Key words
trisomy - cell-free DNA - first trimester screening - termination of pregnancy
Introduction
In recent years, antenatal aneuploidy screening has evolved considerably [1], [2].
In the 1990s, the antenatal risk evaluation was still primarily based on the maternal
age risk [3]. In the following years, with the introduction of the combined first trimester screening
(FTS), screening using only the material age risk was largely replaced [4]. The advantage primarily concerned the significantly higher test quality. Using
FTS, about 90 – 95% of foetuses with trisomy 21 and 95% of foetuses with trisomy 18
and 13 could be detected, while the detection rate based on maternal age was only
around 50% for trisomy 21 and 10% for trisomy 18/13 [5], [6], [7]. Even more significant was the decrease in the false-positive rate from 25 to 5%.
Hui et al. demonstrated for Australia that amniocenteses significantly decreased as
a consequence of the introduction of FTS starting in 2000 [8].
In recent years, a new paradigm shift can be observed with the introduction of cell-free
DNA (cfDNA) in antenatal diagnostics. Using this screening method, about 99% of pregnancies
with trisomy 21 and 93% and 84% of pregnancies with trisomy 18 and 13, respectively,
can be detected with a false-positive rate of about 0.05% in each case [9]. This method was initially regarded with reserve due to its high cost, but now much
more affordable prices have led to a steadily growing importance in antenatal screening
for trisomy 21. As a consequence, a study has investigated whether cfDNA analysis
in combination with a detailed ultrasound examination could also be used as a primary
screening strategy and demonstrated it can be used as such [10]. Along with the improved test quality, the simple handling of the cfDNA analysis
is advantageous since it involves only a blood draw and counselling as defined by
the German Genetic Diagnostics Act (GenDG).
With the introduction of FTS, the earliest possible time of diagnosis of a chromosome
disorder has been shifted from the second to the first trimester. The cfDNA analysis
enables an even earlier risk assessment. It is feared that as a result of aneuploidy
screening occurring earlier and becoming less complicated, the attitude towards pregnancies
with a foetal chromosome disorder will change and the rate of pregnancy terminations
will increase. A recently published meta-analysis by Hill et al. investigated patientʼs
attitude regarding terminating a pregnancy with trisomy 21 identified using cfDNA
analysis. Interestingly, the percentage of terminations remained the same or even
decreased in comparison to the pre-cfDNA era [11].
This work is intended to investigate whether in a large perinatal centre – providing
healthcare regionally and transregionally – the time of diagnosis of a foetal trisomy
21, 18 and 13 as well as the frequency of pregnancy terminations has changed in the
past 10 years. The 10-year period is characterised by the increased use of the first-trimester
screening and, for the past several years, also through screening using cfDNA analysis.
Material and Methods
Description of the study collective
About 12 000 patients are seen annually in the Department of Antenatal Medicine of
the Tübingen University Hospital. A total of four physicians, two of whom are DEGUM
III-certified, work in the department. Patients are referred for screening examinations
and for second opinion, diagnosis, counselling and management of abnormal findings.
The entire spectrum of screening examinations is offered. Since 2012, this has also
included cfDNA analysis. All pregnant women with an abnormal ultrasound, cfDNA or
other abnormal screening finding are offered an invasive diagnostic procedure, generally
amniocentesis or chorionic villus sampling. If this is not desired, postnatal diagnostic
testing is indicated.
The pregnancy is not terminated alone on the basis of suspected trisomy 21. This always
requires karyotyping beforehand. If trisomy 18 or 13 is suspected, the pregnancy may
be terminated due to multiple deformities and the resulting stress. In general, an
attempt is also made in these cases to perform karyotyping before terminating the
pregnancy. If this is not possible, post-mortem karyotyping is always performed.
Pregnancy terminations are performed without any time restriction. Foeticide is performed
beforehand, if necessary. If the patient decides to continue the pregnancy, the newborn
is cared for according to standard care in the case of trisomy 21. In the case of
newborns with trisomy 18 and 13, palliative care or, in isolated cases, maximum care
is discussed.
If the delivery takes place at another birth centre, the birth data and karyotype
are subsequently entered into the Viewpoint database.
All patients who are referred for termination of pregnancy according to section 218a
German Penal Code (StGB) para.2 are seen and counselled beforehand in the Department
of Antenatal Medicine.
All information collected is stored in the digital Viewpoint database. In addition
to the ultrasound examinations, this also includes findings from the screening tests
as well as those of the ante- and postnatal karyotyping. In addition, all pregnancy
terminations are noted according to section 218a StGB para. 2.
A query of the Viewpoint database was performed for this study in order to find the
pregnancies in which foetal trisomy 21, 18 and 13 were diagnosed ante- and postnatally
and which were seen in the Department of Antenatal Medicine. The maternal age and
gestational age at the time of suspicion and at the time of diagnosis, the test method,
and the outcome of the pregnancy were queried.
Statistical analysis
All results were indicated as the median with the interquartile range or as a percent
of the respective initial population. The percentage of pregnancy terminations per
examination interval was compared by looking at the 95% confidence interval. In the
case of overlapping confidence intervals, a nonsignificant result is assumed. The
gestational age at the time of termination of the pregnancy in the 2007 – 2010 group
was compared with the gestational age of the 2015 – 2017 group using a Mann-Whitney
U test. A normal distribution was excluded beforehand using the Shapiro-Wilk test.
The significance level was < 0.05.
Results
Demographic characteristics
Between 2007 and 2017, trisomy 21, 18 or 13 were diagnosed at the antenatal centre
of the Tübingen University Hospital in 498 foetuses and newborns who were examined
in the Department of Antenatal Medicine. Trisomy 21 was identified in 311 (62.4%)
of the foetuses or newborns, trisomy 18 was identified in 134 (26.9%), and trisomy
13 was identified in 53 (10.6%).
For the subsequent analysis, the pregnancies with foetal trisomy 18 and 13 were analysed
together.
[Tables 1] and [2] summarise the time of diagnosis of trisomy 21 or trisomy 18/13, the examinations
performed at the University Womenʼs Hospital, and the outcome of the pregnancies.
The results are shown separately for the examination periods of 2007 – 2010, 2011 – 2014
and 2015 – 2017.
Table 1 Trisomy 21 cases. The table indicates – divided according to the examination period
– the number of managed cases with the chromosome disorder, the mean maternal age
and gestational age at diagnosis, the percentage of pregnancies which were terminated,
and the gestational age at the time the pregnancy was terminated. In addition, the
percentage of pregnancies in which a cell-free DNA analysis and an invasive diagnostic
procedure were performed is shown.
|
|
2007 – 2010 (3 years)
|
2011 – 2014 (3 years)
|
2015 – 2017 (2 years)
|
|
* The diagnosis was made using ante- or postnatal karyotyping.
IQR = 25 – 75% interquartile range, n = number, WOP = weeks of pregnancy
|
|
Ante- and postnatally diagnosed foetuses and newborns with trisomy 21, n
|
81
|
120
|
110
|
|
Maternal age at diagnosis
Years, median (IQR)
|
37.3 (35.1 – 39.7)
|
36.1 (32.2 – 39.9)
|
37.2 (35.2 – 39.7)
|
|
Cell-free DNA analysis, n (%)
|
0 (0)
|
3 (2.5)
|
28 (25.5)
|
|
Diagnostic puncture, n (%)
|
76 (93.8)
|
101 (84.2)
|
106 (96.4)
|
|
Gestational age at diagnosis*
WOP, median (IQR)
|
14.4 (12.9 – 16.8)
|
13.6 (12.6 – 15.7)
|
13.9 (12.9 – 16.6)
|
|
Up to 13 + 6 WOP, n (%)
|
41 (50.6)
|
64 (53.3)
|
63 (57.3)
|
|
14 + 0 to 17 + 6 WOP, n (%)
|
24 (29.9)
|
20 (16.7)
|
29 (26.4)
|
|
18 + 0 to 22 + 6 WOP, n (%)
|
4 (4.9)
|
11 (9.2)
|
9 (8.2)
|
|
After 23 + 0 WOP, n (%)
|
7 (8.6)
|
5 (5.0)
|
5 (4.5)
|
|
Post partum, n (%)
|
5 (6.2)
|
19 (15.8)
|
4 (3.6)
|
|
Termination of pregnancy
n (% [95% CI])
|
54 (66.7 [55.3 – 76.8])
|
82 (68.3 [59.2 – 76.2])
|
83 (75.5 [66.3 – 83.1])
|
|
Gestational age termination of pregnancy
WOP, median (IQR)
|
14.9 (13.9 – 18.1)
|
15.0 (13.7 – 16.9)
|
14.9 (13.9 – 18.3)
|
Table 2 Trisomy 18 and 13 cases. The table indicates – divided according to the examination
period – the number of managed cases with the chromosome disorder, the mean maternal
age and gestational age at diagnosis, the percentage of pregnancies which were terminated,
and the gestational age at the time the pregnancy was terminated. In addition, the
percentage of pregnancies in which a cell-free DNA analysis and an invasive diagnostic
procedure were performed is shown.
|
|
2007 – 2010 (3 years)
|
2011 – 2014 (3 years)
|
2015 – 2017 (2 years)
|
|
* The diagnosis was made using ante- or postnatal karyotyping.
IQR = 25 – 75% interquartile range, n = number, WOP = weeks of pregnancy
|
|
Ante- and postnatally diagnosed foetuses and newborns with trisomy 13/18
|
47
|
69
|
71
|
|
Maternal age at diagnosis
Years, median (IQR)
|
38.5 (34.0 – 40.5)
|
35.8 (33.4 – 39.9)
|
36.2 (33.0 – 40.2)
|
|
Cell-free DNA analysis, n (%)
|
0 (0)
|
1 (1.4)
|
3 (4.2)
|
|
Diagnostic puncture, n (%)
|
42 (89.4)
|
66 (95.7)
|
67 (94.4)
|
|
Gestational age at diagnosis*
WOP, median (IQR)
|
13.8 (12.4 – 21.9)
|
14.6 (12.4 – 20.6)
|
13.6 (12.6 – 18.1)
|
|
Up to 13 + 6 WOP, n (%)
|
24 (51.1)
|
35 (50.7)
|
41 (57.7)
|
|
14 + 0 to 17 + 6 WOP, n (%)
|
2 (4.3)
|
11 (15.9)
|
10 (14.1)
|
|
18 + 0 to 22 + 6 WOP, n (%)
|
8 (17.0)
|
10 (14.5)
|
11 (15.5)
|
|
After 23 + 0 WOP, n (%)
|
8 (17.0)
|
11 (15.9)
|
7 (9.9)
|
|
Post partum, n (%)
|
5 (10.6)
|
2 (2.9)
|
2 (2.8)
|
|
Termination of pregnancy
n (% [95% CI])
|
27 (57.4 [42.2 – 71.7])
|
45 (65.2 [52.8 – 76.3])
|
49 (69.0 [56.9 – 79.5])
|
|
Gestational age at termination of pregnancy
WOP, median (IQR)
|
15.1 (13.6 – 21.0)
|
15.0 (13.3 – 21.1)
|
15.1 (13.4 – 18.0)
|
Trisomy 21
Overall, a steady increase in the diagnosed cases with foetal trisomy 21 can be observed.
The median gestational age at diagnosis using karyotyping was between 14.4 and 13.6
weeks of pregnancy. Half of the cases were diagnosed before 13 + 6 weeks of pregnancy,
with a slightly increasing trend.
The percentage of trisomy 21 pregnancies in which a cell-free DNA analysis was performed
increased over the course of the three investigation periods from 0 to 25.5%. 91.0%
of the pregnant women with foetal trisomy 21 decided to undergo an invasive diagnostic
procedure due to an increased risk, 8.4% decided against a puncture, and in two women
(0.6%), no increased risk was presumed during the pregnancy. Changes over the course
of the investigation period cannot be identified.
The rate of pregnancy terminations increased slightly, from 66.7% between 2007 and
2010 to 75.5% between 2015 and 2017. However, the increase was not significant. The
median gestational age at the time of the termination remained constant at 14.9 and
15.0 weeks of pregnancy (no significant change between 2007 – 2010 to 2015 – 2017,
p = 0.469).
Trisomy 18 und 13
A similar trend is seen in the case of pregnancies with foetal trisomy 18/13 ([Table 2]). The number of diagnosed chromosome disorders increased from 47 to 71 cases per
examination period.
After an increased risk was identified, 89.4 to 94.4% of the patients decided to undergo
a diagnostic test. The median gestational age at diagnosis using karyotyping was between
13.6 and 14.6 weeks of pregnancy. The percentage of diagnoses before 13 + 6 weeks
of pregnancy increased over the course of the examination periods from 51.1 to 57.7%,
while diagnoses after 23 + 6 weeks of pregnancy decreased from 17.0 to 9.9%.
The percentage of pregnancies affected which were terminated in the three time periods
likewise increased slightly but not significantly from 57.4 to 69.0%. However, the
gestational age at termination remained unchanged at 15.0 and 15.1 weeks of pregnancy
(no significant change between 2007 – 2010 to 2015 – 2017, p = 0.760). The cell-free
DNA analysis was not of importance in this collective.
Percentage of pregnancies terminated after diagnosis
[Table 3] shows the percentage of pregnancies terminated in the case of foetal trisomy 21,
18 and 13 as a function of the gestational age at diagnosis. While most pregnancies
were terminated prior to 23 + 0 weeks of pregnancy, most patients after 23 + 0 weeks
of pregnancy decided against terminating the pregnancy. No clear trend can be identified
when comparing the three examination periods.
Table 3 Pregnancy terminations in the case of foetal trisomy 13/18 and 21 as a function of
gestational age at diagnosis.
|
Time of diagnosis
|
2007 – 2010 (3 years)
|
2011 – 2014 (3 years)
|
2015 – 2017 (2 years)
|
|
* Percentage of pregnancies terminated out of all pregnancies with diagnosed chromosome
disorder
n = number, WOP = weeks of pregnancy
|
|
Up to 13 + 6 WOP, n (%)*
|
49 (75.4)
|
82 (82.8)
|
85 (81.7)
|
|
14 + 0 to 17 + 6 WOP, n (%)*
|
20 (76.9)
|
26 (83.9)
|
31 (79.5)
|
|
18 + 0 to 22 + 6 WOP, n (%)*
|
10 (83.3)
|
15 (71.4)
|
14 (70.0)
|
|
After 23 + 0 WOP, n (%)*
|
2 (13.3)
|
4 (23.5)
|
2 (16.7)
|
A cfDNA analysis was performed in 35 pregnancies. In this group, 23 (65.7%) pregnancies
were terminated. In the group of pregnancies without cfDNA analysis, the termination
rate was similarly high (317 [68.5%] out of 463 cases).
Discussion
In this study, the gestational age at diagnosis of trisomy 21, 18 or 13, the frequency
of termination of pregnancy in the case of a corresponding chromosome disorder, and
the gestational age at the time the termination was performed were investigated. This
demonstrated a significant increase in diagnosed cases in the past ten years. The
median gestational age at diagnosis was around 14 weeks of pregnancy in the entire
examination period. The rate of terminations increased slightly but not significantly
from 66.7 to 75.5% for pregnancies with trisomy 21 and from 57 to 69% for pregnancies
with trisomy 18 and 13. The gestational age in the case of a termination remained
unchanged.
Boyed et al. investigated the frequency of pregnancies terminated following antenatal
diagnosis of trisomy 21 in 19 Eurocat centres in Europe from 2002 to 2004. The rates
varied between 76 and 100% and were 96% in the German centres. The diagnosis was made
on average at 15 weeks of pregnancy [12]. In a study from Japan, 94% of pregnancies with trisomy 21 were terminated. In the
case of trisomy 18 and 13, the rates were 85 and 72% [13]. Also, in the study from Hume et al. from the USA which included the years from
2005 to 2014, the rate of pregnancies terminated in the case of trisomy 21 was 94%
[14].
Interestingly more women chose to continue the pregnancy in the case of trisomy 18
or 13 than in the case of pregnancies with trisomy 21.
This is presumably due to the option for accompanying palliative care in the case
of pregnancies with trisomy 18 and 13.
Hill et al. summarised the results of 14 studies which investigated the rate of termination
of pregnancy before and after the introduction of the cfDNA analysis. Depending on
the study, the termination rate before the introduction of the cfDNA analysis was
between 67 and 96%. This rate did not change with the introduction of cfDNA analysis
[11]. With regard to the absolute frequency of pregnancy terminations in the case of
trisomy 21, our own data are concordant with the results from Hill et al. In contrast
to this, a slight increase in terminations of pregnancy could be observed in our study
in previous years. Whether this is a reflection of a changing attitude towards children
with trisomy 21 or actually represents the result of the early screening methods is
a question which cannot be definitively answered.
However, the time of diagnosis of the chromosome disorder has fundamentally not changed,
despite the introduction of cell-free DNA analysis and was at 13 to 14 weeks of pregnancy
on average. This likely demonstrates the already longstanding, broad acceptance of
FTS in Germany. In the study by Hume et al. from the USA, the gestational age upon
diagnosis of a trisomy 21 fell from 16 to 12 weeks of pregnancy between 2005 and 2014.
The authors divided the time into three periods in which FTS was available in all
periods and the cfDNA analysis was available in the last period starting in 2012 [14].
Even if pregnancy terminations are fundamentally the subject of controversy, there
is consensus that they should take place as early as possible in the pregnancy. In
contrast to the first trimester, termination of pregnancy in the 2nd and 3rd trimester
involves far more complications. Bartlett et al. investigated the mortality rate in
pregnancy terminations between 1988 and 1997 in the USA. Overall, the rate was 0.7
per 100 000 terminations and increased by 38% per week starting at the 8th week of
pregnancy [15]. Mark et al. investigated the morbidity rate in surgical terminations in the first
and second trimester as a function of the maternal body mass index [16]. Once again, this revealed an elevated rate of complications in the second trimester
in comparison to the first trimester and this rate rose even further with patientsʼ
increasing overweight. The psychological burden also increased as the gestational
age increased [17]. This applies in particular in the case of a situation involving post-traumatic
stress [18].
Our study is based on the data from a single university hospital. In this respect,
it could be argued that they are not representative. However, since the Tübingen University
Center for Womenʼs Health has an obligation to provide regional care and it also functions
as a transregional reference centre, generally valid conclusions can be drawn from
the data. An advantage is that each pregnant woman with foetal trisomy is seen in
the Department of Antenatal Medicine – independent of gestational age and whether
the pregnancy is continued or ends in a termination. In addition, we endeavour to
look after all pregnancies until the end so that we are informed of the outcome of
all affected pregnancies. It should be critically mentioned that a portion of the
pregnant women with an abnormal cfDNA analysis decide within the first 12 weeks after
conception to terminate the pregnancy in accordance with section 218a para.1 StGB
(period during which termination of pregnancy is legal). These patients forego clarification
by means of invasive diagnostic procedures and indicate psychological stress as the
reason for terminating the pregnancy. A statement regarding the frequency is unfortunately
not possible.
In summary, we were able to show in this study that the number of trisomy 21 and also
trisomy 18/13 diagnoses has increased in recent years. However, the frequency of pregnancy
terminations increased only slightly. The time of the diagnosis and the terminations
also did not change.
