Introduction
Most expectant parents want to know as early as possible whether their unborn child
will be born healthy or with a structural malformation. Particularly with regard to
chromosomal disorders, couples wish to have early diagnostic clarification in order
to consider adjustments needed in the event of giving birth to a child with abnormalities
or to terminate the pregnancy. Trisomy 21 is the most common chromosomal abnormality
in liveborn infants with an incidence of 1/600–1/800 in the general population [1 ]. First Trimester Screening (FTS) at 11+0–13+6 weeks of pregnancy offers an early
assessment of the risk for aneuploidies. Nuchal translucency and other ultrasound
parameters in combination with maternal age and biochemical parameters, like free
beta HCG and PAPP-A, can be used to estimate an individualized risk for the three
most common chromosomal disorders (trisomy 21, 13 and 18) at an early stage [2 ]
[3 ]
[4 ]. With a detection rate of 90% and a false-positive rate of 5%, this is a very sensitive
screening method for detecting trisomies. In the second-trimester anomaly scan, markers
can be used to adjust the risk for trisomy 21. Agaard-Tillery et al. published a study
with 7842 pregnant women at the second-trimester ultrasound scan [5 ].They demonstrated that the detection rate of trisomy 21 can increase from 93–98%
if the basal risk from first-trimester screening was modified with the marker screening
result of the second-trimester ultrasound scan by considering the positive and negative
likelihood ratios in the presence or absence of these markers. Considering this fact,
the detection of second-trimester ultrasound markers may lead to an increased number
of diagnostic procedures [6 ]
[7 ]. Regarding all second trimester markers, the echogenic cardiac focus (ECF) is the
most controversial [8 ] because it is the most prevalent marker among the normal population with a prevalence
of approximately 5–10% in a normal second-trimester collective [9 ]. The vast majority of studies showed a significantly increased risk for trisomy
21 if the echogenic focus occurs in combination with other minor markers [10 ]
[11 ]
[12 ]. There is controversy as to whether the echogenic focus, if it occurs in isolation,
also increases the risk for trisomy 21 and in particular whether this increase in
risk also exists in an unselected normal population. Furthermore, many past studies
have suggested an isolated echogenic cardiac focus (iECF) to be associated with an
increased risk of trisomy in high-risk populations, e. g. due to advanced maternal
age or increased risk of previous screening [13 ]
[14 ]
[15 ]
[16 ]. Other publications reported a tendency towards an increased risk also in low-risk
pregnancies, but failed to show a statistically significant result [5 ]
[14 ]
[17 ]
[18 ]
[19 ]. This may also be due to an insufficient number of cases in the individual low-risk
studies and the associated low statistical power corresponding to the lower prevalence
of trisomy 21 in these low-risk studies. Furthermore, observational databases are
known to suffer from a series of internal validity biases [20 ]. Therefore, a direct interpretation of results at face value could be misleading.
The aim of this study is to assess the clinical relevance of the iECF by combining
the data from our prenatal center with a Bayesian meta-analysis. We also formed a
low-risk subgroup in order to provide information on how to counsel parents in pregnancies
with an iECF. Our aim was to clarify three questions: First, does the discovery of
an isolated echogenic cardiac focus with an otherwise completely normal ultrasound
result change the patientʼs risk to such an extent that this finding must be included
in prenatal counselling? Second, does an iECF increase the risk for trisomy 21 in
the low-risk group with regard to the low prevalence of this disease? Noninvasive
prenatal testing (NIPT) is the analysis of cell-free DNA from maternal blood with
a high negative predictive value, which makes it an option for the clarification especially
of medium-risk cases. However, this method does not cover the same spectrum of anomalies
as classic invasive diagnostic testing, for example structural chromosomal anomalies
are not addressed by the current NIPT tests. Thus, our third question is: Is there
any evidence of other chromosomal abnormalities associated with iECF that would indicate
that a cell-free DNA test is not sufficient for clarification of the iECF?
Methods
This was a retrospective cohort study of ultrasound examinations in a tertiary referral
center that included all singleton pregnancies between 14+0 and 21+6 weeks in the
years 2000–2016 (n=1 25 211). In addition, we performed a subgroup analysis by dividing
the second-trimester anomaly scan collective 18+0 to 21+6 weeks into two a priori
risk groups based on the maternal age and, if available, previous screening test results
and defined a risk cut-off point of 1/300. As a priori high risk we rated: a) maternal
age 35 or older - no screening test, b) age 35 or older with a risk cut-off ≥ 1:300,
and c) younger than 35 but a risk cut-off ≥ 1:300. As a priori low risk we rated d)
younger than 35 with no test, e) younger than 35 with a risk cut-off<1:300, and f)
age 35 or older but a risk cut-off<1:300. We used high-resolution ultrasound equipment
(Toshiba Aplio 500, GE Voluson 730, E8, E10). Ultrasound examinations were performed
by DEGUM II certified specialists in obstetric ultrasound with several years of special
experience in prenatal medicine. We obtained written informed consent from participants
and the Ethics Committee (study number 5588) of the University of Düsseldorf accepted
the study. Information on any fetal chromosomal abnormalities was either taken from
prenatal cytogenetic findings or, if not available, from the requested postnatal U1
reports. Neonates with normal phenotypes were assumed to have normal karyotypes. Any
postnatal phenotypic suspicion of a chromosomal disorder was cytogenetically clarified.
We reviewed our ultrasound database for any entry regarding an echogenic heart focus.
In each identified case, the ultrasound findings were evaluated for any further abnormality
to identify the isolated cases of ECF. The ECF was defined as an echo-rich structure
in or next to the papillary muscle of the right and/or left ventricle that corresponded
to the brightness of bones. We classified an echogenic cardiac focus as “isolated”
(iECF) if there were no further malformations, markers or any other clinically relevant
abnormalities. All cases with known fetal karyotype before examination (n=1586; 1.27%)
were excluded. We also excluded cases with aneuploidies other than 13, 18 or 21 (n=197;
0.16%), all cases without written consent to anonymous study participation (n=11;
0.01%) and all cases “lost to follow up” in which neither the karyotype nor the postnatal
examination findings were clearly known (n=19 416; 15.51%). An overview is presented
in [Table 1 ]. Fetuses with known euploid karyotype or missing stigmata of aneuploidy at birth
were classified as “euploid”. In terms of structural anomalies, we did not distinguish
between unbalanced and balanced findings and we also assigned the microdeletions to
this group. [Table 2 ] gives an overview of study exclusions and karyotypes. After completion of the classification,
we constructed 2×2 tables to calculate the proportion of isolated ECFs among the chromosomally
abnormal and the euploid fetuses. Likelihood ratio was calculated as a quotient of
iECF prevalence among the aneuploid cases divided by the corresponding prevalence
among the euploid cases.
Table 1 Study exclusions and characteristics of the included patients.
Causes for the study exclusion/characteristics
Number/value
Total number of patients
1 25 211
Exclusions
Aneuploidies other than Trisomies 13, 18, 21
197/1 25 211 (0.16%)
Invasive diagnosis before ultrasound
1586/1 25 211 (1.27%)
No study consent
11/1 25 211 (0.01%)
No outcome
19 416/1 25 211 (15.51%)
Total exclusions
21 210/1 25 211 (16 94%)
Included
1 04 001/1 25 211 (8 3 06%)
Mean GA
18.88
Number GA group ʼ14+0 to 17+6ʼ
34 791 (33.45%)
Number GA group ʼ18+0 to 21+6ʼ
69 210 (66.55%)
Mean maternal age during examination
33.96
Age≥35 years
50 600/1 04 001 (48.65%)
Age<35 years
53 401/1 04 001 (51.35%)
Mean maternal age group ʼ14+0 to 17+6ʼ
36.35
Mean maternal age group ʼ18+0 to 21+6ʼ
32.77
Ethnicity
Caucasian
1 03 552 (99.57%)
Asian
106 (0.1%)
Oriental
75 (0.07%)
Black
75 (0.07%)
Mixed
193 (0.19%)
Table 2 Karyotypes of excluded and included cases.
Karyotype
Number of included cases (percent)
Number of excluded cases (percent)
Euploid
1 02 847 (82.14%)
2135 (1.71%)
Trisomy 21
557 (0.44%)
69 (0.06%)
Structural chromosomal anomalies*
431 (0.34%)
80 (0.06%)
Trisomy 18
120 (0.1%)
16 (0.01%)
Trisomy 13
46 (0.04%)
(0%)
No outcome
(0%)
18 661 (14.9%)
Triploidy
(0%)
58 (0.05%)
Other aneuploidy
(0%)
11 (0.01%)
Gonosomal aneuploidy
(0%)
180 (0.14%)
Total
1 0
4 001 (83 06%)
21 210 (16. 94%)
* unbalanced, balanced and microdeletions.
Meta-analysis
For the meta-analysis we investigated all studies that aimed to estimate the population
prevalence of isolated ECF and the associated risk of trisomy 21 in a coherent collective
between 1998–01–01 and 2019–08–01. For this purpose we analyzed all publications used
in the meta-analysis of Agathokleous et al. 2013 [21 ] based on the Supplemental list ʼ [Table 1S ]ʼ. We completed this list of studies for the time from 2010 onwards based on a structured
query in PubMed for the echogenic cardiac focus: (((“echogenic focus” OR “echogenic
foci”)) OR (“hyperechoic focus” OR “hyperechoic foci”)) OR (“echogenic cardiac focus”
OR “echogenic cardiac foci”)) OR (“echogenic heart focus” OR “echogenic heart foci”))
OR (“echogenic intracardiac focus” OR “echogenic intracardiac foci”)) OR “golf ball”)
AND (“2010/01/01” [Date – Publication]: “2019/08/01” [Date – Publication]). From the
results of this query (267 articles in English were found), we then excluded non-medical
studies, studies in uncommon languages, studies not focusing on the ECF as a soft
marker for trisomy 21, reviews/editorials/meta-analysis and overlapping papers for
2010 that were already assessed by Agathokleous. In total, 19 studies from the Agathokleous
list dealt with the subject of ECF plus 14 were left over from our query after primary
exclusions. Among these 33 studies, we classified publications as eligible for our
meta-analysis, if: 1) A 2×2 cross table could be extracted for the incidence of isolated
ECF in both euploid and trisomy 21 fetuses. 2) Study design: prospective or retrospective
cohort studies. 3) No case control studies and case reports. 4) Classifying the risk
characteristic of the study cohort concerning trisomy 21 was possible. 5) The procedure
for collecting outcomes regarding trisomy 21 for the whole collective must be described.
6) The number of exclusions lost to follow-up was given. 7) Gestational age at examination
was between 14+0 and 26+6 weeks (overview in [Fig. 1 ]).
Fig. 1 Selection of literature for the meta-analysis.
From the eligible studies we extracted the number of true positives, true negatives,
false positives and false negatives. We then classified them as ʼhigh riskʼ or ʼnormal/low
riskʼ and ʼprospectiveʼ or ʼretrospectiveʼ according to the indications in the paper.
The included studies and the 2×2 table values for isolated ECF are displayed in [Table 3 ]. LR+was calculated on the basis of these numbers.
Table 3 Studies included in the meta-analysis.
Author
Year
Population
Design
TP
FP
FN
TN
Total
LR+calculated
Manning
[24 ]
1998
high risk
p
2
21
15
863
901
4.95
Sohl
[25 ]
1999
high risk
p
12
151
33
2488
2684
4.66
Thilaganathan
[26 ]
1999
high risk
p
0
143
10
16 763
16 916
0
Wax
[27 ]
2000
high risk
p
2
21
5
751
779
10.5
Winter
2000
high risk
p
5
130
21
2689
2845
4.17
Prefumo
[28 ]
2001
low risk
r
0
239
6
7443
7688
0
Huggon [29]
2001
high risk
p
5
543
75
6361
6984
0.79
Coco [30]
2004
low risk
p
1
432
10
12 229
12 672
2.66
Lamont [31]
2004
low risk
r
1
310
13
10 445
10 769
2.48
Smith-Bindman [32]
2007
high risk
p
15
211
230
8496
8952
2.53
Weisz [17 ]
2007
low risk
r
1
88
11
2232
2332
2.2
Shanks
2009
low risk
r
14
1 998
204
59 895
62 111
1.99
Huang
2010
low risk
p
2
209
23
6884
7118
2.72
Hurt [33]
2016
low risk
p
3
600
28
18 210
18 841
3.03
Ginsberg [34]
2017
low risk
r
20
1 340
42
19 270
20 672
4.96
Total
83
6
436
726
1 75 019
1 82
264
TP=true positives, FP=false positives, FN=false negatives, TN=true negatives.
Statistical methods
In this study, we used a meta-analysis of previously published studies, with diagnostic
test accuracy of the iECF marker to build a bias correction model for the diagnostic
results of our prenatal database. Using the 2×2 tables of published diagnostic results,
we performed a multi-parameter Bayesian meta-analysis of the sensitivities and specificities.
The posterior distributions of the marginal pooled sensitivity and specificity were
used as meta-analytic priors to adjust the results of the prenatal database. This
adjustment was performed on the sensitivities and specificities of the prenatal database
and by handling the LR+and LR- as functional parameters. Therefore, the Bayesian computations
were performed at the level of sensitivity and specificity and results are transformed
on the scale of LR+and LR-.
The studies included in the meta-analysis suffer from a series of uncontrolled variabilities,
e. g., different internal quality, different study design, variation in the study
population and diagnostic settings. Those sources of variation are non-systematic
resulting in a complex random heterogeneity between studies. In addition, the number
of studies included in the meta-analysis is small (n=15). Therefore, a specially designed
Bayesian method has to be used to make a meta-analysis of this kind of data. In this
study, we applied the meta-analysis model based on random effects with scale mixtures
of normal distributions implemented in the Rʼs package bamdit (Bayesian Meta-Analysis
of Diagnostic Test Data). The results of the meta-analysis model are displayed by
plotting the observed TPRs (True-Positive Rates) versus the FPRs (False-Positive Rates).
The Bayesian model is summarized by the 50, 75 and 95% posterior predictive curves.
In addition, we displayed 500 modelʼs prediction of the combination of TPRs and FPRs.
Statistical computations
The statistical analysis was performed with the statistical software R version 3.5.2
(R Core Team, 2019). The Bayesian meta-analysis of diagnostic test accuracy was performed
with R package bamdit [22 ]. Statistical analysis was performed with the statistical software R version 3.5.2
(R Core Team, 2019). Bayesian models are not analytically tractable. Estimation of
posterior probabilities was based on MCMC (Markov Chain Monte Carlo) computations.
In each analysis, we used two MCMC runs of 20 000 iterations and we discarded the
first 5000 for the burn-in period. Convergence was assessed visually using the R package
coda. The results of the Bayesian analyses are presented as posterior distributions
and their summaries: Posterior means, standard deviations, quantiles (2.5, 50, and
97.5%) and the histogram of the posteriors.
Results
A total number of 1 25 211 patients with a singleton pregnancy between 14+0 and 21+6
weeks underwent prenatal ultrasound examination during the study period. See [Table 1 ] for more details and causes for study exclusion. An overview of the karyotypes of
excluded and included cases is given in [Table 2 ]. The overall prevalence of isolated echogenic foci in the current study population
was 4.33% (4480/1 04 001). In total, an isolated ECF was found in 4416 of 1 02 847
euploid fetuses (4.29%) and in 64 of 557 cases with trisomy 21 (11.49%) which led
to a positive likelihood ratio (LR+) of 2.68 (CI: 2.12–3.2) for the entire study population
([Table 4 ]).
Table 4 Results of the meta-analysis.
Type of data
Population
LR+
LR-
TP
FP
FN
TN
Total
Sens.
Spec.
Our center
mixed
2.68 (2.12–3.20)
0.92
64
4416
493
98 431
1 03 404
0.12
0.96
Our center
high risk
3.86 (2.43–5.14)
0.85
19
1251
79
23 630
24 979
0.19
0.95
Our center
low risk
2.59 (1.05–4.00)
0.92
9
2219
60
41 815
44 103
0.13
0.95
Meta-analysis
posterior mean (posterior 95% interval)
3.11 (1.84–4.92)
0.93
0.11
0.97
MA/our center combined
mixed
2.65 (2.11–3.3)
0.93 (0.90–0.94)
MA/our center combined
high risk
2.92 (2.05–3.90)
0.90 (0.85–0.96)
MA/our center combined
low risk
2.33 (1.51–3.30)
0.93 (0.88–0.97)
Posterior LR+of the meta-analysis (MA) and combined LR+of our center+meta-analysis.
TP=true positives, FP=false positives, FN=false negatives, TN=true negatives, sens.=sensitivity,
spec.=specificity.
Subsequently, we divided the 18+0–21+6 second-trimester anomaly scan group into two
subgroups, high and low risk for fetal trisomy 21. The prevalence of iECF was very
similar in both groups with 5.08% (1270/24 979) in the high-risk subgroup and 5.05%
(2228/44.103) in the low-risk subgroup. As expected, the frequency of trisomy 21 was
higher in the first subgroup than in the latter (0.39%, 98/24 979 vs. 0.16%, 69/44 103).
Overall for our center-specific collective these numbers led to better screening performance
of the iECF in the high-risk group compared to the low-risk group with a sensitivity
of 19.39% (CI: 11.56–27.21) vs. 13.04% (CI: 5.1–20.99) at an almost identical FPR
of 5.03% (CI: 4.76–5.3) vs. 5.04% (CI: 4.83–5.24). The LR+was calculated as 3.86 (CI:
2.43–5.14) in the high-risk group and 2.59 (CI: 1.05–4) in the low-risk group ([Table 4 ]).
The ECF in combination with one or more other markers showed a clearly higher LR+(31.9)
than the iECF. The overall consideration of other markers in isolation resulted in
a slightly higher LR+(4.39). The highest LR+(88.9) was found when two or more other
markers than ECF were diagnosed in combination.
Results of the meta-analysis
The meta-analysis included 15 studies with a total of 1 82 264 patients. After combining
all the data from the included studies, the posterior mean LR+was calculated as 3.11
and the posterior 95% confidence interval ranged from 1.84–4.92 ([Table 4 ]). The pooled sensitivity of 1.11 and the specificity of 0.97 were used as meta-analytic
priors to adjust the results of the prenatal database. After the adjustment, the combined
(meta-analysis and our database) mean LR+for the total/mixed collective almost did
not change (2.65 (CI: 2.11–3.3)). In both the high-risk and the low-risk subgroup,
the mean LR+decreased to 2.92 and 2.33 (high-/low-risk) and the 95% confidence intervals
noticeably narrowed to 2.05–3.90 and 1.51–3.30 ([Table 4 ]). [Fig. 2 ] shows the results of the meta-analysis and gives the joint probability distribution.
In order to better display the results, we plotted the false-positive rate (1-specificity)
between 0 and 0.25, and the true-positive rate (sensitivity) is displayed between
0 and 0.5. The area within the lines predicts the region where we expect the results
of an unknown new study. The outer line represents the 90% posterior interval, and
the next 2 lines represent the 75 and 50% posterior interval.(Table 1S ).
Fig. 2 Zoom of the results of the meta-analysis: Data and predictive posterior contours.
Occurrence of trisomy 13, 18 and structural anomalies with echogenic foci
In the entire study group we found no case of trisomy 18 with an isolated ECF. All
120 cases showed further severe malformations or multiple markers of aneuploidy. For
trisomy 13 we found 2 out of 46 cases with ECF and an otherwise completely normal
detailed ultrasound result. The first case was referred at 16+0 weeks of gestation
primarily for invasive diagnostic testing because of high maternal age (44.8 years).
In the ultrasound examination we found no further anatomical abnormalities except
an ECF in the left ventricle. Amniocentesis revealed a mosaic trisomy 13 with the
karyotype 47, XY,+13/46, XY, the child was born alive with 2160 g without phenotypic
abnormalities. In the second case we detected two ECFs, one in the left and one in
the right ventricle, in primary invasive testing in a 34.8-year-old patient at 14+5
weeks. The crown rump length of the fetus corresponded to 13+6 weeks. No further ultrasound
abnormalities were found. Chromosomal analysis in all examined metaphases from two
independent amniotic fluid cultures revealed the karyotype 47, XY+13. The mother decided
to terminate the pregnancy. No autopsy was performed. From these figures, an LR+of
iECF for trisomy 13 of 1.01 was calculated (CI: 0–2.32).The prevalence of structural
chromosomal anomalies in the second-trimester anomaly scan collective was 0.08% (52/68 967),
of which 2 showed an iECF. This resulted in a LR+of 0.76 at a 95%CI of 0–1.75. There
was no association between structural chromosomal anomalies and iECF.
Discussion
The results of our study support the conclusion that an isolated echogenic cardiac
focus also in otherwise inconspicuous ultrasound examinations increases the a priori
risk by a factor that is with 95% probability greater than 1.5. Based on the individual
a priori risk, this risk increase regarding trisomy 21 applies to both high-risk and
low risk pregnancies and should be taken into account in prenatal counselling. By combining
the data from our center with the results of the meta-analysis, the mean LR of the
high-risk group converges substantially with the mean LR of the low-risk group and
the mean LR of the total mixed population. The 95% posterior intervals also overlap
clearly. Assuming that the pre-selection is stronger in the high-risk group and the
investigatorʼs expectations focus more on a possible trisomy 21, which may favor the
detection of an ECF, this approximation of mean LRs supports the assumption that the
effective likelihood ratio for isolated ECF is not markedly dependent on a priori
risk. Furthermore, we found no evidence of association with iECF and structural chromosomal
anomalies in our data. Overall, the prevalence of iECF and trisomy 21 as well as the
distribution of pregnancy weeks in our study are essentially consistent with previous
comparable reports [5 ]
[14 ]
[17 ]
[18 ]
[19 ]. However, these figures must also be seen in the context of a large number of publications
on second-trimester risk calculation for soft marker screening. In 2001, Nyberg et
al. published a statistically significant association with an LR+of 6.8% if isolated
ECF was found without a systematic search for other markers and of 1.8 (CI: 1.0–3.2)
if all other markers were systematically excluded [10 ]. Our results are consistent with this publication. Agathokleous and Nicolaides came
to a slightly different conclusion in their 2013 meta-analysis in which they derived
the LR+for isolated ECF by multiplying the pooled LR+for ECF (5.83, CI: 5.02–6.77)
by the negative LR of each other marker [21 ]. The calculated LR+of an isolated ECF in this study was 0.95, which conflicts with
our observations. However, Nyberg et al. evaluated only 6 soft markers (nuchal thickening,
hyperechoic bowel, short humerus, short femur, pyelectasis and ECF), while Agathokleous
additionally included ventriculomegaly, ARSA (aberrant right subclavian artery) and
present or absent nasal bone. In particular, the detection of ARSA with its high LR+of
21.48 (CI: 11.48–40.1) is indispensably connected to the use of high-resolution ultrasound
techniques Such fluctuations confirm our conviction that, for genetic counselling,
likelihood ratios should be derived from high-quality meta-analyses and not from single-center
publications. The main strength of our study is the high number of cases which allowed
the establishment of a low-risk subgroup with sufficient statistical power to test
the association of iECF and trisomy 21. A further strength is the use of a special
method for combining evidence from different publications with the data of a coherent
collective. Thus, we were able to minimize the bias by uncontrolled variability between
different examination settings and populations.
One weakness of our study is a possible non-response bias by the exclusion of 15%
of cases in which the definitive outcome of pregnancy could not be determined. If
we assume that parents or the referring gynecologists tend to inform the prenatal
medicine unit probably more frequently in cases of abnormal outcome, the exclusion
of all non-responders would increase the LR+of iECF for trisomy 21, if a disproportionate
number of families with trisomy 21 and iECF reported back (true positives). If, however,
we assume that in the 15% with unknown outcome there is no case of trisomy 21 and
distribute these cases between the true negatives and the false positives according
to the prevalence of iECF of about 5%, the LR+would only change slightly from 2.68
to 2.67 for our general collective. However, we can only speculate on the number of
children with Down’s syndrome that are concealed in the 15% figure without outcome.
Another weakness is that an inconspicuous phenotype at birth does not exclude chromosomal
trisomy 21. This may underestimate the number of Down’s syndrome cases detected postnatally.
Karyotyping of all included cases would certainly be the gold standard but we think
that this is very difficult to achieve for such a large coherent collective. Furthermore,
phenotypically normal children could have a cardiac defect that is not immediately
noticeable after birth. Therefore, a potential shortcoming of the term ʼisolated ECFʼ
should be mentioned. Another inherent weakness of our study is the general preselection
of patients, who are referred to a prenatal center, hence having an elevated risk
for trisomy 21. In addition to e. g. maternal age, family genetic predispositions,
drug or radiation exposure, related marriage and a variety of smaller and larger ultrasound
abnormalities become important for the referring gynecologist. Thus, our figures cannot
be representative for an unselected normal collective, even after including evidence
from different studies. Assignment to the “low-risk” group for trisomy 21 was made
only on the basis of maternal age or previous FTS findings. Only a few studies assessed
an increased risk of trisomy 18, trisomy 13 or structural abnormalities based on an
isolated echogenic focus [23 ]
[25 ]
[25 ].
With respect to trisomy 13 and 18, we found no reasonable use for the ECF as a marker.
In summary, finding of an isolated echogenic heart focus presented significant associations
with Down syndrome among pregnant women in both high- and low-risk groups. The individual
risk burden of each patient should be determined and discussed as a part of genetic
counselling. Since 2012 a new assessment tool for chromosomal abnormalities, especially
with regard to trisomy 21, has been available. Noninvasive prenatal testing (NIPT)
is able to detect placental cell-free DNA fragments in maternal blood. The NIPT test
is a useful variant for clarifying patients with a medium-risk constellation [26 ]. The limitations of the NIPT are a lack of feasibility in 5% of cases due to an
insufficient concentration of placental DNA in the maternal plasma, as well as discordant
findings between NIPT and genetic analysis by placental mosaicism [27 ]. Despite the high detection rate for trisomy 21, it should be emphasized that NIPT
is not regarded as a diagnostic procedure, but as a screening test like FTS. In the
case of high-risk constellations, we consider diagnostic procedures by an experienced
examiner to be the better alternative. Regarding the risks of amniocentesis, a 2015
meta-analysis concludes that the combined procedural risk of miscarriage for amniocentesis
is 0.11% (95% CI: − 0.04% to 0.26%) [28 ]. In daily practice, genetic counselling becomes more and more complex due to the
increasingly refined ultrasound techniques and sophisticated screening and diagnostic
capabilities. It is essential for an expectant mother and her family to undergo in-depth
counselling exploring all options.
