The first trimester ‘combined test’ for the detection of Down syndrome pregnancies in 4939 unselected pregnancies

The high detection rate (DR) for Down syndrome (DS) pregnancies which can be achieved by measuring fetal nuchal translucency (NT) early in pregnancy can be improved by combining it with placental hormones [pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (fβ-hCG)] and maternal age (‘combined test’). In this study we wanted to assess the DR using the ‘combined test’ in an unselected population of self-referred pregnant women at a false-positive rate (FPR) of about 5%. NT, PAPP-A, fβ-hCG and maternal age were measured in all women with singleton pregnancies who booked for delivery in our hospital from 1 December 1997 to 31 April 2000 and who were between 10 and 13 completed weeks of gestation [crown–rump length (CRL) 35–70 mm]. The specific DS risk was calculated using the computer program Alpha Version 5aa (Logical Medical Systems, London, UK). A total of 4939 women were tested. Out of 14 DS pregnancies that occurred during this period of time, 12 were detected with the test. A total of 246 women had a false-positive test result in a non-DS pregnancy (FPR 5.0%). This makes the ‘combined test’ by far the best test for the detection of DS pregnancies in a low-risk population. The constant increase in maternal age at the time of delivery can also lead to an improved DR if a simple age-dependant protocol for DS detection is used, but only at the price of a much higher number of amniocenteses and subsequent abortions. The DR for DS can be increased much more markedly using the ‘combined test’ with a FPR that still remains at the level as it was in the early 1970s. Copyright © 2002 John Wiley & Sons, Ltd.     

Karyotypes found in the population declared at increased risk of Down syndrome following maternal serum screening

Of the 65 328 pregnancies of South Australian mothers screened by the South Australian Maternal Serum Antenatal Screening (SAMSAS) Programme between 1 January 1991 and 31 December 1997, 3431 (5.25%) were declared at increased risk of fetal Down syndrome. Fetal or neonatal karyotype was determined in 2737/3431 (79.8%) of these pregnancies, including 16 with early fetal loss. Interrogation of the database of the South Australian Neonatal Screening Service showed 643 live-born infants whose phenotype was not subsequently questioned among the 694 pregnancies whose karyotype was not determined. Of the remaining 51/3431 pregnancies, 19 ended in early fetal loss without karyotyping and no newborn screening or other records could be found for 32 cases. The 129 instances of abnormal karyotype found were Down syndrome (84), trisomy 18 (four), trisomy 13 (three), triploidy (two), female sex chromosome aneuploidy (six) and male sex chromosome aneuploidy (five), inherited balanced rearrangements (19), mosaic or de novo balanced abnormalities (four) and unbalanced karyotypes (two). In the pregnancies declared at increased risk of fetal Down syndrome, only the karyotype for Down syndrome occurred with a frequency greater than that expected for the general, pregnant population. Copyright © 2001 John Wiley & Sons, Ltd.     

Combining nuchal translucency and serum markers in prenatal screening for Down syndrome in twin pregnancies

A method is described to combine the ultrasound marker nuchal translucency (NT) with serum markers so that they can be used together in prenatal screening for Down syndrome in twin pregnancies. For monochorionic twin pregnancies (taken as monozygous), the two fetus-specific NT measurements are averaged before risk is calculated and before the contribution of the serum markers is incorporated. For dichorionic twin pregnancies (taken as dizygous), the risk for each fetus based on the individual NT measurements is calculated, the two fetus-specific risks are added together, and then the contribution of the serum markers is incorporated. In this way, all the screening markers can be used in combination to produce a pregnancy-specific ‘pseudo-risk’, rather than a fetus-specific pseudo-risk. We refer to pseudo-risk because in the absence of sufficient data on the screening markers in affected twin pregnancies, a true risk estimate cannot be calculated. Tentative estimates are given of screening performance in twins using NT, the combined test (NT with first-trimester serum markers), and the integrated test (NT with first- and second-trimester serum markers), all interpreted with maternal age. Copyright © 2003 John Wiley & Sons, Ltd.     

Compromise ultrasound dating policy in maternal serum screening for Down syndrome

Routine ultrasound biometry is the method of choice for gestational dating when screening for Down syndrome. However, it is costly and an alternative policy is to restrict ultrasound to women most likely to have menstrual dating errors. This was evaluated by statistical modelling with parameters from 14 274 women screened between January 1997 and July 2001 using free beta-human chorionic gonadotrophin (free β-hCG), α-fetoprotein (AFP) and unconjugated estriol (uE₃). A total of 12 711 (89%) women had both ultrasound and menstrual gestations, but in 4101 (29%) women either the last menstrual period (LMP) was uncertain or a pill-withdrawal period, or there were irregular or abnormal length cycles. The LMP was not entered in the test request form for a further 1404 (9.8%) women. Routine ultrasound dating yielded a predicted detection rate higher than for menstrual dating by 3.9–7.1%, depending on the marker combination and cut-off. The false-positive rate was reduced by 0.2–1.1%. Selectively scanning the 39% with unreliable dates increased detection by 2.6–4.6%, and reduced the false-positive rate by 0.04–0.6%. Some centres only use the ultrasound estimate of gestation when it differs from the menstrual estimate by more than 7 days. Such a rule reduces the gain in detection rate to 2.5–4.6% for routine ultrasound and 1.7–3.1% with the compromise policy; the false-positive rate reductions are 0.06–0.6% and 0.0–0.3%, respectively. We conclude that if routine ultrasound is not financially and practically feasible, the compromise policy yields a clinically important improvement in screening performance compared to menstrual dating. Copyright © 2002 John Wiley & Sons, Ltd.     

Inaccurate estimation of risk in second trimester serum screening for Down syndrome among women who have already had first trimester screening

Problems can arise in prenatal screening for Down syndrome when tests are performed in the first and second trimester and some women who have a negative first trimester test have a second trimester serum test. The second test result does not usually take account of the previous one being negative. Even if it does, it is often inaccurate. Using published data the extent of the error was examined. The age-specific risk of an affected pregnancy in such women will be lower than if no first trimester test had been performed. The distributions of the screening markers in affected and unaffected pregnancies will be different from those in unscreened women. If the appropriate age-specific risk and marker distributions are not used, error will arise. For example, a 35-year-old woman with nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotrophin (hCG) levels at the normal median would have a risk of 1 in 6500. If she then had the Triple Test with alpha-fetoprotein (AFP), unconjugated oestriol, and hCG levels of 0.7, 0.7 and 1.5 multiples of the median (MoM), respectively, her risk, ignoring the previous result, would be overestimated (1 in 95 compared with the correct estimate of 1 in 705). If the previous result was included, but the age-specific risk and second trimester marker distributions were not revised, her risk would be underestimated (1 in 820). If the correct age-specific risk and screening marker distributions were used, risk estimates would be accurate, but two tests would be less efficient than integrating all the screening information into a single test. The practice of offering second trimester serum screening to women who have already been screened is best avoided. Copyright © 2001 John Wiley & Sons, Ltd.