Is maternal serum total hCG a marker of trisomy 21 in the ®rst trimester of pregnancy? Kevin Spencer 1 *, Esther Berry 2 , Jennifer A. Crossley 2 , David A. Aitken 2 and Kypros H. Nicolaides 3 1 Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Gubbins Lane, Romford, Essex, RM3 0BE, U.K. 2 Institute of Medical Genetics, Yorkhill, Glasgow G3 8SJ, U.K. 3 Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, Denmark Hill, London, U.K. In a study of 130 ®rst trimester cases of trisomy 21 and 959 controls we have shown that the median MoM for alpha-fetoprotein (AFP) is lower (0.82) and that for total human chorionic gonadotrophin (hCG) is higher (1.31) than in the control group. For AFP 15.3% of cases were below the 5th centile and for total hCG 19.8% were above the 95th centile. The median shift observed for AFP and total hCG is poorer than that for pregnancy associated plasma protein-A (PAPP-A) or free b-hCG and together with maternal age, AFP and total hCG could only be expected to detect 40% of cases. In combination with PAPP-A, total hCG would identify 52% of cases, somewhat less than the 67% observed with free b-hCG and PAPP-A. However, we have demonstrated for total hCG a signi®cant temporal change in median MoM with gestational age. Before 70 days the median MoM was less than 0.5, between 70 and 83 days this increased to 1.13, and between 84 and 97 days this increased to 1.52. This median shift has signi®cant implications for interpreting previous studies and even more signi®cant implications for detection rates. When population parameters speci®c to the gestational age in question are used, detection rates with total hCG and PAPP-A increase from 47% at 70±83 days to 60% at 84±97 days. This observation explains much of the confusion around total hCG in the ®rst trimester and shows the importance of selecting analyte pairs and population parameters appropriate to the time in gestation when screening is performed. Copyright # 2000 John Wiley & Sons, Ltd. INTRODUCTION Screening for trisomy 21 in the second trimester by the measurement of maternal serum biochemical markers has become an accepted part of obstetric practice in many countries (Cuckle et al., 1995; Palomaki et al., 1997). In routine practice a combination of maternal age with serum alpha-fetoprotein (AFP) and either free b-human chorionic gonadotrophin (hCG), with or without unconjugated oestriol can identify approxi- mately 65% of cases for a 5% false positive rate (Crossley et al., 1994; Wald et al., 1992; Goodburn et al., 1994; Macri and Spencer, 1996; Spencer, 1999a). In the ®rst trimester of pregnancy much interest is focused on the use of fetal nuchal translucency (NT) thickness in combination with appropriate biochem- ical markers. Of the biochemical markers investigated, AFP and total hCG appear to be weak markers (Aitken et al., 1993) in the ®rst trimester, while only free b-hCG (Spencer et al., 1992; Spencer, 1997 ) and pregnancy associated plasma protein-A (PAPP-A) have been shown to be of any value (Brambati et al., 1991; Spencer et al., 1994; Wald et al., 1996). Large- scale studies (Spencer et al., 1999a) have shown that detection rates of 89±90% can be achieved at a 5% false positive rate when ultrasound, maternal serum PAPP-A and free b-hCG are combined together at 10±14 weeks of gestation. Furthermore, the use of rapid immunodiagnostic technology has allowed the delivery of such screening within a 1 h time frame, leading to the development of a one-stop clinic for assessment of risk of fetal abnormality (OSCAR) (Spencer, 1999b). Despite a general consensus that total hCG is of little value in screening for trisomy 21 in the ®rst trimester (Wald et al., 1997), sporadic reports in small series continue to claim that total hCG is of value at this time (Forest et al., 1995; Haddow et al., 1998; Casals et al., 1999). We have therefore sought to clarify this situation by analysing AFP and total hCG in a large series of trisomy 21 cases, comparing these markers with other ®rst trimester marker data largely from our previous study (Spencer et al., 1999a). METHODS The study population was derived from three groups of women. The ®rst comprised women with singleton pregnancies who were referred to the Harris Birthright Centre for fetal karyotyping, because screening by a combination of maternal age and fetal NT at 10±14 weeks in their hospital identi®ed these patients as being at high risk for trisomy 21 (Snijders et al., 1998). The second group comprised self-referred women for assessment of risk. Blood samples were collected from women at the time of the scan and the serum was aliquoted and stored at x20uC prior to blinded retrospective analysis. Gestational age was determined *Correspondence to: K. Spencer, Endocrine Unit, Department of Clinical Biochemistry, Harold Wood Hospital, Gubbins Lane, Romford, Essex, RM3 0BE, U.K. E-mail: Kevin_Spencer@Compuserve.com PRENATAL DIAGNOSIS Prenat Diagn 2000; 20: 311±317. Copyright # 2000 John Wiley & Sons, Ltd. Received: 25 October 1999 Revised: 5 January 2000 Accepted: 21 January 2000