Serum Markers For Down Syndrome Research Articles

ADAM 12 may be used to reduce the false positive rate of first trimester combined screening for Down syndrome

ADAM12 has been shown to be an efficient maternal serum marker for Down syndrome (DS) in the first trimester; but recent studies, using a second generation assay, have not confirmed these findings. We examined the efficiency of a second generation assay for ADAM12. ADAM12 concentrations were determined in 28 first trimester DS and 503 control pregnancies using a novel Research Delfia ADAM12 kit. Log10MoM distributions of ADAM12 and correlations with other markers were established. Population performance of screening was estimated by Monte Carlo simulation. ADAM12 was significantly reduced in the first trimester in DS pregnancies with a log10MoM of -0.1621 (equivalent to 0.68 MoM) (p < 0.001). The reduction decreased with advancing gestational age. ADAM12 used with PAPP-A + hCG beta + NT (CUB screening) increased the detection rate (DR) from 86% to 89% for a false positive rate (FPR) of 5%. When used for a fixed DR of 90%, the addition of ADAM12 resulted in a 25% reduction of the FPR. ADAM12 is a moderately effective DS marker. It is not a cost-effective addition to CUB screening, but may be used to reduce the FPR in selected high-risk cases.

Prenatal diagnosis of homozygous α0-thalassemia: from an invasive to a noninvasive approach

The birth of babies with homozygous α0-thalassemia can be prevented by prenatal screening and diagnosis. Serial ultrasound examination of fetal cardio–thoracic ratio and placental thickness can exclude an affected pregnancy and, thus, reduce the need for an invasive test. Whether middle cerebral artery Doppler is useful in the prediction is not clear. 3D ultrasound examination, maternal blood-smear screening for fetal hemoglobin Bart’s cells and maternal serum markers for Down syndrome have also been investigated. In view of the recent data on the survival of affected fetuses after in utero transfusion, it is arguable whether the latter should be offered as an alternative to termination of pregnancy after prenatal diagnosis. Preimplantation genetic diagnosis is possible, particularly for couples with repeatedly affected pregnancies.

Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity

To estimate the combined screening performance of first and early second trimester prenatal serum markers for Down syndrome, in screening for the development of preeclampsia, and analyze the correlation among marker levels, week of onset, and severity of the disease. A retrospective cohort study was carried out on 32 women with preeclampsia and 3044 controls. Serum samples from these pregnancies were assayed for pregnancy-associated plasma protein-A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotrophin (hCG), and inhibin-A. A likelihood ratio and the odds of being affected given a positive result (OAPR) of various combinations of markers were calculated and receiver operating characteristic (ROC) curves analysis was performed. In the pregnancies that subsequently developed preeclampsia, first trimester PAPP-A concentration was significantly lower and concentrations of early second trimester inhibin-A and hCG significantly elevated. Levels of early second trimester uE3 and AFP were not significantly altered. We also found that inhibin-A correlates with both onset of the disease and the severity. Down syndrome biochemical markers levels are altered in those patients who subsequently developed preeclampsia and may be a useful screening test for preeclampsia. Inhibin-A is the most predictive marker and correlates with the severity of subsequent preeclampsia and inversely with the week of occurrence of preeclampsia.

ADAM 12 as a second‐trimester maternal serum marker in screening for Down syndrome

ADAM 12 is a placenta-derived glycoprotein that is involved in growth and differentiation. The maternal serum concentration of ADAM 12 is a potential first-trimester maternal serum marker of Down syndrome (DS). Here we examine the potential of ADAM 12 as a second-trimester maternal serum marker of DS. The concentration of ADAM 12 was determined in gestational week 14-19 in 88 DS pregnancies and 341 matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and the distribution of log(10) MoM ADAM 12 values in DS pregnancies and controls determined. Correlations with alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (free beta-hCG) were established and used to model the performance of maternal serum screening with ADAM 12 in combination with other second-trimester serum markers. The ADAM 12 maternal serum concentration was significantly increased with a median MoM of 1.85 and a mean log(10) MoM (SD) of 0.268 (0.2678) compared to a mean log(10) MoM (SD) of 0.013 (0.4318) in controls. ADAM 12 correlated with maternal weight and ethnicity (with the serum concentration increased in Afro-Caribbeans), but neither with maternal age nor gestational age, and only marginally with AFP (r(DS) = 0.078, r(controls) = 0.093) and free beta-hCG (r(DS) = 0.073, r(controls) = 0.144. The increase in detection rate-for a false positive rate of 5%--by adding ADAM 12 to the double test (AFP + free beta-hCG) was 4%, similar to that of adding uE3 to the double test. ADAM 12 is an efficient second-trimester marker for DS. Further studies should be conducted to determine whether it may be a useful additional or alternative marker to those currently used in the second-trimester.

Human placental lactogen is a first‐trimester maternal serum marker of Down syndrome

Human placental lactogen (hPL) is synthesised by the placenta and found in maternal serum. We analysed the potential of hPL as a first-trimester maternal serum-screening marker for fetal Down syndrome (DS). hPL was quantified by ELISA in 47 DS pregnancies and 136 controls in gestational weeks 8-13. Distributions of log multiples of the median (MoMs) were established. The quantity of hPL in DS screening was estimated using Monte Carlo simulation methods. The mean log10 MoM hPL was - 0.1995 (SD: 0.1993) in affected and 0.0026 (SD: 0.2129) in control pregnancies. This corresponds to a MoM of 0.63 in DS pregnancies. hPL correlated significantly with log10 MoM values of hCGbeta (r = 0.320) and PAPP-A (r = 0.590) in controls, but not with hCGbeta (r = 0.228) or PAPP-A (r = 0.090) in DS pregnancies. The inclusion of hPL in the double test (PAPP-A + hCGbeta) increased the detection rate from 67 to 75% for a false-positive rate of 5%. hPL is a DS screening marker that is applicable at weeks 9-13 and could be included in multiple marker first-trimester screening for DS.

ADAM 12 as a first‐trimester maternal serum marker in screening for Down syndrome

A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples. The concentration of ADAM 12 was determined in 10-14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free beta-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored. The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log(10) MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10-11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free beta-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00). Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8-9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free beta-hCG at 11-12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free beta-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy. ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models.

Screening in early pregnancy for pre‐eclampsia using down syndrome quadruple test markers

To estimate the screening performance of early second-trimester prenatal serum markers for Down syndrome, in screening for the development of pre-eclampsia, and analyse the uncertainty over its screening performance. A nested case-control study was carried out on 96 women with pre-eclampsia and 5 controls for each case from among the women attending three hospitals in London for their prenatal care. Record linkage between computerized obstetric and screening databases identified women with pre-eclampsia and unaffected control women. The stored frozen serum samples collected from these pregnancies between 15 and 22 weeks' gestation were retrieved and assayed for alpha-fetoprotein (AFP), unconjugated estriol (uE(3)), total human chorionic gonadotrophin (hCG), free beta-hCG and inhibin-A. Pre-eclampsia was identified from the computerized obstetric records and confirmed by examination of the medical notes. In the pregnancies that went on to develop pre-eclampsia, early second trimester inhibin-A and hCG values were significantly raised and uE(3) values were significantly lowered, while AFP values were not significantly altered. Using the Quadruple test markers (AFP, uE(3), hCG (total or free beta) and inhibin-A), an estimated 34% of pregnancies that developed pre-eclampsia were detected at a 5% false-positive rate. If all the women who had pre-eclampsia in a previous pregnancy (assuming a pre-eclampsia prevalence of 4%) are considered as screen positive and the serum test is applied to the remaining women, then around 42% of pre-eclamptic pregnancies would be detected at a 6.5% false-positive rate. Pre-eclampsia screening performance using the Quadruple test markers was materially better than that using the Triple test markers. Adding screening for pre-eclampsia to an existing Down syndrome screening programme using the Quadruple test markers is simple and worthwhile. It will detect over 40% of pregnancies with pre-eclampsia at an acceptable false-positive rate (about 6%) and with minimal additional costs.

Invasive Trophoblast Antigen (Hyperglycosylated Human Chorionic Gonadotropin) as a First-Trimester Serum Marker for Down Syndrome

Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG with more asparagine (N)-linked triantennary carbohydrates and a serine (O)-linked tetrasaccharide core structure in the β-subunit of hCG (1). Whereas nonhyperglycosylated hCG is secreted by differentiated syncytiotrophoblast cells, hyperglycosylated hCG is secreted solely by invasive cytotrophoblast cells and is therefore also called invasive trophoblast antigen (ITA) (2)(3). Before the sixth week of gestation, ITA appears to be the predominant form of hCG (2)(3)(4). In Down syndrome pregnancies, differentiation of the cytotrophoblast into a syncytiotrophoblast may be delayed, leading to increased production of ITA (5). Urinary ITA is a promising candidate for use as a biochemical marker in Down syndrome screening. In one study conducted during the second trimester of pregnancy, ITA alone detected 78% of the Down syndrome cases at a 5% false-positive rate (6)(7). In a setting that simulated routine use, urinary ITA was reported to be the best single marker in the second trimester (8). In the first trimester of pregnancy, however, the performance of urinary ITA is lower, with a reported 63% Down syndrome detection rate at a 10% false-positive rate (9). ITA is detectable in serum as well as in urine (10). Studies have not been performed with serum ITA because of concerns about the stability of ITA in serum, possible loss of ITA when blood is collected in gel barrier tubes, and possible aggregation. A recently developed automated immunochemiluminometric assay measures ITA in various sample types, including serum (11). In the present study, we investigated the Down syndrome screening performance of serum ITA before 12 weeks of gestation and compared it with the performance of pregnancy-associated plasma protein A (PAPP-A) and free β-subunit in the …

Historical Perspectives

This month’s Historical Perspectives is in a slightly different format, but should be of considerable interest to readers of NeoReviews. Professor Nicholas Wald is an epidemiologist who has evaluated and written about a variety of topics, but he is best known for his work on screening methods, particularly in the area of maternal serum alpha-fetoprotein (AFP) and fetal abnormalities. Because of his continuing heavy commitments and to minimize the disruption of his schedule, I posed a number of questions to him, to which he responded with detailed answers. Before moving to his responses, some background information seems in order. Shortly before publication of the article highlighted this month, evaluation of amniotic fluid in cases of open spina bifida and other neural tube defects had shown increased levels of AFP. (1) Somewhat later, it was shown that abdominal wall defects, as well as neural tube defects, could contribute to increased levels of amniotic fluid AFP. (2) In his responses, Professor Wald documents the sequence of events that followed, noting that Professor David Brock in Edinburgh described the association of increased levels of maternal serum alpha-fetoprotein (MSAFP) with fetal anencephaly, which triggered the idea that this also might be true of open spina bifida. Thus, MSAFP was used as a screening tool for the detection of neural tube and abdominal wall defects. Elevated MSAFP levels were noted in other “at-risk” pregnancies (3) and twin pregnancies. (4) To provide better standardization, Professor Wald introduced the concept of “multiples of the median” (MoM) at different gestational ages. Approximately a decade passed before the association was made between low MoMs for AFP and chromosomal defects, particularly Down syndrome. Soon thereafter, several other serum markers for Down syndrome were described, and by linking them to maternal age, screening became increasingly valuable. In the early 1980s, Dr …

Clinical application of inhibin a measurement: prenatal serum screening for Down syndrome.

Inhibin A is secreted in significant quantities by the corpus luteum and fetoplacental unit, suggesting a role in fertility and pregnancy. Negative feedback regulation of follicle-stimulating hormone during pregnancy is one expected function of inhibin A, but the complete repertoire of actions of this hormone in pregnancy, including paracrine and autocrine actions, is yet to be fully understood. Inhibin A levels have been carefully described throughout normal pregnancy and studied in association with maternal and fetal complication such as intrauterine growth restriction, preterm labor or delivery, and preeclampsia. The first clinical application of inhibin A measurement in pregnancy has been its use as a second-trimester maternal serum marker for Down syndrome. Our laboratory was among the first, in 1998, to implement Quad marker screening, inhibin A measurement in conjunction with alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin, to assess patients' risk of having a Down syndrome baby. The test performance of the Quad test has been validated by several large studies, detecting about 80% of Down syndrome pregnancies at a 5% false-positive rate. The present review describes Down syndrome and the use of inhibin A in second-trimester prenatal screening. We also address the method used for inhibin A measurement, the biology of inhibin A in Down syndrome pregnancy, and the effects of covariates and other fetal abnormalities on inhibin A levels.

The proform of eosinophil major basic protein: a new maternal serum marker for Down syndrome.

The proform of eosinophil major basic protein (proMBP), the most abundant protein in the eosinophil specific granule, is synthesized by the placenta and secreted into the maternal circulation, where it is found complex-bound to pregnancy-associated plasma protein-A (PAPP-A) and other proteins. We examined the potential of proMBP as a maternal serum marker for fetal Down syndrome (DS) by determining its maternal serum concentration (MSpMBP) in 25 Down syndrome (DS) pregnancies and 152 control pregnancies in the first trimester, and in 105 DS pregnancies and 156 control pregnancies in the second trimester. The median (95 per cent confidence interval) MSpMBP MoM in DS pregnancies (n=15) was 0.66 (0.49-0.79) in gestational weeks 5-9; 1.06 (0.71-1.97) in weeks 10-12 (n=10) and 1.62 (1.18-1.98) in weeks 14-20 (n=105). Using parameterized receiver operator characteristics analysis for proMBP as a single marker for DS, detection rates (DRs) of 22 per cent and 38 per cent, for false-positive rates (FPRs) of 5 per cent, were found in weeks 5-9 (using MSpMBP</=cut-off) and weeks 14-20 (using MSpMBP>/=cut-off), respectively. When age and MSpMBP were used as markers in combination, a DR of 36.8 per cent for an FPR of 5.5 per cent was obtained in weeks 5-9 using a risk cut-off of 1:250. In weeks 14-20 the DR was 48.4 per cent for an FPR of 5.3 per cent using the same risk cut-off. This makes proMBP a marker comparable in diagnostic efficiency to human chorionic gonadotrophin (hCG), and exceeding that of alpha-fetoprotein (AFP) and unconjugated oestriol (uE3), in the second trimester.

Maternal serum activin A and follistatin levels in pregnancies with Down syndrome

Inhibin A is now an established second-trimester maternal serum marker of Down syndrome. Since activin A has a common beta-subunit to inhibin A we evaluated this substance and its binding protein, follistatin, as potential markers. We studied 30 affected and 199 unaffected pregnancies at 13-16 weeks' gestation. There was a statistically significant increase in activin A level among the cases with 8 (27 per cent) exceeding the 90th centile in the controls, and 6 (20 per cent) above the 95th centile. However, the extent of overlap was too great to be of value in screening. There was a small decrease in follistatin levels among cases but it did not reach statistical significance.

Maternal serum activin A and follistatin levels in pregnancies with Down syndrome

Inhibin A is now an established second-trimester maternal serum marker of Down syndrome. Since activin A has a common β-subunit to inhibin A we evaluated this substance and its binding protein, follistatin, as potential markers. We studied 30 affected and 199 unaffected pregnancies at 13–16 weeks' gestation. There was a statistically significant increase in activin A level among the cases with 8 (27 per cent) exceeding the 90th centile in the controls, and 6 (20 per cent) above the 95th centile. However, the extent of overlap was too great to be of value in screening. There was a small decrease in follistatin levels among cases but it did not reach statistical significance. Copyright © 1999 John Wiley & Sons, Ltd.

Effect of transportation delays on maternal serum markers for down syndrome

Effect of transportation delays on maternal serum markers for down syndrome

Multiple marker screen positivity in the presence of hydrops fetalis

Three cases of hydrops fetalis presented in the second trimester as screen-positive for Down syndrome using multiple maternal serum markers. One case was a karyotypically normal female; one case was a monosomy X (Turner syndrome); and one case was a trisomy 21 (Down syndrome). In each case, the maternal serum human chorionic gonadotrophin (hCG) was disproportionately elevated. These cases support the contention that hydrops fetalis of any aetiology may present as screen-positive when using multiple maternal serum markers for Down syndrome. Further cases will be necessary before it can be determined whether a disproportionately elevated hCG is predictive of hydrops.