J Korean Med Sci.  2021 Jan;36(4):e26. 10.3346/jkms.2021.36.e26.

Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine:(2) Invasive Diagnostic Testing for Fetal Chromosomal Abnormalities

• Lee JY
• Kwon JY
• Na S
• Choe SA
• Seol HJ
• Kim M
• Kim MA
• Park CW
• Kim K
• Ryu HM
• Hwang HS
• Shim JY

• KMID: 2510965
• DOI: http://doi.org/10.3346/jkms.2021.36.e26

Abstract

The Korean Society of Maternal Fetal Medicine proposed the first Korean guideline on prenatal aneuploidy screening and diagnostic testing, in April 2019. The clinical practice guideline (CPG) was developed for Korean women using an adaptation process based on good-quality practice guidelines, previously developed in other countries, on prenatal screening and invasive diagnostic testing for fetal chromosome abnormalities. We reviewed current guidelines and developed a Korean CPG on invasive diagnostic testing for fetal chromosome abnormalities according to the adaptation process. Recommendations for selected 11 key questions are: 1) Considering the increased risk of fetal loss in invasive prenatal diagnostic testing for fetal genetic disorders, it is not recommended for all pregnant women aged over 35 years. 2) Because early amniocentesis performed before 14 weeks of pregnancy increases the risk of fetal loss and malformation, chorionic villus sampling (CVS) is recommended for pregnant women who will undergo invasive prenatal diagnostic testing for fetal genetic disorders in the first trimester of pregnancy. However, CVS before 9 weeks of pregnancy also increases the risk of fetal loss and deformity. Thus, CVS is recommended after 9 weeks of pregnancy. 3) Amniocentesis is recommended to distinguish true fetal mosaicism from confined placental mosaicism. 4) Anti-immunoglobulin should be administered within 72 hours after the invasive diagnostic testing. 5) Since there is a high risk of vertical transmission, an invasive prenatal diagnostic testing is recommended according to the clinician's discretion with consideration of the condition of the pregnant woman. 6) The use of antibiotics is not recommended before or after an invasive diagnostic testing. 7) The chromosomal microarray test as an alternative to the conventional cytogenetic test is not recommended for all pregnant women who will undergo an invasive diagnostic testing. 8) Amniocentesis before 14 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 9) CVS before 9 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 10) Although the risk of fetal loss associated with invasive prenatal diagnostic testing (amniocentesis and CVS) may vary based on the proficiency of the operator, the risk of fetal loss due to invasive prenatal diagnostic testing is higher in twin pregnancies than in singleton pregnancies. 11) When a monochorionic twin is identified in early pregnancy and the growth and structure of both fetuses are consistent, an invasive prenatal diagnostic testing can be performed on one fetus alone. However, an invasive prenatal diagnostic testing is recommended for each fetus in cases of pregnancy conceived via in vitro fertilization, or in cases in which the growth of both fetuses differs, or in those in which at least one fetus has a structural abnormality. The guidelines were established and approved by the Korean Academy of Medical Sciences. This guideline is revised and presented every 5 years.

Keyword

Invasive Prenatal Diagnostic Testing; Amniocentesis; Chorionic Villus Sampling; CVS; Chromosome; Microarray

Reference

1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins–Obstetrics, Committee on Genetics. Society for Maternal-Fetal Medicine. Practice bulletin No. 162: prenatal diagnostic testing for genetic disorders. Obstet Gynecol. 2016; 127(5):e108–22.

2. Tabor A, Alfirevic Z. Update on procedure-related risks for prenatal diagnosis techniques. Fetal Diagn Ther. 2010; 27(1):1–7. PMID: 20051662.

3. Alfirevic Z, Navaratnam K, Mujezinovic F. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2017; 9:CD003252. PMID: 28869276.

4. Centers for Disease Control and Prevention. Chorionic villus sampling and amniocentesis: recommendations for prenatal counseling. MMWR Recomm Rep. 1995; 44(RR-9):1–12.

5. Redman CW, Dollery E, Jordan JA. Development of the European colposcopy core curriculum: use of the Delphi technique. J Obstet Gynaecol. 2004; 24(7):780–784. PMID: 15763789.

6. Ministry of Health & Welfare, Korean Academy of Medical Science. Korean Appraisal of Guidelines for Research & Evaluation II. Seoul: Korean Academy of Medical Science;2009.

7. SIGN, Network SIG. SIGN 50: a guideline developer's handbook. Updated 2020. Accessed May 6, 2020. https://www.sign.ac.uk/assets/sign_grading_system_1999_2012.pdf.

8. Ogawa K, Urayama KY, Tanigaki S, Sago H, Sato S, Saito S, et al. Association between very advanced maternal age and adverse pregnancy outcomes: a cross sectional Japanese study. BMC Pregnancy Childbirth. 2017; 17(1):349. PMID: 29017467.

9. Alldred SK, Takwoingi Y, Guo B, Pennant M, Deeks JJ, Neilson JP, et al. First trimester ultrasound tests alone or in combination with first trimester serum tests for Down's syndrome screening. Cochrane Database Syst Rev. 2017; 3:CD012600. PMID: 28295158.

10. Sheen JJ, Wright JD, Goffman D, Kern-Goldberger AR, Booker W, Siddiq Z, et al. Maternal age and risk for adverse outcomes. Am J Obstet Gynecol. 2018; 219(4):390.e1–390.15. PMID: 30153431.

11. Wilson RD, Davies G, Gagnon A, Desilets V, Reid GJ, Summers A, et al. Amended Canadian guideline for prenatal diagnosis (2005) change to 2005-techniques for prenatal diagnosis. J Obstet Gynaecol Can. 2005; 27(11):1048–1062. PMID: 16529673.

12. Audibert F, Gagnon A. No. 262-prenatal screening for and diagnosis of aneuploidy in twin pregnancies. J Obstet Gynaecol Can. 2017; 39(9):e347–61. PMID: 28859779.

13. Grati FR, Molina Gomes D, Ferreira JC, Dupont C, Alesi V, Gouas L, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn. 2015; 35(8):801–809. PMID: 25962607.

14. Ghi T, Sotiriadis A, Calda P, Da Silva Costa F, Raine-Fenning N, Alfirevic Z, et al. ISUOG Practice Guidelines: invasive procedures for prenatal diagnosis. Ultrasound Obstet Gynecol. 2016; 48(2):256–268. PMID: 27485589.

15. WHO/PAHO consultation on CVS, evaluation of chorionic villus sampling safety. Prenat Diagn. 1999; 19(2):97–99. PMID: 10215062.

16. Kuliev A, Jackson L, Froster U, Brambati B, Simpson JL, Verlinsky Y, et al. Chorionic villus sampling safety. Report of World Health Organization/EURO meeting in association with the Seventh International Conference on Early Prenatal Diagnosis of Genetic Diseases, Tel-Aviv, Israel, May 21, 1994. Am J Obstet Gynecol. 1996; 174(3):807–811. PMID: 8633647.

17. The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group. Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. Lancet. 1998; 351(9098):242–247. PMID: 9457093.

18. Winsor EJ, Tomkins DJ, Kalousek D, Farrell S, Wyatt P, Fan YS, et al. Cytogenetic aspects of the Canadian early and mid-trimester amniotic fluid trial (CEMAT). Prenat Diagn. 1999; 19(7):620–627. PMID: 10419609.

19. Farrell SA, Summers AM, Dallaire L, Singer J, Johnson JA, Wilson RD. Club foot, an adverse outcome of early amniocentesis: disruption or deformation? CEMAT. Canadian Early and Mid-Trimester Amniocentesis Trial. J Med Genet. 1999; 36(11):843–846. PMID: 10544229.

20. Sundberg K, Bang J, Smidt-Jensen S, Brocks V, Lundsteen C, Parner J, et al. Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet. 1997; 350(9079):697–703. PMID: 9291904.

21. Brambati B, Simoni G, Travi M, Danesino C, Tului L, Privitera O, et al. Genetic diagnosis by chorionic villus sampling before 8 gestational weeks: efficiency, reliability, and risks on 317 completed pregnancies. Prenat Diagn. 1992; 12(10):789–799. PMID: 1475247.

22. Goldberg JD, Wohlferd MM. Incidence and outcome of chromosomal mosaicism found at the time of chorionic villus sampling. Am J Obstet Gynecol. 1997; 176(6):1349–1352. PMID: 9215195.

23. Baffero GM, Somigliana E, Crovetto F, Paffoni A, Persico N, Guerneri S, et al. Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome. Prenat Diagn. 2012; 32(11):1102–1108. PMID: 22961322.

24. Tabor A, Jerne D, Bock JE. Incidence of rhesus immunisation after genetic amniocentesis. Br Med J (Clin Res Ed). 1986; 293(6546):533–536.

25. Murray JC., Karp LE, Williamson RA, Cheng EY, Luthy DA.Rh isoimmunization related to amniocentesis. Am J Med Genet. 1983; 16(4):527–534. PMID: 6419606.

26. Royal College of Obstetricians and Gynaecologists. The Use of Anti-D Immunoglobulin for Rhesus D Prophylaxis. Green-top Guideline No. 22. London: RCOG;2011.

27. Centers for Disease Control. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. MMWR Morb Mortal Wkly Rep. 1991; 40(RR-13):1–19. PMID: 1898620.

28. Yi W, Pan CQ, Hao J, Hu Y, Liu M, Li L, et al. Risk of vertical transmission of hepatitis B after amniocentesis in HBs antigen-positive mothers. J Hepatol. 2014; 60(3):523–529. PMID: 24269471.

29. Towers CV, Asrat T, Rumney P. The presence of hepatitis B surface antigen and deoxyribonucleic acid in amniotic fluid and cord blood. Am J Obstet Gynecol. 2001; 184(7):1514–1518. PMID: 11408875.

30. Grosheide PM, Quartero HW, Schalm SW, Heijtink RA, Christiaens GC. Early invasive prenatal diagnosis in HBsAg-positive women. Prenat Diagn. 1994; 14(7):553–558. PMID: 7971756.

31. Gagnon A, Davies G, Wilson RD, Audibert F, Brock JA, Campagnoto C, et al. Prenatal invasive procedures in women with hepatitis B, hepatitis C, and/or human immunodeficiency virus infections. J Obstet Gynaecol Can. 2014; 36(7):648–653. PMID: 25184985.

32. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol. 2007; 110(6):1459–1467. PMID: 18055749.

33. Delamare C, Carbonne B, Heim N, Berkane N, Petit JC, Uzan S, et al. Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study. J Hepatol. 1999; 31(3):416–420. PMID: 10488698.

34. Tess BH, Rodrigues LC, Newell ML, Dunn DT, Lago TD. Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo Collaborative Study for Vertical Transmission of HIV-1. AIDS. 1998; 12(5):513–520. PMID: 9543450.

35. Maiques V, García-Tejedor A, Perales A, Córdoba J, Esteban RJ. HIV detection in amniotic fluid samples. Amniocentesis can be performed in HIV pregnant women? Eur J Obstet Gynecol Reprod Biol. 2003; 108(2):137–141. PMID: 12781400.

36. Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongain A, Pannier E, et al. ANRS French Perinatal Cohort (EPF). Amniocentesis and mother-to-child human immunodeficiency virus transmission in the Agence Nationale de Recherches sur le SIDA et les H'epatites Virales French Perinatal Cohort. Am J Obstet Gynecol. 2009; 200:160.e1–160.e9. PMID: 18986640.

37. Somigliana E, Bucceri AM, Tibaldi C, Alberico S, Ravizza M, Savasi V, et al. Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series. Am J Obstet Gynecol. 2005; 193(2):437–442. PMID: 16098867.

38. Shapiro DE, Sperling RS, Mandelbrot L, Britto P, Cunningham BE. Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol 076 Study Group. Obstet Gynecol. 1999; 94(6):897–908. PMID: 10576173.

39. Society for Maternal-Fetal Medicine (SMFM). Berry SM, Stone J, Norton ME, Johnson D, Berghella V. Fetal blood sampling. Am J Obstet Gynecol. 2013; 209(3):170–180. PMID: 23978246.

40. Royal College of Obstetricians and Gynaecologists. Amniocentesis and chorionic villus sampling: green-top guideline No. 8. Updated 2013. Accessed May 6, 2020. https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_8.pdf.

41. Giorlandino C, Cignini P, Cini M, Brizzi C, Carcioppolo O, Milite V, et al. Antibiotic prophylaxis before second-trimester genetic amniocentesis (APGA): a single-centre open randomised controlled trial. Prenat Diagn. 2009; 29(6):606–612. PMID: 19294678.

42. Alfirevic Z, Pilu G. Antibiotic prophylaxis for amniocentesis. Prenat Diagn. 2009; 29(11):1094. PMID: 19859907.

43. Ferrazzi E. Antibiotic prophylaxis before second-trimester genetic amniocentesis. Prenat Diagn. 2010; 30(2):188. PMID: 20101625.

44. Hobbins JC, Pilu G, Abuhumad A, Alfirevic Z, Bahado-Singh RO, Benacerraf BR, et al. Antibiotic prophylaxis before amniocentesis. Prenat Diagn. 2011; 31(12):1213–1214. PMID: 22120439.

45. Gramellini D, Fieni S, Casilla G, Raboni S, Nardelli GB. Mid-trimester amniocentesis and antibiotic prophylaxis. Prenat Diagn. 2007; 27(10):956–959. PMID: 17607664.

46. Mujezinovic F, Alfirevic Z. Technique modifications for reducing the risks from amniocentesis or chorionic villus sampling. Cochrane Database Syst Rev. 2012; 8(8):CD008678.

47. Wilson RD, Gagnon A, Audibert F, Campagnolo C, Carroll J, Wilson RD, et al. Prenatal diagnosis procedures and techniques to obtain a diagnostic fetal specimen or tissue: maternal and fetal risks and benefits. J Obstet Gynaecol Can. 2015; 37(7):656–668. PMID: 26366824.

48. Boulot P, Deschamps F, Lefort G, Sarda P, Mares P, Hedon B, et al. Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases. Prenat Diagn. 1990; 10(2):93–100. PMID: 2343027.

49. Johnstone-Ayliffe C, Prior T, Ong C, Regan F, Kumar S. Early procedure-related complications of fetal blood sampling and intrauterine transfusion for fetal anemia. Acta Obstet Gynecol Scand. 2012; 91(4):458–462. PMID: 22356474.

50. Tangshewinsirikul C, Wanapirak C, Piyamongkol W, Sirichotiyakul S, Tongsong T. Effect of cord puncture site in cordocentesis at mid-pregnancy on pregnancy outcomes. Prenat Diagn. 2011; 31(9):861–864. PMID: 21706506.

51. Tongsong T, Wanapirak C, Kunavikatikul C, Sirirchotiyakul S, Piyamongkol W, Chanprapaph P. Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases. Prenat Diagn. 2000; 20(3):224–228. PMID: 10719326.

52. Aina-Mumuney AJ, Holcroft CJ, Blakemore KJ, Bienstock JL, Hueppchen NA, Milio LA, et al. Intrahepatic vein for fetal blood sampling: one center's experience. Am J Obstet Gynecol. 2008; 198(4):387.e1–387.e6. PMID: 18191806.

53. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367(23):2175–2184. PMID: 23215555.

54. Jansen FA, Blumenfeld YJ, Fisher A, Cobben JM, Odibo AO, Borrell A, et al. Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015; 45(1):27–35. PMID: 25319878.

55. Grande M, Jansen FA, Blumenfeld YJ, Fisher A, Odibo AO, Haak MC, et al. Genomic microarray in fetuses with increased nuchal translucency and normal karyotype: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015; 46(6):650–658. PMID: 25900824.

56. Callaway JL, Shaffer LG, Chitty LS, Rosenfeld JA, Crolla JA. The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn. 2013; 33(12):1119–1123. PMID: 23983223.

57. Reddy UM, Page GP, Saade GR, Silver RM, Thorsten VR, Parker CB, et al. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med. 2012; 367(23):2185–2193. PMID: 23215556.

58. Society for Maternal-Fetal Medicine (SMFM). Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016; 215(4):B2–9.

59. Committee on Genetics and the Society for Maternal-Fetal Medicine. Committee opinion No.682: microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol. 2016; 128(6):e262–8. PMID: 27875474.

60. Borrell A, Costa D, Delgado RD, Fuster JJ, Soler A, Cararach J, et al. Transcervical chorionic villus sampling beyond 12 weeks of gestation. Ultrasound Obstet Gynecol. 1996; 7(6):416–420. PMID: 8807757.

61. Botto LD, Olney RS, Mastroiacovo P, Khoury MJ, Moore CA, Alo CJ, et al. Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies. Am J Med Genet. 1996; 62(2):173–178. PMID: 8882399.

62. Calzolari E, Manservigi D, Garani GP, Cocchi G, Magnani C, Milan M. Limb reduction defects in Emilia Romagna, Italy: epidemiological and genetic study in 173,109 consecutive births. J Med Genet. 1990; 27(6):353–357. PMID: 2359096.

63. Olney RS, Khoury MJ, Alo CJ, Costa P, Edmonds LD, Flood TJ, et al. Increased risk for transverse digital deficiency after chorionic villus sampling: results of the United States Multistate Case-Control Study, 1988–1992. Teratology. 1995; 51(1):20–29. PMID: 7597654.

64. Millaire M, Bujold E, Morency AM, Gauthier RJ. Mid-trimester genetic amniocentesis in twin pregnancy and the risk of fetal loss. J Obstet Gynaecol Can. 2006; 28(6):512–518. PMID: 16857119.

65. Lenis-Cordoba N, Sánchez MA, Bello-Muñoz JC, Sagalá-Martinez J, Campos N, Carreras-Moratonas E, et al. Amniocentesis and the risk of second trimester fetal loss in twin pregnancies: results from a prospective observational study. J Matern Fetal Neonatal Med. 2013; 26(15):1537–1541. PMID: 23544929.

66. Cahill AG, Macones GA, Stamilio DM, Dicke JM, Crane JP, Odibo AO. Pregnancy loss rate after midtrimester amniocentesis in twin pregnancies. Am J Obstet Gynecol. 2009; 200(3):257.e1–257.e6. PMID: 19136086.

67. Agarwal K, Alfirevic Z. Pregnancy loss after chorionic villus sampling and genetic amniocentesis in twin pregnancies: a systematic review. Ultrasound Obstet Gynecol. 2012; 40(2):128–134. PMID: 22125091.

68. Wapner RJ, Johnson A, Davis G, Urban A, Morgan P, Jackson L. Prenatal diagnosis in twin gestations: a comparison between second-trimester amniocentesis and first-trimester chorionic villus sampling. Obstet Gynecol. 1993; 82(1):49–56. PMID: 8515925.

69. Simonazzi G, Curti A, Farina A, Pilu G, Bovicelli L, Rizzo N. Amniocentesis and chorionic villus sampling in twin gestations: which is the best sampling technique? Am J Obstet Gynecol. 2010; 202(4):365.e1–365.e5. PMID: 20060095.

70. Audibert F, Gagnon A, Douglas Wilson R, Audibert F, Blight C, Brock JA, et al. Prenatal screening for and diagnosis of aneuploidy in twin pregnancies. J Obstet Gynaecol Can. 2011; 33(7):754–767. PMID: 21749753.

71. Evans MI, Goldberg JD, Horenstein J, Wapner RJ, Ayoub MA, Stone J, et al. Selective termination for structural, chromosomal, and mendelian anomalies: international experience. Am J Obstet Gynecol. 1999; 181(4):893–897. PMID: 10521749.

72. Casals G, Borrell A, Martínez JM, Soler A, Cararach V, Fortuny A. Transcervical chorionic villus sampling in multiple pregnancies using a biopsy forceps. Prenat Diagn. 2002; 22(3):260–265. PMID: 11920906.

73. Kidd SA, Lancaster PA, Anderson JC, Boogert A, Fisher CC, Robertson R, et al. A cohort study of pregnancy outcome after amniocentesis in twin pregnancy. Paediatr Perinat Epidemiol. 1997; 11(2):200–213. PMID: 9131711.

74. McFadyen I. The dangers of intra-amniotic methylene blue. Br J Obstet Gynaecol. 1992; 99(2):89–90. PMID: 1554680.

75. Morin L, Lim K, Morin L, Lim K, Bly S, Butt K, et al. Ultrasound in twin pregnancies. J Obstet Gynaecol Can. 2011; 33(6):643–656. PMID: 21846456.

76. Weisz B, Rodeck CH. Invasive diagnostic procedures in twin pregnancies. Prenat Diagn. 2005; 25(9):751–758. PMID: 16170858.

77. Grande M, Goncé A, Stergiotou I, Bennasar M, Borrell A. Intertwin crown-rump length discordance in the prediction of fetal anomalies, fetal loss and adverse perinatal outcome. J Matern Fetal Neonatal Med. 2016; 29(17):2883–2888. PMID: 26466907.

78. Litwinska E, Syngelaki A, Cimpoca B, Sapantzoglou I, Nicolaides KH. Intertwin discordance in fetal size at 11–13 weeks' gestation and pregnancy outcome. Ultrasound Obstet Gynecol. 2020; 55(2):189–197. PMID: 31710737.

79. Harper LM, Roehl KA, Odibo AO, Cahill AG. First-trimester growth discordance and adverse pregnancy outcome in dichorionic twins. Ultrasound Obstet Gynecol. 2013; 41(6):627–631. PMID: 22744892.

80. Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Chorionic villus sampling before multifetal pregnancy reduction. Am J Obstet Gynecol. 2000; 183(5):1078–1081. PMID: 11084544.

81. Brambati B, Tului L, Guercilena S, Alberti E. Outcome of first-trimester chorionic villus sampling for genetic investigation in multiple pregnancy. Ultrasound Obstet Gynecol. 2001; 17(3):209–216. PMID: 11309169.

82. van den Berg C, Braat AP, Van Opstal D, Halley DJ, Kleijer WJ, den Hollander NS, et al. Amniocentesis or chorionic villus sampling in multiple gestations? Experience with 500 cases. Prenat Diagn. 1999; 19(3):234–244. PMID: 10210122.

83. Schmid O, Trautmann U, Ashour H, Ulmer R, Pfeiffer RA, Beinder E. Prenatal diagnosis of heterokaryotypic mosaic twins discordant for fetal sex. Prenat Diagn. 2000; 20(12):999–1003. PMID: 11113914.

84. Shalev SA, Shalev E, Pras E, Shneor Y, Gazit E, Yaron Y, et al. Evidence for blood chimerism in dizygotic spontaneous twin pregnancy discordant for Down syndrome. Prenat Diagn. 2006; 26(9):782–784. PMID: 16927328.