I. Dhaifalah 1; L. Dusek 2; J. Santavy 1
Department of Genetic and Fetal Medicine, University Hospital, Olomouc, Czech Republic
1; Institut of Biostatistics and Analysis, Masaryk University, Brno, Czech Republic
Čes. Gynek.2011, 76, č. 4 s. 292-306
Objectives: Implementation and introducing of first trimester screening using nuchal translucency (NT), nasal bone (NB), maternal serum pregnancy associated plasma protein-A and free β-human chorionic gonadotropin (PAPP-A and fß-hCG) as a new method of screening for Down’s Syndrome in a One-Stop-Clinic for Assessment of Risk for chromosomal abnormalities in the Czech Republic. To prove its effectiveness and make it part of our daily practice. Modify and/or withdraw the existing current practice.
Methods: Prospective study of 5010 singleton pregnancies who attended our clinic for prenatal screening for chromosomal and congenital abnormalities between 11-13+6 weeks gestation from January 2005 to December 2007. Pregnancies were followed up to ascertain live birth of Down syndrome babies.
Conclusion: The uptake was 100% for screening and around 95% for invasive testing in the screen positive group. All expected trisomies 21 were detected along with many other aneuploidies for false positive rate of 4.4%. The study demonstrated the feasibility and efficacy of introducing OSCAR for chromosomal abnormalities in a University Hospital setting. The introduction of an examination of nasal bone reduced our false positive results and increased our sensitivity. Women who participated in our screening strategy were no longer advised to undergo the triple test.
Key words: implementation of first trimester screening, one stop clinic (OSCAR), nuchal translucency, nasal bone.
is well recognized that any screening program will confer some benefit and some
harm on the population served by that program. Screening programs of poor
quality, and those that have been introduced on the basis of insufficient
evidence, may produce more harm than good. However, when screening for Down’s
syndrome, an assessment of the benefits and costs of the program is further
complicated by different people’s understanding of benefit and harm in this
situation. Despite inherent difficulties, there should be certain criteria that
should be used to assess the performance of screening programs. These should be
evidence based and the implementation should ensure equality of access and
a uniform standard of care.
evaluating a screening test for use on a large scale, it is necessary
not only to investigate the test, but also determine the extent of the
infrastructure required to underpin its implementation. This may involve many
different clinical services, departments, and health professionals. For the
benefit of health professionals providing the service and the users of that
service, it is necessary to develop policies and protocols governing the local
screening providers. Coordinating the various services comprising screening at
the local level and informing and training the staff who offer these services
is mandatory [9, 10, 11, 14, 20].
Audit and monitoring needs to be an integral part of the
service, to ensure continuous quality improvement and to provide information
from which the demand and need for future service provision within the local
population, and its associated costs, can be extrapolated.
trimester screening which is considered to be the most effective method of
screening is used at our centre. It is the method of choice for screening of
trisomy 21 (Down’s syndrome) and for other chromosomal abnormalities as well as
for routine scanning between 11-13+6 weeks of pregnancy. We use The
Fetal Medicine Foundation (FMF), London, UK recommendation as the guidelines
for implementing this method [3, 17, 23].
ultrasound scan examination of the fetus, measurement of the markers for
chromosomal abnormalities (NT and NB) and blood sampling to measure free ß-hCG
and PAPP-A, is be out on the same day (OSCAR) [5, 16]. The women are
informed of their results within 24–48 hours. If a problem is identified,
invasive testing is offered during the same visit or immediately the next day.
The invasive testing is preceded by genetic counseling to help women to make
decisions prior to and after the tests have been provided.
main aim is to withdraw the less effective methods used in our current practice
and substitute them with more effective method of a one stop manner for
the first time in the Czech Republic.
study was conducted at the Medical Genetic and Foetal Medicine
Department, University Hospital Olomouc. This department is located in Olomouc,
in the Moravian part of the Czech Republic. Palacky University Hospital,
Olomouc is one of the twelve hospitals directly managed by the Ministry of
Health of the Czech Republic, and is the top medical facility in Olomouc region.
The Department provides a full range of services in prenatal diagnosis and
genetics. It has an average of 12 000
examinations (ultrasound, genetic consultations and laboratory examinations
including cytogenetic and molecular genetic investigations) per year.
Design and sample
is a prospective study covering singleton pregnant women (5010) booked for
screening between 11-13+6 weeks of pregnancy between January 2005
and December 2007.
are initially seen in the community by their obstetricians in about 99% of
cases. They receive an information leaflet about the one-stop clinic service
and the screening tests that are available either from their obstetrician, with
their initial booking appointment, or on arrival to our department before the
attending the clinic, women have a consultation with the sonographers
(obstetricians with a genetic specialization, certified from FMF)
concerning the available tests and, if they elect to have prenatal screening
for chromosomal anomalies, all relevant clinical information is recorded on the
request forms. After pre-test counselling, women opting into the screening
program undergo US scanning and at the same time blood samples are taken for
serum biochemical screening after signing an informed consent.
Process of screening
in the first trimester is based mainly on ultrasound. If the gestational age is
between 11–13+6 weeks; the foetal NT, presence or
absence of the NB and crown–rump length (CRL) are investigated and measured.
The whole ultrasound process is completed within a 15–20 minute period in
95% of cases. Ultrasound examinations are performed trans-abdominally with the
Toshiba Power Vision 6000 (convex probe 3.5–5 MHz) (Toshiba, Tokyo, Japan) or
the GE-Voluson 730 Expert (convex probe 3.5–5 MHz) (GE Healthcare Technologies,
ZIPf, Austria). The blood samples are sent to the hospital laboratory (situated
about 50 meters from our clinic) within one hour. Serum is separated and
analysed for free ß-hCG and PAPP-A using B.R.A.H.M. Kryptor, Germany.
the results are available (within 2 hours) they are logged onto the fetal
database and a composite risk report is produced. Patient-specific risks
are calculated by a multivariate approach using population’s parameters
established by FMF. Women with an increased risk (risk ≥1 in 300) for trisomy
21, 18 and 13 are referred to a genetic counsellor who discusses with the
woman the appropriate risk and its management. If the woman agrees she
undergoes chorionic villous sampling (or amniocentesis later) and fetal
karyotyping in the procedure room of the department.
Molecular and cytogenetic diagnosis of
a high-risk/screen-positive result
methods as quantitative polymerase chain reaction (QF-PCR) and in some cases
fluorescent in-situ hybridization (FISH) are used. Results are available within
24–48 hours. These methods are used for the confirmation of trisomy 21, 18, 13
and abnormalities of sex chromosomes. In all cases samples undergo further
diagnosis by conventional karyotyping providing the results in three weeks.
A woman who has a definitive diagnosis of chromosomal abnormalities
is offered genetic consultation and support whilst making a decision on
the future of the pregnancy and for planning for future pregnancies.
Termination of pregnancy is possible for chromosomal abnormalities in the Czech
Republic up to the 24th week of pregnancy and most women with
confirmed trisomy 21, 13 or 18 in the fetus elect to terminate the pregnancy.
health professionals responsible for providing information to users of the
service are familiar with the various screening tests available and were
trained in the use of the database software. Obstetricians performing the scans
were trained, and certified by FMF. The training was done by practical training
and theoretical courses.
were organized and information (including information leaflets) were
disseminated to all who look after pregnant women (e.g. private obstetricians).
Audit and quality assurance
internal audit was held on a monthly basis and an external one annually.
In an audit, the performance of the obstetricians carrying out the scan was
judges as satisfactory in cases in which they were able to demonstrate good
performance in measuring the NT through a control of some of their images
and a search of their distribution curve. The audit of the centre was
based on the detection rate and false positive rates and the performance of the
obstetricians performing the scans.
laboratory providing maternal serum screening tests participated and was
successful in internal and external audits of its performance. The internal
audit is carried out by the Czech Society of Clinical Biochemistry and the
external audit is undertaken by the United Kingdom National External Quality
Assessment Service (UKNEQAS).
e-mail and helpline facilities (www.ulgrs. upol.cz), were created to enable
information to be passed directly and quickly to health professionals and to
method of screening was introduced gradually over a period of one year
(January 2004 to December 2004). The risk of trisomy 21 was estimated for 695
singleton pregnancies. The specific risk was calculated using the FMF calculation
risk model software by an accredited obstetrician. The Immulite DPC 2000
(Diagnostic Products Corporation, Los Angeles, USA) was used for blood analysis
and Toshiba Power Vision 6000 for US examinations. Women with risk of ≥1 in 300
were offered CVS and fetal karyotyping. Only 17% women of the study group were
older than 35 years. All cases of trisomy 21 (2) and three cases of other
chromosomal abnormalities were detected for a 6% false positive rate. The
whole group of women had a second trimester screening test by age and
triple test those with positive results had been offered amniocentesis.
showed high sensitivity with a low false positive rate in comparison to
our current routine practices and we also demonstrated that it could be offered
in an efficient manner. Therefore we decided to introduce it to our daily
practice, replacing the previously deployed methods.
the pilot study many modifications and improvements were made. The
obstetricians and health professional staff were trained and certified,
information leaflets and consent forms were written, we obtained a new
high quality ultrasound machine and a new instrument (KRYPTOR) for blood
analysis. Network installation of the software risk calculation model and
computer facilities were developed by the Department of Information Technology
in our hospital in cooperation with the software owners in Germany. Many
modifications were made in the software to improve the printouts, the language
was changed to fulfill our requirements. We chose the 1:300 risk as the cut-off
for positive result to overcome inter-observer differences and errors. We
advised that women who were tested by our method of screening do not need to be
tested with triple test also; instead we recommended an anomaly scan examination
for NTD and other organs at the 20–22 week of pregnancy.
COLLECTION AND ANALYSIS
database software FMF calculation risk model (Astraia, SRN, and Munich,
Germany) was used for calculation of risk, data collection, monitoring and
audit. QF-PCR and cytogenetic results were recorded also in this database
software. The outcome of pregnancies in women included in this study was
collected by questionnaires sent by post. In cases where no reply was received,
the patients were contacted by phone.
review of completed data was carried out and database information was prepared in
Microsoft Excel (Microsoft Corp, USA). Experts from the Biostatistics and
Analyses Institute, Faculty of Medicine, Masaryk University, Brno, analyzed the
statistical significance of differences in relative frequency of categories
among several groups of patients was analyzed by means of maximum likelihood
chi-square test . Statistical significance of differences among categories
in continuous variables was analyzed using the Kruskal-Wallis test followed by post
hoc multiple comparisons of mean ranks .
of ultrasonography and blood markers for gestational age based on Crown Rump
Length was computed by means of linear regression prior to comparison of
patients’ categories .
achieved performance for the screening examination was described using false
positive and false negative discovery rates, together with their sensitivity
and specificity for 1:300 risk „Cut-off“(empirically given). Receiver operating
characteristics (ROC curves) were adopted for the visualization of sensitivity
and specificity of this standard „Cut-off“ and for the analysis of the
relationship between computed continuous risk for trisomy and its specificity
and sensitivity for trisomy detection [15, 26, 29].
area under the ROC curve, its confidence interval and statistical significance
was computed and adopted for the evaluation of statistical significance of
trisomy screening test performance [2, 12, 13].
were performed using SPSS 17.0 (SPSS, Inc.) and Statistica 8.0 software for
Windows (Statsoft, Inc.).
The screened population was mainly drawn from Olomouc
(79.9%), Moravian-Silesian (12.6%) and Zlin (4.4%) districts; the remainder
came from the adjacent areas. Over the three-year study period a total of
5010 women with singleton pregnancies were offered first trimester screening in
the OSCAR clinic. Most (97.2%) of the screened women were primiparous.
uptake of first trimester screening was 100%. The ethnic origins of the
population studied consisted of 99.9% Caucasian, 0.12% Asian and one
Afro-Caribbean. The median maternal age was 29 years (range between 16 to 38),
16.4% women were older than 35 years.
were 99.9% (5006) normal intrauterine pregnancies and 0,1% (4) cases of missed
abortion at the time of the scan. 12.2% (373) of the women received an invasive
testing, 94 for age > 35 years, 21 for positive triple test and 56 for other
reasons (age with minor ultrasound markers or family history). Table 1 show the
basic description of our sample data.
1 summarizes and structures the screening process of our sample. In the
screened population 4613 women had a screen negative result and 221 had
a screen positive result (4.4% false positive). 197 of them chose to have
the invasive test at our department. Of these, 135 had CVS and 62 had
amniocentesis. The rest of the group (24) underwent different management. 14
refused the test, 3 had invasive test at their regional clinic and 7 were
advised for further management (mostly having border line risk). In the group
that underwent invasive testing at our department, 23 cases of trisomies were
detected of which 17 were trisomies 21 and another 17 other chromosomal
the screen negative group, 176 women (3.5%) opted for invasive testing for
other reasons such as age, triple test and family history. Trisomies were
detected in only two pregnancies of this group (45,X0, 47,XX +mar) and one case
of tuberous sclerosis was detected. In these three cases, family history was
the indication, and in each case the parents opted for termination.
Table 2 and table 3 show the outcome of all pregnancies
in our sample in which we ascertained the outcome of as well as the difference
in the outcome in women with invasive testing and without termination in
comparison with the other women. There were 4772 (97.9%) normal live births, 58
(1.2%) had termination for various reasons, 38 (0.8%) aborted and 5 (0.1%) had
stillbirths. The non-invasive group had a higher number of normal live
births, spontaneous delivery and fewer terminations generally. In the group
that underwent invasive testing, if termination was indicated for reasons other
than chromosomal aneuploidy, this was earlier in gestation and the women were
of higher maternal age.
age is the most important factor in our screening test. It is from where the
background coefficient of risk is calculated. The relationship of maternal age,
nuchal translucency and biochemical markers, as well as the relationship of
these markers with the gestational age is shown in figure 2.
can clearly be seen that the age of the mother is independent of all of them
and this is why it can be used as a priori risk factor. On the other hand,
the gestational age have a correlation with each marker. NT and PAPP-A
increase with the increase in the crown-rump length (gestational age) with
a peek between 60 and 70 mm, β‑hCG shows early increase and early decrease.
Table 4 and table 5 show the statistical significance of
ultrasound and biochemical markers used for screening over the whole of our
data sample. Nuchal translucency was highest among terminated cases due to
positive screening with an average of 3.7mm. Fetal heart rate was the lowest
among live births 158/beats per minute. Nasal bone was absent in 35.4% in
positively screened terminated cases, in 3% among cases terminated for other
reasons than positive screening and in 7% among aborted cases; and only in 0.5%
of live births. The proportion of fetuses with two vessels in the umbilical
cord was also the highest among the group of terminated fetuses following
a positive screening test. This group also showed significantly low level
of PAPP-A in maternal serum with no big difference in the level of β-hCG among different
Analyzing the markers in relation to our screening
processs, the relationship between categorical variables was more statistically
significant. Nuchal translucency was the most sensitive markers for trisomies
21 and 18+13. Fetal heart rate was lower among negative screened women. In cases
with trisomy 18+13 fetal heart rate was significantly higher. The nasal bone
was more sensitive indicator for trisomy 21 (52.9%) than trisomy 18+13. Two
umbilical vessels were also of statistical significance as expected among
trisomy 18+13 (16.7%) and nearly the same for trisomy 21 and other chromosomal
abnormalities. Important in this table are the biochemical markers as they
showed the lowest level of PAPP-A and free β-hCG in trisomy 18+13. For trisomy
21, PAPP-A was low and free β-hCG was much higher as it was also expected. It
is interesting to notice in this analysis the lower level of both markers in
positive screen group and those with other pathologies.
The influence of the presence or absence of the nasal
bone or even its uncertainty is clearly seen in our test. The risk coefficient
decreases when the nasal bone is present for all trisomies, being most
sensitive for trisomy 21. On the other hand the risk increases dramatically
when the nasal bone is reported as being absent. This has a big influence
on our border line risk coefficients (table 6).
risk probability ratio in relation to the gestational outcome is summarised in
table 7. The background risk coefficient was highest among the women with still
birth. When the risk for trisomy 21 was 1:280 the risk for still birth was as
high as 1:175. When the risk for trisomy 18+13 was 1:489 the background risk
for still birth was 1:305. Nuchal translucency risk coefficient was highest for
trisomy 21 (1:24) and for trisomy 18+13 (1:58) and was the most sensitive
marker for all trisomes.
biochemical markers (PAPP-A and β-hCG)
risk coefficient was more sensitive for trisomy 21 (1:92), trisomy 18+13
(1:470) and for still birth (1:901) when risk is calculated for trisomy 21.
overall adjusted risk for the screening test (combining all markers) was most
sensitive for trisomy 21 (1:11) and less sensitive for trisomes 18+13 (1:184).
is to notice the important of biochemical profiles among women with still birth
(they have higher risk on the bases of their biochemical markers (low PAPP-A).
The risk probability ratio of the test was most sensitive for trisomies 21, 18,
13 with no difference among the group with positive testing and physiological
karyotype (table 8).
Receiver operative curve describes the attained
sensitivity and specificity of the test. A combination of maternal age,
foetal nuchal translucency thickness, nasal bone, maternal serum free β-hCG and PAPP-A) showed
100% sensitivity for all trisomies with 3.5% and 1.6% false positives for
trisomies 21 and 18+ 13 respectively when the “Cut-off“ risk coefficient is
1:300 (figure 3 and 4).
the “Cut-off“ level risk is reduced to 1:150, the sensitivity and the false
positive rates of the test are reduced (sensitivity; 76.5% and 66.7%, false
positive 2.77% and 0.78%) for trisomy 21 and 18+13 respectively.
point 1:300 seems to be well selected as no case with proven trisomy was
detected above this level (figure 5).
of the test and the relationship between probabilistic risk ratios calculated for
trisomy 21 and 18+13 are shown in figure 6.
of the coefficients for trisomy 21 and 18+13 is noticed, with greater
sensitivity for trisomy 21.
the number of abortions and termination is higher within the area under the
curve analysis of either trisomy 21 or trisomy 18+13.
scatterplot documents that screening scoring for trisomy 21 and for trisomy
18+13 is generally significantly correlated and follow the same trend in
overall data. Cut-off point 1:300 seems to be well located as none case with
proved trisomy was detected above this level, neither trisomy 21 nor trisomy
18+13. The level of risk Cut-off should not be decreased as some positively
detected cases were found nearby the Cut-off level, both trisomy 21 and trisomy
it is apparent that the cut-off itself has some intrinsic variability which
necessarily leads to some inconclusive areas where the risk is indicated for
relatively many cases, with subsequent negative outcome of the screening test.
Therefore, the “Cut-off“ level should be addressed by uncertainty analysis and
the confidence limits should be supplied as additional support for the clinical
The aim of antenatal screening for Down syndrome is to
offer women during pregnancy a screening test which can identify those
women at higher risk of having a child with Down’s syndrome. The group at
increased risk is then offered diagnostic tests. With high quality counseling,
parents can then make an informed choice about how to proceed. In the Czech
Republic the state supports and finances the prenatal screening and diagnosis
for all of its pregnant population. But the intention to ensure that women
across the country receive a high standard of screening and care is still
The study has demonstrated the feasibility and efficacy
of introducing OSCAR for chromosomal abnormalities in a university
hospital. All cases of trisomy 21 had been detected for a 4.4% false
positive rate, the prevalence of trisomy 21 and other aneuploidies is
considerably greater than at term or in the second trimester. Our prevalence of
21 cases per 501 women is consistent with that expected from the maternal age
profile population and the risk of trisomy 21 at 12 weeks of gestation .
findings of the study confirm the prediction that a combination of
maternal serum free β-hCG and PAPP-A with
fetal nuchal translucency thickness at 11–14 weeks of gestation would identify
about 90% of trisomy 21 pregnancies for a 5% false positive rate . The
introduction of the nasal bone as an ultrasound marker has reduced our false
positive results from 6% in our pilot study to 4.4%  and dramatically
increased our detection rate. This is far superior to the average sensitivity
of 65% achievable by second trimester biochemical screening .
the combined first trimester OSCAR screening method had reduced the invasive
procedures from 16.5 % on base of age and 18% on the base of current practice
all over the country to 4.4 % in our population [24, 25].
other congenital abnormalities were identified and managed accordingly in the
first trimester. Shifting our practice from screening in the second trimester
to the first trimester had to be accompanied by the anomaly scan at 20 weeks of
pregnancy. Women who undergo our screening strategy are no longer advised to
take the triple test. The anomaly scan at 20 to 22 weeks of pregnancy was
a sufficient step in our strategy to detect any case of neural tube
defects or abnormality that could be seen only during the later stages of
view of the evidence in favor of first trimester screening, this method has
been widely adopted in many European countries. In the Czech Republic, however,
the Czech Society of Gynecology and Obstetrics and the Ministry of Health are
recommending a National Screening Program based on the second trimester triple
test and age at present. This strategy results in a high number of
invasive procedures in the country (18–19%) for 80% detection rate.
aim of our OSCAR clinic is to improve patient satisfaction by reducing the
number of visits and minimizing travel costs, patient anxiety and patient
stress, while offering maximum utilization of hospital outpatient resources [1,
6, 7, 18, 19, 21].
setting up of our one-stop clinic required little change to our normal prenatal
care practice. Since the beginning of 2005, our first trimester ultrasound
scans has been part of the every-day routine scanning and the introduction of
fetal nuchal translucency thickness scanning was carried out by reorganizing
scanning times and required only minimal additional resources.
Ishraq Dhaifalah, MD,
Department of Medical
Genetic and Fetal Medicine
I. P. Pavlova
557 52 Olomouc
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