Weight adjustment of serum markers in early first-trimester prenatal screening for Down syndrome

OBJECTIVE: To assess whether existing weight correction formulas for PAPP-A and free-beta-hCG developed for weeks 11 to 14 can be applied to pregnancies in weeks 8 to 10. METHODS: Development of formulas based on limited data sets of 8- to 10-week pregnancies and comparison with existing formulas. Calculation of median MoMs adjusted with different formulas for weight correction. RESULTS: Weight correction formulas for the gestational age of 11 to 14 weeks were not appropriate in the 8- to 10-week gestational age interval for PAPP-A, whereas existing weight correction formulas could be applied to free-beta-hCG, independent of gestational age interval. CONCLUSION: If PAPP-A is used in different gestational age intervals, weight corrections should be developed for the interval.     

Adverse infant outcomes associated with first-trimester vaginal bleeding

We assessed the association between first-trimester vaginal bleeding and singleton infant outcomes in a hospital-based population of 11,444 nondiabetic women. Low birth weight (LBW), shortened gestation, LBW at term, and neonatal death occurred more often in women reporting first-trimester bleeding than in those who never bled. These relationships remained statistically significant after adjusting for confounding factors. Women who experienced vaginal bleeding limited to the first trimester (N = 1174) had double the risk of delivering a preterm infant compared with those experiencing no bleeding (adjusted risk ratio = 2.0; 95% confidence interval 1.6-2.5). Bleeding limited to the first trimester was associated with a 1.6-fold risk of delivery of a term LBW infant (95% confidence interval 1.3-2.0). These results suggest that first-trimester vaginal bleeding is an important correlate of adverse infant outcomes.     

The effect of cigarette or sheesha smoking on first-trimester markers of Down syndrome

Objective  To investigate the influence of cigarette or sheesha smoking on first-trimester markers of Down syndrome.
Design  A prospective observational study.
Setting  Primary care centres and antenatal clinics of Maternity and Children Hospital, King Abdulaziz University Hospital and New Jeddah Clinic Hospital, Jeddah, Saudi Arabia.
Population  Women with a singleton pregnancy who were either nonsmokers ( n = 1736) or cigarette smokers ( n = 420) or sheesha smokers ( n = 181).
Methods  Fetal nuchal translucency thickness (fetal NT), maternal serum free beta-human chorionic gonadotrophin (free β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) were measured at 11 weeks 0 days to 13 weeks 6 days of gestation in all women. Women were grouped according to smoking status, confirmed by maternal serum cotinine measurements, and analyte levels between groups were compared.
Main outcome measures  Fetal NT, maternal serum free β-hCG, PAPP-A and cotinine measurements.
Results  Compared with nonsmoking women, fetal NT was significantly increased and free β-hCG and PAPP-A levels were significantly decreased in both cigarette and sheesha smokers. There were significant relationships between all three markers and the number of sheeshas consumed per day.
Conclusions  Cigarette and sheesha smoking significantly affect first-trimester markers of Down syndrome (fetal NT, free β-hCG and PAPP-A). Correction for this effect in women who smoke might improve the effectiveness of first-trimester screening for Down syndrome in these women. The underlying mechanism(s) relating smoking to the changes in first-trimester markers require further studies.     

Serum leptin in first-trimester Down syndrome pregnancies

BACKGROUND: Leptin is a key regulator of satiety; and the serum concentration is considered to reflect nutritional status. Expressed predominantly by the adipocytes, leptin is also expressed in placenta, which is a major source of both leptin and the leptin receptor in pregnancy serum. As a placenta protein, leptin serum concentrations may be perturbed in Down syndrome (DS) pregnancies as seen for pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin-beta (hCGbeta). We examined whether leptin is a maternal serum marker for foetal DS in the first trimester. MATERIALS AND METHODS: Serum samples from 44 pregnant women with a DS foetus, and 135 control pregnant women in week 8 to 14 had the leptin concentration determined by immunoassay and the concentrations were converted into multiples of the median (MoM) of controls based on log-regression analysis. The distributions of log10 MoM leptin was compared in DS and control pregnancies. RESULTS: Serum leptin increased significantly with gestational age in controls (p = 0.02). The mean log10 MoM in controls was - 0.0486, with a median empirical MoM of 0.89, and - 0.0618, with a median empirical MoM of 0.80, in DS pregnancies. This difference was not significant. The log10 MoM leptin values in DS pregnancies did not change with gestational age (p = 0.32). CONCLUSION: Leptin is not a first-trimester marker for foetal DS.     

Ultrasound markers for Down syndrome

Trisomy 21 (Down syndrome) is the most common chromosomal abnormality. Sonographic findings in fetuses with Down syndrome include both structural abnormalities and nonstructural abnormalities or "markers." These markers are known as "soft markers" of aneuploidy. These markers are nonspecific, often transient. The most commonly studied soft markers of aneuploidy include a thickened nuchal fold, long bones shortening, mild fetal pyelectasis, echogenic bowel, echogenic intracardiac focus, FMF angle > 90 degrees, pathologic velocity of Ductus venosus and choroid plexus cyst.     

Appropriate biochemical parameters in first-trimester screening for Down syndrome.

Meta-analysis was used to calculate maternal serum marker distribution parameters for Down syndrome risk estimation in the first trimester. Data from 44 series were combined: relating to pregnancy associated plasma protein (PAPP)-A in 18, free beta human chorionic gonadotrophin (hCG) in 17, alpha-fetoprotein (AFP) in 26 and unconjugated oestriol (uE3) in 9. All levels were expressed in multiples of the normal median (MOM) for gestational age. Individual PAPP-A levels were available for 439 first and second-trimester Down syndrome pregnancies. The median MOM value increased with gestation: 0.35 at 6-8 weeks (31 cases), 0.40 at 9-11 weeks (197), 0.62 at 12-14 weeks (113) and 0.94 thereafter (98). A cubic regression equation was fitted so it could be estimated for each week of gestation. For the other markers the median value in Down syndrome was estimated from the weighted mean across all first-trimester series: 1.98 MOM for free beta-hCG in 579 cases; 0.79 MOM for AFP in 243 and 0.74 MOM for uE3 in 226. Variance-covariance matrices were calculated directly in unaffected pregnancies and from the difference between affected and unaffected pregnancies in Down syndrome. Based on these parameters we estimate that screening at 9-11 weeks with PAPP-A and free beta-hCG will yield a 64.6 per cent detection rate for a 5 per cent false-positive rate. Adding a third marker will increase detection to 66.6 per cent for AFP and 68.6 per cent for uE3; using all four markers it increases to 70.1 per cent. Routine ultrasound nuchal translucency measurement in addition to serum testing will increase the rates to 86.4 per cent, 87.2 per cent, 87.9 per cent and 88.3 per cent, respectively.     

First-trimester biochemical markers for Down syndrome

The value of maternal serum pregnancy-associated protein A (PAPP-A), free and total beta human chorionic gonadotrophin (fbetahCG, betahCG) and alpha-fetoprotein (AFP) in screening for Down syndrome (DS) in early pregnancy has been assessed. To evaluate the different biochemical markers, 32 DS pregnancies and 267 controls were used for AFP, betahCG and PAPP-A. A subgroup of those (17 DS and 136 controls) were used to evaluate fbetahCG. All analytes were determined in fresh serum samples. Our results give support to the feasibility of maternal serum levels of PAPP-A as the best biochemical marker for DS in the first trimester, and either betahCG or fbetahCG as the second marker. No differences were found between betahCG and fbetahCG distribution levels as expressed as MoMs in normal and DS pregnancies in this study.     

ADAM12: a novel first-trimester maternal serum marker for Down syndrome

OBJECTIVES: The concentration of bioavailable insulin-like growth factor (IGF) I and II is important to foetal growth. It is regulated by insulin-like growth factor binding proteins (IGFBP) 1 through 6. Proteolytic cleavage of IGFBP-3 takes place in human pregnancy serum; accordingly, IGFBP-3 serum levels decrease markedly during pregnancy. ADAM12 (A disintegrin and metalloprotease) is an IGFBP-3 and IGFBP-5 protease and is present in human pregnancy serum. The goal of this study was to determine whether ADAM12 concentration in maternal serum is a useful indicator of foetal health. METHODS: We developed an enzyme-linked immunosorbent assay (ELISA) for the quantification of ADAM12 in serum. The assay range was 42 to 667 micro g/L. Recombinant ADAM12 was used as the standard for calibration. RESULTS: We found that ADAM12 was highly stable in serum. Serum concentration increased from 180 micro g/L at week 8 of pregnancy to 670 micro g/L at 16 weeks, and reached 12 000 micro g/L at term. In 18 first-trimester Down syndrome pregnancies, the concentration of ADAM12 was decreased, thus the median multiple of mean (MoM) value was 0.14 (0.01-0.76). A detection rate for foetal Down syndrome of 82% for a screen-positive rate of 3.2% and a 1:400 risk cut-off was found by Monte Carlo estimation using ADAM12 and maternal age as screening markers. CONCLUSION: ADAM12 is a promising marker for Down syndrome.     

Early genetic sonogram for Down syndrome detection

OBJECTIVE: The purpose of this study was to determine the Down syndrome sensitivity of early genetic sonography (14-<16 weeks of gestation) and to compare its diagnostic accuracy with that later in the mid trimester (16-24 weeks of gestation). STUDY DESIGN: Nuchal thickness, humerus and femur lengths, hyperechoic bowel, hypoplastic fifth digit (clinodactyly), and any gross anatomic defects were measured or ascertained in singleton pregnancies that were undergoing genetic amniocentesis. Multiple stepwise logistic regression analysis was used to determine the significant sonographic markers for Down syndrome detection in each group. Multivariate gaussian algorithms that included maternal age were used to estimate patient-specific Down syndrome risk. Sensitivity and false- positive rates, receiver-operating characteristic curves, and area under the curves were calculated and compared for both groups. RESULTS: There were 1,727 pregnancies with 22 Down syndrome fetuses (1.27%) in the early group versus 3,914 pregnancies with 86 Down syndrome fetuses (2.2%) in the later group. The mean +/- SD ages were 15.5 +/- 0.4 weeks versus 17.6 +/- 1.4 weeks, respectively. Early genetic sonography (14-<16 weeks) had a 100% detection rate, with a 21.2% false-positive rate. The early versus later genetic sonography had an 81.8% versus 61.6% detection rate, respectively, at a fixed 4.8% false-positive rate. Early sonography had significantly higher diagnostic accuracy (area under the curve, 0.962 vs 0.871, respectively; P =.005). In fetuses at 14 to 15 weeks, the genetic sonography was also highly accurate, with 100% detection with a 21.9% false-positive rate. CONCLUSION: Early genetic sonography is highly sensitive and statistically superior to later ultrasonography for Down syndrome detection. Early midtrimester sonography achieved a diagnostic accuracy similar to that currently reported for first-trimester nuchal translucency.     

Combined first-trimester versus second-trimester serum screening for Down syndrome: a cost analysis

OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of combined first-trimester screening for fetal Down syndrome with second-trimester maternal serum triple screening. STUDY DESIGN: A first-trimester screening approach that used nuchal translucency measurement and maternal serum screening was evaluated against second-trimester maternal serum triple screening in a hypothetic population. Screening sensitivities and screen-positive rates were 91% and 5% for the first-trimester approach and 70% and 7.5% for the second-trimester approach, respectively. The costs of fetal Down syndrome, live-born Down syndrome cost, and total costs (screening plus live-born costs) were calculated for each screening program. RESULTS: First-trimester screening was associated with lower screening and live-born Down syndrome costs versus second-trimester serum screening. Total Down syndrome screening costs were 29.1% lower with first-trimester screening. CONCLUSION: In this hypothetic model, combined first-trimester screening for fetal Down syndrome was more cost-effective than universal second-trimester triple serum screening.     

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

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Multi-centre first-trimester screening for Down syndrome in the Netherlands in routine clinical practice

OBJECTIVES: This is the first report on the results of a first-trimester combined-test screening programme in the Netherlands in a multi-centre routine clinical setting. METHODS: Between July 2002 and May 2004, blood samples were taken from subjects in 44 centres in the Netherlands and sent to our laboratory to assay for maternal serum concentrations of fbeta-hCG and PAPP-A. Fetal nuchal translucency (NT) was measured in the participating centres at a gestational age (GA) of 10-14 weeks. Results of those pregnancies for which a combined biochemical and NT risk was calculated were included in the epidemiological analysis of this study. RESULTS: A total of 4033 singleton pregnancies were included in the analysis. The median maternal age of the analysed group was 36.5 years. The distribution of GA was biphasic, with median GA of 10.3 and 12.1 weeks, respectively. The detection rate using the combined ultrasound and serum screening at a cut-off level of 1 in 250 was 71% (15/21), with a screen-positive rate of 4.7%. CONCLUSION: The results of this study show that the first-trimester combined test is suitable as a prenatal screening test in a multi-centre routine clinical setting in the Netherlands. Strict performance evaluation should identify weaknesses in the organisation that impair the performance of the test. Here, the performance of NT was especially identified as a candidate for improvement.     

Comparison of serum markers in first-trimester down syndrome screening

OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free beta-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency. METHODS: Seventy-nine matched case-control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free beta-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated. RESULTS: Median multiples of the median levels of free beta-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free beta-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other. CONCLUSION: Although levels of free beta-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11-13 weeks of pregnancy. LEVEL OF EVIDENCE: II-2.     

The predictive role of sTWEAK levels in pregnant women with first-trimester vaginal bleeding*

Purpose: To investigate the relationships of TNF-related weak inducer of apoptosis (sTWEAK), a cytokine related to the TNF superfamily, its newly described soluble receptor sCD163, and the sTWEAK/sCD163 ratio with perinatal outcomes in women with first-trimester vaginal bleeding.

Materials and methods: Seventy (41 threatened abortion and 29 control) gestational-age-matched (6–14?weeks) pregnant women were included in the study. Antenatal complications (gestational diabetes, preeclampsia, intrauterine growth restriction, oligohydramniosis, polyhydramniosis), and perinatal outcomes (delivery mode, birth weight, delivery week) were recorded. Women with vaginal bleeding were divided into subgroups by pregnancy outcome (miscarriage or live birth) and subchorionic hematoma incidence. Statistical analyses were performed using the Student’s t test, Mann–Whitney U test, chi-square test, and Pearson’s correlation coefficient. p Values?<.05 were considered as statistically significant.

Results: There were no statistically significant differences in sTWEAK or sCD163 levels, in sTWEAK/sCD163 ratios, or antenatal complications between threatened abortion and control patients. Higher sTWEAK levels were significantly correlated with higher rates of miscarriage in the threatened abortion group (p?=?.014). sCD163 levels were significantly lower in the subchorionic hematoma subgroup of the threatened abortion group (p?=?.043).

Conclusions: sTWEAK levels may predict the risk of miscarriage in pregnant women with first-trimester vaginal bleeding.     

Informed choice in women attending private clinics to undergo first-trimester screening for Down syndrome

OBJECTIVES: Informed choice for prenatal screening has long been considered an essential aspect of service provision, and has been researched extensively in the second trimester. This study aims at examining whether women having first-trimester screening in a private clinic had made an informed choice. METHODS: A cross-sectional survey recruited women having first-trimester screening at specialist ultrasound practices. Two questionnaires containing a validated Multidimensional Measure of Informed Choice (MMIC) were self-administered pre- and post-screening. RESULTS: MMIC was completed by 81% (163/202) of women. Ninety-nine percent of women had a positive attitude towards screening, therefore informed choice was essentially measured on knowledge alone. Pre-screening, 68% made an informed choice, compared with 74% post-screening (chi2 = 1.6, p = 0.21 (McNemar)). Knowledge was associated with education level, information sources and perception of screening as routine or optional. CONCLUSIONS: The Australasian Guidelines on prenatal screening state that all women having testing should be provided with written information, and it should be ensured that they have appropriate understanding of the test(s). These guidelines are not being met, even in private clinical care. Health professionals should ensure that all women are provided with suitable information about prenatal screening that is tailored to their level of education and individual needs, and should emphasise that screening is optional.