Human Reproduction Vol.17, No.5 pp. 1358–1362, 2002

Comparison between disclosure and non-disclosure approaches for trisomy 21 screening tests

Arie Herman1, Eli Dreazen, Joseph Tovbin, Zvi Weinraub, Yan Bukovsky and Ron Maymon

Department of and Gynecology, Assaf Harofeh Medical Center, Zerifin and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 1To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, 70300 Israel. E mail: [email protected]

BACKGROUND: First-trimester nuchal translucency (NT) and second-trimester triple test (TT) are common screening programmes for trisomy 21. The aim of this study was to compare disclosure and non-disclosure approaches of combining those tests. METHODS: Likelihood ratios of both NT and TT tests, among 508 normal and 23 trisomy 21-affected , were used for calculating population-adjusted risks. Disclosure approach incorporated all cases which, by either NT or TT, exhibited a risk ≥1:250 whereas non-disclosure approach generated a new integrated figure ≥1:250. RESULTS: Among women aged ≤34 years, the disclosure and non- disclosure approaches were associated with false positive rates of 4.3 and 1.1%, detection rates of 76.4 and 61.2%, positive predictive value (PPV) of 1:53 and 1:17, and false negative rate of 1:3129 and 1:1985 respectively. CONCLUSIONS: The disclosure approach resulted in considerably higher detection rates. The non-disclosure approach, however, was four times better regarding the number of invasive procedures required to detect one case of trisomy 21. However, the positive predictive value associated with the disclosure policy was still much more beneficial than that obtained in women aged ജ37 years, who are routinely referred to fetal karyotyping.

Key words: disclosure/non-disclosure/nuchal translucency/triple test/trisomy 21

Introduction generating a single risk. By using non-disclosure statistical Screening approaches for the detection of trisomy 21 have modelling of different studies, the authors (Wald et al., 1999) undergone remarkable changes during the last decade. The showed the potential benefit of reaching a detection rate above traditional second-trimester serum screening, introduced in the 85%, associated with a low FPR of ~1%. Cuckle recently 1980s (Cuckle and Wald, 1984), had been improved to detect discussed at length the question of how to combine different about 60% of trisomy 21 cases, yielding a false positive rate screening modalities, and concluded that this question needs (FPR) of ~5% (Haddow et al., 1992; Wald and Hackshaw, to be evaluated in terms of efficiency, without overlooking the 1997). A decade ago, first-trimester ultrasound screening issues of individual choice (Cuckle, 2001). The dilemma which programmes broke through (Nicolaides et al., 1992) and their bothers many investigators and clinicians alike is which feasibility and effectiveness were reconfirmed by numerous modality to use: (i) disclosure approach (in which the tests are reports (Snijders et al., 1998; Hafner et al., 1998; Thilaganathan performed sequentially)—this approach leads to relatively high et al., 1999). Except for the advantage of being able to apply FPR and, probably, a better detection rate (DR); or (ii) non- it at an earlier stage of gestation, the overall performance of disclosure approach—an approach which expresses the risk in nuchal translucency (NT) in detecting trisomy 21 was quite one figure and is associated with much lower FPR, but its similar to that of the second-trimester test (Wald and Hackshaw, clinical performance still requires validation. 1997; Hafner et al., 1998; Thilaganathan et al., 1999). When The aim of the present study was to compare the results of the NT approach was first introduced, it was met with some the disclosure and non-disclosure approaches, using the clinical reluctance because of the possibility that the addition of yet data of first-trimester ultrasound and second trimester serum another screening modality could cause confusion due to screening tests, among the same groups of normal and trisomy potentially contradictory results of the various tests. The main 21-affected pregnancies. argument against its routine incorporation, however, was the apparently higher FPR that it yielded. To overcome this Materials and methods problem, Wald et al. recently proposed integrating the results The study included 508 consecutive normal pregnancies and 23 of the first-trimester and second trimester screening tests and trisomy 21-affected pregnancies. All underwent both first-trimester

1358 © European Society of Human Reproduction and Embryology Trisomy 21 screening: disclosure versus non-disclosure ultrasound screening (operated at Assaf Harofeh Medical Center, population-adjusted results referred to maternal ages at yearly Israel, since 1997) and second-trimester maternal serum screening. increments, Table I presents the results between 20 and 30 years First-trimester ultrasound screening was principally based on nuchal in 5 year increments and between 30 and 44 years in 2 year translucency (NT) measurements between 10 and 14 weeks gestation, increments. Both the FPR and the DR could quite clearly be according to the method described by others (Nicolaides et al., 1992). seen to increase in parallel to maternal age for each of the Institutional review board approval was obtained for this study and tests. The DR of both NT and TT analyses were Ͻ50% in each subject gave her signed informed consent to participate in it. Trisomy 21 risk calculation was based on the software provided the youngest group of patients and it approached 100% in the by the Fetal Medicine Foundation. Second-trimester biochemical oldest ones. The reason for the last feature is that when the screening was performed at 16–19 weeks gestation and included the prior odds are very high (e.g. 1:20), even a low LR of 0.15 three components of the ‘triple test’ (TT), i.e. alpha-fetoprotein, intact will still result in a final risk that is Ͼ1:250. The disclosure human chorionic gonadotrophin and unconjugated . approach was consistently associated with a four-fold higher The methodology of collecting data among the 508 normal pregnan- FPR compared with the non-disclosure approach. Those FPR cies was previously published by us (Herman et al., 2000). The were still reasonable for young patients: 3.5, 6.3 and 7.5% for detailed information of the 23 cases with trisomy 21 was obtained patients of 20, 30 and 32 years of age respectively. However, from various sources: eight cases from our local first-trimester this modality was associated with the extremely high FPR of ultrasound screening programme, 11 cases which were scanned 29.3 and 42.7% for the 38 and 40 year old patients respectively. elsewhere and referred to our facility for termination of , Compared with each test alone the non-disclosure approach two cases from neighbouring hospitals and two cases which were identified as trisomy 21 after birth. Only those cases for which the was associated with lower FPR and higher DR. It demonstrated NT images were of sufficiently good quality, as defined elsewhere remarkably low FPR, across most maternal ages, starting with (Herman et al., 1998), were included. Second-trimester serum test 0.8% for 20 year old patients, 1.8% for patients of 30 years results were available in all cases and, whenever was of age, 4.9% for patients of 36 years of age and reaching performed, blood was drawn before the invasive procedure was 10.2% for patients of 40 years of age. The DR of the disclosure undertaken. approach were consistently higher than those obtained by the Each test was analysed by eliminating the maternal age-derived non-disclosure approach. Whereas they were ജ80% for patients background risk and obtaining its likelihood ratio (LR). Those LR of Ͼ30 years of age by the first method, they reached this were used to calculate age-adjusted FPR and DR for: NT alone, TT figure only for patients of Ͼ38 years of age by the second alone, the disclosure and the non-disclosure approaches. Age-adjusted approach. risk was calculated for maternal ages between 20 and 44 years in 1 year Population-based calculations, i.e. dividing the screened increments. Age-related (prior) odds during the second trimester, expressed in 1:, was derived from previous studies (Snijders et al., population according to age groups, are presented in Table II. ഛ 1994; Nyberg et al., 1998) using a threshold value of 1:250. Data for In patients of 34 years the non-disclosure approach was calculating FPR were obtained from normal pregnancies group, and associated with a low FPR (1.1%) and a remarkably high PPV the DR were calculated from the data of the trisomy 21-affected (1:17) but with relatively low DR of 61.2% and an FNR of pregnancies group. Positive predictive values (PPV) and false negative 1:1985. The disclosure approach in this group resulted in a rates (FNR) were calculated from both groups in conjunction. much higher FPR (4.3%), a lower PPV (1:53), higher DR Calculations of NT alone and TT alone were straightforward, using (76.4%) and a much lower FNR (1:3129). The figures for the age-derived background risks and the LR of the tests, but the the total population showed that disclosure approach was application of the non-disclosure and disclosure modalities requires associated with highest DR close to 90% and FNR of 1:2640. further explanation. The disclosure approach means that a single case The non-disclosure approach was associated with low FPR of was considered ‘positive’ if either the NT and/or the TT age-adjusted 2.4% and higher PPV of 1:12. risk was ജ1:250. The non-disclosure approach involves the generation of a new integrated risk derived from the multiplication of the LR (LR ϭ LRNTϫLR ) (Orlandi et al., 1997; Cuckle and Integrated TT Discussion Sehmi, 1999) and was considered as ‘positive’ only if this integrated age-adjusted risk was ജ1:250. Our present results validate theoretical calculations performed Comparison of the disclosure versus the non-disclosure approach (Wald et al., 1999) and statistical modelling presented (Cuckle, was examined by evaluating population-adjusted figures including: 2001), that the non-disclosure approach concomitantly FPR, DR, PPV (odds of being affected given a positive result) and improves trisomy 21 detection and lowers the FPR, compared FNR (odds of being affected given a negative result). The methodology with each test alone. Although our findings fall short of being of population-adjusted calculations was described previously (Pandya absolutely accurate, because of a bias that will be discussed et al., 1995; Biagiotti et al., 1997) and since the calculations require later, they do faithfully incorporate the major properties of overall maternal age distribution, we used information provided (The each of the two approaches. This is the first report of such an Central Bureau of Statistics, Israel, 2000) on maternal age distribution. The comparison referred to three populations: patients of ഛ34 years, undertaking, based on clinical findings, and we hope that our all patients of ഛ39 and the total population. data will help diagnostic centres to solve the dilemma of choosing the most appropriate modality. Sequential screening means that patients identified as being Results at an increased risk by the first test undergo karyotyping and Age-adjusted figures—FPR and DR for NT alone, TT alone, the rest are referred to a second test and act upon its disclosure approach and non-disclosure approach—are pre- results. However, the absence of data of both screening tests sented in Table I. Although the calculations used later for simultaneously, for those undergoing early karyotyping, may 1359 A.Herman et al.

Table I. Age-adjusted false positive rate (FPR) and detection rate (DR) according to trisomy 21 screening test and approach of combination using a threshold of 1:250

Age Prior Disclosure Non-disclosure (years) oddsa NT alone TT alone approach approach

FPR DR FPR DR FPR DR FPR DR 1: (%) (%) (%) (%) (%) (%) (%) (%)

20 1176 0.8 47.8 2.8 39.1 3.5 65.2 0.8 56.5 25 1040 1.0 56.5 3.3 39.1 4.3 73.9 0.8 56.5 30 690 1.6 60.9 4.7 43.5 6.3 78.3 1.8 65.2 32 508 2.2 60.9 5.3 47.8 7.5 82.6 2.6 65.2 34 342 2.6 60.9 8.1 52.2 10.2 82.6 3.5 65.2 36 216 3.9 65.2 15.6 78.3 18.5 95.7 4.9 65.2 38 129 7.9 69.6 23.8 78.3 29.3 95.7 7.1 78.2 40 74 13.0 69.6 35.2 82.6 42.7 100 10.2 87.0 42 42 80.3 100 59.6 91.3 92.7 100 17.5 95.7 44 23 100 100 93.5 100 100 100 28.9 95.7

aAge-derived background risk of being affected during the second trimester. NT ϭ nuchal translucency; TT ϭ ‘triple test’.

Table II. Population-based calculated false-positive rate (FPR), trisomy 21 detection rate (DR), positive predictive value (PPV) and false-negative rate (FNR), according to screened population and using a threshold of 1:250

Screened population Disclosure approach Non-disclosure approach

FPR DR PPV FNR FPR DR PPV FNR (%) (%) (%) (%)

Patients ഛ34 years old 4.3 76.4 1:53 1:3129 1.1 61.2 1:17 1:1985 Patients ഛ39 years old 7.2 83.8 1:47 1:2963 1.9 67.2 1:15 1:1548 All patients 9.5 88.7 1:41 1:2640 2.4 75.3 1:12 1:1478 prohibit any comparison between the approaches. Recently, acceptable ranges. The only bias that could not be overcome others (Audibert et al., 2001; Schuchter et al., 2001) reported resides in the fact that we are dealing with two tests that had on results of sequential screening by first-trimester ultrasound been performed during substantially different time periods. and second-trimester biochemistry. In those studies the FPR This refers mainly to cases with a markedly thickened NT, among 4130 and 9342 low-risk patients were between 5 and which involve women who opt for early karyotyping or even 7.2% respectively; and trisomy 21 DR, among 12 and 19 termination of pregnancy. A non-disclosure policy would not affected cases, were around 90%. Nevertheless, their methodo- appear to be practical in all cases in such circumstances. First- logy could not allow a meaningful comparison between the trimester ultrasound screening is not an anonymous test whose disclosure policy, utilized by them, and the non-disclosure results are usually mailed days later, as is the case for TT one. In order to compare between the two approaches a results. The women undergoing real-time ultrasound examina- prospective mass population study, for whom results of both tion invariably carefully scrutinize both the ultrasound screen tests are available simultaneously, is needed. Since such a and the examiner’s face, and are highly sensitive to any hint study is not yet available we applied an age-adjustment risk of some abnormality. Neither the examiner nor the woman’s technique that might help to close the gap between a theoretical obstetrician can or should overlook the meaning of test results, statistical model and such a large undertaking. This method nor attempt to shield them from her. This is especially true in uses the net results of the tests, i.e. their LR, and its utilization light of the fact that a thickened NT may also suggest an is based on the fact that the distributions of the tests’ results increased risk for other , cardiac anomalies as are not influenced by maternal age in normal or trisomy well as a variety of syndromes that warrant genetic counselling. 21 pregnancies. In essence, this constitutes the principle Therefore, a method which requires complete data, of both of ‘calculated risk’ which uses the maternal age-derived tests for all cases, will inevitably miss some of those that are background risk and the test’s LR. Thus, the major possible screen-positive by the first-trimester ultrasound test. The fact bias that should be considered in the current study concerns that disclosure approach resulted in a similar FPR of 7.2% in the selection of our cases: normal pregnancies on the one hand another study (Schuchter et al., 2001) as well as this one, and trisomy 21 on the other. among similar populations, points to minimal bias on this part. Our data on normal pregnancies were gathered prospectively The issue of possible bias among the trisomy 21-affected in a consecutive manner and the FPR found were within the pregnancies requires further clarification. The fact that most 1360 Trisomy 21 screening: disclosure versus non-disclosure of the cases were screened elsewhere does not introduce a that balance the high positive TT results. Namely, following bias as long as both tests were performed according to the a disclosure approach of the NT test a non-disclosure approach, same protocol that was applied to the originally screened group integrating low risk NT results with TT, may be utilized. (Wald and Hackshaw, 1997). The findings obtained from the A different study, among pregnancies achieved by assisted trisomy 21 group are not intended to serve for the comparison reproduction, may clarify the properties associated with each between the screening programmes but rather for the examina- approach. tion of interrelationship between the net results of the tests in In summary, the results of this study validate previous the same affected individuals. These data are utilized for the theoretical calculations that the non-disclosure approach calculations of the DR, adjusted to different maternal ages or decreases the FPR and improves the DR compared with each populations, as had been done in other studies (Snijders et al., test alone. The yield of this approach in terms of high PPV is 1994; Pandya et al., 1995; Biagiotii et al., 1997; Nyberg most favourable. Although the PPV of the disclosure approach et al., 1998). are three times worse, they are still much more fruitful than Healthcare planners would probably prefer the non-disclos- the current policy of referring all patients who are 35 or 37 ure approach, which may save costs by performing less invasive years old for routine karyotyping. Serious ethical aspects and procedures, identify more cases of trisomy 21 (compared with other implications make the non-disclosure approach less each test performed alone), and reduce the number of post- attractive and sometimes impractical. The disclosure approach testing abortions. Nevertheless, besides the already mentioned overcomes these problems, is associated with higher detection unique features associated with first-trimester NT examina- and may contribute to the avoidance of unnecessary invasive tions, our current findings provide relevant information which testing. More studies are needed to supplement objective data may affect the clinician’s attitude. The overall results of the to resolve the controversy surrounding prenatal screening. disclosure approach show that the trade-off of the high FPR are its reasonable PPV between 1:40–50. This is a ratio which is much more fruitful than the prior odds of 1:250 or 1:300 in References patients of 37 or 35 years old, who are routinely referred for Audibert, F., Doomergues, M., Benattar, C., Taieb, J., Thalabard, J.C. and Frydman, R. (2001) Screening for using first-trimester invasive testing. In light of the fact that genetic counselling is ultrasound and second-trimester maternal serum markers in a low-risk aimed towards helping patients to come to their own decisions population: a prospective longitudinal study. Ultrasound Obstet. Gynecol., and respecting their autonomy (Holzgreve and Miny, 1993), 18,26–31. Biagiotti, R., Petri, E., Brizzi L., Vanzi, E. and Cariati, E. (1997) Comparison this finding may prove a non-disclosure policy to be a between two methods of standardization for differences in problematic one. fetal nuchal measurement in first-trimester screening for trisomy 21. Another issue that deserves attention is that of non-indicated Ultrasound Obstet. Gynecol., 9, 248–252. karyotyping among young women. In an earlier study (Herman Central Bureau of Statistics (2000) Israel in Figures 1999. Statistical Abstract of Israel. et al., 2000), we showed that 20% of women aged 30–34 Copel, J.A. and Bahado-Singh, R.O. (1999) Editorial. Performing screening years underwent amniocentesis despite receiving reassuring for Down’s syndrome – a search for the family’s values. N. Engl. J. Med., results of both screening tests. A previous study, also carried 341, 521–522. Cuckle, H. (2001) Integrating antenatal Down’s syndrome screening. Curr. out in our country, reported that one case of trisomy 21 was Opin. Obstet. Gynecol., 13, 175–181. detected for 917 amniocentesis procedures performed in women Cuckle, H.S. and Wald. N.J. (1984) Maternal serum alpha-fetoprotein with a negative triple test (Shohat et al., 1995). This shows a measurement: a screening test for Down’s syndrome. Lancet, i, 926–929. lack of confidence in the screening tests, on the part of our Cuckle, H. and Sehmi I. (1999) Calculating correct Down’s syndrome risks. Br. J. Obstet. Gynaecol., 106, 371–372. population, and our present study’s results may contribute to Hafner, E., Schuchter, K., Liebhart, E. and Philipp, K.(1998) Results of routine a change in this trend. We have found that the odds of being fetal nuchal translucency measurement at weeks 10–13 in 4233 unselected affected given a negative result (FNR), of both approaches, pregnant women. Prenat. Diagn., 18,29–34. were much lower than the values obtained by a single screening Haddow, J.E., Palomaki, G.E., Knight, G.J., Williams, J., Pulkkinen, A., Canick, J.A., Saller, D.N. Jr and Bowers, G.B. (1992) Prenatal screening test. This was 1:1478 for the non-disclosure approach and for Down’s syndrome with use of maternal serum markers. N. Engl. J. almost one-half, 1:2640, with the disclosure policy. Thus, the Med., 327, 588–593. latter approach affords another advantage by possibly helping Herman, A., Maymon, R., Dreazen, E., Caspi, E., Bukovsky, I. and Weinraub, Z. (1998) Nuchal translucency audit: a novel image scoring method. to reassure young women that their individual risk of having Ultrasound Obstet. Gynecol., 12, 398–403. a trisomy 21 is, indeed, very low. The issue of elevating Herman, A., Weinraub, Z., Dreazen, E., Arieli, S., Rozansky, S., Bukovsky, the maternal age threshold for routine karyotyping is beyond I., Maymon, R. (2000) Combined first-trimester nuchal translucency and second-trimester biochemical screening tests among normal pregnancies. the scope of the current study. However, in pregnancies with Prenat. Diagn., 20, 781–784. correct dating of gestational age, our findings may support Holzgreve, W. and Miny, P. (1993) Genetic counselling in prenatal diagnosis. considering an elevation of the threshold to the age of 40 years Eur. J. Obstet. Gynecol. Reprod. Rev., 49, 125–129. when all the screening tests are reassuring. Maymon, R., Dreazen, E., Rozinsky, S., Bukovsky, I., Weinraub, Z. and Herman, A. (1999) Comparison of nuchal translucency measurement and It has already been shown that pregnancies achieved by mid-gestation serum screening in assisted reproduction versus naturally assisted reproduction presented high serum screening FPR conceived singleton pregnancies. Prenat. Diagn., 19, 1007–1011. compared with natural pregnancies, whereas results of NT Nicolaides, K.H., Azar, G., Byrne, D., Mansur. C. and Marks, K.. (1992) screening were unaffected by the mode of conception (Maymon Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. Br. Med. J., 304, 867–869. et al., 1999). Here, a semi-sequential approach may prove to Nyberg, D.A., Luthy, D.A., Resta, R.G., Nyberg, B.C. and Williams, M.A. be beneficial and low risk NT results may serve as a buffer (1998) Age-adjusted ultrasound risk assessment for fetal Down’s syndrome 1361 A.Herman et al.

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