda B, Steindl K, Masood R. et al. Noninvasive prenatal testing: more caution in counseling is needed in high risk pregnancies with ultrasound abnormalities. European journal of obstetrics, gynecology, and reproductive biology 2016; 200: 72-75
• 85 Wellesley D, Dolk H, Boyd PA. et al. Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. EJHG 2012; 20: 521-526
• 86 Alamillo CM, Krantz D, Evans M. et al. Nearly a third of abnormalities found after first-trimester screening are different than expected: 10-year experience from a single center. Prenatal diagnosis 2013; 33: 251-256
• 87 Petersen OB, Vogel I, Ekelund C. et al. Potential diagnostic consequences of applying non-invasive prenatal testing: population-based study from a country with existing first-trimester screening. Ultrasound Obstet Gynecol 2014; 43: 265-271
• 88 Kagan KO, Avgidou K, Molina FS. et al. Relation between increased fetal nuchal translucency thickness and chromosomal defects. Obstetrics and gynecology 2006; 107: 6-10
• 89 Äyräs O, Tikkanen M, Eronen M. et al. Increased nuchal translucency and pregnancy outcome: a retrospective study of 1063 consecutive singleton pregnancies in a single referral institution. Prenatal diagnosis 2013; 33: 856-862
• 90 Christiansen M, Ekelund CK, Petersen OB. et al. Nuchal translucency distributions for different chromosomal anomalies in a large unselected population cohort. Prenatal diagnosis 2016; 36: 49-55
• 91 Srebniak MI, de Wit MC, Diderich KE. et al. Enlarged NT (>/=3.5 mm) in the first trimester – not all chromosome aberrations can be detected by NIPT. Molecular cytogenetics 2016; 9: 69
• 92 Lund IC, Christensen R, Petersen OB. et al. Chromosomal microarray in fetuses with increased nuchal translucency. Ultrasound Obstet Gynecol 2015; 45: 95-100
• 93 Maya I, Yacobson S, Kahana S. et al. Cut-off value of nuchal translucency as indication for chromosomal microarray analysis. Ultrasound Obstet Gynecol 2017; 50: 332-335
• 94 Tørring N, Petersen OB, Becher N. et al. First trimester screening for other trisomies than trisomy 21, 18, and 13. Prenatal diagnosis 2015; 35: 612-619
• 95 Tørring N, Petersen OB, Uldbjerg N. Ten years of experience with first-trimester screening for fetal aneuploidy employing biochemistry from gestational weeks 6+0 to 13+6. Fetal diagnosis and therapy 2015; 37: 51-57
• 96 Akolekar R, Beta J, Picciarelli G. et al. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015; 45: 16-26
• 97 Wulff CB, Gerds TA, Rode L. et al. Risk of fetal loss associated with invasive testing following combined first-trimester screening for Down syndrome: a national cohort of 147987 singleton pregnancies. Ultrasound Obstet Gynecol 2016; 47: 38-44
• 98 Kagan KO, Eiben B, Kozlowski P. Combined first trimester screening and cell-free fetal DNA – “next generation screening”. Ultraschall in der Medizin (Stuttgart, Germany: 1980) 2014; 35: 229-236
• 99 Zelig CM, Knutzen DM, Ennen CS. et al. Chorionic Villus Sampling, Early Amniocentesis, and Termination of Pregnancy Without Diagnostic Testing: Comparison of Fetal Risk Following Positive Non-invasive Prenatal Testing. Journal of obstetrics and gynaecology Canada: JOGC = Journal d’obstetrique et gynecologie du Canada: JOGC 2016; 38: 441-445.e442
• 100 Van Opstal D, Srebniak MI. Cytogenetic confirmation of a positive NIPT result: evidence-based choice between chorionic villus sampling and amniocentesis depending on chromosome aberration. Expert review of molecular diagnostics 2016; 16: 513-520
• 101 Grati FR. Implications of fetoplacental mosaicism on cell-free DNA testing: a review of a common biological phenomenon. Ultrasound Obstet Gynecol 2016; 48: 415-423
• 102 Sagi-Dain L, Peleg A, Sagi S. First-Trimester Crown-Rump Length and Risk of Chromosomal Aberrations-A Systematic Review and Meta-analysis. Obstetrical & gynecological survey 2017; 72: 603-609
• 103 Syngelaki A, Pergament E, Homfray T. et al. Replacing the combined test by cell-free DNA testing in screening for trisomies 21, 18 and 13: impact on the diagnosis of other chromosomal abnormalities. Fetal diagnosis and therapy 2014; 35: 174-184
• 104 Tercanli S, Vial Y, Merz E. Non-invasive chromosome test raises new questions in prenatal diagnosis about the significance of ultrasound and questions about new screening strategies. Ultraschall in der Medizin (Stuttgart, Germany: 1980) 2013; 34: 417-420
• 105 Ferreira JC, Grati FR, Bajaj K. et al. Frequency of fetal karyotype abnormalities in women undergoing invasive testing in the absence of ultrasound and other high-risk indications. Prenatal diagnosis 2016; 36: 1146-1155
• 106 Coe BP, Witherspoon K, Rosenfeld JA. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature genetics 2014; 46: 1063-1071
• 107 Srebniak MI, Joosten M, Knapen M. et al. Frequency of submicroscopic chromosome aberrations in pregnancies without increased risk for structural chromosome aberrations: a systematic review of literature and meta-analysis. Ultrasound Obstet Gynecol 2017;
• 108 Hillman SC, McMullan DJ, Hall G. et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 41: 610-620
• 109 Donnelly JC, Platt LD, Rebarber A. et al. Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstetrics and gynecology 2014; 124: 83-90
• 110 Iuculano A, Pagani G, Stagnati V. et al. Pregnancy outcome and long-term follow-up of fetuses with isolated increased NT: a retrospective cohort study. Journal of perinatal medicine 2016; 44: 237-242
• 111 Lee CN, Lin SY, Lin CH. et al. Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG: an international journal of obstetrics and gynaecology 2012; 119: 614-625
• 112 Pergament E, Alamillo C, Sak K. et al. Genetic assessment following increased nuchal translucency and normal karyotype. Prenatal diagnosis 2011; 31: 307-310
• 113 Schramm T, Gloning KP, Minderer S. et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34: 160-170
• 114 [Anonym]. Online Mendelian Inheritance in Men OMIM. http://www.omim.org In
• 115 Eddleman KA, Malone FD, Sullivan L. et al. Pregnancy loss rates after midtrimester amniocentesis. Obstetrics and gynecology 2006; 108: 1067-1072
• 116 Odibo AO, Dicke JM, Gray DL. et al. Evaluating the rate and risk factors for fetal loss after chorionic villus sampling. Obstetrics and gynecology 2008; 112: 813-819
• 117 Odibo AO, Gray DL, Dicke JM. et al. Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center’s 16-year experience. Obstetrics and gynecology 2008; 111: 589-595
• 118 Tabor A, Philip J, Madsen M. et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet (London, England) 1986; 1: 1287-1293
• 119 Simpson JL. Invasive procedures for prenatal diagnosis: any future left?. Best practice & research Clinical obstetrics & gynaecology 2012; 26: 625-638
• 120 Evans MI, Wapner RJ, Berkowitz RL. Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor. American journal of obstetrics and gynecology 2016; 215: 298-305
• 121 Benn P. Expanding non-invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y. Clinical genetics 2016; 90: 477-485
• 122 Pescia G, Guex N, Iseli C. et al. Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6388 consecutive cases. Genetics in medicine: official journal of the American College of Medical Genetics 2017; 19: 169-175
• 123 Malvestiti F, Agrati C, Grimi B. et al. Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis. Prenatal diagnosis 2015; 35: 1117-1127
• 124 Bianchi DW. Should we “open the kimono” to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing?. Prenatal diagnosis 2017; 37: 123-125
• 125 Gregg AR, Skotko BG, Benkendorf JL. et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genetics in medicine: official journal of the American College of Medical Genetics 2016; 18: 1056-1065
• 126 Lau TK, Cheung SW, Lo PS. et al. Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage whole-genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center. Ultrasound Obstet Gynecol 2014; 43: 254-264
• 127 Palomaki GE, Kloza EM, Lambert-Messerlian GM. et al. Circulating cell free DNA testing: are some test failures informative?. Prenatal diagnosis 2015; 35: 289-293
• 128 Meck JM, Kramer DuganE, Matyakhina L. et al. Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. American journal of obstetrics and gynecology 2015; 213: 214.e211-215
• 129 Snyder MW, Simmons LE, Kitzman JO. et al. Copy-number variation and false positive prenatal aneuploidy screening results. The New England journal of medicine 2015; 372: 1639-1645
• 130 Bianchi DW, Parsa S, Bhatt S. et al. Fetal sex chromosome testing by maternal plasma DNA sequencing: clinical laboratory experience and biology. Obstetrics and gynecology 2015; 125: 375-382
• 131 Mennuti MT, Chandrasekaran S, Khalek N. et al. Cell-free DNA screening and sex chromosome aneuploidies. Prenatal diagnosis 2015; 35: 980-985
• 132 Cheung SW, Patel A, Leung TY. Accurate description of DNA-based noninvasive prenatal screening. The New England journal of medicine 2015; 372: 1675-1677
• 133 Neufeld-Kaiser WA, Cheng EY, Liu YJ. Positive predictive value of non-invasive prenatal screening for fetal chromosome disorders using cell-free DNA in maternal serum: independent clinical experience of a tertiary referral center. BMC medicine 2015; 13: 129
• 134 Grati FR, Bajaj K, Zanatta V. et al. Implications of fetoplacental mosaicism on cell-free DNA testing for sex chromosome aneuploidies. Prenatal diagnosis 2017; 37: 1017-1027
• 135 Lynch TA, Ruzzo K, Sack V. et al. Fetal sex determination using NIPT and ultrasound as a method for diagnosing important fetal sex abnormalities. Prenatal diagnosis 2016; 36: 888-890
• 136 Dondorp W, de Wert G, Bombard Y. et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. European journal of human genetics: EJHG 2015; 23: 1438-1450
• 137 Kemp MW, Newnham JP, Challis JG. et al. The clinical use of corticosteroids in pregnancy. Human reproduction update 2016; 22: 240-259
• 138 Everett TR, Chitty LS. Cell-free fetal DNA: the new tool in fetal medicine. Ultrasound Obstet Gynecol 2015; 45: 499-507
• 139 Wapner RJ, Levy B. The impact of new genomic technologies in reproductive medicine. Discovery medicine 2014; 17: 313-318
• 140 Yaron Y, Jani J, Schmid M. et al. Current Status of Testing for Microdeletion Syndromes and Rare Autosomal Trisomies Using Cell-Free DNA Technology. Obstetrics and gynecology 2015; 126: 1095-1099
• 141 Lo KK, Karampetsou E, Boustred C. et al. Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities. American journal of human genetics 2016; 98: 34-44
• 142 Benn P, Grati FR. Genome-wide non-invasive prenatal screening for all cytogenetically visible imbalances. Ultrasound Obstet Gynecol 2018;
• 143 Grati FR, Benn P. Comment on “The clinical utility of genome-wide non invasive prenatal screening”. Prenatal diagnosis 2017; 37: 1050-1052
• 144 Helgeson J, Wardrop J, Boomer T. et al. Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing. Prenatal diagnosis 2015; 35: 999-1004
• 145 Lefkowitz RB, Tynan JA, Liu T. et al. Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants. American journal of obstetrics and gynecology 2016; 215: 227.e221-227.e216
• 146 Sahoo T, Hovanes K, Strecker MN. et al. Expanding noninvasive prenatal testing to include microdeletions and segmental aneuploidy: cause for concern?. Genetics in medicine: official journal of the American College of Medical Genetics 2016; 18: 275-276
• 147 Wapner RJ, Babiarz JE, Levy B. et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. American journal of obstetrics and gynecology 2015; 212: 332.e331-339
• 148 Valderramos SG, Rao RR, Scibetta EW. et al. Cell-free DNA screening in clinical practice: abnormal autosomal aneuploidy and microdeletion results. American journal of obstetrics and gynecology 2016; 215: 626.e621-626.e610
• 149 (ACOG) ACoOaG. Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstetrics and gynecology 2015; 126: e31-e37
• 150 (SMFM) SfM-FM. Consult Series #36: Prenatal aneuploidy screening using cell-free DNA. American journal of obstetrics and gynecology 2015; 212: 711-716
• 151 Chitty LS, Finning K, Wade A. et al. Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ (Clinical research ed) 2014; 349: g5243
• 152 Scheffer PG, van der Schoot CE, Page-Christiaens GC. et al. Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7-year clinical experience. BJOG: an international journal of obstetrics and gynaecology 2011; 118: 1340-1348
• 153 Drury S, Hill M, Chitty LS. Cell-Free Fetal DNA Testing for Prenatal Diagnosis. Advances in clinical chemistry 2016; 76: 1-35
• 154 Martin A, Krishna I, Badell M. et al. Can the quantity of cell-free fetal DNA predict preeclampsia: a systematic review. Prenatal diagnosis 2014; 34: 685-691
• 155 Hartley JD, Ferguson BJ, Moffett A. The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia. American journal of obstetrics and gynecology 2015; 213: 268-277
• 156 Levine RJ, Qian C, Leshane ES. et al. Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia. American journal of obstetrics and gynecology 2004; 190: 707-713
• 157 Poon LC, Musci T, Song K. et al. Maternal plasma cell-free fetal and maternal DNA at 11–13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal diagnosis and therapy 2013; 33: 215-223
• 158 Rolnik DL, O’Gorman N, Fiolna M. et al. Maternal plasma cell-free DNA in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2015; 45: 106-111
• 159 Thurik FF, Lamain-de Ruiter M, Javadi A. et al. Absolute first trimester cell-free DNA levels and their associations with adverse pregnancy outcomes. Prenatal diagnosis 2016; 36: 1104-1111
• 160 Kim SY, Kim HJ, Park SY. et al. Early Prediction of Hypertensive Disorders of Pregnancy Using Cell-Free Fetal DNA, Cell-Free Total DNA, and Biochemical Markers. Fetal diagnosis and therapy 2016; 40: 255-262
• 161 Sifakis S, Zaravinos A, Maiz N. et al. First-trimester maternal plasma cell-free fetal DNA and preeclampsia. American journal of obstetrics and gynecology 2009; 201: 472.e471-477
• 162 O’Gorman N, Wright D, Syngelaki A. et al. Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11–13 weeks gestation. American journal of obstetrics and gynecology 2016; 214: 103.e101-103.e112
• 163 O’Gorman N, Wright D, Poon LC. et al. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation. Ultrasound Obstet Gynecol 2017; 49: 751-755
• 164 O’Gorman N, Wright D, Poon LC. et al. Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks’ gestation: comparison with NICE guidelines and ACOG recommendations. Ultrasound Obstet Gynecol 2017; 49: 756-760
• 165 Wright D, Syngelaki A, Akolekar R. et al. Competing risks model in screening for preeclampsia by maternal characteristics and medical history. American journal of obstetrics and gynecology 2015; 213: 62.e61-10
• 166 Karagiannis G, Akolekar R, Sarquis R. et al. Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11–13 weeks. Fetal diagnosis and therapy 2011; 29: 148-154
• 167 Akolekar R, Bower S, Flack N. et al. Prediction of miscarriage and stillbirth at 11–13 weeks and the contribution of chorionic villus sampling. Prenatal diagnosis 2011; 31: 38-45
• 168 Syngelaki A, Pastides A, Kotecha R. et al. First-Trimester Screening for Gestational Diabetes Mellitus Based on Maternal Characteristics and History. Fetal diagnosis and therapy 2015; 38: 14-21
• 169 Syngelaki A, Kotecha R, Pastides A. et al. First-trimester biochemical markers of placentation in screening for gestational diabetes mellitus. Metabolism: clinical and experimental 2015; 64: 1485-1489
• 170 Beta J, Akolekar R, Ventura W. et al. Prediction of spontaneous preterm delivery from maternal factors, obstetric history and placental perfusion and function at 11–13 weeks. Prenatal diagnosis 2011; 31: 75-83
• 171 Royston P, Moons KG, Altman DG. et al. Prognosis and prognostic research: Developing a prognostic model. BMJ (Clinical research ed) 2009; 338: b604
• 172 Altman DG, Vergouwe Y, Royston P. et al. Prognosis and prognostic research: validating a prognostic model. BMJ (Clinical research ed) 2009; 338: b605
• 173 Yaron Y, Hyett J, Langlois S. Current controversies in prenatal diagnosis 2: for those women screened by NIPT using cell free DNA, maternal serum markers are obsolete. Prenatal diagnosis 2016; 36: 1167-1171
• 174 Kleinrouweler CE, Cheong-See FM, Collins GS. et al. Prognostic models in obstetrics: available, but far from applicable. American journal of obstetrics and gynecology 2016; 214: 79-90.e36
• 175 Park FJ, Leung CH, Poon LC. et al. Clinical evaluation of a first trimester algorithm predicting the risk of hypertensive disease of pregnancy. The Australian & New Zealand journal of obstetrics & gynaecology 2013; 53: 532-539
• 176 Sonek J, Krantz D, Carmichael J. et al. First-trimester screening for early and late preeclampsia using maternal characteristics, biomarkers, and estimated placental volume. American journal of obstetrics and gynecology 2018; 218: 126.e121-126.e113
• 177 Scazzocchio E, Figueras F, Crispi F. et al. Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting. American journal of obstetrics and gynecology 2013; 208: 203.e201-203.e210
• 178 Rolnik DL, Wright D, Poon LC. et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. The New England journal of medicine 2017; 377: 613-622
• 179 Khalil A, Akolekar R, Syngelaki A. et al. Maternal hemodynamics in normal pregnancies at 11–13 weeks’ gestation. Fetal diagnosis and therapy 2012; 32: 179-185
• 180 Khalil A, Garcia-Mandujano R, Maiz N. et al. Longitudinal changes in maternal hemodynamics in a population at risk for pre-eclampsia. Ultrasound Obstet Gynecol 2014; 44: 197-204
• 181 Stirnemann JJ, Chalouhi GE, Forner S. et al. First-trimester uterine scar assessment by transvaginal ultrasound. American journal of obstetrics and gynecology 2011; 205: 551.e551-556
• 182 Naji O, Wynants L, Smith A. et al. Predicting successful vaginal birth after Cesarean section using a model based on Cesarean scar features examined by transvaginal sonography. Ultrasound Obstet Gynecol 2013; 41: 672-678
• 183 Stirnemann JJ, Mousty E, Chalouhi G. et al. Screening for placenta accreta at 11–14 weeks of gestation. American journal of obstetrics and gynecology 2011; 205: 547.e541-546
• 184 Timor-Tritsch IE, Khatib N, Monteagudo A. et al. Cesarean scar pregnancies: experience of 60 cases. Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 2015; 34: 601-610
• 185 Timor-Tritsch IE, Monteagudo A, Bennett TA. et al. A new minimally invasive treatment for cesarean scar pregnancy and cervical pregnancy. American journal of obstetrics and gynecology 2016; 215: 351.e351-358
• 186 Salomon LJ, Alfirevic Z, Audibert F. et al. ISUOG updated consensus statement on the impact of cfDNA aneuploidy testing on screening policies and prenatal ultrasound practice. Ultrasound Obstet Gynecol 2017; 49: 815-816
• 187 Pfeifer I, Benachi A, Saker A. et al. Cervical trophoblasts for non-invasive single-cell genotyping and prenatal diagnosis. Placenta 2016; 37: 56-60
• 188 Breman AM, Chow JC, U’Ren L. et al. Evidence for feasibility of fetal trophoblastic cell-based noninvasive prenatal testing. Prenatal diagnosis 2016; 36: 1009-1019
• 189 Kanda E, Yura H, Kitagawa M. Practicability of prenatal testing using lectin-based enrichment of fetal erythroblasts. The journal of obstetrics and gynaecology research 2016; 42: 918-926
• 190 Kamhieh-Milz J, Moftah RF, Bal G. et al. Differentially expressed microRNAs in maternal plasma for the noninvasive prenatal diagnosis of Down syndrome (trisomy 21). BioMed research international 2014; 2014: 402475
• 191 Erturk B, Karaca E, Aykut A. et al. Prenatal Evaluation of MicroRNA Expressions in Pregnancies with Down Syndrome. BioMed research international 2016; 2016: 5312674
• 192 Bolnick JM, Kilburn BA, Bajpayee S. et al. Trophoblast retrieval and isolation from the cervix (TRIC) for noninvasive prenatal screening at 5 to 20 weeks of gestation. Fertility and sterility 2014; 102: 135-142.e136
• 193 Giambona A, Leto F, Passarello C. et al. Fetal aneuploidy diagnosed at celocentesis for early prenatal diagnosis of congenital hemoglobinopathies. Acta obstetricia et gynecologica Scandinavica 2018; 97: 312-321