Risk‐based prenatal screening for trisomy 18 using alpha‐fetoprotein, unconjugated oestriol and human chorionic gonadotropin

Abstract

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Using record linkage and manual follow-up to evaluate the Victorian maternal serum screening quadruple test for Down's syndrome, trisomy 18 and neural tube defects

“…While using a risk threshold of Z1 in 100, as demonstrated by Palomaki et al, the sensitivity was unchanged but the FPR was lower and equivalent to other populations. 3 As the prevalence of trisomy 18 is low, estimates of sensitivity are not as robust as for Down's syndrome. This study has demonstrated that the trisomy 18 algorithm needs to be monitored for this population and may need adjusting, once more data are examined.…”

“…19 A study examining cases and controls to estimate the test characteristics of the triple test for trisomy 18 showed a higher sensitivity of 60% with a 0.2% FPR. 3 However, these studies select cases on the basis of a known pregnancy outcome matched with a control and are biased towards trisomy 18 cases that are detected because of congenital abnormalities. Thus, they may result in an over-estimate of the test characteristics than can actually be achieved in practice.…”

“…The maternal serum screening (MSS) quadruple test is offered between 14 and 20 weeks gestation at Genetic Health Services Victoria (Genetic Health). The quadruple test has been described as the test of choice for Down's syndrome screening in the second trimester, 2 and is also used to provide a risk estimate for trisomy 18 3 and neural tube defects (NTDs). 4 Eligibility for prenatal diagnosis (amniocentesis or chorion villus sampling [CVS]) in Victoria requires pregnant women to be categorized at 'increased risk' -either because they are of advanced maternal age (37 years and over) or have an increased risk result from a prenatal screening test.…”

Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories

“…Published algorithms are available that estimate an individual pregnancy's risk of trisomy 18. 25 Usually the false-positive rate is kept at 0.3% or lower, and the corresponding detection rate using maternal age in combination with AFP, uE3, and hCG measurements is about 70%. Maternal weight correction is an important component of trisomy 18 screening.…”

Reliability of second trimester triple screening for Down syndrome in rhesus-negative women

“…4 Following the introduction of maternal serum screening for fetal Down syndrome, it was noted that fetal trisomy 18 (Edward syndrome) is associated with decreased levels of all three screening analytes, 3 making screening for trisomy 18 feasible within a Down syndrome screening program. 5,6 Besides the chromosomal constitution of the fetus, a variety of other factors are known or thought to influence marker concentrations, for example maternal weight, smoking habits 7 ethnic origin, 8 twins, 9 insulin-dependent diabetes mellitus 10 and multigravidity. 11,12 Adjustment for such factors is necessary to avoid erroneous individual risk estimates.…”