References

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

Population Studies

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 Eurofins NTD, LLC. 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

References for PreeclampsiaScreen™ I T1:

36Eurofins NTD, LLC. Data on file.
37von Dadelszen P, Magee LA, Roberts JM. Subclassification of pre-eclampsia. Hypertens Pregnancy 2003;22:143-8.
38Hernández-Díaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ 2009 Jun 18;338:b2255.
39Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension 2009 May;53(5):812-8. Epub 2009 Mar 9.
40Onwudiwe N, Yu CK, Poon LC, Spiliopoulos I, Nicolaides KH. Prediction of pre-eclampsia by a combination of maternal history, uterine artery Doppler and mean arterial pressure. Ultrasound Obstet Gynecol 2008;32:877-83.
41Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2012. Published online Aug 16, 2012.
42U.S. National Library of Medicine. Preeclampsia. (Sept. 12, 2011). http://www.nlm.nih.gov/medlineplus/ency/article/000898.htm. Accessed online May 9, 2012.
43Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest J-C, Giguère Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a metaanalysis. Obstet Gynecol 2010;116:402-14.
44Lu JF, Nightingale CH. Magnesium sulfate in eclampsia and preeclampsia: pharmacokinetic principles. Clin Pharmacokinet 2000 Apr;38(4):305-14.
45Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in preeclampsia. Proc Natl Acad Sci 1986 Feb;83(4):1075-8.
46North RA, Ferrier C, Gamble G, Fairley KF, Kincaid-Smith P. Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease. Aust N Z J Obstet Gynaecol 1995 Nov;35(4):357-62.
47Akolekar R, Zaragoza E, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2008;32:732-9.
48Waller DK, Lustig LS, Cunningham GC, Feuchtbaum LB, Hook EB. The association between maternal serum alpha-fetoprotein and preterm birth, small for gestational age infants, preeclampsia, and placental complications. Obstet Gynecol 1996 Nov;88(5):816-22.
49Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11–13 weeks. Prenat Diagn 2011;31:66-74.
50Foidart JM, Munaut C, Chantraine F, Akolekar R, Nicolaides KH. Maternal plasma soluble endoglin at 11-13 weeks’ gestation in pre-eclampsia. Ultrasound Obstet Gynecol 2010;35:680-7.
51Poon LC, Akolekar R, Lachmann R, Beta J, Nicolaides KH. Hypertensive disorders in pregnancy: screening by biophysical and biochemical markers at 11-13 weeks. Ultrasound Obstet Gynecol 2010;35:662-70.
52Poon LC, Stratieva V, Piras S, Piri S, Nicolaides KH. Hypertensive disorders in pregnancy: combined screening by uterine Doppler, blood pressure and serum PAPP-A at 11-13 weeks. Prenat Diagn 2010;30:216-23.

References for Additional Report Flags

53Dugoff L, et al. Obstet Gynecol. 2010;115:1052–61.
54Krantz DA, et al. Am J Obstet Gynecol. 2004;191:1452–8.
55Morris RK, et al. BMC Pregnancy and Childbirth. 2008;33(8):1–19.
56Krause TG, et al. Obstet Gynecol. 2001;97:277–82.
57Dreux S, et al. Prenatal Diagnosis. 2012;32:1010–12.
58Baschat AA, et al. Obstet Gynecol. 2002;99:531–6.
59Dugoff L, et al. Obstet Gynecol. 2005;106:260–7.

References for alpha fetoprotein (AFP):

60. Aitken et al. First-trimester biochemical screening for fetal chromosome abnormalities and neural tube defects. Prenat Diagn. 1993 Aug;13(8):681-9.
PMID: 8284287
61.Barkai et al. First trimester alpha-fetoprotein levels in normal and chromosomally abnormal pregnancies. Lancet. 1987 Aug 15;2(8555):389.
PMID: 2441219
62.Berry et al. Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters. Br J Obstet Gynaecol. 1997 Jul;104(7):811-7.
PMID: 9236646
63.Brambati et al. Fetal chromosomal aneuploidies and maternal serum alpha-fetoprotein levels in first trimester. Lancet. 1986 Jul 19;2(8499):165-6
PMID: 2425203
64.Bredaki et al. First-trimester screening for trisomy 21 using alpha-fetoprotein. Fetal Diagn Ther. 2011;30(3):215-8
PMID: 21952001
65.Brock et al. First-trimester maternal serum biochemical indicators in Down syndrome. Prenat Diagn. 1990 Apr;10(4):245-51.
PMID: 1694994
66.Biagiotti. Maternal serum screening for Down's syndrome in the first trimester of pregnancy. Br J Obstet Gynaecol. 1995 Aug;102(8):660-2.
PMID: 7544611
67.Brizot. First trimester maternal serum alpha-fetoprotein in fetal trisomies. Br J Obstet Gynaecol. 1995 Jan;102(1):31-4.
PMID: 7530490
68.Casals et al. First-trimester biochemical screening for Down syndrome with the use of PAPP-A, AFP, and beta-hCG. Prenat Diagn. 1996 May;16(5):405-10.
PMID: 8843997
69.Crandall et al. First-trimester maternal serum unconjugated oestriol and alpha-fetoprotein in fetal Down's syndrome. Prenat Diagn. 1991 Jun;11(6):377-80.
PMID:1717969
70.Crandall et al. Maternal serum screening for alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin between 11 and 15 weeks of pregnancy to detect fetal chromosome abnormalities. Am J Obstet Gynecol. 1993 Jun;168(6 Pt 1):1864-7; discussion 1867-9.
PMID:7686337
71.Cuckle et al. First-trimester biochemical screening for Down syndrome. Lancet. 1988 Oct 8;2(8615):851-2.
PMID: 2902296
72.de Graaf et al. Co-variables in first trimester maternal serum screening. Prenat Diagn. 2000 Mar;20(3):186-9.
PMID: 10719318
73.Donalson et al. Maternal serum placental growth factor and α-fetoprotein testing in first trimester screening for Down syndrome. Prenat Diagn. 2013 May;33(5):457-61
PMID: 23529706
74.Forest et al. Screening for Down syndrome during first trimester: a prospective study using free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Clin Biochem. 1997 Jun;30(4):333-8.
PMID:9209792
75.Fuhrman et al. First-trimester alpha-fetoprotein screening for Down syndrome. Prenat Diagn. 1993 Mar;13(3):215-8.
PMID: 7685089
76.Hogdall et al. CA-125 as a maternal serum marker for Down's syndrome in the first and second trimesters. Prenat Diagn. 1992 Mar;12(3):223-7.
PMID: 1375379
77.Johnson et al. First-trimester maternal serum alpha-fetoprotein and chorionic gonadotropin in aneuploid pregnancies. Prenat Diagn. 1991 Jul;11(7):443-50.
PMID: 1721715
78.Johnson et al. First-trimester Down syndrome screening using additional serum markers with and without nuchal translucency and cell-free DNA. Prenat Diagn. 2013 Nov;33(11):1044-9.
PMID: 23836291
79.Milunski et al. First-trimester maternal serum alpha-fetoprotein screening for chromosome defects. Am J Obstet Gynecol. 1988 Nov;159(5):1209-13.
PMID: 2461080
80.Mantingh et al. Low maternal serum alpha-fetoprotein at 10 weeks gestation and fetal Down's syndrome. Br J Obstet Gynaecol. 1989 Apr;96(4):499-500
PMID: 2473774
81.Nebiolo et al. First-trimester maternal serum alpha-fetoprotein and human chorionic gonadotropin screening for chromosome defects. Prenat Diagn. 1990 Sep;10(9):575-81.
PMID: 1702539
82.Spencer. First trimester biochemical screening for trisomy 21: the role of free beta hCG, alpha fetoprotein and pregnancy associated plasma protein A. Ann Clin Biochem. 1994 Sep;31 ( Pt 5):447-54.
PMID: 7530437
83.Spencer et al. Temporal changes in maternal serum biochemical markers of trisomy 21 across the first and second trimester of pregnancy. Ann Clin Biochem. 2002 Nov;39(Pt 6):567-76.
PMID: 12564838
84.Tsukerman et al. Maternal serum screening for Down syndrome in the first trimester: experience from Belarus. Prenat Diagn. 1999 Jun;19(6):499-504.
PMID: 10416962
85.Van Lith. First-trimester screening for fetal chromosomal abnormalities. Preliminary results. Dutch Working Party on Prenatal Diagnosis. Prenat Diagn. 1991 Aug;11(8):621-4.
PMID:1722579
86.Van Lith. First-trimester maternal serum alpha-fetoprotein as a marker for fetal chromosomal disorders. Dutch Working Party on Prenatal Diagnosis. Prenat Diagn. 1994 Oct;14(10):963-71
PMID:7534926
87.Wenger et al. First trimester maternal serum alpha-fetoprotein screening for Down syndrome and other aneuploidies. Am J Med Genet Suppl. 1990;7:89-90.
PMID: 1705804
88.Wald et al. Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy. International Prenatal Screening Research Group. Br J Obstet Gynaecol. 1996 May;103(5):407-12.
PMID: 8624312
89.Wald et al. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess. 2003;7(11):1-77.
PMID: 12709291
90.Zimmermann et al. Serum parameters and nuchal translucency in first trimester screening for fetal chromosomal abnormalities. Br J Obstet Gynaecol. 1996 Oct;103(10):1009-14.
PMID: 8863700
91.Carmichael, et al. Incorporation of dried blood alpha fetoprotein into traditional first trimester Down syndrome screening. Prenatal Diagnosis.
April 2015. Open access at: http://onlinelibrary.wiley.com/doi/10.1002/pd.4596/abstract. doi: 10.1002/pd.4596.
92. Society for Maternal-Fetal Medicine. Five things physicians and patients should question. Handout. Released February 3, 2014.
93. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015 Sep;126(3):e31-7.
94. Kaimal AJ, Norton ME, Kuppermann M. Prenatal testing in the genomic age: clinical outcomes, quality of life, and costs. Obstet Gynecol. 2015 Oct;126(4):737-46. http://journals.lww.com/greenjournal/Abstract/2015/10000/Prenatal_Testing_in_the_Genomic_Age_Clinical.8.aspx.
95. Society for Maternal-Fetal Medicine Statement: clarification of recommendations regarding cell-free DNA aneuploidy screening. Am J Obstet Gynecol. Article in press; published online ahead of print October 09, 2015. https://www.smfm.org/publications/212-smfm-statement-clarification-of-recommendations-regarding-cell-free-dna-aneuploidy-screening.
96. Goetzl L. Adverse pregnancy outcomes after abnormal first- trimester screening for aneuploidy. Clin Lab Med. 2010 Sep;30(3):613-28.

DISCLAIMER: Pursuant to applicable federal and/or state laboratory requirements, Eurofins NTD, LLC has established and verified the accuracy and precision of its testing services. Tests are developed and performance characteristics determined by Eurofins NTD, LLC. The methods and performance characteristics have been reviewed and approved by the New York State Department of Health.