Between pregnancy biological variability of first trimester markers of Down syndrome: implications for screening in subsequent pregnancies

In a group of 149 women who had undergone routine first trimester screening using fetal nuchal translucency thickness (NT) and maternal serum free β-hCG and pregnancy associated plasma protein-A (PAPP-A) in two consecutive pregnancies the within person between pregnancy biological variability of these markers has been assessed. For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r=0.0800). For maternal serum free β-hCG MoM a significant correlation was observed (r=0.4174) as was also found for PAPP-A MoM (r=0.3270). The implications for such between pregnancy marker association is that women who have an increased risk of Down syndrome in their first pregnancy are 1.5–2 times more likely to repeat this event in their next pregnancy. This observation may be useful in counselling women in the first trimester screening of a subsequent pregnancy. Copyright © 2001 John Wiley & Sons, Ltd.     

Maternal serum levels of dimeric inhibin A in pregnancies affected by trisomy 21 in the first trimester

Dimeric inhibin A was measured in maternal serum samples from 45 pregnancies affected by trisomy 21 and 493 samples from unaffected pregnancies at 10–14 weeks of gestation. Inhibin A levels in affected pregnancies were compared with levels of free β-hCG and PAPP-A in the same series. In the trisomy 21 group, the median multiple of the median (MoM) inhibin A was not significantly elevated (1.28 vs 1.00) with only 15.5% being above the 95th centile. In contrast, the median MoM free β-hCG was significantly increased (2.05 vs 1.00) with 36% above the 95th centile and PAPP-A was significantly reduced (0.49 vs 1.00) with 42% below the 5th centile. Inhibin A levels in the trisomy 21 group were significantly correlated with gestational age such that median levels rose from 1.04 at 11 weeks to 1.30 at 12 weeks and 1.67 at 13 weeks. These findings suggest that first trimester biochemical screening for trisomy 21, which is currently optimised using maternal serum free β-hCG and PAPP-A and fetal nuchal translucency, will not benefit from the inclusion of inhibin A. Copyright © 2001 John Wiley & Sons, Ltd.     

Accuracy of Down syndrome risks produced in a first-trimester screening programme incorporating fetal nuchal translucency thickness and maternal serum biochemistry

Over the past three years approximately 12 000 women have been screened in the first trimester through our OSCAR programme, which utilizes fetal NT and maternal serum free β-hCG and PAPP-A. During this time 30 cases of Down syndrome were identified either prenatally or postnatally. Using an established procedure the accuracy of predicted risk for Down syndrome was assessed in a population of 30 cases of Down syndrome and 11 758 unaffected pregnancies. The correlation between predicted risk and prevalence of Down syndrome was very high (r=0.9995). It is concluded that risks produced by the Fetal Medicine Foundation combined risk algorithm agree very closely with Down syndrome prevalence and can be used with confidence when counselling women of their risk. Copyright © 2002 John Wiley & Sons, Ltd.     

A first trimester trisomy 13/trisomy 18 risk algorithm combining fetal nuchal translucency thickness,maternal serum free β-hCG and PAPP-A

This study examines 45 cases of trisomy 13 and 59 cases of trisomy 18 and reports an algorithm to identify pregnancies with a fetus affected by trisomy 13 or 18 by a combination of maternal age fetal nuchal translucency (NT) thickness, and maternal serum free β-hCG and PAPP-A at 11–14 weeks of gestation. In this mixed trisomy group the median MoM NT was increased at 2.819, whilst the median MoMs for free β-hCG and PAPP-A were reduced at 0.375 and 0.201 respectively. We predict that with the use of the combined trisomy 13 and 18 algorithm and a risk cut-off of 1 in 150 will for a 0.3% false positive rate allow 95% of these chromosomal defects to be identified at 11–14 weeks. Such algorithms will enhance existing first trimester screening algorithms for trisomy 21. Copyright © 2002 John Wiley & Sons, Ltd.     

Maternal serum activin A and inhibin A in trisomy 18 pregnancies at 10–14 weeks

In 45 cases of trisomy 18 and 493 control pregnancies at 10–14 weeks of gestation, maternal serum inhibin A, total activin A, free β-hCG and PAPP-A were measured. In the trisomy 18 pregnancies the median values were 0.74 MoM for inhibin A, 1.23 MoM for activin A, 0.38 MoM for free β-hCG and 0.16 MoM for PAPP-A. The degree of deviation from normal in the levels of inhibin and activin is small in comparison with free β-hCG and PAPP-A and they are therefore unlikely to be of value in improving the sensitivity of 90% for a 1% false-positive rate achieved by screening with fetal nuchal translucency and maternal serum free β-hCG and PAPP-A. Copyright © 2001 John Wiley & Sons, Ltd.     

First trimester serum screening for down's syndrome

Screening for Down's Syndrome has been shown to be effective at 10 weeks of pregnancy. A multicentre study (the First trimester serum screening study) has shown that there are two biochemical markers of choice at this time in pregnancy, namely pregnancy associated placental protein A (PAPP-A) and the free β-sub-unit of human chorionic gonadotrophin (free β-hCG). When used together with maternal age these two biochemical markers have an estimated detection rate of 62% and a 5% false-positive rate. The results are consistent with those obtained from a systematic review of the world literature. Other markers are less predictive of Down's syndrome though there is still some uncertainty over the value of dimeric inhibin-A at 10 weeks of pregnancy. Nuchal translucency measurement, from an ultrasound examination performed at about 10 weeks of pregnancy, is associated with Down's syndrome and is emerging as an important potential screening marker. At present there is uncertainty over its quantitative performance and performance when combined with biochemical markers. The resolution of these issues is currently the subject of active research. Ten week screening for Down's syndrome is an advance that is now technically possible though there is still insufficient information to justify its use in routine screening practice.     

Second trimester two-step trisomy 18 screening using maternal serum markers

Trisomy 21 maternal serum marker screening has led to screening for other anomalies, including trisomy 18. Trisomy 18 is generally prenatally diagnosed because of major morphological defects. However, in up to 30% of cases ultrasound signs are unclear, and in most cases diagnosis is performed late in pregnancy. Of the different maternal serum markers, PAPP-A is now considered as the best for trisomy 18 screening. However, pregnancy-associated plasma protein A (PAPP-A) is of value in first trimester screening for trisomy 21, but not in the second trimester. We therefore propose a two-step screening strategy. Based on 45 trisomy 18 cases, we confirm the values of alpha-fetoprotein (AFP) (median 0.61 MoM), free β-human chorionic gonadotrophin (β-hCG) (median 0.24 MoM) and of PAPP-A (median 0.08 MoM). In the first step, a 0.5 MoM cut-off for AFP or for free β-hCG resulted in detection of 37/45 trisomy 18 cases (82%) with a 10% false-positive rate. The second step consisted of the measurement of PAPP-A for all these false-positive cases. Using a PAPP-A cut-off of 0.5 MoM, all the 37 trisomy 18 cases were detected, but now with a 0.1–0.2% false-positive rate. Amniocentesis was only offered to these few patients. This two-step second trimester screening will be of value for patients who have not been included in first trimester screening based on nuchal translucency (NT) measurement combined with the first trimester markers, PAPP-A and free β-hCG. Copyright © 2002 John Wiley & Sons, Ltd.