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.     

Down syndrome maternal serum marker screening after 18 weeks' gestation

Women having access to prenatal care late in pregnancy may still wish to benefit from maternal serum screening for Down syndrome. Therefore, we established reference values for α-feto protein (AFP) and free β-human chorionic gonadotrophin (β-hCG), and assessed the diagnostic value of maternal serum marker screening at 18–35 weeks' gestation based upon a series of 4072 sera from unaffected pregnancies and 118 sera from pregnant women with fetuses affected by Down syndrome. Using a 1/250 risk cut-off, a detection rate of 72.9% (95% CI = 71.5–74.3%) was achieved with a false-positive rate of 7.51% (95% CI = 6.71–8.3%). This was not significantly different from the percentages observed in our 14–17 weeks routine screening (50 596 patients): 71.9% (95% CI = 71.5–72.3%) and 6.48% (95% CI = 6.28–6.68%), respectively. Detection and screen-positive rates were, respectively, 51.3% (95% CI = 35.6–67.0%) and 5.95% (95% CI = 5.12–6.68%) in women aunder 35 years of age, and 84.8% (95% CI = 76.9–92.7%) and 24% (95% CI = 20.7–27.3%) in women aged 35 years and over. In conclusion, maternal serum marker screening is feasible at 18 weeks' gestation and later, which may be of interest in selected cases. Copyright © 2002 John Wiley & Sons, Ltd.     

Serum PAPP-A measurements in first-trimester screening for Down syndrome

Serum PAPP-A measurements taken from 254 women in the first trimester are reported. Eleven chromosomal abnormalities were detected. The mean serum PAPP-A levels in cases of Down syndrome were 0.44 MOM at 9 weeks gestation, 0.15 MOM at 10 weeks, and 0.29 MOM at 11 weeks. The PAPP-A level at 10 weeks was below those of pregnancies which aborted spontaneously. At 11 weeks, the pregnancies with Down syndrome recorded the lowest PAPP-A levels at that gestation. On this small sample, offering chorionic villus sampling to women with singleton pregnancies and a PAPP-A level below 0.3 MOM (approximately 6.5 per cent of this at-risk group) would have detected all the Down syndrome fetuses at 10 weeks and 50 per cent at 11 weeks without selecting those cases destined to abort. This suggests that serum PAPP-A should continue to be investigated as a potential first-trimester screening test for Down syndrome.     

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.     

Second-trimester prenatal screening markers for Down syndrome in women with insulin-dependent diabetes mellitus

Published studies have shown that some serum markers used in screening for Down syndrome tend to be lower among women with insulin-dependent diabetes mellitus (IDDM). On this basis, many screening programmes adjust the marker levels to take account of this difference. Recent studies suggested that the marker levels were not different, and so adjustment may no longer be needed, possibly because of better diabetic control. Data from a prenatal screening programme for Down syndrome were examined to see whether the median values of second-trimester screening markers were still reduced in pregnant women with IDDM. A total of 366 women with IDDM singleton pregnancies without Down syndrome were identified from the screening programme at Barts from 1989 to 2002. After allowing for maternal weight, the median multiples of the median (MoM) for IDDM-unaffected singleton pregnancies were as follows: 0.88 (95% confidence interval 0.84–0.93) for alphafetoprotein (AFP), 0.95 (0.91–0.99) for unconjugated oestriol (uE₃), 0.90 (0.80–1.01) for total human chorionic gonadotrophin (total hCG), 0.98 (0.88–1.08) for free β-hCG, and 0.99 (0.89–1.10) for inhibin-A. The median levels for AFP and uE₃ were statistically significantly lower in pregnant women with IDDM. The other markers were not significantly different in women with and without IDDM. There remains a case for adjusting AFP and uE₃ levels in women with IDDM in prenatal screening programmes for Down syndrome. Copyright © 2004 John Wiley & Sons, Ltd.     

Detection and false-positive rates of maternal serum markers for Down syndrome screening according to maternal age in women over 35 years of age. A study of the agreement of eight dedicated software packages

Maternal serum markers for trisomy 21 screening (MSS) can be assayed in women ≥35 years in an attempt to reduce the need for invasive procedures and thereby avoid their side effects. Our objective was to compare, in women ≥35, eight different software packages dedicated to second trimester MSS, thus providing reliable data for patient counselling. A simulation study was carried out on 189 sera from women with Down syndrome fetuses and 11 962 sera from mothers of unaffected babies. The first step was to estimate the joint distribution of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (β-hCG). The second step was to calculate trisomy 21 detection and false-positive rates for each software according to maternal age (35–45 years), using the usual 1:250 risk threshold. Agreement between software packages was measured using 2×2 kappa coefficients. Detection rates and false-positive rates increased with maternal age. Depending on the software, 57–71% detection rates were achieved at 35 years with 12–18% false-positive rates. At 45 years, 61–100% detection rates were achieved with 66–95% false-positive rates. Up to 39 years, all softwares were concordant (kappa coefficients >0.75). In the range 35–45 years, false-positive and detection rates increased substantially with maternal age and differences between software packages are observed. Copyright © 2002 John Wiley & Sons, Ltd.