Urinary multiple marker screening for down's syndrome

Abstract

We have examined the possibility of using multiple markers in maternal urine rather than serum in order to screen for Down's syndrome. Urine samples were available from 36 cases (24 Down's syndrome, five Edwards' syndrome, three Turner's syndrome, one Klinefelter's syndrome, one triploidy, one triple-X, one twin discordant for Down's syndrome) and 294 controls, including three twins. Three markers were tested: the beta-core fragment of human chorionic gonadotrophin (hCG), total oestrogen (tE) and the free alpha subunit of hCG. Levels were corrected for creatinine excretion and expressed as multiples of the gestation-specific median (MOM) level from the singleton controls. The median value for the singleton Down's syndrome cases was 6.02, 0.74, and 1.08 MOM for beta-core-hCG, tE, and alpha-hCG, respectively. The increases in beta-core-hCG and the reduction in tE levels were highly significant (P < 0.0001 and 0.005, respectively; Wilcoxon rank sum test) but the increase in free alpha-hCG was not (P = 0.40). On the basis of a mathematical model, the expected detection rate for a 5 per cent false-positive rate was 79.6 per cent for beta-core-hCG alone, which increased to 82.3 per cent when combined with tE. Aneuploidies other than Down's syndrome were characterized by low levels of tE and either low or high beta-core-hCG.

Urinary free beta hCG, beta core fragment and total oestriol as markers of Down syndrome in the second trimester of pregnancy

“…Cuckle et al (1994) first reported that levels of the beta core fragment of hCG were markedly (6·24 MoM) elevated in the maternal urine of pregnancies affected by Down syndrome. Expanding on the initial 7-case study with an additional 17 cases, Cuckle et al (1995) confirmed the initial observation with a median MoM of 6·02. Canick et al (1995Canick et al ( , 1996 in two separate studies further confirmed elevations close to 5 MoM.…”

“…Our study has confirmed that urine beta core is elevated in Down syndrome cases, with a median MoM of 4·95 being similar to the consensus (Table 3). The median MoM is higher than in our previous studies using the Chiron (Ciba Cuckle et al (1994) 7 6·24 Exclude, data included in Cuckle et al, 1995study Cuckle et al (1995 24 6·02 Canick et al (1995) 14 5·34 Exclude, data included in Kellner et al, 1997Canick et al (1996 18 5·02 Hayashi and Kozu (1995) 5 1·33 Spencer et al (1996) 29 2·35 Isozaki et al (1997) 13 4·10 Hallahan et al (1998) 8 2·18 Lam et al (1997) 29 3·44 Kellner et al (1997) 32 5·42 Cole et al (1997b) 12 4·50 Exclude, data included in Isozaki et al, 1997 study Total 158 4·14 Corning/Triton) assay. If we exclude those samples beyond 22 weeks for which we had no control population and extrapolated medians, the median MoM and SD were not significantly different from the total data (5·3 MoM versus 5·0 MoM and 0·595 versus 0·597 for the SD).…”

“…Of the markers studied, beta core showed some initial promise in the second trimester but further studies have been unable to reproduce the median values in excess of 6 MoM showed by the early studies of Cuckle (Cuckle et al, 1994(Cuckle et al, , 1995. There may be many reasons for the wide variation in published data as shown in the meta analysis (Table 3).…”

“…Canick et al (1988) some 16 years later extended this association by demonstrating low levels of unconjugated oestriol in the maternal serum of women with pregnancies affected by Down syndrome and some five years later (Cuckle et al (1995) confirmed low levels of total oestrogens in second-trimester maternal urine of affected cases and Spencer et al (1997b) confirmed these low levels in the first trimester of affected cases. Recently, it has been proposed by Cole et al (1997c) and by Kellner et al (1997), that a ratio of beta core:total oestriol may be of value in obviating the need to employ a creatinine correction for urine dilution, since by taking the ratio, dilution effects would be cancelled out.…”

Invasive Trophoblast Antigen (Hyperglycosylated Human Chorionic Gonadotropin) in Second-Trimester Maternal Urine as a Marker for Down Syndrome: Preliminary Results of an Observational Study on Fresh Samples

“…The earliest report of a urine marker was the ␤-core fragment of hCG. Two initial studies (25,26 ) estimated detection rates of 60 -70% (at a 5% false-positive rate). However, subsequent studies failed to confirm these initial findings (27,28 ).…”