prenatal screening for congenital abnormalities:...
TRANSCRIPT
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Prenatal screening for congenital abnormalities:
role of the 13 week scan
Student
Francesca Bardi
S2448572
Faculty and daily supervisor
Prof. dr. C.M. Bilardo
Department
Prenatal diagnosis, Obstetrics & Gynecology
Date
May 10th
2017
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List of abbreviations
Abbreviation Full world
CT Combined test
Estimated date of delivery
Nuchal translucency
Non-invasive prenatal testing
Chorionic villous sampling
Cell-free fetal DNA
structureel echo onderzoek
Central nervous system
Geavanceerd ultrageluid onderzoek
Termination of pregnancy
Intrauterine death
Crown-rump length
Biparietal diameter
Abdominal circumference
Head circumference
Femur length
pregnancy-associated plasma protein A
free beta-human chorionic gonadotropin
Single umbilical artery
Intrauterine growth restriction
Fetal medicine foundation
Multiple congenital abnormalities
Body mass index
Medical Ethical committee
Standard deviation
Interquartile range
Atrioventricular septum defect
Ventricular septum defect
Deletion
EDD
NT
NIPT
CVS
cfDNA
SEO
CNS
GUO
TOP
IUD
CRL
BPD
AC
HC
FL
PAPPA-A
hCG
SUA
IUGR
FMF
MCA
BMI
METc
SD
IQR
AVSD
VSD
Del
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Summary (English)
Background and aim The primary aim of this study is to determine the percentage of fetal congenital abnormalities
found at the 13 week gross-anatomy survey performed in concomitance of the dating scan or the
combined test (CT). Secondly, the research investigates how many and which of the defects
observed at the 20 week anomaly scan were not identified by the ultrasound scan performed
earlier in gestation.
Methods
This is a retrospective study performed on a prospectively collected database of consecutive
ultrasound scans in a large primary care center in The Netherlands. Pregnancies were included in
the study if an ultrasound scan was performed between 11 and 13+6 weeks of gestation and if the
estimated date of delivery (EDD) was between 01-01-2012 and 01-01-2016. Pregnancies were
excluded from the study when a non-viable fetus was seen at the time of the first scan, or when
no information on the second trimester structural anomaly scan (18-22+6 weeks) was available.
When an abnormal marker or an anomaly was found at any point during the course of pregnancy,
postnatal follow-up outcome was searched for that pregnancy and if this was not present, the case
was excluded.
Results
10899 pregnancies were included in the study. Mean maternal age and median bodyweight were
30.9 ± 4.7 years and 67 kg (60-76). Of all first trimester scans, 4204 (38.6%) were dating scans
and 6685 (61.4%) were CT. At the time of evaluation mean gestational age was 12+1 ± 5 days
for dating scans and 12+3 ± 3 days for CTs. Out of all 10889 pregnancies, 196 (1.8%) reported an
abnormality; 81 (0.7%) were chromosomal and 115 (1.1%) were structural anomalies diagnosed
at first or second trimester scan. NT was increased (NT≥95th
percentile) in 364 (5.4%) fetuses
who received a CT: 45 (12.4%) of these had a chromosomal anomaly and 12 (3.3%) an isolated
structural defect. Also, 15.8% of fetuses affected by cardiac anomalies had an increased
NT≥95th. Also, 27% (N=32) of all structural abnormalities were already detected during the first
trimester, including all cases of the following: anencephaly (N=4), encephalocele (N=1),
exomphalos (N=9), megacystis (N=4) and missing limb (N=1). Detection rate for gastroschisis
was 67% (N=2), while heart abnormalities were detected in the first trimester in only 14% of
cases (N=3).
Conclusions
In a primary care setting, a gross anatomical survey performed in concomitance of a dating scan
or of the CT, can already detect about 1/3 of all major structural anomalies during the first
trimester of pregnancy; especially lethal and very severe defects are identified. Although gross
and severe anomalies are already detected by a global survey, as performed during a dating scan,
adoption of a systematic protocol and additional training of the sonographers can maximize
diagnostic performance to include also less obvious, though severe anomalies. The
implementation of an ultrasound scan at 12-13 weeks of gestation, including a protocol for
systematic organs visualization, would have important implications for the further refinement and
cost-effectiveness of the prenatal screening program in The Netherlands.
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Samenvatting (Nederlands)
Achtergrond en doel
Het primaire doel van deze studie is het bepalen van het percentage foetale congenitale
afwijkingen gevonden bij week 13 bij een ‘gross anatomy survey’ in samenhang met een termijn
echo of een combinatie test (CT). Secundair wordt er onderzoekt hoe veel en welke afwijkingen
werden geobserveerd bij het 20 week structureel echoscopisch onderzoek (SEO) die eerder
tijdens de zwangerschap niet werden geïdentificeerd.
Materiaal en methoden
Dit is een retrospectieve cohort studie gedaan in een groot eerstelijnscentrum in Nederland.
Zwangerschappen werden geïncludeerd in de studie als er een echo was uitgevoerd tussen week
11 en 13+6 en als de a-terme datum tussen 01-01-2012 en 01-01-2016 was. Zwangerschappen
werden geëxcludeerd wanneer er tijdens de eerste scan een niet-levensvatbare foetus werd gezien,
of wanneer er geen informatie beschikbaar was over de tweede trimester SEO (18-22+6 weken).
Wanneer er tijdens de zwangerschap op een bepaald moment een abnormale marker of anomalie
werd gevonden, werd na de zwangerschap de postnatale follow-up uitkomst gezocht en als deze
niet aanwezig was, werd de zwangerschap ook geëxcludeerd.
Resultaten In totaal zijn er 10899 zwangerschappen geïncludeerd in de studie. De gemiddelde leeftijd van de
vrouwen en het gemiddeld maternaal gewicht waren 30.9 ± 4.7 jaar en 67 kg (60-76). Van alle
eerste trimester scans waren 4204 (38.6%) termijn echos en 6685 (61.4%) waren CT. Tijdens het
evaluatie moment was de zwangerschapsduur 12+1 ± 5 dagen bij de termijn echos en 12+3 ± 3
dagen voor de CTs. Van alle 10889 zwangerschappen zijn er 196 (1.8%) abnormaliteiten
gevonden; 81 (0.7%) waren chromosomaal en 115 (1.1%) waren structurele afwijkingen
gediagnosticeerd bij de eerste of tweede trimester scan. NT was verhoogd (NT≥95e percentiel) in
364 (5.4%) foetussen die een CT kregen: 45 (12.4%) hiervan hadden een chromosomale
afwijking en 12 (3.3%) hadden een geïsoleerde structurele defect. Tevens, had 15.8% van de
foetussen met cardiale afwijkingen een verhoogd NT≥95e percentiel. Verder, 27% (N=32) van
alle structurele abnormaliteiten werden in het eerste trimester al gezien, waaronder de volgende:
anencefalie (N=4), encefalocele (N=1), omfalocele (N=9), megablaas (N=4) en ontbrekende voet
(N=1). De detectiepercentage van gastroschisis was 67% (N=2), terwijl cardiale afwijkingen in
het eerste trimester maar 14% was (N=3).
Conclusies
In een eerstelijnscentrum waar een ‘gross anatomy survey’ wordt uitgevoerd in samenhang met
een CT of termijn echo kan bijna 1/3 van alle grote structurele afwijkingen al worden
gedetecteerd tijdens het eerste trimester van de zwangerschap; vooral de dodelijke en zeer
ernstige defecten worden geïdentificeerd. Met verder training, meer tijd toegewezen aan het
ultrasound onderzoek en de uitvoering van een systematisch echoscopisch onderzoek kan de
detectiepercentage verder toenemen. Het instellen van en echoscopisch onderzoek bij 12-13
weken met een protocol om de organen systematisch te visualiseren zou belangrijke gevolgen
kunnen hebben voor de verfijning en de optimalisatie van de kosten van de prenatale screening.
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Acknowledgments
First and foremost, my sincere gratitude goes to my supervisor, prof. Bilardo for her continuous
guidance and support. For always having an open door for me, for being a great leader but also a
kind, warm and caring teacher who made our research group feel like home. For making me
passionate about research and about prenatal diagnosis and giving me the chance of learning so
much by attending congresses and meeting new people. Her enthusiasm and knowledge have
motivated me from the very first day we met and still do so.
Moreover, I would like to thank Rosalinde Snijders for her help with follow-up retrieval and data
analysis, for teaching me how to use Microsoft Access and working with big data.
Also, a big word of thank to Maja Kuilman and Eric Smith for having given me the chance of
using the data without which this thesis could not have been possible and for their continuous
eagerness to improve data collection and registration.
Likewise, I would like to thank the department of Prenatal Diagnosis at UMCG and all the people
who somehow contributed to this research.
In my daily work I have had the pleasure of working with a cheerful group of fellow researchers.
I would like to thank Luana for making me laugh in the rainy and gloomy Dutch days and for
always having time for a cup of coffee and a chat. I would also like to say a big ‘grazie’ to
Federica, who has listened to my worries, complains and ideas since day one and has always
encouraged and supported me, whether that meant providing me with some advice, teaching me
how to perform an ultrasound or bringing me a cappuccino.
Finally, I thank my boyfriend, Filipe, for his support, for the jokes, the dances and the sweet
attentions. And I thank my incredible parents and my little sister for continuously loving and
supporting me throughout my studies and always believing in me.
Francesca
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Table of contents
List of abbreviations ......................................................................................................................... 2
Summary (English) .......................................................................................................................... 3
Samenvatting (Nederlands) .............................................................................................................. 4
Acknowledgments ............................................................................................................................ 5
Background and introduction ........................................................................................................... 7
First trimester screening ....................................................................................................... 7
Anomalies detected in the first trimester .............................................................................. 9
Second trimester screening / Anomalies detected in the second trimester........................... 9
Relevance of the topic ........................................................................................................ 10
Aim of the study ................................................................................................................. 11
Material and methods ..................................................................................................................... 12
Study design and study population ..................................................................................... 12
Inclusion and exclusion criteria .......................................................................................... 12
Data collection .................................................................................................................... 12
11-13+6 week scan ............................................................................................................. 14
18-22+6 week scan ............................................................................................................. 14
Classification of structural abnormalities ........................................................................... 15
Data analysis ...................................................................................................................... 15
Statistical analysis .............................................................................................................. 16
Information sources and Search strategy ........................................................................... 16
Informed consent and METc .............................................................................................. 16
Results ............................................................................................................................................ 17
Aneuploidies ....................................................................................................................... 18
Structural anomalies ........................................................................................................... 21
Organs visualization ........................................................................................................... 24
Discussion ...................................................................................................................................... 26
Detection of congenital abnormalities ................................................................................ 26
Structural abnormalities ..................................................................................................... 26
Ultrasound markers ............................................................................................................ 28
Chromosomal abnormalities .............................................................................................. 28
Spontaneous fetal deaths .................................................................................................... 29
Limitations ......................................................................................................................... 29
Conclusion ...................................................................................................................................... 30
References ...................................................................................................................................... 31
Appendix ........................................................................................................................................ 34
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Background and introduction
Around 2-3% of neonates are born with one or more congenital abnormalities (1). Severe
congenital abnormalities are associated with substantial long-term disability which is a burden
not only for the individual, but also for the family and the society. For this reason, and because of
the development of new theraupeutical options for some of the conditions, it has become
particularly important to identify congenital abnormalities during pregnancy in order to optimize
perinatal care. The field of prenatal diagnosis comprises a wide range of screening and diagnostic
procedures, either invasive or non-invasive, aimed at investigating, during the course of the
pregnancy, whether a developing fetus may be affected by chromosomal, structural or other
abnormalities. Prenatal screening has been rapidly and continously evolving since its very
beginning in the seventies, when maternal age above 35 years was the only indication to
recognize women at higher risk of carrying a chromosomally abnormal pregnancy (2). In the last
decades prenatal screening has acquired a vital role in the detection of fetal anomalies and is
nowadays broadly adopted all over the world. Screening programs are different in each country.
In The Netherlands, since 2007, the screening protocol offers every woman the opportunity to
choose for the combined test (CT) during the first trimester of pregnancy and the structural
anomaly scan at 20 weeks of gestation. Additionally, from April 1st 2017, a new form of
screening, non-invasive prenatal testing (NIPT), has been made available to all women in The
Netherlands who wish to undertake the test from 10 weeks of pregancy onwards.
As some anomalies are severe and untreatable, the option of termination of pregnancy (TOP) is
offered to parents. In view of the legal term for TOP in the Netherlands (24 weeks) and in order
to reduce the psychological and physical impact of such an event, there has been a move in the
last decades towards earlier prenatal diagnosis of severe fetal anomalies, such as chromosomal
and structural anomalies. This was also made possible by the ongoing improvements in
ultrasound imaging and emerging new screening and diagnostic techniques. Early diagnosis
enables for parents more time to make a conscious and unrushed decision on the course of action
allowing, in cases where TOP is elected, for safer procedures with less psychological sequelae
(16).
First trimester screening
First trimester screening is mainly focused on the detection of chromosomally abnormal
pregnancies and is especially vital for the identification of aneuplodies including trisomies 21, 18
and 13 and Turner Syndrome (45X0). The combined test involves the analysis of placental
hormones in the maternal blood as well as ultrasound measurement of nuchal translucency (NT)
(3). For the former, maternal serum levels of two biomarkers, namely, free beta-human chorionic
gonadotropin (b-hCG) and pregnancy-associated plasma protein A (PAPP-A), are obtained. The
level of free b-hCG in maternal blood normally decreases in the course of pregnancy, while the
contrary is true for PAPP-A levels, which increase with gestation. When a fetus is affected by
trisomy 21, increased free b-hCG and decreased PAPP-A levels for that gestational age are
recorded (4). On the other hand, decreased levels of b-hCG are reported in fetuses affected by
trisomy 13 and trisomy 18 (5). The analysis of the serum levels of these two biomarkers,
combined with the NT measurement and the a-priori maternal risk for aneuplodiy, gives an
estimate of the risk of a mother carrying a chromosomally abnormal pregnancy. The a-priori risk
is based on maternal age, obstetric and general medical history and/or other pregnancy-related
risk factors (e.g. diabetes, smoking etc). Furthermore, as mentioned above, the CT includes the
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ultrasound measurement of fetal nuchal translucency. NT is defind as the subcutaneous
accumulation of fluid behind the fetal neck, which can effectively be measured by ultrasound
only between 11+0 and 13+6 weeks of gestation. The CT has an accuracy of 85 - 90% in the
detection of congenital abnormalities, with a false positive rate of about 5% (6). Likewise,
increased nuchal translucency is not only strongly associated with fetal chromosomal anomalies,
but it is also a marker of structural abnormalities, such as pulmonary, gastrointestinal,
genitourinary, musculoskeletal anomalies (7) and especially cardiac defects (8). Also genetic
syndromes are associated with an increased NT (43). Women choosing for the combined test
undergo an early ultrasound scan by sonographers experienced in the NT measurement. During
the scan it is also possible to rapidly check at least the milestones of fetal anatomy; especially
gross and severe anomalies are detectable at this early stage of pregnancy. Consequently, the scan
performed at the time of the CT can identify fetuses with an increased NT, which is also a marker
for structural anomalies. Also, it can detect especially severe fetal anomalies by the anatomical
survery that occurs while waiting for the optimal fetal position for accurate NT measurement.
Moreover, as most chromosomal anomalies (i.e trisomies) are also associated with structural
defects, the visualization of these defects can serve in itself as screening for chromosomal
abnormalities. Despite its general value in prenatal screening, in The Netherlands, only about
30% of the women choose for the CT. One of the reasons may be that this is exclusively offered
as screening for chromosomal anomalies, without mentioning its additional value as potential
screening for severe structural defects. The prevalence of congenital abnormalities in
chromosomally normal fetuses with a normal NT (<p95) is around 1.6%, but it can significantly
increase to up to 45% in case of a NT≥p99 (9).
When a woman is found to have an increased risk for chromosomal abnormalities at the CT, (i.e.
higher than 1:250) or an NT equal to or higher than 3.5 cm is measured even in the presence of a
risk below 1:250 (10), further diagnostic testing is offered, either in the form of Chorionic villus
sampling (CVS) or amniocentesis. These procedures, however are often feared by mothers, as
even in experienced hands they carry a low (about 1; 500-1000), but present procedure-related
risk of miscarriage (11). In recent years a new screening option has become available for
mothers: Cell-free fetal DNA (cfDNA) testing in moternal blood. This is a non-invasive prenatal
test (NIPT) enabling, in case of a fetal trisomy, identification of excessive DNA fragments from
the extra fetal chromosome, next to the maternal DNA fragments count. Some companies are also
able to quantify the fetal DNA fraction in the maternal blood. The test can be performed from ten
weeks of gestation onwards (12). CfDNA testing can detect Down syndrome with a high
sensitivity (>99%) and to a lesser extent, trisomy 18 (97%–99%) and trisomy 13 (87%–99%) and
is more sensitive and specific than the CT (13). One of the biggest advantages of cfDNA is that,
in view of its high specificity, there are very few (false) positive cases where a diagnostic
invasive procedure is indicated. This minimizes the number of procedure-related miscarriages
(14). On the other hand, though, cfDNA has a significant limitation; while an abnormal CT, in
view of an increased NT and/or abnormal serum markers can be associated with a wide spectrum
of chromosomal abnormalities, including microscopic genetic aberrations, cfDNA is especially
valuable as screening for trisomy 21, 18 and 13, and of limited value in sexual chromosomal
anomalies, triploidy and chomosomal disarrangements which can be identified by arrays CGH on
fetal material (13). Moreover, cfDNA is of no value as screening for structural anomalies. cfDNA
was introducted in The Netherlands in 2014, when it was offered to women after an increased
first trimester risk at the time of the CT. However, because of its high sensitivity and specificity,
as well as its non-invasive nature, since April 1st 2017, CfDNA is offered as first tier test to all
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pregnant women in The Netherlands. Both the CT and cfDNA are offered at a cost of 165 and
175 Euros, respectively.
Looking at potential future developments of the Dutch screening program, there is a real
possibility that, because of its higher sensitivity, cfDNA may almost entirely replace the CT. If
that happened, the NT would no longer be measured in the first trimester and therefore also the
option of an early scan may disappear. The first moment when the fetus could be examined for
structural anomalies would then be the 20 week anomaly scan. As in the Netherlands the legal
limit for termination of pregnancy is 24 weeks (15), this means that, in case of severe anomalies,
parents have to decide relatively quickly on a possible termination of pregnancy and at a moment
when the mother already for weeks feels the baby moving. Additionally, a late termination of
pregnancy carries a higher risk of complications and is a heavier psychological burden for the
parents (16). Therefore, an undiscussed advantage on an early recognition of structural anomalies
is that it offers parents more time to follow-up the evolution of the anomaly, perform additional
investigations and in case of major malformations, to make a well informed decition on
pregnancy termination or to be prepared for the birth of a child in need of special care.
Anomalies detected in the first trimester
Detection rates of structual anomalies during the first trimester can vary significantly. Previous
studies have reported a range varying between 18% to 70% (17, 18), depending on the patient
population, experience of the sonographers and setting of the screening.
According to a recent study by Syngelaki et al (19) over 40% of all congenital abnormalities can
already be identified between 11-13+6 weeks of pregnancy. Different types of congenital defects
can be detected; ranging from lethal to surgically correctable. A wide range of congenital
malformations, most of which are extremely severe, can always be identified during the first
trimester. These include: acrania, alobar holoprosencephaly, exomphalos, gastroschisis,
megacystis and body stalk anomalies. Additionally, some abnormalities, such as facial cleft, renal
agenesis and multicystic kidneys, are potentially, but not always, detectable during the first
trimester of pregnancy. The detection rate depends on a number of factors, including gestational
age, experience of the sonographer, method of ultrasound examination (abdominal/vaginal) and
time allocated to the ultrasound examination. Finally, some anomalies can never be seen during a
first trimester scan because the affected anatomical structures only develop during the second or
third trimester; these include posterior fossa anomalies, corpus callosum agenesis and migration
disorders, some forms of congenital heart disease, pulmonary and gastro-intestinal anomalies,
some late onset fetal tumors, ovarian cysts and severe hydronephrosis caused by ureteric stenosis
or vesicoureteric reflux (19). Table 1 shows which of the anomalies reported in this study were
detectable early, sometimes early or late during pregnancy.
Second trimester screening / Anomalies detected in the second trimester
The 20 week structural anomaly scan (in Dutch: ‘structureel echo onderzoek’; SEO) is a thorough
investigation of the fetal anatomy performed by examining systematycally every fetal organ-
system, although originally its main aim was screening for spina bifida and anencephaly.
However, by exmaining in a systematic way the fetal anatomy many other structural defects can
be detected (20). Examples are abnormalities of the central nervous system (CNS) such as small
encephaloceles, corpus callosum agenesis and subtle forms of holoprosencephaly, such as lobar
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or semi-lobar. Moreover many facial, thoracis, cardiac, pulmonary, abdominal, gastrointestinal,
renal and skeletal anomalies can be seen (21). If fetal abnormalities are observed at the 20 week
scan, the mother is referred to a specialized fetal medicine unit (tertiary center), where an
advanced ultrasound examination (in Dutch: ‘Geavanceerd ultrageluid onderzoek’; GUO) and
additional investigations take place. The diagnostic work-up in case of anomalies, including
repeated detailed ultrasound examinations, karyotyping and additional investigations, takes about
1-3 weeks. In The Netherlands, around 95% of women choose for the 20 week scan.
Relevance of the topic
The introduction of cfDNA requires a critical re-evaluation of the current pregnancy screening
paradigm. From a point of view of cost-benefit it is important to establish whether, given the
expected disappearance or strong reduction in the numbers of CTs being performed, the
introduction of a formal 13 week scan, as new screening step for the earlier detection of fetal
structural abnormalities is justified, or if early screening for structural anomalies can occurr at the
time of the dating scan, also necessary in case of cfDNA. In order to clarify investigate the yield
of the 13 week scan, an exemption of the Population screening Act (WBO) was granted by the
Dutch Health Council to perform a study on the effectiveness of the 13 weeks scan in the region
Groningen. The study was conducted between 2012 and 2015 and has recently been published
(27). The Health Council has also recently published an advise, regarding Prenatal Screening in
which, next to the cfDNA offered to all women, the 13 weeks scan is recommended, although
more evidence (in the form of research) on its performance is recommended before a definitive
decision can be taken on the merit. At the moment, Dutch women are differently exposed to a
first trimester scan. The majority receives a dating scan at about 10 weeks and then no more
scans until 20 weeks, about 30% chooses for the CT and receives a sort of “unofficial” and
simplified early anomaly scan. In the West of the country, where relatively more women choose
for the CT there are already large datasets availble on the yield of a gross global fetal anatomy
survey at the time of the CT. However it is not yet known what the yield of a dating scan,
performed by experienced sonographers at 12-13, instead of that at 10 weeks would be for the
early detection of structural anomalies. It was for us a unique opportunity to find out that such a
dataset was available and had been collected prospectively, over the years by the large ultrasound
clinic Bovenmaas, in Rotterdam, The Netherlands. In our study all women attending the clinic for
early scans received a scan at 11-13 weeks, either as dating scan or in the context of the CT, for
women opting for this test. This is unique to the ultrasound clinic in Bovenmaas and does not
reflect the situation in the rest of the county. Indeed, a dating scan is routinely offered at 10
weeks of pregnancy to date the pregnancy, confirm viability and number of the fetuses. At this
early gestation it is not yet possible to examine fetal anatomy as the organs have not sufficiently
developed yet. Thus, even though this is beyond the scope of a dating scan, In Bovenmaas, in
order to quickly check gross fetal anatomy, the scan is often performed at around 12-13 weeks.
During a dating scan the fetal anatomy is not specifically or systematically investigated, whereas
in fetuses who receive a CT the following aspects are investigated while waiting for the fetus to
assume the right position for the NT measurement: presence of falx in the head, closure of the
cranial vault, presence of nasal bone, lung fields and 4 chamber view of the heart, closure of the
abdominal wall, bladder filling, presence and normality of extremities, NT measurement. This
represents a simplified fetal anatomical survey protocol.
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Aim of the study
The primary aim of this study is to determine the percentage of fetal congenital abnormalities
found at the 13 week gross-anatomy survey performed in concomitance of the dating scan or of
the CT. Secondly, the research investigates how many and which of the defects observed at the
20 week anomaly scan (SEO) were not identified by the ultrasound scan performed earlier in
gestation.
Hypothesis
As the prevalence of (all) congenital anomalies is about 1.6% - 2.5% and assuming that not all
can be detected in pregnancy, we expect that:
1) Especially severe one will be detected at the first trimester scan
2) That (1) will represent about 1/3 of the anomalies detected in pregnancy.
Thus, out of a total of 10899 pregnancies, we expect to find at the early and at the 20
weeks scan a total of 110-200 anomalies and that of these about 1/3 (40- 65) will already
be detected early in pregnancy.
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Material and methods
Study design and study population
This is a retrospective study performed on a prospectively collected database of consecutive
ultrasound scans performed in a large first line ultrasound clinic in the region of Rotterdam, The
Netherlands.
Inclusion and exclusion criteria
All patients and ultrasound data were entered in a database called Astraia (clinical package
Astraia Gmbh Munchen). Pregnancies were included in the study if an ultrasound scan was
performed between 11 and 13+6 weeks of gestation and if the estimated date of delivery (EDD)
was between 01-01-2012 and 01-01-2016. Pregnancies were excluded from the study when a
non-viable fetus was seen at the time of the first scan, or when no information on the second
trimester structural anomaly scan (18-22+6 weeks) was available. When an abnormal marker or
an anomaly was found at any point during the course of pregnancy, postnatal follow-up was
searched and if this was not available, the case was excluded. (Figure 1)
Data collection
Data were collected prospectively and patients data, ultrasound findings and ultrasound images
were stored in the clinical software package (Astraia Gmbh Munchen) at Bovenmaas US clinic.
For the purposes of this study all needed data collected in the study period were retrieved from
the database using predefined queries and then exported into a research dataset. When the patient
was referred to the regional University Center (Erasmus Medical Center, EMC) an attempt was
made to complete the data with the information available at the Erasmus Medical Center (EMC).
Postnatal outcome data were retrieved from local databases, the national birth registry, the
pathology department of the EMC and information provided by the parents. Finally, information
on karyotyping was provided by the clinical genetics department of the tertiary care center. The
total number of cases included in the database was screened in order to avoid duplicates and
incomplete cases. Multiple pregnancies were examined and each fetus was considered
independently. The final number of pregnancies included in the study was 10889. Before the
examination, all women had been counseled by their primary caregiver regarding the potential
benefits and limitations of the first-trimester ultrasound scan. Details which could be linked to a
single individual were deleted and all subjects received a random number, creating an anonymous
dataset for further analysis.
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Figure 1 – Inclusion criteria
11-13+6 week scan
N= 13417 Spontaneous fetal death N=154
No 18-22 week scan N=2374
CT scan
N=6685 (61.4%) Dating scan
N=4204 (38.6%)
No anomaly
N=10839 Anomaly
N= 14
Anomaly
N=35
20 week scan
N=10739
Chromosomal
anomaly*
N=46
TOP** N=8
IUD*** N=46
No anomaly
N=10439 Marker
N=202 Anomaly
N=100
Chromosomal anomaly
N=1
False positive N=1
Structural anomaly confirmed
N=12
Anomaly at birth
N=5
Chromosomal anomaly N=10
Lost to follow-up N=7
Structural anomaly confirmed
N=83
Chromosomal anomaly
N=16
False positive N=3
Structural anomaly confirmed
N=16
Chromosomal anomaly
N=5
Chromosomal anomaly
N=3
*34 patients with NT≥95th
, 5 patients with NT≥95th
plus other markers, 7 high risk at CT
**3 patients with NT≥95th
and high risk at CT but not karyotype, others TOP for social reasons (N=5)
***3 patients with NT≥95th
but not karyotype, others spontaneous intrauterine death < 20 weeks (N=43) **TOP: termination of pregnancy ***IUD intrauterine death
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11-13+6 week scan
All women attending the clinic for early scans received an ultrasound examination at 12-13
weeks, either as dating scan or in the context of the CT, for women opting for this test. The
sonographers working at Bovenmaas clinic were instructed to, firstly, confirm viability and
determine the number of viable fetuses and, secondly, measure crown-rump length (CRL),
biparietal diameter (BPD), abdominal circumference (AC), head circumference (HC) and femur
length (FL) to accurately establish gestational age. Additionally, when parents opted for a CT,
maternal blood samples to measure PAPPA-A and hCG levels were taken and ultrasound
measurement of nuchal translucency (NT) was performed to calculate the risk of aneuploidy.
Also, while waiting for the fetus to assume the right position for the NT measurement, the
following aspects were investigated: presence of falx in the head, closure of the cranial vault,
presence of nasal bone, lung fields and 4 chamber view of the heart, closure of the abdominal
wall, bladder filling and presence and normality of extremities. This represents a simplified fetal
anatomical survey protocol. However, in all first trimester scans no standard checklist was used
for the anatomical assessment of the fetus which was a general gross anatomical survey and not a
systematic anatomical assessment of the various organs. Furthermore, in women who opted for a
CT, special attention was devoted to the examination of markers for anomalies. Markers are
subtle variations of normal ultrasound appearance, commonly associated with an increased risk of
congenital anomalies but, by themselves, with no consequence for the health of the fetus. The
following markers were reported: NT 95th
-99th
percentile, absence of the nasal bone and
measurement of the fronto-maxillary angle, abnormal skull shape, ventriculomegaly, choroid
plexus cyst, single umbilical artery (SUA), abnormal Ductus Venosus Doppler, tricuspid
regurgitation, abnormal heart axis and intrauterine growth restriction (IUGR). When a fetuses
showed both a marker and a structural abnormality it was counted in the structural anomaly
group. All first trimester CTs were performed by Fetal Medicine Foundation (FMF)-certified
sonographers (22), while dating scans were performed by non FMF-trained sonographers. Organs
were either considered as normal, abnormal or not adequately visualized. When an abnormality
was found, a follow-up appointment was made for further investigation. Ultrasound examinations
were performed trans-abdominally and, only in a minority of cases with poor image quality due
to maternal obesity or other technical difficulties, were trans-vaginal ultrasounds performed. The
following US systems were used for the examinations: IU22xMatrix, Aloka SSD 3500, Aloka
alpha 6, Philips HD (7, 11 and 15), Philips CX50 and ATL HDI 5000 with curved array
transducers. EPIQ 7 was used for fetal echocardiography. Trans-abdominal and trans-vaginal
scans were performed with 9-1 and 10-3MHz probes, respectively. Time allocated for the first
trimester ultrasound examination was 20 minutes with 10 additional minutes for NT
measurement and risk assessment if a CT was requested.
18-22+6 week scan
The ultrasound examination offered between 18 and 22+6 weeks of gestation was performed
according to the national screening protocol, which involves the assessment of the development
of the fetal organs, the growth of the fetus and measurement of amount of amniotic fluid.
Anatomical assessment of the fetus comprises systematical examination of central nervous
system (skull and brain, including presence of midline cavum septum pellucidum and assessment
of the lateral ventricles and cerebellum), vertebral column, face (assessment of the eyes, profile
and lips), thorax (including evaluation of the echogenicity of the lungs and presence of
diaphragmatic hernia), heart (including size, position, insertion of aorta and pulmonary artery, 3
15
and 4 chamber views), abdomen (abdominal wall, stomach and stomach filling, intestines,
presence of both kidneys, evaluation of renal parenchymal echogenicity, and measurement of the
pyela) and extremities (upper and lower extremities including measurement of femur length,
presence and correct attachment of both hands and feet). Time allocated to the ultrasound
examination of the fetus was 40 minutes. As with the first trimester scan, when an abnormality or
markers were found or in case of inadequate assessment, a follow-up appointment was made for
further investigation. Equally to the first trimester, we made use of ultrasonographic markers. The
markers found were the same as those in the first trimester and, additionally, echogenic focus
of the heart, pyelectasis (pyelum>5mm) and echogenic bowel .
Classification of structural abnormalities
All fetal abnormalities reported in this study were retrospectively subdivided into different
categories depending on the organ-system affected; the following subgroups were used: nervous
system (including neural tube defects and brain), facial, respiratory, cardiac, gastro-intestinal,
abdominal wall, urinary, genital, skeletal and others. Fetuses for which two or more different (i.e.
different localized errors in morphogenesis) major abnormalities were observed were included in
the ‘multiple congenital abnormalities’ (MCA) group (23). Cases of fetuses with more than one
abnormalities of different severity were classified based on the most severe anomaly. Also, for
fetuses with more than one abnormality, the diagnosis was considered as prenatally made when
the most severe anomaly was prenatally identified. A complete list of all major abnormalities, as
well as a brief explanation of the defects detected in this study and subdivided according to the
organs affected, is provided in table 1 (appendix). Table 1 also further specifies which anomalies
are always early- detectable, sometimes early, late or are frequently missed prenatally. Structural
abnormalities in fetuses with a serious chromosomal abnormality confirmed by amniocentesis or
chorionic villous sampling (CVS) were not included in the structural abnormalities group.
Physiological familial variants from normal anatomy (e.g. familial short femur, persistent left
vena cava) were not considered as structural abnormalities either. Also, the distinction between
cystic hygroma and NT≥3.5mm has not been used because there is an overlap between these two
ultrasound definitions of excessive nuchal fluid collection. Lastly, cardiac defects detected by
identification of one or more abnormal ultrasound markers (i.e. abnormal Ductus Venosus
Doppler, abnormal heart axis and tricuspid regurgitation) observed at 11-13+6 weeks and
confirmed later in pregnancy were considered as detected during the first trimester.
Data analysis
Initially, the total number of pregnancies in the inclusion period was calculated. Out of all
identified pregnancies, the ones for which an ultrasound examination took place between 11 and
13+6 weeks as well as in the second trimester, were calculated. After excluding non-eligible
cases, the number of fetuses affected by chromosomal anomalies was calculated and f this group
first trimester ultrasound findings and pregnancy outcomes were searched. Subsequently, the
number and types of structural anomalies detected by ultrasound between 11 and 13+6 weeks,
and those detected at 18-22+6 weeks of pregnancy were identified. Then, postnatal follow up for
all fetuses with a prenatally detected anomaly or marker was searched in order to confirm the
presence of the structural defect at birth and calculate false positives rates.
16
Statistical analysis
Maternal weight, length and gestational age at assessment are provided as continuous variables.
Weight and length are used to calculate the maternal body mass index (BMI). For each
ultrasound examination the route is recorded (abdominal, vaginal) and data are collected on the
visualization of the different organ systems (not visualized; visualized –appearance normal,
abnormality suspected) and prenatal diagnosis at a tertiary center (normal, abnormal, uncertain)
documented. All above data are categorical.
Normally distributed data were defined using mean and standard deviation (SD) whereas non-
normally distributed variables were described using median and interquartile range (IQR). SPSS
Statistics Version 23.0 (IBM Corporation, NY, USA) was used to perform descriptive and
comparative statistics. Chi-Square test was used to test for the difference between the number of
structural anomalies detected at 11-13+6 during dating scan and CT. Also, binary logistic
regression was used to test whether maternal BMI, gestational age at the time of ultrasound
examination, quality of ultrasound image, type of investigation (CT or dating scan) and route of
examination (vaginal / abdominal) could predict whether the individual organs would be
visualized or not visualized during ultrasound. All results were considered statistically significant
with alpha<0.05.
Information sources and Search strategy
An internet based literature research was performed; most information was obtained from
PubMed. PubMed search made use of the “Mesh” tool. Most searched words were “First
trimester” OR “13 week” AND “anatomy” OR “anomaly” OR “abnormality” OR “defect” OR
“detection”.
Informed consent and METc
All women attending the ultrasound clinic were asked to give their consent for the use of
anonymised data for local statistics and medical studies. This study does not fall under the
category of research involving human subjects (Niet WMO-plichtig (Medisch-wetenschappelijk
onderzoek met mensen)) and does therefore not require medical ethical approval from the
Medical Ethical Committee (METc) (appendix 1).
17
Results
During the inclusion period 13417 pregnancies were screened between 11 and 13+6 weeks.
Firstly, 154 (1.1%) cases were excluded from the final analysis because of spontaneous fetal
demise witnessed at the time of the first ultrasound; of these 81 (52%) were seen at 11 weeks, 60
(39%) at 12 and 13 (8%) at 13 weeks. Secondly, 2374 (17.7%) were excluded because no
information on the 18-23 week scan was available. Thus, 10889 pregnancies in total finally met
the inclusion criteria. Mean maternal age and median bodyweight were 30.9 ± 4.7 years and 67
kg (60-76), with a minimum and maximum of 15 - 46 years and 42 – 162 kg, respectively.
Median BMI was 24 (21 – 26) kg/m2. Of all first trimester scans, 4204 (38.6%) were dating scans
and 6685 (61.4%) were CT. At the time of evaluation mean gestational age was 12+1 ± 5 days
for dating scans and 12+3 ± 3 days for CTs (ranges 11-13+6) (table 2). Out of all 10889
pregnancies, 196 (1.8%) reported an abnormality; 81 (0.7%) were chromosomal and 115 (1.1%)
were structural anomalies diagnosed at the first or the second trimester scan.
Table 2 – Demographic characteristics of study population.
Characteristics Total
(N=10889)
Maternal age –years
Mean ± SD
Minimum-maximum
30.9 ± 4.7
15 - 46
Maternal weight – kilograms
Median (IQR)
Minimum-maximum
67 (60-76)
42 - 163
Maternal height – centimeters
Mean ± SD
Minimum-maximum
168 ± 7
146 - 192
Maternal BMI – kg/m2
Median (IQR)
Minimum-maximum
24 (21 – 26)
16.2 – 50.1
Gestational age at FTS scan— wk. + dd
Mean ± SD
Dating scan
CT
12+1 ± 5
12+3 ± 3
18
Aneuploidies
Of all 10889 pregnancies, 81 (0.7%) reported a chromosomal anomaly. The majority of these
were trisomy 21 (N=38, 46.9%), trisomy 18 (N=11, 13.6%) and trisomy 13 (N=6, 7.4%). Turner
syndrome (45X0) and Triploidy were diagnosed in 5 fetuses. Of the remaining 16 (19.7%)
chromosomal anomalies, 15 (18.5%) were microscopic aberrations detected by microarrays
(MiA) and in 1 case (1.2%) the karyotype was described as abnormal but was not specified. In
total, 77.7% (N=63) of chromosomal abnormalities was detected during the first trimester, while
16% (N=13) and 6.2% (N=5) at 18-22 weeks and after 22 weeks, respectively. Overall rate of
TOP was 75.6%; all mothers carrying fetuses with trisomy 18 and 13 opted for a termination,
while the rate was 84.2% for fetuses with trisomy 21, 80% for Triploidy, 60% for Turner
syndrome and 26.7% for fetuses with microscopic aberrations. (Table 3).
Table 3 – Chromosomal abnormalities in the study population
Diagnosis Outcome
Fetal chromosomal
abnormality
Total 11-13
weeks
18-22
weeks
>22
weeks
TOP IUD Live birth
N (%) N (%) N (%) N (%) N (%) N (%) N (%)
Trisomy 21 38 (46.9) 28 (73.7) 8 (21.1) 2 (5.2) 32 (84.2) 1 (2.6) 5 (13.2)
Trisomy 18 11 (13.6) 11 (100) - - 11 (100) - -
Trisomy 13 6 (7.4) 6 (100) - - 6 (100) - -
Turner syndrome (45X0)* 5 (6.2) 3 (60) - 2* (40) 3 (60) - 2* (40)
Triploidy 5 (6.2) 5 (100) - - 4 (80) 1 (20) -
Microscopic aberrations** 15 (18.5) 9 (60) 5 (33.3) 1 (6.7) 4 (26.7) 3 (20) 8 (53.3)
Unknown 1 (1.2) 1 (64.3) - - 1 (100) - -
Total 81 63 (77.7) 13 (16) 5 (6.2) 59 (75.6) 5 (6.4) 14 (17.9)
*2 patients with mosaic 45X0
**Including: gain 16p13.11p12.3 (N=1), gain 22q11.2 (N=2), (1-22) x2 (XY) x1(N=1), 4q del (N=1), LMX1B
mutation (N=1), del 22q11.2 (N=2), del 2q37 (N=1), gain 1q21.1 (N=1), q5 del (N=1), trans 9-13 (N=1), q13 del
(N=1), q2 duplication (N=1), 3q2 del (N=1)
Table 4 presents the ultrasound markers and abnormalities observed in fetuses with chromosomal
anomalies. The table shows that 79% (N=63) of the pregnancies had a high risk at the combined
test and 5% (N=4) had a low risk. Sixteen percent (N=13) had no risk calculation as they only
underwent a dating scan. In 52.5% of scans, a NT >95th was the only identified marker for fetal
abnormalities, while structural abnormalities were observed in 29.6% (N=24) of first and 8.8%
(N=7) of second trimester scans.
19
Table 4 – Ultrasound markers and abnormalities observed in fetuses with chromosomal
anomalies
Chromosomal
anomaly
Dating scan
(N)
CT risk (N) Ultrasound marker / abnormality (N)
Low High Only NT
>95th
11-13+6 weeks 18-22+6 weeks
Trisomy 21
(N=38)
7
1 30 23 -Omphalocele + NT (N=2)
-Heart anomaly, absent
nasal bone, tricuspid
regurgitation (N=1)
-NT, tricuspid
regurgitation, abnormal
Ductus Venosus doppler
(N=1)
-Absent nasal bone (N=1)
-Absent nasal bone,
abnormal Ductus Venosus
Doppler, choroid plexus
cyst (N=1)
-NT, tricuspid
regurgitation, abnormal
Ductus Venosus Doppler
(N=1)
-IUGR,
oligohydramnios,
echogenic bowel
(N=1)
-Heart defects and
duodenal atresia
(N=1)
Trisomy 18
(N=11)
1 - 10 5 -NT + big omphalocele
(N=2)
-NT, omphalocele,
overlapping fingers, SUA
(N=1)
-NT, hart anomalies,
holoprosencephaly,
bilateral club feet
-SUA, big omphalocele
(N=2)
-SUA (N=1)
-
Trisomy 13
(N=6)
- 1 5 4 -NT, omphalocele,
holoprosencephaly,
AVSD, echogenic kidneys,
heart abnormalities (N=1)
- Cleft lip + palate, heart
abnormalities (N=1)
-Multiple heart
abnormalities (N=1)
NT, heart abnormalities,
megacystis (N=1)
-
20
Turner
syndrome
(45X0) (N=5)
- - 5 2 NT, missing nasal bone,
omphalocele, abnormal
posterior fossa, heart
abnormality (N=1)
-NT, omphalocele, heart
abnormality, echogenic
bowel, IUGR (N=1)
-
Triploidy
(N=5)
1 - 4 1 -IUGR (N=2)
-Holoprosencephaly (N=1)
-IUGR, echogenic kidneys,
heart abnormalities (N=1)
-
Microscopic
aberrations
(N=15)
4 2 9 7 -NT, SUA (N=1) -Overlapping
fingers left, bilateral
rocker bottom feet,
plexus choroid cysts
(N=1)
-VSD's,
palatoschisis (N=1)
-Rocker bottom
feet, arachnoid
plexus cyst, choroid
plexus cyst (N=1)
-Anhydramnios,
unilateral renal
agenesis (N=1)
-Multiple plexus
choroid cysts (N=1)
Total (80) 13 (16) 4 (5) 63 (79) 42 (52.5) 24 (29.6) 7 (8.8)
SUA: single umbilical artery
IUGR: intrauterine growth restriction
21
Structural anomalies
A total of 115 structural abnormalities were detected in the study population. This gives a
prevalence of 1.1%. Of these, 31 (27%) were already observed at the first trimester scan. There
was no significant difference in the detection rate of structural abnormalities between the CT and
the dating scan groups (p=0.55). As shown in figure 2, anomalies of the genitourinary system
were the most frequent in our patient population (N=31), followed by cardiac (N=19) and skeletal
(N=17) defects. Abdominal wall defects had the highest detection rate in the first trimester
(11/12, 91.7%), followed by anomalies of the CNS with an overall first trimester detection rate of
43% (6/14). All (N=4) cases of acrania/anencephaly, encephalocele (N=2), omphalocele (N=9),
megacystis (N=4) and limb reduction (N=1) were detected during the first trimester. Sixty-two
percent (N=13) of these pregnancies were terminated during the first trimester while 1 fetus with
a missing limb and 2 fetuses with a megacystis which spontaneously resolved in the second
trimester were born alive (table 5). Also, 5 fetuses with omphalocele, 2 of which (bowel only)
disappeared later in pregnancy, resulted in a live birth. The first trimester detection rate for
gastroschisis was 67% (2/3), followed by a detection rate of 25% for unilateral renal agenesis
(1/4). All other genitourinary anomalies, including multicystic renal dysplasia, hydronephrosis,
ureterocele and double collecting kidneys were seen at second trimester scan. Among skeletal
anomalies, a first trimester detection rate of 33% was reported for skeletal dysplasia (1/3); the
case diagnosed early in pregnancy was very severe and resulted in a termination of pregnancy,
while the other 2 cases detected at 20 weeks were milder and both resulted in live-births. All
other minor skeletal abnormalities, with the exception of polydactyly which was detected in 1/3
cases, were overseen at the first trimester. As reported in figure 2, overall detection of cardiac
anomalies at 13 weeks was 21% (4/19); 2 cases of Tetralogy of Fallot (2/4) and 2 cases of
complex heart defects (one with dextrocarida, mitral valve atresia and hypoplastic aorta the other
with transposition of the great arteries double outlet right ventricle) were seen during the first
trimester. All other cardiac defects were diagnosed during the 20 week scan. Also, 40% (2/5) of
fetuses with multiple congenital anomalies was identified at 13 weeks. Finally, all overall cases
of gastrointestinal, respiratory and facial anomalies were not detected during the first trimester:
these include 3 hernia diaphragmatica, 1 esophageal and 1 duodenal atresia, 5 congenital
adenomatoid malformation of the lung and 7 cases of cleft lip and/or palate. There was a total of
4 false positive diagnosis; 2 cases of mild megacystis and 2 with a bowel only omphalocele
which resolved spontaneously later in pregnancy. This gives a false positive rate of first trimester
diagnosed anomalies of 0.04%.
NT was increased (NT≥95th
percentile) in 364 (5.4%) fetuses who underwent the CT and in 3.3%
of all fetuses. Of all the fetuses with increased NT, 57 (15.7%) were diagnosed with an anomaly.
45 were chromosomal anomalies and 12 isolated structural defects. Also, 3 pregnancies were
terminated and 3 ended in intrauterine death. Table 5 presents the abnormalities associated with
an increased NT: the highest number was cardiac anomalies (N=3), followed by CNS,
genitourinary, abdominal wall and MCA (N=2). 15.8% of fetuses affected by cardiac anomalies
had an increased NT≥95th
percentile.
22
Figure 2 - Structural anomalies divided by organ system – detection at 11-13 weeks and 18-
22 weeks
Table 5 – Structural abnormalities in the study population
Diagnosis Pregnancy outcome
Total
11-13 weeks
20-23 weeks TOP IUD Live
birth CT NT ≥ 95th Dating scan
Fetal abnormality N N(%) N(%) N(%) N(%) N(%) N(%) N(%)
Central nervous system
Acrania / exencephaly 4 - - 4 - 4 - -
Encephalocele 2 2 1 - - 2 - -
Hydrocephaly 2 - - - 2 1 - 1
Schizencephaly 1 - - - 1 1 - -
Corpus callosum agenesis 1 - - - 1 1 - -
Craniosynostose 1 - 1 - 1 - - 1
Spina bifida 3 - - - 3 2 1 -
Facial
Cleft lip 1 - - - 1 - - 1
Cleft palate 1 - - - 1 - - 1
Cleft lip + palate 5 - - - 5 - - 5
Respiratory
Congenital adenomatoid
malformation of the lung
(CAML)
5 - - - 5 - - 5
Cardiac
Double outlet right
ventricle
1 - 1 - 1 - - 1
Transposition great arteries 1 - 1 - 1 - - 1
Coarctation of the Aorta 1 - - - 1 - - 1
Extended aortic arch 1 - - - 1 - - 1
Tetralogy of Fallot 4 2 - - 2 2 - 2
05
101520253035
18-22 weeks
11-13 weeks
23
Hypoplastic left heart 1 - - - 1 1 - -
Atrial septal defect 1 - - - 1 - - 1
Atrioventricular septal
defect
1 - - - 1 - - 1
Cor Triatriatum dexter 1 - - - 1 - - 1
Aortic valve stenosis 1 - - - 1 1 - -
Tricuspid insufficiency 1 - - - 1 - - 1
Aortic aneurysm 1 - - - 1 - - 1
Right aortic arch 1 - - - 1 - - 1
Complex heart defect* 3 2 1 - 1 2 1 -
Gastro-intestinal
Esophageal atresia 1 - 1 - 1 - - 1
Duodenal atresia 1 - - - 1 - 1 -
Hernia diaphragmatica 3 - - - 3 1 - 2
Abdominal wall
Gastroschisis 3 2 1 - 1 - 1 2
Omphalocele*** 9 4 1 5 - 4 - 5
Genitourinary
Unilateral renal agenesis 4 1 - - 3 - - 4
Megacystis 4*** 2 - 2 - 2 - 2
Unilateral multicystic renal
dysplasia
8 - 1 - 8 - - 8
Bilateral multi cystic renal
dysplasia
2 - - - 2 2 - -
Unilateral hydronephrosis 6 - - - 6 - - 6
Bilateral hydronephrosis 4 - 1 - 4 1 - 3
Unilateral ureterocele 1 - - - 1 - - 1
Double collecting system 2 - - - 2 - - 2
Skeletal
Limb reduction 1 1 - - - - - 1
Polydactyly 3 1 - - 2 - - 3
Syndactyly + oligodactyly 1 - - - 1 - - 1
Club foot unilateral 2 - - - 2 - - 2
Club feet bilateral 6 - - - 6 - - 6
Rocker bottom feet 1 - - - 1 - - 1
Skeletal dysplasia 3 1 - - 2 1 - 2
Others
MCA** 5 2 2 1 2 3 - 2
TOTAL 115 19 12 13 83 31 4 80
* 1 case with dextrocarida, hypoplastic aorta, aplastic mitral valve.
1 case with transposition of the great arteries and double outlet right ventricle
1 case with unspecified multiple heart defects
** MCA: multiple congenital anomalies
1 case with omphalocele, split hand, dimorphic face, abnormal skull shape
1 case with omphalocele and missing foot
1 case with bilateral hydronephrosis, polydactyly and ventriculomegaly – postnatal: Charge syndrome
1 case with nasal tumor, cleft lip and palate, hypertelorism, flat nose, dilated heart, atrial septal defect
1 case with unspecified heart anomaly, increased NT, missing nasal bone (no karyotype done)
***2 cases of megacystis with spontaneous resolution and 2 cases of omphalocele with spontaneous resolution
24
Second Trimester Ultrasound markers in chromosomally normal fetuses
The following ultrasound markers were observed in 199 euploid fetuses, SUA (N=83),
pyelectasis (N=63), echogenic bowel (N=17), abnormal growth (N=10), echogenic focus of the
heart (N=9), ventriculomegaly (N=7), choroid plexus cyst (N=4), polyhydramnios (N=4) and
pericardial effusion (N=2). 2.5% (N=5) of all reported a structural abnormality diagnosed later in
pregnancy at follow-up appointments or at birth. The 5 diagnosed structural abnormalities were 1
case of anal atresia in a fetus with SUA, 1 case of achondroplasia in a fetus with short femur, 1
case on multiple anomalies in a fetus with polyhydramnios and 1 intestinal obstruction and 1
unilateral hydronephrosis diagnosed in 2 fetuses with pyelectasis. (figure 3)
Figure 3 - Prevalence of structural anomalies in euploid fetuses with ultrasound markers
Organs visualization
The likelihood of good visualization of different organs was significantly higher (p<0.001) for
women who underwent a CT compared to women who received a dating scan (table 6). This was
especially evident for the abdominal wall (OR 16.8), and the skull/brain (OR 13.6). Table 6 also
shows that women who received an abdominal examination had a 1.4 fold increase in successful
visualization of the skull/brain (p=0.02), 1.5 fold increase for both hands and feet (p=0.003 and
p=0.007 respectively) and 1.3 fold increase for the spine (p=0.03). Visualization of the heart was
0.9 times more likely with a vaginal examinations; however this result was not statistically
significant (p=0.095). When the quality of the ultrasound image was good and women had a BMI
<30, the rate of successful visualization of each of the organs was significantly higher than with
poor quality image and a BMI ≥30 (p<0.001) (OR in table 6). Similarly, increasing the gestational
age of one week significantly increased the likelihood of visualizing all fetal organs (p≤0.01).
Finally, in 4919 (73.4%) of the 6685 CT and in 1015 (24.1%) of the 4204 dating scans all organs
were successfully visualized. This difference is statistically significant (p<0.001).
83 63
17 10 9 7 4 4 2
199
1 2 0 1 0 0 0 1 0 5 0
50
100
150
200
250Structural anomalies in fetuses with ultrasound markers
Second trimester markers
Structural abnormalities
25
Table 6 -Visualization of body organs – logistic regression analysis
B S.E. Wald P-value OR 95% C.I for OR
Lower Upper
Ultrasound
type*
Skull / Brain 2.6 0.11 591.31 <0.001 13.6 11.0 16.8
Heart 1.83 0.05 1484.70 <0.001 6.2 5.7 6.8
Stomach 1.34 0.07 411.13 <0.001 3.8 3.4 4.3
Hands 2.07 0.09 483.02 <0.001 7.9 6.6 9.5
Feet 1,744 ,081 462,210 <0.001 5.7 4.9 6.7
Spine 1.22 0.05 569.84 <0.001 3.4 3.1 3.8
Abdominal wall 2.82 0.09 983.25 <0.001 16.8 14.1 20.1
Bladder / kidneys 1.27 0.05 625.53 <0.001 3.54 3.2 3.9
Route
exam**
Skull / Brain 0.35 0.15 5.70 0.02 1.4 1.1 1.9
Heart -0.16 0.10 2.79 0.095 0.9 0.7 1.0
Stomach 0.07 0.13 0.27 0.60 1.1 0.8 1.4
Hands 0.43 0.14 8.75 0.003 1.5 1.2 2.0
Feet 0.37 0.14 7.35 0.007 1.5 1.1 1.9
Spine 0.23 0.10 4.98 0.03 1.3 1.0 1.5
Abdominal wall 0.18 0.14 1.66 0.198 1.2 0.9 1.6
Bladder / kidneys 0.08 0.10 0.53 0.467 1.1 0.9 1.3
Ultrasound
image
quality
Skull / Brain 0.41 0.10 18.71 <0.001 1.5 1.3 1.8
Heart 0.90 0.06 252.04 <0.001 2.5 2.2 2.8
Stomach 0.43 0.08 31.34 <0.001 1.5 1.3 1.8
Hands 0.46 0.09 26.99 <0.001 1.6 1.4 1.9
Feet 0.53 0.09 38.32 <0.001 1.7 1.4 2.0
Spine 0.59 0.06 92.93 <0.001 1.8 1.6 2.0
Abdominal wall 0.31 0.08 13.38 <0.001 1.4 1.2 1.6
Bladder / kidneys 0.72 0.06 142.04 <0.001 2.0 1.8 2.3
Gestational
age (weeks)
Skull / Brain 0.31 0.06 27.87 <0.001 1.4 1.2 1.5
Heart 0.60 0.04 257.98 <0.001 1.8 1.7 2.0
Stomach 0.76 0.05 210.41 <0.001 2.1 1.9 2.4
Hands 0.21 0.06 12.01 0.001 1.2 1.1 1.4
Feet 0.19 0.06 5.95 0.01 1.2 1.0 1.3
Spine 0.34 0.04 68.17 <0.001 1.4 1.3 1.5
Abdominal wall 0.25 0.05 24.99 <0.001 1.29 1.2 1.4
Bladder / kidneys 0.72 0.06 142.04 <0.001 2.05 1.8 2.3
BMI ≥ 30
kg/m2
Skull / Brain 0.43 0.10 18.24 <0.001 1.5 1.3 1.9
Heart 0.60 0.07 69.92 <0.001 1.8 1.6 2.1
Stomach 0.56 0.08 43.49 <0.001 1.7 1.5 2.1
Hands 0.51 0.10 26.25 <0.001 1.7 1.4 2.0
Feet 0.52 0.09 30.44 <0.001 1.7 1.4 2.0
Spine 0.61 0.07 75.28 <0.001 1.8 1.6 2.1
Abdominal wall 0.37 0.09 17.16 <0.001 1.5 1.2 1.7
Bladder / kidneys 0.59 0.07 71.60 <0.001 1.8 1.6 2.1
*US type refers to women who received a CT versus women who received a dating scan
**Route of exam: abdominal versus vaginal
B: coefficient for the constant S.E.: standard error.
OR: odds ratio. 95% C.I: 95% confidence interval
26
Discussion
This study was primarily designed to determine the percentage of fetal congenital abnormalities
found at the 13 week gross-anatomy survey performed in concomitance of the dating scan or the
CT. Secondly, the study investigated how many and which defects were only observed at the 20
week anomaly scan (SEO) and therefore not identified by the ultrasound scan performed earlier
in gestation.
Detection of congenital abnormalities
The results show that out of all 10889 pregnancies, 196 (1.8%) reported an abnormality; 81
(0.7%) were chromosomal and 115 (1.1%) were structural anomalies, diagnosed at first or second
trimester scan. These numbers are lower than those reported by EUROCAT, where the
prevalence of all congenital abnormalities in The Netherlands between 2012 and 2015 was
reported to be 2.9% (26). A possible explanation for this difference lays in the fact that the
EUROCAT registry includes also subtle anomalies, such as ipo/epispadias, syndactyly etc.,
which are rarely identified before birth, while our study only presents prenatally diagnosed
anomalies. The prevalence of anomalies identified in our study was 1.8%: 0.7% was
chromosomal and 1.1% was structural anomalies. These numbers are exactly the same as those
reported by Syngelaki et al (19) in a larger recent study. Additionally, in their study, the
prevalence of anomalies identified in the first trimester was 0.47%, similar to the 0.3% reported
in our study.
Structural abnormalities
The First trimester detection rate achieved by our study was 27%. Two recent large studies by
Syngelaki et al (19) and Grande et al (18) reported higher detection rates: 43% and 49%,
respectively. A recent Dutch study by Kenkhuis et al (27) reported detection for structural
anomalies at the 12-13 weeks scan of 49%, again in line with the previous studies. There are two
likely explanations for these differences in first trimester detection rates. Firstly, the present study
includes data collected in a primary care center in a low-risk population. This could explain the
lower total prevalence of anomalies. Secondly, in the study by Kenkhuis the sonographers were
specifically instructed to check systematically the fetal anatomy, whereas in the present study this
was done less systematically, and especially in the “dating scan” group. A recently published
study by Karim et al. has shown significant difference in detection rates ranging from 32% in low
risk to over 60% in high risk groups (28). In this study no specific protocol was used for the
examination of the different fetal organs, and thus no clear guidelines were given to sonographers
with regards to time allocated and mode of visualization of the organs. This has probably affected
the number of anomalies detected during the first trimester. Indeed, from the literature it is known
that a systematic anatomical assessment significantly improves abnormalities detection rates (28,
29). Notably, in our study most severe and lethal anomalies were detected during the first
trimester of pregnancy; this is important because an early diagnosis gives parents more time to
decide on the course of pregnancy, whether the decision involves a termination of pregnancy or
preparation of post-partum care for their child. As shown by Syngelaki et al (19), some structural
abnormalities are potentially always detectable during the first trimester; these include
holoprosencephaly, anencephaly, large exomphalos, megacystis and severe limb defects. Another
abdominal wall defect, gastroschisis, is more challenging to identify in the first trimester and it
27
was identified in 67% (2/3) of cases, whereas all the above mentioned had a detection rate of
100%. The only reported case of fetus with missing limb was also detected in the first trimester
and thus detection rate was 100%. Potentially detectable anomalies (19) like skeletal dysplasia
and renal agenesis were detected in 33% and 25% of cases, while others such as spina bifida, and
hernia diaphragmatica were overseen during the first trimester. These findings suggest that first
trimester scan in a low-risk primary care setting mostly identifies very severe anomalies, while
the majority of less severe anomalies is observed during the second trimester. Detection of
cardiac anomalies at 13 weeks was 22% (4/18), which is lower than the 56% reported by Grande
et al (18), but similar to the 21% reported by Syngelaki et al (19) but is higher than the detection
rates described by other previous research (30, 31). Indeed, detection of cardiac defects in the
first trimester ranges between 2.3% (30) and 82.1% (45). More precisely, in out study detection
of tetralogy of Fallot was 50%, which is higher than the 17.6% reported in literature (47). While
one complex cardiac anomaly, a case of double outlet right ventricle with transposition of the
great arteries, was diagnosed during the first trimester, other severe anomalies, such as
hypoplastic left heart (HLHS), with reported detection rate in the first trimester of 51.2%, was
only detected in the second trimester in our study (47). These findings suggest that there is a great
variablity in early detection of cardiac abnormalities and adoption of a systematic examination of
the heart might be a helpful tool in improving detection rates (29). Furthermore, increased nuchal
translucency (NT≥95th
) was reported in 5.4% of all CTs and in 10.4% of pregnancies with
structural anomalies. It has been shown that an increased NT is not only associated with
chromosomal, but also with structural anomalies (7) and especially cardiac defects (8, 41, 43) In
our study, 15.8% of foetuses with cardiac anomalies also had an increased NT.
Even though no significant difference between first trimester detection rates was found between
CT and dating scan groups, the structural abnormalities identified during dating scans (acrania,
omphalocele and megacystis) are more apparent, compared to the more subtle ones detected at
CT like cardiac anomalies, renal agenesis and polydactyly. The percentage of fetuses in which all
organs were successfully visualized was 73.6% for CT and 24.1% for dating scans. This
difference was statistically significant (p<0.001) and suggests that the use of a simplified
anatomical survey protocol and training of sonographers contribute to higher rates of
visualization of all organs. Indeed, regression analysis has shown that the likelihood of being able
to visualize all different organs was significantly higher (p<0.001) for women who received a CT
compared to women who received a dating scan. More precisely, sonographers who performed
the CT were 16.8 times more likely to visualize the abdominal wall compared to sonographers
who were performing a dating scan. The OR was very high for all other organs as well, especially
for skull/brain (OR 13.6). As mentioned in the method section, is important to once again point
out that sonographers who performed combined tests were FMF-trained, while sonographers who
performed dating scans did not have such certification. These results, in line with those of a
previous study (32) therefore suggest that advanced ultrasound training and education play a
primary role in the ability of sonographers to successfully complete an ultrasound examination by
examining all the different organs. This would not only result in higher first trimester detection
rates but also in a decrease in costs due to the referral of patients to secondary and tertiary care
centers in order to complete the examination. A study from Harper L.M. et al (33) has indeed
shown that the number of referral in low-risk groups after a first trimester scan is still high.
Minimizing this number by successfully completing all organ visualization is therefore of
primary importance.
28
Our findings have revealed that other factors had an impact on rates of organs visualization as
well: route of exam (abdominal versus vaginal), quality of image, maternal BMI and gestational
age at ultrasound examination. In our study a BMI ≥ 30 kg/m2 was associated with a significant
decrease in all-organs visualization (p<0.001): these results seem to be consistent with those of
previous studies (34- 37). Moreover, our findings show the importance of gestational age for the
likelihood of organs visualization. This is in line with previous studies (37-38). This study shows
that trans-abdominal examination had a 1.4 fold increase in successful visualization of the
skull/brain (p=0.02), 1.5 fold increase for both hands and feet (p=0.003 and p=0.007 respectively)
and 1.3 fold increase for the spine (p=0.03), compared to trans-vaginal ultrasound. These
numbers are contrary to previous research which has suggested that trans-vaginal ultrasound is
more accurate than trans-abdominal scan for fetal organ visualization (39, 40). Two likely
explanations for this are that, in our study, sonographers were especially experienced with trans-
abdominal examination and that the trans-vaginal route was especially chosen in cases with high
BMI or poor trans-abdominal visualization.
Ultrasound markers
One interesting finding of this study displayed (table 3) is that only 5 of the 199 (2.5%) euploid
fetuses with ultrasound markers identified during a second trimester scan were born with a
structural abnormality. These numbers suggest that, in fetuses with a normal karyotype, the
identification of isolated markers has a low PPV for structural anomalies and that therefore
parents are often alarmed (in 97.5% of the cases) without no reasons. Minimizing the number of
referrals to third line centers for advanced ultrasound investigations not only increase parents’
anxiety but also has economic implications. In our study, none of the fetuses with echogenic
bowel presented an abnormality at birth. This finding is in agreement with previous studies which
have concluded that isolated echogenic is a benign condition and, only when accompanied by
other markers or anomalies or by intrauterine growth restriction, is predictive of a poor pregnancy
outcome (48-49). Similarly to echogenic bowel, all fetuses with echogenic focus of the heart,
ventriculomegaly, choroid plexus cyst and pericardial effusion showed an uneventful outcome
and no abnormalities at birth, while 2 fetus of the 63 with pyelectasis, 1 with intrauterine growth
restriction, 1 with polyhydramnios and 1 with SUA presented an anomaly at birth. A number of
studies have reported that, these markers increase their predictive value for congenital
abnormalities only when combined with other markers or growth-restriction, whereas when
isolated they lose their value. (50- 57). Some studies have suggested that isolated
ventriculomegaly is associated with childhood mental impairments, however because of lack of
long-term FU we cannot say whether this happened in our patients (58). All these findings are
very important when counselling parents and can contribute to reassuring them and providing
them with better information regarding the expected outcome of pregnancy.
Chromosomal abnormalities
In our study population the incidence of chromosomal anomalies was 0.7% (N=81). This number
is comparable to the value reported by other studies in the literature (58) and increases with
maternal age. Table 3 showed that almost 80% of the chromosomal anomalies were already
detected during the first trimester and that 75% of all resulted in a termination of pregnancy.
Early termination of pregnancy has been proven to be medically safer, come with less
complications for the mother and carry a lower psychological burden for parents compared to a
29
later one (16). For this reason it is extremely important to identify chromosomal anomalies as
early as possible, so that parents have time to make a decision on how to further proceed. In our
study, 16% (N=13) of all chromosomal abnormalities were identified during the second trimester,
and only 6% (N=5) after birth. These were mostly microscopic aberrations detected by
microarrays (N=5) and trisomy 21 (N=8). Of the 8 cases of trisomy 21, 5 had only dating scans
and no risk assessment and in 3 there was a high risk at the CT, but parents did not decide to have
karyotyping and the diagnosis was only made later in pregnancy, after that structural anomalies
were identified at the 20 week scan. Of the 5 fetuses with microscopic aberrations, 3 had received
a dating scan in the first trimester, 1 had a high risk at the CT but no karyotyping and 1 had a low
risk at the CT. Finally, the cases diagnosed post-partum were 2 cases of trisomy 21, 2 of mosaic
Turner syndrome and 1 of microscopic aberrations: 3 of these had received a dating scan, 1 had a
low and 1 had a high risk at CT. In other words, excluding the patients who only had a dating
scan, the CT showed a ‘false’ low-risk in only 2 of the fetuses who were diagnosed with a
chromosomal abnormality in the second trimester or later. These findings suggest that, even when
no structural abnormalities are identified at first trimester scans; chromosomal anomalies are
successfully identified by risk calculation at the CT. No single case of trisomy 18 and 13 was
missed by the CT. The only chromosomal anomalies which were missed by CT were 1 case of
Down syndrome (detected after birth) and 2 cases of (non-severe) microscopic aberrations.
Spontaneous fetal deaths
The number of spontaneous fetal deaths witnessed at first trimester scan in the study population
was 154 (1.1%). Since spontaneous abortions mostly happen in fetuses with severe chromosomal
anomalies, one might think that the majority of these foetuses could have been affected by some
genetic disorders. In our study the majority of spontaneous fetal deaths were recorded when an
ultrasound was performed at 11 weeks (N=81, 52%). Thereafter the number decreased
exponentially with advancing gestation (N=60, 39% at 12 weeks and N=13, 8% at 13 weeks),
suggesting that there is a rational for postponing a screening to 13 weeks’ gestation after most of
the early pregnancy losses have occurred. It may be argued that more losses could still happen
also after 13 weeks, but, based on the trend, we assume the rate to be very low. It is known that
after 12-13 weeks pregnancy losses until term still occur in about 3% of the pregnancies (59).
An important implication of these findings is that in view of the relatively high rate of
spontaneous losses it is not advisable to perform any form of screening in pregnancy before 12-
13 weeks.
Limitations
One important limitation of this study is that postnatal follow-up in fetuses with no prenatally
diagnosed abnormalities or markers could not be retrieved in a large number of cases. This
implies that we were unable to report on possible anomalies diagnosed after birth and on the
number of false negatives. The main reason for the missing follow-up is that this was not reported
in the electronic software where ultrasound images were stored or in the national birth registry.
One might assume that the vast majority of those cases reported no abnormalities at birth and
ended in uneventful deliveries and were hence not updated by midwives. However, this
hypothesis cannot be confirmed and for the quality of future research it is fundamental to increase
and improve follow-up registration.
30
Another limitation of this study is that it does not entirely reflect the current practice of dating
scans in the Netherlands. At variance with Bovenmaas, in the majority of midwives practices and
US clinics dating scans are performed at around 10 weeks or even earlier. The reason why in
Bovenmaas a different approach is used is that in this clinic the advantage of a later scan, even if
it is only for dating, are known and determine the choices of the practise in term of the ideal
moment for dating the pregnancy.
Conclusion
In a low-risk primary care setting, a gross anatomical survey performed in concomitance of a
dating scan or of the CT, can already detect about 1/3 of all major structural anomalies during
the first trimester of pregnancy; especially lethal and very severe defects are identified.
Although gross and severe anomalies are already detected by a global survey, as performed
during a dating scan, adoption of a systematic protocol and additional training of the
sonographers can maximize diagnostic performance to include also less obvious, though severe
anomalies. The implementation of an ultrasound scan at 12-13 weeks of gestation, including a
protocol for systematic organs visualization, would have important implications for the further
refinement and cost-effectiveness of the prenatal screening program in The Netherlands.
31
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34
Appendix
Table 1 – Congenital abnormalities in the study population and moment of detection (19, 24, 25)
Major fetal
abnormality
Detection
moment
Description
Nervous system
Acrania / anencephaly E Absence of the fetal cranium / brain
Encephalocele E Midline cranial defects through which the brain and/or meninges have
herniated outside of the skull (uptodate)
Spina Bifida SE Failure of the neural tube to close properly during embryonic development
resulting in an opening of the vertebral column.
Hydrocephaly L Abnormal accumulation of fluid in the cerebral ventricles causes
enlargement of the skull and compression of the brain
Schizencephaly L Abnormality of neuronal migration in which one or more fluid-filled clefts
in the cerebral hemisphere communicate with the lateral ventricle
Craniosynostosis L Premature ossification of one or more of the skull’s fibrous sutures
Holoprosencephaly
(semilobar or lobar)
L The prosencephalon (the forebrain of the embryo) fails to completely
develop into two separate hemispheres
Ventriculomegaly L, SE Dilated lateral ventricles in the fetal brain
Corpus callosum
agenesis
L Complete or partial absence of the corpus callosum
Face
Cleft lip L, SE Defect of the upper lip in which a longitudinal fissure extends into one or
both nostrils.
Cleft palate L, SE Fissure in the roof of the mouth, resulting from incomplete fusion of the
palate during embryonic development (may involve the uvula or whole
palate).
Cleft lip + cleft palate L, SE Combination of the previous 2 anomalies
Respiratory
Cystic adenomatous
malformation of lung
L Pulmonary airway malformations (CPAMs) are hamartomatous lesions that
are comprised of cystic and adenomatous elements arising from tracheal,
bronchial, bronchiolar, or alveolar tissue. (uptodate)
Cardiac
Double outlet right
ventricle (DORV)
L Both the aorta and the pulmonary artery have their attachments in the right
ventricle
Transposition of great
arteries
L The pulmonary artery arises from the left ventricle while the aorta arises
from the right ventricle
Coarctation of the
aorta
L Narrowing of the aorta
Extended aortic arch L
Tetrallogy of Fallot L Ventricular septum defect + pulmonary stenosis + hypertrophy of right
ventricle + overriding aorta
Hypoplastic left heart L, SE Significant underdevelopment of the left side of the heart
Atrial septal defect Opening between the two atria
Ventricular septal
defect
L Opening between the two ventricles
35
Aortic valve stenosis L Narrowing of the aortic valve
Tricuspid valve
insufficiency
L Failure of the tricuspid valve to properly close during the systolic phase
Right aortic arch L A right aortic arch crosses the right bronchus and runs down along the right
side of the spine.
Gastro-intestinal
Oesophageal atresia L Failure of the esophagus to normally develop, with blind-ended pouch end
rather than normal connection to the stomach
Duodenal atresia L Absence or complete closure of a portion of the lumen of the duodenum
Ano-rectal atresia L Failure of the anus/rectum to normally develop
Hernia
diaphragmatica
L, SE Failure of the diaphragm to normally close, causing the abdominal contents
to move into the chest cavity through an opening.
Abdominal wall
Gastroschisis E Defect in the anterior abdominal wall through which the abdominal contents
(without surrounding membrane) freely protrude
Omphalocele E Defect in the anterior abdominal wall through which the abdominal contents
(in a sac because of a defect in the development of the muscles of the
abdominal wall) freely protrude
Genitourinary
Unilateral renal
agenesis
L Failure to develop of one of the kidneys
Bilateral renal
agenesis
L Failure to develop of both kidneys
Megacystis E Abnormally enlarged bladder
Multi cystic renal
dysplasia
L Numerous non-communicating cysts separated by dysplastic tissue with no
or little functional renal tissue left
Congenital
hydronephrosis
L Abnormal distension and dilation of the renal pelvis and calyces
Ureterocele L Cystic dilatation of the terminal ureter within the bladder and/or the urethra
Double collecting
system
L Complete or partial duplication of the renal collecting system
Skeletal
Limb reduction SE One or more missing limb(s)
Polydactyly L, SE Extra digit
Syndactyly L Two or more fused digits
Club foot - talipes
equinovarus
L, SE Congenital deformity of the foot (twisted)
Rocker bottom foot L, SE Flat and rigid foot with convex underside
Skeletal dysplasia** SE Group of disorders characterized by abnormal development of the skeletal
system
*E: early (1st trimester) detectable
SE: sometimes early (1st trimester) detectable
L: late (2nd
and 3rd
trimester ) detectable (most anomalies given as late have been reported to be diagnosed early but
this only applies to a minority of cases and mostly in highly specialized center with highly trained personnel and are
thus not applicable to our study population)
**sometimes early depending on severity
36
Appendix 1