MASARYK UNIVERSITY
Faculty of Medicine
Department of Paediatrics
First Trimester Screening of Congenital Heart Defects
in Pregnancy: More Risk than Benefit?
Habilitation Thesis
Commented Collection of Publications
MUDr. Hana Jičínská, Ph.D.
Brno 2020
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Acknowledgements
I would like to thank prim. MUDr. Jan Škovránek CSc.; MUDr. Viktor Tomek Ph.D.
(Children’s Cardiac Centre, Prague); Professor Jan Marek M.D., Ph.D., FESC. (Great Ormond
Street Hospital, London); prim. MUDr. Pavel Vlašín (Centre for Fetal Care, Brno); MUDr. Jiří
Navrátil (University Hospital Brno) and MUDr. Zdeněk Jelínek (Paediatric Cardiology Clinic,
Brno) who examined pregnant women and contributed clinical cases to the study.
I would also like to thank MUDr. Ilga Grochová who covered the genetic parts of the study.
In addition, I would like to thank Professor Jan Marek and MUDr. Pavel Vlašín for their support
and help with the study.
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Content
COMMENTARY……………………………………………...………………..………………..6
1. INTRODUCTION TO PAEDIATRIC AND PRENATAL CARDIOLOGY IN THE CZECH
REPUBLIC……………………………………………………………………………..…...8
1.0.1 ANNEX 1. Jicinska H. Prenatal cardiology in the Czech Republic. CeskoSlovenska
Pediatrie. 2010;65(11):623-625..........................................................11
2. PRENATAL SCREENING AND PRENATAL DETECTION OF CONGENITAL HEART
DEFECTS, ARRHYTHMIAS AND OTHER HEART DISEASE…………...………….…….15
2.0.1. ANNEX 2. Tomek V, Marek J, Jicinska H, Skovranek J. Fetal Cardiology in the
Czech Republic: Current Management of Prenatally Diagnosed Congenital Heart
Diseases and Arrhythmias. Physiological Research 2009;58(2):159-166………..16
2.0.2 ANNEX 3. Tomek V, Jicinska H, Gilik J, Skovranek J, Navratil J, Janousek J.
Prenatal diagnosis of congenital heart defects in the Czech Republic during the
years 1986-2012. Actual Gyn 2014; 6:67-72……………………………………..25
2.0.3 ANNEX 4. Tomek V, Gilik J, Jicinska H, Pavlicek J, Navratil J, Cutka D,
Vlasin P, Lacinova M, Marek J, Skovranek J. Prenatal detection of congenital
heart defects and its consequences. Cesko-Slovenska Pediatrie 2018;73(5):284-
290……………………………………………………………………………...…32
2.1 FIRST-TRIMESTER SCREENING...................................................................................40
2.1.1 ANNEX 5. Jicinska H, Vlasin P, Jicinsky M, Grochova I, Tomek V, Volaufova
J, Skovranek J, Marek J. Does First-Trimester Screening Modify the Natural
History of Congenital Heart Disease? Analysis of Outcome of Regional Cardiac
Screening at 2 Different Time Periods. Circulation 2017;135:1045-1055……….40
3. LEFT HEART LESIONS…………………………………………………………..……….52
3.0.1 ANNEX 6. Gardiner H.M., Kovacevic A., Tulzer G., Sarkola T., Herberg U.,
Dangel J., Öhman A., Bartrons J., Carvalho J.S., Jicinska H., Fesslova V. Averiss
I., Mellander M., Fetal Working Group of the AEPC. Natural history of 107 cases
of fetal aortic stenosis from a European multicenter retrospective study.
Ultrasound in Obstetrics and Gynecology 2016; 48:373-381…………………….53
3.0.2 ANNEX 7. Kovacevic A, Öhman A, Tulzer G, Herberg U, Dangel J, Carvalho J
S, Fesslova V, Jicinska H, Sarkola T, Pedroza C, Averiss I E, Mellander M,
Gardiner H, the Fetal Working Group of the AEPC. Fetal hemodynamic response
to aortic valvuloplasty and postnatal outcome: a European multicenter study.
Ultrasound in Obstetrics and Gynecology; 2018, 52:221-229................................63
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3.0.3 ANNEX 8. Navratil J, Jicinska H, Jelinek Z. The incidence and the outcome of
fetuses with hypoplastic left heart syndrome in the region of Morava and Silesia
from 2002 to 2003. Cesko-Slovenska Pediatrie. 2005; 60(7):393-396……….…..73
3.0.4 ANNEX 9. Matsui H, Mellander M, Roughton M, Jicinska H, Gardiner H.
Morphological and Physiological Predictors of Fetal Aortic Coarctation.
Circulation 2008;118: 1793-1801………………………………………………...78
3.0.5 ANNEX 10. Jowett V, Aparicio P, Santhakumaran S, Seale A, Jicinska H,
Gardiner HM. Sonographic predictors of surgery in fetal coarctation of aorta.
Ultrasound in Obstetrics nad Gynecology; 2012; 40:47-54…………………...….88
4. RARE MORPHOLOGICAL ABNORMALITIES……………………………………………..97
4.0.1 ANNEX 11. Jičínská H, Tax P, Pádr R, Jičínský M, Marek J. Rare congenital
umbilical arteriovenous malformation. European Heart Journal Cardiovascular
Imaging [online]. 2020; 21(10):1172. doi:10.1093/ehjci/jeaa102..........................97
4.0.2 ANNEX 12. Fotaki A, Novaes J, Jicinska H, Carvalho J S. Fetal
aortopulmonary window: case series and review of the literature. Ultrasound in
Obstetrics & Gynecology[online].2017; 49(4):533-539. ISSN 0960-7692.
doi:10.1002/uog.15936…………………………………………………………...99
4.0.3 ANNEX 13. Krupickova S, Rigby M L, Jicinska H, Marais G, Rubens M,
Carvalho J S. Total anomalous pulmonary venous connection to unroofed
coronary sinus diagnosed in a fetus with spinal muscular atrophy Type I.
Ultrasound in Obstetrics& Gynecology. [online]. 217;50(5):657+. ISSN 0960-
7692. doi:10.1002/uog.17432...............................................................................107
5. FETAL ARRHYTHMIAS………………………………………...……………..…………110
5.0.1 ANNEX 14. Eliasson H, Sonesson S E, Sharland G, Granath F, Simpson M S,
Carvalho J S, Jicinska H, Tomek V, Dangel J, Zelinsky P, Respondek-Liberska M,
Freund M W, Mellander M, Bartroons J, Gardiner H M. Isolated Atrioventricular
Block in the Fetus. A retrospective multinational, multicenter study of 175
patients. Circulation [online]. 2011;124(18):1919-1926. ISSN 0009-7322.
doi:10.1161/CIRCULATIONAhA.111.041970…………………………………110
6. ASSOCIATED GENETIC ABNORMALITIES……………………………….……………..120
6.0.1 ANNEX 15. Jicinska H, Marek J, Brysova V, Gaillyova R, Kuglik P, Tlaskal T,
Litzman J, Tax P, Navratil J. Deletion of Chromosome 22q11 in Congenital Heart
Disease. Cesko-Slovenska Pediatrie. 1998;53(11):650-664………………….…120
7. CONSENSUS STATEMENT AND RECCOMENDATION……… ……………..….127
7.0.1 ANNEX 16. Tomek V, Jicinska H, Klaskova E, Jehlicka P, Balatka P, Vit P,
Hecht P, Reich O, Janousek J. Expert consensus statement on prenatal cardiology
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organization in the Czech Republic. Prepared by the Working Group on Pediatric
Cardiology of the Czech Society of Cardiology.
Cor et Vasa 2020; 62(1): 60-63……………………………………………….…127
7.0.2 ANNEX 17. Zatocil T, Antonova P, Rubackova, Popelova J, Zakova D,
Pokorna O, Chaloupecky V, Rohn V, Skalsky I, Jicinska H, Taborsky M, Kautzner
J, Janousek J. Recommendations to organize care for adults with congenital heart
disease in the Czech Republic. Cor et Vasa 2018;60(3): e331-e334……..……..131
8. CONCLUSIONS..................................................................................................................135
Cited literature is a part of the attached publications.
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Commentary
Congenital heart defects (CHDs) are very common defects in fetuses and in children. The
prevalence of CHDs varies from 6 to 10 per 1000 live births. 35% of CHDs are critical CHDs.
Neonates born with critical CHDs often need to be treated immediately after birth: some of
them need some medication, the others need to be treated by cardiac catheterization or by
surgery. To be prepared to take care of such patients soon after birth, we need to diagnose
critical CHDs prenatally.
In the Czech Republic, the nationwide prenatal cardiac screening program during the second
trimester was introduced in 1986. This Habilitation Thesis is divided into 7 parts. After the
introduction, the second part is focused on the organization and the results of the second
trimester screening program in Czechoslovakia (later in the Czech Republic) from 1986. This
part of the Habilitation Thesis also deals with first-trimester screening, and with the difficulties
and limitations of screening during the first trimester.
The third part of the Thesis focuses on left heart lesions, severe CHDs, which can be detected
by screening – aortic stenosis (AS), hypoplastic left heart syndrome (HLHS), and coarctation
of the aorta (COA). Possible fetal interventions in this group of fetal patients are presented as
well. Very rare congenital heart abnormalities are discussed in the fourth part of the Thesis,
congenital complete heart block in the fifth part, and associated genetic abnormalities in the
sixth part.
The main aim of the study was to assess the impact of first trimester screening on the spectrum
of CHDs and the outcomes of fetuses with CHD later in pregnancy. The first trimester
ultrasound screening program was implemented in the Southern Moravia region in most fetal
medical centres by 2003. The spectrum of CHDs, associated comorbidities and outcome of
fetuses, either diagnosed with CHD in the first or only in the second trimester in the South
Moravian region of the Czech Republic, were compared retrospectively from 2007 to 2013.
Fetuses diagnosed with CHD between 2007 and 2013 in the second trimester were also
compared with fetuses diagnosed with CHD in the second trimester between 1996 to 2001, the
period before first-trimester screening was introduced.
Our results confirmed the significant impact of first-trimester screening on the spectrum of
CHDs later in pregnancy and on the outcomes of pregnancies with a CHD, in that more severe
forms of cardiac abnormalities and higher comorbidities resulted in an increase in early
termination of first-trimester pregnancies. In the second trimester, less severe forms of cardiac
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abnormalities were diagnosed. These fetuses had better postnatal outcomes because of more
frequent biventricular circulation and fewer associated comorbidities.
This Habilitation Thesis is designed as a commented collection of publications with the
candidate being either the main author of five manuscripts, (in one case, the publication has
two main authors who contributed equally), or the co-author significantly contributing to ten
manuscripts. All manuscripts were published in their final version in the relevant medical
journals or books. International medical journals where the manuscripts were published had an
impact factor>18 in one case, IF>14 in two cases, IF>5 in three cases, and IF from 1.43 to 4.7
in four cases.
Keywords: prenatal cardiology, fetus, first-trimester screening, congenital heart defect, fetal
arrhythmia
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1. Introduction to paediatric and prenatal cardiology in the Czech Republic
Prenatal cardiology is a part of paediatric cardiology. Paediatric cardiology started to develop
after World War II as the result of a high incidence of rheumatic carditis in rheumatic fever in
children. Thanks to continuing treatment, the incidence of rheumatic fever decreased and
congenital heart defects became the main area of interest for paediatric cardiologists. In the
past, making a correct diagnosis of CHD was very difficult. The diagnosis was possible to be
made only by clinical evaluation, chest X-ray and electrocardiogram. After implementation of
cardiac catheterization to the diagnostic process in 1947, cardiac diagnosis became much easier.
Since 1947, some treatment options in some CHDs improved — it was possible to surgically
close a patent arterial duct from 1947, to perform a subclaviopulmonary anastomosis in
Tetralogy of Fallot from 1949, and to repair coarctation of the aorta.
A fundamental change in paediatric cardiology in the Czech Republic occurred in 1977 when,
thanks to professor Šamánek, the Children’s Cardiac Centre in Prague was established. After
some time, the Prague Children’s Cardiac Centre experienced a unique accomplishment, in
comparison to other units in Europe and in the world, involving the system of care for such
serious paediatric morbidities. It was due to mutual cooperation between paediatric
cardiologists and surgeons, and due to further specialization of paediatric cardiologists in
different fields of paediatric cardiology — echocardiography, arrhythmology, cardiac
catheterization, surgery, intensive postoperative care. It was also due to increased follow-up
exams of cardiac outpatients in the Children’s Cardiac Centre and subsequently in a network
of paediatric cardiac outpatient clinics in the entire country. This organization of the system of
care was unique in the world and this system guaranteed early diagnosis of CHD after birth,
early transport to the Cardiac Centre, and early and necessary cardiac care after birth.
The development of echocardiography and the possibility of medical treatment keeping open a
patent arterial duct in CHDs with duct-dependent circulation lead to further developments in
paediatric cardiology. Echocardiography became “the gold standard” of the diagnostic process
of CHDs. Cardiac catheterization became a more therapeutic method over time.
Thanks to the important development of ultrasound diagnostic methods and the effort to
diagnose CHDs as soon as possible, prenatal cardiology as a new branch of paediatric
cardiology was established. The first correlation of parallel imaging of a fetal heart was done
by a pathologist (light photograph) and by cardiologist Lindsey Allan (ultrasound scan), who
published the correlation in 1980. New possibilities of the evaluation of a fetal heart and making
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the cardiac diagnosis in the early stages of pregnancy were opened up. Today, prenatal
cardiology plays an important role in the diagnostic process of CHDs and other cardiac diseases.
The Czech Republic was one of the first countries to start a prenatal cardiac screening program
— the first ultrasound examination of a fetal heart was performed by Dr. Škovránek in 1981; a
nationwide cardiac second-trimester screening programe was started in 1986.
What is possible to be prenatally diagnosed in the fetus today? The majority of prenatal cardiac
abnormalities are congenital heart defects, which are one of the most common structural
abnormalities in the fetus. The prevalence of CHDs is 6.16/1000 live births in the Czech
Republic (Šamánek). Fetal arrhythmias, cardiomyopathies, inflammatory heart disease,
tumours and other heart diseases can be detected as well. It is also possible to detect the signs
of heart failure or failure of the whole fetoplacental circulation as the result of other conditions
having an effect on circulation, such as twin-to-twin transfusion syndrome, anemia,
arteriovenous malformation and others.
What’s possible to be treated in the fetus during pregnancy? For example, in severe aortic or
severe pulmonary stenosis, it is possible to perform fetal balloon aortic or pulmonary
valvuloplasty in order to protect the left or right ventricle from remodeling and progressing to
hypoplastic left heart syndrome or to severe hypertrophy of the right ventricle, which, in the
event of these consequences, could further progress to univentricular circulation with a very
unfavourable prognosis. In some fetuses with hypoplastic left heart syndrome, the foramen
ovale spontaneously will become restricted or completely closed. This leads to the
development of pulmonary lymphangiectasia and increased pulmonary vascular resistance,
which results in higher mortality after birth. In order to protect against this unfavourable
outcome, it is possible to perform fetal balloon atrioseptostomy in the fetus and thereby improve
the outcome of the fetus.
In fetuses with severe fetal arrhythmias (supraventricular or ventricular arrhythmias) it is
possible to treat the fetus during pregnancy by giving an antiarrhythmic drug to the mother
(transplacental administration) or to the fetus (direct fetal therapy). Using this treatment we can
protect against or reduce the signs of heart failure and protect against the subsequent
development of hydrops and fetal death.
When is it possible to perform an ultrasound examination of the fetal heart? An ultrasound
examination of the fetal heart is a part of second-trimester screening from the 19th to the 22nd
week of gestation. This scan is crucial for the detection of structural abnormalities in the fetus.
At the end of the 20th century, in an effort to display, as soon as possible, morphologic
structures including basic heart structures of the fetus, first-trimester screening arose. First-
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trimester screening is performed between the 11th and the 13th (+ 6) weeks of gestation. In the
first trimester it is not always possible to see all details of the fetal heart. It is also not possible
to detect CHDs that will develop later in pregnancy. So it is necessary to know the limitations
of first-trimester screening and to respect them.
If there is a suspicion of cardiac abnormality detected at the screening examination, the heart
of the fetus is examined by a specialized fetal cardiologist and the final diagnosis is made. The
finding of CHD is also a reason for a detailed specialized anomaly scan in order to detect
additional extracardiac abnormalities. Genetic counselling and genetic evaluation is offered to
the parents as well. The aim of these evaluations is to obtain as much information as possible
in order to give parents complex information about the disease in the fetus, about possible
developments of the disease, about possible interventions after birth, and about the most likely
outcome after birth. Based on this information and on the character of the family, the parents
make decisions about the outcome of the pregnancy. In cases where the pregnancy is continued,
we follow up the fetus and monitor the development of CHD and the pregnancy. We arrange
the pregnant woman to give birth close in the Cardiac Centre in order to take care of the baby
immediately after birth, and in order to start with conservative treatment or to perform cardiac
catheterization or heart surgery as soon as it is indicated. As is mentioned earlier herein, in
some cases it is possible to treat fetuses before birth. In some cases with severe complex
abnormalities and associated extracardiac or genetic abnormalities, the parents make the
decision to terminate the pregnancy.
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Commented publications
1.0.1 ANNEX 1
Jicinska H
Fetal Cardiology in the Czech Republic
Cesko-slovenska Pediatrie. 2010;65(11):623-625
Main points of the publication:
The paper is focused on the history of prenatal cardiology in the Czech Republic and on the
main points of prenatal cardiology: screening of congenital heart defects, the detection rate of
CHDs, management of pregnancy with CHD in the fetus, possible treatment in pregnancy and
the first-trimester screening.
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2. Prenatal screening and prenatal detection of congenital heart defects,
arrhythmias and other heart disease
In Czechoslovakia (later in the Czech Republic), a prenatal cardiology program developed very
early. The nationwide prenatal second-trimester cardiac screening program was started in 1986.
Screenings were performed by gynecologists, paediatric cardiologists and rentgenologists in
the beginning. Thanks to the personal activities of some paediatric cardiologists (prof. Jan
Marek, Dr. Jan Škovránek in Prague, prof. Jaroslav Homola in Ústí nad Labem, Dr. Zdeněk
Jelínek and Dr. Jiří Navrátil in Brno), excellent results in the detection rate of CHDs and other
heart diseases were achieved. Professor Jan Marek has contributed to further development of
prenatal cardiology and education of prenatal cardiologists in Czechoslovakia and later in the
Czech Republic.
First-trimester cardiac screening in the Czech Republic was implemented in fetal care in 2003.
In the Czech Republic, two ultrasound screening scans are performed and financially supported
by the government: one in the first trimester (from 11 to 13+6 weeks of gestation) and one in
the second trimester (from 18 to 22 weeks of gestation) of pregnancy. To perform cardiac
screening, it was necessary to image a four-chamber view in the fetus from 1986. Evaluations
of both outflow tracts (from 1996), and 3-vessel views (from 2010) were implemented to the
ultrasound screening protocol in the fetus.
The following publications include information about cardiac screening from 1986 to 2015,
about the results of screening, about the improvement in detection rates in the Czech Republic,
and about the outcomes of fetuses with CHDs.
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2.0.1 ANNEX 2
Tomek V, Marek J, Jicinska H, Skovranek J
Fetal Cardiology in the Czech Republic: Current Management of Prenatally Diagnosed
Congenital Heart Diseases and Arrhythmias
Physiological Research 2009;58(2):159-166
Impact factor in 2009 = 1, 430
Main points of the publication:
The management of fetal cardiology and the results of this management in Czechoslovakia
(later in the Czech Republic) are presented in this paper. The results of the screening of CHDs
from 1986 to 2007, the detection rate of CHDs prenatally and postnatally, and the detection rate
of individual CHDs are presented.
From 1986 to 2007, the detection rate of critical CHDs increased from 2.3% to 38% in the
Czech Republic. There was a different detection rate of CHDs prenatally and postnatally, and
a different detection rate of specific CHDs. The highest detection rate was in cases of double
outlet right ventricle, hypoplastic left heart syndrome prenatally, and in ventricular septal defect
and aortic stenosis postnatally.
In addition, the paper deals with the most important arrhythmias in the fetus: supraventricular
tachycardia and complete atrioventricular block. The possibilities of prenatal treatment of these
arrhythmias and the effect of medical treatment were evaluated.
The candidate contributed significantly to the manuscript.
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2.0.2 ANNEX 3
Tomek V, Jicinska H, Gilik J, Skovranek J, Navratil J, Janousek J
Prenatal diagnosis of congenital heart defects in the Czech Republic during the years 1986 -
2012
Actual Gyn 2014;6:67-72
Main points of the publication:
The results of prenatal detection of congenital heart defects in fetuses in Czechoslovakia (later
in the Czech Republic) from 1986 to 2012 and the improvement in the detection rate were
published in this paper. The prenatal CHDs detection rate from 1986 to 2012 was compared to
the postnatal prevalence of CHDs in accordance with the Bohemia Survival Study (BOSS),
which is the study of postnatal prevalence of CHDs, published by professor Šamánek. The valid
indication criteria for the specialized echocardiographic evaluation in the fetus, the spectrum of
CHDs detected prenatally and the outcomes of fetuses with CHDs were presented as well.
From 1986 to 2012, in total 2996 fetuses with CHD in the Czech Republic were detected.
Pregnancies were terminated in 54% of the total (there was additional extracardiac abnormality
in 49% of terminated pregnancies). Intrauterine death occurred in 3% of the total; 43% of the
total were born. Due to detection of CHDs prenatally and termination of pregnancy in some of
them, there was a change in the spectrum of CHDs postnatally. The number of neonates born
with hypoplastic left heart syndrome, atrioventricular septal defect, pulmonary atresia,
persistent arterial trunk, single ventricle, and Ebstein anomaly decreased.
The candidate contributed to the manuscript and with cases to this study.
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2.0.3 ANNEX 4
Tomek V, Gilik J, Jicinska H, Pavlicek J, Navratil J, Cutka D, Vlasin P, Lacinova M, Marek
J, Skovránek J
Prenatal diagnosis of congenital heart defects and its consequences
Cesko-slovenska Pediatrie 2018;73(5): 284-290
Main points/highlights of the publication:
In the study the detection rate of CHDs in the Czech Republic from 2006 to 2015 was assessed.
In that period the detection rate of CHDs increased significantly and was very high in the CR:
from 2006 to 2015, the prenatal detection rate was 39-49% of all CHDs and 80-90% of critical
CHDs. The effectiveness of the prenatal detection rate of CHDs was assessed by the Bohemian
Survival Study (BOSS study) published by professor Šamánek. The detection rates of
individual CHDs and the very high detection rates of some CHDs (100% detection rate of single
ventricle, atrioventricular septal defect and hypoplastic left heart syndrome) were presented.
The very high termination rate of pregnancy in the Czech Republic (54%) and the impact of
this termination rate was presented. The high prenatal termination rate of some CHDs changed
the spectrum of CHDs postnatally.
The candidate contributed to the manuscript and with cases to this study.
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2.1 First-trimester screening
2.1.1 ANNEX 5
Jicinska H, Vlasin P, Jicinsky M, Grochova I, Tomek V, Volaufova J, Skovranek J, Marek J.
Does First-Trimester Screening Modify the Natural History of Congenital Heart Disease?
Analysis of Outcome of Regional Cardiac Screening at 2 Different Time Periods.
Circulation 2017;135:1045-1055
Impact factor in 2017 = 18.881
In this study we aimed to assess the impact of first-trimester screening on the spectrum of CHDs
later in pregnancy, and on the outcome of fetuses and children with CHD. First-trimester
screening was implemented to prenatal care by 2003 in the Czech Republic. The Spectrum of
CHD, associated comorbidities and outcome of fetuses were compared between:
Group I (fetuses diagnosed with CHD in the first trimester from 2007 to 2013 and
Group II (fetuses diagnosed with CHD in the second trimester from 2007 to 2013
Fetuses diagnosed with CHD only in the second trimester from 2007 to 2013 (Group IIb)
were compared with Group III (fetuses with CHD diagnosed in the second trimester from 1996
to 2001 before first-trimester screening started).
The spectrum of CHDs diagnosed in the first and second trimesters in the same time period
differed significantly, with a greater number of comorbidities, CHDs with univentricular
outcome, intrauterine death and terminations of pregnancy in Group I compared with Group II.
In Group III, significantly more cases with univentricular outcome, intrauterine demise, and
early termination were identified compared with fetuses diagnosed with CHDs in the second
trimester between 2007 and 2013.
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3. Left heart lesions
The aim of prenatal detection of CHDs is to detect severe CHDs, mainly critical CHDs, which
present with signs of heart failure or with cyanosis soon after birth. CHD cases need to be
treated by conservative treatment or by invasive procedures (cardiac catheterization or heart
surgery) soon after birth.
Most left heart lesions (severe aortic stenosis, aortic atresia, mitral stenosis, mitral atresia,
hypoplastic left heart syndrome) belong to the most severe CHDs. It is known that in some
cases severe aortic stenosis detected during prenatal life can develop into hypoplastic left heart
syndrome by the time of birth. In such cases it is impossible to use the left ventricle for
circulation after birth and such cases result in CHD with univentricular circulation and with an
uncertain prognosis. Prenatally in some cases, it is possible to perform fetal aortic balloon
valvuloplasty and to protect the left ventricle from remodeling and progression to hypoplastic
left heart syndrome. But it is very difficult to recognize which fetus, with aortic valve stenosis,
will develop hypoplastic left heart syndrome and which fetus will profit from this invasive
procedure. There are morphological and physiological parameters which should help to provide
answers to these questions. Subsequent studies tested these parameters retrospectively and they
looked into the natural history of fetuses with aortic valve stenosis and their outcomes, i.e., if
the development of the left ventricle lead to univentricular or biventricular circulation. In
addition, the studies looked into the outcomes of fetuses with and without fetal aortic balloon
valvuloplasty.
Coarctation of the aorta definitely develops after arterial duct closure after birth. Because of
this reason it is very difficult to predict the development of coarctation of the aorta before birth
when the arterial duct is still open. Later publications tested and presented some parameters
which can help to make the diagnosis of COA. If there is suspicion of COA or diagnosis of
COA prenatally, we do follow up in such fetuses postnatally and we indicate surgery at the right
time. There is mainly a very good prognosis for this CHD.
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3.0.1 ANNEX 6
Gardiner H M, Kovacevic A, Tulzer G, Sarkola T, Herberg U, Dangel J, Öhman A, Bartrons J,
Carvalho J S, Jicinska H, Fesslova V, Averiss I, Mellander M, Fetal Working Group of the
AEPC
The natural history of 107 cases of fetal aortic stenosis from a European multicenter
retrospective study
Ultrasound in Obstetrics and Gynecology 2016;48:373-381.
Impact factor in 2016 = 4.710
Main points of the publication:
In some fetuses fetal aortic valve stenosis progresses to hypoplastic left heart syndrome
(HLHS), which results in postnatal univentricular (UV) circulation. Fetal aortic valvuloplasty
aims to prevent the remodeling of the left ventricle and a univentricular circulation outcome.
The aim of the study was to describe the natural history of fetal aortic stenosis and to test
previously published criteria designed to identify emerging HLHS cases with the potential for
a biventricular (BV) outcome after fetal valvuloplasty (FV).
The main finding of this study: of 147 fetuses with Aortic Stenosis who did not undergo FV,
80 of them (54%) underwent a postnatal procedure, with 44 fetuses (55%) resulting in a BV
outcome.
Our data show that a substantial proportion of fetuses meeting the criteria for emerging HLHS,
with or without favorable selection criteria for FV, had a sustained BV circulation without fetal
intervention. This indicates that further work is needed to refine the selection criteria to offer
appropriate therapy to fetuses with aortic stenosis.
The candidate contributed to the manuscript and with cases to this international study.
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3.0.2 ANNEX 7
Kovacevic A, Ohman A, Tulzer G, Herberg U, Dangel J, Carvalho J S, Fesslova V, Jicinska
H, Sarkola T, Pedroza C, Averiss I E, Mellander M, Gardiner H, the Fetal Working Group of
the AEPC
Fetal hemodynamic response to aortic valvuloplasty and postnatal outcome: a European
multicenter study
Ultrasound in Obstetrics and Gynecology; 2018; 52:221-229
Impact factor in 2018 = 5.654
Main points of the publication:
Fetal aortic stenosis may progress to hypoplastic left heart syndrome. Fetal valvuloplasty (FV)
has been proposed to improve left heart hemodynamics and maintain biventricular (BV)
circulation. The aim of this study was to assess FV efficacy by comparing survival and postnatal
circulation between fetuses that underwent FV and those that did not.
Similar proportions of fetuses had BV circulation (36% for the FV cohort and 38% for the NH
cohort). Successful FV cases showed improved hemodynamic response and less deterioration
of left heart growth compared with natural history (NH) cases (P ≤ 0.01).
FV survivors showed improved survival. However, FV is associated with a 10% procedure‐
related loss and therefore the risk‐to‐benefit ratio remains uncertain.
The candidate contributed to the manuscript and with cases to this international study.
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3.0.3 ANNEX 8
Navratil J, Jicinska H, Jelinek Z
The incidence and the outcome of fetuses diagnosed with hypoplastic left heart syndrome in
the region of Moravia and Silesia in 2002 and 2003
Cesko-slovenska Pediatrie. 2005; 60(7): 393-396
Main points of the publication:
The authors monitored the occurrence and the outcome of fetuses diagnosed with severe
congenital heart defect (hypoplastic left heart syndrome) in the region of Moravia and Silesia
prenatally. They looked for the risk factors associated with the incidence and with the detection
of hypoplastic left heart syndrome prenatally. In conclusion, the ultrasonographic examination
of the fetal heart is the only reliable method to detect HLHS prenatally.
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3.0.4 ANNEX 9
Matsui H, Mellander M, Roughton M, Jicinska H, Gardiner H
Morphological and Physiological Predictors of Fetal Aortic Coarctation
Circulation 2008;118:1793-1801
Impact factor in 2008:14.816
Main points of the publication:
The study tested the applicability of previously published aortic arch and ductal Z scores and
their ratios. Secondly, the study tested the ability of serial Z scores to distinguish fetuses with
coarctation of aorta within a cohort of fetuses with right-to-left disproportion on a ventricular
and/or arterial level. Finally, the study evaluated the diagnostic significance of associated
cardiac lesions and coarctation shelf and isthmus flow disturbance.
In conclusion, isthmus Z scores and isthmus-to-duct ratios < 0.75 are sensitive indicators of
fetal coarctation. Serial measurements and abnormal isthmus flow patterns improve diagnostic
specificity and may reduce false positive cases.
The candidate contributed to the manuscript and with cases to this study.
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3.0.5 ANNEX 10
Jowett V, Aparicio P, Santhakumaran S, Seale A, Jicinska H, Gardiner H M
Sonographic predictors of surgery in fetal coarctation of the aorta
Ultrasound in Obstetrics and Gynecology 2012; 40:47-54
Impact factor is 2012 = 3.557
Main points of the publication:
The aim of the study was to determine whether within a group of cases prenatally diagnosed
with COA, four sonographic features — the isthmus diameter Z-scores, the ratio of isthmus to
duct diameters, the visualization of coarctation of the aortic shelf, and the isthmus flow
disturbance — could differentiate cases that would require neonatal surgery.
An isthmus diameter score < -2 was the most powerful predictor for surgery. An isthmus to
duct ratio < 0.74 on the last scan required surgery in all patients, the aortic shelf was identified
in 66% of cases, and isthmus flow disturbance was present in 50% of fetuses with COA. In this
study the combination of these four parameters allowed us to predict COA correctly in 81% of
cases at the first assessment and in 86% of cases using serial measurements. The incorporation
of these four parameters into the prenatal assessment of fetal COA in tertiary centres was
proposed by the authors.
The candidate contributed to the manuscript and with cases to this study.
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4. Rare morphological abnormalities
Thanks to the development of new ultrasound methods, we occasionally detect very rare and
unusual structural abnormalities in the fetus. In this part, some of them are presented.
4.0.1 ANNEX 11
Jicinska H, Tax P, Padr R, Jicinsky M, Marek J
Rare congenital umbilical arteriovenous malformation
European Heart Journal Cardiovascular Imaging [online]. 2020; 21(10):1172.
doi:10.1093/ehjci/jeaa102
Impact factor in 2020 = 5.26
Main points of the publication:
A very rare case with arteriovenous malformation involving the umbilical vein was presented.
This unique case of vascular abnormality was detected at a very early prenatal stage (at the 16th
week of gestation), confirmed postnatally, and successfully treated by coil embolization at the
age of three months.
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4.0.2 ANNEX 12
Fotaki A, Novaes J, Jicinska H, Carvalho J S.
Fetal aortopulmonary window: case series and review of the literature.
Ultrasound in Obstetrics & Gynecology[online].2017; 49(4):533-539. ISSN 0960-7692.
doi:10.1002/uog.15936
Impact factor in 2017 = 5.654
Main points of the publication:
Aortopulmonary window (APW) is a rare congenital cardiac anomaly characterized by
communication between the pulmonary artery and the aorta. Prenatal diagnosis of this lesion is
rare. Only isolated case reports have been reported so far.
In this paper four cases with aortopulmonary window were reported. The diagnosis of APW
was made prenatally in two of them: in the first case with atrioventricular (AV) and
ventriculoarterial (VA) concordance and no additional cardiac or extracardiac anomalies, and
in the second case with atrioventricular and ventriculoarterial concordance and interrupted
aortic arch.
The diagnosis of APW was made postnatally in the third case with transposition of the great
arteries. Similarly in the fourth case, diagnosis of APW was made with a criss-cross relationship
of the ventricles, and with a superoinferior relationship of the great vessels. There were no
additional extracardiac or chromosomal abnormalities in any of them.
In cases with APW and normal cardiac connections, the diagnosis can be made prenatally with
a standard three-vessel view. However, when there are associated abnormalities affecting the
spacial orientation of the great arteries, the diagnosis of APW can be challenging. In APW
cases, additional cardiac defects are common, while extracardiac and genetic abnormalities are
uncommon.
The candidate contributed to the manuscript and with a case to this study.
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4.0.3 ANNEX 13
Krupickova S, Rigby M L, Jicinska H, Marais G, Rubens M, Carvalho J S. Total anomalous
pulmonary venous connection to unroofed coronary sinus diagnosed in a fetus with spinal
muscular atrophy Type I. Ultrasound in Obstetrics& Gynecology. [online]. 217;50(5):657+.
ISSN 0960-7692. doi:10.1002/uog.17432
Impact factor in 2017 = 5.654
Main points of the publication:
A totally anomalous pulmonary venous connection (TAPVC) to an unroofed coronary sinus is
a very rare condition. In this paper the first case of prenatal diagnosis of TAPVC to an unroofed
coronary sinus was reported. In addition, due to generalized hypotonia and pathological reflexes
in the patient postnatally, genetic testing was carried out which revealed a homozygous
mutation in the SMN1 gene confirming the diagnosis of spinal muscular atrophy in the patient.
The candidate contributed to the manuscript and with a case to this study.
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5. Fetal arrhythmias
Fetal arrhythmias can be detected during a prenatal ultrasound examination. The most severe
fetal arrhythmias are supraventricular and ventricular tachycardias and congenital complete
atrioventricular block in the fetus. It is necessary to detect and to assess signs of heart failure in
the fetus and in the whole fetoplacental circulation during fetal examination.
5.0.1 ANNEX 14
Eliasson H, Sonesson S E, Sharland G, Granath F, Simpson M S, Carvalho J S, Jicinska H,
Tomek V, Dangel J, Zelinsky P, Respondek-Liberska M, Freund M W, Mellander M,
Bartroons J, Gardiner H M
Isolated Atrioventricular Block in the Fetus. A retrospective multinational, multicenter study
of 175 patients.
Circulation [online]. 2011;124(18):1919-1926. ISSN 0009-7322
doi:10.1161/CIRCULATIONAhA.111.041970
Impact factor in 2011 = 14.739
Main points of the publication:
Isolated congenital complete heart block in the fetus is one of the most severe fetal arrhythmias
and can cause heart failure and fetal death. The aim of this multicenter study was to find risk
factors associated with fetal death and the influence of steroid therapy. 175 fetuses diagnosed
with second or third degree atrioventricular block from 2000 to 2007 were studied. Of 175
fetuses, 80% were anti-Ro and 59% anti-La positive. 67 fetuses (38%) were treated with
transplacental steroids and 41 fetuses (23%) were treated with betamimetics. Of 175 fetuses,
26 died before birth or in the neonatal period, 11 were lost to follow-up. In steroid treated
groups and non-steroid treated groups of fetuses, there was the same survival rate of 91%.
Neonatal survival was 95% in the steroid treated group and 82% in the non-treated group.
10 fetuses with AV block second degree were exposed to maternal anti-Ro antibodies. Seven
of them were treated with steroids. In 3 of the 7 treated fetuses, AV block converted to sinus
rhythm, but only one of these three fetuses was known to stably remain in sinus rhythm by the
age of 12 months. Eight fetuses developed cardiomyopathy and pacemakers were implanted in
69% of the fetuses within one year.
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A gestational age < 20 weeks of gestation, a ventricular rate < 50 bpm, a presence of hydrops,
and impaired left ventricle function are risk factors for intrauterine death.
The candidate contributed to the manuscript and with cases to this international study.
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6. Associated genetic abnormalities
In cases with cardiac abnormalities, it is also necessary to find possible additional structural
extracardiac or genetic abnormalities, because these additional findings can change the
prognosis and the outcome of the fetus.
Recently, new genetic methods have been developed and new associations between cardiac
abnormalities and genetic disease have been found.
6.0.1 ANNEX 15
Jicinska H, Marek J, Brysova V, Gaillyova R, Kuglik P, Tlaskal T, Litzman J, Tax P, Navratil
Deletion of Chromosome 22q11 in Congenital Heart Disease.
Cesko-Slovenska Pediatrie. 1998;53(11):650-664
Main points of the publication:
The development of new genetic methods and genetic testing recently shows that the proportion
of genetic congenital heart defects is higher than previously assumed. At the end of the 20th
century, the etiology of some congenital heart defects called “conotruncal malformations” was
discovered. It was after the implementation of the “fluorescence in situ hybridization” (FISH)
method to the diagnostic process. It was found that some conotruncal malformations are
associated with a 22q11 deletion.
The Genetic Department in the University Hospital Brno started with FISH examinations very
early. The aim of our study was to present the early results of FISH examinations in patients
with conotruncal malformations. From 1996 to 1998, in total 27 children and 5 fetuses with
CHD were examined using the FISH method. The 22q11 deletion was found in 5 children
(18%) and in 1 fetus (20%). In total, 22q11 deletions were diagnosed in 6 patients (26%) with
conotruncal malformation. Thymus aplasia was found in 3 patients, a low level of T
lymphocytes was found in 5 patients, and face dysmorphia was found in 3 patients. In 4 fetuses
parents decided to terminate pregnancy. In total, 5 children died.
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7. Consensus Statement and Reccomendation
Both documents were prepared in accordance with international recommendations and in
accordance with the need of specialized care in the Czech Republic.
7.0.1 ANNEX 16
Tomek V, Jicinska H, Klaskova E, Jehlicka P, Balatka P, Vít P, Hecht P, Reich O, Janousek J
An expert consensus statement on prenatal cardiology organization in the Czech Republic was
prepared by the Working Group on Pediatric Cardiology of the Czech Society of Cardiology
Cor et Vasa 2020; 62(1):60-63
Main points of the publication:
The consensus statement was prepared by the Working Group on Pediatric Cardiology of the
Czech Society of Cardiology. The aims of fetal cardiology, the screening program, and the
connection between screening and specialized echocardiographic evaluation in the Czech
Republic, and the indications for such evaluation were presented. The document defines who
should perform specialized echocardiographic evaluations in the fetus, and who should counsel
parents and other family members as may be necessary. Professor Jan Marek’s experience in
prenatal cardiology, especially regarding family counselling, was used in this consensus
statement as well.
The publication has two main authors who contributed equally to the manuscript.
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7.0.2 ANNEX 17
Zatocil T, Antonova P, Rubackova, Popelova J, Zakova D, Pokorna O, Chaloupecky V, Rohn
V, Skalsky I, Jicinska H, Taborsky M, Kautzner J, Janousek J
Recommendations to organize care for adults with congenital heart disease in the Czech
Republic.
Cor et Vasa 2018; Cor60(3): e331-e334
Main points of the publication:
This document was written by the Expertise committee of the Czech Society of Cardiology for
adults with CHD based on the recommendations for organization of care for adults with
congenital heart disease, and for training in the subspecialty of “Grown-up Congenital Heart
Disease” in Europe, which is a position paper of the Working Group on Grow-up Congenital
Heart Disease of the European Society of Cardiology.
The number of adults with CHD and survivals with CHD increased significantly in accordance
with the development of paediatric cardiology and paediatric heart surgery. The prevalence of
CHDs in adults is around 5 per 1000 adults. So there was a need to publish a study discussing
the care of adults with congenital heart defects.
The care of adults with CHDs should follow the care of children with CHDs. Severe and
complex CHDs should be followed up in specialized centres for adults with CHDs with
appropriate personal and technical equipment. Currently there are three specialized centres for
adults with CHD in the Czech Republic: the Hospital Na Homolce, the University Hospital
Motol in Prague, and the Centre for complex care of CHDs in adults in Brno.
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8. Conclusions
In the last 40 years, the outcome of children born with CHD became significantly better due to
important developments of paediatric cardiology, heart surgery, imaging methods,
extracorporeal circulation and specialized postoperative care. Since 1999, the mortality in
children with CHD is below 1% in the Prague Children’s Cardiac Centre. The development of
prenatal cardiology in the last 35 years, including the implementation of second-trimester and
later first-trimester screening into the complex care protocol of pregnancy, contributed, as well,
to these excellent results. Because of important developments in ultrasound technology, more
and more structures were included to the screening protocol of the fetal heart. For example, a
4-chamber view became available in 1986, evaluation of outflow tracts in 1996, and a 3-vessel
view in 2010. At the end of the 20th century, first-trimester screening was implemented to fetal
care in most countries and in most fetal medical centres (4-chamber view and outflow tracts
imaging). Also “risk factors” of CHD – increased nuchal translucency, tricuspid regurgitation
and abnormal flow in the ductus venosus — were found and examined. This development and
the increased detection rate of CHD are possible not only because of new ultrasound methods,
but also because of the development of other new imaging methods. Recently, fetal magnetic
resonance imaging is playing a more and more important role in the imaging of fetal structures.
It must also be mentioned that the training of physicians and technicians who perform screening
scans in pregnant women has been an important factor in the detection rate of CHDs. Recently,
the detection rate of all CHDs is about 45% prenatally, and the detection rate of critical CHDs,
which can cause heart failure immediately after birth, is about 80 – 85%. It would not be
possible to achieve such excellent results without the optimal management of pregnancies with
CHDs. Nor would it be possible without reciprocal cooperation by all participating fields —
obstetrics and gynecology, genetics, surgery and pathology. On the other hand, the Czech
Republic has one of the highest percentages of terminations of pregnancy in Europe (54%)
because of CHD. Many factors play a role in the decision-making process of parents about the
outcome of pregnancy. From the cardiology point of view, it is important that a fetus with CHD
must be examined by a paediatric cardiologist specialized in prenatal cardiology in order to
make the correct diagnosis in all details, to inform parents about the possible development of
CHD, the available options of invasive procedures, and the possible prognoses of CHD in an
infant after birth.
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In our study, we confirmed that first-trimester fetuses are mostly diagnosed with CHD with
univentricular circulation, which is often associated with additional extracardiac and
chromosomal abnormalities and has a very poor prognosis. Therefore most parents with such
fetuses (85%) decided for termination of pregnancy in the first trimester. In the second
trimester, CHDs mostly exhibit with biventricular circulation and less associated comorbidities
allowing a better prognosis. Therefore fewer parents decided to terminate pregnancy (32%). In
addition, we confirmed that first-trimester screening changed the spectrum of CHDs in the
second trimester in comparison to first trimester during the same time period (2007 to 2013),
and also in comparison to the time period before the implementation of first-trimester screening
in fetal care (1996 to 2001).
In the study, we also showed the pitfalls and limitations of first-trimester screening. In some
cases of first-trimester screening, it was impossible to detect some serious heart conditions with
duct-dependent circulation, to detect all details of some particular type of CHD, or to detect
CHD which will develop later in pregnancy. Similarly, it was not always possible to predict the
development and the outcome of CHD in the first trimester, because a first-trimester fetus is,
of course, only in the earliest stage of pregnancy and we know that CHD can later develop into
the wider spectrum of CHD. In such cases we unfortunately create quite a lot of stress for the
family by saying, “The heart of the baby is not all right.” We are able to discuss main
information about CHD with the parents, but then we must tell them that,“CHD has such a
huge spectrum of possible development that we are only able to predict the outcome of the baby
in greater detail later in the pregnancy.”
So there is still the question of whether or not, in some cases, first-trimester screening produces
more risk than benefit for some families. In view of all these facts, we think that the secondtrimester
screening program still has its place as an integral diagnostic component in a
multimodality screening program in pregnancy.