The variation of risk estimates through pregnancy in second trimester maternal serum screening for Down syndrome

Abstract

The variation of risk estimates in second trimester maternal serum screening for Down's syndrome has been shown to be considerable in quality control schemes, i.e. UKNEQAS. We studied the biological variation of risk estimates in 16 women through pregnancy. The maternal serum markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and beta-hCG were determined six times during late first to late second trimester, and the associated likelihood ratios for Down syndrome were calculated. The interpersonal variation of markers, as well as that of the likelihood ratio, was much greater than the intrapersonal variation. The average intrapersonal standard deviation (SD) of the triple test log likelihood ratio was 0.2291, corresponding to a central 95-percentile interval 0.36-2.81 of the likelihood ratio. The interpersonal SD of the log likelihood ratio was 0.5482, corresponding to a central 95-percentile interval 0.08-11.87 of the likelihood ratio. The large difference between the intra- and interpersonal variation makes it unlikely that biological variation through pregnancy is a major contributor to the variation of risk estimates obtained several times in the same pregnancy. Rather, improvements in analytical quality and laboratory management must be expected to result in reduced variation and, in consequence, better performance of screening.

Biological variation of free β chorionic gonadotropin and pregnancy-associated plasma protein A in first trimester pregnancies

“…It has been reported that the risk estimate changes when the test is repeated in the same pregnancy (2,3). In this study, a difference in trisomy 21 risk between samples 1 and 2 was seen, but was not statistically significant.…”

“…Trisomy 21 risk estimates change throughout the same pregnancy when the risk is estimated repeatedly in the same individual and/or by different laboratories (2,3). Moreover, temporal changes in maternal biochemical markers of trisomy 21 have been shown across the first and second trimesters of pregnancy (4,5).…”

The effects of analytical factors on second trimester risk estimations

“…Although MacRae et al had previously reported that the contributions of likely analytical variations in hCG, AFP and uE3 determinations on the estimation of trisomy 21 are negligible [11] as well as many other articles emphasizing various conclusions on this subject, a consensus that the borderline cases are the most problematic is almost accepted by many authors [4,5,7,8].…”

“…This has been made feasible with the use of modern automated analytical techniques and equipment in laboratories with high throughput screening and by employing standardized quality control procedures. Although MacRae et al had previously reported that the contributions of likely analytical variations in hCG, AFP and uE3 determinations on the estimation of trisomy 21 are negligible [11] as well as many other articles emphasizing various conclusions on this subject, a consensus that the borderline cases are the most problematic is almost accepted by many authors [4,5,7,8].…”

“…The variations of the test results may arise from methodological differences of immunoassays, biological changes during pregnancy, the use of different risk algorithms and quality control procedures [3]. Since analytical variations directly affect the precision of an individual risk estimation [4,5], an inadequacy in the performance of any component of the triple test may lead to invasive, expensive and even inappropriate diagnostic procedures those carrying the risk of misconception [6]. Accordingly, these estimations are advised to be carried out under strict quality control programs [1,2].…”