OBJECTIVE

To compare a contingent strategy with a combined strategy for prenatal detection of Down's syndrome (DS) in terms of cost, outcomes and safety.

METHODS

The contingent strategy was based on a simulation, removing measurement of the free beta subunit of human chorionic gonadotropin (free βhCG) and calculating the DS risk retrospectively in 32,371 pregnant women who had been screened with the combined strategy in the first trimester. In the contingent strategy, a risk between 1:31 and 1:1000 in the first trimester indicated further testing in the second trimester (alpha-fetoprotein, inhibin A, unconjugated oestriol and free βhCG). The cut-off risk values for the contingent and combined strategies in the first trimester were 1:30 and 1:250, respectively, and the cut-off risk value for integrated screening in the second trimester was 1:250. Costs were compared in terms of avoided DS births, and the ratio of loss of healthy fetuses following invasive procedures per avoided DS birth was calculated.

RESULTS

The combined strategy had sensitivity of 40/44 (90.9%) and a false-positive rate of 2.8%. Corresponding values for the contingent strategy were 39/44 (88.6%) and 1.3%, respectively. Only 11% of pregnant women required tests in the second trimester, and the approximate cost reduction for each avoided DS birth was 5000€. The ratio of lost healthy fetuses following invasive procedures per avoided DS birth improved by up to 0.65.

CONCLUSIONS

The contingent strategy has similar effectiveness to the combined strategy, but has lower costs and fewer invasive procedures.

To establish gestational age-specific and body weight-specific mid-trimester normal median equations for the prenatal serum markers α-fetoprotein (AFP), free β subunit human chorionic gonadotropin (fβHCG), and unconjugated oestriol (uE3) for a Chinese population; to compare and replace the median equations built in LifeCycle software; to evaluate the effect of equations used for gestation correction on estimating risk in Down's syndrome, Edward's syndrome, and neural tube defect (NTD).A total of 353,065 cases of prenatal screening data of pregnant women were screened by 13 prenatal screening institutions in China. The local median equations of each institution and the large data were fitted by the least square regression, and then the difference was compared between large data equations and local median equations. The applicability of the localized median equations was evaluated by the determination coefficient. Based on the established median equations, multiples of median (MoM) of each values were calculated and compared with the latest Down's syndrome quality assurance support service (DQASS).There is no significant difference between the local median equations of each institution and the large sample median equations, which are various from LifeCycle built-in median equations. Besides, the determination coefficient of localized median equations are >0.99. 97.0% MoM medians obtained by using local median equations are consistent with latest standard of DQASS.The median established by large sample data represents the median level of a Chinese population, and can be used to replace the software built-in median equations to achieve better screening results.

The effect of repeat testing in maternal serum multiple marker screening for Down's syndrome was estimated using samples stored in an antenatal serum bank. Human chorionic gonadotropin (hCG) and unconjugated oestriol (uE3) levels were determined in 142 pairs of routinely collected samples which had already been tested for alpha-fetoprotein (AFP). For each marker, about two-thirds of the pairs of values were within 20 per cent of each other and most were within 40 per cent. A multivariate Gaussian model was used to estimate the detection and false-positive rates for different repeat testing policies. A policy of repeat testing those with a high risk of a Down's syndrome term pregnancy given age and marker levels would reduce the false-positive rate but there would also be a reduction in the detection rate. For example, using all three markers and a 1 in 250 cut-off risk, the estimated false-positive rate would fall from 5.3 to 3.8 per cent but the detection rate would decrease from 58 to 55 per cent. A policy of repeating those with either high or borderline risks would produce a modest improvement in screening efficiency. Repeating the 11 per cent with a risk exceeding 1 in 500 yields an estimated false-positive rate of 5.0 per cent and a detection rate of 60 per cent. A policy of selective repeat testing is not recommended as it would not substantially improve screening efficiency. Nonetheless, if a repeat test has been performed, the parameters given in this paper will enable an unbiased estimate of the Down's syndrome risk to be calculated for individual women.

Our aim was to compare the results of first trimester combined test, second trimester triple test, and integrated test in the same pregnant population. We retrospectively studied 927 women, all giving birth to an unaffected baby except for two cases of Down's syndrome. The women underwent a nuchal translucency ultrasound measurement and a blood sampling for pregnancy-associated plasma protein A and free beta-hCG subunit (free total chorionic gonadotropin subunit) assay in the first trimester of pregnancy. A second trimester biochemical screening (alpha-fetoprotein, unconjugated oestriol and total hCG) was performed later. The correlations between each pair of markers and between each marker level and maternal age were calculated. No marker showed significant correlation with any other or with maternal age, with the obvious exception of free beta-hCG subunit and total hCG. The false-positive rate (cut-off level: 1 in 350 at term) was 1.5% for the first trimester test, 3.6% for the second trimester test and 0.54% for the integrated test. In 10/14 pregnancies, the increased risk in the first trimester was not confirmed neither in the second trimester nor by the integrated test. In 29/33 women with an increased risk in the second trimester, the first trimester and the integrated test results were discordant. The absence of correlation among different marker levels suggests that the information supplied by the first and second trimester tests is different. Integrating first and second trimester markers in a single test could pose the ethical problem of withholding first trimester results and thus denying the possible advantages of an earlier pregnancy termination.

OBJECTIVE

Choice of parameter sets used to calculate Down's syndrome risks is complicated. Published population statistics were compared with assay-specific parameters to optimise screening efficiency.

METHODS

Weight-corrected Gaussian population statistics for alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE(3)), expressed as log(10) multiples of median (MoM) were established for a Belgian cohort of 748 unaffected pregnancies. Using Cuckle's method and Access-specific data, Down's syndrome parameters were tailored to the Belgian cohort. Correlated marker triplets for affected and unaffected pregnancies were modelled and combined with maternal age to calculate term risks for Trisomy 21. Receiver-Operator-Curve (ROC) analysis was performed to identify the optimally-performing population set.

RESULTS

Log-normal distributions for the Access markers had geometric mean MoM values close to zero and standard deviation values equal to 0.1460 (AFP), 0.2185 (HCG) and 0.1317 (uE(3)). Correlation between AFP and other markers was significant (p < 0.001). Correlation between HCG and uE(3) was not significant (p = 0.4818). The median ratio between the lowest and highest risk outcomes for the test MoM set was 4.3. Areas under ROC curves differed significantly (p < 0.001) between the models and the analyser-assay specific parameters resulted in the largest area. At a 1 in 250 threshold, sensitivity and specificity were 69% and 96%. At false-positive rates (1-specificity) = 5%, sensitivity was 72.5%.

CONCLUSIONS

Population parameters significantly affect risk outcome and hence screening performance. Highest efficiency may be obtained with parameters tailored to an assay-specific population model. Consequently models from literature, without knowledge of the assay/analyser combination may lead to suboptimal performance.

A retrospective study on screening methods for fetal trisomy 18 has been carried out in two different laboratories using the serum parameters: total human chorionic gonadotropin (hCG), unconjugated oestriol (uE3), and alpha-fetoprotein (AFP) in different combinations and in single marker protocols. Laboratory A (L(A)) utilized a radio-immunoassay to examine 38 fetal trisomy 18 cases and laboratory B (L(B)) utilized an enzyme-immunoassay to examine 33 trisomy 18 cases. As unaffected references the whole routine cohorts of each laboratory were used (L(A): 29 043; L(B): 4264). In both trisomy 18 study groups the median hCG and uE3 multiples of the median (MoM) values were markedly declined (L(A): 0.21 MoM, 0.37 MoM; L(B): 0.31 MoM, 0.44 MoM). Even after exclusion of trisomy 18 cases with combined neural tube or ventral wall defects the medians of AFP MoM values were only moderately declined (L(A): 0.73 MoM; L(B): 0.8 MoM). Receiver-operator characteristic (ROC) curves after multivariate discriminance analysis and single marker evaluation demonstrated that the difference of efficiency between a combination of hCG, uE3 and AFP, and a combination of hCG and uE3 is small but that any of these combinations are more efficient than a combination of hCG and AFP or single marker protocols, respectively. At a risk cut-off generating a false-positive rate of one per cent the most effective marker combination detected 31 of 38 (81.6 per cent) affected pregnancies in L(A) and 25 of 33 (75.8 per cent) in L(B). The differences in sensitivity and specificity seem to be due to the different analytical systems being utilized by the two laboratories.

With the object of obtaining information about the technology use employed in Danish maternity departments, a questionnaire was sent to the 58 maternity departments which existed in Denmark in May 1989. These maternity departments covered 99% of the 55,660 births in Denmark (in 1987). Deliveries at home (a total of 511) and delivers in departments with less than four deliveries annually (a total nine) were responsible for the remaining 1%. 100% of the departments returned a completed questionnaire. The following percentages are based on the deliveries included in this investigation. The review revealed that 93.5% of Danish women are delivered in departments with access to carditocographic equipment (CTG), 34% in departments where this is offered routinely to all parturient women. Sixteen departments which did not possess CTG equipment all had fewer than 400 deliveries per annum and 12 of these stated that they wished they had had CTG. Only four of the 58 maternity departments (managing 3.4% of the deliveries in 1987) never employ human placental lactogen (HPL) or oestriol (O3) analyses. The most commonly employed hormone parameter is HPL which is undertaken on appropriate indications in 51 of 54 departments and routinely in the remaining three. Scalp-pH is carried out in 13 of the Danish maternity departments. Thus 41.7% of all the parturient women have access to this analysis. However, only 20% are delivered in maternity departments where this test is employed frequently. Cord-blood-pH is employed routinely in 31.7% of the neonates. Measurement of intrauterine pressure is employed in six out of the 58 maternity departments which are responsible for 25% of Danish deliveries. It is concluded that the slightly increased employment of technology use during delivery in 1989 as compared with practice in 1984 may primarily be due to the closing of several small maternity units during the past five years. In general, the use of technologies are less intensive than in England, Germany, France and the USA.

OBJECTIVE

Screening for fetal abnormalities in the second trimester of pregnancy, based on the concentrations of various markers in serum and maternal age, has become widely used in the past decade. In the first trimester fetal malformations are associated with high values for fetal NT.

METHODS

We propose a new screening method in which measurements obtained during both trimesters are integrated to provide a single estimate of a woman's risk of having a pregnancy affected by genetic syndrome.

METHODS

Study groups comprised 775 pregnant women where examinations were done between 11th-14th and 15th-19th pregnancy weeks. Nuchal translucency thickness was measured by ultrasound examination in both trimesters of pregnancy. AFP, -HCG and oestriol were measured by ELISA assays. Derived risks were then calculated.

RESULTS

Eight fetal aneuploidies were diagnosed. When we used a risk of 1:250 as the cutoff to define a positive result on the integrated test, the rate of detection of fetal abnormalities was 100%, with a false positive rate of 0.6%.

CONCLUSIONS

Integrated test, which is a combination of the ultrasound examination and the triple test allows to achieve high sensitivity and the decrease in the percentage of false positive results, which leads to the reduction in the number of amniocentesis to be performed.

OBJECTIVE

To validate individual risk estimates in antenatal serum screening for Down's syndrome.

METHODS

Women screened for Down's syndrome using maternal serum alpha fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) with maternal age (the triple test) or AFP, uE3, free beta subunit and free alpha subunit of hCG with maternal age (the quadruple test) were grouped according to their predicted risk of having an affected pregnancy. The mean predicted risk in each category was then compared with the observed prevalence based on the number of affected and unaffected pregnancies in each category.

METHODS

About 100,000 pregnant women screened for Down's syndrome from 1989 to 1995.

RESULTS

There was close agreement between the predicted term risk and the prevalence at birth for both the triple test and the quadruple test. For example, with the quadruple test the predicted risk in the highest risk group was 1 in 3.3 and the prevalence was 1 in 2.6; in the lowest risk group these were 1 in 3000 and 1 in 2300 respectively.

CONCLUSIONS

Risk estimates based on multiple marker screening for Down's syndrome are accurate. The technique used to demonstrate this is simple and offers a useful empirical check on screening performance.

OBJECTIVE

To compare the Down's syndrome screening performance of a simplified dimeric inhibin-A assay (Diagnostic Systems Laboratories (DSL)) with an assay whose clinical utility has been established (Serotec).

METHODS

A case control set consisting of 51 Down's syndrome and 245 matched unaffected pregnancies collected as part of an earlier multicentre cohort study.

METHODS

Sera were assayed for dimeric inhibin-A using the DSL assay and Serotec reference assay. Data analysis included a method comparison of mass values, fit of data to a logarithmic Gausian distribution, and determination of detection and false positive rates. In addition, 234 fresh sera were assayed using the simplified method.

RESULTS

The two assays showed a high correlation (r = 0.93) but average concentrations of the DSL assay were 48% higher. However, the differences were basically proportional over the range of values important for screening. The detection rate was essentially equivalent for the DSL assay whether analysed univariately or in combination with other markers (for example, 79% v 75% at a 5% false positive rate for the DSL and Serotec assays for the combination of alpha fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, and dimeric inhibin-A, respectively). The 234 dimeric inhibin-A values measured on fresh sera fitted a logarithm Gaussian distribution for the DSL assay, as indicated by the fit to a probability plot.

CONCLUSIONS

The Down's syndrome screening performance of a simplified dimeric inhibin-A immunoassay was equivalent to a more labour intensive established dimeric inhibin-A assay.