Down's syndrome screening with nuchal translucency at 12+0–14+0 weeks and maternal serum markers at 14+1–17+0 weeks: a prospective study

P. Rozenberg1,9, L. Malagrida1, H. Cuckle2, I. Durand-Zaleski3, I. Nisand1, F. Audibert4, C. Benattar4, S. Tribalat5, M. Cartron5, P. Lemarié6, J. Stoessel6, P. Capolagui6, J. Jansé-Marec7, D. Barbier7, C. Allouch8, M. Perdu1, A. Roberto1, Z. Lahna1, Y. Giudicelli1 and Y. Ville1

1 Poissy-Saint Germain Hospital, Centre hospitalier Poissy-Saint Germain, 10, rue de Champ Gaillard, 78303 Poissy Cédex, France, 2 Reproductive Epidemiology, University of Leeds, UK, 3 Public health evaluation and study unit, Henri Mondor Hospital, 51 avenue Maréchal de Lattre de Tassigny, 94000 Creteil, University Paris XII, 4 Antoine Béclère Hospital, 157 rue Porte de Trivaux, 92140 Clamart, 5 Dreux Hospital, 92 rue Rieuville, 28100 Dreux, 6 Metz-Thionville Hospital, 28 rue XXème Corps Américain, 57000 Metz, 7 Franco-Britannic Hospital,3 rue Barbès, 92300 Levallois Perret 8 Evreux Hospital, 17 rue St Louis, 27000 Evreux, Centre hospitalier Poissy-Saint Germain, 10 rue de Champ Gaillord, Poissy Cédex, France


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Sonographic and biochemical methods for Down's syndrome screening have developed simultaneously, but independently. As a consequence, the rate of invasive procedures for fetal karyotyping has dramatically increased and become an important public health issue which needs to be controlled. One approach is to combine sonographic and biochemical results into a single risk assessment. METHODS: In a multicentre interventional study, nuchal translucency (NT) was measured between 12+0 and 14+0 weeks of gestation. Maternal serum markers (MSM) were measured between 14+1 and 17+0 weeks of gestation. Karyotyping was advised when: (i) NT was >=3 mm; or (ii) the MSM-related risk was >=1 in 250 at term. Karyotyping was delayed until after a maternal blood sample had been taken. NT and MSM were expressed as multiples of the medians (MoMs), and risks were calculated and tailored to the study population. A combined risk for NT and MSM was estimated retrospectively. Costs per case diagnosed, and the cost per case averted were calculated for the three screening strategies. RESULTS: A total of 9444 women was screened. Twenty-one fetuses (0.22%) had Down's syndrome, whilst 326 women (3.4%) were lost to follow-up. Among 9118 women followed up, 5506 had both NT and MSM, 821 had only NT, and 2791 had only MSM. Median maternal age was 30.5 years. False-positive rates for NT, MSM and NT combined with MSM were 3.0, 5.8 and 0.23% respectively. The false-positive rate generated by a sequential two-stage screening was 8.6%. Detection rates of Down's syndrome were 62 and 55% for NT and MSM respectively. Seven cases with Down's syndrome (35%) had raised NT and MSM, and 17 (81%) had either raised NT, MSM, or both. For a 5% false-positive rate, detection rates were 55 and 80% for NT alone and for combined NT and MSM respectively. Ultrasound alone appears to be more cost-effective (£50 per case diagnosed) than both tests (£61 per case diagnosed). CONCLUSIONS: The study results suggest a 25% increase in the detection rate of Down's syndrome using a combination of NT measurement at 12+0–14+0 weeks and MSM at 14+1–17+0 weeks for a 5% false-positive rate, with modest increase in cost.

Key words: alpha-fetoprotein/Down's syndrome/free ß-HCG/screening/ultrasound


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In recent years, the demand for Down's syndrome screening has grown considerably in some countries. In France, the cases screened by second-trimester maternal serum markers has increased from 22 000 in 1991 to >484 000 in 1998 (Association ABA, 1999Go). A review of 17 large prospective studies using multiple serum markers (MSM) including HCG, free ß-HCG, alpha-fetoprotein (AFP) and unconjugated estriol showed that a 60–70% detection rate can be achieved for a 5% false-positive rate (Cuckle, 1996Go). Ultrasound examination performed at 11–14 weeks gestation can also screen for Down's syndrome effectively, by measuring nuchal translucency (NT) (Nicolaides et al., 1992Go). Three large prospective studies (Taipale et al., 1997Go; Snijders et al., 1998Go; Schwarzler et al., 1999Go) have reported detection rates of 54 to 78% for false-positive rates of 0.8 to 5%. However, several authors (Bewley et al., 1995Go; Roberts et al., 1995Go; Kornman et al., 1996Go; Haddow et al., 1998Go) have suggested that inter-operator variability may be too high to justify the widespread use of NT screening.

Sonographic and biochemical screening methods have developed simultaneously and independently. As a consequence, many women undergo a sequential two-stage screening with NT measurement followed by MSM at 14–18 weeks when NT screening is negative. Although each method was developed to generate a 5% false-positive rate, a two-stage screening has a cumulative false-positive rate. Thus, the proportion undergoing invasive prenatal diagnosis can be as high as 10%, or even higher in countries offering invasive prenatal diagnosis to women aged >35 years, regardless of any screening result. This leads to an increase in iatrogenic loss of normal pregnancies and in all related costs. Therefore, the rate of invasive procedures for fetal karyotyping has become an important public health issue which needs to be controlled. One approach is to combine NT and MSM results into a single risk assessment and not to consider their results independently.

Thus, a multicentre prospective study was carried to assess the performance of a combined screening. The objective was to: (i) evaluate a potential increase in the detection rate with a combined screening programme; and (ii) examine the difference in related cost (Hagard and Carter, 1976Go; Ganiats, 1996Go).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between March 1994 and December 1997, six centres participated in a prospective interventional study, as approved by the institutional ethics committee. There were two tertiary referral centres and four primary referral centres. All women having prenatal care at a participating hospital and requesting Down's syndrome screening were recruited for the study. The eligibility criteria were: maternal age between 18 and 37 years; no family history (sibling or child) of Down's syndrome; singleton pregnancy; and intention to deliver in a participating hospital. Detailed information was given and informed consent obtained for screening and participation in the study.

Ultrasound examination was carried out between 12+0 weeks and 14+0 weeks of gestation. A 7.5 MHz transvaginal probe was used primarily, and a 5 MHz transabdominal probe was then used when the fetal position prevented a satisfactory examination. The aims were to confirm gestational age by crown–rump length measurement, to look for major fetal abnormalities, and to measure NT using a previously described technique (Nicolaides et al., 1992Go).

Maternal venous blood was taken at between 14+1 weeks and 17+0 weeks of gestation. A separating gel was used in dry glass bottles (Beckton-Dickinson). Centrifugation was performed within 30 min, and serum was kept at 4°C to be assayed within 3 days. Free ß-HCG and AFP were assayed by immunoradiometric assay (ELISA-FBHCG and ELISA-AFP; CISBio International SA). Marker levels were expressed in multiples of the gestation-specific median (MoMs), and risks were estimated from maternal age and MoMs using commercial software (Free-ß-screen; CISBio International SA) that uses normal median values derived from a population of French pregnant women tested at 14–17 weeks.

Amniocentesis was advised in two circumstances: (i) when NT was >=3 mm and the procedure was delayed until after maternal blood was taken; and (ii) when the risk based on MSM results was >=1 in 250 at term.

Some women had only ultrasound or only MSM but have nevertheless been included in the study statistical analysis, as the prevalence of Down's syndrome would otherwise be flawed. Pregnancies lost to follow-up or ending in spontaneous abortions without karyotyping were excluded from the analysis.

Retrospective statistical analysis of the data collected in the study was performed. NT measurements and MSM levels were expressed in MoMs using our own dataset, and risks were calculated from parameters based on meta-analyses and tailored to the study population as described previously (Cuckle, 1995Go; Cuckle and van Lith, 1999Go). MSM MoMs were calculated using a regression equation based on median levels observed in the study for each completed week of gestation, and regressing median level on median days weighted for the number of women tested. Maternal weight was available for all pregnancies, and MoM values were divided by the expected weight-specific MoM obtained by regression analysis. Log Gaussian modelling was also carried out using standard methods (Royston and Thompson, 1992Go) to estimate the predicted detection and false-positive rates from our parameters when applied to a population with a mean maternal age of 28 years and a coefficient of variation of 16%.

Economic evaluation
With regard to the cost of each of the three strategies, ultrasound alone, serum markers combined with maternal age alone, and the combination of ultrasound and serum markers were estimated from the viewpoint of the healthcare system. A cost per case diagnosed was computed, but this did not include the outcome of the pregnancy with an abnormal karyotype. The costs were computed from the second trimester through to the end of the pregnancy. Only empirical data were used for the economic analysis, and hence the lifetime cost of a person with Down's syndrome was not modelled. Societal costs were not included, and neither were intangible costs such as the loss of a normal baby or the unwanted birth of a child with Down's syndrome. The costs included were: the ultrasound performed in the hospital; maternal serum markers; one genetic counselling clinic; amniocentesis and karyotyping for patients with a positive test result; and termination of pregnancy for patients with abnormal fetal karyotype.

The costs of hospital procedures were derived from the national hospital cost database which estimated a cost per diagnosis-related group from accounting data. The costs of tests and genetic counselling were estimated from the cost program used by the national public insurer. Both are available on the Internet at www.le-pmsi.fr and www.cnam.fr. In order to estimate the cost of a given strategy, the cost of each event was multiplied by the probability of its occurrence. For any of the three strategies tested, the average cost per patient was: the cost of the initial test or tests; the costs of amniocentesis and karyotype for all patients with a positive test result (i.e. both true-positive and false-positive results); and the cost of termination of pregnancy for patients with an abnormal fetal karyotype. True- and false-positive rates were computed from the present patient population. Costs in French francs (2001) were converted into UK£ using the OECD purchasing power parity index (1 UK£ = 10 FF).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 9444 women was screened during the study period, including 21 fetuses (0.22%) affected with Down's syndrome diagnosed prenatally or after delivery. The outcome was not known in 326 women (3.4%) women, and these were excluded from the analysis. These included 113 women (1.2%) who miscarried before 24 weeks without karyotyping. Among the 9118 cases screened and available for follow-up, a total of 5506 women had both NT and second-trimester MSM, 821 had only ultrasound examination, and 2791 had only second-trimester serum screening. Among the 5506 women who had both NT and second-trimester MSM, 875 cases have also been included in a single-centre data published elsewhere (Audibert et al., 2001Go).

The median (25th; 75th centiles) maternal age was 30.5 (27.8; 33.9) years.

Ultrasound examination was carried out in 6327 women, and NT was successfully measured in 6234 of these (98.6%) by 41 operators. The mean duration of the scan was 12 min (range 5–26 min). NT was measured at >=3 mm in 187 women (3.0%). Second-trimester MSM screening was carried out in 8297 women, and was positive in 486 (5.8%) who subsequently underwent amniocentesis. A total of 5506 women had both NT and serum screening, of whom only 13 (0.23%) had both raised NT and positive MSM. However, the proportion of invasive testing generated by this two-stage screening was 8.6%.

NT was >=3 mm in 13/21 Down's syndrome pregnancies, giving a detection rate of 62%. Second-trimester MSM screening was carried out in 20 cases and was positive in 11, giving a detection rate of 55%. Seventeen cases (81%) had either raised NT or positive MSM screening, or both (7/20, 35%). Thus, the overall detection rate was 81% (17/21), for an invasive testing rate of 8.6%. One patient with a 4.3 mm NT at 12 weeks underwent chorionic villus sampling at 12 weeks and requested a termination of pregnancy before the MSM screening could be performed.

The median, 25th centile, 75th centile and standard deviation of each marker in both unaffected and Down's syndromes cases are listed in Table IGo.


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Table I. Median, 25th centile, 75th centile, and standard deviation (SD) for each marker in unaffected cases and Down's syndrome
 
Having expressed NT measurements and second-trimester MSM levels in MoMs using our own data set, the results of the retrospective statistical analysis are shown in Table IIGo. For a 5% false-positive rate, the detection rate was 55% for NT measurement alone, and 80% when combining NT with the MSM in the second trimester of pregnancy.


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Table II. Detection rates (%) for each method alone and combined, calculated retrospectively
 
In the strategy of serum markers alone, 5.9% women had a positive test leading to an amniocentesis (5.8 and 0.1%, false-positive and true-positive rates respectively), versus 3.1% (3 and 0.1%, false-positive and true-positive rates respectively) with ultrasound screening alone, and 0.4% when combining both tests (0.23 and 0.17%, false-positive and true-positive rates respectively). When the karyotype was abnormal, all women in the present series requested termination of their pregnancy. The unit costs used in the economic analysis are shown in Table IIIGo; the average cost per patient, sensitivity of the test and cost per case diagnosed are shown in Table IV.


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Table III. Unit costs used in the economic analysis in 2001
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Prenatal screening for Down's syndrome relies on an increasing number of markers—both biochemical and ultrasonographic—among which NT measurement appears to be the most promising. These advances have been accompanied by an increasing demand from informed pregnant women about the current possibilities of screening- and invasive procedures-related risks. The rapid introduction of these new methods into clinical practice has led to independent, and most often cumulative use of ultrasound and biochemical screening programmes. However, although each of these methods was designed to generate not more than a 5% karyotyping rate, the invasive testing rates from each method are often combined as they are assessed sequentially.

Using both ultrasound and MSM screening programmes had the advantage of confirming the independence of ultrasound and biochemical tests, and it was possible to assess the sensitivity and false-positive rates of both strategies for the same patients. In the present study, 8.6% of patients underwent an amniocentesis because of an increased risk with any of the tests. This was generated by the addition of the false-positive rates induced by each method. Because ultrasound and biochemical tests are independent risk markers, they select different populations. Indeed, only 0.2% of the patients were at high risk for both screening programmes. The present results are in agreement with those of others (Herman et al., 2000Go), who showed that in 508 normal pregnancies the screen-positive rates differed significantly in NT and second-trimester MSM screening programmes; moreover, when either test showed an increased risk for Down's syndrome, the probability of the other test predicting the outcome same was negligible.

A cumulative effect on the false-positive rate was also found by using a combination of ultrasound and biochemical screening (Audibert et al., 2001Go; Schuchter et al., 2001Go). Although the methodology of one of these studies (Audibert et al., 2001Go) was similar to the present investigation, the sensitivity for a 5% false-positive rate of combined screening (NT and MSM) was lower in the present study (80 and 90% respectively). This difference might be explained by the small size of Audibert et al.'s series, however.

Others (Kadir and Economides, 1997Go) also examined the effect of introducing first-trimester NT measurement on the results of second-trimester MSM. The likelihood ratio for a positive result and the positive predictive value of biochemical screening decreased from 9.1 to 5, and from 2.7% to 0.45% respectively. It was also found that implementation of NT screening significantly reduced the positive predictive value of second-trimester maternal serum biochemistry testing (Thilaganathan et al., 1997Go).

Sequential screening programmes also increase the invasive procedure-related pregnancy loss rate. The present study involved women among whom the prevalence of Down's syndrome was below 1 in 1000 births, and an invasive testing rate of 8.6% might therefore be considered unacceptably high in this population who were at relatively low risk.

It was possible, however, to take advantage of the independence of ultrasound and biochemical markers to evaluate a single risk assessment that integrated results of NT measurement, free ß-HCG and AFP assays together with maternal age. The present results suggest that, with such an algorithm, it would be possible to keep the sensitivity as high as that obtained with sequential screening while maintaining an invasive testing rate at 5%. However, this would imply that a 25% increase in detection rate would delay risk calculation and invasive testing by 2–4 weeks. When termination of pregnancy is an issue, this has potential serious societal, medical and economic implications on screening policies.

Only women <38 years were included in the present study for two reasons: (i) the aim was to avoid an inclusion bias due to maternal age; and (ii) in France, invasive testing for fetal karyotype is routinely offered to women >38 years. Thus, it did not seem ethical to delay the invasive procedure once this had been planned and requested.

In the present study, NT measurement was reproducible: it could be performed in 98.6% of the cases, and the median value did not differ significantly between centres and between operators at centres where there were between three and 12 operators. Consequently, the present results varied from those reported elsewhere (Bewley et al., 1995Go; Roberts et al., 1995Go; Kornman et al., 1996Go; Haddow et al., 1998Go), with the latter authors finding NT measurement to be unsuitable for screening due to its great inter-centre variability.

The results of the present study using ultrasound screening were also different from those reported in the three largest recent trials on the subject (Taipale et al., 1997Go; Snijders et al., 1998Go; Schwarzler et al., 1999Go). In the present study, sensitivity (66%) was higher than that published by others (54%; Taipale et al., 1997Go), using the same threshold of 3 mm. However the present false-positive rate was much higher (3.0 versus 0.8%). It was suggested by others (Taipale et al., 1997Go) that different equipment may explain differences in false-positive rates. Although in the present study high-resolution transvaginal ultrasonography was used primarily, transabdominal ultrasonography was also used when necessary. The difference in gestational age might also explain the difference in test performances; whilst other groups performed ultrasound screening until up to the 16th week of gestation, NT was not taken into account until after 14 weeks in the present study. Indeed, NT screening has been validated up to 14 weeks only (Nicolaides et al., 1992Go; Snijders et al., 1998Go).

Sensitivity in the present study, when based on a 95th percentile threshold (54.6%), was much lower than that of others (Snijders et al., 1998Go; Schwarzler et al., 1999Go), who reported sensitivities of 77 and 78% respectively. In the present study, a threshold of 3 mm was used primarily to increase the risk of a patient on the basis of NT measurement. This had initially been reported by others (Nicolaides et al., 1992Go) at the time this study had started. The same authors moved towards a continuous risk assessment by integrating maternal age, gestational age and previous history, as well as NT measurement. Although the present data were corrected for continuous assessment of NT with maternal age and gestational age by using multiples of the median, the data were recorded prospectively, with the aim of identifying cases with NT >=3 mm. It is therefore reasonable to assume that our NT measurements distribution might be less accurate below 3 mm, and therefore may have led to a lower sensitivity. Another explanation might be that the present report relates to a low-risk population with only 21 cases of trisomy 21, though conclusions drawn from a rather small population must be considered with caution.

The most interesting aspect of the present study was to evaluate prospectively two screening strategies for trisomy 21. Such a comparison has been attempted previously only once (Haddow et al., 1998Go), but that study was hindered by poor reproducibility of the ultrasound measurements between centres. A combination of maternal serum pregnancyassociated plasma protein-A (MS PAPP-A) and ß-HCG has been shown to be promising, however. Others (Orlandi et al., 1997Go; Spencer et al., 1999Go; Krantz et al., 2000Go) have confirmed the value of PAPP-A and free ß-HCG in combination with NT measurement, though this approach must be evaluated prospectively in a large series.

The present study confirms that ultrasound examination has an important role in prenatal screening for Down's syndrome. Ultrasound has the advantage over biochemical screening in that it may detect several severe malformations which can be recognized in early pregnancy.

The economic aspects of screening for Down's syndrome have been studied previously both in empirical investigations and models (Goldstein and Philip, 1990Go; Moatti et al., 1990Go; Seror et al., 1992Go; Wald et al., 1992Go; Shackley et al., 1993Go; Fletcher et al., 1995Go; Torgerson, 1996Go). Results ranged from beneficial (where savings exceed costs) to £52 000 per case averted, depending on the hypothesis and the methods of cost computation employed.

An economic evaluation of the present study showed the use of ultrasound alone to be more cost-effective than the use of both tests. However, whilst the additional cost per case diagnosed following screening with a combined method is modest, a combination of ultrasound and serum markers reduces the false-positive rate dramatically and in turn also reduces the risk of performing iatrogenic amniocentesis.

Recently, the cost effectiveness of various antenatal screening strategies for Down's syndrome was compared (Gilbert et al., 2001Go). These authors concluded that the choice of screening strategy should be between integrated test, first-trimester combined test, quadruple test or NT measurement, depending on how much service providers are willing to pay, the total budget available, and safety values. Screening based on either maternal age, second-trimester double test or first-trimester serum test was less effective, less safe, and more expensive.

In conclusion, the results of the present study suggest that, for a 5% false-positive rate, a 25% increase in detection rate could be obtained by a single risk assessment at 16 weeks using the results of NT and MSM screening at 12+0–14+0 weeks and 14+1–17+0 weeks respectively. However, this would delay risk assessment and invasive testing by 2–4 weeks when compared with NT alone. Such information should form part of genetic counselling, especially when the termination of a pregnancy for a fetal abnormality is an issue. Societal implications of antenatal screening policies were beyond the scope of this report. The combination of NT and first-trimester MSM screening appears feasible on the basis of only one small prospective series (Krantz et al., 2000Go). This combination remains to be established as an effective screening strategy in a large, population-based series as it may overcome any delay in risk assessment.


    Notes
 
9 To whom correspondence should be addressed. E-mail: prozenberg{at}chi-poissy-st-germain.fr Back


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 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on March 5, 2001; accepted on December 20, 2001.