Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome,using a sialic acid-specific lectin immunoassay

In a series of 54 cases of pregnancies complicated by Down syndrome and 224 unaffected pregnancies we examined maternal serum levels of hyperglycosylated human chorionic gonadotrophin (HhCG) in samples collected in the first trimester (11–13 weeks) using a sialic acid-specific lectin immunoassay. We compared these levels with those of other potential first trimester serum markers [free β-hCG, pregnancy-associated plasma protein A (PAPP-A) and total hCG (ThCG)] and modeled detection rates and false-positive rates of various biochemical markers in conjunction with fetal nuchal translucency (NT) and maternal age using an maternal age standardized population. Maternal serum HhCG in cases of Down syndrome were significantly elevated (median MoM 1.97) with 24/54 (44%) of cases above the 95th centile for unaffected pregnancies. Free β-hCG was also elevated (median MoM 2.09) with 33% of cases above the 95th centile. PAPP-A levels were reduced (median MoM 0.47) with 38% below the 5th centile. ThCG levels, whilst elevated (median MoM 1.34), had only 20% of cases above the 95th centile. Maternal serum HhCG levels were not correlated with fetal NT but showed significant correlation with ThCG and free β-hCG and with PAPP-A in the Down syndrome group (r=0.536). Maternal serum HhCG levels in cases with Down syndrome had a significant correlation with gestational age, increasing as the gestation increased. When HhCG was combined together with fetal NT, PAPP-A and maternal age, at a 5% false-positive rate the modeled detection rate was 83%, some 6% lower than when free β-hCG was used and some 4% better than when ThCG was used. Maternal serum HhCG is unlikely to be of additional value when screening for Down syndrome in the first trimester. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

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 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.     

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.     

Risk of amniocentesis in women screened positive for Down syndrome with second trimester maternal serum markers

In routine obstetrical practice, prior to offering invasive prenatal diagnosis, it is crucial to weigh the risks attendant on amniocentesis against the individual's risk of aneuploidy. We took advantage of a policy of follow-up of patients undergoing Down syndrome maternal serum screening to compare the rates of fetal loss before 24 weeks and of early premature delivery at 24–28 weeks between women who underwent amniocentesis and women who did not. A total of 54 902 patients entered the study, of whom 4039 (7.35%) were lost to follow-up and 387 were excluded because of a severe fetal abnormality. Of the 50 476 remaining patients, 3472 had an amniocentesis whereas 47 004 had not and served as controls. In the amniocentesis group, the fetal loss rate before 24 weeks was 1.12% (95% CI=1.08–1.15) and the 24–28 weeks premature delivery rate was 0.40% (95% CI=0.39–0.41) which was significantly higher than in controls (0.42% with 95% CI 0.41–0.43 and 0.24% with 95% CI 0.23–0.25, respectively). The 0.86% difference in adverse outcome rates between the amniocentesis and control groups may be attributable to amniocentesis and compares favourably with the positive predictive value of maternal serum markers (1.70%) observed in the present study. Copyright © 2002 John Wiley & Sons, Ltd.     

First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18

Placenta growth factor (PIGF), an angiogenic factor belonging to the vascular endothelial growth factor family, pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG) were measured in maternal serum from 45 pregnancies with trisomy 21, 45 with trisomy 18 and 493 normal controls at 10–13 completed weeks of gestation. In the normal pregnancies maternal serum PIGF levels increased exponentially with gestation. The median multiple of the median (MoM) PIGF concentration in the trisomy 21 group (1.26 MoM) was significantly higher (p<0.0001) than in the control group (1.00 MoM). In the trisomy 18 group the median PIGF was lower (0.889 MoM) but this did not quite reach significance (p=0.064). The corresponding median MoM values for PAPP-A were 1.00 MoM for the controls, 0.49 MoM for trisomy 21 and 0.16 MoM for trisomy 18. The median MoM values for free β-hCG were 1.00 MoM for the controls, 2.05 MoM for trisomy 21 and 0.38 MoM for trisomy 18. In the control group there was a small but significant correlation of PIGF with free β-hCG (r=+0.1024) and PAPP-A (r=+0.2288). In the trisomy 18 group there was a significant association between PIGF and free β-hCG (r=+0.2629) but not with PAPP-A (r=+0.0038). In the trisomy 21 group there was a small but significant association with PAPP-A (r=+0.1028) but not with free β-hCG (r=+0.0339). The separation of affected and unaffected pregnancies in maternal serum PIGF is small, and therefore it is unlikely that measurement of PIGF would improve screening for these abnormalities provided by the combination of fetal nuchal translucency and maternal serum PAPP-A and free β-hCG. Copyright © 2001 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.