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Ultrasound Obstet Gynecol 2013; 42: 300–309
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12489
Improved detection rate of structural abnormalities in the
first trimester using an extended examination protocol
D. ILIESCU*†, S. TUDORACHE*†, A. COMANESCU*, P. ANTSAKLIS‡, S. COTARCEA*,
L. NOVAC*, N. CERNEA*† and A. ANTSAKLIS‡
*Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Craiova, Craiova, Romania; †Department of
Obstetrics and Gynecology, University Emergency Hospital, Craiova, Romania; ‡Department of Obstetrics and Gynecology, University of
Athens, Athens, Greece
KEYWORDS: color Doppler; congenital abnormalities; first trimester; prenatal diagnosis; screening; ultrasound
ABSTRACT
Objective To assess the potential of first-trimester
sonography in the detection of fetal abnormalities using
an extended protocol that is achievable with reasonable
resources of time, personnel and ultrasound equipment.
Methods This was a prospective two-center 2-year
study of 5472 consecutive unselected pregnant women
examined at 12 to 13 +6 gestational weeks. Women were
examined using an extended morphogenetic ultrasound
protocol that, in addition to the basic evaluation, involved
a color Doppler cardiac sweep and identification of early
contingent markers for major abnormalities.
Results The prevalence of lethal and severe malforma-
tions was 1.39%. The first-trimester scan identified 40.6%
of the cases detected overall and 76.3% of major struc-
tural defects. The first-trimester detection rate (DR) for
major congenital heart disease (either isolated or associ-
ated with extracardiac abnormalities) was 90% and that
for major central nervous system anomalies was 69.5%.
In fetuses with increased nuchal translucency (NT), the
first-trimester DR for major anomalies was 96%, and in
fetuses with normal NT it was 66.7%. Most (67.1%) cases
with major abnormalities presented with normal NT.
Conclusions A detailed first-trimester anomaly scan using
an extended protocol is an efficient screening method
to detect major fetal structural abnormalities in low-
risk pregnancies. It is feasible at 12 to 13 +6 weeks
with ultrasound equipment and personnel already used
for routine first-trimester screening. Rate of detection
of severe malformations is greater in early- than in
mid-pregnancy and on postnatal evaluation. Early heart
investigation could be improved by an extended protocol
involving use of color Doppler. Copyright 2013
ISUOG. Published by John Wiley & Sons Ltd.
Correspondence to: Dr D. Iliescu, Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Craiova, Craiova,
200349, Dolj, Romania (e-mail: dominic.iliescu@yahoo.com)
Accepted: 28 November 2012
INTRODUCTION
Screening for fetal structural and chromosomal abnor-
malities is an essential part of antenatal care1,2. Pregnant
women have a right to choose not to continue an affected
pregnancy. Therefore, the earlier they are made aware
of any problems, the better3; earlier termination of preg-
nancy has fewer medical and surgical complications4and a
decreased risk for long-term morbidity, with considerable
reduction in emotional and economic costs5.
First-trimester fetal structural assessment has evolved
rapidly, due to the routine application of genetic screening,
advances in ultrasound technology and increasing
numbers of trained fetomaternal specialists. Using a basic
structural checklist, screening studies3,6 –27 have produced
encouraging results regarding the detection of major
structural defects in the first trimester, contributing to
the formation of a new first-trimester-orientated pyramid
of prenatal care28. However, in current practice, the
expectations from first-trimester structural evaluation are
generally low and its effectiveness has been reported
with considerable variation, with anomaly detection
rates (DRs) ranging between 12.5%9and 83.7%20.
The performance of the first-trimester anomaly scan
has been evaluated in high-risk29,30, medium-risk20
and unselected low-risk6,10,17,27 populations and its
effectiveness has been compared to that of the second-
trimester anomaly scan7,16,21,31. Differences between their
sensitivities are probably related to differences in their
anatomical checklists, as the use of similar protocols at
each examination produces comparable DRs for fetal
anomalies21.
It has been shown previously that first-trimester assess-
ment of the fetal heart using an approach similar to that
of the second-trimester anomaly scan is feasible, with
similar sensitivity for the detection of congenital heart
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. OR I G I N A L PA P E R
Early anomaly scan 301
disease (CHD)20,32,33 . Furthermore, assessment of early
contingent markers has been shown to identify preg-
nancies at high risk for cardiac29 –34, neurological35,36 ,
facial37,38, skeletal39 and diaphragmatic40 defects. Our
study aimed to screen a low-risk unselected population,
using an extended first-trimester morphological protocol,
taking a reasonable amount of time and using existing per-
sonnel and ultrasound equipment in our fetal diagnostic
units, while aiming to achieve DRs comparable to those
of the second-trimester detailed structural assessment, at
least for major fetal abnormalities.
METHODS
This was a 2-year prospective study, from January
2010 to March 2012, involving two university centers:
Craiova (Romania) and Athens (Greece); two centers were
included to allow detection of any differences involved in
implementation of the protocol in different settings and
in the DRs achieved. In both institutions, the university’s
ethics committee approved the research protocol. Written
informed consent from the women was obtained before
ultrasound examination.
First-trimester evaluation
The first-trimester ultrasound examination was performed
at 12 +0to13+6 gestational weeks in the prenatal
units affiliated to the university hospitals involved in
the study. The rationale for choosing this gestational
age was our intention to implement in the screening
protocol an extended study of the fetal heart by the
transabdominal (rather than the transvaginal) route and
without involving significant supplementary resources
(time, equipment). Gestational age was verified by first-
trimester measurement of fetal crown–rump length. We
recorded maternal characteristics and medical history. We
decided not to exclude chromosomally abnormal cases,
because structural abnormalities other than first-trimester
genetic markers may lead to the diagnosis, as described
in previous papers and also found in the current study
(Figure S1).
Our study aimed to assess in a single scanning session
the genetic and morphological parameters suitable for
evaluation at this gestational age, following the protocol
presented in Table 1. Color Doppler cardiac sweep
was performed in order to identify normal flow at
the level of the four-chamber view, emergence and
crossing of the great vessels and the confluence of aortic
and ductal arches. Furthermore, contingent markers for
early detection of major structural abnormalities were
included in the protocol. Examinations were performed by
obstetricians specializing in prenatal diagnosis (including
the anomaly scan and echocardiography) who had held
accreditation for the 11–14-week assessment for at least
5 years prior to the start of the study period. They
performed the evaluations after having several days
training on early fetal cardiac assessment. Each patient
underwent transabdominal ultrasound examination with
a Voluson 730 Pro or Expert (GE Medical Systems,
Zipf, Austria) ultrasound machine, equipped with a 4–8-
MHz curvilinear transducer. Transvaginal examination
with a 5–9-MHz curvilinear transducer was performed
additionally when necessary for better visualization of
fetal anatomy or abnormalities. The examiner tried to
minimize the fetal exposure time, aiming to complete the
scan within 30 min, although the evaluation was not
interrupted if it had not been completed within this time
(e.g. in cases with unfavorable fetal position or when
additional time was needed for proper documentation of
fetal abnormalities). The lowest possible power output
needed to obtain diagnostic information was used,
following the ALARA principle41.
In cases of incomplete visualization of the targeted
structures, women were reexamined after a short break,
or the scan was rescheduled during the next few days.
We attempted to obtain additional two-dimensional (2D)
cineloops demonstrating cardiac sweep features, three-
dimensional (3D) volumes of the fetal head from a
mid-sagittal plane of the fetal face and 3D volumes of the
fetal trunk and limbs. This supplementary information
was obtained for the purposes of later evaluation in
cases in which the first-trimester scan failed to detect
structural abnormalities. 3D ultrasound was also useful
for confirmation in the assessment of suspicious cases and
aided in counseling, by showing parents more realistic and
understandable pictures (Figure S2). The first-trimester
sonographic markers were assessed according to the
standards outlined by The Fetal Medicine Foundation
(FMF). Women with a risk of aneuploidy of 1/250 or
higher were offered invasive prenatal diagnosis.
Follow-up
All studied fetuses underwent a detailed second-trimester
anomaly scan routinely, at 16–26 gestational weeks
(preferably 18–22 weeks). This was performed by the
same examiners and using the same equipment as for the
first-trimester scan, following the protocols proposed by
the Clinical Standards Committee of the International
Society of Ultrasound in Obstetrics and Gynecology
(ISUOG)1,42,43. With the exception of a wellbeing scan at
32–36 weeks, which was offered routinely to all women
and performed in 68.5% of cases, any further evaluations
were carried out on the obstetrician’s recommendations.
In order to reduce the false-positive rate (FPR), in
cases suspected of abnormality, team evaluation by two
experienced examiners, using transvaginal sonography
and/or an additional evaluation, was carried out within
a week, to confirm the diagnosis in first-trimester
cases. After confirmation, appropriate counseling and
management were provided by an interdisciplinary team
(including obstetrician, geneticist, neonatal pediatrician
and pediatric surgeon).
In all live births a general clinical evaluation was
performed by a neonatal pediatrician. A newborn was
classified as normal if no anomaly was suspected until
discharge (at least 3 days after delivery). The design of
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
302 Iliescu et al.
Table 1 First-trimester ultrasound protocol for fetal morphogenetic evaluation
Skull and brain Transverse plane:
-contour and shape
-choroid plexus and cerebral peduncles
Sagittal plane:
-posterior brain morphometry: IT, brainstem diameter to brainstem– occipital bone distance ratio when
abnormal IT is suspected
Face and neck Transverse plane:
-orbits
-anterior palate
Frontal plane:
-examination of orbits (if not properly visualized in transverse plane)
-retronasal triangle
Sagittal plane (facial profile):
-measurement of NT and frontomaxillary angle
-nasal bone assessment
-normal rectangular palate
Spine Longitudinal plane (preferably using posterior insonation of fetus):
-regularity of spine
-continuity of underlying skin layer (take special care to note presence of any cystic masses)
Thorax Transverse plane (transverse cardiac sweep):
-situs evaluation
-heart area in relation to chest area (it should be one quarter to one third of chest) and angle from
anteroposterior midline (it should be 45±15◦by subjective evaluation, measure only if seems abnormal)
-atrioventricular valve offsetting in four-chamber view and tricuspid valve flow assessment using pulsed Doppler
-(not mandatory) aorta arising from left ventricle and pulmonary trunk arising from anteriorly placed right
ventricle and crossing to fetal left side over ascending aorta
-color-flow investigation of: four-chamber plane to show atrioventricular flow (should be equal on both sides)
and emergence of outflow tracts (should be equal in size and should cross); and three vessels and trachea
view plane to show presence of ‘v’ sign (connection of aortic arch and ductus arteriosus)
-ductus venosus flow assessment using pulsed Doppler
Abdomen -presence of stomach (should be in left upper abdomen)
-abdominal wall and umbilical cord insertion
-bowel echogenicity
Kidney and urinary tract -presence of both kidneys; renal artery investigation if kidneys not visualized
-renal pelvic dimensions (to rule out pyelectasis)
-evaluation of bladder
-paravesical presence of umbilical arteries
Extremities -symmetry of limbs and segments
-movements
-presence, subjective appearance and echogenicity of long bones
-presence and number of the fingers, presence of toes and hallux posture
IT, intracranial translucency; NT, nuchal translucency.
the study was such that fetuses following termination of
pregnancy or intrauterine demise were examined by an
interdisciplinary team of pathologists and obstetricians.
Data collection and analysis
A data collection sheet was used for recording ultrasound
examination findings. Digital information showing the
morphological features was stored during the examina-
tion. First-trimester abnormal scan findings were con-
firmed by first-trimester re-examination by FMF-certified
examiners, second/third-trimester scans and neonatal or
pathological evaluations.
We included all abnormalities diagnosed prenatally by
ultrasound and those identified on postnatal neonatal and
pathological examination. For the purposes of analysis,
we did not consider as fetal abnormalities virtually
undetectable conditions (e.g. metabolic disorders, skin
lesions, phimosis or congenital hip dysplasia) or isolated
anatomical variants of normal (e.g. mild pyelectasis,
intra-abdominal umbilical vein varix, persistent right
umbilical vein, single umbilical artery, aberrant right
subclavian artery (ARSA)). Increased nuchal translucency
(NT) in itself was not considered an abnormality. Cystic
hygroma was considered an abnormality requiring
further assessment and invasive tests44,45. However, due
to the study design that allowed us to perform genetic
evaluation and follow-up evaluations, we decided not to
consider first-trimester isolated cystic hygroma as a major
abnormality. Regarding first-trimester isolated exompha-
los and megacystis <15 mm, we included in our statistics
only cases that were confirmed to be abnormal when
followed up at the beginning of the second trimester. We
included cases of intrauterine congenital infections with
evident intrauterine markers, but not cases that did not
show ultrasonographic features of fetal infection (such as
congenital varicella associated with blindness, but with no
other prenatal ultrasound or postnatal clinical findings).
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
Early anomaly scan 303
Regarding timing of detection during pregnancy, we
considered an abnormality to have been detected at the
ultrasound scan when the diagnosis was first suspected,
even for cases in which the diagnosis was only confirmed
at a later ultrasound exam or on neonatal or pathological
evaluation.
Fetal abnormalities were grouped into two categories
according to their likely clinical consequences, following
the proposal by the Royal College of Obstetricians and
Gynaecologists46. Abnormalities were considered major
(lethal or severe) in cases incompatible with life or
associated with possible survival but severe immediate
or long-term morbidity. Abnormalities were classified as
moderate or minor in cases associated with short- or
long-term morbidity of minor or moderate severity. A
case with multiple abnormalities was considered to have
been detected by ultrasound if at least one of the major
malformations present was detected. When more than one
malformation was found in a fetus, this was considered
as one abnormal case in further calculations.
Statistical analyses were carried out using the Statistical
Package for the Social Sciences (IBM SPSS Statistics 19.0).
The statistical significance of differences in proportions
was determined using Fisher’s exact test or the chi-square
test. P<0.05 was considered statistically significant.
RESULTS
During the study period, 5472 consecutive unselected
pregnancies were evaluated in the two centers (2927
+2545). The median maternal age was 28 years (26
and 28 years, respectively). The prevalence of lethal and
severe malformations in our study population was 1.39%
(76/5472) (Figure 1); this was similar between the centers
(1.43% and 1.33%, respectively) and was within the
range of other studies performed in unselected low-risk
groups. Structural abnormalities detected during the first-
trimester scan and at follow-up are presented in Tables
S1 and S2 online, showing their type and severity as well
as the presence of contingent markers. A large majority
(76.31%; 58/76) of the major congenital anomalies were
diagnosed during the first trimester (78.57% and 73.52%
in the two centers), representing 1.06% (58/5472) of
the total first-trimester population scanned. Previously
undetected major fetal abnormalities were discovered in
new cases at later ultrasound examinations in 0.31%
(16/5109) of the population scanned and in a further
0.04% (2/4744) of the population examined postpartum.
Conversely, it was the follow-up evaluations rather than
the first-trimester scan that detected the vast majority
(89.88%, 80/89) of minor/medium anomalies. Overall,
the first-trimester scan contributed 40.6% (n=67) of the
165 cases detected (Figure 1).
Regarding the severity of malformations, 86.57%
of cases detected in the first trimester and 18.37%
of those detected at follow-up were considered to
have severe or lethal abnormalities. The prevalence of
major CHD and neurological structural abnormalities
(isolated or syndromic) was 0.54% (30/5472) and
0.42% (23/5472), respectively. The first-trimester DRs
for major CHD reached 90% (27/30) using the extended
cardiovascular investigation protocol and 69.5% (16/23)
for major central nervous system anomalies using the
early neurosonogram. All examiners participating in our
study declared themselves more confident in assessing
the fetal heart using the color cardiac sweep technique
than without the use of color Doppler. Four of the 14
(28.57%) isolated heart anomalies detected in the first
trimester were considered mild and the prognosis of these
fetuses was confirmed as favorable.
Major chromosomal abnormalities were diagnosed in
21 (0.38%) cases, 20 of them during the first-trimester
evaluation. Six pregnancies in which chromosomal
anomalies were strongly suspected were lost to follow-up.
Chromosomal disorders accounted for 29.82% (17/57)
of the major structural anomalies in those in whom
karyotyping was performed. However, it should be noted
that 19 of the pregnant women diagnosed with structural
abnormalities declined invasive genetic testing.
A total of 288 fetuses (5.26% of the first-trimester
study group) presented with NT >95th percentile. In
this group of fetuses with increased NT, the prevalence
of major anomalies was 8.68% (25/288) and their
first-trimester DR was 96% (24/25). In the 5184 fetuses
with normal NT, the prevalence of major anomalies was
0.98% and the first-trimester DR was 66.67%. However,
the differences in DRs for major CHD between the two
groups (increased vs normal NT) were not significant
(93.75 vs 85.71% for all CHD and 80.0 vs 85.71%
for isolated CHD). 67.1% (51/76) of the major abnor-
malities were detected in the group with normal NT,
including 58.62% (34/58) of the first-trimester-detected
major anomalies and 94.44% (17/18) of the major
anomalies detected at follow-up. NT was increased in
32.89% (25/76) of the fetuses with major abnormalities.
Regarding the association with CHD, NT was increased
in 55.17% (16/29), 53.33% of all severe cases involving
the heart, in 41.66% (5/12) of cases with isolated severe
CHD and in 64.70% (11/17) of cases with complex
major abnormalities associated with severe CHD.
There were no cases with strongly suspected anomalies
that were not confirmed at pathological evaluation. How-
ever, there were cases in which the pathological evaluation
led to adjustment of the diagnosis (e.g. pulmonary atresia
instead of common arterial trunk) or added new informa-
tion to the ultrasound diagnosis (e.g. ARSA) (Figure 2).
First-trimester pathological evaluation was not performed
in the majority of cases; in such cases of termination and
intrauterine demise without postmortem examination,
the ultrasound findings were assumed to be correct.
A precise global FPR for the first-trimester anomaly
scan could not be calculated because a pathological
evaluation was not performed in all terminated fetuses.
The individual FPR (i.e. malformations suspected at the
first completed examination but not confirmed at the team
evaluation) was 3.67% (Table 2). The rate was similar
between the two centers, but significantly different (P<
0.05, chi-square test) when comparing overall the 2 years
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
304 Iliescu et al.
76 major structural abnormalities:
1.39% of screening number
1.06%
5472 first-trimester
evaluations
5109 second-trimester
evaluations*
4744 neonatal evaluations*
645 cases lost to follow-up:
11.79% of screening number
225 missed second-trimester anomaly scan
(no follow-up)
51 miscarriage normal fetuses
15 TOP at request / therapeutic
5 genetic abnormalities without
evident major structural abnormalities
309 unknown birth outcome
38 fetal death – normal first/second-
trimester anomaly scan
2 therapeutic TOP
92.86%
0.04%
6.83%
9 new mild structural abnormalities
2 new major structural abnormalities
71 new mild structural abnormalities
9 TOP
6 live birth
1 fetal death
3 TOP
5 first-trimester TOP
1 second-trimester TOP
47 first-trimester TOP
9 second-trimester TOP
2 fetal deaths
93.37%
5.41%
0.31%
58 major structural abnormalities
(including 13 genetic abnormalities)
6 major genetic abnormalities –
no evident major structural defects
9 mild structural abnormalities
16 new major structural abnormalities
(including 1 major genetic)
296 lost to second-trimester anomaly scan:
349 lost to neonatal evaluation:
Figure 1 Flow chart summarizing the study group. *Numbers exclude those lost to follow-up and those terminated (TOP) since previous
evaluation as well as those identified as having major structural abnormalities at previous evaluation.
of the study (Table 2). A marked decrease in FPR, of more
than a quarter in one center and almost a third in the
other, was noted (Table 2). Analysis of the most frequent
suspected abnormalities shows that the cardiovascular
system was involved in more than half (57.75%) of the
false-positive diagnoses, which included mainly ventric-
ular septal defect (communication between ventricles
suspected on B-mode/color Doppler) and conotruncal
anomalies (discordance of arterial arches). Facial defects
were suspected in 12.8% of the false positives, because
of abnormal appearance of the retronasal triangle or
poor visualization of the palate in the transverse plane.
Cardiac septal defects had both the highest FPR and the
highest false-negative rate (none of the isolated muscular
defects was diagnosed during first-trimester evaluation).
In order to complete the investigation protocol during
the first-trimester anomaly scan, 7.80% (n=427) of
cases required a transvaginal scan, due mainly to persistent
unfavorable fetal position (in 5.59% (n=306) of cases) or
when unfavorable maternal conditions, such as high body
mass index, retroverted uterus, fibroids or abdominal scar
made visualization difficult transabdominally (2.21% (n
=121) of cases); 2.10% (n=115) of patients had a
scan rescheduled within a week because of non-diagnostic
images at the initial scan.
The time required for the first-trimester examination
ranged from 18 to 52 (median, 34) min, an average of
almost 10 min additional to the time generally allocated
(25 min) for the routine first-trimester examination in
our centers. Structurally abnormal cases were excluded
from this time interval analysis because, in most of
these, we conducted evaluations both transabdominally
and transvaginally, using 3D/4D, high-definition power
Doppler and B-flow techniques, which required sup-
plementary resources in terms of time and personnel.
The latter approach was aimed at achieving an optimal
diagnosis and properly documenting the anomalies,
and such an examination deviates from the screening
purposes of the first-trimester protocol. In 13.72% (n=
751) of the cases a time longer than 34 min was needed.
A considerable number of images and volumes were
stored per case during the first-trimester evaluation
(24–62 (median, 36) images and three to eight (median,
five) volumes) in order to demonstrate optimally the
appropriate sectional planes. Extra images, videoclips,
and/or 3D and 4D acquisitions were stored if better views
of the structures were obtained during the same examina-
tion, at re-evaluation because of poor local conditions or
transitory physiological situations (e.g. transient absent
stomach or bladder), in cases with suspected structural
abnormalities (for better exploration/imaging of defects),
and in cases in which, for proper evaluation of certain
parameters, a series of scans was required (e.g. multiple
evaluations for NT and investigation of flow across all
tricuspid valve cusps). Stored 2D and 3D information
also served for later re-evaluation, when structural
abnormalities were missed during the first-trimester scan,
as in the case of a facial defect, presented in Figure 3.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
Early anomaly scan 305
Figure 2 Example in a 15-week fetus showing how pathological evaluation can confirm or lead to adjustment of ultrasound diagnosis:
ultrasound findings (a,b,c) and pathological evaluation (d,e,f). Agenesis of ductus venosus was suspected at ultrasound examination (a) and
confirmed at pathological evaluation (d). Common arterial trunk was suspected at two-dimensional ultrasound examination (b) and on
three-dimensional evaluation, so tomographic imaging was applied (c), but pathological examination instead revealed pulmonary atresia (e),
as well as an additional finding of aberrant right subclavian artery (f).
Table 2 Individual false-positive rates (FPR) following first-trimester ultrasound examination in 5100* consecutive unselected pregnant
women according to center, year of study and fetal organ system involved
Both centers Center 1 Center 2
FPR (%) (number of FPs)
Overall 3.67 (187/5100) 3.17 (86/2709) 4.22 (101/2391)
Year 1 4.34 (106/2443) 3.84 (49/1277) 4.89 (57/1166)
Year 2 3.05 (81/2657) 2.58 (37/1432) 3.59 (44/1225)
Percentage decrease in FPR between Years 1 and 2 29.72 32.81 26.58
Overall FPs according to system involved in FP diagnosis (% (n))
Cardiovascular 57.75 (108) 51.16 (44) 63.37 (64)
Facial 12.83 (24) 15.12 (13) 10.89 (11)
Skeletal 6.95 (13) 6.98 (6) 6.93 (7)
Central nervous 6.95 (13) 5.81 (5) 7.92 (8)
Renourinary 6.41 (12) 8.14 (7) 4.95 (5)
Respiratory 4.81 (9) 6.98 (6) 2.97 (3)
Digestive 4.28 (8) 5.81 (5) 2.97 (3)
*Excluding 296 of the original 5472, which were lost to-follow up, and 76 major abnormalities detected during the study. FP, false-positive.
DISCUSSION
Although, in our study, the first-trimester scan detected
only around 40% of anomalies overall, its efficiency in
identifying major malformations (76% detected) is the
most important argument in favor of this examination,
with DRs similar in both centers and to rates reported
for detailed second-trimester or other detailed first-
trimester evaluations1,20. Before termination of abnormal
fetuses, a detailed first-trimester protocol may provide
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
306 Iliescu et al.
Figure 3 Bilateral palate defect missed during initial evaluation (a,b,c), but considered detectable on retrospective assessment of saved data
(d,e,f). (a) Retronasal triangle (RNT) considered normal at first-trimester screening. (b,c) Bilateral palate defect with maxillary protrusion
diagnosed at 18 gestational weeks on two-dimensional (b) and three-dimensional (c) ultrasound evaluation. (d,e,f) Retrospective evaluation
of saved data: (d) coronal insonation showing abnormal RNT; (e,f) sagittal insonation, showing bony discontinuity in rectangular shape of
palate (red arrows) with maxillary protrusion and narrow facial angle (e).
supplementary information that would prove useful in
counseling, particularly as regards future pregnancies.
Seventy percent of major CHDs were associated with
extracardiac abnormalities and/or chromosomal syn-
dromes, which may have contributed to their high (90%)
first-trimester DR. Technical and pathophysiological
obstacles may mean this detection rate cannot always
be achieved, as severe CHD may develop progressively
during pregnancy. Examiners should be cognizant of the
early normal and pathological appearances and of the
equipment that is most appropriate for evaluation at this
stage of pregnancy. Malformations detected in the first
trimester tended to be severe and major abnormalities
were more prevalent (86.6%) than in second-trimester
anomaly scan studies reported in the literature.
Although we could not calculate a global FPR, we
would have expected it to be low after completion of
the protocol, because major abnormalities were always
confirmed when pathological evaluation was carried out
in terminated fetuses, and when the couples declined or
delayed first-trimester termination, follow-up confirmed
the severe malformations. The 3.7% individual FPR
seems acceptable in terms of supplementary time and
personnel required for the team evaluations. The analysis
showed a marked decrease in the individual FPRs during
the study, confirming the importance of the examiners’
experience. Although it may increase the examination
time, completion of the protocol with satisfactory,
auditable images enhances accuracy, raising the DR and
lowering the individual FPR.
Extended cardiac examination using color Doppler
increases significantly the DR of CHD20,32,33,asmost
gray-scale cardiac sweeps do not offer enough information
regarding the heart structure and function (Videoclip S1).
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
Early anomaly scan 307
In our experience, it was not time-consuming: the required
time interval was shorter than or similar to that required
for tricuspid valve flow evaluation and necessitates similar
angle of incidence and magnification and similar state
of fetal quiescence. Direct investigation of the heart
by color Doppler mapping was also more efficient at
identifying CHD than other early markers used for this
purpose (analysis of the four-chamber view, tricuspid
and ductal flow, increased NT), these early markers
being normal in almost one third of abnormal cases
(30%).
The first-trimester DR of major anomalies was signif-
icantly lower in cases with normal NT than in cases with
increased NT (67% vs 96%). It is generally considered
that when NT is increased the awareness of the operator
and/or the severity of the defect is greater. We found com-
parable DRs for major CHDs, whether associated with
extracardiac defects or isolated, in normal and increased
NT groups, suggesting that all screened fetuses received
equal attention, irrespective of the NT result. However,
the pattern of the missed first-trimester anomalies (Table
S2) is consistent with another explanation: that there is
an overlap between the malformations associated with
normal NT and the malformations that are undetectable
in the first trimester27.
The equipment and personnel used in our units to
evaluate accurately morphological and functional aspects
of small structures such as NT, nasal bone, TV and
ductus venosus (DV) were technically sufficient for an
extended scan protocol. The main argument against a
routine detailed first-trimester anomaly scan concerns
the increased examination time. We found that our
extended protocol added on average an extra 10 min
to our previous standard examination time of 25 min,
similar to the findings of other detailed first-trimester
morphological screening research20. This represents a
significant increase in examination time, being almost half
again with respect to the former allocated time. However,
a certain amount of our additional examination time
can be discounted as not being part of the structural
assessment, instead being specifically for the purposes
of this study: i.e. the time spent on 2Dcineloop/3D
acquisitions stored for re-evaluation purposes, and on
evaluation of amniotic fluid, placenta, uterine flow and
cervical length. Furthermore, if standard spine evaluation
were replaced with a rapid assessment of the posterior
brain35,47 and if the color Doppler cardiac sweep were
proved equal or superior to tricuspid and ductal flow
assessment, the examination time could be reduced,
diminishing the energy administered to the fetus by
pulsed Doppler. Reported in previous research between
1%27 (basic structural evaluation) and 29%20 (detailed
scan), the transvaginal approach proved valuable in
reducing examination time by allowing completion of
the investigation in the 7.8% of cases which were
hindered by unfavorable fetal position or maternal
conditions.
The obvious advantage of an extended protocol is
that parents are offered the option of earlier and safer
termination of pregnancy for the large majority of
severe/lethal abnormalities. However, a detailed first-
trimester examination protocol involves supplementary
resources: additional examination time and specialized
personnel for the abnormal suspected/detected cases.
Thus, healthcare systems should determine whether
early first-trimester diagnosis of most major structural
abnormalities is cost-effective. Previous research, albeit
using inferior ultrasound technology and a less extended
protocol, found that the first-trimester anomaly scan was
cost-efficient in terms of medical and economic expenses,
although they obtained lower DRs11,48.
The main issue is that these results are achievable and
reproducible only by highly skilled operators in specialized
centers. Two alternative approaches may be considered to
implement the protocol. One option would be to reserve
this examination for at-risk pregnancies; however, in our
population, similar to in previous studies49, the majority
of severe cases derived from low-risk pregnancies. An
alternative would be to confine first-trimester evaluation
to specialized, experienced and audited centers, making
the first-trimester detailed protocol feasible and cost-
efficient in large population groups.
We acknowledge that our study had some weaknesses.
The pathological evaluation was not performed system-
atically and this could have led to bias in DRs for fetal
abnormalities. Also, although we have presented the con-
tribution of contingent markers and a color Doppler
cardiac sweep, there were insufficient abnormal cases
to determine specific DRs for a general screening pol-
icy. Finally, there was a high rate of loss to follow-up,
related to the increased mobility of the population in
the socioeconomic context of our developing countries.
However, given the low prevalence of major abnormal-
ities and the high DR in the patients fully studied, we
estimate that this would not have influenced significantly
our results.
REFERENCES
1. Salomon LJ, Alfirevic Z, Berghella V, Bilardo C, Hernandez-
Andrade E, Johnsen SL, Kalache K, Leung KY, Malinger G,
Munoz H, Prefumo F, Toi A, Lee W, ISUOG Clinical Standards
Committee. Practice guidelines for performance of the routine
mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol
2011; 37: 116– 126.
2. Nicolaides KH. Screening for fetal aneuploidies at 11 to 13
weeks. Prenat Diagn 2011; 31: 7– 15.
3. Achiron R, Tadmor O. Screening for fetal anomalies during the
first trimester of pregnancy: transvaginal versus transabdominal
sonography. Ultrasound Obstet Gynecol 1991; 1: 186–191.
4. Ecker JL, Frigoletto FD. Routine ultrasound screening in low-
risk pregnancies: imperatives for further study. Obstet Gynecol
1999; 93: 607– 610.
5. Filly RA, Crane JP. Routine obstetric sonography. J Ultrasound
Med 2002; 21: 713– 718.
6. Hernadi L, Torocsik M. Screening for fetal anomalies in the
12th week of pregnancy by transvaginal sonography in an
unselected population. Prenat Diagn 1997; 17: 753–759.
7. D’Ottavio G, Mandruzzato G, Meir YJ, Rustico MA, Fischer-
Tamaro L, Conoscenti G. Comparisons of first trimester and
second trimester screening for fetal anomalies. Ann NY Acad
Sci 1998; 847: 200– 209.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
308 Iliescu et al.
8. Bilardo CM, Pajkrt E, de Graaf I, Mol BW, Bleker OP. Outcome
of fetuses with enlarged nuchal translucency and normal
karyotype. Ultrasound Obstet Gynecol 1998; 11: 401–406.
9. Hafner E, Schuchter K, Liebhart E, Philipp K. Results of routine
fetal nuchal translucency measurement at weeks 10–13 in 4233
unselected pregnant women. Prenat Diagn 1998; 18: 29–34.
10. Economides DL, Braithwaite JM. First trimester ultrasono-
graphic diagnosis of fetal structural abnormalities in a low risk
population. BrJObstetGynaecol1998; 105: 53–57.
11. Whitlow BJ, Chatzipapas IK, Lazanakis ML, Kadir RA,
Economides DL. The value of sonography in early pregnancy for
the detection of fetal abnormalities in an unselected population.
BrJObstetGynaecol1999; 106: 929–936.
12. Guariglia L, Rosati P. Transvaginal sonographic detection
of embryonic-fetal abnormalities in early pregnancy. Obstet
Gynecol 2000; 96: 328– 332.
13. Carvalho MH, Brizot ML, Lopes LM, Chiba CH, Miyadahira
S, Zugaib M. Detection of fetal structural abnormalities at the
11– 14 week ultrasound scan. Prenat Diagn 2002; 22:1–4.
14. Markov D, Chernev T, Dimitrova V, Mazneikova V, Leroy Y,
Jacquemyn Y, Ramaekers P, Van Bulck B, Loquet P. Ultrasound
screening and diagnosis of fetal structural abnormalities
between 11– 14 gestational weeks. Akush Ginekol (Sofiia) 2004;
43: 3– 10.
15. Souka AP, Pilalis A, Kavalakis Y, Kosmas Y, Antsaklis P,
Antsaklis A. Assessment of fetal anatomy at the 11–14-week
ultrasound examination. Ultrasound Obstet Gynecol 2004; 24:
730– 734.
16. Taipale P, Ammala M, Salonen R, Hilesmaa V. Two-stage
ultrasonography in screening for fetal anomalies at 13– 14 and
18– 22 weeks of gestation. Acta Obstet Gynecol Scand 2004;
83: 1141– 1146.
17. Chen M, Lam YH, Lee CP, Tang MH. Ultrasound screening of
fetal structural abnormalities at 12 to 14 weeks in Hong Kong.
Prenat Diagn 2004; 24: 92–97.
18. Von Kaisenberg CS, Kuhling-von Kaisenberg H, Fritzer E,
Schemm S, Meinhold-Heerlein I, Jonat W. Fetal transabdominal
anatomy scanning using standard views at 11 to 14 weeks’
gestation. Am J Obstet Gynecol 2005; 192: 535–542.
19. Souka AP, Von Kaisenberg CS, Hyett JA, Sonek JD, Nicolaides
KH. Increased nuchal translucency with normal karyotype. Am
J Obstet Gynecol 2005; 192: 1005–1021.
20. Becker R, Wegner RD. Detailed screening for fetal anomalies
and cardiac defects at the 11–13-week scan. Ultrasound Obstet
Gynecol 2006; 27: 613– 618.
21. Saltvedt S, Almstrom H, Kublickas M, Valentin L, Grunewald
C. Detection of malformations in chromosomally normal fetuses
by routine ultrasound at 12 or 18 weeks of gestation— a
randomised controlled trial in 39,572 pregnancies. BJOG 2006;
113: 664– 674.
22. Cedergren M, Selbing A. Detection of fetal structural
abnormalities by an 11– 14-week ultrasound dating scan in
an unselected Swedish population. Acta Obstet Gynecol Scand
2006; 85: 912– 915.
23. Dane B, Dane C, Sivri D, Kiray M, Cetin A, Yayla M.
Ultrasound screening for fetal major abnormalities at 11–14
weeks. Acta Obstet Gynecol Scand 2007; 86: 666–670.
24. Chen M, Lee CP, Lam YH, Tang RY, Chan BC, Wong
SF, Tse LH, Tang MH. Comparison of nuchal and detailed
morphology ultrasound examinations in early pregnancy for
fetal structural abnormality screening: a randomized controlled
trial. Ultrasound Obstet Gynecol 2008; 31: 136–146.
25. Oztekin O, Oztekin D, Tınar S, Adıbelli Z. Ultrasonographic
diagnosis of fetal structural abnormalities in prenatal screening
at 11– 14 weeks. Diagn Interv Radiol 2009; 15: 221 – 225.
26. Ebrashy A, El Kateb A, Momtaz M, El Sheikhah A, Aboulghar
MM, Ibrahim M, Saad M. 13– 14-week fetal anatomy scan: a
5-year prospective study. Ultrasound Obstet Gynecol 2010; 35:
292– 296.
27. Syngelaki A, Chelemen T, Dagklis T, Allan L, Nicolaides
KH. Challenges in the diagnosis of fetal non-chromosomal
abnormalities at 11–13 weeks. Prenat Diagn 2011; 31: 90 –102.
28. Nicolaides KH. A model for a new pyramid of prenatal care
based on the 11 to 13 weeks’ assessment. Prenat Diagn 2011;
31:3–6.
29. Hyett J, Sonek J, Nicolaides K; FASTER Consortium. Nuchal
translucency and the risk of congenital heart disease. Obstet
Gynecol 2007; 109: 1455– 1456; author reply 1456 – 1457.
30. Yagel S, Achiron R, Ron M, Revel A, Anteby E. Transvaginal
ultrasonography at early pregnancy cannot be used alone for
targeted organ ultrasonographic examination in a high-risk
population. Am J Obstet Gynecol 1995; 172: 971–975.
31. D’Ottavio G, Meir YJ, Rustico MA, Pecile V, Fischer-Tamaro
L, Conoscenti G, Natale R, Mandruzzato GP. Screening for
fetal anomalies by ultrasound at 14 and 21 weeks. Ultrasound
Obstet Gynecol 1997; 10: 375–380.
32. Lombardi CM, Bellotti M, Fesslova V, Cappellini A. Fetal
echocardiography at the time of the nuchal translucency scan.
Ultrasound Obstet Gynecol 2007; 29: 249–257.
33. Persico N, Moratalla J, Lombardi CM, Zidere V, Allan L,
Nicolaides KH. Fetal echocardiography at 11– 13 weeks by
transabdominal high-frequency ultrasound. Ultrasound Obstet
Gynecol 2011; 37: 296– 301.
34. Chelemen T, Syngelaki A, Maiz N, Allan L, Nicolaides KH.
Contribution of ductus venosus Doppler in first trimester
screening for major cardiac defects. Fetal Diagn Ther 2011;
29: 127– 134.
35. Chaoui R, Nicolaides KH. From nuchal translucency to
intracranial translucency: towards the early detection of spina
bifida. Ultrasound Obstet Gynecol 2010; 35: 133–138.
36. Lachmann R, Chaoui R, Moratalla J, Picciarelli G, Nicolaides
KH. Posterior brain in fetuses with open spina bifida at 11 to
13 weeks. Prenat Diagn 2011; 31: 103–106.
37. Sepulveda W, Wong AE, Martinez-Ten P, Perez-Pedregosa J.
Retronasal triangle: a sonographic landmark for the screening
of cleft palate in the first trimester. Ultrasound Obstet Gynecol
2010; 35: 7– 13.
38. Martinez-Ten P, Adiego B, Perez-Pedregosa J, Illescas T, Wong
AE, Sepulveda W. First-trimester assessment of the nasal bones
using the retronasal triangle view: a 3-dimensional sonographic
study. J Ultrasound Med 2010; 29: 1555–1561.
39. Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal
anomalies. Prenat Diagn 2011; 31: 115– 124.
40. Sebire NJ, Snijders RJ, Davenport M, Greenough A, Nicolaides
KH. Fetal nuchal translucency thickness at 10–14 weeks’
gestation and congenital diaphragmatic hernia. Obstet Gynecol
1997; 90: 943– 946.
41. Abramowicz JS, Kossoff G, Marsal K, Ter Haar G. Safety
Statement, 2000 (reconfirmed 2003). International Society of
Ultrasound in Obstetrics and Gynecology (ISUOG). Ultrasound
Obstet Gynecol 2003; 21: 100.
42. International Society of Ultrasound in Obstetrics and Gyne-
cology. Cardiac screening examination of the fetus: guidelines
for performing the ‘basic’ and ‘extended basic’ cardiac scan.
Ultrasound Obstet Gynecol 2006; 27: 107–113.
43. International Society of Ultrasound in Obstetrics &
Gynecology Education Committee. Sonographic exam-
ination of the fetal central nervous system: guidelines
for performing the ‘basic examination’ and the ‘fetal
neurosonogram’. Ultrasound Obstet Gynecol 2007; 29:
109– 116.
44. Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade GR,
Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE,
Carr SR, Wolfe HM, Dukes K, Canick JA, Bianchi DW, D’Alton
ME. First-trimester septated cystic hygroma: prevalence, natural
history, and pediatric outcome. Obstet Gynecol 2005; 106:
288– 294.
45. Ganapathy R, Guven M, Sethna F, Vivekananda U, Thi-
laganathan B. Natural history and outcome of prenatally
diagnosed cystic hygroma. Prenat Diagn 2004; 24: 965–968.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
Early anomaly scan 309
46. RCOG. Ultrasound screening for fetal abnormalities. Report of
the RCOG Working Party. The Royal College of Obstetricians
and Gynaecologists: London, 1997.
47. Chaoui R, Benoit B, Mitkowska-Wozniak H, Heling KS,
Nicolaides KH. Assessment of intracranial translucency (IT)
in the detection of spina bifida at the 11–13-week scan.
Ultrasound Obstet Gynecol 2009; 34: 249–252.
48. Dolkart LA, Reimers FT. Transvaginal fetal echocardiography
in early pregnancy: normative data. Am J Obstet Gynecol 1991;
165: 688– 691.
49. Makrydimas G, Sotiriadis A, Huggon IC, Simpson J, Sharland,
Carvalho JS, Daubeney PE, Ioannidis JPA. Nuchal translucency
and fetal cardiac defects: A pooled analysis of major fetal echo-
cardiography centers. Am J Obstet Gynecol 2005; 192: 89–95.
SUPPORTING INFORMATION ON THE INTERNET
The following supporting information may be found on the online version of this article:
Videoclip S1 Hypoplastic right heart: tricuspid atresia without septal defect. Cardiac anomaly is
unremarkable on gray-scale imaging, but is evident on color Doppler examination, because of abnormal flow
in right ventricle (unequal ventricular filling) and in right outflow tract (reversed pulmonary flow).
Figure S1 Initial anatomy scan (a–g) in a 12-week fetus with trisomy 18 showed normal findings for facial
profile, cranium shape, midline and choroid plexus, tricuspid flow, diaphragm, stomach, bowel, bladder,
umbilical arteries, segments of the limbs. However, on extended first-trimester scanning protocol, fixed flexed
position of hands (h) and pyelectasis (j) were noted and atrioventricular septal defect was suspected on color
Doppler imaging (l). Pathological examination confirmed the ultrasound findings of clenched hands (i) and
septal defect (m), and added supplementary information: horseshoe kidneys (k) and low insertion of ears (n).
Figure S2 Fetal tetramicromelia and severe facial defect at 12 weeks in a woman with high body mas index
and an abdominal scar. (a) Transabdominal longitudinal view of fetus with apparently normal crown–rump
length (CRL) and nuchal translucency thickness in relation to gestational age, but poor discrimination of
fetal structures. (b) Transvaginal imaging revealed abnormal facial profile in longitudinal plane used for
measurement of CRL. (c,e,f) Rendering of fetal face and body, very useful for parental counseling, showed
tetramicromelia and severe facial defect. (d,g) Pathological examination following termination of pregnancy
demonstrated the accuracy of the three-dimensional rendering ultrasound technique in the first trimester.
Table S1 Structural anomalies detected during first-trimester ultrasound examination in 5472 consecutive
unselected pregnant women
Table S2 Supplementary findings during second or third trimester or postnatally in 5109 consecutive
unselected pregnant women
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 300–309.
