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Laboratory issues related to maternal serum screening for Down syndrome

Authors
Geralyn M Messerlian, PhD
Glenn E Palomaki, PhD
Section Editor
Louise Wilkins-Haug, MD, PhD
Deputy Editor
Vanessa A Barss, MD, FACOG

INTRODUCTION

Screening markers are used to calculate a pregnant woman's risk of having a child with Down syndrome, thereby allowing her to make an informed choice about invasive diagnostic testing, which is costly and associated with some risk of pregnancy loss. A variety of serum markers are used to screen for Down syndrome in the first and/or second trimesters. This topic will review laboratory issues related to use of these markers. Clinical issues related to Down syndrome are discussed separately:

(See "Down syndrome: Overview of prenatal screening".)

(See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)

SCREENING TESTS

Quadruple marker test — The quad test is performed in the early second trimester (optimally at 15 to 18 weeks of gestation) and consists of alpha fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (beta-hCG), and inhibin A (inhA) measurements. (See "Down syndrome: Overview of prenatal screening".)

Combined test — The combined test is performed in the late first trimester (11 to 13 weeks). It involves sonographic determination of fetal nuchal translucency combined with measurement of the serum markers pregnancy-associated plasma protein-A (PAPP-A) and beta-hCG.

                                    

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Literature review current through: Nov 2016. | This topic last updated: Thu Feb 04 00:00:00 GMT+00:00 2016.
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References
Top
  1. Lambert-Messerlian GM, Eklund EE, Malone FD, et al. Stability of first- and second-trimester serum markers after storage and shipment. Prenat Diagn 2006; 26:17.
  2. Wald NJ. The detection of neural-tube defects by screening maternal blood. In: Prenatal diagnosis, Boue A (Ed), INSERM, 1976. p.227.
  3. Palomaki GE, Messerlian G, Canick JA. A summary analysis of Down syndrome markers in the late first trimester. In: Advances in Clinical Chemistry, Makowski G (Ed), Academic Press, 2007. Vol 43, p.177.
  4. Haddow JE, Palomaki GE, Knight GJ, et al. Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A. J Med Screen 1998; 5:115.
  5. Wald N. Down's Syndrome. In: Antenatal and Neonatal Screening, Wald N, Leck I (Eds), Oxford University Press, Oxford 2000. p.85.
  6. Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome. J Med Screen 1997; 4:181.
  7. Cuckle HS, Wald NJ, Densem JW, et al. The effect of smoking in pregnancy on maternal serum alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, progesterone and dehydroepiandrosterone sulphate levels. Br J Obstet Gynaecol 1990; 97:272.
  8. Ryall RG, Staples AJ, Robertson EF, Pollard AC. Improved performance in a prenatal screening programme for Down's syndrome incorporating serum-free hCG subunit analyses. Prenat Diagn 1992; 12:251.
  9. Bartels I, Lindemann A. Maternal levels of pregnancy-specific beta 1-glycoprotein (SP-1) are elevated in pregnancies affected by Down's syndrome. Hum Genet 1988; 80:46.
  10. Chard T. Biochemistry and endocrinology of the Down's syndrome pregnancy. Ann N Y Acad Sci 1991; 626:580.
  11. Lambert-Messerlian GM, Saller DN Jr, Tumber MB, et al. Second-trimester maternal serum progesterone levels in Turner syndrome with and without hydrops and in trisomy 18. Prenat Diagn 1999; 19:476.
  12. Qin QP, Christiansen M, Nguyen TH, et al. Schwangerschaftsprotein 1 (SP1) as a maternal serum marker for Down syndrome in the first and second trimesters. Prenat Diagn 1997; 17:101.
  13. Golbus MS. Development in the first half of gestation of genetically abnormal human fetuses. Teratology 1978; 18:333.
  14. Shepard TH, FitzSimmons JM, Fantel AG, Pascoe-Mason J. Placental weights of normal and aneuploid early human fetuses. Pediatr Pathol 1989; 9:425.
  15. Eldar-Geva T, Hochberg A, deGroot N, Weinstein D. High maternal serum chorionic gonadotropin level in Downs' syndrome pregnancies is caused by elevation of both subunits messenger ribonucleic acid level in trophoblasts. J Clin Endocrinol Metab 1995; 80:3528.
  16. Lambert-Messerlian GM, Luisi S, Florio P, et al. Second trimester levels of maternal serum total activin A and placental inhibin/activin alpha and betaA subunit messenger ribonucleic acids in Down syndrome pregnancy. Eur J Endocrinol 1998; 138:425.
  17. Dalgliesh GL, Aitken DA, Lyall F, et al. Placental and maternal serum inhibin-A and activin-A levels in Down's syndrome pregnancies. Placenta 2001; 22:227.
  18. Frendo JL, Vidaud M, Guibourdenche J, et al. Defect of villous cytotrophoblast differentiation into syncytiotrophoblast in Down's syndrome. J Clin Endocrinol Metab 2000; 85:3700.
  19. Canick JA, Knight GJ, Palomaki GE, et al. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome. Br J Obstet Gynaecol 1988; 95:330.
  20. Cuckle HS, Wald NJ, Densem JW, et al. Second trimester amniotic fluid oestriol, dehydroepiandrosterone sulphate, and human chorionic gonadotrophin levels in Down's syndrome. Br J Obstet Gynaecol 1991; 98:1160.
  21. Wald, NJ, Cheng, R, Cuckle, HS, et al. Maternal serum levels of the estriol precursor, 16 alphaOHDHEAS, are low in Down syndrome pregnancy. Am J Hum Genet 1992; 51:1046.
  22. Newby D, Aitken DA, Crossley JA, et al. Biochemical markers of trisomy 21 and the pathophysiology of Down's syndrome pregnancies. Prenat Diagn 1997; 17:941.
  23. Newby D, Aitken DA, Howatson AG, Connor JM. Placental synthesis of oestriol in Down's syndrome pregnancies. Placenta 2000; 21:263.
  24. Frendo JL, Guibourdenche J, Pidoux G, et al. Trophoblast production of a weakly bioactive human chorionic gonadotropin in trisomy 21-affected pregnancy. J Clin Endocrinol Metab 2004; 89:727.
  25. Tul N, Spencer K, Noble P, et al. Screening for trisomy 18 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation. Prenat Diagn 1999; 19:1035.
  26. Breathnach FM, Malone FD, Lambert-Messerlian G, et al. First- and second-trimester screening: detection of aneuploidies other than Down syndrome. Obstet Gynecol 2007; 110:651.
  27. Spencer K, Liao AW, Ong CY, et al. Maternal serum activin A and inhibin A in trisomy 18 pregnancies at 10-14 weeks. Prenat Diagn 2001; 21:571.
  28. Kagan KO, Wright D, Maiz N, et al. Screening for trisomy 18 by maternal age, fetal nuchal translucency, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol 2008; 32:488.
  29. Palomaki GE, Haddow JE, Knight GJ, et al. Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin. Prenat Diagn 1995; 15:713.
  30. Aitken DA, Wallace EM, Crossley JA, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. N Engl J Med 1996; 334:1231.
  31. Lambert-Messerlian GM, Saller DN Jr, Tumber MB, et al. Second-trimester maternal serum inhibin A levels in fetal trisomy 18 and Turner syndrome with and without hydrops. Prenat Diagn 1998; 18:1061.
  32. Kagan KO, Wright D, Valencia C, et al. 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.
  33. Saller DN Jr, Canick JA, Schwartz S, Blitzer MG. Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome. Am J Obstet Gynecol 1992; 167:1021.
  34. Laundon CH, Spencer K, Macri JN, et al. Free beta hCG screening of hydropic and non-hydropic Turner syndrome pregnancies. Prenat Diagn 1996; 16:853.
  35. Kagan KO, Anderson JM, Anwandter G, et al. Screening for triploidy by the risk algorithms for trisomies 21, 18 and 13 at 11 weeks to 13 weeks and 6 days of gestation. Prenat Diagn 2008; 28:1209.
  36. Benn PA, Gainey A, Ingardia CJ, et al. Second trimester maternal serum analytes in triploid pregnancies: correlation with phenotype and sex chromosome complement. Prenat Diagn 2001; 21:680.
  37. Oyer CE, Canick JA. Maternal serum hCG levels in triploidy: variability and need to consider molar tissue. Prenat Diagn 1992; 12:627.
  38. Tint GS, Irons M, Elias ER, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994; 330:107.
  39. Palomaki GE, Bradley LA, Knight GJ, et al. Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome. J Med Screen 2002; 9:43.
  40. Bradley LA, Palomaki GE, Knight GJ, et al. Levels of unconjugated estriol and other maternal serum markers in pregnancies with Smith-Lemli-Opitz (RSH) syndrome fetuses. Am J Med Genet 1999; 82:355.
  41. Craig WY, Haddow JE, Palomaki GE, et al. Identifying Smith-Lemli-Opitz syndrome in conjunction with prenatal screening for Down syndrome. Prenat Diagn 2006; 26:842.
  42. Craig WY, Haddow JE, Palomaki GE, Roberson M. Major fetal abnormalities associated with positive screening tests for Smith-Lemli-Opitz syndrome (SLOS). Prenat Diagn 2007; 27:409.
  43. Kratz LE, Kelley RI. Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet 1999; 82:376.
  44. Nowaczyk MJ, Garcia DM, Eng B, Waye JS. Rapid molecular prenatal diagnosis of Smith-Lemli-Opitz syndrome. Am J Med Genet 2001; 102:387.
  45. Bzdúch V, Kozák L, Francová H, Behúlová D. Prenatal diagnosis of Smith-Lemli-Opitz syndrome by mutation analysis. Am J Med Genet 2000; 95:85.
  46. Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005; 353:2001.
  47. Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. BJOG 2004; 111:521.
  48. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007; 109:217.
  49. Eddleman KA, Malone FD, Sullivan L, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 2006; 108:1067.
  50. Tabor A, Philip J, Madsen M, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986; 1:1287.
  51. Savva GM, Morris JK, Mutton DE, Alberman E. Maternal age-specific fetal loss rates in Down syndrome pregnancies. Prenat Diagn 2006; 26:499.
  52. Morris JK, De Vigan C, Mutton DE, Alberman E. Risk of a Down syndrome live birth in women 45 years of age and older. Prenat Diagn 2005; 25:275.
  53. Stene J, Stene E, Mikkelsen M. Risk for chromosome abnormality at amniocentesis following a child with a non-inherited chromosome aberration. A European Collaborative Study on Prenatal Diagnoses 1981. Prenat Diagn 1984; 4 Spec No:81.
  54. Warburton D, Dallaire L, Thangavelu M, et al. Trisomy recurrence: a reconsideration based on North American data. Am J Hum Genet 2004; 75:376.
  55. Noble J. Natural history of Down's syndrome: a brief review for those involved in antenatal screening. J Med Screen 1998; 5:172.
  56. Warburton D, Kline J, Stein Z, et al. Does the karyotype of a spontaneous abortion predict the karyotype of a subsequent abortion? Evidence from 273 women with two karyotyped spontaneous abortions. Am J Hum Genet 1987; 41:465.
  57. Morris JK, Mutton DE, Alberman E. Recurrences of free trisomy 21: analysis of data from the National Down Syndrome Cytogenetic Register. Prenat Diagn 2005; 25:1120.
  58. Kagan KO, Wright D, Spencer K, et al. 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.
  59. Hsu JJ, Hsieh TT, Hsieh FJ. Down syndrome screening in an Asian population using alpha-fetoprotein and free beta-hCG: a report of the Taiwan Down Syndrome Screening Group. Obstet Gynecol 1996; 87:943.
  60. Watt HC, Wald NJ, Smith D, et al. Effect of allowing for ethnic group in prenatal screening for Down's syndrome. Prenat Diagn 1996; 16:691.
  61. Benn PA, Clive JM, Collins R. Medians for second-trimester maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol; differences between races or ethnic groups. Clin Chem 1997; 43:333.
  62. Nix B, Wright D, Baker A. The impact of bias in MoM values on patient risk and screening performance for Down syndrome. Prenat Diagn 2007; 27:840.
  63. Reynolds TM, Vranken G, Van Nueten J. Weight correction of MoM values: which method? J Clin Pathol 2006; 59:753.
  64. Huang T, Meschino WS, Okun N, et al. The impact of maternal weight discrepancies on prenatal screening results for Down syndrome. Prenat Diagn 2013; 33:471.
  65. Wald NJ, Cuckle H, Boreham J, et al. Maternal serum alpha-fetoprotein and diabetes mellitus. Br J Obstet Gynaecol 1979; 86:101.
  66. Thornburg LL, Knight KM, Peterson CJ, et al. Maternal serum alpha-fetoprotein values in type 1 and type 2 diabetic patients. Am J Obstet Gynecol 2008; 199:135.e1.
  67. Sprawka N, Lambert-Messerlian G, Palomaki GE, et al. Adjustment of maternal serum alpha-fetoprotein levels in women with pregestational diabetes. Prenat Diagn 2011; 31:282.
  68. Evans MI, Harrison HH, O'Brien JE, et al. Correction for insulin-dependent diabetes in maternal serum alpha-fetoprotein testing has outlived its usefulness. Am J Obstet Gynecol 2002; 187:1084.
  69. Martin AO, Dempsey LM, Minogue J, et al. Maternal serum alpha-fetoprotein levels in pregnancies complicated by diabetes: implications for screening programs. Am J Obstet Gynecol 1990; 163:1209.
  70. Milunsky A, Alpert E, Kitzmiller JL, et al. Prenatal diagnosis of neural tube defects. VIII. The importance of serum alpha-fetoprotein screening in diabetic pregnant women. Am J Obstet Gynecol 1982; 142:1030.
  71. Sancken U, Bartels I. Biochemical screening for chromosomal disorders and neural tube defects (NTD): is adjustment of maternal alpha-fetoprotein (AFP) still appropriate in insulin-dependent diabetes mellitus (IDDM)? Prenat Diagn 2001; 21:383.
  72. Reece EA, Davis N, Mahoney MJ, Baumgarten A. Maternal serum alpha-fetoprotein in diabetic pregnancy: correlation with blood glucose control. Lancet 1987; 2:275.
  73. Baumgarten A, Robinson J. Prospective study of an inverse relationship between maternal glycosylated hemoglobin and serum alpha-fetoprotein concentrations in pregnant women with diabetes. Am J Obstet Gynecol 1988; 159:77.
  74. Baumgarten A, Reece EA, Davis N, Mahoney MJ. A reassessment of maternal serum alpha-fetoprotein in diabetic pregnancy. Eur J Obstet Gynecol Reprod Biol 1988; 28:289.
  75. Henriques CU, Damm P, Tabor A, et al. Decreased alpha-fetoprotein in amniotic fluid and maternal serum in diabetic pregnancy. Obstet Gynecol 1993; 82:960.
  76. Huttly W, Rudnicka A, Wald NJ. Second-trimester prenatal screening markers for Down syndrome in women with insulin-dependent diabetes mellitus. Prenat Diagn 2004; 24:804.
  77. Evans MI, O'Brien JE, Dvorin E, et al. Similarity of insulin-dependent diabetics' and non-insulin-dependent diabetics' levels of beta-hCG and unconjugated estriol with controls: no need to adjust as with alpha-fetoprotein. J Soc Gynecol Investig 1996; 3:20.
  78. Spencer K, Cicero S, Atzei A, et al. The influence of maternal insulin-dependent diabetes on fetal nuchal translucency thickness and first-trimester maternal serum biochemical markers of aneuploidy. Prenat Diagn 2005; 25:927.
  79. Lambert-Messerlian G, Palomaki GE, Canick JA. Adjustment of serum markers in first trimester screening. J Med Screen 2009; 16:102.
  80. Wald NJ, White N, Morris JK, et al. Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening. Br J Obstet Gynaecol 1999; 106:1304.
  81. Lambert-Messerlian G, Dugoff L, Vidaver J, et al. First- and second-trimester Down syndrome screening markers in pregnancies achieved through assisted reproductive technologies (ART): a FASTER trial study. Prenat Diagn 2006; 26:672.
  82. Maymon R, Shulman A. Comparison of triple serum screening and pregnancy outcome in oocyte donation versus IVF pregnancies. Hum Reprod 2001; 16:691.
  83. Räty R, Virtanen A, Koskinen P, et al. Maternal serum beta-hCG levels in screening for Down syndrome are higher in singleton pregnancies achieved with ovulation induction and intrauterine insemination than in spontaneous singleton pregnancies. Fertil Steril 2001; 76:1075.
  84. Amor DJ, Xu JX, Halliday JL, et al. Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome. Hum Reprod 2009; 24:1330.
  85. Gjerris AC, Loft A, Pinborg A, et al. First-trimester screening markers are altered in pregnancies conceived after IVF/ICSI. Ultrasound Obstet Gynecol 2009; 33:8.
  86. Wald NJ, Huttly WJ, Rudnicka AR. Prenatal screening for Down syndrome: the problem of recurrent false-positives. Prenat Diagn 2004; 24:389.
  87. Wald NJ, Barnes IM, Birger R, Huttly W. Effect on Down syndrome screening performance of adjusting for marker levels in a previous pregnancy. Prenat Diagn 2006; 26:539.
  88. Bartels I, Hoppe-Sievert B, Bockel B, et al. Adjustment formulae for maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated oestriol to maternal weight and smoking. Prenat Diagn 1993; 13:123.
  89. Spencer K. The influence of smoking on maternal serum AFP and free beta hCG levels and the impact on screening for Down syndrome. Prenat Diagn 1998; 18:225.
  90. Ferriman EL, Sehmi IK, Jones R, Cuckle HS. The effect of smoking in pregnancy on maternal serum inhibin A levels. Prenat Diagn 1999; 19:372.
  91. Spencer K, Bindra R, Cacho AM, Nicolaides KH. The impact of correcting for smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy. Prenat Diagn 2004; 24:169.
  92. Urato AC, Quinn R, Pulkkinen A, et al. Maternal smoking during pregnancy and false positive maternal serum alpha-fetoprotein (MSAFP) screening for open neural tube defects. Prenat Diagn 2008; 28:778.
  93. Zhang J, Lambert-Messerlian G, Palomaki GE, Canick JA. Impact of smoking on maternal serum markers and prenatal screening in the first and second trimesters. Prenat Diagn 2011; 31:583.
  94. Rudnicka AR, Wald NJ, Huttly W, Hackshaw AK. Influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance. Prenat Diagn 2002; 22:893.
  95. Wald NJ, Densem JW, Smith D, Klee GG. Four-marker serum screening for Down's syndrome. Prenat Diagn 1994; 14:707.
  96. Hackshaw AK, Wald NJ. Repeat testing in antenatal screening for Down syndrome using dimeric inhibin-A in combination with other maternal serum markers. Prenat Diagn 2001; 21:58.
  97. Einstein FH, Wright RL, Trentacoste S, et al. The impact of protease inhibitors on maternal serum screening analyte levels in pregnant women who are HIV positive. Am J Obstet Gynecol 2004; 191:1004.
  98. Yudin MH, Prosen TL, Landers DV. Multiple-marker screening in human immunodeficiency virus-positive pregnant women: Screen positivity rates with the triple and quad screens. Am J Obstet Gynecol 2003; 189:973.
  99. Weintrob N, Drouin J, Vallette-Kasic S, et al. Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene. Pediatrics 2006; 117:e322.
  100. Cheng PJ, Liu CM, Chang SD, et al. Elevated second-trimester maternal serum hCG in patients undergoing haemodialysis. Prenat Diagn 1999; 19:955.
  101. Le Meaux JP, Tsatsaris V, Schmitz T, et al. Maternal biochemical serum screening for Down syndrome in pregnancy with human immunodeficiency virus infection. Obstet Gynecol 2008; 112:223.
  102. Pekarek DM, Chapman VR, Neely CL, et al. Medication effects on midtrimester maternal serum screening. Am J Obstet Gynecol 2009; 201:622.e1.
  103. Benachi A, Dreux S, Kaddioui-Maalej S, et al. Down syndrome maternal serum screening in patients with renal disease. Am J Obstet Gynecol 2010; 203:60.e1.
  104. Savvidou MD, Samuel I, Syngelaki A, et al. First-trimester markers of aneuploidy in women positive for HIV. BJOG 2011; 118:844.
  105. Valentin M, Muller F, Beaujard MP, et al. First-trimester combined screening for trisomy 21 in women with renal disease. Prenat Diagn 2015; 35:244.