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.     

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.     

Maternal serum free α-human chorionic gonadotrophin levels in twin pregnancies: Implications for screening for Down's syndrome

Maternal serum free α-human chorionic gonadotrophin (free α-hCG) levels were determined in twin and singleton pregnancies at 15–22 weeks of gestation using a set of stored serum samples relating to 200 twin pregnancies and 600 singleton control pregnancies matched for gestational age and duration of storage. Free α-hCG values are, on average, 1·66 times greater in twin pregnancies than in singleton pregnancies (95 per cent confidence interval 1·56–1·76). If maternal serum free α-hCG is used in screening for Down's syndrome, values in twin pregnancies can be adjusted using this result so that screening can be performed in twin pregnancies as well as in singleton pregnancies.     

Four-marker serum screening for Down's syndrome

The value of measuring the separate sub-units of human chorionic gonadotrophin (free α-hCG and free β-hCG) instead of total hCG together with alpha-fetoprotein (AFP) and unconjugated oestriol (uE₃) was examined to determine the effect on the performance of serum screening for Down's syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples relating to 75 singleton pregnancies with fetal Down's syndrome and 367 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the serum sample, supplemented by data from 970 white women with unaffected pregnancies. Using the four serum markers AFP, uE₃, free β-hCG, and free α-hCG, in addition to maternal age, 65 per cent of Down's syndrome pregnancies were detected for a 5 per cent false-positive rate compared with 59 per cent with the conventional triple test (AFP, uE₃, total hCG with maternal age). If gestation was based on an ultrasound scan examination, the detection rate was 72 per cent using the four serum markers compared with 67 per cent with the triple test. As an alternative illustration, if the detection rate was kept at 60 per cent and gestation was estimated by an ultrasound scan examination the four-marker test reduced the false-positive rate by one-third from 3 per cent using the triple test to 2 per cent with the four-marker test. Screening performance was hardly affected by adjusting marker levels for maternal weight. The four-marker test is, both from a medical and from a financial perspective, the most effective method of prenatal screening for Down's syndrome suitable for routine use.     

Maternal serum levels of total activin-A in first-trimester trisomy 21 pregnancies

Maternal serum total activin-A concentration was measured in 45 pregnancies affected by trisomy 21 and 493 control unaffected pregnancies at 10–14 weeks of gestation. In the trisomy 21 pregnancies total activin-A concentration was significantly higher (1.36 MoM of the unaffected pregnancies) and in 16% of cases the level was above the 95th centile of normal. The log₁₀ SD for the control group and the trisomy 21 group were 0.17 and 0.22, respectively. The median pregnancy associated plasma protein-A (PAPP-A) in this trisomy 21 series was 0.49 and for free β-hCG was 2.05. In the trisomy group there were significant positive associations between total activin-A and PAPP-A (0.6071) and free β-hCG (0.4255). The low median difference and the high overlap in values between trisomic and unaffected pregnancies make total activin-A of little practical use in first-trimester screening for trisomy 21. 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.     

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.     

Maternal serum free β-human chorionic gonadotrophin levels in twin pregnancies: Implications for screening for down's syndrome

Free β-human chorionic gonadotrophin values are, on average, 1·90 times greater in twin pregnancies than in singleton pregnancies [95 per cent confidence interval (CI) 1·69–2·13]. This information can be used in screening for Down's syndrome, so that twin pregnancies can be interpreted in addition to singleton pregnancies.     

Screening for trisomy 21 in twin pregnancies in the first trimester: does chorionicity impact on maternal serum free β-hCG or PAPP-A levels?

In a study of 180 twin pregnancies I have examined the distribution of maternal serum free β-human chorionic gonadotrophin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A), in addition to fetal nuchal translucency thickness (NT), in twins classified as monochorionic or dichorionic, based on ultrasound appearance at 10–14 weeks of gestation. In 45 monochorionic and 135 dichorionic twin pregnancies the median MoM free β-hCG was not significantly different (1.00 vs 1.01), whilst that for PAPP-A was lower (0.89 vs 1.01) but again with no statistical significance. Previous reports of an increased fetal NT in monochorionic twins pregnancies could not be confirmed (1.03 vs 1.00). It is concluded that the existing pseudo risk twin correction algorithm is appropriate for both monochorionic and dichorionic twins in providing accurate first trimester risks for trisomy 21. Copyright © 2001 John Wiley & Sons, Ltd.