1. No category

NUCHAL TRANSLUCENCY MEASUREMENT
IN THE FIRST TRIMESTER OF PREGNANCY
FOR SCREENING OF TRISOMY 21 AND
OTHER AUTOSOMAL TRISOMIES
May 2002
MSAC reference 04
Assessment report
© Commonwealth of Australia 2003
ISBN
0 642 82139 9
ISSN (Print)
ISSN (Online)
1443-7120
1443-7139
First printed August 2003
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part
may be reproduced by any process without prior written permission from the Commonwealth
available from the Department of Communications, Information Technology and the Arts.
Requests and inquiries concerning reproduction and rights should be addressed to the Manager,
Copyright Services, Info Access, GPO Box 1920, Canberra ACT 2601.
Electronic copies of the report can be obtained from the Medical Services Advisory Committee’s Internet site
at:
http://www.msac.gov.au
Hard copies of the report can be obtained from:
The Secretary
Medical Services Advisory Committee
Department of Health and Ageing
Mail Drop Point 107
GPO Box 9848
Canberra ACT 2601
Inquiries about the content of the report should be directed to the above address.
The Medical Services Advisory Committee (MSAC) is an independent committee which has been
established to provide advice to the Commonwealth Minister for Health and Ageing on the strength of
evidence available on new and existing medical technologies and procedures in terms of their safety,
effectiveness and cost-effectiveness. This advice will help to inform Government decisions about which
services should attract funding under Medicare.
This report was prepared by MSAC with the assistance of Dr Elmer Villanueva and Ms Alexandra Raulli of
the Australasian Cochrane Centre and Mr Anthony Harris of the Health Economics Unit,
Monash University.
The report was endorsed by the Commonwealth Minister for Health and Ageing on 16 October 2002.
Publication approval number: 3142
MSAC recommendations do not necessarily reflect the views of all
individuals who participated in the MSAC evaluation.
Contents
Executive summary.................................................................................................ix
Introduction.............................................................................................................. 1
Background .............................................................................................................. 2
Nuchal translucency measurement in the first trimester of pregnancy.................... 2
Clinical need and burden of disease ............................................................................15
Existing procedures .......................................................................................................21
Comparators ...................................................................................................................24
Current reimbursement arrangements ........................................................................26
Approach to assessment......................................................................................... 28
Review of literature........................................................................................................28
Expert advice ..................................................................................................................32
Results of assessment............................................................................................. 33
Is it safe?..........................................................................................................................33
Is it effective?..................................................................................................................46
What are the economic considerations? .....................................................................60
Conclusions ............................................................................................................ 73
Safety................................................................................................................................73
Effectiveness...................................................................................................................73
Cost-effectiveness ..........................................................................................................73
Recommendations.................................................................................................. 74
Appendix A MSAC terms of reference and membership.................................... 75
Appendix B Supporting committee..................................................................... 77
Appendix C Studies included in the review ........................................................ 79
Appendix D Existing recommendations ............................................................. 80
Appendix E Ongoing primary studies ................................................................ 87
Appendix F
Summary of meta-analysis of studies on nuchal translucency
measurement in the detection of trisomy 21 applying set cutoff
measures.......................................................................................... 89
Appendix G Summary of comparative studies of cost-effectiveness in screening
for trisomy 21 using NT ultrasound, biochemical and age screening
......................................................................................................... 91
Nuchal translucency measurement in the first trimester of pregnancy
iii
Appendix H Modelled economic evaluation of nuchal translucency ultrasound
screening under various alternative assumptions........................... 95
Appendix I
Contact details for Australian centres accredited by the Fetal
Medicine Foundation...................................................................... 97
Abbreviations.........................................................................................................121
References .............................................................................................................123
iv
Nuchal translucency measurement in the first trimester of pregnancy
Tables
Table 1
Distribution of trisomy 21 and other chromosomal abnormalities
detected in a multicentre trial of screening for trisomy 21 at 10 to 14
weeks of gestation using maternal age and nuchal translucency
thickness ...................................................................................................................15
Table 2
Number of chorionic villus sampling and amniocentesis procedures,
Victoria, 1989–99 ....................................................................................................18
Table 3
Indications for prenatal diagnostic testing by chorionic villus
sampling or amniocentesis, Victoria, 1999 ..........................................................18
Table 4
Indications for prenatal diagnostic testing via chorionic villus
sampling or amniocentesis in cases where trisomy 21 was diagnosed,
Victoria, 1999...........................................................................................................19
Table 5
Frequency of reported outcomes of trisomy 21, Australia, 1987–96 ..............19
Table 6
Frequency and rate of trisomy 21, by State and Territory and
nationally, 1991–96 .................................................................................................20
Table 7
Frequency and rate of terminations of pregnancy following a
diagnosis of trisomy 21, Australia, 1993–96........................................................20
Table 8
Frequency distribution of terminations of pregnancy for trisomy 21
by gestational age, Australia, 1993–96..................................................................21
Table 9
Number of primary studies examining the use of selected maternal
biochemical markers in the screening of trisomy 21 according to
trimester of pregnancy............................................................................................23
Table 10
Distribution of Australian centres accredited by the Fetal Medicine
Foundation to conduct nuchal translucency measurements, by State
or Territory...............................................................................................................24
Table 11
Number of services in calendar year 2000 for specific Medicare item
numbers ....................................................................................................................27
Table 12
Electronic databases (including edition) used in the review .............................28
Table 13
Search terms used to identify citationsa ...............................................................28
Table 14
Criteria for validity ..................................................................................................31
Table 15
Designation of levels of evidence .........................................................................31
Table 16
Summary of published recommendations by major international
organisations on the safety of diagnostic ultrasound.........................................37
Table 17
Review of studies on the effects of prenatal screening for trisomy 21
on parental psychological outcomes and behaviours.........................................43
Table 18
The generic relationship between results of a screening procedure and
disease status ............................................................................................................46
Table 19
General characteristics of retrieved studies focusing on the use of
nuchal translucency measurement for the screening of trisomy 21 in
the first trimester of pregnancy.............................................................................49
Table 20
Pooled MoM values for selected maternal biochemical marker studies
during the second trimester of pregnancy ...........................................................53
Nuchal translucency measurement in the first trimester of pregnancy
v
Table 21
Estimated detection rate (%) for a false positive rate of 5 per cent for
selected maternal biochemical marker combinations during the
second trimester of pregnancy ..............................................................................54
Table 22
Pooled MoM values for selected maternal biochemical marker studies
during the first trimester of pregnancy ................................................................55
Table 23
Estimated detection rate for a false positive rate of 5 per cent for
selected biochemical markers and combinations of markers measured
from 9 to 11 weeks of gestation............................................................................55
Table 24
Estimated detection rate (per cent) for a false positive rate of 5 per
cent for selected biochemical markers and combinations of markers,
according to gestational age...................................................................................56
Table 25
General characteristics of retrieved studies focusing on the use of
nuchal translucency measurement in the first trimester and maternal
biochemical markers in the second trimester for the screening of
trisomy 21.................................................................................................................56
Table 26
Estimated detection rate for a fixed false positive rate of 5 per cent
for variations of the "integrated test"...................................................................57
Table 27
Estimated detection rate for a 5 per cent false positive rate for the
combined use of NT and selected biochemical markers and
combinations of markers measured from 9 to 11 weeks of gestation.............58
Table 28
Estimated detection and false positive rates for combinations of
screening modalities................................................................................................59
Table 29
Prevalence of trisomy 21 per 1,000 live births by age .......................................64
Table 30
Natural history of trisomy 21 pregnancy and screening characteristics
assumed in primary analysis...................................................................................66
Table 31
Screening and diagnostic test characteristics assumed in
primary analysis .......................................................................................................67
Table 32
Unit cost assumptions in primary analysis...........................................................67
Table 33
NT ultrasound screening for trisomy 21 for all pregnant women
(260,000 live births).................................................................................................62
Table 34
Biochemical screening for trisomy 21 for all pregnant women
(260,000 live births).................................................................................................69
Table 35
Primary cost-effectiveness analysis of pregnancy screening strategies
for trisomy 21 compared with next best strategy: cost per trisomy 21
case detected ............................................................................................................69
Table C-1 General characteristics of studies on NT measurement meeting entry
criteria .......................................................................................................................79
Table F-1 Performance characteristics of nuchal translucency measurements in
collected studies, arranged according to cutoff values.......................................90
Table H-1 Cost per trisomy 21 case detected in women aged 35 years or overa ..............95
Table H-2 Cost per trisomy 21 case detected in women aged 30 years or overa ..............96
vi
Nuchal translucency measurement in the first trimester of pregnancy
Table H-3 Cost-effectiveness analysis of ultrasound screening plus biochemical
screening compared with biochemical screening alone: cost per
trisomy 21 case detecteda .......................................................................................97
Table H-4 Incremental cost-effectiveness of ultrasound and biochemical
screening compared with biochemical screening alone by age groupa ............97
Table H-5 Cost-effectiveness where NT ultrasound screening increases the
uptake of screening to 100% compared with 50% for biochemical
screeninga ..................................................................................................................98
Table H-6 Cost per trisomy 21 case detected where nuchal translucency
ultrasound screening substitutes for first trimester dating ultrasound
in 80 per cent of pregnanciesa ...............................................................................99
Table H-7 Cost-effectiveness analysis of NT ultrasound screening plus
biochemical screening in the first trimester compared with
biochemical screening in the second trimester with varying levels of
substitution for early ultrasound scanninga .........................................................99
Table H-8 Incremental cost-effectiveness of combined nuchal translucency
ultrasound plus biochemical screening and biochemical screening
alone under optimistic assumptions by age groupa ..........................................102
Nuchal translucency measurement in the first trimester of pregnancy
vii
Figures
Figure 1
Fetus with subcutaneous collection of fluid at the back of the neck ................ 2
Figure 2
Sonogram (top) and schematic (bottom) showing measurement of
nuchal translucency in an 11 week old fetus ......................................................... 3
Figure 3
Calliper placement on ultrasonographic images used in nuchal
translucency................................................................................................................ 4
Figure 4
Maternal age-specific prevalence of trisomy 21 at various gestational
ages .............................................................................................................................. 9
Figure 5
Risk for trisomy 21 for maternal age and nuchal translucency
thickness ...................................................................................................................10
Figure 6
Distribution of selected age ranges of the Australian female
population, nationwide and by State and Territory, June 2000 (per
cent of total women)...............................................................................................16
Figure 7
Frequency of trisomy 21 live births and stillbirths and total birth rate
for Australia, 1987–96 ............................................................................................16
Figure 8
Estimated frequency of trisomy 21 births (adjusted for terminations),
by maternal age (completed years) and sex in South Australia, 1960–
1989 ...........................................................................................................................17
Figure 9
Schematic of proposed screening pathway showing broad choices and
decisions available to the general population and expected outcomes ...........25
Figure 10 Frequency of amniocentesis services (MBS Item 16600) by State and
Territory, 1998–2000 ..............................................................................................26
Figure 11 Frequency of chorionic villus sampling (CVS) services (MBS Item
16603) by State and Territory, 1998–2000 ..........................................................26
Figure 12 Outline of the search, retrieval and selection process .......................................30
Figure 13 Estimated positive predictive value (PPV) and negative predictive
value (NPV) according to prevalence in the underlying populations..............47
viii
Nuchal translucency measurement in the first trimester of pregnancy
Executive summary
The procedure
Nuchal translucency (NT) refers to an ultrasound appearance that represents a
subcutaneous accumulation of fluid seen in the neck of all late first trimester fetuses.
Measurement of NT involves assessing the fetus in a similar plane to that used to
measure the Crown Rump Length (CRL). The measurement and accurate calliper
placement for an NT measurement is more prone to error than the CRL measurement
and its accuracy relies heavily on operator experience and machine quality. A sagittal
sonographic section of the fetus is acquired and the maximum reproducible thickness of
the subcutaneous translucency between the skin and the subcutaneous tissues is
measured. Measurement combined with maternal age and gestational age is used to
determine whether there is a relatively high or low of the fetus being affected by
trisomy 21 (also known as Down syndrome) in the fetus. Risk assessment for trisomy 18
and 13 is also calculated.
Medical Services Advisory Committee – role and approach
The Medical Services Advisory Committee (MSAC) is a key element of a measure taken
by the Commonwealth Government to strengthen the role of evidence in health
financing decisions in Australia. The MSAC advises the Commonwealth Minister for
Health and Ageing on the evidence relating to the safety, effectiveness and costeffectiveness of new and existing medical technologies and procedures, and under what
circumstances public funding should be supported.
A rigorous assessment of the available evidence is thus the basis of decision making
when funding is sought under Medicare. A team from the Australasian Cochrane Centre
and the Health Economics Unit of Monash University was engaged to conduct a
systematic review of literature and other available data on NT measurement and assess
the strength of the evidence. A supporting committee with relevant expertise was
established to ensure the assessment was clinically relevant and took into account
consumer interests. The supporting committee evaluated the evidence and provided
advice to the MSAC.
Nuchal translucency measurement in the first trimester of pregnancy
ix
MSAC’s assessment of nuchal translucency measurement
Clinical need
During the period from 1987 to 1996, the national rate of trisomy 21 was relatively
constant at about 12.8 per 10,000 births despite an ageing population of pregnant
women.
In 1999, about one in every 10 pregnant women had a prenatal diagnostic test. Although
diagnostic testing of women less than 35 years of age has been increasing, most
diagnostic tests relate to women aged 37 years or older. Moreover, diagnostic testing
continues to be performed in a large number of women for which there is no indication
other than ‘age’. In young women, maternal biochemical screening and ultrasound
screening for the detection of fetal abnormalities is increasingly used.
Safety
The literature on the safety of ultrasound in pregnancy is scant considering its
widespread use and acceptance. However numerous professional organisations have
released recommendations about the use of specific types of ultrasonic imaging
modalities based on maternal and fetal characteristics, and the potential for adverse
outcomes. Most advocate the prudent use of the technology, stressing the importance of
minimum output levels and exposure times.
Effectiveness
When used as a single modality, screening by measurement of NT in the first trimester
has a detection rate for trisomy 21 of approximately 73-82 per cent at a false positive rate
(FPR) of 5-8 per cent. For maternal biochemical screening, the comparable detection rate
using double markers ((pregnancy-associated plasma protein-A (PAPP-A) and free beta
human chorionic gonadotrophin (free β-hCG)) in the first trimester of pregnancy is
65 per cent at a FPR of 5 per cent. For maternal biochemical screening during the
second trimester, the detection rate is approximately 67-69 per cent using triple marker
testing (PAPP-A, free β-hCG and either alpha-fetoprotein (AFP) or unconjugated
oestriol (uE3)) and approximately 70 per cent using the quadruple marker test (PAPP-A.,
free β-hCG, AFP and uE3).
If used in combination in the first trimester, the detection rate with a 5 per cent FPR is
86 per cent for NT screening plus double markers, 87-88 per cent for NT screening plus
triple markers and 88 per cent for NT screening plus quadruple markers. While an
ultrasound examination at 11-13 weeks has a number of potential clinical benefits, this
analysis examines only the assessment of NT screening as an alternative to biochemical
screening for trisomy 21 as this is the most common cause of intellectual disability.
x
Nuchal translucency measurement in the first trimester of pregnancy
Cost-effectiveness
Complete and reliable information on current screening activity is unfortunately not
available. Therefore the cost-effectiveness of NT ultrasound screening has been
examined by comparing the expected cost of universal screening using each modality
compared with no screening. The cost of a universal maternal biochemical screening
program in the second trimester with 100 per cent uptake of pregnant women would be
approximately $21.3m. If a combined screening program (incorporating NT ultrasound
plus maternal biochemical screening in the first trimester) could achieve a 20 per cent
improvement in the detection rate of trisomy 21 compared with second trimester
biochemical screening, then this would cost $26.7 million more per year, with 253 more
trisomy 21 cases detected. This represents an incremental cost was $105,484 per extra
case detected.
However if screening was restricted to women aged 30 years or over, then the cost per
case detected would be one third less. If screening was restricted to women aged 35 years
or over, then the cost per case detected would be halved. Sensitivity analysis around the
main parameters of uncertainty suggested that, depending on the true detection rate in
practice and the extent of substitution for current ultrasound and follow-up diagnostic
tests in high risk pregnancies, the incremental cost per extra case detected would be
between $43,825 and $141,664.
When first trimester NT ultrasound screening alone is compared with maternal
biochemical screening in the second trimester, it costs an additional $12.5m and detects
an extra 188 cases of trisomy 21.
It is worth noting that none of the above cost effectiveness ratios considers the social
value of and cost of care for, a trisomy 21 birth. In addition, the report focuses on the
relative performance of different screening modalities in the detection of trisomy 21
although it is understood that the inclusion of other abnormalities detected by ultrasound
would most likely improve the cost effectiveness of NT screening.
Recommendations
The MSAC considers that nuchal translucency screening (NTS), and NTS in conjunction
with first trimester maternal biochemical screening (T1MBS), are safe and effective
where provided by individuals with appropriate expertise in NTS. Hence NTS providers
need to be appropriately accredited. However, the MSAC recommends that public
funding should not be supported for NTS or NTS in conjunction with T1MBS as stand
alone services, due to their poor cost-effectiveness.
Consideration should be given to public funding of NTS or NTS in conjunction with
T1MBS by incorporating, as far as possible, provision of the services into existing
services provided in early pregnancy.
The Minister for Health and Ageing accepted these recommendations on
16 October 2002
Nuchal translucency measurement in the first trimester of pregnancy
xi
Introduction
The Medical Services Advisory Committee (MSAC) has reviewed the use of nuchal
translucency (NT) measurement in the first trimester of pregnancy for screening of
trisomy 21 and other autosomal trisomies. The MSAC evaluates new and existing health
technologies and procedures for which funding is sought under the Medicare Benefits
Scheme in terms of their safety, effectiveness and cost-effectiveness, while taking into
account other issues such as access and equity. The MSAC adopts an evidence-based
approach to its assessments, based on reviews of the scientific literature and other
information sources, including clinical expertise.
The MSAC’s terms of reference and membership are shown in Appendix A. The MSAC
is a multidisciplinary expert body, comprising members drawn from such disciplines as
diagnostic imaging, pathology, surgery, internal medicine and general practice, clinical
epidemiology, health economics, consumer affairs and health administration.
This report summarises the assessment of current evidence for NT measurement in the
first trimester for screening of trisomy 21 and other autosomal trisomies.
Nuchal translucency measurement in the first trimester of pregnancy
1
Background
Nuchal translucency measurement in the first trimester of
pregnancy
The procedure
In the first trimester of pregnancy, the subcutaneous accumulation of fluid behind the
neck (Figures 1 and 2) was termed nuchal translucency (NT) due to features seen on
ultrasound (Brizot et al 1994, Nicolaides et al 1999a). Increased NT thickness was found
to be associated with chromosomal defects in a number of case series reports during the
last decade (Cullen et al 1990, Watson et al 1991, Shulman et al 1992, Suchet et al 1992,
van Zalen-Sprock et al 1992, Johnson et al 1993, Nadel et al 1993). As a result of this
finding, it was proffered that the measurement of NT might be a useful method in the
screening of trisomy 21. Together with data gathered from ultrasonographic studies
performed in the second trimester, these results formed the basis of the notion that NT
might be a useful component in screening for Trisomy 21.
Figure 1
Fetus with subcutaneous collection of fluid at the back of the neck
Source: Nicolaides et al (1999a)
The procedure involves techniques similar to the measurement of the fetal crown-torump length (CRL) with a sagittal sonographic section of the fetus viewed. The
maximum thickness of the subcutaneous translucency between the skin and soft tissue
overlying the cervical spine is then measured, with appropriate attention being given to
the distinction between the fetal skin and the amnion, as both structures appear as thin
membranes (Wald et al 1998).
The fetus must be away from the amniotic membrane for a measurement to be taken.
The fetus may be made to move by asking the pregnant woman to cough or by tapping
the maternal abdomen. Measurement is achieved by placing the ultrasound callipers on
the skin and soft tissue (Figure 3).
2
Nuchal translucency measurement in the first trimester of pregnancy
Figure 2
Sonogram (top) and schematic (bottom) showing measurement of nuchal translucency in
an 11 week old fetus
Source: Hyett et al (1999)
A few points of note are summarised below (Brizot et al 1994, Nicolaides et al 1999a,
Stewart and Malone 1999):
•
Techniques, procedures and criteria must be standardised to achieve uniform results
among different operators (Monni et al 1997, Blakemore 1998). Certification of
sonographers has been suggested as a prerequisite to the performance of the
procedure.
•
Personnel performing the ultrasonographic measurements should be able to reliably
measure the fetal CRL and obtain a proper sagittal image of the fetus. Braithwaite et
al (1996) suggested that an operator must have the ability to obtain accurate and
reproducible results over approximately 80 transabdominal scans and about 100
scans using the transvaginal route, while Roberts et al (1995) and Bewley et al (1995)
believe that external motivating factors may also have roles to play.
•
A transabdominal sonographic scan is the approach of choice in visualising the NT.
Abdominal and vaginal ultrasounds produce similar results, but while there is some
evidence that the use of a transvaginal probe improves reproducibility (Braithwaite
and Economides 1995), the use of the transvaginal probe has been limited to cases in
which the transabdominal approach has failed.
Nuchal translucency measurement in the first trimester of pregnancy
3
Figure 3
Calliper placement on ultrasonographic images used in nuchal translucency
Sources: Nicolaides et al (1999a) and Hyett et al (1999)
4
•
The image should be magnified such that the fetus occupies 75 - 100 per cent of the
scanned image. It is also important to increase magnification to a level where 0.1 mm
increments between the sonogram callipers can be identified.
•
The ideal fetal CRL length is between 45 and 79 mm. The optimal age of gestation is
between 11 weeks and 13 weeks and six days (Wald et al 1998, Nicolaides et al
1999a). The rates of success for taking NT measurements are inversely related to
gestational age, peaking at 98 - 100 per cent at 11 to 13 weeks and falling to about
90 per cent at 14 weeks (Braithwaite et al 1996, Whitlow and Economides 1998,
Nicolaides et al 1999a).
•
Measurements should be taken with the fetus in the neutral position. The position of
the fetal neck has been shown to influence the measurement of NT, with
hyperextension leading to increased sizes, and flexion to decreased sizes (Whitlow et
al 1998, Nicolaides et al 1999a).
Nuchal translucency measurement in the first trimester of pregnancy
•
The maximum thickness of the subcutaneous translucency should be measured by
placing the callipers on the fetal structures as shown in Figure 3 (Nicolaides et al
1999a, Herman et al 2000). At least three separate measurements should be obtained
and the mean value of these measurements reported (Stewart and Malone 1999).
•
Continuous assessment of the quality of processes and procedures is important
(Blakemore 1998) since operator variability is a potential problem (although a few
studies have demonstrated that inter- and intra-observer measurements vary by about
0.5 and 0.6 mm, respectively (Pandya et al 1995a, Pajkrt et al 1998, Schuchter et al
1998)). Herman et al (1998) recommend that regular reviews (audits) be instituted
using the quality of scanned images in terms of magnification, section, calliper
placement, and visualisation of the amnion separate from the nuchal membrane.
Information from the scan may be used to determine other outcomes, which includes
determination of fetal viability, detection of multiple pregnancies, dating of pregnancy
and identification of chorionicity as well as providing reassurance to parents on the fetal
status. An ultrasound can detect major fetal defects, which allows medical staff to be
forewarned.
Some abnormalities may be treated before birth and it is sometimes important to know
that an abnormality is present to allow a delivery to be brought early, thus helping to
minimise continuing damage from that abnormality before birth. Some abnormalities
detected on ultrasound may require urgent treatment at birth if the baby is to have the
best chance of healthy survival (de Crespigny and Dredge 1997).
This dating, viability and other information are currently obtained from the early
ultrasound scans (referred to in this report as ‘dating ultrasound scans’). A new
ultrasound marker, the status of the fetal nasal bone in the NT scan, has been observed.
A study by Cicero et al (2001) found that at 11-14 weeks of gestation, the nasal bone is
visible by ultrasonography in 99.5 per cent of chromosomally normal fetuses. The
absence of the nasal bone is not related to the NT thickness but is an independent
marker for trisomy 21. It has been suggested that the NT thickness and the nasal bone
markers can be combined to provide a substantial increase in sensitivity (Cicero et al
2001).
The results of the sonogram are used to arrive at an estimation of risk. The results of
other tests, as well as maternal factors including previous trisomy pregnancy, adjust these
estimates. This use of screening for risk assessment purposes, known as “risk screening”,
allows information from various sources to be combined into a common measure
(Cuckle 1994). Risk screening has its basis in statistical theory and thus has both
advantages and limitations (Royston and Thompson 1992, Wald et al 1996b). For
instance, empirical validation has corroborated aspects of the method, as well as
confirmed the importance of explicitly specifying both the underlying assumptions and
models used, and the quality of the data utilised in model generation. This is because of
their impacts on outcomes, recognising that any model has limits which temper
inferences that may be made (Cuckle et al 1987, Wald et al 1988, Royston and Thompson
1992, Wald et al 1996b).
Nuchal translucency measurement in the first trimester of pregnancy
5
Biochemical markers
Biochemical markers are currently being used to screen for trisomy 21 in both the first
and second trimesters. The most commonly used biochemical markers are alphafetoprotein (AFP), intact human chorionic gonadotrophin (hCG), unconjugated oestriol
(uE3) and free beta-hCG. AFP is a glycoprotein produced by the fetal yolk sac. Merkatz
et al (1984) first reported that maternal biochemical concentrations of AFP were
approximately 25 per cent lower in the presence of fetal Down syndrome compared to
unaffected singleton pregnancies. The decrease in AFP concentrations was shown to be
independent of maternal age and therefore AFP measurements have been combined to a
patient’s age related risk to compute an individualised risk for fetal trisomy 21 (Palomki
1987).
Human chorionic gonadotrophin is a glycoprotein made up of two subunits, an alpha
subunit and a beta-subunit (Morgan 1975) produced by the placental syncytiotrophoblast
(Kurman 1984). The subunits exist either in their free form or are non-covalently bound
to form intact hCG. The molecule is commonly measured as either intact human
chorionic hormone (hCH) or hCG plus free beta (total hCG), the role of the free alphasubunit of hCG in screening for trisomy 21 has not been fully defined (Loncar et al
1995). Levels of hCG appear in maternal blood soon after implantation and increase
rapidly until 8 weeks of gestation, remains constant to 12 weeks, declines to 18 weeks
and remains constant until term (Kletzky 1985). Bogart et al (1987) first reported a
raised maternal serum hCG associated with fetal trisomy 21. It is thought the association
is due to trisomy 21 fetuses being immature. Given that maternal serum levels of hCG
decline between 12-18 weeks of gestation, an immature trisomy 21 fetus will have a
higher concentration of hCG than an unaffected fetus (Chew 1995).
Oestriol is produced from fetal precursors by syncytiotrophoblasts and is secreted into
the maternal blood where levels rise progressively throughout gestation (Chew 1995). In
maternal serum it is measured as an unconjugated steroid. The association between low
second trimester uE3 levels and pregnancies with trisomy 21 was first observed by Canick
et al (1988). Once again it is thought that the association is due to trisomy 21 fetuses
being immature.
Other markers have also been considered useful in screening for trisomy 21, including
pregnancy-associated plasma protein-a (PAPP-A), the beta subunit of human chorionic
gonadotrophin (free β-hCG), and unconjugated oestriol (uE3) (Wald et al 1988, 1995,
1998), schwangerschaftsprotein 1 (SP1), cancer antigen 125 (CA-125), and dimeric and
α-inhibin (Wald et al 1998).
Schwangerschaftsprotein or pregnancy specific beta-1 glycoprotein is a non-hormonal
protein produced by the syncytiotrophoblast of the placenta. The association between
raised maternal serum SP-1 levels and trisomy 21 was first observed by Bartels and
Lindermann (1988).
CA-125 is an antigenic determinant on a high molecular weight glycoprotein. Hogdall et
al (1992) suggested that maternal CA-125 levels may be associated with fetal aneuploidy.
However a study by Van Blerk et al (1992) did not find a significant association between
trisomy 21 and CA-125 levels. The physiological role of CA-125 is not currently
understood (Chew 1995).
6
Nuchal translucency measurement in the first trimester of pregnancy
Inhibins are circulating dimeric glycoprotein hormones synthesised by the gonads and
the placenta (Haddow et al 1998a) and made up of several subunits. The alpha subunit
can combine with one of two beta subunits (beta-A and beta-B) to form inhibin A or
inhibin B. Van Lith et al (1992) found that inhibin levels in trisomy 21 pregnancies were
significantly higher than in unaffected pregnancies.
The philosophy of screening in pregnancy
Screening in pregnancy aims to provide couples with increased reproductive choice. It
should be voluntary and women should give informed consent. Screening in pregnancy is
defined as the application of a test to pregnancies where risk of a particular disorder to
the fetus is unknown. Screening tests alone cannot diagnose the disorder. Women whose
pregnancies are classified to be “at increased risk” are offered further evaluation by a
diagnostic test that can confirm or exclude the presence of the disorder in the fetus. If
the diagnostic test confirms the presence of the disorder, the prospective parents can
then decide whether or not to continue the pregnancy.
There are risks to the fetus and financial outlays associated with screening and
subsequent diagnostic procedures. While the concept of screening may appear
straightforward and beneficial, these risks and outlays must be rigorously evaluated when
considering a screening test.
Some diseases or conditions may not be suitable for the application of a screening
program. Moreover, broad criteria have been used to determine suitability relating to
issues of cost-effectiveness and ethics (Hennekens and Buring 1987). These include some
indication that the disorder is considered to be serious, has a significant prevalence in the
population to be screened, and a possibility of exercising reproductive choice if a fetus is
shown to be affected.
Screening procedures should be convenient, easy to apply, virtually free of discomfort or
risk, lead to a high level of case detection and a reasonably low level of false positive test
results (Rothman and Greenland 1998). These characteristics are also expected to apply
to further diagnostic tests that a person may undergo, although the sensitivity, specificity,
level of discomfort, and risk associated with these diagnostic tests are often higher.
When multiple screening tests are used, they may be applied sequentially or
simultaneously. Sequential screening, also called two-stage screening, usually involves a
less expensive, invasive and uncomfortable test initially. Those who screen positive then
undergo the second test, which usually has a greater sensitivity and specificity and is
usually more expensive, invasive and uncomfortable than the first test. The rationale
behind sequential testing is that the combination produces a reduction in false positive
rates (FPRs) and a higher net specificity (Gordis 2000).
Simultaneous testing, also called parallel screening, involves applying multiple screening
tests simultaneously. People are usually considered to have tested positive if they have a
positive result on one or more of the tests, and are considered to have tested negative if
they have a negative result on all of the tests. The rationale behind simultaneous testing is
achieving fewer false negatives and higher net sensitivity. The decision to use either
sequential or simultaneous testing is based on a number of practical considerations, the
objectives of the testing and the setting in which the testing is done (Gordis 2000).
Nuchal translucency measurement in the first trimester of pregnancy
7
The autosomal trisomies
Autosomal trisomies arise when individuals have 47 chromosomes, instead of the normal
number of 46. Trisomy occurs during the formation of a new individual. The most
common type of viable human trisomy is trisomy 21 (Down syndrome). Others include
trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome).
Trisomy 21 (Down syndrome)
Trisomy 21, or Down syndrome, is named after the English physician J. Langdon Down
(1826–96) who described its characteristics in 1866 (Down 1866, Booth 1985), although
isolated reports suggestive of the condition may be found as far back as the fifteenth
century (Smith and Berg 1976, Booth 1985). Trisomy 21 manifests as short stature;
brachycephaly (having a short head) and flattening of the skull along the antero-posterior
aspect; hypotonia (diminished skeletal muscle tone); upslanting palpebral fissures;
epicanthus (a fold of skin over the inner corner of the eye); tiny white spots (called
Brushfield spots) on the iris; flat-bridge nose; protruding tongue; small ears; short, broad
hands with deviation of the fifth finger (clinodactyly); and a single transverse palmar
crease (called the simian crease) formed by the fusion of the proximal and distal palmar
creases. Also associated with the condition are malformations of the cardiac and
gastrointestinal systems, intellectual handicap and increased risks for hydrocephalus,
cerebral palsy, epilepsy, hypothyroidism, leukaemia, and the early onset of Alzheimer’s
disease (Fort et al 1984, Franceschi et al 1990, McVicker et al 1994, Brookes and
Alberman 1996).
The historical development of screening for trisomy 21
In 1909, Shuttleworth reported on the association between increased maternal age and
the risk for trisomy 21 (Shuttleworth 1909). In the 1930s, Penrose presented incidence
data in five year maternal age intervals to support the claim that the probability of giving
birth to an infant with trisomy 21 rises rapidly after the age of 35. At about the same
time, chromosomal abnormalities were postulated to be associated with the condition.
Twenty five years later, Lejeune and colleagues demonstrated that the karyotype of
persons with trisomy 21 had a total chromosomal number of 47, later discovered to be
an extra copy of chromosome 21 (hence the term trisomy 21) (Lejeune et al 1959a, b).
Subsequent discoveries identified other forms of trisomy 21 arising from translocation
and mosaicism (Korenberg et al 1992). Since the mid 1960s, karyotyping of cells from
the amniotic fluid has been used to diagnose trisomy 21 (Steele and Breg 1966, Valenti et
al 1968).
Following the hypothesis put forth by Shuttleworth (1909) and the ability to diagnose
trisomy 21 through the use of karyotypes, the early 1970s saw the use of maternal age as
the screening criterion on which to recommend amniocentesis (Figure 4). The cutoff
maternal age for screening, first determined to be 40 years or older, was subsequently
reduced to between ages 35 and 37, following widespread acceptance of the concept and
general use of amniocentesis as a diagnostic technique. Overall, these potentially
identified about 30 per cent of the total population of trisomy 21 cases in the oldest 5 to
10 per cent of the total pregnant population at a FPR of 5 per cent (Wald et al 1998,
Nicolaides et al 1999b).
8
Nuchal translucency measurement in the first trimester of pregnancy
Kuppermann et al recently reviewed the historical bases of the 35 year cutoff age. They
suggested that four reasons led to the adoption of this specific policy in the late 1970s
(Kuppermann et al 1999):
•
the desire to restrict access to prenatal diagnostic services because of the limited
availability of providers who could perform the procedures and laboratories that
could conduct cytogenetic analyses (NICHHD 1979);
•
economic analyses suggesting that at this age prenatal diagnosis was “cost beneficial”
(i.e. the costs incurred by offering testing would be more than compensated for by
the savings associated with averting births of infants with Trisomy 21) (Hook and
Chambers 1977);
•
trisomy 21 incidence data showing an increase in risk at this maternal age
(Shuttleworth 1909, Penrose 1934, Hook and Chambers 1977); and
•
risk benefit considerations suggesting that ‘the risk for the disease should be greater
than the risk of the procedure’.
10
45 yrs
Log risk (%)
40 yrs
1
35 yrs
30 yrs
25 yrs
0.1
20 yrs
10
15
20
25
30
35
40
Gestational age (weeks)
Figure 4
Maternal age-specific prevalence of trisomy 21 at various gestational ages
Source: Snijders et al (1999b)
In the 1980s, the levels of certain maternal biochemical markers were found to be
different in trisomy 21 compared with unaffected pregnancies. The basis of the “triple
test” – composed of three maternal biochemical markers (alpha-fetoprotein, human
chorionic gonadotrophin, and unconjugated oestriol) – was used in conjunction with
maternal age to potentially identify about 60 per cent of trisomy 21 pregnancies in the
second trimester at an FPR of 5 per cent (Wald et al 1988, 1998, Nicolaides et al 1999a).
The discovery of other markers led to a proliferation of various combinations being
used.
Nuchal translucency measurement in the first trimester of pregnancy
9
At about the same time, the first report of an increase in the nuchal (neck) thickness in
trisomy 21 pregnancies during the second trimester was reported by Benacerraf et al
(1985). Correlates during the first trimester were found a few years later by Szabo and
Gellen (1990), eventually giving rise to a screening procedure that combined ultrasound
markers and maternal age (Nicolaides et al 1992).
Figure 5 shows the risk of trisomy 21 according to maternal age and NT thickness
(Taipale and Hiilesmaa 1999).
100
10
Log risk for trisomy 21
Age & NT > 4 mm
Age & NT = 4 mm
1
Age & NT = 3 mm
Age alone
0.1
Age & NT < 3 mm
0.01
20
25
30
35
40
45
Maternal age (years)
Figure 5
Risk for trisomy 21 for maternal age and nuchal translucency thickness
Source: Taipale and Hiilesmaa (1999)
Other trisomies
Trisomy 13
Trisomy 13 is a frequently lethal condition characterised by multiple congenital
abnormalities involving virtually every organ system. Eighty per cent of liveborn affected
babies die during the first month of life (Benacerraf 1998). Trisomy 13 occurs in about
one in every 5,000 births and, due to the high mortality, prevalence is low (Benacerraf
1998). The major diagnostic features of trisomy 13 are microphthalmia (small eyes),
holoprosencephaly (midline facial defects) including cleft lip and palate, and polydactyly
(extra digits) (de Grouchy and Turleau 1983). One or all of the three features may be
absent.
The syndrome may still be suspected if specific clinical features are found. Those
invariably present include profound mental and developmental handicap and
undescended testes. Those present in about 80 per cent of cases include hypertelorism
(abnormally increased distance between eyes) and low set ears.
10
Nuchal translucency measurement in the first trimester of pregnancy
In more than half of cases, the following features present:
•
•
•
•
•
•
•
•
•
•
•
•
•
jitteriness and apneic spells;
microcephaly (small head);
congenital heart disease including ventricular septal defects;
epicanthal folds (folds of skin over the inner corner of the eye);
presumptive deafness;
micrognathia (small jaw);
extra skin at the nape of a relatively short neck;
capillary hemangiomata (benign tumour involving blood vessels);
long and narrow hyperconvex nails;
retroflexible thumbs;
flexion deformities of the fingers;
single transverse palmar crease; and
prominent calcaneus (heel bone) (Buyse 1990).
Trisomy 13 is detectable in pregnancy by ultrasound and can be diagnosed prenatally by
chorionic villus sampling (CVS) or amniocentesis. Clinical examination and
chromosomal analysis can be used to diagnose infants. On autopsy, it is often diagnosed
without chromosomal analysis as, in addition to the different malformations, histological
evidence of organ abnormality in the central nervous system, eyes, pancreas, kidneys, and
ovaries are characteristic. The pancreatic abnormality is a very specific feature that
confirms the diagnosis (Buyse 1990). Prenatal sonographic detection has been established
at as early as 12 weeks gestation, based on the presence of holoprosencephaly.
The sonographic detection rate has been reported to be between 90 per cent and 100 per
cent when a complete structural survey (including the heart) is accomplished (Benacerraf
1998). Ease of detection is attributable to the severity of the defects and the number of
organ systems involved.
Trisomy 18
As with trisomy 13, trisomy 18 is also usually lethal with up to 90 per cent of liveborn
patients dying in their first year of life (Mange and Mange 1990). Trisomy 18 occurs in
about one in every 3,333 births. Due to high mortality the prevalence is low (Benacerraf
1998).
Nuchal translucency measurement in the first trimester of pregnancy
11
Trisomy 18 manifests as:
•
•
•
•
•
•
•
•
•
•
•
•
profound mental and developmental handicap;
undescended testes (all in 100 per cent of cases);
difficulty with sucking;
congenital heart disease (in more than 95 per cent of cases);
low-set, fawn like ears with pointed upper portions;
a long skull;
a narrow palate and small mouth;
small eyes;
a short sternum;
a single umbilical artery;
overlapping fingers with flexion deformity and simple arches on six or more digits;
a small, narrow pelvis and limited hip abduction (all in more than 80 per cent of
cases).
Certain features that occur more frequently and help diagnose trisomy 18 include:
•
•
•
•
•
•
•
•
•
•
•
•
•
heart and kidney defects;
hypertonia (increased tone of skeletal muscles);
high pitched cry;
prominent occiput;
meningomyelocele (hernial protrusion of the spinal cord);
webbed neck;
short sternum;
thinning of the diaphragm;
horseshoe kidney;
limited hip abduction;
distally implanted and retroflexible thumb;
simple arches on the fingertips; and
rocker-bottom feet (Buyse 1990).
Trisomy 18 can be diagnosed in pregnancy through CVS or amniocentesis. Sonographic
detection is possible in the early second trimester in 80 per cent of affected fetuses
(Benacerraf 1998).
12
Nuchal translucency measurement in the first trimester of pregnancy
Abnormalities detectable by ultrasound are:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
agenesis of the corpus callosum;
choroid plexus cysts;
posterior fossa abnormalities;
micrognathia;
low set ears;
microphthalmos;
hypertelorism;
short radial ray;
clenched hand with overlapping index finger;
clubbed foot or rocker-bottom feet;
renal anomalies;
omphalocele (congenital herniation of viscera into the base of the umbilical cord);
diaphragmatic hernia;
undescended testes;
heart defects;
intrauterine growth restriction;
polyhydramnios (excess of amniotic fluid); and
increased NT thickness (detectable in the first trimester).
Clinical examination and chromosomal analysis can be used to diagnose infants. There
are also characteristic fetal features that are suggestive of trisomy 18 such as a small
placenta, decreased fetal movement and small biparietal diameter of the fetal head (Buyse
1990). A dermatoglyphic inspection of the fingers and toes for simple arch patterns is
also used.
Nuchal translucency measurement in the first trimester of pregnancy
13
Other Conditions that can be Detected through Ultrasound Screening
There are a number of other conditions that are frequently picked up in obstetric
ultrasounds. These include:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ventriculomegaly (enlarged ventricles);
enlarged cisterna magna;
microcephaly;
agenesis of the corpus callosum;
cleft lip and palate;
midface hypoplasia (incomplete development);
cyclopia (eye orbits fused into one cavity containing one eye);
microphthalmia;
hypotelorism (abnormally decreased distance between the eyes);
nuchal thickening;
neural tube defects;
omphalocoele (protrusion of abdominal organs through a defect in the abdominal
wall);
echogenic enlarged kidneys;
echoic bowel;
echogenic chordae tendinaea and a single umbilical artery;
cardiac defects;
radial aplasia (absence of the radius); and
polydactyly (Benacerraf 1998).
Intended purpose
The ultrasonographic measurement of NT is proposed as a method of identifying fetuses
at risk for abnormalities, especially autosomal trisomies.
It is acknowledged that the scan may be used to determine other outcomes, including
dating of pregnancy, detection of multiple pregnancies, assessment of fetal viability,
identification of chorionicity, and detection of structural organ defects. Moreover, nearly
all cases of neural tube defects are detected by ultrasonography at 18 weeks of gestation.
This report focuses on the use of ultrasonography as a screening test during the first
trimester of pregnancy for trisomy 21.
14
Nuchal translucency measurement in the first trimester of pregnancy
Detection of chromosomal defects other than trisomy 21
A large multicentre study in the United Kingdom on trisomy 21 screening in the first
trimester of pregnancy (using maternal age and NT thickness) found almost as many
cases of other chromosomal defects as those of trisomy 21 (about 325 cases in each
group) (Snijders et al 1998). The results of the study are presented in Table 1.
Table 1
Distribution of trisomy 21 and other chromosomal abnormalities detected in a multicentre
trial of screening for trisomy 21 at 10 to 14 weeks of gestation using maternal age and
nuchal translucency thickness
Number of cases (%)
from a population
of 96,127
Number with NT thickness for CRL
above the 95th centile (%)
n=4,767
Trisomy 21
326 (0.34)
234 (71.78)
Other chromosomal abnormalities
Trisomy 18
Turner syndrome
Trisomy 13
Triploidy
Other abnormalitiesa
119 (0.12)
54 (0.06)
46 (0.05)
32 (0.03)
74 (0.08)
89 (74.79)
47 (87.04)
33 (71.74)
19 (59.38)
41 (55.40)
CRL = crown-to-rump length; NT = nuchal translucency
a Includes deletions, partial trisomies, unbalanced translocations and sex-chromosome aneuploidies
Source: Snijders et al (1998)
Sonographic findings (Nicolaides et al 1999a) associated with chromosomal
abnormalities include:
Trisomy 18 - intrauterine growth retardation (IUGR), bradycardia (heart beating more
slowly than normal), and exomphalos (protrusion of the umbilicus) (Sherod et al 1997);
Trisomy 13 - IUGR, failure of cleavage of the nascent prosencephalon resulting in
deficits in brain and midline facial development (holoprosencephaly), and exomphalos
(Snijders et al 1999);
Turner syndrome - tachycardia and IUGR (Sebire et al 1998); and
Triploidy - asymmetrical IUGR, bradycardia, holoprosencephaly, exomphalos, posterior
fossa cysts and molar changes in the placenta (Jauniaux et al 1997).
Clinical need and burden of disease
Figure 6 shows the relative distributions of resident female Australians by age and State
or Territory of residence as of June 2000. Nationwide, about 45.5 per cent of women
were aged between 15 and 45, 16.7 per cent were 35 – 45 years of age and 13.7 per cent
were between 37 and 45 years old. Of the women aged between 15 and 45, 36.8 per cent
were between the ages of 35 and 45 while 30.1 per cent were aged between 37 and 45.
There are also differences among States and Territories.
Nuchal translucency measurement in the first trimester of pregnancy
15
60
15 to 45
35 to 45
Percentage of female population (%)
37 to 45
50
40
30
20
10
0
Australia NSW
VIC
QLD
SA
WA
TAS
NT
ACT
Region
Figure 6
Distribution of selected age ranges of the Australian female population, nationwide and by
State and Territory, June 2000 (per cent of total women)
Source: Australian Bureau of Statistics (2000)
During the period from 1987 to 1996, the national rate of trisomy 21 was relatively
constant at around 12.8 per 10,000 births despite an older population of pregnant
women. The frequency of trisomy 21 births over the same period was also relatively
stable (Figure 7) (Hurst et al 1999).
400
350
15
Live births
Still births
Total birth rate
12
Frequency
250
9
200
6
150
Rate per 10,000 births
300
100
3
50
0
0
1987 1988 1989 1990 1991 1992 1993 1994 1995 1996
Year
Figure 7
Frequency of trisomy 21 live births and stillbirths and total birth rate for Australia, 1987–96
Source: Hurst et al (1999)
16
Nuchal translucency measurement in the first trimester of pregnancy
While national estimates are not available, Figure 8 shows the estimated frequency of
trisomy 21 births for South Australia after adjustment for prenatally diagnosed and
terminated trisomy 21 pregnancies (Staples et al 1991).
The sex distribution of trisomy 21 births was about 351 males (58.9%) to 245 (41.4%)
females, significantly different from the nontrisomy 21 live-birth sex distribution of 51.4
per cent males to 48.6 per cent females. Even after adjustment for terminated trisomy 21
pregnancies, the difference remains statistically significant.
50
45
Maternal age (years)
40
35
30
25
20
15
10
30
20
10
0
10
20
30
Trisomy births (frequency)
Figure 8
Estimated frequency of trisomy 21 births (adjusted for terminations), by maternal age
(completed years) and sex in South Australia, 1960–1989
Source: Staples et al (1991)
In August 2000, the Victorian Perinatal Data Collection Unit and the Murdoch
Children’s Research Institute released a report on the use of prenatal diagnostic testing in
the State during 1999. It highlighted the following findings (Webley and Halliday 2000):
•
about 8.7 per cent of all pregnant women giving birth in Victoria had a prenatal
diagnostic test done;
•
60 per cent of those having a test done were 37 years or older. However diagnostic
testing of women less than 35 years of age continues to increase;
•
a large number of women aged 35 to 36 continue to undergo diagnostic testing
despite no indication other than ‘age’ being reported;
•
twenty per cent of the women proceeding to diagnostic testing chose this course of
action on the basis of an abnormal ultrasound finding while another 9.5 per cent
were responding to an abnormal maternal biochemical test;
•
over half of abnormal ultrasounds reported abnormal NT measurements; and
•
109 fetuses with trisomy 21 were detected. An abnormal ultrasound was the
indication in 62 per cent of these cases. In women aged less than 35, trisomy 21 was
detected in 34 fetuses.
Nuchal translucency measurement in the first trimester of pregnancy
17
Table 2 shows the number of CVS and amniocentesis procedures in Victoria from 1989
to 1999 (Webley and Halliday 2000). In 1999, for the first time since 1989, there was a
decrease in the number of diagnostic procedures conducted in Victoria, mainly due to a
decrease in the number of CVS procedures performed in the State.
Table 2
Year
1989
Number of chorionic villus sampling and amniocentesis procedures,
Victoria, 1989–99
Chorionic villus sampling
694
Amniocentesis
Total
1,806
2,500
1990
916
1,861
2,777
1991
1,239
2,266
3,505
1992
1,448
2,383
3,831
1993
1,537
2,524
4,061
1994
1,559
2,823
4,382
1995
1,689
2,899
4,588
1996
1,957
3,036
4,993
1997
2,072
3,211
5,283
1998
2,179
3,121
5,300
1999
2,043
3,220
5,263
Source: Webley and Halliday (2000)
A majority of Victorian women undergoing prenatal diagnostic testing by CVS or
amniocentesis in 1999 did so due to advanced maternal age (i.e. being 37 years of age or
more) alone. Of those undergoing diagnostic testing due to abnormal ultrasound results,
52.5 per cent cited an abnormal NT measurement (Webley and Halliday 2000). These
findings are presented in Table 3.
Table 3
Indications for prenatal diagnostic testing by chorionic villus sampling or amniocentesis,
Victoria, 1999
Indication
Age of at least 37 as the only indication
37 to 39 years old
40 years or older
Subtotal
Other indications within current guidelines
Abnormal ultrasound
Abnormal nuchal translucency screening result
Fetal abnormality
Increased maternal biochemical screening result
Previous chromosome abnormality
Single gene disorder
History of chromosome rearrangement
History of neural tube defect
Repeat test
Other reasonsa
Subtotal
Chorionic villus
sampling
Amniocentesis
Total
694
452
1,146
1,089
524
1,613
1,783
976
2,759
444
368
76
1
112
74
21
0
5
5
662
598
178
420
502
33
6
13
5
32
19
1,208
1,042
546
496
503
145
80
34
5
37
24
1,870
a Includes infections in pregnancy (n=12), uniparental disomy test required (n=6), egg from older donor (n=2), risk of chromosome breakage
(n=1), and others (n=3)
Source: Webley and Halliday (2000)
18
Nuchal translucency measurement in the first trimester of pregnancy
Table 4 shows, by indication, the number of fetuses detected with trisomy 21 by CVS
and amniocentesis in Victorian women in 1999 (Webley and Halliday 2000). An
abnormal ultrasound was an indication for diagnostic testing in 62.4 per cent of fetuses
found to have trisomy 21. Of these, 50 per cent (34 of 68) were in pregnant women aged
37 or older.
Table 4
Indications for prenatal diagnostic testing via chorionic villus sampling or amniocentesis in
cases where trisomy 21 was diagnosed, Victoria, 1999
Chorionic villus
sampling
Indication and maternal age
Amniocentesis
Total
Abnormal ultrasound
Less than 35 years
35 to 36 years
37 to 39 years
40 years and above
12
3
12
13
16
3
3
6
28
6
15
19
Subtotal
40
28
68
Less than 35 years
35 to 36 years
37 to 39 years
40 years and above
0
0
1
15
6
6
8
5
6
6
9
20
Subtotal
16
25
41
56
53
109
Other indication
Total
Source: Webley and Halliday (2000)
The number of reported induced abortions performed after prenatal diagnosis of trisomy
21 by amniocentesis or CVS increased over the period 1987 to 1996, reaching a high of
130 in 1994 (Table 5). About 9.2 per cent of infants with trisomy 21 were stillborn and
3.9 per cent of those born alive subsequently died in the neonatal period.
Table 5
Frequency of reported outcomes of trisomy 21, Australia, 1987–96
Year
Stillbirths
Live births
Induced
abortions
Neonatal
deaths
1987
24
265
46
16
1988
21
282
55
8
1989
19
306
37
24
1990
29
312
71
8
1991
26
305
94
12
1992
42
277
113
5
1993
25
291
117
7
1994
41
261
130
11
1995
35
284
102
11
1996
27
255
113
9
Source: Hurst et al (1999)
State and Territory specific estimates of trisomy 21 from 1991 to 1996 are summarised in
Table 6. New South Wales, Victoria, and Queensland consistently accounted for about
80 per cent of all cases of trisomy 21 (Hurst et al 1999).
Nuchal translucency measurement in the first trimester of pregnancy
19
Rates in New South Wales were consistently greater than Australia-wide averages. In
1996, the rates of trisomy 21 in New South Wales and Queensland were more than
25 per cent above the national rate. In the ACT, rates were approximately 50 per cent
higher than the national rate in 1996.
Table 6
Frequency and rate of trisomy 21, by State and Territory
and nationally, 1991–96
State
1991–96
1995
1996
NSW
757 (14.4)a
148 (16.9)
132 (15.3)
VIC
494 (12.7)
85 (13.3)
55 (8.7)
QLD
379 (13.4)
58 (12.0)
75 (15.6)
WA
160 (10.5)
29 (11.4)
22 (8.6)
SA
121 (10.2)
25 (12.7)
16 (8.4)
TAS
44 (10.7)
7 (10.3)
2 (2.9)
ACT
44 (15.4)
6 (12.2)
9 (18.8)
NT
16 (7.5)
3 (8.2)
1 (2.9)
361 (13.9)
312 (12.1)
Australia
2,015 (12.9)
a Figures in parentheses are rates per 10,000 births
Source: Hurst et al (1999)
National estimates of the frequency and rate of pregnancy terminations following a
diagnosis of trisomy 21 over a four year period from 1993 to 1996 are shown in Table 7
(Hurst et al 1999).
Table 7
Frequency and rate of terminations of pregnancy following a diagnosis of trisomy 21,
Australia, 1993–96
Type of termination
1994
1995
1996
(4.5)b
130 (5.0)
106 (4.1)
116 (4.5)
Induced births (20 to 27 weeks)
20 (0.8)
25 (1.0)
17 (0.7)
4 (0.2)
All terminations (up to 27 weeks)
138 (5.3)
155 (5.9)
123 (4.7)
120 (4.7)
Induced abortions (< 20
1993
weeks)a
118
a Includes terminations at unstated gestational ages
b Figures in parentheses are rates per 10,000 births
Source: Hurst et al (1999)
Table 8 shows the frequency of terminations for trisomy 21 by gestational age in
Australia from 1993 to 1996. Although most terminations appear to occur between 16
and 21 weeks, data on a significant number of terminations did not allow determination
of gestational age. About 5 per cent of fetuses are terminated at less than 12 weeks and
another 5 per cent more than 22 weeks into the pregnancy (Hurst et al 1999).
20
Nuchal translucency measurement in the first trimester of pregnancy
Table 8
a
Frequency distribution of terminations of pregnancy for
trisomy 21 by gestational age, Australia, 1993–96
Gestational age (weeks)
Frequency (%)a
< 10
5 (0.9)
10–12
27 (5.0)
13–15
46 (8.6)
16–18
107 (20.0)
19–21
113 (21.1)
22–24
22 (4.1)
25–27
1 (0.2)
Unstated
215 (40.1)
All terminations
536 (100.0)
Frequencies in parantheses are percentages of all trisomy 21 terminations
Source: Hurst et al (1999)
About 80 per cent of infants with trisomy 21 survive to age five (Dupont et al 1986,
Baird and Sadovnick 1987, Hayes et al 1997) with about 40 per cent of survivors having
major health problems (Brookes and Alberman 1996). Despite this, life expectancy has
increased dramatically throughout the world (Merrick 2000). A study published in 1982
estimated the life expectancy of an individual with trisomy 21 to be about 35 years
(Thase 1982). More recent estimates indicate the average age at death to be about
55 years (compared with the general population average of 66 years) in a United States
cohort (Janicki et al 1999). Findings from this study also showed that, in spite of the
increased morbidity associated with the condition, adults with trisomy 21 had similar
causes of death to those of the general population. A Canadian cohort reported an
average life expectancy of 68 years for people with trisomy 21 (Baird and Sadovnick
1989).
Existing procedures
Diagnostic tests
The prenatal diagnosis of autosomal trisomies is made by amniocentesis or CVS. The
tests are reviewed briefly below. Safety issues are discussed in the Results section.
Amniocentesis
Amniocentesis was introduced in the 1880s as a surgical procedure to treat
polyhydramnios. In 1952, its first application as a diagnostic procedure was pioneered by
Bevis (1952), who used the technique in the prediction of haemolytic disease in the
newborn. Others soon showed that it was possible to determine the sex of the fetus
using the technique (Fuchs and Riis 1956).
Nuchal translucency measurement in the first trimester of pregnancy
21
In 1966, Steele and Breg demonstrated the feasibility of conducting karyotypic analysis of
amniotic fluid cells (Steele and Breg 1966). Shortly thereafter, both Valenti et al (1968)
and Nadler (1968) reported its use in the prenatal diagnosis of trisomy 21. It has since
become an integral part of obstetric care and is considered the gold standard of invasive
prenatal karyotyping procedures.
Amniocentesis involves the aspiration of a small amount of amniotic fluid from the
amniotic cavity through an ultrasound-guided percutaneous transabdominal puncture.
Karyotyping of cellular material and biochemical tests are then performed to establish
diagnoses. The procedure is traditionally carried out after 15 weeks of gestation. In the
late 1980s, a technique called “early amniocentesis” was introduced, allowing for the
collection of amniotic fluid before 15 weeks of gestation (Drugan et al 1988, Evans et al
1988).
Chorionic villus sampling (CVS)
CVS involves the ultrasound-guided insertion of a needle transabdominally or a catheter
transcervically to aspirate a sample of placental tissue. Its use was suggested in the late
1960s (Mohr 1968) and was performed by direct endoscopic observation (Kullander and
Sandahl 1973, Hahnemann 1974) or blindly (Horwell et al 1983) prior to the advent of
ultrasound.
CVS permits cellular karyotyping to be performed in the first trimester. It is generally
accepted that the lower limit of gestational age for sampling is about 10 weeks although
its use as early as the sixth week of pregnancy has been reported (Brambati et al 1991,
Brambati 1992). CVS has the risk of inducing oromandibulofacial limb (OMFL)
hypogenesis syndrome (involving craniofacial and limb abnormalities) in genetically
normal infants where it is carried out too early in pregnancy. The malformations are
thought to be due to lack of oxygen to developing tissues from either fetal blood loss or
thrombus formation at the site of biopsy (WHO and PAHO 1999, Kaufman and Chang
2000).
Maternal biochemical markers
Biochemical testing has had an established place in screening for trisomy 21 (Loncar et al
1995, Muller and Bussieres 1996) since the first biochemical marker, alpha-fetoprotein
(AFP) was found to be lower in serum taken from women with autosomal trisomy
pregnancies (Merkatz et al 1984). Recent reviews have suggested the usefulness of
pregnancy-associated plasma protein-a (PAPP-A), the beta subunit of human chorionic
gonadotrophin (free β-hCG), and unconjugated oestriol (uE3) (Wald et al 1988, 1995,
1998). Other markers of interest include total and alpha (α) hCG,
schwangerschaftsprotein 1 (SP1), cancer antigen 125 (CA-125), and dimeric and αinhibin (Wald et al 1998).
The use of particular markers or combinations of markers in screening for trisomy 21 has
been studied at different times during pregnancy (Table 9). In Australia, first trimester
biochemical screening uses PAPP-A and free β-hCG.
22
Nuchal translucency measurement in the first trimester of pregnancy
Table 9
Number of primary studies examining the use of selected
maternal biochemical markers in the screening of trisomy 21
according to trimester of pregnancy
Maternal biochemical marker
First trimester
Second trimester
uE3
9
21
AFP
26
38
CA-125
2
5
PAPP-A
12
3
Free α-hCG
6
7
SP1
6
7
α inhibin
2
4
Dimeric inhibin A
3
6
Total hCG
14
28
Free β-hCG
17
12
uE3 = unconjugated oestriol; AFP = alpha-fetoprotein; CA-125 = cancer antigen 125;
PAPP-A = pregnancy-associated plasma protein-a; hCG = human chorionic gonadotrophin; SP1 = schwangerschaftsprotein 1
Source: Wald et al (1998), Cuckle and van Lith (1999)
International recommendations
Existing international recommendations, position papers, and best practice guidelines are
described in Appendix D.
Fetal Medicine Foundation
The UK-based Fetal Medicine Foundation (FMF) is supported by the International
Society of Ultrasound in Obstetrics and Gynecology. The FMF conducts a process of
training, certification and audit to ensure a high standard for NT scanning.
The FMF awards certificates of competence to sonographers who have attended a
theoretical course and passed relevant practical examinations.
More specifically the FMF’s process of certification in the 11-14 week NT scan includes:
•
attendance at a theoretical course;
•
submission of a logbook of 50 images of NT measurements for assessment by the
FMF; and
•
a practical examination in the measurement of NT at a recognised training centre.
The conditions for continued involvement in the FMF program are:
•
submission of an automated six monthly audit report that details the distribution of
NT measurements for each accredited centre;
•
submission of a back-up disc for a more detailed annual audit; and
•
submission of five images of NT measurements, along with the back-up, each year.
Nuchal translucency measurement in the first trimester of pregnancy
23
The certification is open to anyone involved in obstetric ultrasound, including
obstetricians, radiologists, radiographers and midwives. Only by complying with the
regulations will an individual remain certified in the measurement of NT by the FMF
(FMF 2000). Evidence that this results in increased detection rates was provided by
Stewart and Malone (1999), who compared detection rates from FMF-affiliated centres
with other independent centres (72% versus 50% respectively).
Australian centres
The FMF has accredited 121 centres in Australia (Table 10). Pooled preliminary data
from two centres, the Melbourne Ultrasound for Women and Sydney Ultrasound for
Women, suggest that Australian screening results are comparable with those reported for
the FMF. O’Callaghan et al (2000) published an evaluation of 2,000 cases presenting for
trisomy 21 risk estimation via first trimester ultrasound measurement of NT in
Newcastle, New South Wales. Over a period of two years from September 1997, the
authors followed the progress (either to birth or termination) of the first 1,000 cases,
calculating a screen-positive rate of about 6.8 per cent using a risk cutoff of 1 in 300. Of
11 fetuses or babies with cytogenetically proven chromosomal abnormalities, eight were
trisomy 21, two were trisomy 18, and one was 47 XXX. Of these 11 cases, nine screened
positive with both of the exceptions being cases of trisomy 21.
Recent estimates from regular FMF audits of Australian centres note that of 48,117 scans
reported, 150 cases of trisomy 21 were detected with a detection rate of 87 per cent
(Amanda Sampson, member of the supporting committee for MSAC Reference 04a,
personal communication, 2002). A list of centres accredited by the FMF appears in
Appendix I.
Table 10
Distribution of Australian centres accredited by the Fetal Medicine Foundation to conduct
nuchal translucency measurements, by State or Territory
State
a
24
Number of centres (%)a
NSW
47 (39)
VIC
30 (25)
QLD
18 (15)
WA
16 (13)
TAS
2 (2)
SA
4 (3)
NT
0 (0)
ACT
4 (3)
Total
65 (100)
Calculated from information provided by Ann Robertson, Special Projects Officer, RANZCOG, personal communication,
August 2002
Nuchal translucency measurement in the first trimester of pregnancy
Comparators
For the purposes of this evaluation it was decided to compare NT screening with second
trimester biochemical screening and also with first trimester biochemical screening where
data were available. The diagnostic characteristics of both NT and biochemical screening
procedures were compared when used as stand-alone tests and when used in
combination. The screening pathway that was used in this evaluation is shown in
Figure 9.
CVS = chorionic villus sampling; NT = nuchal translucency
Figure 9
Schematic of proposed screening pathway showing broad choices and decisions available
to the general population and expected outcomes
Data gained during the NT or biochemical screening procedure can be combined with
information on other relevant factors (such as the mother’s age and clinical history) to
arrive at an overall risk estimate. Depending on the result, a woman may choose to
undergo a more definitive yet invasive test such as amniocentesis or CVS.
Nuchal translucency measurement in the first trimester of pregnancy
25
Current reimbursement arrangements
Figure 10 shows the frequency of amniocentesis services by State and Territory
according to Health Insurance Comission (HIC) statistics from July 1998 to June 1999
and July 1999 to June 2000. However, these figures do not include procedures performed
in the public sector for which no Medicare rebate was paid. The frequency of CVS
services is shown in Figure 11.
1998-1999
1999-2000
Australian States & Territories
TAS
ACT
SA
WA
QLD
VIC
NSW
0
1000
2000
3000
4000
Frequency of amniocentesis services
Figure 10
Frequency of amniocentesis services (MBS Item 16600) by State and Territory, 1998–2000
Source: Health Insurance Commission (2000)
1998-1999
1999-2000
Australian States & Territories
ACT
TAS
SA
WA
QLD
VIC
NSW
0
1000
2000
3000
4000
Frequency of CVS services
Figure 11
Frequency of chorionic villus sampling (CVS) services (MBS Item 16603) by State and
Territory, 1998–2000
Source: Health Insurance Commission (2000)
26
Nuchal translucency measurement in the first trimester of pregnancy
Table 11 shows the frequencies of relevant items from the Medicare Benefits Schedule
(MBS). Data relating to corresponding items obtained through the public sector were not
available.
Table 11
MBS
Item
numbera
Number of services in calendar year 2000 for specific Medicare item numbers
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Total
35639
97
89
116
92
107
71
96
77
87
119
121
100
1,172
35640
1,412
1,550
2,064
1,596
2,061
1,794
1,916
2,273
1,825
1,737
2,050
1,710
21,988
35643
6,217
6,341
6,776
4,985
6,500
6,138
6,044
7,140
6,076
6,534
6,422
5,805
74,888
55054
2,304
2,802
3,170
2,766
3,372
3,415
3,422
4,112
3,742
3,849
3,904
3,391
40,249
55704
–
2, 994
5, 341
4,485
6,024
5,376
5,163
5,980
5,605
5,800
5,769
5,040
57,577
55705
–
431
1,192
826
1,153
999
969
1,085
1,074
960
1, 102
951
10,742
55706
–
6,440
10,656
8,973
13,190
11,674
10,764
12,858
12,671
13,481
13,492
11,593
125,792
2,918
3,365
2,520
3,943
3,735
4,038
4,433
4,243
4,520
4,485
3,431
45,216
66740
3,585
– = data not available
a Item numbers:
35639: Uterus, curettage of [by a General Practitioner], with or without dilatation (including curettage for incomplete miscarriage) under general
anaesthesia or under epidural or spinal (intrathecal) nerve block where undertaken in a hospital or approved day hospital facility, including
procedures to which item 35626, 35627 or 35630 applies, where performed;
35640: Uterus, curettage of [by a specialist], with or without dilatation (including curettage for incomplete miscarriage) under general
anaesthesia or under epidural or spinal (intrathecal) nerve block where undertaken in a hospital or approved day hospital facility, including
procedures to which item 35626, 35627 or 35630 applies, where performed;
35643: Evacuation of the contents of the gravid uterus by curettage or suction curettage not being a service to which item 35639 or 35640
applies, including procedures to which item 35626, 35627 or 35630 applies, where performed;
55054: Ultrasonic cross-sectional echography, in conjunction with a surgical procedure using interventional techniques, not being a service
associated with a service to which any other item in this group applies;
55704: Pelvis or abdomen, pregnancy related or pregnancy complication, fetal development and anatomy, ultrasound scan of, by any or all
approaches, performed by or on behalf of a medical practitioner, where: (a) the patient is referred by a medical practitioner; and (b) the dating
of the pregnancy (as confirmed by ultrasound) is 12 to 16 weeks of gestation; and (c) the service is not associated with a service to which an
item in subgroup 2 or 3 of this group applies; and (d) the referring practitioner is not a member of a group of practitioners of which the first
mentioned practitioner is a member; and (e) one or more of the following conditions are present: (i) hyperemesis gravidarum; (ii) diabetes
mellitus; (iii) hypertension; (iv) toxaemia of pregnancy; (v) liver or renal disease; (vi) autoimmune disease; (vii) cardiac disease; (viii)
alloimmunisation; (ix) maternal infection; (x) inflammatory bowel disease; (xi) bowel stoma; (xii) abdominal wall scarring; (xiii) previous spinal or
pelvic trauma or disease; (xiv) drug dependency; (xv) thrombophilia; (xvi) significant maternal obesity; (xvii) advanced maternal age; (xviii)
abdominal pain or mass (xix) uncertain dates; (xx) high risk pregnancy; (xxi) previous post dates delivery; (xxii) previous caesarean section;
(xxiii) poor obstetric history; (xxiv) suspicion of ectopic pregnancy; (xxv) risk of miscarriage; (xxvi) diminished symptoms of pregnancy; (xxvii)
suspected or known cervical incompetence; (xxviii) suspected or known uterine abnormality; (xxix) pregnancy after assisted reproduction; (xxx)
risk of fetal abnormality);
55705: Pelvis or abdomen, pregnancy related or pregnancy complication, fetal development and anatomy, ultrasound scan of, by any or all
approaches, where: (a) the patient is not referred by a medical practitioner; and (b) the dating of the pregnancy (as confirmed by ultrasound) is
12 to 16 weeks of gestation; and (c) the service is not associated with a service to which an item in subgroup 2 or 3 of this group applies; and
(d) one or more of the following conditions are present: (i) hyperemesis gravidarum; (ii) diabetes mellitus; (iii) hypertension; (iv) toxaemia of
pregnancy; (v) liver or renal disease; (vi) autoimmune disease; (vii) cardiac disease; (viii) alloimmunisation; (ix) maternal infection; (x)
inflammatory bowel disease; (xi) bowel stoma; (xii) abdominal wall scarring; (xiii) previous spinal or pelvic trauma or disease; (xiv) drug
dependency; (xv) thrombophilia; (xvi) significant maternal obesity; (xvii) advanced maternal age; (xviii) abdominal pain or mass; (xix) uncertain
dates; (xx) high risk pregnancy; (xxi) previous post dates delivery; (xxii) previous caesarean section; (xxiii) poor obstetric history; (xxiv)
suspicion of ectopic pregnancy; (xxv) risk of miscarriage; (xxvi) diminished symptoms of pregnancy; (xxvii) suspected or known cervical
incompetence; (xxviii) suspected or known uterine abnormality; (xxix) pregnancy after assisted reproduction; (xxx) risk of fetal abnormality;
55706: Pelvis or abdomen, pregnancy related or pregnancy complication, fetal development and anatomy, ultrasound scan (not exceeding one
service in any one pregnancy) of, by any or all approaches, with measurement of all parameters for dating purposes, where: (a) the patient is
referred by a medical practitioner; and (b) the dating for the pregnancy (as confirmed by ultrasound) is 17 to 22 weeks of gestation; and (c) the
service is not associated with a service to which an item in subgroup 2 or 3 of this group applies; and (d) the referring practitioner is not a
member of a group of practitioners of which the first mentioned practitioner is a member; and (e) the service is not performed in the same
pregnancy as item 55709;
66740: Quantitation, in pregnancy, of alpha-fetoprotein, human chorionic gonadotrophin, oestriol and any other substance to detect foetal
abnormality, including a service described in one or more of items 66743, 66746, 73527 and 73529 (if performed) - one patient episode in a
pregnancy.
Source: Commonwealth Department of Health and Aged Care (1999).
Nuchal translucency measurement in the first trimester of pregnancy
27
Approach to assessment
Review of literature
This review follows methods outlined in the Cochrane Collaboration Handbook (Clarke
and Oxman 1999), the recommendations of the Cochrane Methods Group on Systematic
Reviews of Screening and Diagnostic Tests (Cochrane Methods Group 1996), and other
published guidelines on the assessment of diagnostic tests (Irwig et al 1994).
Literature search
The medical literature was searched to identify relevant studies and reviews for the
period between 1966 and 2000. Searches were conducted using the databases shown in
Table 12 and the search terms within Table 13.
Table 12
Electronic databases (including edition) used in the review
Database
Period covered
Best Evidence (Ovid)
1991 to March/April 2000
Biological Abstracts (Ovid)
1980 to June 2000
CINAHL (Ovid)
1982 to April 2000
Cochrane Library, including the Cochrane Database of Systematic Reviews, the Database
of Abstracts of Reviews of Effectiveness, the Cochrane Controlled Trials Register, the
Health Technology Assessment database, and the NHS Economic Evaluation database
Issue 2, 2000
HealthSTAR
1975 to May 2000
Journals@Ovid
1993 to 2000
Medline (Ovid)
1966 to July 2000
National Guidelines Clearinghouse
June 2000
Science Citation Index
June 2000
Table 13
Search terms used to identify citationsa
Safety
(((prenatal or pre-natal or antenatal or ante-natal) and ultrasound) or (ultrasound and pregnancy))
and (adverse event or safety)
(amniocentesis or chorion villus sampling) and (((first trimester or second trimester) and pregnancy)
or ((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or screening)))
((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or screening)) and (anxiety or
attitude to health or patient acceptance of health care)
Ethics
((ethics or ethical) and ((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or
screening)))
Effectiveness
(((((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or screening)) or ((prenatal or prenatal or antenatal or ante-natal) and ultrasound)) and (neck and first trimester pregnancy))
(((((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or screening)) or ((prenatal or prenatal or antenatal or ante-natal) and ultrasound)) and (pregnancy associated plasma protein A or
human chorionic gonadotrophin or unconjugated oestriol or alpha-fetoprotein or cancer antigen 125
or dimeric inhibin A or alpha inhibin)
Cost-effectiveness
a
28
(((prenatal or pre-natal or antenatal or ante-natal) and (diagnosis or screening)) or ((prenatal or prenatal or antenatal or ante-natal) and ultrasound)) and (cost or cost-effectiveness))
Terms were searched as text words. A medical subject heading (MeSH) term search was conducted if allowed by the database
Nuchal translucency measurement in the first trimester of pregnancy
Electronic searching included the Internet sites of the following health technology
assessment groups:
• International Society of Technology Assessment in Health Care;
• International Network of Agencies for Health Technology Assessment (and 28
•
•
•
•
•
•
•
•
•
•
member organisations);
British Columbia Office of Health Technology Assessment (Canada);
German Health Technology Assessment Project;
Center for Medical Technology Assessment (Sweden);
Scottish Health Purchasing Information Centre (Scotland);
Medical Technology and Practice Patterns Institute (USA);
National Institutes of Health (NIH) Office of Medical Applications of Research
(USA);
Office of Technology Assessment Archive (USA);
RAND Corporation (USA);
University HealthSystems Consortium (USA); and
the Veterans Affairs Technology Assessment Program (USA).
Relevant textbooks and book chapters were also obtained and read. Reference lists of
publications were scanned and pertinent citations retrieved.
Entry criteria
Collected citations were filtered through a multilevel review process involving a team
with skills in clinical medicine, public health, health information, basic science, clinical
epidemiology and biostatistics. Articles were excluded if they met any of the following
criteria:
•
focus was not on the measurement of NT or biochemical screening for trisomy 21 in
the first or second trimesters of pregnancy;
•
studies enrolled fewer than 10 subjects;
•
studies neither presented data on the diagnostic characteristics of NT or biochemical
screening nor contained data data from which these characteristics could be derived;
•
articles included data published in later studies; or
•
publications were in a language other than English.
Figure 12 summarises the process of article selection and exclusion. An initial assessment
of abstracts of collected citations selected out articles that did not meet inclusion criteria.
Ambiguous or uncertain citations proceeded to the next stage. From the initial search of
1,269 articles there were 1,065 articles rejected. This left 204 articles to be assessed in full
text form.
Nuchal translucency measurement in the first trimester of pregnancy
29
The full text of the remaining citations was retrieved for further assessment. Any final
decision made to reject a given article was based on a thorough reading of the complete
article. Only the studies that successfully passed through all stages of this process are
discussed in this report (138 studies).
Initial search
1,269 articles
Initial rejection
1,065 articles
Full-text
assessment
204 articles
Final rejection
66 articles
Articles accepted
138 articles
Figure 12
Outline of the search, retrieval and selection process
Data extraction
The review extracted data from the included articles using an instrument created for this
assessment. Two independent reviewers examined each article with differences in
opinion resolved through consensus.
Assessment of quality
All accepted articles underwent an assessment of study quality based on criteria that
focus on important aspects of study design (Table 14).
30
Nuchal translucency measurement in the first trimester of pregnancy
Table 14
a
Criteria for validity
Criterion
Description
Possible ratings
A
Was the test compared with a valid reference standard?
Yes, No, Unclear
B
Were the test and reference standard measured independently (blind) of each other?
1 – 5a
C
Was the choice of patients who were assessed by the reference standard independent
of the test’s results?
Yes, No, Unclear
D
Was the test measured independently of all other clinical information?
Yes, No, Unclear
E
Was the reference standard measured before any interventions were started with
knowledge of test results?
Yes, No, Unclear
Rating scale used is: 1 = test measured independently of reference standard and reference standard independently of test;
2 = test measured independently of reference standard but not vice versa; 3 = reference standard measured independently of test but not
vice versa; 4 = test and reference standard not measured independently of each other; 5 = unclear
Source: Cochrane Methods Group (1996)
The review assessed evidence presented in the selected studies and classified it according
to the National Health and Medical Research Council (NHMRC) revised hierarchy of
evidence (Table 15).
Table 15
Designation of levels of evidence
I
Evidence obtained from a systematic review of all relevant randomised controlled trials.
II
Evidence obtained from at least one properly designed randomised controlled trial.
III-1
Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other
method).
III-2
Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort
studies), case-control studies or interrupted time series with control group.
III-3
Evidence obtained from comparative studies with historical control, two and more single arm studies or interrupted
time series without a parallel control group.
IV
Evidence obtained from case series, either post-test or pre-test and post-test.
Source: NHMRC (2000)
Conduct of meta-analysis
Methods to assess heterogeneity in meta-analyses of diagnostic test accuracy are not fully
developed. When the degree of homogeneity was acceptable on clinical grounds,
summary estimates were derived using a random-effects model (DerSimonian and Laird
1986). Standard statistical convention was followed and a type I error (the probability of
detecting a difference when one is not actually present) was assumed for all analyses to
be 5 per cent (α=0.05).
Nuchal translucency measurement in the first trimester of pregnancy
31
Expert advice
Contact with primary authors and experts, in Australia and internationally, was initiated
to supplement evidence drawn from the literature search.
A supporting committee with expertise in obstetrics and gynaecology, clinical
biochemistry, general practice, public health and consumer issues was established to
evaluate the evidence and provide advice to the MSAC from a clinical perspective. In
selecting members for supporting committees, the MSAC’s practice is to approach the
appropriate medical colleges, specialist societies and associations for nominees.
Membership of the supporting committee is provided at Appendix B.
32
Nuchal translucency measurement in the first trimester of pregnancy
Results of assessment
Is it safe?
There are two key safety issues relating to NT measurement that need to be considered.
These relate to the use of ultrasound in pregnancy and issues surrounding follow-up
diagnostic tests for trisomy 21. A brief discussion of relevant psychological and ethical
issues is also provided in this report.
Safety of ultrasound in pregnancy
The literature focusing on the safety of ultrasound in pregnancy is scant relative to its
widespread use and acceptance, although it is expected that major adverse events would
have come to light due to the ubiquitousness of the procedure. Miller et al (1998) raised
concerns regarding studies having been conducted on older devices that did not have the
power outputs of more modern equipment.
US National Institutes of Health Consensus Development Program
In 1984, the NIH and the Food and Drug Administration (FDA) Center for Devices and
Radiological Health convened a joint Consensus Development Conference to examine
the use of diagnostic imaging in pregnancy (Anonymous 1984). The theoretical risks
posed by ultrasound to the fetus and the pregnant woman were among the many
questions considered.
The panel of experts conducted extensive reviews of the available primary literature and
examined reports by the FDA, the Bureau of Radiological Health, the World Health
Organization, and the National Council on Radiation Protection and Measurement. The
panel observed that while epidemiological studies tended to support the safety of
diagnostic ultrasound exposure in humans, with observed teratologic effects in animal
studies seemingly due to exposure to significant hyperthermia, the effects were too
important to be ignored. The panel recommended that further studies be conducted to
determine the effects of ultrasound on biological systems, with the aim of identifying risk
estimates applicable to human fetal development.
European Federation of Societies for Ultrasound in Medicine and Biology and the
World Federation of Ultrasound in Medicine and Biology
A clinical safety statement released by the European Federation of Societies for
Ultrasound in Medicine and Biology (EFSUMB) in 1998 noted that modern ultrasound
equipment is subject to regulation of output signals (Anonymous 1998a).
Nuchal translucency measurement in the first trimester of pregnancy
33
Provided that equipment meets international or specific national safety requirements and
is used by competent and trained personnel, the EFSUMB makes the following
recommendations:
•
there is no reason to withhold B- or M-mode scans for any clinical application,
including the routine clinical scanning of every woman during pregnancy;
•
pulsed Doppler at maximum machine outputs and colour flow imaging with small
colour boxes have the greatest potential for biological effects. In general, the
informed use of Doppler ultrasound is not contraindicated. However, significant
thermal effects on bone surfaces could not be excluded, especially at maximum
machine outputs. Limited exposure of critical structures including regions of bone
and gas is recommended; and
•
until further scientific information is available, prudence in limiting exposure of
critical structures such as the fetal skull or spine during pulsed or colour Doppler
scans, should be observed.
In a subsequent statement published in the same year, the World Federation of
Ultrasound in Medicine and Biology (WFUMB) endorsed similar statements on the
biological effects of ultrasound (Anonymous 1998b). Relevant observations include:
34
•
known diagnostic ultrasound equipment that is used for simple B-mode imaging,
operates at acoustic outputs that are not capable of producing harmful temperature
rises. Its use in medicine is, therefore, not contraindicated on thermal grounds. This
includes endoscopic, transvaginal and transcutaneous applications; and
•
some Doppler diagnostic equipment has the potential to produce biologically
significant temperature rises, specifically at bone/soft tissue interfaces. The effects of
elevated temperatures may be minimised by keeping the time for which the beam
passes through any one point in tissue, as short as possible. Where output power can
be controlled, the lowest available power level consistent with obtaining the desired
diagnostic information should be used. Although the data on humans are sparse, it is
clear from animal studies that exposures resulting in temperatures less than 38.5°C
can be used without reservation on thermal grounds. This includes obstetric
applications.
Nuchal translucency measurement in the first trimester of pregnancy
Based on the EFSUMB and WFUMB statements, international consensus was achieved
on the following recommendations:
•
•
•
Thermal effects
–
a diagnostic exposure that produces a maximum in situ temperature rise of no
more than 1.5°C above normal physiological levels (37°C) may be used clinically
without reservation on thermal grounds;
–
a diagnostic exposure that elevates embryonic and fetal in situ temperature above
41°C (4°C above normal) for five minutes or more should be considered
potentially hazardous;
–
for diagnostic ultrasound systems that are capable of producing a tissue
temperature increase greater than 1.5°C above normal, users should be provided
with worst-case estimates of likely temperature increase for all pertinent
operating modes;
–
the risk of adverse effects from heating increases with the duration of exposure.
Thus, safety guidelines should include an appropriate duration factor; and
–
care should be taken to avoid unnecessary additional embryonic and fetal risk
from ultrasound examinations of febrile patients.
Non thermal effects
–
the possible occurrence of cavitation, either inertial or non-inertial, should be
considered in assessing the safety of diagnostic or other forms of medical
ultrasound; and
–
caution is required in applying results of studies on in vitro ultrasound biological
effects, to medical ultrasound exposures in vivo.
Education
–
diagnostic ultrasound has the potential to produce both false positive and false
negative results. Misdiagnosis is far more dangerous than any effect that might
result from ultrasound exposure. For this reason diagnostic ultrasounds should
only be performed by people with sufficient training.
American Institute of Ultrasound in Medicine
The American Institute of Ultrasound in Medicine (AIUM) noted that ‘there are no
confirmed biological effects on patients or instrument operators caused by exposures
from present diagnostic ultrasound instruments. Although the possibility exists that such
biological effects may be identified in the future, current data indicate that the benefits to
patients of the prudent use of diagnostic ultrasound outweigh the risks, if any, that may
be present’ (AIUM 2000).
Nuchal translucency measurement in the first trimester of pregnancy
35
Australasian Society for Ultrasound in Medicine
In late 1998 the following safety statements and recommendations were endorsed by the
Australasian Society for Ultrasound in Medicine (ASUM 1998):
36
•
grey scale imaging (by transcutaneous and transvaginal routes) is a well established
procedure in diagnostic medicine. Nevertheless care should be exercised to ensure
that examinations are performed prudently using the ALARA (as low as reasonably
achievable) principle of applying the lowest acoustic output and dwell time necessary
to obtain the necessary diagnostic information;
•
diagnostic exposure that produces a maximum temperature rise of 1.5°C above
normal physiological levels may be used without reservation in clinical examination;
•
diagnostic exposure that elevates embryonic or fetal temperature above 41°C
(i.e. 4°C above normal body temperature) for five minutes or more should be
considered potentially hazardous; and
•
due to the potential for hyperthermia, duplex/Doppler ultrasound in febrile patients
might present an additional embryonic or fetal risk.
Nuchal translucency measurement in the first trimester of pregnancy
Table 16
Issue
Summary of published recommendations by major international organisations on the safety of
diagnostic ultrasound
ASUM
WFUMB
B-mode
Exercise prudent use. Not contraindicated on
thermal grounds when
no gas is present.
Doppler
Use ALARA output
and dwell time,
particularly when
bone or gas is
present.
Exposure
levels
User should pay
attention to output or
risk indicator.
Thermal
effects
As per WFUMB +
effects of heating
reduced by
minimising duration of
exposure.
Duplex/Doppler in
febrile patients may
present additional risk
to the fetus or
embryo.
Nonthermal
effects
Presence of contrast
agents should be
considered in
benefit/risk
assessment of
ultrasound
examinations.
First trimester
exposure
Use lowest available
power consistent with
obtaining good
diagnostic information.
Minimise time that the
beam passes through
one point.
EFSUMB
AIUM
ODS/FDA
Prudent use involves
minimum output
levels and exposure
times.
Refer to ODS.
FDA upper intensity
limit: ophthalmic
exposures at
<50 mW/cm2; others
at <720 mW/cm2.
Temperature rises
≤1.5°C (38°C) can be
used without
reservation. Obstetric
exposures resulting in a
temperature increase of
4°C for 5 minutes or
more are potentially
hazardous.
At the FDA regulatory
limit, the maximum
temperature increase
in the conceptus can
exceed 2°C.
FDA does not
regulate TI. For
general use, TI
should be <6.
When gas (including
contrast agents) is
present, exposure
levels and duration
should be reduced to
the minimum to obtain
required information.
The threshold value
of MI for
extravasation of
blood cells in mouse
lungs is
approximately 0.3.
For general use, MI
should be <1.9.
Absence of
knowledge about first
trimester ultrasound
exposures means
that care is required
in application of
transvaginal
ultrasound in early
pregnancy.
Epidemiology
Insufficient evidence
of a causal
relationship between
diagnostic ultrasound
and adverse effects.
Other
Non medical use
discouraged.
AIUM = American Institute of Ultrasound in Medicine; ALARA = as low as reasonably achievable; ASUM = Australasian Society for Ultrasound in Medicine;
EFSUMB = European Federation of Societies for Ultrasound in Medicine and Biology; FDA = Food and Drug Administration; MI = mechanical index; ODS =
output display standard; TI = thermal index; WFUMB = World Federation of Ultrasound in Medicine and Biology
Source: Barnett et al (2000)
Nuchal translucency measurement in the first trimester of pregnancy
37
International recommendations and guidelines
Barnett et al (2000) summarised published recommendations by major organisations
(Table 16). They also identified gaps in which they believed research and policy to be
required as follows:
Use of ultrasound in the first trimester
There is no published international policy on the safe use of ultrasound to examine
uncomplicated pregnancy in the first trimester.
Effects on the human central nervous system
• Biological effects on the central nervous system may be found when sufficiently
sensitive end points are used. Careful examination is needed to determine the
possibility of adverse developmental effects and to establish whether there is a
plausible epidemiological link to ultrasound exposure; and
• Data are needed on human exposures at the levels currently available for obstetric
examinations.
Non clinical use of ultrasound imaging
It would be appropriate for an international authority to develop guidelines since there is
no agreed policy on clinically unnecessary, possibly inappropriate, uses of ultrasound.
International Society for Ultrasound in Obstetrics and Gynecology
The International Society for Ultrasound in Obstetrics and Gynecology (ISUOG)
released a statement in 2000 affirming the recommendations that various organisations
had previously made. The ISUOG stated that:
•
real time B-mode imaging is not contraindicated for routine clinical scanning of every
pregnant woman;
•
the risk of damage to the fetus due to teratogenic agents such as heat, is great in the
first trimester. Exposure time and output should be kept to the lowest levels
consistent with obtaining diagnostic information and be limited to medically
indicated procedures; and
•
education of ultrasound operators is of the utmost importance.
Primary studies on second trimester exposure
As previously noted, primary studies retrieved by the search focused on its use in the
second trimester of pregnancy. The use of ultrasound in pregnancy has been
hypothesised to be associated with increased risks of intrauterine growth retardation and
low birth weight, childhood malignancies, delays in neurological development, and poor
school performance (Pastore et al 1999, Ziskin 1999).
38
Nuchal translucency measurement in the first trimester of pregnancy
Newnham et al (1993) studied 2,834 pregnant Western Australian women in a
randomised controlled trial (RCT) examining the effects of intensive ultrasound and
continuous Doppler flow imaging (at gestational ages of 18, 24, 28, 34 and 38 weeks)
versus a single scan at 18 weeks. Further scans were conducted only at the request of a
clinician. Women attending the public antenatal clinic at King Edward Memorial
Hospital or the nearby private practices between May 1989 and November 1991 were
enrolled. One of the criteria for enrolment was a gestational age of between 16 and 20
weeks. Ultrasound examinations were conducted by qualified sonographers.
Measurements were made of the fetal biparietal and occipitofrontal diameters, head
circumference, abdominal circumference, and femur length. The amniotic fluid volume
was classified into one of five categories and the placental morphology and location
carefully described. After the ultrasound, each woman in the intensive group had further
biometry with amniotic fluid index calculated and umbilical cord and placental sites
recorded. Systolic/diastolic ratios were determined from waveforms in the umbilical and
arcuate arteries located within the placental vascular bed. Details of pregnancies,
deliveries, and neonatal outcomes were taken from hospital notes. The allocation of each
newborn to birth weight percentiles was done with charts that take into account
variations based on maternal height, parity and fetal sex. Poor obstetric history was
defined as three or more first trimester abortions, one or more second trimester
abortions, a perinatal death or a preterm birth. Obstetric intervention was defined as
induction of labour or elective caesarean section.
Those receiving more frequent ultrasound examinations were found to be at increased
risk of delivering infants with lower birth weights. Compared with controls, these women
were 35 per cent (95% confidence interval (CI)=9, 67%; P=0.006) more likely to deliver
babies at less than the 10th percentile for weight. The authors suggest that this is more
likely to be due to restrictions in bone growth rather than to a reduction in placental
nutrient supply (Evans et al 1996). Results from follow-up of the infants showed that the
differences in birth weight were no longer present at one year of age. Weight and length
at one year were similar between the groups, with babies exposed to more frequent
ultrasound examinations in the womb gaining weight more rapidly postnatally than those
in the control group (Macdonald et al 1996).
Larger studies have failed to support this finding (Ziskin 1999). Using a database of more
than 13,000 pregnancies, Grisso et al (Grisso et al 1994) found no suggestion of an
increased risk for low birthweight in women having ultrasound during the first two
trimesters of pregnancy. An RCT in Sweden enrolling 4,637 singleton pregnancies
concluded that ultrasound exposure had no impact on childhood growth rates (Kieler et
al 1997). A meta-analysis published in 1999 similarly failed to uncover an association
(Salvesen and Eik-Nes 1999a).
Nuchal translucency measurement in the first trimester of pregnancy
39
An association between ultrasound exposure and childhood cancers has not been
demonstrated. In a matched case-control study enrolling 1,284 children in China, Shu et
al (1994) failed to detect an association between ultrasound exposure and acute
leukaemia, brain tumours, lymphomas or other childhood neoplasms. A population
based case-control study using Swedish birth, death and cancer registers from 1973 to
1989 found that children with myeloid leukaemia were just as likely to have been exposed
to ultrasound during the perinatal period as controls (odds ratio (OR)=0.85; 95%
CI=0.62, 1.16) (Naumburg et al 2000). Results were similar for children with lymphatic
leukaemia (OR=1.00; 95% CI=0.42, 2.40). Two other studies in the mid-1980s likewise
failed to demonstrate an association (Cartwright et al 1984; Kinnier, Wilson and
Waterhouse 1984). A recent meta-analysis has also confirmed this conclusion (Salvesen
and Eik-Nes 1999a).
There is mixed information regarding the effect of ultrasound on neurological
development in infants and children. A small case-control study in Canada found that
children with delayed speech (as evaluated by a speech pathologist) were almost three
times more likely than controls to have been exposed to ultrasound during the perinatal
period (OR=2.8; 95% CI=1.5, 5.3; P=0.001) (Campbell et al 1993).
In another study from Sweden, 3,265 children of mothers participating in an RCT of
ultrasound screening during pregnancy were followed up until the age of nine. In selfreports, parents did not detect delays in the development of their child’s speech, motor
function or behaviour. The study failed to find any association between exposure to
ultrasound and neurological deficits. Odds ratios for exposure to ultrasound versus non
exposure were 1.19 for delayed speech (95% CI=0.79, 1.88) and 1.08 for delayed motor
development (95% CI=0.83, 1.40) (Kieler et al 1998a). Similar long term follow-up of
2,011 children of subjects enrolled in two RCTs of routine ultrasonography in pregnancy
in Norway failed to detect significant differences in school performance. Selected
indicators were scores for reading, spelling, arithmetic and overall performance (as rated
by the children’s teachers who were blinded to exposure status) as well as the incidence
of dyslexia (Salvesen et al 1992).
While not in itself an adverse event, there is some evidence from randomised controlled
trials (Kieler et al 1998b) and a meta-analysis (Salvesen and Eik-Nes 1999b) that suggests
an association between perinatal ultrasound exposure and an increased incidence of non
right-handedness, especially in boys.
Risks associated with trisomy 21 diagnosis
Most of the available comparative data focusing on amniocentesis and CVS are derived
from studies conducted in the 1980s. Expert clinical opinion suggests that these results
do not reflect current experience in Australia.
Amniocentesis
Severe or life threatening adverse events from amniocentesis are extremely rare. Minor
medical problems are not as infrequent, with two to three per cent of women in a US
national registry reporting transient vaginal spotting or amniotic fluid leakage following
the procedure (NICHHD Study Group 1976). Both are self-limiting and generally
require only expectant management and reassurance.
40
Nuchal translucency measurement in the first trimester of pregnancy
Following the procedure, there is a 0.5-1 per cent risk of spontaneous abortion above the
natural background loss rate for a given age of gestation (NICHHD Study Group 1976,
Tabor et al 1986).
Chorionic villus sampling
Two studies examining the fetal loss rate associated with CVS have given inconsistent
results. A Canadian RCT (Lippman et al 1992) did not find a statistically significant
difference in fetal loss rate in women assigned to CVS compared to those receiving
amniocentesis. However, a European trial enrolling women across 31 centres in the
United Kingdom, the Netherlands, Finland, Denmark, Switzerland and Germany showed
statistically significantly higher rates in those having CVS (MRC 1991).
While CVS is known to be more technically demanding than amniocentesis, with a
steeper learning curve (Brambati et al 1990, Silver et al 1990), both require technical
competence in medical and nursing staff (Brambati 1992). Obstetricians performing the
procedure should have adequate training and experience to be able to successfully obtain
tissue samples at the initial attempt in about 99 per cent of cases (Brambati 1992).
A systematic review by Alfirevic et al (2000) compared classic amniocentesis with CVS
using data from three large trials and the combined experience of about 9,000 women.
Differences in maternal complication rates were apparent but none were life threatening.
There were no differences in the rates of neonatal complications such as stillbirths or
neonatal deaths. While some technical difficulties were reported, recent data collected by
various Australian hospitals show a trend of decreasing laboratory failure rates for both
CVS and amniocentesis, as well as decreasing rates of mosaicism. Maternal cell
contamination rates have also fallen, with this drop attributed to greater experience in the
operators providing the samples.
Psychological issues associated with screening for trisomy 21
Patients often view screening as a means of reassurance rather than a way of identifying
risk of abnormality, and they usually do not have a omprehensive understanding of the
meaning of test results (Roelofsen et al 1993, Smith et al 1994). Screening tests can be
perceived to be completely accurate and most patients are not aware of their limitations
(Hall et al 2000). When patients receive negative test results, some believe that this rules
out the possibility of an affected pregnancy (Hall et al 2000). In the same way, a positive
test result can be perceived to be confirmation of an affected pregnancy. It is important
that patients undergoing a screening test are given appropriate information and personal
support so that misunderstandings and patient anxiety are better managed.
Mulvey and Wallace (2000) studied 100 women on their first antenatal visit to the
Monash Medical Centre to assess their knowledge and attitudes regarding screening for
trisomy 21. The women had limited knowledge of trisomy 21 and of the available
screening and diagnostic tests. When informed, the majority of women expressed a clear
preference for first trimester screening tests for trisomy 21, regardless of the rate of
miscarriage of trisomy 21 pregnancies between 10 and 15 weeks of gestation (Mulvey and
Wallace 2000).
Nuchal translucency measurement in the first trimester of pregnancy
41
For parents, the psychological issues associated with screening for trisomy 21 are anxiety
and, on confirmation of a positive test result, emotions such as shock, disbelief, anger,
resentment, bitterness, hostility, fear, loneliness and helplessness (Department of Human
Services 2000). Having a child with a disability affects the whole family. Some common
problems include pressure on the parents’ relationship with mothers often providing
most of the care and fathers feeling left out. Fathers may miss out on support groups
because they are at work. Siblings are also affected with many becoming resentful
because they get less parental attention (Department of Human Services 2000).
Table 17 lists studies that assess pregnant women’s experiences with screening tests for
trisomy 21. In particular, they assessed women’s emotional well being in terms of anxiety
and depression levels. All these studies have shown that, to some degree, screening
causes anxiety. This is inevitable as screening identifies individuals with an increased risk
of a serious medical disorder. Several authors have regarded anxiety as an adverse
outcome, but it can only be interpreted as such if it is excessive and could have
responsibly been avoided. While it is difficult to ascertain what level of anxiety the
subjects experienced, it is clear from the studies that the degree of anxiety can be
lessened by properly informing women of the risks and limitations of the screening tests
and through appropriate counselling (Statham and Green 1993).
42
Nuchal translucency measurement in the first trimester of pregnancy
Table 17
Reference
Review of studies on the effects of prenatal screening for trisomy 21 on parental psychological
outcomes and behaviours
Participants
Results
Main conclusions
Hall et al (2000)
Parents of trisomy 21 children born
from January 1992 to December
1993 were sampled from the National
Down Syndrome Cytogenetics
Register. After completion of five
steps to obtaining informed consent
from eligible parents, a final sample
of 179 mothers (86 with a false
negative result, 59 not offered a test,
and 34 having declined a test) and
122 fathers (55 with a false negative
result, 44 not offered a test, and 23
who had declined a test) was
available. Seven mothers and six
fathers did not complete the
adjustment measures.
Overall, regardless of screening history, parents
adjusted well to having a child with trisomy 21.
Mothers in the false negative group had higher
parenting stress and more negative attitudes towards
their children than mothers who declined the test.
Fathers in the false negative group had higher
parenting stress scores than fathers not offered a test.
Parents in the false negative group were more likely to
blame others for this outcome than parents who had
declined the test. Blaming others was associated with
poorer adjustment in both mothers and fathers.
A false negative result on
prenatal screening seems to
have a small adverse effect
on parental adjustment which
is evident two to six years
after the birth of an affected
child.
Goel et al (1998)
2,418 pregnant women in eight
geographically diverse sites across
Ontario. 2,020 (83.5%) were enrolled
with 1,741 (86.2%) completing the
follow-up. Baseline assessment was
taken at 15 to 18 weeks gestation
and follow-up at 24 weeks gestation.
1,177 (67.6%) underwent maternal serum screening.
No overall adverse psychological effects as a result of
testing were found at 24 weeks gestation. Women with
a false positive result had a mean increase in anxiety
score of 1.6, whereas women with a true negative
result had a mean decrease of 1.1. Women who were
not tested had a mean decrease of 0.4. The mean
depression score increased by 0.5 in the false positive
group, was unchanged in the true negative group, and
increased by 0.2 in the group not tested.
The results suggest that
maternal serum screening in
Ontario is not causing serious
psychological harm to
women.
Santalahti et al
(1996)
45 women with positive screening
results were enrolled. Two women
who underwent termination of
pregnancy after the diagnosis of
abnormality and one patient who had
a miscarriage after amniocentesis
were excluded. 46 controls (either
with negative screening results or
who were not screened) were
matched for age, parity, education
and previous miscarriages.
Of the remaining 42 case women, 7 decided not to
undergo further diagnostic tests, 2 had second serum
testing with a normal result and 33 had amniocentesis
or chorionic villus sampling. The positive screening
result and wait for the final results negatively affected
most of the 33 women and 6 were still worried after
receiving final reassuring results.
Receiving a positive serum
screening result has a
negative influence on
women’s emotional well
being.
Williamson et al
(1996)
621 women older than 38 years
identified from the National Down
Syndrome Cytogenetics Register
from 1990 to 1991 who had
pregnancies known to involve trisomy
21. In 577 (93%) cases, sufficient
details were available to allow the
distribution of a questionnaire to a
named obstetrician. Questionnaires
were completed (providing details
based only on documentation in the
antenatal case notes) on 430
pregnancies (75%).
The outcome of pregnancy was a termination in 268
(62%) cases, a live born child with trisomy 21 in 144
(34%) instances, a stillbirth for 9 (2%) patients, and a
miscarriage on 8 (2%) occasions. The outcome was
not known in one case. Prenatal diagnosis was not
offered in 7% of pregnancies, with late booking given
as the main reason. Of women offered prenatal
diagnosis, 76% accepted. There was no report of a
normal fetus having been terminated as a
consequence of incorrect prenatal diagnosis.
However, in 10% of cases examined in the laboratory,
the diagnosis of trisomy 21 could not be confirmed.
The results suggest late
booking was the main factor
precluding the offer of
prenatal diagnosis to women
older than 38 years in the
UK. The rate of confirmation
of trisomy 21 in terminated
fetuses was incomplete.
Thornton et al
(1995)
1,691 women booking antenatal care
before 15 weeks gestation were
randomised to three groups: control
(routine information, n=587),
individual information (n=561), and
class information (n=563).
Attendance at classes was lower than at individual
sessions (OR=0.45). Uptake of screening for trisomy
21 was slightly increased when extra information was
offered individually (OR=1.45). Offer of individual
information reduced anxiety later in pregnancy and
had no adverse effects. Women offered extra
information had improved understanding and were
more satisfied with the information they received.
The results suggest that the
offer of extra information
does not cause undue
anxiety and reduces the
uptake of blood tests when
background uptake rate is
high (but not when it is low).
High uptake of prenatal blood
tests suggests compliant
behaviour and the need for
more information.
Kidd et al (1993)
Women less than 30 years of age
presenting for antenatal care at less
than 16 weeks of pregnancy. 309
were tested and 30 were not.
21 of 309 did not think that they had been tested;
seven of 30 who were not tested thought they had
been. There were no significant differences between
the groups in anxiety, certainty or worry about the
baby’s health.
The results suggest that
receipt of a negative result
does not provide
reassurance.
Nuchal translucency measurement in the first trimester of pregnancy
43
Table 17 (contd) Review of studies on the effects of prenatal screening for trisomy 21 on parental psychological
outcomes and behaviours
Reference
Participants
Results
Main conclusions
Smith et al (1994)
353 women at less than 18 weeks
gestation who attended one of five
hospitals in the UK that offered
routine serum screening for trisomy
21.
72% of women knew the screening test was a blood
test, and 89% knew it was performed between 16 and
18 weeks of pregnancy. 32% knew that most women
with positive results have normal babies and 38%
knew that the test screened for trisomy 21.
Screening program
counselling did not manage
the women’s information
needs adequately,
particularly the implications of
screening results.
Roelofsen et al
(1993)
Group A were women younger than
36 years who were not eligible for
prenatal diagnosis (n=105). Group B
were women aged 36 years or more
who were eligible for prenatal
diagnosis and who underwent either
chorionic villus sampling or
amniocentesis but not serum
screening (n=155).
Group A – 80% of respondents opted for the serum
screening test either for reassurance (32%) or
because it was the “obvious thing to do” (26%). 65%
were not aware of possible drawbacks. 60% were
satisfied with the information given. More than 70%
would have accepted amniocentesis if they were found
to be at increased risk.
Serum screening was seen
as a means of reassurance.
Statham and Green
(1993)
20 women who contacted Support
After Termination For Abnormality
about their experiences of serum
screening for trisomy 21.
All women were made anxious by their positive
screening test regardless of who told them. The
women’s experiences suggested that medical staff
were unclear about the implications of screening tests
and risk interpretation. Some women remained
anxious even after a negative amniocentesis result.
Staff did not always recognise women’s concerns
while awaiting amniocentesis results.
Implementation of serum
screening does not always
meet the needs of women
that receive positive results.
Appropriate support for
participants should be
ensured before screening is
offered.
Marteau et al (1992)
Women younger than 38 years who
had undergone maternal serum
alpha-fetoprotein screening, including
346 women who received a negative
result and 26 women who received
an initial positive result. 637 were
excluded for failure to complete
questionnaires.
Women who received initially positive results had
higher levels of anxiety than women who received
negative results. Women with initial positive results
who went on to have amniocentesis were less worried
about their baby’s health than those who did not have
the amniocentesis.
Initial positive results were
associated with high levels of
anxiety. The results suggest
that amniocentesis can
reduce anxiety following an
abnormal AFP result.
Keenan et al (1991)
Controls (n=25) were women
younger than 35 years with normal
maternal serum alpha-fetoprotein
results. Cases were 52 women
younger than 35 years with low levels
of alpha-fetoprotein.
Anxiety was significantly lower in the control group
than the group with low AFP before and after
counselling. Counselling reduced anxiety in women
with low AFP whether or not amniocentesis was
performed.
Although the increased
anxiety level may persist at
least until a definite
chromosomal diagnosis by
amniocentesis, this initial
anxiety can be reduced
through comprehensive
genetic counselling.
Group B – 55% would apply for serum screening for
future pregnancy. 76% would accept amniocentesis if
at higher risk.
AFP = alpha-fetoprotein; OR = odds ratio
Several studies have identified that health professionals often provide inadequate
counselling support and are poorly informed, which can result in additional anxiety to
patients (Marteau et al 1992b, Khalid et al 1994, Smith et al 1995, Sadler 1997). One of
the ultimate choices of a screening test is termination of a pregnancy, with the personal
feelings of health professionals sometimes affecting their objectivity in counselling
(Khalid et al 1994). Inadequate training and the ethical dilemmas of health professionals
can affect patient outcomes and should be considered when managing a screening
program.
Screening tests for trisomy 21 provide the opportunity to inform parents of the
likelihood of birth of an affected child. This can lead to counselling about the
consequences of the condition, allowing more informed decisions to be made about
optimal care. The usefulness of the information derived from screening depends on
parental preferences (Reed et al 1988) and has been found to be associated with the
parents’ views on the acceptability of induced abortion and the perceived risk of the fetal
abnormality.
44
Nuchal translucency measurement in the first trimester of pregnancy
This perception of risk often plays a major role in any subsequent decisions and may
sometimes outweigh the actual probability of the occurrence (Ekwo et al 1987, Drugan et
al 1990, Evans et al 1990, Marteau et al 1991).
Generally, this translates to the observation that the majority of women whose fetuses
are diagnosed as having trisomy 21 seek elective terminations of the pregnancy (DiMaio
et al 1987, Lustig et al 1988, Wald et al 1988, Haddow et al 1992, Phillips et al 1992,
Spencer and Carpenter 1993, Morris et al 1994).
The long term psychosocial consequences of second trimester termination of pregnancy
for fetal abnormalities were examined in 84 women and their spouses two years after the
event (White-van Mourik et al 1992). Most couples reported a state of emotional turmoil,
with about 20 per cent of the women still experiencing regular bouts of crying, sadness
and irritability. Husbands reported increased listlessness, loss of concentration, and
irritability for up to 12 months after the termination. Confusing and conflicting feelings
often led to social isolation and lack of communication (White-van Mourik et al 1992).
Ethical issues associated with screening for trisomy 21
Screening during the prenatal period raises many important ethical concerns that relate to
the pregnant woman and fetus. Most experts agree that before screening tests are
performed, a clear statement of goals must be defined. Studies must show that these
goals can be achieved with acceptable costs and benefits, that the population to be
screened is informed about the issues, and that traditional standards of informed consent
and confidentiality are maintained (Gross et al 1983, Fost 1992).
Stranc et al (1997) noted four broad issues that apply to the dilemmas arising from
prenatal screening and diagnosis:
•
Attitudes towards disability. Pressures acting on the parents to decide on termination or
acceptance of a child with ‘preventable’ disability (or disability in general) must be
explored. Decisions must be made about the degree of defect beyond which
termination of the pregnancy is to be considered.
•
Clarity of benefit. The reason prenatal testing is to be performed must be made clear.
The accrual of benefit to certain stakeholders must be understandable.
•
Freedom of choice. Prenatal diagnosis is an option exercised voluntarily by the patient.
However, the physician may be required, either by law or by professional policy, to
inform high risk patients of its availability.
•
Prioritisation. Choices may be limited by economic, as well as medical, constraints.
The authors concluded that, while society may wish to reach a shared understanding of
the bearing these diagnosed conditions have on the population, it will not be easy to
reach this understanding (Gordon 1995, Mori et al 1995, Schafer et al 1995, Eisenberg
and Schenker 1997).
Nuchal translucency measurement in the first trimester of pregnancy
45
Is it effective?
How is the effectiveness of screening and diagnostic tests measured?
Diagnostic test results may be summarised in two-by-two tables as in Table 18. A
screening test must be able to discriminate between those with disease and those without
disease. In this discussion, we arbitrarily define a ‘positive’ test result as one in which
disease status is implied, given a particular cutoff defined by the authors. Individuals who
test positive for the disease in follow-up diagnostic testing are represented in cell ‘a’ and
are called true positives (TPs). Individuals without the disease who test negative (the ‘d’
cell) are called true negatives (TNs).
The result of a screening test may not reflect the actual disease status. When this occurs a
false result is reported. These situations are illustrated by cells ‘b’ and ‘c’ in Table 18. In
the case of the former (b), the test is positive in individuals without the disease; in the
latter case (c), the test is negative in diseased individuals. These two sets of false results
are called false positives (FPs) and false negatives (FNs), respectively.
Table 18
The generic relationship between results of a screening procedure and disease status
Screening test results
True disease status
Diseased
Not diseased
Total
Positive
a
b
a+b
Negative
c
d
c+d
Total
a+c
b+d
a+b+c+d
a = number of diseased individuals detected by the test; b = number of individuals without disease detected by the test;
c = number of diseased individuals not detected by the test; d = number of individuals without disease not detected by the test;
a+b = total number of individuals testing positive; c+d = total number of individuals testing negative; a+c = total number of diseased individuals;
b+d = total number of individuals without disease; a+b+c+d = total number of individuals studied
Test accuracy is measured using four primary variables: sensitivity (Sen), specificity (Spe),
positive predictive value (PPV), and negative predictive value (NPV). Sensitivity, also
known as detection rate (DR), is the proportion of diseased individuals who test positive.
It is a measure of the probability of correctly diagnosing a case, or the probability that
any given case will be identified by the test. Referring to Table 18:
DR =
a
TP
=
a + c TP + FN
Specificity is the proportion of individuals without disease who test negative. It is the
probability of correctly identifying a non diseased person with the screening test.
Spe =
d
TN
=
b + d TN + FP
The complement of specificity is called the false positive rate (FPR).
FPR = 1 − Spe
A successful screening test seeks to increase the detection rate for a given specificity or
for a given FPR.
46
Nuchal translucency measurement in the first trimester of pregnancy
Another perspective is gained by calculating the predictive values, PPV and NPV. The
PPV is the probability that a person with a positive test has the disease. The NPV is the
probability that a person with a negative test does not have the disease. The predictive
values of a screening test depend on the detection rate, the specificity of the test and the
prevalence of the condition in the population in which the test is being used.
PPV =
NPV
=
a
TP
=
;
a + b
TP + FP
d
TN
=
TN + FN
c + d
In many situations, the predictive values of a diagnostic test are more relevant to patients
than its detection rate and specificity. However, the predictive values are directly related
to the underlying prevalence of the condition in the population through the following
expressions:
PPV =
NPV =
DR × Prevalence
(DR × Prevalence ) + FPR (1 − Prevalence
[(1 −
FPR
)
;
(1 − FPR ) × (1 − Prevalence )
) × (1 − Prevalence )] + [(1 − DR ) × Prevalence ]
Therefore, a screening test is most effectively applied in populations at high risk for the
condition (Figure 13). Screening the entire population for a relatively infrequent
condition may yield comparatively few previously undiagnosed cases for the effort
involved.
100
Estimated PPV or NPV (per cent)
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
Prevalence (per cent)
Note: Detection rate and specificity are both set at 95%
Figure 13
Estimated positive predictive value (PPV) and negative predictive value (NPV) according to
prevalence in the underlying populations
Nuchal translucency measurement in the first trimester of pregnancy
47
Likelihood ratios (LRs) offer the benefit of adjusting estimates of risk prior to
undergoing the screening test (called the pre-test or prior odds of disease) to arrive at the
probability of disease once test results are known (called the post-test or posterior odds
of disease). Seen in another way, LRs express the odds that a given level of a test result
would be expected in a patient with the condition compared with one without the
condition. The likelihood ratio is related to detection rate and FPR as follows:
LR =
DR
FPR
Derivation of the post-test odds using LR is achieved through simple multiplication by
the pre-test odds of disease:
Pre-test odds × Likelihood ratio = Post-test odds
Effectiveness of nuchal translucency screening in the first trimester
The literature search identified 18 articles that met the entry criteria (Table 19). Most
studies were in Europe, with the majority conducted in the United Kingdom. The studies
present the findings from a total of 804 cases of trisomy 21 seen over a 13 year period.
Most studies used amniocentesis or CVS as a “gold standard” for diagnosis, although
some did not detail the reference test used.
48
Nuchal translucency measurement in the first trimester of pregnancy
Table 19
General characteristics of retrieved studies focusing on the use of nuchal translucency
measurement for the screening of trisomy 21 in the first trimester of pregnancy
First author and
year of
publication
Schwarzler et al
(1999)
Thilaganathan et
al (1999)
Snijders et al
(1998)
Martinez et al
(1997)
Kornman et al
(1996)
Hyett et al (1996)
Scott et al (1996)
Hafner et al (1995)
Hyett et al (1995)
Bewley et al
(1995), Roberts et
al (1995)
Brambati et al
(1995)
Borrell et al (1996,
1997)
Pandya et al
(1995b)
Szabo et al (1995)
Nicolaides et al
(1994), Pandya et
al (1994)
Hewitt (1993)
Ville et al (1992)
Savoldelli et al
(1993)
Population
Quality
criteria
(ABCDE)b
Location
Dates of
enrolment
Cases
UK
1996 to 1997
12
29.4c
Y1YNY
Karyotyping,
pregnancy outcome
UK
1994 to 1998
21
28.6c
Y5NUY
CVS
UK
?
326
31
Y2YNY
A or CVS
Spain
?
9
38
Y2YNY
CVS
The Netherlands
1994
7
38
Y2YNY
A or CVS
UK
Australia
Austria
UK
1993 to 1995
1993 to 1995
1993 to 1994
?
70
8
4
36
?
38c
26
?
Y2NNY
Y2YNY
Y2NNY
Y2NUY
CVS
CVS
A
CVS
UK
1992 to 1993
3
29.8c
Y1YNY
Karyotyping,
pregnancy outcome
Italy
1992 to 1993
26
?
Y2YNY
CVS
Spain
1991 to 1993
47
?
Y2YNY
A or CVS
UK
1990 to 1994
101
35
Y2NNY
A or CVS
Hungary
?
31
?
Y2YNY
CVS, cordocentesis
UK
1990 to 1994
61
35
Y1YYY
A or CVS
Australia
France
1989 to 1993
1988 to 1991
5
9
35c
?
Y1YNY
Y2YNY
A or CVS
A or CVS
Switzerland
1985 to 1991
28
?
Y2YNY
CVS
Maternal agea
Reference test
A = amniotomy; CVS = chorionic villus sampling; N = no; U = unclear; Y = yes; ? = unknown or unstated
a Values are medians unless otherwise stated
b Quality criteria are listed in Table 14
c Mean
Three studies (Snijders et al 1998, Schwarzler et al 1999, Thilaganathan et al 1999) used
CRL adjusted cutoff levels applied to NT thickness to estimate risk, since thickness
normally increases with CRL length. Given this current perspective, best exemplified by
Snijders et al (1998) and subsequent authors, those studies applying a set cutoff are
reviewed for historical interest only (Ville et al 1992, Hewitt 1993, Savoldelli et al 1993,
Nicolaides et al 1994, Pandya et al 1994, Bewley et al 1995, Brambati et al 1995, Comas et
al 1995, Hafner et al 1995, Hyett et al 1995, Pandya et al 1995b, Roberts et al 1995, Szabo
et al 1995, Borrell et al 1996, Hyett et al 1996, Kornman et al 1996, Scott et al 1996,
Borrell et al 1997, Martinez et al 1997). Summaries of these studies are found in
Appendix G.
Nuchal translucency measurement in the first trimester of pregnancy
49
Snijders et al (Snijders et al 1998) reported on a multicentre study in the United Kingdom
involving 22 centres and 96,127 women. A combination of maternal age and NT
thickness at 10 to 14 weeks (from 306 sonographers with FMF certification) was used to
estimate the risk for trisomy 21. The following criteria were used to standardise the
results:
•
acquisition of a good sagittal section of the fetus;
•
appropriate image magnification, with the fetus occupying at least 75 per cent of the
image; and
•
proper distinction made between fetal skin and amnion; and measurement of the
maximum thickness of the subcutaneous translucency between the skin and the soft
tissue overlying the cervical spine achieved.
The NT thickness and CRL were measured transabdominally unless poor visualisation
prompted a transvaginal ultrasound examination. Risk assessment was based on previous
data and updated on the basis of a validation sample. After counselling, patients were
offered a diagnostic test.
For a risk cutoff of 1 in 300 for trisomy 21, the authors reported DR=82.2 per cent (268
out of 326), FPR=8.3 per cent (7,907 of 95,476), PPV=3.2 per cent (268 of 8,428) and
NPV=99.9 per cent (87,569 of 87,699). For an FPR of 5 per cent, the sensitivity was
77 per cent (95% CI=72%, 82%).
Of the 268 pregnancies affected by trisomy 21, early termination was chosen in 250
(93.3%) cases. Since intrauterine death of fetuses with trisomy 21 from 12 weeks to term
is about 40 per cent, the authors could not be certain how many of the early terminations
would have otherwise resulted in a live birth.
Schwarzler et al (1999) prospectively evaluated 4,523 consecutive fetuses at 10 to 14
weeks of gestation in women attending a single London hospital from July 1996 to
November 1997. Specially trained sonographers measured NT as the maximal
sonoluscent zone between the inner aspect of the fetal skin and the outer aspect of the
cervical spine. The maximum value of three measurements was recorded. Applying a 1 in
270 risk cutoff for trisomy 21, the authors reported the following results:
DR=76.9 per cent, FPR=4.9 per cent; PPV=4.4 per cent, and NPV=99.9 per cent.
Thilaganathan et al (1999) examined 9,802 pregnant women in the setting of a district
general hospital. Using a 1 in 300 risk cutoff for trisomy 21, the authors reported
DR=80.9 per cent (17 of 21) and PPV=2.1 per cent (1 in 49). Using these data, the
estimated FPR and NPV were 8.2 per cent and 99.9 per cent, respectively.
50
Nuchal translucency measurement in the first trimester of pregnancy
Factors affecting the effectiveness of the screening procedure
Due to concerns about the generalisability of results, Wald et al (1998), Nicolaides et al
(1999a), Malone et al (2000) and Stewart and Malone (1999) called for further studies to
characterise and quantify the effect of sources of heterogeneity from physical, clinical and
programmatic perspectives. Some probable causes of heterogeneity are described below.
Physical factors
The resolution of sonographic images depends on the wavelength of sound used. The
use of 3 MHz transducers gives an effective resolution of about 1 mm with greater
frequencies offering higher resolutions. Since NT measurements lie between 0 and
5 mm, image resolution influences the validity and repeatability of results.
Clinical factors
The variation of screening performance with age of gestation has not been fully
determined (Wald et al 1998). In addition, the full natural history of increased NT in
euploid fetuses with autosomal trisomies or affected pregnancies with NT measurements
in the normal range have not been completely described (Borrell et al 1998, Maymon et
al 1999, Stewart and Malone 1999).
A common criticism applied to relevant prospective studies is that screening by NT
detects cases of aneuploidy that would otherwise have died in utero. This gives inflated
detection rates and implies that unnecessary procedures would have been performed on
pregnant women when termination of the affected pregnancy is chosen. Snijders et al
(1995) estimated that up to 40 per cent of affected fetuses identified at 10 to 14 weeks of
gestation will die in the uterus. Some authors have used this finding to adjust the
detection rate from the 82 per cent reported by Snijders et al (1998) to about 78 per cent
(Cuckle 1998), 60 per cent (Haddow 1998), or 56 per cent (Reynolds 1998).
Verification bias has been put forward by Mol and others as a possible explanation for
the discrepancies in published detection rates (Hackshaw et al 1996, Mol et al 1996, Mol
et al 1999). Verification bias arises when there are differential rates of diagnostic testing
according to the results of a screening test. In the case of NT, the group with positive
screening results is more likely to undergo karyotyping than the group screening negative.
Mol et al suggested that this, coupled with the increased spontaneous fetal loss rates
associated with increased NT, might lead to an overestimation of the detection rate. Mol
et al conducted a systematic review of 25 published reports, 15 of which were assessed as
being affected by verification bias. Detection rates for studies with verification bias were
found to be higher than those without the bias (77% versus 55%). After adjusting for the
bias and accounting for the increased fetal loss rate, the authors reported an estimated
detection rate of 63 per cent (Mol et al 1999).
Programmatic factors
Standardisation of definitions and procedures
Biagiotti et al (1997) examined the controversy of the proper definition of an abnormal
NT measurement stemming from the proper choice of cutoff. They reported that the
CRL dependent measures confer a potential advantage over absolute increases in NT by
significantly reducing the FPR.
Monni et al (1997) reported that the modification of techniques to adhere to published
FMF guidelines improved detection rates from 30 per cent to 84 per cent.
Nuchal translucency measurement in the first trimester of pregnancy
51
Quality assurance, monitoring and control
Haddow et al (1998) reported that the overall success rate for obtaining NT images
among 16 centres that had no specific training of sonographers or quality control
measures was 83 per cent (61–100%).
Pandya et al (1995a) prospectively assessed the repeatability of NT thickness
measurement in fetuses of 10 to 14 weeks gestation by asking two of four operators to
make six measurements each in 200 women (a total of 1,200 measurements). The authors
found that the intraobserver, interobserver and caliper placement repeatability of fetal
NT measurements were less than 0.54, 0.62 and 0.58 mm respectively, 95 per cent of the
time. The authors concluded that measurement is highly reproducible when NT
thickness is measured by well trained operators.
A study by Roberts et al (1995), however, showed that 36 per cent of second
measurements of NT by the same sonographer differ by about 1 mm. Readings in which
two sonographers independently measured NT were found to vary by more than 1 mm
in 71 per cent of cases.
There is evidence to suggest that differences in calliper placement account for a large part
of the variation in measurements (Pandya et al 1995a, Schuchter et al 1998), a situation
that is expected to improve when automated imaging techniques are used (Bernardino et
al 1998, Nicolaides et al 1999a).
Implementation in routine practice
Demonstration projects examining the feasibility of implementing routine screening for
trisomy 21 using NT have shown that operator variability and variations in detection
rates may be reduced with unified criteria addressing procedural aspects of the
examination (Nicolaides et al 1999a).
Reviews published by Malone et al (2000) and Stewart and Malone (1999) suggest that
procedural factors might explain the large difference in procedural sensitivity when FMFaffiliated centres were compared with other independent centres (72% versus 50%
respectively).
Effect of a first trimester NT screening program on screening for trisomy 21 using
maternal serum markers in the second trimester
Due to the expected reduction in the prevalence of trisomy 21 if NT screening were
implemented as a population screening technique, screening for trisomy 21 using
maternal biochemical markers in the second trimester will suffer increases in FPRs and
decreases in positive predictive values, sometimes by as much as five fold. Risk
assessment calculations must take into consideration this shift in prevalence, especially as
it applies to local experience (Stewart and Malone 1999, Malone et al 2000).
52
Nuchal translucency measurement in the first trimester of pregnancy
Effectiveness of maternal biochemical marker screening
Second trimester
This section incorporates the results of a technology assessment and studies conducted
by Wald et al (1994, 1996a, 1997a, 1998). Results are given in terms of median estimates
for multiples of the median (MoM), which compare median levels of biochemical
markers in affected pregnancies to those in unaffected pregnancies. A MoM of 1.00
implies that the biochemical marker level in affected pregnancies is at the level found in
unaffected pregnancies. MoM values below 1 indicate that a lower median level is found.
Values above 1 are interpreted as being higher than the norm.
Only biochemical markers whose confidence intervals do not cross 1 demonstrate
statistically significant differences between affected an non-affected pregnancies.
Table 20 summarises results for particular biochemical markers in screening for trisomy
21.
Table 20
Pooled multiple of the median (MoM) values for selected maternal biochemical marker
studies during the second trimester of pregnancy
Biochemical marker
uE3
AFP
CA-125
PAPP-A
Free α-hCG
SP1
α-inhibin
Dimeric inhibin A
Total hCG
Free β-hCG
Number of
studies
Number of
trisomy 21 cases
Pooled MoM
95% CI
21
38
5
3
7
733
1,328
81
64
239
0.72
0.75
0.94
0.97
1.43
0.68, 0.75
0.72, 0.78
0.74, 1.21
0.84, 1.11
1.12, 1.82
7
4
379
64
1.47
1.63
1.23, 1.76
1.01, 2.62
6
28
12
375
907
562
1.92
2.06
2.20
1.75, 2.15
1.95, 2.17
2.07, 2.33
AFP = alpha-fetoprotein; CA-125 = cancer antigen 125; CI = confidence interval;
hCG = human chorionic gonadotrophin; MoM = multiple of the median; PAPP-A = pregnancy-associated plasma protein-a;
SP1 = schwangerschaftsprotein 1; uE3 = unconjugated oestriol
Source: Wald et al (1998)
Pooled results indicate that eight markers are useful in the detection of trisomy 21: uE3,
AFP, SP1, α-inhibin, dimeric inhibin A, total hCG, α- and β-hCG.
Expected detection and false positive rates
Estimated detection rates for 5 per cent FPRs of selected maternal biochemical markers
used alone or in double, triple or quadruple combinations, are given in Table 21.
Nuchal translucency measurement in the first trimester of pregnancy
53
Table 21
Estimated detection rate (%) for a false positive rate of 5 per cent for selected maternal
biochemical marker combinations during the second trimester of pregnancy
Biochemical marker
Single markers
AFP
uE3
Total hCG
α-hCG
β-hCG
Inhibin A
36
41
49
38
49
44
Double marker combinations
uE3
45
Total hCG
54
56
α-hCG
45
53
51
β-hCG
54
57
–
55
Inhibin A
53
57
58
51
58
–
Triple marker combinations
uE3, inhibin A
60
–
–
uE3, β-hCG
60
–
–
uE3, α-hCG
56
–
uE3, total hCG
59
Total hCG, inhibin A
64
–
Total hCG, α-hCG
57
–
α-hCG, β-hCG
60
–
–
β-hCG, inhibin A
64
–
–
α-hCG, inhibin A
58
–
–
64
62
63
60
–
64
59
–
–
–
61
–
–
Quadruple marker combinations
uE3, total hCG, inhibin A
67
uE3, α-hCG, inhibin A
66
–
–
uE3, β-hCG, inhibin A
67
–
uE3, total hCG, α-hCG
63
uE3, β-hCG, α-hCG
65
α-hCG, β-hCG, inhibin A
67
68
Total hCG, α-hCG, inhibin A
65
66
–
–
–
–
–
–
–
–
–
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; MoM = multiple of the median; uE3 = unconjugated oestriol
– = data not available
Source: Wald et al (1994, 1996a, 1997a, 1998)
First trimester
This section incorporates the results of a meta-analysis conducted by Cuckle and van
Lith (1999), and Wald et al (1998). Results are given in terms of mean or median MoM
(Table 22).
However, Wald et al (1998) noted some limitations of maternal biochemical markers. For
instance PAPP-A is known to lose discrimination after 13 to 14 weeks of gestation
(Cuckle 1994). Similarly, free α-hCG is low in affected pregnancies before 12 weeks of
gestation and dimeric inhibin A is relatively nondiscriminatory before 14 weeks of
gestation.
54
Nuchal translucency measurement in the first trimester of pregnancy
Table 22
Pooled multiple of the median (MoM) values for selected maternal biochemical marker
studies during the first trimester of pregnancy
Biochemical marker
Number of
studies
Number of
trisomy 21 cases
PAPP-A
Pooled MoM
95% CI
12
297
0.38
0.33, 0.43
uE3
8
9
210
226
0.71
0.74
0.59, 0.86
?
AFP
16
26
335
542
0.78
0.79
0.73, 0.84
?
SP1
6
111
0.81
?
Free α-hCG
6
162
1.00
0.85, 1.17
CA-125
2
34
1.14
0.72, 1.81
α-inhibin
2
34
1.27
0.92, 1.75
Total hCG
14
352
1.29
1.16, 1.44
Dimeric inhibin A
Free β-hCG
3
112
1.59
0.96, 2.65
12
17
308
579
1.83
1.98
1.65, 2.03
?
MoM = multiple of the median; AFP = alpha-fetoprotein; CA-125 = cancer antigen 125; CI = confidence interval; hCG = human chorionic
gonadotrophin; PAPP-A = pregnancy-associated plasma protein-a; SP1 = schwangerschaftsprotein 1; uE3 = unconjugated oestriol; ? =
unstated or unknown; a = estimate for gestational age of 8-14 weeks
Source: Wald et al (1998), Cuckle and van Lith (1999)
Expected detection and false positive rates
Discriminatory power of biochemical markers used alone or in combination is reported
using estimates of the detection rate for a particular FPR. Table 23 shows the overall DR
for selected biochemical markers. All values are estimated at a fixed FPR of 5 per cent.
Table 23
Estimated detection rate for a false positive rate of 5 per cent for selected biochemical
markers and combinations of markers measured from 9 to 11 weeks of gestation
Biochemical marker
Detection rate (%)
Single markers:
uE3
30.0a
AFP
32.0 a
Free β-hCG
41.8
PAPP-A
52.2
Double markers:
PAPP-A and free β-hCG
64.6
Triple markers:
PAPP-A, free β-hCG, and AFP
66.6
PAPP-A, free β-hCG, and uE3
68.6
Quadruple markers:
PAPP-A, free β-hCG, AFP, and uE3
70.1
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; PAPP-A = pregnancy-associated plasma protein-a;
uE3 = unconjugated oestriol
a Estimate for 8–14 weeks age of gestation
Source: Wald et al (1998), Cuckle and van Lith (1999)
Discriminatory power is inversely related to gestational age (Table 24), with DR
decreasing by as much as 50 per cent from 9 to 13 weeks (Cuckle 1994, Cuckle and van
Lith 1999).
Nuchal translucency measurement in the first trimester of pregnancy
55
Table 24
Estimated detection rate (per cent) for a false positive rate of 5 per cent for selected
biochemical markers and combinations of markers, according to gestational age
Gestational age (weeks)
9
10
11
12
13
PAPP-A and free β-hCG
71.6
65.6
58.2
50.9
46.4
PAPP-A, free β-hCG and AFP
73.1
67.5
60.4
53.7
49.3
PAPP-A, free β-hCG and uE3
74.6
69.3
63.0
57.3
53.9
PAPP-A, free β-hCG, AFP and uE3
75.8
70.8
64.9
59.4
56.1
Biochemical marker
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; PAPP-A = pregnancy-associated plasma protein-a;
uE3 = unconjugated oestriol
Source: Cuckle and van Lith (1999)
Effectiveness of a combination of nuchal translucency and maternal biochemical
markers
First trimester nuchal translucency plus second trimester maternal biochemical
markers
Table 25 shows some characteristics of three studies that examined the effect of
introducing NT measurement in the first trimester on screening rates for trisomy 21 in
women subsequently undergoing second trimester biochemical screening. The search
identified a modelling study by Wald et al (1999) using data from previously published
estimates and retrieved two primary studies by Kadir and Economides (1997) and
Thilaganathan et al (1997) conducted in the United Kingdom in 1997. The two primary
studies used CRL adjusted cutoffs for NT.
Table 25
General characteristics of retrieved studies focusing on the use of nuchal translucency
measurement in the first trimester and maternal biochemical markers in the second
trimester for the screening of trisomy 21
Reference
Location
Dates of
enrolment
Population
Cases
Wald et al (1999)
Maternal agea
Quality criteria
(ABCDE)b
Reference test
not applicable
Kadir and
Economides (1997)
UK
1995 to 1996
8
?c
Y2NNY
Karyotyping,
pregnancy
outcome
Thilaganathan et al
(1997)
UK
1994 to 1996
8
28.8
Y2NNY
Karyotyping,
pregnancy
outcome
N = no; Y = yes
a Values are means
b Quality criteria are listed in Table 14
c Unknown or unstated
56
Nuchal translucency measurement in the first trimester of pregnancy
Wald et al (1999) used an “integrated test” involving a combined assessment of results
from tests conducted in the first two trimesters of pregnancy. Specifically this
incorporated serum inhibin A and ultrasonographic NT measurements in the first
trimester, with subsequent quadruple maternal biochemical marker assays in the second
trimester (AFP, uE3, hCG, and inhibin A). They estimated that this test would show
DR=94 per cent for FPR=5 per cent (Wald et al 1999). The authors asserted that:
• the integrated test makes use of the fact that different screening markers are best used
at different times during the pregnancy to take full advantage of the full discriminatory
power of such testing;
• the procedure’s accuracy could not be established if results from first trimester tests
were conducted independently of second trimester tests; and
• giving pregnant women different estimates of risk at different times of the pregnancy
would lead to confusion.
The approach has been criticised on the grounds that it undermines patient choice and
defeats the purpose of the screening test as a means of providing meaningful guidance to
pregnant women (Jenkins and Wapner 1999). It introduces an unacceptable delay that
arises from combining the results of the screening test over two trimesters (Jenkins and
Wapner 1999, Reynolds et al 1999). The combination of NT and maternal biochemical
screening has not been assessed in a single large group of pregnant women (Malone et al
1999).
Table 26 shows the estimated detection rates for variations of the integrated test.
Table 26
Estimated detection rate for a fixed false positive rate of 5 per cent for variations of the
“integrated test”
Detection rate
(%)
Per cent increase over second
trimester triple test DRb
Second trimester triple test alone
69
–
Second trimester quadruple test alone
76
10.1
Test variationa
First trimester NT and serum inhibin A
85
23.2
First trimester serum inhibin A and second trimester quadruple test
85
23.2
First trimester NT and second trimester quadruple test
92
33.3
First trimester NT and serum inhibin A, and second trimester
quadruple test
94
36.2
DR = detection rate; NT = nuchal translucency
a The second trimester triple test includes serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin
(hCG). The second trimester quadruple test includes all triple test markers plus inhibin A.
b Calculated as (DRVariation – DRTriple Test)/DRTriple Test × 100
Source: Wald et al (1999)
Kadir and Economides (1997) reported that adding first trimester NT screening for
trisomy 21 to second trimester maternal biochemical screening with AFP and free βhCG in a population of “low-risk” women produced a combined DR of 87.5 per cent
(seven of eight affected fetuses) at an FPR of 9.1 per cent. Similar results for DR were
reported by Thilaganathan et al (1997) although no estimates on FPR were provided.
Nuchal translucency measurement in the first trimester of pregnancy
57
First trimester nuchal translucency plus first trimester maternal biochemical
markers
The combined use of sonographic and biochemical measurements increases sensitivity
over the level attained by the use of each test alone (Cuckle and van Lith 1999). This is
illustrated in Table 27.
With the use of NT screening, the detection rate of biochemical screening increases by as
much as 85 per cent over original values. When the serum test using all four biochemical
markers is used, the DR increases from 70.1 per cent to about 88 per cent, an increase of
26 per cent. Gestational age-dependent estimates of sensitivity are similarly increased.
Table 27
Estimated detection rate for a 5 per cent false positive rate for the combined use of NT and
selected biochemical markers and combinations of markers measured from 9 to 11 weeks of
gestation
Detection rate (%)
Serum alonea
Biochemical marker
NT alone
Serum with NT
Increase over
serum aloneb
Single markers:
Free β-hCG
41.8
*72.7
77.7
85.9
PAPP-A
52.2
*72.7
81.2
55.6
64.6
*72.7
86.4
33.7
PAPP-A, free β-hCG and AFP
66.6
*72.7
87.2
30.9
PAPP-A, free β-hCG and uE3
68.6
*72.7
87.9
28.1
70.1
*72.7
88.3
26.0
Double markers:
PAPP-A and free β-hCG
Triple markers:
Quadruple markers:
PAPP-A, free β-hCG, AFP and uE3
AFP = alpha-fetoprotein; DR = detection rate; hCG = human chorionic gonadotrophin; NT = nuchal translucency;
PAPP-A = pregnancy-associated plasma protein-a; uE3 = unconjugated oestriol
a From Table 23
b Calculated as (DR
Serum with NT – DRSerum Alone)/ DRSerum Alone × 100
* Please note that NT detection rate was calculated from a meta-analysis by Cuckle and van Lith (1999)
Source: Cuckle and van Lith (1999)
58
Nuchal translucency measurement in the first trimester of pregnancy
Summary of data on the effectiveness of screening using nuchal
translucency measurement and maternal biochemical tests
Table 28 presents point estimate ranges for the detection rates and FPRs of various
screening techniques and combinations of techniques.
Table 28
Estimated detection and false positive rates for combinations of screening modalities
Range of point estimates (%)
Screening technique
Detection rate
False positive
rate
77–82*
5–8
30–52
65
67–69
70
5
5
5
5
36–44
45–58
57–64
63–68
5
5
5
5
78–81
86
87–88
88
5
5
5
5
See Table 27 and discussion for
details
88
92
9.1
5
See Table 27 and discussion for
details
Comments
Single modalities
Nuchal translucency measurement in the
first trimester
CRL-adjusted cutoff levels used.
Reference tests were CVS,
amniocentesis or pregnancy
outcome. See Table 19 and
discussion for details.
Maternal biochemical markers in the first
trimester
Single marker
Double markers
Triple markers
Quadruple markers
Maternal biochemical markers in the
second trimester
Single marker
Double markers
Triple markers
Quadruple markers
Estimates arising from systematic
reviews of specific biochemical
markers and combinations of
markers. See Tables 21, 23 and
discussion for details.
Combination modalities
First trimester nuchal translucency and
first trimester maternal biochemical
measurement
NT plus single marker
NT plus double markers
NT plus triple markers
NT plus quadruple markers
First trimester nuchal translucency and
second trimester maternal biochemical
measurement
NT plus double markers
NT plus quadruple markers
CRL = crown-to-rump length; CVS = chorionic villus sampling; NT = nuchal translucency
* NT detection rate was calculated from primary studies identified by literature search that met inclusion criteria (Table 19)
Nuchal translucency measurement in the first trimester of pregnancy
59
What are the economic considerations?
Review of the literature
In addition to the electronic databases in Table 12 and Internet sites listed under
‘Literature search’ in the section ‘Approach to assessment’, searched economic databases
included EconLit, HEED and DARE. Only studies with a formal economic evaluation
of screening for trisomy 21 by ultrasound were included. Neverteheless the summary of
results (Appendix H) includes a study of biochemical markers for the detection of
trisomy 21 in the UK, as it forms the basis of the modelling method adopted in this
report.
A comparison across studies of the cost-effectiveness of ultrasound screening in
pregnancy is limited by the major differences in assumptions about detection rates, FPRs,
rates of diagnostic procedures, procedure-induced fetal losses and unit costs across
countries. While most studies report an average cost per case detected, the differing scale
of the programs (i.e. number of screened pregnancies) makes an assessment of the
incremental cost compared with existing practice vary from country to country (even
where the technology has the same effectiveness). The incremental cost per extra case
detected depends on the number of cases detected, even where there are no economies
of scale in the screening program. A further difficulty is the lack of a standardised
outcome measure. Studies often report a cost per trisomy 21 pregnancy detected but the
cost per outcome is not constant over the level of outcome. As the detection rate rises
(with the risk cutoff falling), the cost per case detected rises from a certain point due to
the number of false positives.
In addition, the meaning of a single outcome is questionable if the rate of procedureinduced fetal losses rises as the detection rate rises. It is conceivable that two strategies
could have the same cost per case detected, even with different:
• numbers of cases detected;
• procedure-induced fetal loss rates; and
• rates of unnecessary procedures.
Where we are concerned with both cases detected and the consequences of false positive
screens, we either have to consider both outcomes together or keep one constant. In one
approach, Wald et al (1997b) kept the detection rate constant across interventions and
thus the number of cases detected was the same in each strategy for a given sized group
of women. Such an approach allows the use of an average cost-effectiveness ratio as a
guide to decision making. An alternative is to keep the FPR constant and to calculate the
extra cost per case detected for a given number of procedure-induced fetal losses.
Another option which is common in the literature, is to present the trade-off between
cost, detection and fetal losses. The last approach is more difficult to implement and
makes decision making more difficult. While there is clinical trial evidence of the
effectiveness of ultrasound screening for trisomy 21 in the first trimester, either on its
own or in combination with first trimester biochemical screening, there remains some
uncertainty about the effectiveness of this strategy in practice.
60
Nuchal translucency measurement in the first trimester of pregnancy
Wald et al (1997b) have suggested a number of areas of concern that would affect the
economics of ultrasound screening. In particular:
•
Evidence to date suggests only a small difference in detection rates between first and
second trimester. However, the overall cost difference in screening is likely to be
substantial if the uptake is higher, and the cost of combined ultrasound and
biochemical screening is more than three times the cost of biochemical screening
alone.
•
Screening performance is operator-dependent and involves repeated measurement,
especially where there is a failure to obtain a measurement. The cost of providing
ultrasound screening is therefore uncertain, not only because of the time taken for
the scan, but also because of sonographer training and quality control.
•
While women prefer early screening, the benefits of providing the option of an
earlier, less physically traumatic, termination are reduced by the fact that about a
quarter of trisomy 21 pregnancies miscarry between 10 and 15 weeks of gestation.
Thus, this proportion of women will be offered an induced abortion when they
would have miscarried spontaneously in the next few weeks.
•
Serum testing in the first trimester will not detect neural tube defects. Therefore, if a
screening strategy restricts serum screening to the first trimester, the opportunity for
AFP screening in the second trimester will be lost. Screening for neural tube defects
would then be based on ultrasound, performed either in association with an NT
screen or as part of the second trimester ultrasound scan that checks for fetal
abnormality. This strategy may result in a fall in the overall detection of neural tube
defects. An alternative strategy, involving serum screening in both the first and
second trimesters to pick up neural tube defects, would require additional funding.
•
It may be that the introduction of first trimester NT screening would reduce the rate
of diagnostic tests in higher risk pregnant women. This would lead to a cost saving
with some reduction in detection but a reduction in procedure related fetal losses.
On the other hand some high-risk women may have amniocentesis in the second
trimester irrespective of the results of early screening. Once a screening policy is in
place it may not be possible to distinguish screening and non-screening ultrasound in
the first trimester. Since many of these women currently have an ultrasound in the
first trimester for other purposes (e.g. for dating of pregnancy), replacing a dating
ultrasound with a NT ultrasound in this group of women could increase costs
without improving detection.
There are a number of options for ultrasound screening in pregnancy:
•
first trimester ultrasound for all pregnant women;
•
first trimester biochemical screening for all pregnant women;
•
second trimester biochemical screening for all pregnant women;
•
combined first trimester biochemical screening and ultrasound for all pregnant
women; or
•
application of an age cutoff to any of the above.
Nuchal translucency measurement in the first trimester of pregnancy
61
In order to provide some guidance on the likely costs and outcomes associated with
some of these options, the next section presents a modelled decision analysis of
ultrasound and biochemical screening for trisomy 21 in pregnancy, based on Australian
data.
Cost-effectiveness: a modelled decision analysis
This section presents estimate of the potential cost-effectiveness of the widespread
introduction of NT ultrasound screening of pregnant women for trisomy 21 compared
with alternative screening practices in Australia. In principle, the cost-effectiveness of
NT screening in the first trimester should be calculated as the incremental costeffectiveness ratio compared with current practice. That is to say
(Ca − Cb )
(Oa − Ob )
where: Ca and Cb are the cost of ultrasound screening and current practice respectively,
and Oa and Ob are the outcomes of ultrasound screening and current practice
respectively.
Outcomes reported in all analyses are cases of trisomy 21 detected and number of losses
of unaffected fetuses. While ultrasound may be able to detect other congenital
abnormalities, this evaluation has focussed on alternatives to biochemical screening for
trisomy 21 alone, as this is the most common cause of intellectual disability.
Nevertheless, to the extent that ultrasound screening may be capable of detecting other
abnormalities, the estimates of cost-effectiveness are underestimated. The estimation of
cost-effectiveness is done with a simple decision analysis similar to that used in Wald et al
(1998), in a Microsoft Excel spreadsheet.
Cost-effectiveness analysis in a decision analytic framework allows consideration of the
potential cost-effectiveness of a technology in the absence of either high quality
randomised controlled trial evidence of effectiveness or high quality prospective cost
data. It allows identification of a range of potential costs and outcomes associated with
screening strategies and the uncertainties associated with each. While the results of the
analysis remain subject to considerable uncertainty given the quality of the underlying
clinical and economic data, they nevertheless provide the basis for an assessment of the
potential for the technology to provide health gains at an acceptable cost.
Three screening strategies are considered in the following analyses:
1. NT in the first trimester followed by CVS for those with a positive test;
2. NT and biochemical screening in the first trimester, followed by CVS for those with
a positive test; and
3. NT and biochemical screening for high-risk women (applying a lower age cutoff) in
the first trimester, with biochemical screening in the second trimester for other
women.
62
Nuchal translucency measurement in the first trimester of pregnancy
The appropriate comparator is current screening practice. This is difficult to model since
it consists of a combination of ultrasound screening and biochemical screening that takes
into account age and other risk factors, followed by diagnostic testing (particularly for
those over the age of 35). It is unclear how much of each of these parts of screening
activity is being done currently and the likely degree of substitution if NT screening were
to be implemented. Accordingly, the analysis begins with a simple comparison of
universal screening, with each modality compared with no screening. The sensitivity
analysis considers variations on key assumptions including detection rates, uptake and the
extent of substitution of NT screening for dating ultrasound scans and diagnostic tests in
those at higher risk.
There are a number of possible outcomes of a screening program. The main aim of
screening in pregnancy is to provide women with information on fetal status.
Information prior to birth may in itself be valuable to women and may also allow them
to make a choice on whether or not to continue with a pregnancy. However, increased
information comes at a cost, both in terms of resources associated with screening and
the trade-off between improved information from the test and negative consequences
such as anxiety from a positive screen and the risk of inducing the loss of unaffected
fetuses. For all the screening options, an increase in the rate of detection leads to an
increase in the rate of false positive results and therefore procedure-related miscarriage in
follow-up diagnostic tests. The primary outcome of interest in this assessment is the
number of cases of trisomy 21 detected. However, the report takes the view that any
consideration regarding the resource implications of providing screening for women
should take into account downstream costs such as subsequent diagnostic tests and
terminations. Accordingly, the number of diagnostic procedures and their outcomes have
been calculated to provide the total cost of screening.
As a secondary outcome measure, the number of live births with trisomy 21 is also
calculated for each strategy. Some studies have gone further and calculated the lifetime
extra cost of care for infants born with trisomy 21. For example Gill et al (1987)
estimated the lifetime care cost in the United Kingdom as equivalent to about
US$500,000. Since there are no reliable estimates of the money value of a life with or
without trisomy 21, including just the cost of care provides a distorted picture of the
cost-effectiveness of screening. Therefore the analysis does not consider the lifetime cost
of care.
Cost-effectiveness analysis is designed to consider a single outcome such as cost per case
of trisomy 21 detected. Where there is a trade-off between outcomes (e.g. trisomy 21
cases detected versus procedure-induced fetal losses), cost-effectiveness analysis cannot
provide a single number to compare strategies. In this case analysis is further
compounded by the nature of the test, which does not provide a definitive result but
rather provides a risk assessment. Reducing the risk threshold of the test increases both
the detection rate and the FPR.
As discussed above, one approach is to compare strategies at a given detection rate (Wald
et al 1997b). Since the primary outcome of interest is the number of cases detected, a
second strategy is to compare tests at a given FPR (specificity) with detection rates then
varying across tests. The third approach, of comparing tests at the trial reported levels of
sensitivity and specificity, is likely to be potentially misleading and open to manipulation,
particularly in the absence of the known quality of the screening program in practice.
Nuchal translucency measurement in the first trimester of pregnancy
63
The analysis can be further complicated if comparing strategies at different risk
thresholds and consequent detection and FPRs. This led Wald et al (1998) to argue that
average ratios are appropriate to compare strategies and that incremental analysis should
be restricted to determining the cost-effectiveness of different risk thresholds within a
given strategy (e.g. whether the risk threshold for biochemical screening should be 1:250
or 1:300). The authors of this review believe that in comparing mutually exclusive
strategies for detecting cases of trisomy 21, it is appropriate to keep the FPR constant
and use the incremental cost per case detected to aid decision making. Even with the
same FPR, the actual number of fetal losses will differ across strategies if either the
uptake of screening or the diagnostic procedure varies across strategies.
However, the use of an incremental cost-effectiveness ratio (ICER) is complex when the
ICER is not monotonic (i.e. it does not always move in the same direction as you
increase the number screened). In this case one needs to know what the total expenditure
on screening would be under each strategy. A number of possible strategies are simulated
in a decision analytic model, and the incremental cost per case detected compared with
the next best alternative screening strategy determined. The total costs and outcomes of
each strategy are also reported.
There are about 260,000 births in Australia each year. It is unknown what the prevalence
of trisomy 21 would be without any screening program. Assuming an underlying
prevalence of 1.6 per 1,000 live births (Jane Halliday, Manager, Victorian Perinatal Data
Collection Unit, Department of Human Services, Victoria, personal communication,
2000), there would be approximately 416 trisomy 21 births each year. As shown in Table
29, the prevalence of trisomy 21 increases with maternal age.
Table 29
Prevalence of trisomy 21 per 1,000 live births by age
Maternal age (years)
<30
<35
>30
>35
Prevalence of trisomy 21 births
0.6
0.9
2.6
3.2
Source: Jane Halliday, Manager, Victorian Perinatal Data Collection Unit, Department of Human Services,
Victoria, personal communication, 2000.
There is a high spontaneous rate of miscarriage of trisomy 21 fetuses. Between the first
trimester and term, the rate is reported to be 40-48 per cent and between the second
trimester and term, 23-30 per cent (Snijders et al,1995 Cuckle et al, 1990). This suggests
that the rate of trisomy 21 pregnancies screened in the first trimester would be 2.7 to 3.1
per 1,000 compared with 2.1–2.3 per 1,000 in the second trimester. These data are not
precise and do not accord exactly with the dates of NT and biochemical screening. For
the purposes of the primary modelled analysis, the assumption was a 40 per cent rate of
spontaneous miscarriage of trisomy 21 between the time at which NT screening would
occur and term. The rate of fetal loss between the time when a second trimester
biochemical screen would be done and term was assumed to be 23 per cent. This
suggests a prevalence of 693 affected pregnancies when first trimester NT screening
would be done and 540 in the second trimester when biochemical screening would be
done.
64
Nuchal translucency measurement in the first trimester of pregnancy
Current practice
The number of women screened, the test type used and the timing of screening varies
across Australia. In some States, NT ultrasound screening in the first trimester is part of
current practice. However, a common practice, and the one funded by Medicare, is a
combination of maternal age and biochemical marker screening in the second trimester.
The detection rate for triple marker biochemical screening in the second trimester (AFP,
total hCG and inhibin A) has been estimated at no more than 64 per cent (Table 21).
Those at an increased risk of fetal abnormality (primarily based on age) are advised to
consider a diagnostic test. There are no complete data on the extent of screening, but
between October 1999 and September 2000 there were 41,410 claims for biochemical
screening (Medicare item 66740), which represents about 16 per cent of all pregnant
women. In Victoria some 30 per cent of pregnant women had a biochemical screen in
2001 (Halliday, 2002). South Australia has reported rates of biochemical screening in
excess of 80 per cent. Some women currently have an ultrasound screen that includes
NT measurement. It has been suggested that Victorian rates of NT screening may
already be in excess of 25 per cent.
CVS or amniocentesis is offered to those who have a risk in excess of 1:250 in second
trimester and 1:300 in first trimester. Such risk assessments are based on screening results
that take into account maternal age. An amniocentesis has been reported to have a
procedure-related fetal loss rate of 0.9 per cent (95% CI=1.2 per cent, 0.6%) in the
second trimester of pregnancy (Wald et al 1997b). The current uptake of amniocentesis
among women with a positive screen has been reported to be 85 per cent (SABDR
1998). Ninety per cent of women with a diagnosis of a chromosomal abnormality
terminate the pregnancy.
Nuchal translucency screening
Screening for trisomy 21 using ultrasound is possible in the first or second trimester. The
primary cost-effectiveness analysis considers universal NT ultrasound screening for all
pregnant women in the first trimester. While the current rate of ultrasound in the first
trimester is unknown, between April and September 2000 there were 32,633 claims on
Medicare item 55704 (pregnancy ultrasound between 12 and 16 weeks of gestation) and
70,130 claims for Medicare item 55706 (pregnancy ultrasound between 17 and 22 weeks
of gestation). These represent 24 per cent and 54 per cent of pregnancies respectively.
However, these item numbers only became available in 2000 and service providers may
not yet charge against the appropriate Medicare item number.
Moreover, many women use non Medicare providers of antenatal care, and the number
of Medicare funded ultrasound services in the first trimester is likely to be a substantial
underestimate of the total. Overall, the number of pregnancy ultrasounds claimed under
Medicare was 243,345 in the six months from April to September 2000. Some women
may have 3 or 4 scans during a pregnancy while others have none, but the available data
suggests that the mean number of scans per woman during pregnancy was greater than
two. NT ultrasound screening may substitute for the current use of ultrasound in the first
trimester, with considerable implications for the cost-effectiveness of ultrasound
screening.
Nuchal translucency measurement in the first trimester of pregnancy
65
The extra cost of NT screening over current ultrasound examinations at either less than
12 weeks (MBS item number 55700 - $60) or 12-16 weeks (MBS item number 55704 $70) may be $30-40 rather than $100 (the fee applying to MBS item number 55706 genetic defect screening ultrasound 17-22 weeks). While the primary analysis assumes
there will be no substitution for current first trimester ultrasound, the sensitivity analysis
considers an 80 per cent substitution in the first trimester at a marginal cost of $40.
Evidence from Snijders et al (1998) suggests that with a FPR of 5 per cent, the sensitivity
of NT screening for trisomy 21 is 77 per cent (95% CI=72%, 82%). A figure of
77 per cent has been used for the detection rate of NT ultrasound screening in the
primary modelled cost-effectiveness analysis. A combination of NT ultrasound, double
biochemical markers and age screening might raise the detection rate to 86.4 per cent.
Based on Table 27, double markers on their own would give a 64.6 per cent detection
rate. Women who screen positive are assumed to be offered CVS or amniocentesis. The
uptake of diagnostic testing following a positive screen is assumed to be 85 per cent with
a 100 per cent detection rate and a procedure-related rate of fetal loss of 0.9 per cent
irrespective of the test. The sensitivity analysis considers alternative assumptions about
the detection rate and target risk group.
Model construction
The cost and outcomes associated with each strategy are calculated using a decision
analytic model. The underlying assumptions about the natural history of trisomy 21
pregnancies and the characteristics of screening assumed in the primary analysis are
presented in Tables 30 and Table 31 respectively. The economic assumptions are
presented in Table 32. Table 33 shows the structure of the primary model with respect to
NT ultrasound screening while Table 34 explains the model as it applies to biochemical
screening. Variations on the assumptions of the primary model, including the age of
women screened, are described and analysed in Appendix H.
Table 30
Natural history of trisomy 21 pregnancy and screening characteristics assumed in primary
analysis
Factor in analysis
Rate of trisomy 21 births
Spontaneous loss of fetus from time of NT to term
Spontaneous loss of fetus from time of second trimester
biochemical screen to term
NT ultrasound detection rate
NT ultrasound false positive rate
Second trimester biochemical screening detection rate
Serum testing false positive rate
Combined NT ultrasound and first trimester biochemical
screening detection rate
Occurrence (%)
0.16
40
23
77
5
64
5
86
NT = nuchal translucency
66
Nuchal translucency measurement in the first trimester of pregnancy
Table 31
Screening and diagnostic test characteristics assumed in
primary analysis
Level of uptake / fetal losses associated with test
Uptake of antenatal diagnostic test
Amniocentesis procedure-induced fetal loss rate
CVS procedure-induced fetal loss rate
Termination of affected pregnancy
Screening coverage with biochemical markers
Screening coverage with ultrasound
Occurrence (%)
85
0.9
0.9
90
100
100
CVS = chorionic villus sampling
Table 32
Unit cost assumptions in primary analysis
Resource type
Unit cost
Source
$54.50
Fee applying to MBS item number 66740 (second
trimester biochemical test)
NT ultrasound screening cost per woman
$100.00
Fee applying to MBS item number 55706 (second
trimester ultrasound)
Antenatal diagnosis cost first trimester CVS
$683.00
MBS costs of ultrasound and karyotyping
Antenatal diagnosis cost second trimester
amniocentesis
$782.90
MBS costs of ultrasound and karyotyping
Biochemical screening cost per woman (first or
second trimester)
Additional counselling for positive screens who do
not have a diagnostic procedure
$20.00
Estimate based on expert opinion
Dating first trimester ultrasound
$60.00
Fee applying to MBS item number 55700 (first
trimester ultrasound)
$1,016.00
DRG based costs from National Hospital Cost
Database
$905.00
DRG based costs from National Hospital Cost
Database
Cost of termination
Cost of procedure-induced fetal loss
CVS = chorionic villus sampling; DRG = diagnostic related group; MBS = Medicare Benefits Schedule; NT = nuchal translucency
The decision analysis framework is identical for both NT ultrasound and serum
screening, with changes only in the probability of detection and associated costs. The
framework is very similar to previous models in the literature. In particular, the formal
methods of calculation are identical to Wald et al (1997b) in calculating the cost per
trisomy 21 pregnancy detected. However in the current model no explicit calculation of
the cost per trisomy 21 birth avoided has been undertaken. Note that, given the high rate
of natural miscarriage in trisomy 21 pregnancies, the cost per case detected gives more
emphasis to early risk information and less to the actual outcome at birth. The earlier the
screening, the lower the cost per affected fetus detected, compared with the cost per
future trisomy 21 birth detected.
For each strategy, the model starts with a cohort of births and calculates the number of
affected and unaffected births screened in a given trimester. An assumed spontaneous
fetal loss rate allows the model to calculate the number of affected and unaffected
pregnancies screened. The calculation of the number of trisomy 21 pregnancies detected
would be (the number of affected pregnancies screened) × (detection rate). The number
of trisomy 21 births prevented is (the number of affected births screened) × (detection
rate) × (uptake of antenatal diagnosis) × (uptake of termination).
Nuchal translucency measurement in the first trimester of pregnancy
67
The cost of pre-test information and counselling, including any dating ultrasound scan, is
assumed to be the same for each screening modality and is therefore excluded from the
primary analysis. In the sensitivity analysis the assumption that NT screening will
substitute the dating ultrasound to some extent is incorporated by limiting the cost of
NT screening (to the excess over a dating ultrasound).
The cost of screening affected pregnancies must include not only the cost of the test, but
for those who have a positive screen, the cost of counselling and for a proportion, the
cost of antenatal diagnosis, an additional ultrasound scan and, for some, termination of
the pregnancy. The NT ultrasound screen may involve post-test counselling at the time
of the screen for those who screen positive, given the immediacy of the results.
Biochemical screening will probably involve an additional visit to discuss the results.
Nevertheless, it may be that there is little difference in the actual time spent counselling,
and, in this analysis, any differences have been ignored. Given the comparatively small
number of positive cases, this is unlikely to have any significant impact on the economic
analysis.
Those who decline further diagnosis are likely to receive additional counselling, and a
cost of $20 has been included for this. For those who accept the diagnostic test, there is
the risk of loss of an unaffected fetus. For those affected and who test positive, there is
the risk of an “unnecessary” termination if the pregnancy would have resulted in
spontaneous miscarriage. The cost of that termination is offset against the resource cost
of a miscarriage.
Table 33
NT ultrasound screening for trisomy 21 for all pregnant women (260,000 live births)
Trisomy 21 pregnancies
NT
screening
12 weeks
Detection
rate
CVS
Decline
Accept
77
15
85
No. of
women
Cost per
woman
693
$100
Unaffected pregnancies
$69,333
534
80
No. of
women
Total cost
FPR
5%
$20
$1,602
Decline
15%
85%
454
$626
$283,980
Accept
Termination
90%
408
$905
$369,609
Fetal loss 0.9%
Spontaneous
miscarriage
40%
114
$905
$103,143
Live trisomy
21 births
Total cost
Cost per
woman
Total cost
259,584
$100
$25,958,400
1,947
$20
$38,938
$626
$6,904,026
$905
$89,858
99
171
$827,667
Total cost of screening
$32,991,222
$33,818,889
CVS = chorionic villus sampling; FPR = false positive rate; NT = nuchal translucency
68
Nuchal translucency measurement in the first trimester of pregnancy
Table 34
Biochemical screening for trisomy 21 for all pregnant women (260,000 live births)
Trisomy 21 pregnancies
No of
women
1st trimester
Cost per
woman
Unaffected pregnancies
Total cost
No of
women
Cost per
woman
Total cost
259,584
$54.50
$14,147,328
693
Miscarriage
rate
22%
2nd trimester
153
540
$905
$54.50
$138,532
$29,444
– Biochemical
screen
Detection
rate
64%
346
– Amniocentesis
Decline
15%
52
$20
$1,037
Decline
1,947
$20
$38,938
Accept
85%
294
$581
$170,698
Accept
11,032
$581
$6,407,571
Termination
90%
265
$1,016
$268,743
Fetal
loss
99
$905
$89,858
Spontaneous miscarriage
23%
63
$905
$57,397
Live trisomy 21 births
12,979
212
Total cost
$665,851
$20,683,695
Total cost of screening
$21,349,547
Results
In the absence of screening or diagnosis in a population of 260,000 live births, 693
trisomy 21 pregnancies could be expected at 11 weeks, with 540 cases at 16 weeks and
416 live trisomy 21 births.
Table 35 suggests that second trimester biochemical screening will detect 346 cases of
trisomy 21 per year at a cost of $21.4million ($61,746 per case detected). If NT
ultrasound screening is introduced, it will add an additional $12.5 million but detect a
further 188 cases. If universal NT ultrasound screening was implemented and combined
with biochemical screening in the first trimester, the extra cost would be $14.3 million
but there would be 65 additional cases detected. If we only consider NT ultrasound
screening plus biochemical screening in the first trimester compared with biochemical
screening in the second trimester, the extra cost is $26.7 million with an extra 253 cases
detected ($105,484 per extra case detected). The likely number of trisomy 21 births with
second trimester biochemical screening, NT ultrasound, or a combination of NT and
biochemical screening in the first trimester would be 212, 171 and 141, respectively.
Table 35
Primary cost-effectiveness analysis of pregnancy screening strategies for trisomy 21
compared with next best strategy: cost per trisomy 21 case detected
Number of
cases
detected
Total cost
($)
Cost per case
detected ($)
∆ cases
detected
∆ cost ($)a
∆ cost per
case detected
($)a
Biochemical screening (second
trimester)
346
21,349,547
61,746
346
21,349,547
61,746
NT ultrasound screening
534
33,818,889
63,347
188
12,469,342
66,291
NT ultrasound screening + first
trimester biochemical testing
599
48,065,939
80,238
65
14,247,051
218,602
∆ = incremental; NT = nuchal translucency
a Rounded to the nearest whole number
Nuchal translucency measurement in the first trimester of pregnancy
69
The economic analysis of NT ultrasound screening has been limited by the nature of the
data on the true detection rate for ultrasound screening. The primary analysis has
assumed that ultrasound screening boosts detection compared with biochemical
screening in the second trimester from 64.0 per cent to 77 per cent, while maintaining a 5
per cent FPR. If NT ultrasound is combined with first trimester biochemical screening, a
detection rate of 86.4 per cent has been assumed. This key assumption is subject to
considerable uncertainty given the quality of the trial data and the operator dependent
characteristics of NT ultrasound screening in practice. While there is training and quality
assurance in place, it is always unclear what level of detection is achieved in clinical
practice. The modelling exercise has by necessity made a number of other assumptions
on utilisation, costs and risk. The reviewers have made the best assumptions from the
data available but there remains considerable uncertainty surrounding the parameters of
the model. The results should therefore be viewed as only indicative of the range of likely
costs and outcomes of alternative screening modalities.
Figure 14: Cost effectiveness of universal screening options
with 100% take up
60
NT and serum
screening in 1st
trimester
50
$ million
40
NT
30
Serum
screening in
2nd trimester
20
10
0
0
100
200
300
400
500
600
cases detected
Figure 14 illustrates the comparative costs and outcomes for the three screening options
considered in the main analysis. The results of the modelling exercise suggest that if a
difference in detection rate of 20 percentage points between combined screening with
NT ultrasound plus biochemical markers in the first trimester and biochemical screening
in the second trimester can be maintained in a universal NT screening program, then the
former may cost an extra $26.7 million per year, with 253 more trisomy 21 cases detected
and 71 fewer trisomy births a year. The incremental costs are $105,484 per extra case
detected (see Appendix H; Table H-3).
70
Nuchal translucency measurement in the first trimester of pregnancy
If screening was restricted to women aged 30 years or over, then the cost per case
detected would be one third less. If screening was restricted to women aged 35 years or
over, then the cost per case detected would be halved.
With a high level of substitution of NT ultrasound screening for dating ultrasound in
pregnancy and a reduction in the total amount of biochemical screening, it would be
possible to achieve a resource saving. However, this is an unlikely scenario as most
observers expect that NT screening would be combined with biochemical screening and
is unlikely to replace more than half of dating ultrasound scans. The main analysis has
not taken account of the current level of diagnostic testing in those 35 or over. Taking
into account the conservative estimate that a third of women aged 35 years or more have
an amniocentesis in the second trimester because of the risk associated with their age,
one would expect to see 56 cases detected at a cost in excess of $9 million.
Screening is less expensive than amniocentesis, with a lower detection rate. If done
earlier in pregnancy it could, however, detect a higher absolute number of cases of
trisomy 21 (a proportion of which would have resulted in spontaneous abortion) than
amniocentesis. Provided that the take up of screening exceeded 43 per cent, and the
detection rate was at least 86 per cent, the combination of NT and biochemical screening
would dominate testing with amniocentesis (see Appendix H). In other words screening
43 per cent of women would save money and detect more cases compared to testing a
third of women aged over 35 with amniocentesis.
Taking account of the current rate of amniocentesis would improve the overall cost
effectiveness of NT screening compared to current screening and diagnostic testing. It
needs to be said, however, that screening by amniocentesis and CVS is already falling as a
consequence of increased levels of biochemical screening and it is not known if a greater
use of NT screening will lead to a reduction in diagnostic testing in women aged over 35.
Although NT screening may offer greater direct visual reassurance to women, it may be
that those at higher risk of an abnormal pregnancy may prefer to have the certainty of
amniocentesis or CVS and may not be willing to accept the results of ultrasound and
biochemical screening tests. If that is a common view, there might be little substitution in
this age group.
Sensitivity analysis around the main parameters of uncertainty suggests that, depending
on the true detection rate in practice and the extent of substitution for dating ultrasound,
the incremental cost per extra case detected would be in the range of $43,825 - $141,664.
While considerable doubt remains about both its comparative effectiveness and its true
comparative cost in clinical practice, it seems likely that the substitution of universal NT
ultrasound screening for universal biochemical screening for trisomy 21 would lead to an
extra cost of at least $11 million per year (with see Appendix H; Table H-7) and possibly
closer to $27 million (Table 35). This estimate does not take into account the range of
current screening practices in Australia. It is based on a subsidised screening test without
consideration of the costs or outcomes of a coordinated population screening program
with either maternal biochemical testing or ultrasonography. In addition, it should be
noted that in calculating these figures no attempt has been made to take account of the
social value of trisomy 21 births, in terms of either their potential future social
contribution or costs of care.
Nuchal translucency measurement in the first trimester of pregnancy
71
Relative cost-effectiveness has been calculated on the basis of costs per case detected.
These are taken as proxies for the range of outcomes of screening. An important
outcome is an increase in the quality and improvement in the timing of information of a
potential fetal abnormality as this allows women to have an earlier, less physically (and
perhaps emotionally) traumatic termination if they so choose.
However, for others there would be an increase in unnecessary anxiety, invasive
procedures and terminations of affected fetuses that would have otherwise miscarried
before second trimester biochemical screening was done. The economic analysis suggests
that the combination of NT ultrasound and biochemical screening in the first trimester
when compared with biochemical screening in the second trimester, would lead to 155
“less traumatic” terminations, but also 44 additional terminations that would have
otherwise resulted in a fetal loss before 16 weeks.
72
Nuchal translucency measurement in the first trimester of pregnancy
Conclusions
Safety
The literature focusing on the safety of ultrasound in pregnancy is not of high quality.
However, the ubiquitousness of the procedure and the fact that no major adverse events
have come to light suggests that ultrasound in pregnancy is safe. Several professional
organisations have issued recommendations about the use of specific types of ultrasonic
imaging modalities based on indication, maternal and fetal characteristics and the
potential for teratogenic or other adverse outcomes. These support the prudent use of
the technology, stressing the importance of minimum output levels and exposure times.
Effectiveness
When used as a single modality, screening by measurement of NT in the first trimester
has a detection rate for trisomy 21 of approximately 77-82 per cent at a false positive rate
(FPR) of 5-8 per cent. For maternal biochemical screening, the comparable detection rate
using double markers (PAPP-A and free β-hCG) in the first trimester of pregnancy is
65 per cent at an FPR of 5 per cent. For maternal biochemical screening during the
second trimester using the triple marker test, the detection rate is 57-64 per cent and
using the quadruple marker test the detection rate is 63-68 per cent.
If used in combination in the first trimester, the detection rate with a 5 per cent FPR is
86 per cent for NT screening plus double markers (PAPP-A and free β-hCG), 87 and
88 per cent for NT plus triple markers PAPP-A, free β-hCG, AFP and PAPP-A, free βhCG, uE3 respectively and 88 per cent for NT plus quadruple markers (PAPP-A, free βhCG, AFP and uE3).
Cost-effectiveness
A universal maternal biochemical screening program in the second trimester with
100 per cent uptake by pregnant women would cost $21.3m. If a screening program of
NT ultrasound plus maternal biochemical markers in the first trimester could achieve a
20 percentage point improvement in the detection rate of trisomy 21 compared with
biochemical screening in the second trimester, then the modelled evaluation suggests that
it may cost $26.7 million more per year, with 253 more trisomy 21 cases detected. The
incremental cost is $105,484 per extra case detected. If screening was restricted to
women aged 30 years or over, then the cost per case detected would be one third less. If
screening was restricted to women aged 35 years or over, then the cost per case detected
would be halved. Sensitivity analysis around the main parameters of uncertainty suggests
that, depending on the true detection rate in practice and the extent of substitution for
dating ultrasound and diagnostic tests in high risk pregnancies, the incremental cost per
extra case detected would be in the range of $43,825 - $141,664.
Nuchal translucency measurement in the first trimester of pregnancy
73
If a comparison is made between NT ultrasound in first trimester and biochemical
screening in the second trimester then the additional cost is $12.5m with 188 extra cases
detected. None of these cost effectiveness ratios considers the social value or cost of care
for a trisomy 21 birth.
Recommendations
The MSAC considers that nuchal translucency screening (NTS), and NTS in conjunction
with first trimester maternal biochemical screening (T1MBS), are safe and effective
where provided by individuals with appropriate expertise in NTS. Hence NTS providers
need to be appropriately accredited. However, the MSAC recommends that public
funding should not be supported for NTS or NTS in conjunction with T1MBS as stand
alone services, due to their poor cost-effectiveness.
Consideration should be given to public funding of NTS or NTS in conjunction with
T1MBS by incorporating, as far as possible, provision of the services into existing
services provided in early pregnancy.
The Minister for Health and Ageing accepted these recommendations on
16 October 2002.
74
Nuchal translucency measurement in the first trimester of pregnancy
Appendix A
MSAC terms of reference and
membership
The MSAC's terms of reference are to:
•
advise the Minister for Health and Ageing on the strength of evidence pertaining to
new and emerging medical technologies and procedures in relation to their safety,
effectiveness and cost-effectiveness and under what circumstances public funding
should be supported;
•
advise the Minister for Health and Ageing on which new medical technologies and
procedures should be funded on an interim basis to allow data to be assembled to
determine their safety, effectiveness and cost-effectiveness;
•
advise the Minister for Health and Ageing on references related either to new and/or
existing medical technologies and procedures; and
•
undertake health technology assessment work referred by the Australian Health
Ministers’ Advisory Council (AHMAC) and report its findings to the AHMAC.
The membership of the MSAC comprises a mix of clinical expertise covering pathology,
nuclear medicine, surgery, specialist medicine and general practice, plus clinical
epidemiology and clinical trials, health economics, consumer affairs and health
administration and planning:
Member
Expertise or Affiliation
Dr Stephen Blamey (Chair)
general surgery
Professor Bruce Barraclough
general surgery
Professor Syd Bell
pathology
Dr Paul Craft
clinical epidemiology and oncology
Professor Ian Fraser
reproductive medicine
Professor Jane Hall
health economics
Dr Terri Jackson
health economics
Ms Rebecca James
consumer health issues
Professor Brendon Kearney
health administration and planning
Mr Alan Keith
Assistant Secretary, Diagnostics and Technology Branch,
Commonwealth Department of Health and Ageing
Associate Professor Richard King
internal medicine
Dr Ray Kirk
health research
Dr Michael Kitchener
nuclear medicine
Mr Lou McCallum
consumer health issues
Emeritus Professor Peter Phelan
paediatrics
Dr Ewa Piejko
general practice
Dr David Robinson
plastic surgery
Professor John Simes
clinical epidemiology and clinical trials
Nuchal translucency measurement in the first trimester of pregnancy
75
76
Member
Expertise or Affiliation
Professor Richard Smallwood
Chief Medical Officer,
Commonwealth Department of Health and Ageing
Dr Robert Stable
Representing the Australian Health Ministers’ Advisory
Council
Professor Bryant Stokes
neurological surgery
Professor Ken Thomson
radiology
Dr Douglas Travis
urology
Nuchal translucency measurement in the first trimester of pregnancy
Appendix B
Supporting committee
Supporting committee for MSAC Reference 04a – Nuchal translucency
measurement in the first trimester of pregnancy for screening of trisomy 21 and
other autosomal trisomies
Dr Paul Hemming (Chair)
MB, ChB, FRACGP, FRCGP, FAMA
President
Royal Australian College of General Practitioners
member of the MSAC
Dr Matthew Andrews
MBBS (Hons), MMed, FRANZCR
Radiologist,
Linacre Private Hospital, Hampton
nominated by the Royal Australian
and New Zealand College of
Radiologists
Associate Professor Lachlan de Crespigny
MD, BS, FRCOG, FRANZCOG, DDU, COGU
Honorary Fellow Murdoch Children’s Research
Institute, Melbourne;
Department of Obstetrics and Gynaecology
University of Melbourne
nominated by the Australian
Association of Obstetrical and
Gynaecological Ultrasonologists
Professor David A Ellwood
MA, DPHIL (Ocon), FRANZCOG, DDU
Associate Dean, Canberra Clinical School University
of Sydney;
Professor of Obstetrics & Gynaecology
Director of Fetal Medicine Unit
The Canberra Hospital
nominated by the Royal Australian
and New Zealand College of
Obstetricians and Gynaecologists
Dr Peter Garcia-Webb
MBBS, MD, FRCPA, FAACB
Head, Department of Clinical Biochemistry
Mayne Health, Western Diagnostic Pathology
nominated by the Pathology
Services Advisory Committee
Associate Professor Eric Haan
BMedSc, MBBS, FRACP
Clinical Geneticist and Head
South Australian Clinical Genetics Service
Women's and Children's Hospital, North Adelaide
co-opted clinical geneticist
Ms Dell Horey
BAppSc, MMedSc
Convenor, Maternity Alliance
consumer representative
Dr John Primrose
MB, BS (Hons), FRANZCR
Senior Medical Adviser
Health Access and Financing Division
Department of Health and Ageing
Medical Advisor to the MSAC
Nuchal translucency measurement in the first trimester of pregnancy
77
Dr Amanda Sampson
MBBS, DObstRCOG, FRANZCOG, DDU, COGU
Ultrasonologist
Women's Imaging Centre
Freemasons Hospital Medical Centre
East Melbourne
nominated by the Royal Australian
and New Zealand College of
Obstetricians and Gynaecologists
Dr Peter Warren
MB, ChB, Dip Obst, FRANZCR, DDU
Director of Medical Imaging
Royal Hospital for Women, Randwick
nominated by the Royal Australian
and New Zealand College of
Radiologists
Ms Linda Marshall
BSc, BA, MBA
MSAC Project Manager
Diagnostics and Technology Branch
Department of Health and Ageing
78
Nuchal translucency measurement in the first trimester of pregnancy
Appendix C
Table C-1
Studies included in the review
General characteristics of studies on NT measurement meeting entry criteria
Location
Date of
enrolment
Cases
Maternal agea
Quality
criteria
(ABCDE)b
UK
1992 to 1993
3
29.8c
Y1YNY
Borrell et al (1996,
1997)
Spain
1991 to 1993
47
?
Y2YNY
A or CVS
Brambati et al
(1995)
Italy
1992 to 1993
26
?
Y2YNY
CVS
Austria
1993 to 1994
4
26
Y2NNY
A
Australia
1989 to 1993
5
35c
Y1YNY
A or CVS
Hyett et al (1995)
UK
?
36
?
Y2NUY
CVS
Hyett et al (1996)
UK
1993 to 1995
70
?
Y2NNY
CVS
Kornman et al
(1996)
The
Netherlands
1994
7
38
Y2YNY
A or CVS
Martinez et al
(1997)
Spain
?
9
38
Y2YNY
CVS
Nicolaides et al
(1994, Pandya et al
(1994)
UK
1990 to 1994
61
35
Y1YYY
A or CVS
Pandya et al
(1995b)
UK
1990 to 1994
101
35
Y2NNY
A or CVS
Salvoldelli et al
(1993)
Switzerland
1985 to 1991
28
?
Y2YNY
CVS
Schwarzler et al
(1999)
UK
1996 to 1997
12
29.4c
Y1YNY
Karyotyping,
pregnancy outcome
Scott et al (1996)
Australia
1993 to 1995
8
38c
Y2YNY
CVS
UK
?
326
31
Y2YNY
A or CVS
Szabo et al (1995)
Hungary
?
31
?
Y2YNY
CVS, cordocentesis
Thilaganathan et al
(1999)
UK
1994 to 1998
21
28.6c
Y5NUY
CVS
France
1988 to 1991
9
?
Y2YNY
A or CVS
Reference
Bewley et al (1995),
Roberts et al (1995)
Hafner et al (1995)
Hewitt (1993)
Snijders et al (1998)
Ville et al (1992)
Population
Reference test
Karyotyping,
pregnancy outcome
A = amniocentesis; CVS = chorionic villus sampling; N = no; Y = yes; ? = unknown or unstated
a Values are medians unless otherwise stated
b Quality criteria are listed in Table 16
c Mean
Nuchal translucency measurement in the first trimester of pregnancy
79
Appendix D
Existing recommendations
US National Institutes of Health Consensus Development
Programs
Following an earlier Consensus Development Conference convened by the US National
Institutes of Health (NIH) in 1984 (Anonymous 1984), the Routine Antenatal Diagnostic
Imaging with Ultrasound Study (RADIUS) Group conducted a randomised controlled trial
on the routine use of ultrasound screening for women at low risk of poor pregnancy
outcomes (Ewigman et al 1993, LeFevre et al 1993, Crane et al 1994). The study examined
the experience of more than 15,000 women over several years with results published in the
early 1990s.
One of the substudies focused on fetal anomalies, examining the impact of detection on
management and survival. It found that while ultrasonography detected more than three
times as many anomalous fetuses, it did not significantly influence the management or
outcome of pregnancies complicated by congenital malformations. In addition,
ultrasonography had no significant impact on survival rates among infants with potentially
treatable, life threatening anomalies despite the opportunity to take precautionary measures
such as delivery in a tertiary centre (Crane et al 1994).
Reanalysis of the RADIUS results by other authors raised concerns that the main findings
were predicated on a certain level of operator skill or that there were system-wide
differences in detection rates for the screening of malformed fetuses. Romero (1993)
found that the detection rate in six European centres was 7.5 per 1,000 compared with
about 6.8 per 1,000 in tertiary centres participating in the US study. Tertiary centres in
Europe were found to be 4.4 times (95% CI=2.1, 9.5) more likely to identify a structural
malformation than centres in the RADIUS Group (OR=3.9; 95% CI=1.6, 9.8) (Romero
1993). Extending this argument, DeVore suggested that reimbursement by third-party
payers which is dependent on the diagnostic skill of the operator, will produce a favourable
cost-effectiveness profile for the screening procedure (DeVore 1994).
In 1993, the NIH Technology Assessment Workshop was convened to discuss the impact
of the results on public health and reimbursement policies. It did not reach a policy
position.
Canadian Task Force on the Periodic Health Examination
The Canadian Guide to Clinical Preventive Health Care was released by the Canadian Task
Force on the Periodic Health Examination in 1994. It states that there is “fair evidence” to
support offering triple marker screening (alpha-fetoprotein, human chorionic
gonadotrophin and unconjugated oestriol) to women under 35 years of age when a
comprehensive screening and prenatal diagnosis program (with education, interpretation
and follow-up) is available. Screening with maternal biochemical markers outside a fully
coordinated program is deemed undesirable. Triple marker screening followed by prenatal
diagnosis may be offered to women over 35 years of age as an alternative to prenatal
diagnostic techniques alone.
80
Nuchal translucency measurement in the first trimester of pregnancy
Ultrasonographic screening using nuchal translucency (NT) is not recommended for
trisomy 21 as part of the periodic health examination of pregnant women due to concerns
about measurement reliability and generalisability.
US Preventive Services Task Force
The Guide to Clinical Preventive Services is a series of recommendations from the US
Preventive Services Task Force (USPSTF) that is intended to provide clinicians with
information on the effectiveness of different clinical preventive services and the quality of
evidence on which recommendations are made. The second edition of the Guide,
published in 1996, recommends offering screening for trisomy 21 using multiple maternal
biochemical markers at 15-18 weeks of gestation to all pregnant women although it does
not recommend a particular marker combination. It suggests patients have access to
counselling and follow-up services, skilled high-resolution ultrasound and amniocentesis
capabilities, and reliable and standardised laboratories.
The Guide states that there is insufficient evidence to recommend for or against routine
ultrasound examination as a screening test for trisomy 21.
Royal College of Obstetrics and Gynaecology
In 1997, the Royal College of Obstetrics and Gynaecology Study Group on Screening for
Down Syndrome in the First Trimester published the following findings (RCOG 1997):
1) Although there appeared to be insufficient evidence to recommend routine screening
for trisomy 21 in the first trimester by biophysical and biochemical markers:
a) there were sufficient data to consider screening for trisomy 21 by the measurement
of NT at 10-14 weeks gestation an acceptable procedure. Preliminary reports
indicated that the detection rate for a given FPR are at least similar, if not superior,
to biochemical screening with multiple markers at 15-22 weeks gestation. However
NT screening should only be conducted where:
i) centres had staff with a high level of ultrasound competence and had been
certified by an external agency and subjected to external quality control
procedures; and
ii) centres had high standard precision equipment, clinical protocols and external
systems of quality assurance and ongoing audit.
Nuchal translucency measurement in the first trimester of pregnancy
81
b) there were sufficient data to consider that specific biochemical markers for trisomy
21 at 9-13 weeks gestation (notably pregnancy-associated plasma protein-a and beta
human chorionic gonadotrophin) were as effective as those biochemical markers in
established use at 15-22 weeks gestation. There may be additional biochemical
markers that will become applicable in the first trimester. The introduction of
biochemical markers in first trimester screening for trisomy 21 should only be
considered when:
i) robust assay kits, which meet international standards, were available;
ii) centres demonstrated that their staff had expertise and experience in the use of
these tests; and
iii) centres had clinical protocols and systems of quality assurance and ongoing
audit.
c) the combined use of screening with NT and biochemical markers in the first
trimester (9-13 weeks gestation) might have a detection rate for trisomy 21 superior
to either biochemical markers or NT screening alone.
2) As screening for trisomy 21 in the first trimester with biochemical and ultrasound
markers requires the active participation of the health professions in the community as
well as institutions, the following issues need to be addressed:
a) education and training of health professions such as family doctors, midwives,
obstetricians and health visitors;
b) increased provision of information to health professionals and pregnant women;
c) expansion of counselling services;
d) expansion of expertise on regularly performed diagnostic tests such as chorionic
villus sampling (CVS) and early amniocentesis. This may require a policy of
centralisation of these services until the safety of these techniques is demonstrated
by clinicians intending to provide these interventions. Recommendation of
minimum numbers of cases to be performed is important;
e) a revision in the provision of therapeutic abortion services;
f) central quality assurance of a continuing audit of counselling, information and
education as well as biochemical and biophysical tests;
g) a recommendation regarding the advisability of nationwide screening for trisomy
21; and
h) evaluation of the cost implications of the introduction of a national policy of
screening for trisomy 21.
82
Nuchal translucency measurement in the first trimester of pregnancy
Particularly for Point 1 and its subpoints, three members of the study group held a
dissenting opinion. They raised the following points (see RCOG 1997):
•
it has not been shown that NT measurement is a better screening test than second
trimester screening using four biochemical markers (refer to Point 1a);
•
NT measurement required quality control, but they did not agree that a case had been
made to limit NT measurement to centres certified by an external agency (refer to
Point 1ai);
•
first trimester biochemical screening was, on current evidence, not as effective as
second trimester screening using four markers (refer to Point 1b);
•
since the results of first trimester biochemical and ultrasound testing were not
correlated, their combination must be more effective than either alone, although the
precise method of combining these two tests was still being developed (refer to Point
1c); and
•
further research was needed to compare the performance of first and second trimester
screening to determine which should be recommended for use in routine screening
practice.
In 1998, RCOG convened a working group to recommend a standard format for
ultrasound scans conducted in the 20th week of gestation. In its report, the working group
concluded that current evidence suggested that scanning for NT was an effective way of
determining babies at risk of trisomy 21 and was best performed at 10-14 weeks. Whether
NT screening was preferable to serum testing remained to be decided and it was most
likely that a combination of serum testing and NT measurement would produce the
highest sensitivity for the lowest FPR. However, whether or not NT screening would be
introduced was a funding issue (see RCOG 2000).
Human Genetics Society of Australasia
A policy endorsed by the Human Genetics Society of Australasia (HGSA) in 1997 made
the following recommendations:
•
The increasing indications for prenatal diagnosis make it necessary to have available a
specialised team for prenatal diagnosis of birth defects and genetic diseases. This team
should consist of clinical and laboratory services;
•
Each State requires at least one specialised prenatal diagnostic service that may be a
discrete unit or a group of collaborating health professionals working in a coordinated
service. Such clinical units should be located in tertiary obstetric facilities;
•
Each such clinical service requires the services of a clinical geneticist, genetic
counsellor or nurse specialising in prenatal diagnosis, obstetrician (skilled in antenatal
diagnosis and ultrasound), social worker, clinic coordinator and secretarial assistance.
Some services also have another clinician skilled in antenatal ultrasound
(ultrasonologist) as well as the obstetrician;
Nuchal translucency measurement in the first trimester of pregnancy
83
84
•
Each prenatal diagnosis service should have an expert ultrasound team led by a
subspecialty trained medical specialist (obstetrician or radiologist) who is well versed in
fetal and obstetric ultrasound. Ultrasonologists should have the qualifications of
Certification in Obstetric and Gynaecological Ultrasound (COGU), Certification in
Maternal-Fetal Medicine (CMFM) or the equivalent in experience and knowledge. If
sonographers are used, they should also have special training in fetal anomaly detection
and obstetric ultrasound and be appropriately supervised. The units should use
modern, high-resolution ultrasound equipment;
•
Clinical management where a fetal anomaly is found and the implications are unclear
should include seeking further opinions from relevant specialists (e.g. clinical geneticist,
paediatric surgeon or neurosurgeon). A multidisciplinary group discussion to consider
options for management should be encouraged;
•
Amniocentesis, CVS and fetal blood sampling should be performed in a prenatal
diagnosis service where the operator(s) have sufficient training and annual experience
of the procedure to keep the complication rates as low as possible. There is evidence
that fetal loss rate for CVS is operator and experience-dependent. Prenatal diagnosis
services that do not perform large numbers of specific procedures per year should be
encouraged to refer their cases to a prenatal diagnostic service that does. Each prenatal
diagnosis service should be expected to monitor its own performance of prenatal
diagnosis procedures and make available statistics about its sampling success rate,
proportion of abnormalities detected, fetal loss rate and other complications;
•
The prenatal diagnostic service should be closely associated with clinical genetic and
diagnostic facilities in each State to allow effective counselling of the extended family if
required;
•
Maternal biochemical screening for trisomy 21 and neural tube defects should be
considered an accepted prenatal diagnostic option. Laboratories offering maternal
biochemical screening should have sufficient throughput to maintain standards and
audit results. The maternal biochemical screening service should be part of a well
organised program which coordinates laboratory testing, education of patients and
doctors, and counselling of patients. The prenatal diagnosis and ultrasound
investigations should be the responsibility of the prenatal diagnostic service;
•
Facilities for prenatal diagnosis should be available at least for the following:
–
all women of 37 years and over (some States offer prenatal diagnosis at the age of
35 years and over, and this policy statement is not meant to alter this practice, but
states 37 years as a minimum standard);
–
all women who have previously had a child with a neural tube defect or been
determined to be at increased risk for such, in light of a serum alpha-fetoprotein
test;
–
all women who have had a biochemical screening test for trisomy 21 that suggests
the chromosome abnormality risk is greater than the accepted cutoff being used in
the protocol; and
–
all other women who have a high risk of a fetus with a diagnosable defect, (e.g.
ultrasound-detected abnormality, inborn error of metabolism, DNA-identifiable
condition).
Nuchal translucency measurement in the first trimester of pregnancy
•
The choice between CVS, amniocentesis, biochemical screening and ultrasound should
be on the basis of informed consent that takes into consideration the test risks, timing,
accuracy and method of termination (if affected);
•
Couples should receive appropriate counselling, ideally well before the diagnostic
procedures are performed. This must include at least discussion of the risk of
recurrence, the benefits and risks of the procedure, and the couple’s intended response
to an abnormal result. Educational material should be supplied.
•
Interpretation of results should be a team responsibility. The results should be
communicated to the referring doctor and patient as soon as possible and in a manner
that ensures clear understanding.
•
The action to be taken on the basis of abnormal results is a decision for the couple
concerned, based on the information given with full counselling support. Where
termination of pregnancy is undertaken, it should be on the basis of a written
diagnostic report.
•
The outcome of all pregnancies where prenatal diagnosis has taken place should be
monitored in a standard manner. Each prenatal diagnostic unit should monitor the
outcome of all CVS, amniocentesis and fetal blood sampling at regular intervals. The
pathological examination of the aborted fetus and placenta should be done by a
pathologist experienced in fetal pathology with due regard to confirmation of the
amniocentesis result. This should include fetal radiography, cytogenetic analysis and
any appropriate biochemical investigation.
In October 2000, draft guidelines were made available for comment.
Royal Australian and New Zealand College of Obstetricians and
Gynaecologists
A statement endorsed in June 2000 by the Royal Australian and New Zealand College of
Obstetricians and Gynaecologists (RANZCOG) makes the following “best practice”
recommendations:
•
Women who are considered to be at increased risk for aneuploidy, based on clinical
history (advanced maternal age or previous affected pregnancy), should be offered the
choice of screening by nuchal translucency screening or second trimester maternal
biochemical screening, or diagnostic testing (either CVS or amniocentesis). All
procedures should be performed by experienced operators who have had appropriate
training. Access to consultation with a clinical geneticist should be available. General
counselling support for women and their families should also be available as part of the
prenatal diagnosis service;
•
Women who are not considered to be at increased risk should be made aware of the
availability of screening tests for trisomy 21 and other chromosomal abnormalities.
This should include NT screening and second trimester maternal biochemical testing.
The relative advantages and disadvantages of the available screening tests should be
discussed, as well as performance information based on the audit figures of local
providers of the screening services. Regional variations in access to different forms of
testing should also be taken into account when recommending a screening test to
individual women;
Nuchal translucency measurement in the first trimester of pregnancy
85
86
•
NT screening should only be performed by trained operators, using a risk assessment
program that incorporates NT, crown-to-rump length (CRL) and maternal age. This
test should be done when the fetus has a CRL of 45-84 mm, which corresponds to 1113 weeks;
•
The second trimester biochemical screen should usually be done between 15 and 18
weeks gestation and a risk assessment performed incorporating maternal age and
weight, using a software package developed for that purpose. Some programs may
offer a wider gestational age range, and referring practitioners should be aware of local
guidelines;
•
Sequential testing (e.g. NT screening followed by second trimester biochemical
screening) is not currently recommended as a population screening method. However,
it should be recognised that some women may choose to have a number of different
screening tests and accept that this may increase their chance of a high-risk result;
•
All women who choose to have an antenatal screening test for trisomy 21 and other
fetal aneuploidy should have appropriate pre-test counselling, including the provision
of written information to ensure they have a complete understanding of the test and its
accuracy. All women receiving a high-risk test result should be provided with adequate
post-test counselling. The level of counselling support needed may vary with the type
of result and the resources of the referring practitioner to deal with the issues
surrounding an abnormal result. Abnormal screening test results should be treated as
urgent clinical problems requiring early referral to an individual or centre able to
provide both counselling and diagnostic procedures for prenatal diagnosis;
•
All providers of biochemical and ultrasound based screening tests for trisomy 21 and
other fetal aneuploidy should maintain comprehensive records and appropriate followup of cases so they know their own screening test characteristics. They should maintain
a continuing audit of their screening practice and be able to provide the users of their
service with accurate and current information on the numbers of pregnancies screened,
the detection rate and the screen positive rate. Ideally, providers should contribute data
to a central body to facilitate pooling of data and allow for external scrutiny of results;
and
•
Women’s understanding of, and satisfaction with, the screening methods should be
assessed so that appropriate information and education can be offered.
Nuchal translucency measurement in the first trimester of pregnancy
Appendix E
Ongoing primary studies
Serum, Urine and Ultrasound Screening Study
The UK National Health Service (NHS) Research and Development Health Technology
Assessment Programme, through the National Coordinating Centre for Health
Technology Assessment (NCCHTA), commissioned a study to assess the individual and
combined performance of serum, urine and ultrasound markers in the first trimester of
pregnancy. The study – called the Serum, Urine and Ultrasound Screening Study
(SURUSS) (NHS 2000) – started in 1996 and is expected to involve 52,000 women
recruited from 15 centres. Ultrasound nuchal translucency (NT) measurements will be
taken at 10-12 weeks gestation and serum and urine samples collected at this time and also
at the time of routine screening (about 16 weeks gestation). The study is also expected to
specify the organisational arrangements necessary for the implementation of the most
effective screening method. Results are expected to be released in early 2001.
First and Second Trimester Screening Study
The First and Second Trimester (FaST) Screening Study is an Australian project that
commenced in 1998, involving Monash University and Monash Medical Centre. It is
funded jointly by Monash University and the Victorian State Government through the
Department of Human Services (Anonymous 2000). The study is attempting to assess the
relative merits of screening for trisomy 21 in a multiracial Australian population by
enrolling up to 15,000 pregnant women. The study is expected to be completed in late
2001.
The specific aims of FaST are:
•
to evaluate NT as a prenatal screening marker for trisomy 21 in an Australian
population;
•
to evaluate free beta human chorionic gonadotrophin (β-hCG) and pregnancyassociated plasma protein as first trimester biochemical markers for trisomy 21 in an
Australian population;
•
to evaluate urinary β-core fragment and hyperglycosylated hCG as prenatal screening
markers for trisomy 21 in an Australian population in both the first and second
trimesters of pregnancy;
•
to define the optimum second trimester biochemical marker combination of inhibin A,
free α-hCG, free β-hCG, alpha-fetoprotein (AFP) and unconjugated oestriol (uE3) in
an Australian population;
•
to assess the relationships between the above markers and to evaluate the usefulness of
the various combinations, comparing these to current second trimester “quadruple
screening” (free β-hCG, free α-hCG, AFP, uE3);
Nuchal translucency measurement in the first trimester of pregnancy
87
•
to provide cost analyses, in terms of cost per trisomy 21 pregnancy identified, for each
of the above screening strategies, alone and in combination, to describe the optimal,
most cost-effective prenatal screening strategy for trisomy 21 in an Australian
population;
•
to record women’s preferences for the timing of, and approach to, trisomy 21
screening; and
•
to define preferences and screening uptake rates by ethnicity.
First and Second Trimester Evaluation of Risk Trial
The First and Second Trimester Evaluation of Risk (FaSTER) Trial is funded under a
US$10 million three year grant from the National Institutes of Health (NIH) and the US
National Institute of Child Health and Human Development (NICHHD). The study is a
multicentre, non randomised longitudinal study enrolling concurrent controls. It uses a
non interventional trial design to compare the accuracy of first and second trimester non
invasive screening methods for trisomy 21 and other chromosomal abnormalities versus
diagnosis at delivery or fetal loss. The study is in the early stages of recruiting, through
participating obstetric centres, pregnant women between the ages of 16 and 45 years;
measurements will be taken before 10-14 weeks gestation, with a minimum sonographic
fetal crown-to-rump length (CRL) of 38-84 mm.
FaSTER is expected to enrol 62,000 patients in 11 centres across the United States.
Participating centres include the New England Medical Center, Tufts University School of
Medicine, Boston; Women and Infants Hospital, Brown University School of Medicine,
Providence; Mount Sinai Medical Center, Montefiore Medical Center, Albert Einstein
College of Medicine, New York; Intermountain HealthCare System, University of Utah
School of Medicine, Salt Lake City; William Beaumont Hospital, Royal Oak; University of
Texas Medical Branch, Galveston; University of Colorado Health Sciences Center, Denver;
and the Swedish Hospital Medical Center, Seattle.
As of April 2000, all staff training and software development had been completed and first
semester laboratory norms established. About 2,600 women had been recruited. An
interactive FaSTER trial website has been established (http://www.firsttrimester.org). It
assists patients in establishing their due date and deciding on their eligibility for enrolment
in the FaSTER trial.
88
Nuchal translucency measurement in the first trimester of pregnancy
Appendix F
Summary of meta-analysis of studies
on nuchal translucency measurement
in the detection of trisomy 21 applying
set cutoff measures
Table F-1 summarises the diagnostic test characteristics of nuchal translucency (NT)
measurement according to cutoff value. Most studies used a sonographic transducer of
3.5 MHz or above, although five studies failed to report this information. Reported
sensitivities ranged from 13.8 per cent (Ville et al 1992) to 100 per cent (Hewitt 1993),
although most fell between 40 and 70 per cent. Only about half the studies reported a
value for specificity. In these studies, the probability of the test correctly detecting people
without disease ranged from 68 per cent (Martinez et al 1997, Kornman et al 1996, Scott et
al 1996) to close to 100 per cent.
A meta-analysis was performed on six studies that gave results for both sensitivity and
specificity at a cutoff of ≥ 3 mm. Application of a random effects model to the data
resulted in a pooled measure of sensitivity and specificity of 62 per cent (95% CI=40, 80%)
and 93 per cent (95% CI=79, 98%), respectively. A likelihood ratio of 8.8 is computed
from pooled results, implying that a positive test result is 8.8 times more likely to occur in
pregnancies affected with trisomy 21 compared with those without trisomy 21.
Nuchal translucency measurement in the first trimester of pregnancy
89
Table F-1
Performance characteristics of nuchal translucency measurements in collected studies,
arranged according to cutoff values
Ultrasound characteristics
Route
Age of
gestation
(weeks)b
Detection
rate
(%)
False
positive rate
(%)
Likelihood
ratio
5
TA
12
50.0
1.2
41.7
Borrell et al
(1996, 1997),
Comas et al
(1995)
3.5
TA
13-18c
40.4d
3.7
10.9
Martinez et al
(1997)
6.5
TV
11
44.4 d
NA
NA
5
TA
12
72.8 d
NA
NA
3.5, 5
TA
10–13 c
50.0
NA
NA
Scott et al (1996)
5
TA
10–13 c
37.5 d
NA
NA
Bewley et al
(1995), Roberts
et al (1995)
3.5, 5
?
11
33.3
6.1
5.4
Brambati et al
(1995)
3.5, 5
TA/TV
8-15 c
26.9
3.2
8.4
Hyett et al (1995)
?
?
10–13 c
69.4 d
NA
Pandya et al
(1995b)
5
TA
12
76.0 d
31.4
2.4
Szabo et al
(1995)
3.5, 6.5
TA/TV
9-12 c
90.3 d
6.8
32.2
Pandya et al
(1994),
Nicolaides et al
(1994)
5
TA
11
73.8 d
31.6
2.3
Ville et al (1992)
?
TA/TV
9–14 c
13.8
NA
Hewitt (1993)
?
?
11w 4de
100.0
NA
NA
Savoldelli et al
(1993)
2.5, 3.75
TA
9w 3d – 12w
5d c
53.6
NA
NA
Referencea
Transducer
(MHz)
2.5 mm cutoff:
Hafner et al
(1995)
3.0 mm cutoff:
Hyett et al (1996)
Kornman et al
(1996)
4.0 mm cutoff:
NA
NA
NA
CRL = crown-to-rump length; d = days; NA = not available; TA = transabdominal; TV = transvaginal; w = weeks; ? = unknown or unstated
a Studies shaded and in bold type are included in a meta-analysis of diagnostic test characteristics
b Values are medians unless otherwise stated
c Figures presented are ranges
d Indicates that while various cutoffs are presented, the results for a thickness of ≥ 3 mm are given
e Figures presented are mean
90
Nuchal translucency measurement in the first trimester of pregnancy
Appendix G
Summary of comparative studies of
cost-effectiveness in screening for
trisomy 21 using NT ultrasound,
biochemical and age screening
Roberts et al (1998) Choosing options for ultrasound screening in pregnancy and
comparing cost effectiveness: a decision analysis approach
Country: UK
Screening strategy and comparators: Ultrasound screening alternatives including
ultrasound screening in the first trimester compared with no screening.
Comments: Assumes that ultrasound screening has an expected detection rate of 5085 per cent for trisomy 21 and 10-30 per cent for other lethal abnormalities. The average
cost for ultrasound screening in the first trimester in 1996 pounds was £30,583-217,099
per 1,000 women, with 1.58 cases detected and 8.93 cases missed. This suggests a cost per
case detected of £19,356-255,410. False positives and procedure-related miscarriages
appear to have been costed but the numbers are not reported. A cost per malformation
avoided is not reported either. The study does not appear to take account of the natural
rate of miscarriage and assumes a pregnancy prevalence of trisomy 21 of 1.5 per 1,000
(rather than a birth prevalence). It therefore underestimates the costs of screening and
diagnosis and bases the number of cases detected as the number of cases detected at term.
Serra-Pratt et al (1998) Trade-offs in prenatal detection of Down syndrome
Country: Spain
Screening strategy and comparators: Eight options were considered:
1.
Do nothing.
2.
Offer amniocentesis to all women (average 50 per cent uptake).
3.
Offer amniocentesis to pregnant women aged over 35 and ultrasound screening to
others.
4.
Triple test biochemical screening for all women, applying a 1:250 risk cutoff.
5.
As above, with a 1:100 risk cutoff.
6.
Offer amniocentesis to women aged over 38, triple biochemical screening to others
and, if the risk is above 1:270, offer ultrasound screening.
7.
Offer triple biochemical screening to all women aged over 30 with a risk threshold of
1:250 and ultrasound screening to those aged under 30.
8.
As 7, but with a 1:100 risk cutoff.
Comments: Compares eight screening strategies in the second trimester. Baseline
detection rates in strategies 3 and 4 are 52.1 per cent and 43.8 per cent respectively, with a
5 per cent FPR. Results are very sensitive to the assumed detection and false positive rates.
Option 6 had the highest number of cases detected but also the highest cost per case
detected. The baseline cost per case detected for options 2–8 is 19.75, 4.62, 3.45, 3.06, 4.8,
2.63 and 2.68 million pesetas.
Nuchal translucency measurement in the first trimester of pregnancy
91
The results are insensitive to uptake rates. The assumed costs appear to be low and
ultrasound is assumed to have zero cost. According to the reviewers’ calculations, the
incremental cost-effectiveness ratio (ICER) for strategy 3 compared with strategy 4 is
10.2 million pesetas.
Cusick and Vintzileos (1999) Fetal Down syndrome screening: a cost effectiveness
analysis of alternative screening programs
Country: United States
Screening strategy and comparators: Five age stratified screening strategies in the
second trimester of pregnancy, as follows:
1.
Amniocentesis for women 35 years and older.
2.
Triple marker biochemical screening for women aged under 35 followed by
amniocentesis for those with positive results.
Amniocentesis for women 35 years and older.
3.
Triple marker biochemical screening for all women followed by amniocentesis for
those with positive results.
4.
For women under 35, triple marker biochemical screening followed by genetic
sonogram where positive. Amniocentesis where the sonogram is positive.
For women 35 years and older, triple marker biochemical screening followed by
amniocentesis for those with positive results.
5.
Triple marker biochemical screening for all women followed by genetic sonogram
where positive and amniocentesis if this is also positive.
Comments: Compares five programs. The second program is currently a common
screening protocol. In the base case scenario it was assumed that the sensitivity of
ultrasound was 70 per cent and the FPR was 13 per cent. The five screening programs
were estimated to identify 30.0 per cent, 68.5 per cent, 62.3 per cent, 50.7 per cent and
35.8 per cent of all cases respectively. The screen positive rates (using an outcome of
increased risk of trisomy 21 in women with normal pregnancies) were 8.4 per cent, 14.9 per
cent, 8.3 per cent, 2.7 per cent and 1.2 per cent for strategies 1 to 5, respectively. The
number of normal pregnancies lost due to amniocentesis in the five programs was 56, 100,
55, 17 and 7. The costs per trisomy 21 case detected in the five programs were estimated to
be US$181,000, US$203,000, US$162,000, US$151,000 and US$194,000, respectively. The
total costs of these screening programs for 167,654 pregnant women (8.4% of whom
would be aged over 34 years) were calculated to be US$14.1 million, US$36.1 million,
US$26.1 million, US$20.0 million and US$18.0 million.
The following costs were used in the analysis: maternal biochemical triple screen - US$80;
ultrasound exam - US$200; amniocentesis - US$1,000. Programs 4 and 5, which use
sonography, appear to be the most favourable options, with the cost per case detected
comparable to that of program 3 but with much lower screen positive rates, fewer losses
due to amniocentesis and a considerably lower number of amniocentesis procedures
required to identify cases of trisomy 21. The variance in detection rate affected the costeffectiveness of the intervention. For instance at 50 per cent, the cost per case detected for
program 4 would be US$178,000, although FPRs and losses due to amniocentesis would
remain much lower than in program 3. However, with a sensitivity rate of 90 per cent,
program 5 would be the most favourable protocol, with a cost per case detected of
US$131,000.
92
Nuchal translucency measurement in the first trimester of pregnancy
The authors suggest that it is cost-effective to offer genetic sonogram prior to
amniocentesis following a positive biochemical test if the ultrasound detection rate is
at least 70 per cent. While biochemical screening alone costs more, it detects more cases of
trisomy 21.
According to the reviewers’ calculations, the ICER for triple screening over triple screening
followed by ultrasound, is US$117,391 per case detected at a 70 per cent detection rate for
the screening program incorporating ultrasound. In addition, the fetal loss per case
detected is 34 per cent compared with 7 per cent.
Wald et al (1997b) Antenatal screening for Down syndrome
Country: United Kingdom
Screening strategy and comparators: Triple marker biochemical screening comparing
first and second trimester and a range of markers.
Comments: Estimates the safety and financial cost-effectiveness of screening using
different combinations of biochemical markers in screening women with a 1.3 per 1,000
risk of a trisomy 21 birth. The calculation of costs for screening in the first trimester, using
maternal age with human chorionic gonadotrophin (hCG) and pregnancy-associated
plasma protein-a (PAPP-A), is based on a detection rate of 62 per cent, 5 per cent FPR,
fetal loss rate of 0.9 per cent and chorionic villus sampling (CVS) screen cost of £250. This
was estimated to be £31,600 per trisomy 21 birth avoided. This is more expensive than any
form of second trimester biochemical screening. The cost per trisomy 21 birth avoided for
second trimester screening is said to be in the range of £23,000–34,000, based on followup diagnostic amniocentesis costing £150. Additionally, first trimester screening precludes
screening for neural tube defects, whereas second trimester screening offers this additional
benefit. Nuchal translucency screening in combination with biochemical testing in the first
trimester is discussed in the expanded report, but is not judged to warrant economic
evaluation.
Vintzileos et al (1998) An economic evaluation of second trimester genetic
ultrasonography for prenatal detection of Down syndrome
Country: United States
Screening strategy and comparators: First trimester genetic sonography versus universal
CVS in women aged 35 years and over.
Comments: Varies the detection and FPRs for first trimester ultrasound screening for
women who are 35 years old or more with a prevalence of trisomy 21 of 1:100 to achieve
break even cost with universal CVS. Benefits are defined as financial savings associated
with a reduction in trisomy 21 births. The lifetime cost of neonates born with trisomy 21 is
assumed to be US$500,000. The CVS fetal loss rate is 1:100 and the uptake of ultrasound
and CVS is assumed to be the same (53 per cent of pregnancies). CVS has been assumed
to be 100 per cent accurate. The results include a FPR of 5 per cent, which requires a
sensitivity of at least 72 per cent for the financial benefits of screening to outweigh the
costs. This is estimated for all possible FPRs. A review of eight published studies detailing
the sensitivity and specificity of genetic sonography in the first trimester revealed that five
studies produced diagnostic accuracy compatible with net benefits.
Nuchal translucency measurement in the first trimester of pregnancy
93
When first trimester genetic ultrasound followed by CVS for those with abnormal results is
compared with universal CVS (applying a sensitivity and false positive rate for genetic
sonography of 77 per cent and 10 per cent respectively and a procedure-related fetal loss
rate of 1:250), savings of approximately US$22 million and 1,785 fetal lives per year would
be expected. It should be noted that this implies that universal CVS in this age group
would cost an extra US$80,000 per trisomy 21 birth avoided and lead to an extra 1,785
fetal losses compared with ultrasound screening in the first trimester.
Based on data in the paper, for a 77 per cent detection rate and 10 per cent FPR, the
reviewers estimate that, ignoring the lifetime cost of care, the cost per case detected for
universal CVS is US$240 million/2,000 = US$120,000 and for ultrasound screening,
US$80 million/0.7× 2,000 = US$57,000. In addition, universal CVS would lead to an
additional 1,785 fetal losses. The ICER for CVS based on these assumptions is
US$160 million/600 = US$267,000 per extra case detected with an additional 1,785 fetal
losses.
Vintzileos et al (2000) Cost-benefit analysis of prenatal diagnosis for Down
syndrome using the British or the American approach
Country: United States
Screening strategy and comparators: First trimester ultrasound screening versus second
trimester screening by age and biochemical marker testing. More specifically:
1.
First trimester ultrasound screening in all pregnant women followed by CVS for
positive screens and second trimester ultrasound for those found to have normal CVS
results; compared to
2.
Second trimester biochemical screening with amniocentesis for those screening
positive and all pregnant women over 35 years of age.
Comments: Cost-effectiveness analysis with benefits defined as live births with trisomy 21
avoided. Trisomy 21 births are attributed a cost of lifetime care of US$500,000. Best case
and worst case scenarios are presented for ultrasound screening with an 80 per cent
detection rate and 5 per cent FPR assumed for the former; and a 50 per cent detection rate
and 10 per cent FPR assumed for the latter. Seventy five per cent of women are said to be
screened by ultrasound. Sixty six per cent of women under 35 are screened by maternal
biochemical screening with an overall detection rate in all ages of 60 per cent applying a
risk threshold of 1:150. Ultrasound examination costs US$200 compared with biochemical
screening at US$70, counselling sessions are valued at US$100 and CVS or amniocentesis
at US$1,200.There is a 70 per cent uptake of invasive diagnostic procedures among screen
positive women. In a population of four million pregnancies the best case for ultrasound
screening is said to have a cost of US$1,995 million, preventing 1,779 trisomy 21 births
while resulting in 1,370 procedure-related fetal losses. The worst case is said to cost
US$2,439 million, prevent 1,212 trisomy 21 births and result in 2,420 fetal losses.
In contrast, the biochemical and age screening approach is costed at US$1,904 million,
with 1,411 trisomy 21 births prevented and 1,680 fetal losses. The introduction of first
trimester ultrasound screening for pregnant women in the US is predicted to cost at least
US$91 million more per year than the biochemical and age screening strategy, but to
reduce by almost one half, the number of invasive procedures and also reduce the number
of fetal losses by 310. The results are sensitive to the assumed detection rates, the fetal loss
rate and the cost of ultrasound. The results are also likely to be sensitive to the assumed
uptake of screening in each strategy, although this is not reported.
94
Nuchal translucency measurement in the first trimester of pregnancy
Appendix H
Modelled economic evaluation of
nuchal translucency ultrasound
screening under various alternative
assumptions
The primary analysis of the cost effectiveness of nuchal translucency (NT) ultrasound
screening is based on the assumptions in Tables 30–32. The following eight scenarios
provide analyses of the cost effectiveness of NT ultrasound screening under a variety of
alternative assumptions.
Alternative scenario 1: screening for those at higher risk only (age-related)
This assumes that screening is offered only to those women aged 35 years or over.
The prevalence of trisomy 21 in this age group is assumed to be 3.2 per 1,000 (Fletcher et
al 1995), with an expected 252 cases at 12 weeks and 131 live trisomy 21 births. All other
assumptions are as in the primary analysis. The results are shown in Table H-1. In women
who are 35 years or older (with twice the incidence of trisomy 21 compared with all
women), the incremental cost per extra case detected by NT ultrasound screening
compared with biochemical screening alone is $44,117, which is about half the cost per
case detected for women of any age. Clearly, targeting a high-risk group reduces the costs
per case detected in proportion to the relative risk. The number of cases detected for
biochemical screening in the first trimester, NT ultrasound alone and a combination of NT
ultrasound and biochemical screening in the first trimester would be 109, 157 and 188
respectively. The number of live trisomy 21 births would be 67, 54 and 44 respectively.
Table H-1
Cost per trisomy 21 case detected in women aged 35 years or overa
Number of
cases
detected
Total cost
($)
Biochemical screening (second
trimester)
109
3,330,627
30,625
109
3,330,627
30,625
NT ultrasound screening
157
5,440,522
34,746
48
2,109,895
44,117
NT ultrasound screening + first
trimester biochemical testing
188
7,693,263
40,830
32
2,252,740
70,753
Cost per
case
detected ($)
∆ cases
detected
∆ cost ($)
∆ cost per
case
detected ($)
∆ = incremental; NT = nuchal translucency
a Costs are rounded to the nearest whole number
Another option is to offer screening to women who are 30 years or older (with a relative
risk of 1.63 compared with all women (Fletcher et al 1995)). Table H-2 shows the costeffectiveness of screening if this age cutoff were to be applied.
Nuchal translucency measurement in the first trimester of pregnancy
95
Table H-2
Cost per trisomy 21 case detected in women aged 30 years or overa
Number of
cases
detected
Total cost
($)
Biochemical screening (second
trimester)
253
9,480,178
37,531
253
9,480,178
37,531
NT ultrasound screening
364
15,349,567
42,207
111
5,869,389
52,841
NT ultrasound screening + first
trimester biochemical testing
438
21,745,350
49,690
74
6,395,783
86,488
Cost per
case
detected ($)
∆ cases
detected
∆ cost ($)
∆ cost per
case
detected ($)
∆ = incremental; NT = nuchal translucency
a Costs are rounded to the nearest whole number
With respect to screening of women aged 30 years or older (with two thirds the incidence
of trisomy 21 compared to all women), the incremental cost per extra case detected by
ultrasound compared with biochemical screening alone is $52,841, which is about two
thirds of the cost per case detected for all women. The number of trisomy 21 live births
would be 155, 125, and 103 for second trimester biochemical screening, first trimester NT
ultrasound screening alone and first trimester biochemical screening plus NT ultrasound,
respectively. The comparative results for other strategies in terms of cost per case detected
are again in proportion to the relative prevalence of trisomy 21 by maternal age.
Victorian and South Australian data suggest that in 1998 and 1999, 41-44 per cent of
women over the age of 34 had a diagnostic test, with 80 per cent of these based on an
indication of age alone (SABDR 1998; Jane Halliday, Manager, Victorian Perinatal Data
Collection Unit, Department of Human Services, Victoria, personal communication).
Assuming that a third of women aged 35 years or more currently have an amniocentesis in
the second trimester solely on the basis of age-related risk, one would expect to see 56
cases detected at a cost in excess of $9 million. If ultrasound and biochemical screening
could achieve a higher rate of uptake, even with a detection rate of only 86 per cent, there
would be more cases detected at a lower total cost. As long as uptake is greater than
43 per cent, the combination of ultrasound and biochemical screening with a detection rate
of 86 per cent would dominate testing with amniocentesis where it involved 33 per cent of
pregnant women aged 35 years or over.
It needs to be stated, however, that high rates of diagnostic testing by amniocentesis and
CVS have persisted in spite of the existence of biochemical screening. It may be that
women at higher risk of an abnormal pregnancy may prefer to have the certainty of
amniocentesis or CVS and may not be willing to accept the results of ultrasound and
biochemical screening tests. If that is a common view, there might be little substitution in
this age group. While the total cost of ultrasound screening would be lower, the costeffectiveness ratios in Table H-1 may be a reasonable approximation of reality.
Alternative scenario 2: ultrasound screening + biochemical screening in first
trimester compared with serum screening in second trimester
Women may well have ultrasound screening and, if negative, have further biochemical
testing in the first or second trimester. Tables H-1–3 show the cost-effectiveness of
ultrasound screening plus biochemical screening compared with biochemical screening
alone.
96
Nuchal translucency measurement in the first trimester of pregnancy
The combination of ultrasound and biochemical screening would add $25.0 million to the
cost of screening but detect an extra 345 cases. The incremental cost-effectiveness is
therefore $72,424 per additional case detected. The number of trisomy 21 live births would
be 212 for second trimester biochemical screening and 141 for the combination of first
trimester biochemical screening and NT ultrasound.
Table H-3
Cost-effectiveness analysis of ultrasound screening plus biochemical screening compared
with biochemical screening alone: cost per trisomy 21 case detecteda
Number of
cases
detected
Total cost
($)
Cost per
case
detected ($)
∆ cases
detected
∆ cost ($)
∆ cost per
case
detected ($)
Biochemical screening (second
trimester)
346
21,349,547
61,746
346
21,349,547
61,704
NT utrasound screening + first
trimester biochemical screening
599
48,065,939
80,238
253
26,716,392
105,484
∆ = incremental; NT = nuchal translucency
a Costs are rounded to the nearest whole number
Table H-4 shows the incremental cost-effectiveness of combined NT ultrasound and
biochemical screening in the first trimester compared with biochemical screening alone for
three age groups: 30 years and over, 35 years and over, and all ages. As expected, the
comparative cost-effectiveness of screening is proportional to the prevalence of trisomy 21
in each age group. However, in each age group the extra costs per trisomy 21 case detected
are greater for combined NT ultrasound and biochemical screening than for biochemical
screening compared with no screening. While the incremental cost-effectiveness ratio for
combined NT ultrasound and biochemical screening may represent good value for money,
it is greater than the average cost-effectiveness of second trimester biochemical screening
currently subsidised under Medicare, even for those aged 35 and over.
Table H-4
Incremental cost-effectiveness of ultrasound and biochemical screening compared with
biochemical screening alone by age groupa
Age 30 and over
Age 35 and over
All ages
37,531
30,625
61,704
54,763
105,598
Biochemical screening (second trimester)
Incremental cost per extra case detected ($)
NT ultrasound screening + first trimester biochemical
screening
66,298
Incremental cost per extra case detected ($)
NT = nuchal translucency
a Incremental costs are rounded to the nearest whole number
Alternative scenario 3: 100 per cent uptake of ultrasound screening or ultrasound
screening plus biochemical screening in the first trimester, compared to an assumed
50 per cent for biochemical screening in second trimester
If one assumes a higher uptake for ultrasound screening than first trimester biochemical
screening, the cost-effectiveness of ultrasound screening improves. If one assumes that
50 per cent of all pregnant women were to have biochemical screening (based on current
levels and future growth), and that the introduction of NT ultrasound screening increases
the rate of screening to 100 per cent, then the incremental cost for NT ultrasound
screening compared with biochemical screening is $64,111 per extra case detected (see
Table H-5). This is not very different from the primary analysis.
Nuchal translucency measurement in the first trimester of pregnancy
97
Both scenarios are hypothetical with the uptake now probably lower than 50 per cent, and
unlikely to ever reach 100 per cent with NT. Nevertheless, the calculations illustrate the
impact of a large increase in uptake. If the uptake of screening doubles with NT ultrasound
screening, so does the cost and the number of cases detected. The incremental cost per
extra case detected for NT ultrasound screening compared with biochemical screening is
not sensitive to uptake levels although total costs of course increase proportionately.
Table H-5
Cost-effectiveness where NT ultrasound screening increases the uptake of screening to 100%
compared with 50% for biochemical screeninga
Number of
cases
detected
Total cost
($)
Cost per
case
detected ($)
∆ cases
detected
Diagnosisrelated fetal
losses
∆ cost ($)
Biochemical screening (second
trimester)
173
10,674,773
61,704
173
50
10,674,773
61,704
NT ultrasound screening
534
33,818,889
63,331
361
99
23,144,115
64,111
48,065,939
80,238
65
99
14,247,051
219,051
NT ultrasound screening + first
trimester biochemical testing
599
∆ = incremental; NT = nuchal translucency
a Costs are rounded to the nearest whole number
∆ cost per
case
detected ($)
Alternative scenario 4: nuchal translucency ultrasound screening substitutes for
dating ultrasound scanning in 80 per cent of pregnancies
It may be that NT ultrasound screening would substitute for dating ultrasound scanning in
the first trimester. This might result in an increase in the cost of ultrasound but by less
than the full $100 for a NT ultrasound screen. On the other hand, a previous early
ultrasound scan to determine the exact date of gestation increases the detection rate of
biochemical screening and might reduce the difference in detection rates between
ultrasound, biochemical screening and the combination of both. Given that a first
trimester ultrasound scan has an MBS fee of $60 (item number 55700), it is estimated that
the increase in cost would only be $40.
Table H-6 reports the results of the scenario where NT ultrasound screening substitutes
for another first trimester ultrasound scan in 100 per cent of pregnancies. The effect is to
reduce the cost of NT ultrasound screening below that of biochemical screening in the
second trimester. Provided that ultrasound screening is at least as effective as biochemical
screening in detecting cases, it would dominate biochemical screening on this assumption.
If more than one third of women substituted NT ultrasound screening for a dating
ultrasound scan in the first trimester, followed by second trimester biochemical screening,
the result would be a financial saving. Provided there was no difference in screening uptake
and the extra cost of NT ultrasound screening over dating ultrasound did not exceed $40,
offering NT ultrasound screening as a substitute for biochemical screening and an early
scan that would have occurred between weeks 9 and 11, would most likely be costeffective.
98
Nuchal translucency measurement in the first trimester of pregnancy
Table H-6
Cost per trisomy 21 case detected where nuchal translucency ultrasound screening
substitutes for first trimester dating ultrasound in 100 per cent of pregnanciesa
Number of
cases
detected
Total cost
($)
Cost per
case
detected ($)
∆ cases
detected
∆ cost ($)
∆ cost per
case
detected ($)
Biochemical screening (second
trimester)
346
21,349,547
60,213
346
21,349,547
61,746
NT ultrasound screening
534
18,202,249
38,479
188
18,202,249
Dominant
NT ultrasound screening + first
trimester biochemical testing
32,449,299
52,654
65
32,449,299
218,602
599
∆ = incremental; NT = nuchal translucency
a biochemical detection rate is assumed to be a weighted average of 64–74 per cent, where the weights are the percentage of women who
have an early scan. The cost of nuchal translucency ultrasound screening is $40 for the percentage who substitute an early scan. Costs are
rounded to the nearest whole number
However, if a combination of ultrasound and biochemical screening is adopted as common
practice, there will not be financial savings at this level of substitution and cost. The
incremental cost per extra case detected is $43,825 for a combination of ultrasound and
biochemical screening in the first trimester compared with biochemical screening in the
second trimester. This is based on an 80 per cent substitution for early ultrasound
scanning. However, the incremental cost per case detected by the combination of
ultrasound and biochemical screening is considerably lower than the cost per case detected
for biochemical screening alone. If the community is willing to pay $61,746 per case
detected for the 346 trisomy 21 cases detected, then paying $43,825 for an extra case
detected might be regarded as value for money.
The cost-effectiveness of NT ultrasound screening is sensitive to the extent of substitution
that might take place. Table H-7 shows the incremental cost per case detected at various
levels of substitution of NT screening for the dating ultrasound. With 50 per cent
substitution of early ultrasound scanning, universal NT ultrasound screening has an
incremental cost (cost per extra case detected) of $33,181, which is less than half that of
biochemical screening in the second trimester ($69,050).
Table H-7
Cost-effectiveness analysis of NT ultrasound screening plus biochemical screening in the first
trimester compared with biochemical screening in the second trimester with varying levels of
substitution for early ultrasound scanninga
Level of substitution for early
ultrasound
Total cost
100% substitution
43,825.1
11,099,752.4
80% substitution
56,156.9
14,223,080.4
60% substitution
68,488.8
17,346,408.4
40% substitution
80,820.6
20,469,736.4
93,152.4
23,593,064.4
20% substitution
No substitution
a
Incremental cost per extra
case detected ($)
105,484
26,716,392.4
The cost for nuchal translucency ultrasound screening is $40 for the percentage that substitute for a dating scan.
Incremental costs are rounded to the nearest whole number.
Nuchal translucency measurement in the first trimester of pregnancy
99
Alternative scenario 5: varying the screening detection rate
In the primary analysis, the sensitivity of biochemical screening, NT ultrasounds and the
combination of NT and biochemical screening in first trimester is assumed to be 0.64, 0.77
and 0.86 respectively. As Table 26 shows, there is considerable uncertainty around these
values. In order to examine the robustness of the cost effectiveness results to variation in
the detection rates for the three screening modalities, a probabilistic sensitivity (Monte
Carlo) analysis has been carried out. Rather than take a single point estimate of the
detection rates, this analysis assumes a probability distribution for each of the detection
rates and samples from that distribution 1000 times in order to produce a distribution of
mean incremental cost per case detected.
Given that we do not have any strong evidence that any of the values in the literature are
more likely than any other, we have assumed a uniform distribution for each of the
detection rates in the range outlined in Table 26. The results are shown in Table H-8. The
results suggest that the estimates used in the primary analysis, of the cost effectiveness of
each strategy, are relatively robust with, for example, a coefficient of variation of 10 for the
combination strategy when compared to biochemical screening in the second trimester.
The only strategy that has very wide confidence intervals is the combination strategy
compared to NT alone. There is a widespread view that if NT and serum screening were
both reimbursed, the combination strategy would be the most likely practice to be
adopted. In this case the relevant ICER for the combination strategy is $121,554 (95% CI
$104,109 $141,664) compared to biochemical screening in the second trimester.
Table H-8
Probabilistic sensitivity analysis of the cost-effectiveness of screening options with uniform
distribution of detection rates as reported in Table 26
Comparator
Screening option
Biochemical screening (second
trimester)
NT ultrasound screening
NT ultrasound screening + first
trimester biochemical testing
No screening
Mean ∆ cost per case
detected (95% CI)
60,388 (58,384 62,459)
Biochemical screening
(second trimester)
71,462 (59,643 84,953)
NT ultrasound screening
alone
345,104 (-1,139,504
1,423,280)
NT ultrasound screening + first
Biochemical screening
trimester biochemical testing
(second trimester)
NT = nuchal translucency
Incremental costs are rounded to the nearest whole number
121,554 (104,109
141,664)
Alternative scenario 6: varying the chorionic villus sampling procedure-induced
fetal loss rate
The primary analysis assumes that the procedure-related rate of loss associated with both
CVS and amniocentesis in each trimester is the same at 9 in 1,000. However, there is some
suggestion in the literature that CVS has a higher procedure-related loss rate (Alfirevic et al
2000), although the general view is that with experienced operators the rates are similar.
The results of assuming a 2.5 per cent procedure-related fetal loss for CVS compared with
a one per cent loss for amniocentesis are considered here. This variation makes little
difference to the cost per trisomy 21 case detected but results in an almost threefold
increase in the number of diagnosis-related fetal losses with NT ultrasound screening.
100
Nuchal translucency measurement in the first trimester of pregnancy
Alternative scenario 7: cost of ultrasound screening $80 compared to $100 in
primary analysis
Table H-9 shows the cost effectiveness of NT screening if a price of $80 is assumed rather
than the equivalent second trimester ultrasound cost of $100.
Table H-9
Cost effectiveness of NT with cost of $80 for NT ultrasound in first trimester
Biochemical screening (second
trimester)
NT ultrasound screening
NT ultrasound screening + first
trimester biochemical testing
Number of cases
detected
Total cost ($)
Cost per case
detected ($)
∆ cases
detected
∆ cost ($)a
∆ cost per case
detected ($)a
346
21,349,547
61,746
346
21,349,547
61,746
534
28,613,342
53,596
188
7,263,795
38,617
599
42,860,392
71,548
65
14,247,051
218,602
NT = nuchal translucency
Incremental costs are rounded to the nearest whole number
If the cost of a NT ultrasound is reduced to $80 then the incremental cost per additional
case detected for NT when compared to second trimester biochemical screening is
$38,617. For a combination of NT and first trimester biochemical screening compared to
second trimester biochemical screening, the cost per extra case detected is $84,931.
Alternative scenario 8: combinations of assumptions favourable to ultrasound
screening
The primary cost-effectiveness analysis is reasonably conservative with respect to the costeffectiveness of ultrasound screening. This alternative examines a combination of
assumptions favourable to NT screening and reports the incremental cost-effectiveness by
age group. The assumptions are as follows:
•
48 per cent natural fetal loss from week 12 to term;
•
50 per cent screening with biochemical markers and 100 per cent with NT ultrasound;
•
80 per cent substitution for early dating ultrasound;
•
NT ultrasound and biochemical screening used in combination in the first trimester;
•
detection rate of 64 per cent for biochemical screening; and
•
a detection rate of 86.4 per cent for the combination of NT ultrasound and
biochemical screening in the first trimester.
Nuchal translucency measurement in the first trimester of pregnancy
101
The results in Table H-10 demonstrate that under an optimistic set of assumptions, the
cost of detecting an extra case of trisomy 21 in pregnancy through the combination of NT
ultrasound and biochemical screening in the first trimester is less than that of biochemical
screening in the second trimester. The relationship between maternal age, the prevalence
of trisomy 21 and the cost-effectiveness of screening remains as in the primary analysis. If
screening is limited to those in older age groups, there is a substantial improvement in the
cost-effectiveness ratios.
Table H-10
Incremental cost-effectiveness of combined nuchal translucency ultrasound plus biochemical
screening and biochemical screening alone under optimistic assumptions by age groupa
Age 35 and
over
All ages
43,171
126
35,666
54
69,050
173
29,370
505
24,204
217
47,185
691
Age 30 and over
Biochemical screening (second trimester)
Incremental cost per extra case detected ($)
Number of cases detected
NT ultrasound screening plus first trimester biochemical
screening
Incremental cost per extra case detected ($)
Number of cases detected
NT = nuchal translucency
a Incremental costs are rounded to the nearest whole number
102
Nuchal translucency measurement in the first trimester of pregnancy
Appendix I
Contact details for Australian centres
accredited by the Fetal Medicine
Foundation
New South Wales
Location
Bankstown
Bankstown-Lidcombe Hospital
Ultrasound Department
Locked Mail Bag 1600
Bankstown NSW 2200
Phone: 02 9722 8194
Fax: 02 9722 8197
Bankstown
Mayne Health Diagnostic
Imaging
50 Kitchener Pde
Bankstown NSW 2200
Phone: 02 9708 4066
Fax: 02 9708 1114
Baulkham Hills
The Hills Ultrasound for Women
Hills Hospital
499 Windsor Road
Baulkham Hills NSW 2153
Phone:
Belmont
Hunter Health Imaging Service
Belmont Hospital
Croudace Bay Rd
Belmont NSW 2280
Phone: 02 4923 2219
Fax: 02 4923 2178
Blacktown
Kempsey St Specialist Centre
3 Kempsey St
Blacktown NSW 2148
Phone: 02 9831 1644
Fax: 02 9672 1319
Bondi Junction
Sydney Ultrasound for Women
17th Floor, Westfield Towers
500 Oxford St
Bondi Junction NSW 2026
Phone: 02 9388 0955
Fax: 02 9388 0933
Contact
Registered
Practitioners
Mr Lambros Wassef
Mr Lambros Wassef
Dr Stephen Mackie
Dr Stephen Mackie
Dr Linda Atkins
Dr Linda Atkins
Dr Criton Kasby
Shona England
Shona England
Dr Criton Kasby
Dr Criton Kasby
Dr Andrew McLennan
Dr Andrew McLennan
Nuchal translucency measurement in the first trimester of pregnancy
103
Burwood
Sydney Ultrasound for Women
Suite 3, 29 Belmore Street
Burwood NSW 2134
Phone: 02 9745 4054
Fax: 02 9744 8854
Burwood
Suite 25, Level 4
12 Railway Parade
Burwood NSW 2134
Phone: 02 9744 7240
Fax: 02 9744 7260
Campbelltown
MacArthur Diagnostic Imaging
14 Warby Street
Campbelltown NSW 2560
Phone: 02 4626 1257/
02 4625 3900
Fax: 02 4628 4975
Camperdown
King George V Memorial
Hospital
Department Ultrasound & Fetal
Medicine
Missenden Road
Camperdown NSW 2050
Phone: 02 9515 6042
Fax: 02 9515 6579
Campsie
Mayne Health Diagnostic
Imaging
Campsie Imaging Centre
308-312 Beamish Street
Campsie NSW 2194
Phone: 02 9922 3018
Fax: 02 9955 0039
Chatswood
Sydney Ultrasound for Women
Level 1, 56 Neridah Street
Chatswood NSW 2067
Phone: 02 9413 9196
Fax: 02 9413 3863
Dee Why
Pittwater Radiology
Dee Why X-Ray
812 Pittwater Road
Dee Why NSW 2099
Phone: 02 9982 4911
Fax: 02 9981 4457
104
Dr Andrew McLennan
Dr Andrew McLennan
Dr Viola Gabriel
Dr Viola Gabriel
Ms Cathy Nelson
Dr Michael Meyerson
Dr Michael Meyerson
Prof Janet Vaughan
Prof Janet Vaughan
Dr Robert Ogle
Kim Brinsmead
Dr Philippa Ramsay
Dr Peter Hunter
Dr Peter Hunter
Dr Andrew McLennan
Dr Andrew McLennan
Ms M Lucas
Dr Alan Farrell
Ms Mandy Finlay
Mrs Belinda Smith
Mrs Leanne Ippolito
Dr Alan Farrell
Dr Alan Gunn
Nuchal translucency measurement in the first trimester of pregnancy
Eastwood
North West Radiology
Ryde Medical Centre
247 Ryedale Road
Eastwood NSW 2122
Phone: 02 9858 4266
Fax: 02 9874 7022
Gosford
Coast Ultrasound
Hills Street Medical Centre
Suite 6, 16-18 Hills Street
Gosford NSW 2250
Phone: 02 4325 7541
Fax: 02 4324 2770
Hamilton
RBR Diagnostic Ultrasound
Service
20 Devon St
Hamilton NSW 2303
Phone: 02 4997 0673
Hornsby
Northside Imaging
53 Palmerston Rd
Hornsby NSW 2077
Phone: 02 9476 3388
Fax: 02 9477 7873
Hornsby
Hornsby Ku-Ring-Gai Hospital
Palmerston Road
Hornsby NSW 2077
Kingswood
Penrith Ultrasound for Women
Suite 7, 1A Barber Avenue
Kingswood NSW 2747
Phone: 02 4721 2195
Fax: 02 4732 3922
Kogarah
St George's Hospital
Women's and Children's Health
Level 2, Pritchard Wing, Gray St
Kogarah NSW 2217
Phone: 02 9350 3635
Fax: 02 9350 3901
Lambton
Women's Health and Ultrasound
Suite 2, 25 Morehead Street
Lambton NSW 2299
Phone: 02 4957 3899
Fax: 02 4957 4083
Dr Sonja Borsky
Dr Sonja Borsky
Dr Malcolm Catt
Dr Robert B Richardson
Dr Robert B Richardson
Ms Linda Walford-Smith
Ms Linda Walford-Smith
Ms Jodi Trace
Ms Beverley Barraclough
Ms Beverley Barraclough
Dr Linda Atkins
Dr Linda Atkins
Mr David Fauchon
Mr Brendan Mein
Ms Narelle Kennedy
Dr Lucy Bowyer
Dr Lucy Bowyer
Dr Steve Raymond
Dr Steve Raymond
Dr Stephen O’Callaghan
Ms Susan Cowie
Ms Veronica McDougall
Nuchal translucency measurement in the first trimester of pregnancy
105
Lismore
North Coast Radiology
17 Orion Street
Lismore NSW 2480
Phone: 02 6621 2085
Fax: 02 6622 4780
Liverpool
Feto-Maternal Unit Liverpool
Hospital
Department of Obstetrics
Feto-Maternal Unit
Caroline Chisholm Building
Liverpool NSW 2170
Phone: 02 9828 4145
Fax: 02 9828 5672
Liverpool
Sydney Ultrasound for Women
Suite 205, 161 Bigge Street
Liverpool NSW 2170
Phone: 02 9822 8447
Fax: 02 9822 7761
Maitland
Maitland Hospital
X-Ray Department
550-560 High St
Maitland NSW 2320
Phone: 02 4939 2000
Mona Vale
Pittwater Radiology
6/60 Barrenjoey Rd
Mona Vale NSW 2103
Phone: 02 9997 4504 /
02 9982 4911
Fax: 02 9981 4457
New Lambton
Hunter Imaging Group
PO Box 192
New Lambton NSW 2305
Phone: 02 4952 8457
Fax: 02 4956 2884
Newcastle
John Hunter Hospital
Hunter Regional Mail Centre
Locked Bag 1
Newcastle NSW 2310
Phone: 02 4921 4385
Fax: 02 4921 4394
106
Mr Peter Murphy
Mr Peter Murphy
Dr John Smoleniec
Dr John Smoleniec
Ms Ann Quinton
Mr Robert Ogle
Dr Andrew McLennan
Dr Andrew McLennan
Ms Kristine Louise Morris
Ms Kristine Louise Morris
Dr Amanda Woodward
Dr Amanda Woodward
Professor Warwick B Giles
& Dr Stephen O'Callaghan
Professor Warwick B Giles
Dr Stephen O'Callaghan
Dr Steve Raymond
Dr Stephen Cole
Nuchal translucency measurement in the first trimester of pregnancy
Newtown
Sydney Ultrasound for Women
RPAH Medical Centre
404/100 Carillon Avenue
Newtown NSW 2042
Phone: 02 9516 2064
Fax: 02 9550 6257
Newtown
Specialised Ultrasound for
Women
412/100 Carillon Avenue
Newtown NSW 2042
Phone: 02 9519 0999
Fax: 02 9519 0606
North Sydney
Mater Imaging
Mater Hospital
Rocklands Road
North Sydney NSW 2060
Phone: 02 9955 4466
Fax: 02 9955 7523
Orange
Orange Base Hospital
Sale Street
Orange NSW 2800
Phone: 02 6362 1411
Pennant Hills
Pennant Hills Diagnostic Centre
12 Fisher Ave,
Pennant Hills NSW 2120
Phone: 02 9875 2911
Fax: 02 9484 1089
Penrith
Nepean Hospital
Perinatal Ultrasound
P.O Box 63, Somerset Road
Penrith NSW 2751
Phone: 02 4724 2578
Fax: 02 4724 3206
Randwick
Royal Hospital for Women
Department for Medical Imaging
PO Box 788
Randwick NSW 2031
Phone: 02 9382 6800
Fax: 02 9382 6806
Dr Andrew McLennan
Dr Andrew McLennan
Dr Philippa Ramsay
Dr Philippa Ramsay
Dr Linda Atkins
Ms Sally Quinn & Peter
Stevenson
Mr Peter Stevenson
Ms Stephanie Martin
Ms Jackie Spurway
Ms Jackie Spurway
Mr Paul O'Keefe
Dr Louis Shulman
Ms Anita Giga
Professor Ron Benzie
Professor Ron Benzie
Mr Brendan Mein
Ms Frances Miceli
Ms Alison Webb
Dr Henry Murray
Mr David Fauchon
Dr Glen McNally
Dr Peter Warren
Dr Glen McNally
Dr Peter Warren
Nuchal translucency measurement in the first trimester of pregnancy
107
Randwick
Hay Street Centre
2 Hay St
Randwick NSW 2031
Phone: 02 9326 4001
Fax: 02 9326 4111
Randwick
Sydney Ultrasound for Women
Randwick Specialist Medical Centre
135 Belmore Street
Randwick NSW 2031
Phone: 02 9399 9255
Fax: 02 9399 9153
St Leonards
Department of Maternal Fetal
Medicine
Royal North Shore Hospital
St Leonards NSW 2065
Phone: 02 9926 7099
Fax: 02 9906 6742
St Leonards
North Shore Obstetric &
Gynaecologic Ultrasound
North Shore Private Hospital
Suite 8, Level 3
Westbourne Street
St Leonards NSW 2065
Phone: 02 9487 9800
Fax: 02 9487 9803
Sydney
Sydney Ultrasound for Women
4 O'Connell Street
Sydney NSW 2000
Phone: 02 9221 8099
Fax: 02 9235 3968
Wagga Wagga
PO Box 5215
Wagga Wagga NSW 2650
Phone: 02 6925 8844
Fax: 02 6925 8866
Wahroonga
SAN Ultrasound for Women
Sydney Adventist Hospital
185 Fox Valley Road
Wahroonga NSW 2076
Phone: 02 9487 9800
Fax: 02 9487 9803
108
Dr Wendy Cox
Dr Andrew McLennan
Dr Andrew McLennan
Mr Jonathan Morris
Mr Jonathan Morris
Dr Andrew McLennan
Ms Suzanne Connard
Ms Beverley Barraclough
Ms Beverley Barraclough
Dr Andrew McLennan
Dr Andrew McLennan
Dr George Angus
Dr George Angus
Dr Philippa Ramsay
Dr Philippa Ramsay
Ms Jo Lennox
Nuchal translucency measurement in the first trimester of pregnancy
Westmead
Suite 1
1A Ashley Lane
Westmead NSW 2145
Westmead
University of Sydney &
Westmead Hospital
Department of Obstetrics and
Gynaecology
Westmead Hospital
Hawkesbury Road
Westmead NSW 2145
Phone: 02 9845 6800
Fax: 02 9845 7793
Westmead
Nuclear Medicine and
Ultrasound Associates
Suite 35, 1A Ashley Lane
Westmead NSW 2145
Phone: 02 9831 3055
Windsor
Sydney Pregnancy & Women’s
Ultrasound Services
10/251 George Street
PO Box 291
Windsor NSW 2756
Phone: 02 4587 8575
Fax: 02 4577 6834
Wollongong
South Coast Ultrasound
363 - 367 Crown St
Wollongong NSW 2500
Phone: 02 4228 9711
Fax: 02 4228 9118
Stephanie The
Stephanie The
Professor Brian Trudinger
Professor Brian Trudinger
Ms Lyn Ryder
Ms Cherie Drinkwalter
Ms Cherie Drinkwalter
Ms Nicole Short
Ms Lisa Kench
Dr Henry Murray
Dr Henry Murray
Dr Michael Peek
Prof Ron Benzie
Ms Narelle Kennedy
Mr David Fauchon
Dr Warren Davis
Ms Anne Oliver
Dr Warren Davis
Ms Anne Oliver
Dr Patricia McPherson
Nuchal translucency measurement in the first trimester of pregnancy
109
Victoria
Ballarat
Ballarat Health Services
Drummond Street North
PO Box 577
Ballarat VIC 3353
Phone: 03 5320 4000
Fax: 03 5320 4828
Ballarat
St John of God Health Care
Department of Nuclear Medicine
& Ultrasound
PO Box 20
Ballarat VIC 3353
Phone: 03 5320 2121
Fax: 03 5320 2194
Ballarat
Radsonic Diagnostic
801 Mair Street
Ballarat VIC 3350
Phone:
Ballarat West
Lake Imaging
PO Box 42W
Ballarat West VIC 3350
Phone: 03 5331 4899
Fax: 03 5333 2083
Berwick
Women's Imaging Centre
Suite 2, 1/8 Langmore Lane
Berwick VIC 3806
Phone: 03 9769 9499
Fax: 03 9769 9599
Boronia
Radclin Medical Imaging
154 Boronia Road
Boronia VIC 3155
Phone: 03 9762 1822
Fax: 03 9762 8102
Carlton
Royal Womens Hospital
Ultrasound Department
132 Grattan Street
Carlton VIC 3052
Phone: 03 9344 2147
110
Dr Jim Mullany
Mr Greg Murray
Dr Jim Mullany
Mr Greg Murray
Dr Gary Gill
Dr Gary Gill
Dr Peter Graham
Dr Jim Mullany
Dr Jim Mullany
Mr Greg Murray
Dr Jim Mullany
Mr Greg Murray
Dr Jacqui Oldham
Dr Jacqui Oldham
Dr Debbie Nisbet
Dr Paul Shekleton
Dr Andrew Ngu
Mrs Julie Koska
Mrs Julie Koska
Ms Yvonne Gray
Dr Amanda Sampson
Dr Amanda Sampson
Nuchal translucency measurement in the first trimester of pregnancy
Carlton
Melbourne Ultrasound for
Women
Level 1, 62 Lygon Street
Carlton VIC 3053
Phone: 03 9663 3999
Fax: 03 9663 3555
Carlton
Women’s & Children’s
Ultrasound Centre
96 Grattan Street
Carlton VIC 3053
Phone: 03 9347 6030
Fax: 03 9347 7645
Clayton
Dr James Grimwade Pty
Limited
14 -16 Dixon Street
Clayton VIC 3168
Phone: 03 9562 8423
Fax: 03 9562 7079
Clayton
Monash Medical Centre
246 Clayton Rd
Clayton VIC 3168
Phone: 03 9594 5303
Fax: 03 9594 6389
Dandenong North
53 Brady Road
Dandenong North VIC 3175
Phone: 03 9790 0333
Fax: 03 9701 1422
Darling South
PO Box 13
Darling South VIC 3145
Phone:
Doncaster East
COGUS
12 Happy Valley Court
Doncaster East VIC 3109
Phone: 03 9840 7199
Fax: 03 9841 0910
Dr Lachlan de Crespigny
Dr Lachlan de Crespigny
Dr Victor Hurley
Dr Nicole Woodrow
Dr Michael Bethune
Ms Ann Kennett
Ms Maria Maxfield
Ms Dorothy McGinnes
Ms Braidy Davies
Ms Nafissa Akhounova
Dr F Rex Betheras
Dr Charles Siles
Dr F Rex Betheras
Dr Charles Siles
Dr James Grimwade
Dr James Grimwade
Dr E M Wallace
Dr Sheila Mulvey
Dr Sheila Mulvey
Dr Paul Shekleton
Dr Jacqui Oldham
Dr James Grimwade
Dr Graeme Atchison
Dr Nicole Woodrow
Dr Peter Lee
Dr Peter Lee
Helen Denise Phillips
Helen Denise Phillips
Dr Steven L S Chow
Dr Steven L S Chow
Nuchal translucency measurement in the first trimester of pregnancy
111
East Melbourne
Women's Imaging Centre
Freemasons
Suite 6, 320 Victoria Parade
East Melbourne VIC 3002
Phone: 03 9417 6788
Fax: 03 9416 1084
East Melbourne
Mercy Hospital for Women
Medical imaging Department
Clarendon Street
East Melbourne VIC 3002
Phone: 03 9827 4065
Fax: 03 6419 0656
Epping
Mayne Health Diagnostic
Imaging
185 Cooper Street
Epping VIC 3076
Phone: 03 9888 5400
Fax: 03 9836 4498
Fitzroy
Central Melbourne Medical
Imaging
55 Victoria Parade
Fitzroy VIC 3065
Phone: 03 9473 1000
Fax: 03 9473 1005
Footscray
MIA Victoria, Taft Diagnostic
Imaging
Western Private Hospital
Cnr Eleanor and Marion Streets
Footscray VIC 3011
Phone: 03 9317 8777
Fax: 03 9317 0106
Geelong
Barwon Medical Imaging
Geelong Hospital
Ryrie Street
PO Box 281
Geelong VIC 3226
Phone: 03 5226 7758
Fax: 03 5246 5149
112
Dr Amanda Sampson
Dr Amanda Sampson
Dr Andrew Ngu
Dr Hugh Robinson
Dr Jacqui Oldham
Dr Debbie Nisbet
Dr Christine Acton
Dr Christine Acton
Ms Braidy Davies
Ms Nafissa Akhounova
Ms Gabrielle Fedai
Dr Simon Meagher
Ms Clare Lee
Dr C M Blecher
Dr C M Blecher
Ms Anna Kennett
Marc Hull
Marc Hull
Mrs Helen Magee
Mrs Helen Magee
Dr Charles Siles
Mr John Bell
Ms Yvonne Gray
Ms Margaret Condon
Mr Marc Hull
Ms Sandra Buckley
Ms Sandra Buckley
Ms Sharon Stafford
Dr Kay Wilson
Nuchal translucency measurement in the first trimester of pregnancy
Geelong
Geelong Radiological Clinic
Obstetric Service
St John of God Health Care
PO Box 1087
Geelong VIC 3220
Phone: 03 5221 3300
Fax: 03 5222 5781
Hoppers Crossing
MIA Victoria Taft Diagnostic
Imaging
267 Heaths Road
Hoppers Crossing VIC 3029
Malvern
Womens Ultrasound Malvern
Suite 2, 147 Wattletree Road
Malvern VIC 3144
Phone: 03 9509 8811
Fax: 03 9509 8711
Melton
Melton X-Ray Centre
390-392 High Street
Melton VIC 3337
Phone: 03 9743 5633
Fax: 03 9743 3650
Mildura
4 Healthscope Court
Private Bag 876
Mildura VIC 3500
Phone: 03 5021 4404
Fax: 03 5021 4405
Morwell
Gippsland Diagnostic Services
4 Hoyle St
Morwell VIC 3840
Phone: 03 5133 9933
Fax: 03 5133 9971
Mulgrave
Obstetric and Gynaecological
Ultrasound
441 Police Road
Mulgrave VIC 3170
Phone: 03 9790 1766
Fax: 03 9790 1100
Mr Russell Artis
Mr Russell Artis
Ms Julie Dew
Ms Michelle Appleford
Dr Kay Wilson
Ms Doxia Bryce
Ms Doxia Bryce
Ms Lyn Lavan
Ms Margaret Condon
Ms Yvonne Gray
Mrs Helen Magee
Dr Amanda Sampson
Dr Amanda Sampson
Dr Jacqui Oldham
Dr Paul Shekleton
Dr Debbie Nisbet
Dr Jim Mullany
Robyn Marshman
Dr Jim Mullany
Dr J.D.P Bowditch
Dr J.D.P Bowditch
Dr R Brownlee
Dr R Brownlee
Dr Simon Meagher
Dr Simon Meagher
Dr Shawn Choong
Nuchal translucency measurement in the first trimester of pregnancy
113
Noble Park
Mayne Health Diagnostic
Imaging
South Eastern Private Hospital
313 Princes Highway
Noble Park VIC 3175
Phone: 03 9562 3433
Fax: 03 9558 5731
Richmond
Monash Ultrasound for Women
Epworth Hospital
Level 4, 89 Bridge Road
Richmond VIC 3121
Phone: 03 9427 7610
Fax: 03 9427 9232
Werribee
MIA Victoria
Taft Diagnostic Imaging
Werribee Mercy Hospital
300 Princess Highway
Werribee VIC 3030
Phone: 03 9748 3200
Fax: 03 9748 0249
Ms Vicki Truelove
Ms Vicki Truelove
Dr Simon Meagher
Dr Simon Meagher
Ms Doxia Bryce
Ms Doxia Bryce
Mrs Helen Magee
Dr Charles Siles
Mr John Bell
Ms Margaret Condon
Ms Lyn Lavan
Ms Yvonne Gray
Queensland
Auchenflower
The Wesley Fetal Medicine Unit
Wesley Medical Centre
Suite 15, Chasely Street
Auchenflower QLD 4066
Phone: 07 3371 4933
Fax: 07 3870 3936
Brisbane
Brisbane Ultrasound for Women
Ballow Chambers
121 Wickham Tce
Brisbane QLD 4000
Phone: 07 3831 1777
Fax: 07 3831 1788
Brisbane
Watkins Medical Centre
225 Wickham Terrace
Brisbane QLD 4000
Phone: 07 3831 0658
Fax: 07 3831 3711
114
Dr Francis Carmody
Dr Gary Pritchard
Dr Gary Pritchard
Ms Helen Gofton
Mr Neil Pennell
Ms Sue Williams
Ms Margo Harkness
Ms Paula Sivyer
Dr F M McMahon
Dr F M McMahon
Nuchal translucency measurement in the first trimester of pregnancy
Buderim
Mayne Health Diagnostic
Imaging - QLD
9 Vista Park Drive
Buderim QLD 4556
Phone: 07 5444 5877
Fax: 07 5444 7098
Burleigh Waters
Gold Coast Medical Imaging
Treetops Specialist Medical Cntr
Classic Way
Burleigh Waters QLD 4220
Phone: 07 5593 6955
Fax: 07 5593 6059
Castletown
Queensland X-Ray
Mater Hospital
PO Box 674
Castletown
Townsville QLD 4812
Phone: 07 4759 2800
Fax: 07 4779 7402
Herston
Royal Womens Hospital
Brisbane
Butterfield Street
Herston QLD 4029
Phone: 07 3636 7849
Fax: 07 3255 0880
Ipswich
Clarke & Robertson Radiology
2 Pring Street
Ipswich QLD 4305
Phone: 07 3281 1099
Fax: 07 3812 3154
Mermaid Beach
South Coast Radiology
5 Markeri St
Mermaid Beech QLD 4218
Phone: 07 556 90 416
Mobile: 041 9313 529
Noosaville
Mayne Health Diagnostic
Imaging
Noosa Hospital
111 Goodchap St
Noosaville QLD 4566
Phone: 07 5455 9393
Fax: 07 5449 1131
Mr Ian Stewart
Mr Ian Stewart
Mrs Anna Galea
Mrs Anna Galea
Ms Susan Boyd
Ms Susan Boyd
Dr Stephen Sinnott
Dr Stephen Sinnott
Dr Carol Portmann
Dr Geoff Stieler
Dr Geoff Stieler
Mr Reginald Viney
Mr Reginald Viney
Ms Jessica Nilsen
Ms Jessica Nilsen
Nuchal translucency measurement in the first trimester of pregnancy
115
South Brisbane
Mater Mother's Hospital
Centre for Maternal Fetal Medicine
Raymond Terrace
South Brisbane QLD 4101
Phone: 07 3840 8844
Fax: 07 3840 1949
South Brisbane
Queensland X-Ray
The Women's Diagnostic Centre
Mater Private Clinic
550 Stanley St
South Brisbane QLD 4101
Phone: 07 3840 6208
Fax: 07 3844 4277
Southport
Gold Coast Medical Imaging
123 Nerang St
Southport QLD 4215
Phone: 07 5591 5422
Fax: 07 5506 7835 / 7855
Spring Hill
Diagnostic Imaging for Women
Ground floor 75, Astor Terrace
(corner Cousins St)
Spring Hill QLD 4000
Phone: 07 3839 8666
Fax: 07 3839 8333
Sunnybank
Queensland X-Ray
The Women's Diagnostic Centre
Suite 15, McCullough Centre 259
McCullough St
Sunnybank QLD 4109
Phone: 07 3345 2033
Fax: 07 3345 2635
Toowoomba
St Vincent's Medical Centre
Scott Street
Toowoomba QLD 4350
Phone: 07 4688 5470
Fax: 07 4688 5469
Tweed Heads
Tweed Heads District Hospital
Medical Imaging Department
Florence Street
Tweed Heads QLD 2485
Phone: 07 5536 0419
Fax: 07 5506 7835
116
Prof Fung Yee Chan
Prof Fung Yee Chan
Ms Donna Amaraddio
Dr Lisa Begg
Dr Robert Cincotta
Ms Alison Lee-Tannock
Dr Kerry McMahon
Dr Kerry McMahon
Dr Bronwyn Rogers
Dr Matthew Lee
Mrs Anna Galea
Mrs Anna Galea
Ms Karen Doust
Ms Karen Doust
Ms Paula Sivyer
Dr Bronwyn Rogers
Dr Bronwyn Rogers
Dr Kerry McMahon
Dr Anthony Cerqui
Dr Anthony Cerqui
Dr Matthew Lee
Mrs Anna Galea
Mrs Anna Galea
Nuchal translucency measurement in the first trimester of pregnancy
Warwick
Warwick Hospital
X-ray Department
PO Box 1155
Warwick QLD 4370
Phone: 07 4661 6892
Mr Mark Yuile
Mr Mark Yuile
Dr Karen Shand
Dr Karen Shand
Ms Maureen Pachulicz
Dr Christina Hayward
Dr Kevin Williams
Dr Kevin Williams
Mrs Kerry Thoirs
Ms Maureen Pachulicz
Ms Maureen Pachulicz
Dr Meegan Gun
Ms Maria Mavrogiorgis
South Australia
Ashford
Ultrasound Specialists for
Women
Ashford Specialist Centre
Suite 29, 57-59 Anzac Highway
Ashford SA 5035
Phone: 08 8293 8880
Fax: 08 8293 8591
Modbury
Benson Radiology
Modbury Hospital
Smart Road
Modbury SA 5092
Phone: 08 8265 5100
Fax: 08 8265 5151
North Adelaide
Women's & Children's Hospital
Perinatal Imaging
72 King William Road
North Adelaide SA 5006
Phone: 08 8204 7750
Fax: 08 8204 7749
Woodville South
The Queen Elizabeth Hospital
Ultrasound Dept
28 Woodville Rd
Woodville South SA 5011
Phone: 08 8222 6894
Fax: 08 8222 6040
Western Australia
Balcatta
Perth Radiological Clinic
Joondalup Radiology
217 Wannerou Rd
Balcatta WA 6021
Phone: 08 9300 2855
Fax: 08 9345 0367
Dr Susan Lamp
Dr Susan Lamp
Nuchal translucency measurement in the first trimester of pregnancy
117
Bunbury
Imaging the South
South West Health Campus
Bunbury WA 6230
Phone: 08 97266999
Fax: 08 97266900
Joondalup
Mayne Health Diagnostic
Imaging
Joondalup Health Campus
PO Box 242
Joondalup WA 6919
Phone: 08 9400 9030
Fax: 08 9400 9033
Joondalup
Joondalup Medical Campus
Perth WA 6027
Kalgoorlie
Kalgoorlie Regional Hospital
PMB 7
Kalgoorlie WA 6430
Phone: 08 90 805 644
Fax: 08 90 805 777
Kalgoorlie
X Ray West
PO Box 513
Kalgoorlie WA 6430
Phone: 08 9021 5044
Fax: 08 9091 1571
Karratha
Pilbara Radiology
PO Box 1399
Karratha WA 6714
Phone: 08 91 44 19 22
Fax: 08 91 44 26 90
Mandurah
Imaging The South
5 Randell St
Mandurah WA 6210
Phone: 08 95 35 54 44
Fax: 008 95 35 70 69
Murdoch
St John of God Medical Clinic
Suite 15/16 100 Murdoch Drive
Murdoch WA 6150
Phone: 08 9366 1771
Fax: 08 9366 1766
118
Sarah Court
Sarah Court
Ms Michelle Pedretti
Ms Michelle Pedretti
Mr Paul Stefanetti
Dr Bev Hewitt
Dr Bev Hewitt
Kerry Harvey
Kerry Harvey
Ms Kerry Harvey
Ms Kerry Harvey
Dr Leila Dekker
Dr Leila Dekker
Ms Eleanor Snell
Ms Eleanor Snell
Mr Paul Stefanetti
Ms Sarah Court
Dr Peter J Hugo
Dr Peter J Hugo
Ms Karen Lines
Ms Rae roberts
Ms Sarah court
Dr Anthony Murphy
Nuchal translucency measurement in the first trimester of pregnancy
Quinns Rocks
Quinns Medical Imaging
PO Box 97
Quinns Rocks WA 6030
Phone: 08 9305 8606
Fax: 08 9305 8609
Subiaco
Perth Ultrasound
442 Barker Road
Subiaco WA 6008
Phone: 08 9382 1500
Fax: 08 9382 1927
Subiaco
Ob/Gyn Ultrasound
St John of God Health Care
Suite 309, 25 McCourt Street
PO Box 1144
Subiaco WA 6008
Phone: 08 9388 1340
Fax: 08 9388 1351
Subiaco
King Edward Memorial
Hospital for Women
Ultrasound Department
374 Bagot Road
Subiaco WA 6008
Phone: 08 9340 2710
Fax: 08 9340 2747
Wembley
Obstetric and Gynecological
Ultrasound - Wembley
166 Cambridge Street
Wembley WA 6014
Phone: 08 9380 4744
Fax: 08 9388 8331
West Perth
Park Ultrasound
11 Ventnor Avenue Suite 7
West Perth WA 6005
Phone: 08 9481 4008
Fax: 08 9481 4080
West Perth
SKG Radiology
30 Ord Street
West Perth WA 6005
Phone: 08 9322 4966
Dr Walter Harmer
Mr Paul Stefanetti
Dr John Phillips
Dr John Phillips
Ms Karen Lines
Ms Dawn Voges
Dr Anthony Murphy
Dr Anthony Murphy
Dr Jan Dickinson
Dr Jan Dickinson
Dr Peter Hugo
Dr John Newnham
Ms Dawn Voges
Ms Rae Roberts
Dr John Phillips
Mr Nevile Phillips
Mr Nevile Phillips
Dr Bev Hewitt
Dr Bev Hewitt
Mrs Gillian Kaye
Ms Kym Webb
Dr Sue Ulreich
Dr Sue Ulreich
Ms Samantha Ward
Ms Tricia Duggin
Nuchal translucency measurement in the first trimester of pregnancy
119
Tasmania
Hobart
Royal Hobart Hospital
48 Liverpool St
Hobart TAS 7000
Phone: 03 6231 4457
Fax: 03 6231 4457
Launceston
Launceston Ultrasound for
Women
Suite 7, 7 High St
Launceston TAS 7250
Phone: 03 6331 3999
Fax: 03 6331 3666
Dr Peter Davies
Dr Peter Davies
Dr Susan James
Dr Susan James
Ms Maree Eastley
Australian Capital Territory
Bruce
Canberra Imaging Group
Dr Wes Cormick
Dr Wes Cormick
Calvary Clinic
Mary Potter Court
Bruce ACT 2617
Deakin
Canberra Imaging Group
Dr Wes Cormick
Dr Wes Cormick
John James Hospital
Strickland Cres
Deakin ACT 2600
Phone: 02 6285 1173
Fax: 02 6282 4252
Garran
The Canberra Hospital
Professor David Ellwood Professor David Ellwood
Fetal Medicine Unit
Ms Jan Curren
Ms Jan Curren
Garran ACT 2605
Phone: 02 6244 3079
Fax: 02 6244 3154
Woden
National Capital Diagnostic
Ms Pam Cooke
Ms Pam Cooke
Imaging
Corinna Chambers,
PO Box 303
Woden ACT 2696
Phone: 02 6282 2888
Fax: 02 6281 4261
Source: Ann Robertson, Special Projects Officer, RANZCOG, personal communication,
August 2002.
120
Nuchal translucency measurement in the first trimester of pregnancy
Abbreviations
AFP
AIUM
ALARA
ASUM
CA-125
CI
CMFM
COGU
CRL
CVS
DR
DS
EFSUMB
FaST
FaSTER
FDA
FMF
FN
FP
FPR
hCG
HGSA
ICER
ISUOG
IUGR
LR
MBS
MI
MoM
MSAC
NCCHTA
NHMRC
NHS
NICHHD
NIH
NPV
NT
NTS
alpha-fetoprotein
American Institute of Ultrasound in Medicine
as low as reasonably achievable
Australasian Society for Ultrasound in Medicine
cancer antigen 125
confidence interval
Certification in Maternal-Fetal Medicine
Certification in Obstetric and Gynaecological Ultrasound
crown-to-rump length
chorionic villus sampling
detection rate; syn. sensitivity
Down syndrome
European Federation of Societies for Ultrasound in Medicine and
Biology
First and Second Trimester Screening Study
First and Second Trimester Evaluation of Risk trial
Food and Drug Administration (United States)
Fetal Medicine Foundation
false negative
false positive
false positive rate
human chorionic gonadotrophin
Human Genetics Society of Australasia
incremental cost-effectiveness ratio
International Society for Ultrasound in Obstetrics and Gynaecology
intrauterine growth retardation
likelihood ratio
Medicare Benefits Schedule
mechanical index
multiple of the median
Medical Services Advisory Committee
National Coordinating Centre for Health Technology Assessment
(United Kingdom)
National Health and Medical Research Council
National Health Service (United Kingdom)
National Institute of Child Health and Human Development (United
States)
National Institutes of Health (United States)
negative predictive value
nuchal translucency
nuchal translucency screening
Nuchal translucency measurement in the first trimester of pregnancy
121
ODS
OMFL
OR
PAPP-A
PPV
RADIUS
RANZCOG
RCOG
RCT
RD
Sen
SP1
Spe
sROC
SURUSS
T1MBS
T2MBS
TI
TN
TP
uE3
USPSTF
WFUMB
122
output display standard
oromandibulofacial limb hypogenesis
odds ratio
pregnancy-associated plasma protein-a
positive predictive value
Routine Antenatal Diagnostic Imaging with Ultrasound Study
Royal Australian and New Zealand College of Obstetricians and
Gynaecologists
Royal College of Obstetrics and Gynaecology
randomised controlled trial
risk difference
Sensitivity; syn. detection rate
schwangerschaftsprotein 1
specificity
summary receiver operator characteristic
Serum, Urine and Ultrasound Screening Study
First trimester maternal biochemical screening
Second trimester maternal biochemical screening
thermal index
true negative
true positive
unconjugated oestriol
US Preventive Services Task Force
World Federation of Ultrasound in Medicine and Biology
Nuchal translucency measurement in the first trimester of pregnancy
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