References

23 population-based studies, including 2 NIH studies, validate free Beta hCG as the superior biomarker.

23 Population-Based Studies

¹ Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW Jr, Macri JN. First-trimester Down syndrome screening using dried blood biochemistry and nuchal translucency. Obstet Gynecol. 2000;96(2):207-213.
² Tsai MS, Huang YY, Hwa KY, Cheng CC, Lee FK. Combined measurement of fetal nuchal translucency, maternal serum free beta-hCG, and pregnancy-associated plasma protein A for first-trimester Down's syndrome screening. J Formos Med Assoc. 2001;100(5):319-325.
³ Niemimaa M, Suonpää M, Perheentupa A, et al. A Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland. Eur J Hum Genet. 2001;9(6):404-408.
⁴ Schuchter K, Hafner E, Stangl G,Metzenbauer M, Höfinger D, Philipp K. The first trimester 'combined test' for the detection of Down syndrome pregnancies in 4939 unselected pregnancies. Prenat Diagn. 2002;22(3):211-215.
⁵ Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003;349(15):1405-1413.
⁶ Borrell A, Casals E, Fortuny A, et al. First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages: an interventional study. Prenat Diagn. 2004;24(7):541-545.
⁷ Stenhouse EJ, Crossley JA, Aitken DA, Brogan K, Cameron AD, Connor JM. First-trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice. Prenat Diagn. 2004;24(10):774-780.
⁸ Scott F, Peters H, Bonifacio M, et al. Prospective evaluation of a first trimester screening program for Down syndrome and other chromosomal abnormalities using maternal age, nuchal translucency and biochemistry in an Australian population. Aust N Z J Obstet Gynaecol. 2004;44(3):205-209.
⁹ Hadlow NC, Hewitt BG, Dickinson JE, Jacoby P, Bower C. Community-based screening for Down's syndrome in the first trimester using ultrasound and maternal serum biochemistry. BJOG. 2005;112(11):1561-1564.
¹⁰ Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol. 2005;25(3):221-226.
¹¹ Wøjdemann KR, Shalmi AC, Christiansen M, et al. Improved first-trimester Down syndrome screening performance by lowering the false-positive rate: a prospective study of 9941 low-risk women. Ultrasound Obstet Gynecol. 2005;25(3):227-233.
¹² 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;10;353(19): 2001-2011.
¹³ Perni SC, Predanic M, Kalish RB, Chervenak FA, Chasen ST. Clinical use of first-trimester aneuploidy screening in a United States population can replicate data from clinical trials. Am J Obstet Gynecol. 2006;194(1):127-130.
¹⁴ Soergel P, Pruggmayer M, Schwerdtfeger R,Muhlhaus K, Scharf A. Screening for trisomy 21 with maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-14 weeks: a regional experience from Germany. Fetal Diagn Ther. 2006;21(3):264-268.
¹⁵ O'Leary P, Breheny N, Dickinson JE, et al. First-trimester combined screening for Down syndrome and other fetal anomalies. Obstet Gynecol. 2006;107(4):869-876.
¹⁶ Kozlowski P, Knippel AJ, Stressig R. Comparing first trimester screening performance: routine care gynaecologists' practices vs. prenatal centre. Ultraschall Med. 2007;28(3): 291-295.
¹⁷ Leung TY, Chan LW, Leung TN, et al. First-trimester combined screening for trisomy 21 in a predominantly Chinese population. Ultrasound Obstet Gynecol. 2007;29(1):14-17.
¹⁸ Valinen Y, Rapakko K, Kokkonen H, et al. Clinical first-trimester routine screening for Down syndrome in singleton pregnancies in northern Finland. Am J Obstet Gynecol. 2007;196(3):278:e1-5.
¹⁹ Jaques AM, Halliday JL, Francis I, et al. Follow up and evaluation of the Victorian first-trimester combined screening programme for Down syndrome and trisomy 18. BJOG. 2007;114(7):812-818.
²⁰ Has R, Kalelioglu I, Yuksel A, Ibrahimoglu L, Ermis H, Yildirim A. Fetal nasal bone assessment in first trimester down syndrome screening. Fetal Diagn Ther. 2008;24(1):61-66.
²¹ Kirkegaard I, Petersen OB, Uldbjerg N, Tørring N. Improved performance of first-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks. Prenat Diagn. 2008;28(9):839-844.
²² Lüthgens K. Comparison of the new PRC software with the established algorithm of the FMF UK for the detection of trisomy 21 and 18/13. Fetal Diagn Ther. 2008;24(4):376-384.
²³ Schaelike M, Kossakiewicz M, Kossakiewicz A, Schild RL. Examination of a first-trimester Down syndrome screening concept on a mix of 11,107 high- and low-risk patients at a private center for prenatal medicine in Germany. Eur J Obstet Gynecol Reprod Biol. 2009;144(2):140-145.

References for NTD Labs' Screening Protocols:

²⁴ Perni SC, Predanic M, Kalish RB, Chervenak FA, Chasen ST. Clinical use of first-trimester aneuploidy screening in a United States population can replicate data from clinical trials. Am J Obstet Gynecol. 2006;194(1):127-130.
²⁵ Cicero S, Bindra R, Rembouskos G, Spencer K, Nicolaides KH. Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal nasal bone, free Fß-hCG and PAPP-A at 11 to 14 weeks. Prenat Diagn. 2003;23(4):306-310.
²⁶ Spencer K, Nicolaides KH. A first trimester trisomy 13/trisomy 18 risk algorithm combining fetal nuchal translucency thickness, maternal serum free Fß-hCG and PAPP-A. Prenat Diagn.2002;22(10):877-879.
²⁷ Palomaki, GE et al. Technical standards and guidelines: Prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements. Genetics in Medicine 2009; 11: 669-681.
²⁸ Evans et al. Meta-Analysis of first trimester Down syndrome screening studies: free Beta human chorionic gonadotropin significantly outperforms intact human chorionic gonadotropin in a multimarker protocol. Am J Obstet Gynecol. 2007;196:198-205.
²⁹ Cuckle H. Biochemical screening for Down syndrome. Eur J Obstet Gynecol Reprod Biol. 2000;92(1):97-101.
³⁰ Cuckle H, Arbuzova S.Multimarker maternal serum screening for chromosomal abnormalities. In:Milunsky A, ed. Genetic Disorders of the Fetus: Diagnosis, Prevention and Treatment. 5th ed. Baltimore, MD: The Johns Hopkins University Press; 2004:822.
³¹ Milunsky A,Jick SS, Bruell CL, et al. Predictive values, relative risks and overall benefits of high and low maternal serum -fetoprotein screening in singleton pregnancies: new epidemiologic data. Am J Obstet Gynecol. 1989;161(2):291-297.

Case-Control or Modeled Studies on Total hCG:

³²Canick JA, Lambert-Messerlian GM, Palomaki GE, et al. Comparison of serum markers in first-trimester down syndrome screening. Obstet Gynecol. 2006;108(5):1192–1199.
³³Palomaki GE, Neveux LM, Knight GJ, Haddow JE, Lee J. Estimating first-trimester combined screening performance for Down syndrome in dried blood spots versus fresh sera. Genet Med. 2007;9(7):458–463.
³⁴Palomaki GE, Neveux LM, Haddow JE, Wyatt P. Hyperglycosylated-hCG (h-hCG) and Down syndrome screening in the first and second trimesters of pregnancy. Prenat Diagn. 2007;27(9):808–813.
³⁵Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen. 2003;10(2):56–104