OBJECTIVE

To establish the median of serum markers for second trimester screening in Qingdao region and to assess the influence of median correction on the performance of screening.

METHODS

Maternal serum alpha-fetoproteins (AFP), human chorionic gonadotrophin, free beta subunit (β -HCG) and unconjugated oestriol (uE3) were assayed for prenatal screening of 18 188 singleton pregnancies at 15-20(+ 6) weeks gestation from January 2009 to July 2010. The median of serum markers was calculated based on above results and applied for risk estimation in screening for fetal aneuploidy from August 2010 to March 2011. The screening performance, specified in terms of detection rates (DRs), false positive rates (FPRs) and odds of being affected given a positive result (OAPR) were compared between the two groups. The risks of 45 affected pregnancies detected during the study were estimated with both Caucasian and corrected medians.

RESULTS

The average level of AFP in local pregnancies was similar to that of the Caucasian population, whilst β -HCG and uE3 were respectively 11% and 33% higher than those of Caucasians. The multiple of median (MoM) value was between 0.94 and 1.02 for the dataset based on the corrected median. At a cut-off of l in 270, FPR has decreased from 5.2% to 4.9%, and DR of Down syndrome has increased from 60% to 69.2%, and OAPR has increased from 1:79 to 1:59 when evaluating risk based on the corrected median. For the 45 affected pregnancies, three Down syndrome pregnancies could be missed because their risk estimates were lower than the cut-off level based on Caucasian median.

CONCLUSIONS

It is useful to establish and apply population and laboratory-specific medians in order to improve the performance of prenatal screening and diagnosis.

OBJECTIVE

Antenatal screening for Down's syndrome relies on the use of multiple markers in combination. Markers that are highly correlated can cause statistical instability. We used the maximum variance inflation factor (VIF(max)) to determine whether a screening test using multiple markers was robust to imprecision in the estimation of the marker distribution parameters.

METHODS

The VIF(max) for a specified screening test was calculated from the correlations between markers in Down's syndrome pregnancies for six tests: integrated and serum integrated tests without repeat measurements, both tests with repeat measurements across trimesters analysed in the standard way, and both tests with repeat measurements analysed as cross-trimester (CT) marker ratios. The screening performance of each test using published parameter values, in terms of the false-negative rates for a 3% false-positive rate (FN(3)), were calculated for simulated populations with medians 0.2 standard deviations (SD) higher or lower than the published values (to reflect imprecision in parameter estimation) for pregnancy-associated plasma protein A and unconjugated oestriol in affected pregnancies. For each test, the VIF(max) value was compared with the coefficient of variation of the FN(3) (FN(3) CV). An independent set of 27 Down's syndrome pregnancies was used to determine how many had meaningless low risks (<1 in 10,000) with each test.

RESULTS

Tests with VIF(max) values greater than 5 had FN(3)CV values over 50%, but those with VIF(max) values less than 5 had FN(3) CV values less than 21%. The numbers of Down's syndrome pregnancies with meaningless low risk estimates in the independent set were 18 (64%) in tests with VIF(max) values>> or =5 and none for those with values <5.

CONCLUSIONS

VIF(max) values of 5 or more suggest instability. The tests using CT marker ratios were stable (VIF(max) < 3), but the tests using repeat measurements in the standard manner were not (VIF(max)>> 5).

OBJECTIVE

To investigate the value of the measurement of free beta human chorionic gonadotrophin (hCG) as a serum marker of Down's syndrome in the second trimester of pregnancy.

METHODS

A prospective observational study using stored antenatal serum samples.

METHODS

Serum samples collected from women receiving routine antenatal care in Oxford.

METHODS

Seventy-five singleton pregnancies with fetal Down's syndrome and 367 unaffected singleton pregnancies. Each affected pregnancy was matched with five control pregnancies for maternal age, gestational age, and duration of storage of the serum sample. None of the pregnancies were associated with neural tube defects.

METHODS

Maternal serum free beta-hCG levels. These were compared with total hCG levels in the same pregnancies. The performance of screening using free beta-hCG was compared with that using the principal markers, namely alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and total hCG together with maternal age.

RESULTS

The median free beta-hCG level in the affected pregnancies was 2.22 multiples of the normal median (MoM), significantly higher than in the unaffected pregnancies (95% confidence interval, 1.84-2.68 MoM). The discriminatory performances of free beta-hCG and total hCG, each considered separately, were similar; with a cut-off level of 2.5 MoM the detection rate was 43% and 5.7 of unaffected pregnancies had raised free beta-hCG levels (likelihood ratio of 7.5 (43/5.7)), somewhat better discrimination than the 32% and 4.6% respectively using total hCG (likelihood ratio of 7.0 (32/4.6)). With a higher cut-off level of 3.5 MoM, the rates were 19% and 2.7% respectively (likelihood ratio of 7.0), using free beta-hCG, worse than the 19% and 1.4% using total hCG (likelihood ratio of 13.6). Screening using maternal age, AFP, uE3 and free beta-hCG (instead of total hCG) yielded a detection rate of 62% (instead of 58%) at a screening risk cut-off level corresponding to a 5% false-positive rated).

CONCLUSIONS

The main advantage in using free beta-hCG instead of total hCG is that there is a small increase in the detection rate (4%) for a given false-positive rate when used with maternal age, AFP and uE3. The main disadvantage is that there is less practical experience with free beta-hCG measurement and insufficient data to screen in certain categories of pregnancy (e.g. twins). The best practical advice is to use total hCG for the present but consider changing to free beta-hCG either (i) after further data are available that will permit the interpretation of screening results in the same way as is currently available with total hCG, or (ii) if its use with another marker confers a worthwhile increase in the detection rate for a given false-positive rate.

Down's syndrome is the most common chromosomal abnormality whose incidence increases with advancing maternal age. However, approximately 70% of all Down's syndrome foetuses occur in mothers aged less than 35. Maternal serum markers have been used in an attempt to identify Down's syndrome pregnancies in these low risk mothers. Numerous second trimester maternal serum markers have been documented in the literature and these are reviewed. The Triple test which uses second trimester maternal serum levels of alpha-feto protein, human chorionic gonadotrophin and unconjugated oestriol is the most popular combination in use today. Although it is associated with a 58% detection rate for Down's syndrome pregnancies at a false positive rate of 5%, the Triple test has its problems and these are discussed. The cost-effectiveness of Down's syndrome screening using the Triple test and its role in mothers aged 35 years or more are also explored. Several workers have reported on first trimester serum markers of foetal Down's syndrome but more data is needed before a first trimester serum screening programme for Down's syndrome is possible.