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  • 2. The research was done at Riga Stradini University Children Cardiology clinic, the Latvian State Children Cardiology Centre in the period from January I, 1998 till April 30,2003 Supervisor of research: Habil. Doctor of Medicine, Professor Aris Lacis Riga Stradini University Children Cardiology clinic, the Latvian State Children's Cardiology Centre Research consultant: Doctor of Medicine, Professor Lindsey D Allan, Harris Birthright Centre for Fetal Medicine Research, King's College Hospital, London, UK Official reviewers: Dr. habil. med., Prof. Laila Feldmane, RigaStradinS University Dr. med.,asoc. Prof. Uldis KalninS, University of Latvia Dr. habil. med., Prof. Alicija Dranenkiene, University of Vilnius, Lithuania The defense of the thesis will take place at the Riga Strading University on the 6 of May 2004 at 3 p.m. Address: 16 Dzirciema Street, Riga, Latvia, LV-1007
  • 3. INTRODUCTION The heart and great arteries anomalies are among the most common pathologies in children. About half of them are lethal or call for a surgical intervention. Congenital heart disease (CHD) according to the data of the leading specialists in the world are seen in 8-11 per 1000 live borns [Allan L.D., 2000; Buskens E. et al., 1996; McGahan J.R, 1991; Stumpfen I. et at., 1996] and in about 30 per 1000 still borns each year [Jeanty P., Pilu G.,1999]. The etiology of heart diseases is not uniform and they are likely to develop as a result of interaction of several factors, such as genetic and environmental factors (for example, the influence of teratogenous factors, virus infections, etc.) [Burn J. etal., 1998; Jeanty P. 1996]. Echocardiography is successfully used in the assessment of fetal heart structures and functions; it is the only prenatal imaging diagnostic method [Eronen M., 1997; Gembruch U., 1997]. Association for European Paediatric Cardiology (AEPC) has defined a fetal cardiology as a subspecialty for children cardiology and has worked out the guidelines to facilitate the development of fetal cardiology [2003]. The beginning of prenatal cardiology development is dated from the end of 1970-ties and the beginning of 1980-ties, when ultrasonography was introduced into the daily obstetrics routine. Consecutively the children cardiologists were examining the neonatal hearts by using the first echocardiographs. Due to close professional cooperation it was possible to develop the methods of fetal heart examination. In the medical centers of Europe and developed countries, the fetal heart examination took an active start by introducing specialized educational syllabuses for gynaecologists whose responsibility was to follow up the pregnant woman and to do the ultrasonography of the fetus [Allan L.D. et al., 1989; Sharland G.K. et al., 1992; The Fetal working Group of AEPC, 2003]. Simultaneously the diagnosing of fetal heart pathologies was undertaken, as well as developing cardiology centres in several countries in the world. Among the pioneers in this field are Wladimiroff group in Rotterdam, the Netherlands, Bobbins group in Yale ,the USA, Lindsay Allan who established a prenatal cardiology clinic in England, in Guy's hospital in London, David Sahn in Portland, the USA, Katrhryn Reed in Tuscon, the USA and Beryl Benacerraf in Harvard, the USA [Woo J., 2001]. In Latvia this field started developing much later - fetal cardiology at the Latvian State Children's Cardiology Centre was begun at the end of 1997 [Zīdere V., Lācis A., 1998}. One of the tasks of prenatal diagnostics is to identify a high risk pregnancy for
  • 4. further referral to specialized centers. There exists a series of signs suggesting a possible heart pathology in a fetus, however, the majority of pregnant women whose fetus has the heart disease does not go into any group at risk [Allan L.D., 2000], About 30% of severe, complicated pathologies are detected in a four-chamber position, though the latest studies [Copel J.A. et al., 1997; Darla B. et al., 1998] have proved that if the attention is paid to the edema of the neck fold in 10-14 gestation week and later, by referring the woman to a specialist, it exceeds 50% [Allan L.D.,2000; Ghi T. et al., 2001, Zosmer N. et al, 1999]. With diagnostic possibilities improving, ultrasonoscopy is occupying the leading role in prenatal diagnostics. High-tech digital echocardiographs are being used in specialized centers for the examination of the heart, thus giving a chance to identify severe, combined heart pathologies already at the end of the first trimester and at the beginning of the second trimester [Huggon I.C. et al., 2002]. If to compare the situation with the period 20 years ago, the surgical tactics has greatly changed in the treatment of heart diseases from palliative to the radical one, for example, tetralogy of Fallot, as well as previously untreatable surgical cases are offered a surgical intervention now, for example, hypoplastic left heart syndrome. Major emphasis has lately been put on the verification of heart diseases as early as possible [Allan L.D., 2003; Huggon I.C. et al, 2002; Stoll C. et al., 2002]. Consequently, it is extremely important to render professional and adequate treatment taking into account the child's age and the type of a heart disease. Fetuses with congenital heart disease, whose systemic or pulmonary circulation after birth depends on the function of the arterial duct, labour is recommended in medical institutions which are close by the children cardiology centers and which can provide a child cardiologist's care when introducing a controlled prostaglandin input, artificial lung ventilation, and if necessary, invasive treatment (ballon atrial septostomy) and in case of need, a surgical correction, thus decreasing the neonatal mortality [Allan L.D., 2000; Berghella V. et al, 2001; Brick H.D. et al., 2002; Gembruch U., Meberg A., 2002], Considering the birth rate in Latvia of late, each year about 200 neonates are born with congenital heart diseases, therefore children cardiology takes an important part in the children health care [LacisA., ZTdere V., 2000], Results of diagnostics of congenital heart diseases much depend on the doctor whose responsibility is pregnancy care, as well as ultrasonography specialist. Therefore, lagging behind in more than 15 years from the leading European children cardiology clinics, the first prenatal cardiology centre in Latvia was established at the end of 1997, starting a close collaboration with the State Medical Genetics Centre and gynaecologists in all regions of Latvia. In parallel to theoretical lectures in the post-diploma training courses at Riga Stradini
  • 5. University, the gynaecologists acquire the necessary skills for a successful fetal heart examination by ultrasonograph at the Latvian State Children's Cardiology Centre which are in line with AEPC recommendations. Jointly with Latvian Association of Children Cardiologists and Latvian Association of Gynaecologists and Obstetricians, there have been written methodical guidelines on fetal heart ultrasonographic examination [Zīdere V. et al., 2003], Both social and psychological aspects are important, the news on a sick child being born, brings unexpected changes in the family. Timely and detailed information on the expected child having a congenital heart disease may give a chance to parents to prepare and to plan for the future, including the interruption of pregnancy, considering the fact that prognosis in each heart disease case and its treatment process is different [Allan L.D., 2000; Berghella V. et al., 2001; Brick H.D. et al., 2002; Gembruch U., Meberg A., 2002]. Topicality of the study Quite commonly the diagnosis of congenital heart disease at early neonatal period is hard to perform if not done by a children cardiologist, or if no indications are found prenatally on heart pathology. As a result, there may be a risk not to render timely professional assistance, thus increasing possibilities for a potentially unfavorable disease outcome [AEPC, 2003]. Aim of the study was to do a prospective research in diagnostics of prenatal heart diseases in Latvia thus facilitating the improvement of prenatal care. The following objectives were undertaken: 1.To perform fetal echocardiograms in not less than 2000 pregnant women within the period from 15 gestation week till the end of gestation. 2.To perform fetal echocardiograms both on those pregnant women who belong to congenital heart pathology risk group and on those who are outside it. 3.To do the study by making use of echocardiograph, fetal heart program, two-dimension, M-mode, spectral and color flow mapping. 4.To video-record all the documented tests, providing a good retrospective analysis, if it is needed, and to document the data of case histories which characterize the possible risk group for congenital heart pathology. 5.To classify the identified heart pathologies into three main groups, such as, non-structural heart pathology, structural heart pathology and cardiac rhythm disorders. To analyze the results of each of the main classified cardiac pathology groups in detail. 6.For statistical model analysis: SPSS program, descriptive and conclusive statistical methods to be used.
  • 6. Novelty of research. For the first time a research was done in Latvia describing the picture of the present situation in diagnostics of prenatal heart diseases in the country- Practical application of research. Taking into account the significance of heart pathologies, their role in children pathology and neonatal care, there is a chance to provide a timely patients' care in a specialized centre. When obtaining grounded information on the problem mentioned, one can introduce the educational programs to students and doctors, thus promoting the improvement of medical care quality. Theses suggested for defense: 1.Congenital heart pathology in Latvia is a very common fetal anomaly. 2.During pregnancy it is possible to diagnose a wide spectre congenital heart pathologies by echocardiographic examination. 3.Timely diagnosed heart pathology in a fetus allows rendering an adequate medical assistance by decreasing the neonatal lethality in the country. 4. Timely diagnosed heart pathology in a fetus allows the family to choose the most suitable treatment tactics. Structure of promotion work: The paper includes 10 chapters: introduction; literature survey; 5 chapters describing the process of research; discussion of results; conclusions; practical recommendations and references. Supervisor of research: Habif. Doctor of Medicine, Professor Aris Lācis Riga Stradini University Children Cardiology clinic, the Latvian State Children's Cardiology Centre. Research consultant: Doctor of Medicine, Professor Lindsey D Allan, Harris Birthright Centre for Fetal Medicine Research, King's College Hospital, London, UK. Research process. The research was done at Riga StradinS University Children's Cardiology clinic, the Latvian State Children Cardiology Centre (head- Habil. Doctor of Medicine, professor Aris Lācis) in the period from January 1, 1998 till April 30, 2003. PUBLICATIONS IN QUOTED SCIENTIFIC EDITIONS ON RESEARCH THEME 1.D.J. Better, H.D. Apfel, V. ZTdere, L. D. Allan. Pattern of pulmonary venous blood flow in the hypoplastic left heart syndrome in the fetus. Heart, 1999;81:646-649. 2.V. Zidere, I. Lubaua, A. Lacis. Giant fibroma of the right ventricle. Cardiol Young 2002; 12:584-586.
  • 7. 3.V. Zīdere, I. Lubaua, A. Lacis. Pirmo četru prenatālās kardioloģijas gadu rezultāti Latvijā. ZRaksti /LMA 2002:68-71. 4.I. Lubaua, V. Zīdere, A. Lācis. Transtorakālās ehokardiogrāfijas metodes pielietojums koronāro artēriju patoloģiju diagnosticēšanā bērniem. ZRaksti /LMA, 2002:65-67. 5.E. Lubaua, V. Zidere, A. Lacis. The Roie of Transoesophagal Echocardography During Repair of Multiple Congenital Coronary Artery Fistulas. Acta medica Lituanica. 2003; 4:189-192. 6.A. Lācis, L. Šmits, V. Zīdere, I. Lubaua, 1. Lāce, J. Auziņš, Z. Straume. Kambaru starpsienas defekta slēgšana mākslīgās asinsrites apstākļos pirmajā dzīves gadā. Latvijas ķirurģijas žurnāls. 2003; 3: 88-93. 7. Vita Zīdere. Rekomendācijas augļa sirds ultrasonogrāfiskajai izmeklēšanai. 2003. ISBN 9984-19-402-7. Presentations at scientific conferences on the research theme. 1.Zīdere V., Lācis A. Pirmais prenatālās kardioloģijas gads Latvijā. Publicēts tēžu krājumā: I Latviešu sieviešu slimību un dzemdību speciālistu kongress. Rīga, Latvija, 1999: 66. lpp. 2.Zīdere V., Ezeriņa D. First tree yearexperience in prenatal cardiologv in Latvia. Published in abstract book: The VIII Baltie Sea Conference on Obstetrics and Gynecology, Riga, Latvia, 2001. 3.V. Zidere, LD Allan, A. Lacis. Initial four-year experience in prenatal Cardiology in Latvia. First Baltie States Conference on Ultrasound in Obstetrics and Gynecology. Vilnius, Lithuania, 2002: p. 14. 4.Lācis, M. Jagmanis, V, Zidere, Z. Garleja, J. Auzins, I. Vanaga, Preisa, I. Lace, L. Smits. A case of organising the special paediatric cardiac centrēs: improved surgical outeomes at the Latvian State Cardiology Centrē for Children. Published in abstract book: 3rd World Congress of Pediatric Cardiology and Cardiac Surgerv, Toronto, Canada, 2001: 881pp. un Published in abstract book: 25 World Congress of the International Society for Cardiovascular Surgery. Cancun, Mexico, Cardiovascular Surgery Published in journal of Cardiovascular Surgery, 2001:9, p.89. 5.V. Zidere, I. Lace, A. Lacis. Non-invasive echocardiogrphic diagnostics of congenital heart defeets for children before and after surgery in The Latvian State Cardiolgy Center for Children. 25 World Congress of the International Society for Cardiovascular Surgery. Cancun, Mexico. Published in journal of Cardiovascular Surgery, 2001:9,p.92.
  • 8. 6.V. Zīdere, I. Lubaua, L. Allan, A. Lācis. Pašreizējā prenatala iedzimtu sirdskaišu diagnostika Latvijā. Publicēts tēžu krājumā: 2002.gada Medicīnas nozares zinatniskā konference. Rīga, Latvija, 431pp. 7.J.Bars, I. Kalke, A.Lapsa, V. Zidere, I. Grivina. Prenatal US markers of fetal cromosomal abnormalities. Published in abstract book: First Baltic States Conference on Ultrasound in Obstetrics and Gynecology. Vilnius, Lithuania, 2000: p. 21 8.I. Lubaua, V. Zidere, A. Lacis. Congenital coronary artery fistulas in children: diagnosis, surgical technique and results. A Marcus Wallenberg International Symposium: The coronary Arteries in Children Anatomy, Flow and Function. Lund, Sweden, 2003. LITERATURE SURVEY Epidemiology of congenital heart diseases The incidence of congenital heart diseases vary according to the investigation methods, i.e. from four to eleven cases per 1000 live borns [Allan L.D., 2000; Buskens E. et al., 1996; McGahan J.P., 1991; Stumpfen I. et al., 1996]. A. Meberg's (2002) study shows that in some regions the incidence of heart diseases is even lower, for example, 3-5% in Norway where ultrasonographic diagnosing of fetal pathology in the second gestation trimester is not the primary task, but it may be high in the countries or regional centres where pathology diagnosis during pregnancy, especially in the second trimester, are included in the special purpose program, for example, London, England [Brick H.D. et al, 2002; Gill H.K. et al., 2003].. Looking through the data on the Baltic States' region, one can conclude that medical care in children cardiology and cardio surgery in each of the Baltic States is organized in a different way. In Latvia the medical care in children cardiology, including fetal cardiology, is organized according to the guidelines of Association for European Paediatric Cardiology. Such a prenatal cardiology care is considered an optimal one which provides concurrent access to specialists who are potentially involved in a child care just after birth, i.e., pediatric cardiologist-neonatologist, pediatric cardio surgeon and geneticist, who are available in the Latvian Sate Children's Cardiology Centre [Zīdere V, et al., 2002]. Pathogenesis of congenital heart disease Etiology of congenital heart disease The heart is a complex organ, however, already in the fifth week after the last menstruation (in the third week after conception) it is developed. Complete septation is accomplished at about the 8 week after the ovulation, the time
  • 9. when atrioventricular septal defect is about to develop, it never disappears and does not regress spontaneously. And still trabecular transformation in the right and left ventricles, as well as complete development of atrioventricular and semilunar valves is continuing up to the 14 -16 gestation week. [Gittenberger- de Groot A.C. et al., 2000]. However, some pathologies may progress all through the pregnancy time or may be exposed in its various periods. As the most characteristic ones are - valvular stenosis, right or left chamber hypoplasia, tumours. Classification of pathogenesis according to Clark: I Ectomesenchvmal tissue migrations abnormalities -conotruncal septation defects, for example, tetralogy of Fallot; -brachial arch defects, for example, double aortic arch -abnormal conotruncal cushion position, D-transposition II Abnormalities of intracardiac blood flow -left heart defects, for example, hypoplastic left heart; -right heart defects, for example, pulmonary valve stenosis; -perimembranous ventricular septal defect IIICell death abnormalities, for example, muscular VSD. IVExtracellular matrix abnormalities, for example, AVSD. V Abnormal target growth , for example, cor triatriatum VIAbnormal situs and looping: situs inversus totalis; heterotaxy; looping abnormalities, for example, L-transposition of the great arteries. Reasons of congenital heart diseases are often unknown, in single cases this risk can be prognosed prior to pregnancy, however, most often pathology is diagnosed during pregnancy [Allan L.D., 2000]. A great number of authors speak about three big risk groups: "maternal", "familial" and "fetal" [Allan L.D., 1986;JeantyP.,PiIuG., 1999] "Maternal" risk factors Metabolic disorders -diabetes meilitus for a mother may be the cause of a fetal hyperinsulinaemia, and as a result, there may develop a transient form of hypertrophic cardiomyopthy, as well as macrosomy and hypoglycaemia for a fetus. The question of gestational diabetes is controversial. Diabetes increases the risk of congenital heart disease up to 4 - 5 times. [Allan L.D. et al., 2000; Cooper M.J. et al., 1992; Wong S.F. et al., 2002]. -phenylketonuria may be the cause for tetralogy of Fallot, left heart obstructive lesions or VSD [Allan L.D. et al., 2000; Rouse B. et al., 2000].
  • 10. Influence of teratogenous factors Maternal exposure to drugs up to 61 -8l' gestation week, the active substances of which contain valproic acid (anticonvulsants), epanutin, retinoic acid and lithium, and may cause severe fetal heart disorders, which most commonly are severe and combined heart diseases [Angelini P., 1995]. The use of NSA1D after 25 -30 gestation week may be the reason for a postnatal right chamber and pulmonary hypertensions in newborns, as well as the closure of arterial duct prenatally. [Benettoni A. et al., 2002]. The effect of alcohol toxicity on fetus is well known, though the view of being a risk factor for a congenital heart disease is controversial. Maternal infection with rubella virus by the 12 gestation week is the reason of the development of pulmonary artery stenosis in fetus. Cytomegalovirus, coxackie, parvovirus, mumps and toxoplasmosis infection during pregnancy are the reasons for cardiac anomalies [Allan L.D., 2002; Jeanty P., 1996;]. Mothers with autoantibodies In cases of mother's autoimmune diseases (such as lupus erythmatosus), fetus may likely develop atrioventricular block, cardiomyopathy and fibroelastosis. In about 70-80% of fetuses with an antibody-induced atrioventricular block, mothers are asymptomatic without a diagnosis of autoimmune disease [Askanase al.,1998; Brucato al., 2003]. Congenital heart disease in mother and familial cardiomyopathy Depending on mother's heart disease type, excluding any genetic pathology, a fetus congenital heart disease risk ranges even by >12%, Table 2. In majority of cases, cardiomyopathies are secondary, however, fetal echocardiography is recommended [Allan L.D., 2000; Jeanty P., 1996]. Mother's age over 35 years Mother's age over 35 years is not considered a specific risk factor for congenital heart disease in a fetus, and still, there is an increased risk for a genetic pathology. To exclude the risk for heart disease, the fetal heart ultrasonographic examination is recommended to be done at a specialized centre [Allan L.D., 2000]. "Familial" risk factors Previous child or fetus with congenital heart disease or congenital atrioventricular block The risk to have heart pathology repeated in the family is inconsistent and it depends on the heart disease type in the family history. Every other individual in the family may have just the same heart pathology like the previous child or fetus, or quite a different congenital heart disease. If the previous child is having a heart disease, then the next one may have a risk to be born with congenital
  • 11. heart disease by 2%, however, if two children in the family are having CHD, then the risk increases up to 10%, as depicted in Table 1. Table 1. reccurence risks for congenital heart defects in siblings. (Reproduced from Nora &Nora, 1988.) Defect I sibling 2 siblings affected affected Ventricular septal defect 3% 10% Patent ductus arteriosus 3% 10% Atrial septal defect 2,5 % 8% Tetralogy of Fallot 2,5 % 8% Pulmonary stenosis 2% 6% Coarctation of aorta 2% 6% Aortic stenosis 2% 6% Transposition of great arteries 1,5% 5% Endocardial cushion defects 3% 10% Fibroelastosis 4% 12% Hypoplastic left heart 2% 6% Tricuspid atresia 1% 3% Ebstein anomaly 1% 3% Truncus arteriosus 1% 3% Puimonaru atresia 1% 3% Congenital heart disease in parents The risk when one of the parents has a congenital heart disease varies between 5% to 10%, depending on the type of heart disease. Table 2. Reccurence risks for congenital heart defects in offspring given one affected parent. (Reproduced from Nora &Nora, 1988.) Defect Father affected Mother affected Aortic stenosis 3% 13-18 % Atrial septal defects 1,5% 4-4,5 % Atrioventricular septa! defect 1% 14% Coarctation of aorta 2% 4% Patent ductus arteriosus 2,5 % 3,5-4 % Pulmonary stenosis 2% 4-6,5 % Tetralogy of Faliot 1,5% 2,5 % Ventricular septal defect 2% 6-10%
  • 12. Chromosomal anomalies, single-gene disoders or syndrome with congenital heart disease or cardiomyopathy. Single-gene disorders in the family history in one or both parents increases the risk for a single gene defect in a fetus, resulting in congenital heart disease or cardiomyopathy from 25% to 50%. The most common single gene disoders are typical with Marfan, Noonan, Holt-Oram, DiGeorge, velofacial, Williams syndromes [Angelini P.,1995; Lacro R., 2000]. "Fetal" risk factors Extracardiac anomalies Results of the studies done allow to draw conclusions: if there exists more than one organ system malformation, the risk of genetic pathology is greater. P.Jeanty's study (1996) proves that heart anomalies are associated with extracardiac anomalies in 5-10% cases, while fetuses with extracardiac pathologies are found to have heart diseases in 7-17% cases. Most commonly cardiac anomalies are combined with: omphalocele, diaphragmatic hernia, nuchal edema, duodenal atresia, tracheo-oesophagealfistula, cystic hygroma, skeletal anomalies and also retardation in fetus growth. Fetal hydrops or polyhydramnios are considered as a complication for the existing baseline pathologies, which in 25% cases are of cardiac type. The most common reasons are disorders of the heart rhythm, a series of structural heart pathologies, such as atrioventricular septal defect, coarctation of aorta, cardiomyopathies, and tumours. Oligohydramnios is not a typical finding in case of congenital heart disease; however, it may likely develop if intrauterine infection is present. Echogenic cardiac focus. Results of extended studies demonstrate that if echogenic cardiac foci exists as an isolated finding, it can be considered as a trisomy 21 marker in correlation to mother's age and the first semester screening test [Huggon al., 2001]. Arrhythmias. Disorders of heart rhythm in a fetus in the last ten gestation weeks, manifested by ectopic beats, both atrial and ventricular, are more of a functional type, however about 2% cases correlate to a structural heart pathology. Certainly, a detailed heart examination is needed, and also the evaluation of hemodynamic status in case of sustained bradychardia and tachycardia [Hata T. et ai., 1988; Hess D.B. et al., 1998; Groves A.M. et al, 1996; Rosenthal E., 2000; Simpson J., 2000]. Genetic pathology in a fetus with heart disease is common in >20% cases. If more than two fetal pathologies exist, there is a greater risk for a genetic syndrome. Majority of syndromes are diagnosed relying on the clinical picture
  • 13. after birth [Fasnacht M.S. et al.,2001; Hess D.B., 1998; Lacro R., 2000]. Heart pathology correlates to: -autosomal recessive syndromes, for example, Ellis- Van Creveld; -autosomal dominant syndromes, for example, Marfan; -X-linked recessive syndromes, for example, Dreifuss; -chromosomal aneuploidies, for example, trisomy 21, trisomy 18, trisomy 13, and 22q deletion. Examination method Echocardiography is the only visual diagnostic method in the diagnostics of structural heart pathologies, heart rhythm and hemodynamic disorders [Eronen M.1997], It is a non-invasive, painless ultrasonographic method. In order to ensure a maximum good examination quality and proper observation of a pregnant woman and a fetus further on, The fetal Working group of AEPC, 2003, recommends to do a detailed fetal heart examination by a child cardiologist with an extra specialization in fetal cardiology and at a children cardiology unit. It is absolutely necessary to have a close cooperation with genetics unit, paediatric cardiothoracic surgical unit, specialists in obstetrics and gynaecology, and neonatal unit [Carvaiho J.S. et al., 2002; Fasnacht M.S. eta!., 2001; HafnerE. etal., 1998]. For fetal heart examination there is used similar echocardiographic equipment as in children cardiology [AEPC, 2003; Gembruch U., 1997], i.e., 5 MHz and 3,5 MHz transducers. High resolution equipment allows earlier and more accurate diagnosis and a special fetal heart programme improves examination quality. During examination one should use B-mode, M-mode, PW and CW Doppler, colour flow imaging. Systematic normal and pathological heart examination in real time using ultrasonographic method was first described by Lindsey Allan (Guy's hospital, London) in 1980. Fetal heart echocardiographic examination is possible already starting from the end of the first trimester of pregnancy and the beginning of the second trimester, i.e. from 12-14 gestation week till its end. [Allan L.D., 2003; Huggon I.C. et al., 2002]. It is considered that in a routine ultrasonographic examination a complete heart analysis can be acquired in 18 gestation weeks, however in high-risk cases this examination is recommended starting from 14th-16th gestation week [Allan L.D., 2003]. On the basis of studies on a possibility of correlation of congenital heart pathology with genetic pathology, it is recommended to have a doctor-genetician's consultation to determine the probable amniocentesis and the caryotype, depending on the diagnosis and the time of pregnancy [Chaoi al., 1999].
  • 14. Results of diagnosed congenital heart diseases in utero Antenatal diagnostics of those pathologies, which can be recognized in four- chamber position, is still insufficient. Although the diagnosed heart disease spectre is increasing with time, the graver pathologies, however, are diagnosed postnatally, therefore any heart disease diagnosed in a fetus during pregnancy, is important, in this way getting a more precise idea about this period [Allan L.D., 2000; Ott W.J., 1995; Strauss al., 2001]. A comparative study by D.H. Brick and L.D. Allan (2000) between London, Yale and Newhaven shows that both atrioventricular septal defect and hypoplastic heart syndrome can be diagnosed in four chamber position, and are seen antenatally twice as often than postnatally. On the contrary, transposition of great arteries which can be diagnosed by examining only major blood vessels is seen twice as often postnatally as during pregnancy. S. Levi study (1998) proves that about 98% of pregnant women are examined ultrasonographically in most of European countries. One should emphasize the professional skills of medical specialists while doing fetal heart ultrasonographic examination [Erenius al., 1999; Stoll al., 2001]. Studies covering a longer time period show that a complete heart examination in routine fetal investigation can give maximum results. By adding great arteries views to the traditional four- chamber view, the diagnosis of combined, severe heart diseases increases from 60% to 90% [Allan L.D., 2000; Carvalho J.S. et ai., 2002]. Diagnostic spectre is influenced by the fact that even >55% pregnancies with prenatally diagnosed heart diseases are terminated [Brick al., 2002; Stoll al., 2002]. Despite the fact that the surgical correction possibilities, invasive cardiology and newborn intensive therapy level have increased in the last twenty years, the long-term survival of those pregnancies that are continued after making a prenatal heart disease diagnosis is about 60% [Brick al., 2002]. General characteristics of patients Material From January 1,1999 till April 30, 2003,at the State Children's Cardiology Centre and outpatient clinic "ARS", 2445 fetal echocardiograms were done on mother, aged from 16-50 years (mean age 26,85+7,56 years), including 21 twin and 1 triplet pregnancies from 14-41 (on average in 28,23±6,72 gestation week) gestation week. Retrospective detailed clinical study includes 225 echocardiograms of pathological findings from 15-41 gestation week in mother at the age of 17-50 years. Fetal echocardiography was done by a peadiatric cardiologist with an extra training in fetal cardinlogy.
  • 15. Selection of patients A mother was referred to fetal echocardiography by a doctor who was following up the pregnancy course (a gynaecologist, in rare cases a family doctor, in single cases - a midwife) or an ultrasonography specialists, doctor-genetician, taking into account the indications for an increased risk of heart disease, or in cases when the examination of the heart was difficult to do in a routine obstetric ultrasonographic examination, or this was the wish of a parents, not being in a group at risk. Mother were referred to do a fetal echocardiogram considering the following indications: maternal indications: maternal metabolic disorders, maternal exposure to cardiac teratogens, maternal collagen disease, maternal congenital heart disease, age over 35 years; familial indications: a congenital heart disease in a previous child or fetus, paternal congenital heart disease, paternal chromolsomal anomalies, gene disoders or syndromes (Noonan, Mar/an, Holt-Oram, DiGeorge syndrome, etc); fetal indications: fetal hydrops, any extracardiac, including, genetic, pathology, any arrhythmia, polyhydramnios, echogenic cardiac focus, suspicion of cardiac malformation or disease during obstettrical scan. Methods Fetal cardiology methods Investigation was done by a certified pediatric cardiologist with extra specialization in fetal cardiology. Fetal heart was examined by using two dimensional (2D) guided, pulse, and continuous wave Doppler echocardiography equipment (Hewlett PackardSonoss 4500, Accuson Aspen and ATL 5000) with a 5-3 MHz transducer, in separate cases 7 and 8 MHz and 2-3 MHz, fetal heart programme. All examinations were performed via transabdominal access. Examination was standardized and in all cases the following investigation positions were used: 2D- five projections were used: four chamber position; five chamber position, long axis, short axis, and arch views. To make the study precise and investigations in all fetal echocardiography cases qualitative, the following parameters were assessed: heart rhythm; situs; heart size in relation to thorax; atrial and ventricular chambers; valves; atrioventricular junctions (Figure 1); aortic and ducta! arch.
  • 16. Figure 1. Four chamber position. In all investigations the colour Doppler was used, pulse wave and continuous wave dopplerography in those cases when a pathology was suspected. Heart rhythm disorders, the type of arrhythmias were analyzed by using M-mode at atrial and ventricular level. All pathological investigations were divided into three large groups: structural heart pathology; non-structural heart pathology; heart rhythm disorders. All investigations were recorded in a video having a potential to analyze them repeatedly in case of need. Each pregnant woman's personal data were registered. After the examination of fetal heart the mother returned back to the doctor who was following up the pregnancy in the medical institution were the woman was signed up. When pathology was diagnosed, the consultation at the genetician's was advised, if a neonate's ondition after birth had been prognosed as severe, pregnancy was recommended to be followed up at Riga Stradini University hospital, Perinatoiogy Centre, where the further neonatal care was done at the Perinatal Centre and /or the newborn was transported to the State Children's hospital
  • 17. "Gailezers" for further treatment. In all those cases where heart pathology had been diagnosed during pregnancy, and in those cases where there was a suspicion for heart pathology only after birth, the recommendations were given to do observation in dynamics after birth at the Latvian State Children's Cardiology Centre. In about 90% cases the information was acquired about the postnatal outcome. Statistical data processing The data acquired were entered into computer and processed by SPSS programme using generally approved descriptive statistical methods. For proportion evaluation the Wilson's method of Confidence Interval Analysis was used. R.G. Newcombe and D.G. Altman say that the traditional method for calculation of proportions' standard error (SEp) can be applied to normally or almost normally distributed data and it is calculated by means of the equation where p is the probability of the direct event and r— scope of selection. The lower and upper border of population 95% confidence interval is estimated by the formulas In the Wilson's method, recommended by the above-mentioned authors, first of all the values are estimated A = 2r +1,96 2 ; where m is the number of beneficial events and n -scope of selection. After that are calculated 95% confidence interval borders from In our work we used Wilson's method, recommended by the above-mentioned authors, since it can be used for processing of any data, despite their distribution. Calculations were done by Altman's specialized computer programme CIA (series Nr.: CYK216C) worked out in the year 2000.
  • 18. RESULTS Within a period of five years and four months 2445 investigations were done. Each year there is seen an increase of the total number of examinations and the increase of the number of pathological examinations (Table 3). 92% of the total number of examinations demonstrates pathological findings. From them in 105 (46,7%) cases, fetuses are with structural heart pathology, 62 (27,6%)- nonstructural heart pathology and 58 (25,8%)- heart rhythm disorders. Table 3. The number of total and pathological examinations, distribution according to the years during which the clinical study was done. Year 1998 1999 2000 2001 2002 2003IV Total 135 131 356 560 764 499 Pathology 4 16 34 62 66 44 Pathology, % 3,0% 12,2% 9,6% 11,1% 8,6% 8,8% By analyzing the pregnancy period in which fetal heart pathology was diagnosed during fetal echocardiography, a conclusion can be drawn that in 68,8% cases this examination is performed after the 22nd gestation week and in 31,2% cases up to the 22nd pregnancy week including. Fetal hearts with a nonstructural heart pathology were examined by special methods in the period up to the 22nd gestation week in 48,4% (30/62) cases, structural heart pathology up to this pregnancy time were found in 22,9% (24/105) cases, in the group of heart rhythm disorders 27,6% (16/58). Mothers up to the age of 35 years were 86,7% (195/225) cases, 10,2% (23/225) between 35 and 40 years and in 3,1% (7/ 225) were older than 45 years. Structural heart diseases was seen in 13,3% (14/105) mothers at the age of 35 years, non-structural in 14,5% (9/62) cases and heart rhythm disorders in 12,1% (7/58) cases at this age group. Family and maternal history as a possible risk factor are seen in 7,6% (17/ 225) cases (Table 4), from them 29,4% (5/17) cases in a non-structural heart pathology group, 5/17 (29,4%) structural heart pathologies and 2/17 (11,8%) in the group of heart rhythm disorders (Table 5).
  • 19. Table 4. Prevalence of family and maternal history incidence in Latvian women assigned to the study. By adding, that VI, VII and VIII are considered as a relative marker for fetal heart disease. Table 5. Correlation of family and maternal history with heart pathology groups.
  • 20. Table 6. Distribution of prevalence of codiagnoses (n=225). Codiagnosis In 25,3% cases (57/225) of pathological heart examinations there were found a codiagnosis in a fetus which may correlate with the existing heart pathology (Table 6), from them 47,4% (27/57) cases in a nonstructural heart pathology group, 43,9% (25/57) structural heart pathologies and 8,8%(5/57) in the group of heart rhythm disorders (Table 7). Echogenic cardiac focus are not defined and analyzed separately as an isolated pathology, it is considered more like a marker. About 5,3% (12/225) cases from all pathological investigations are combined with this finding. By displaying the more severe forms, one can see that in two cases with the diagnosis ,,golf balls", a gynaecologist indicates echocardiogram to fetuses with a grave, combined heart disease - hypoplastic left heart syndrome. Echogenic cardiac focus and extra beats have been the reason for a paediatric cardiologist's consultation in two more severe heart disease cases -transposition of great arteries.
  • 21. Table 7. Prevalence of codiagnoses in groups of heart pathologies. Group Codiagnosis N % 95% TI Lo. Up. I Nonstructural heart pathology (n=62) Diafragmatic hernia 8 12,9% 6,7% 23,4% Oligohydramnios 5 8,1% 3,5% 17,5% Polyhydramnios 4 6,4% 2,5% 15,4% Hydronephrosis 2 3,2% 0,9% 11,0% MDA 2 3,2% 0,9% 11,0% Feto-fetal transfusion 2 3,2% 0,9% 11,0% IUGR 1 1,6% 0,3% 8,6% Oesophagal atresia I 1,6% 0,3% 8,6% Intestinal anomalies 1 1,6% 0,3% 8,6% Lung cysts 1 1,6% 0,3% 8,6% II Structural heart pathology (n = 105) IUGR 6 5,7% 2,6% 11,9% MDA 5 4,8% 2,1% 10,7% Polyhydramnios 5 4,8% 2,1% 10,7% Diafragmatic hernia 2 1,9% 0,5% 6,7% Hydronephrosis 2 1,9% 0,5% 6,7% Hydrops fetalis 2 1,9% 0,5% 6,7% Hydrothorax 1 1,0% 0,2% 5,2% Hand anomalies 1 1,0% 0,2% 5,2% Oligohydramnios 1 1,0% 0,2% 5,2% III Rhythm disorders (n = 58) IUGR 2 3,4% 1,0% 11,7% Hemodinamic disoders 1 1,7% 0,3% 9,1% Oligohydramnios 1 1,7% 0,3% 9,1 % Polyhydramnios 1 1,7% 0,3% 9,1% Abbreviations: IUGR-intrauterine growth retardation; MDA- multiple developmental anomalies Genetic pathology The caryotype was defined during pregnancy in 18,2% (41/225) cases from the number of pathological investigations, from them a normal caryotype answer was received 43,9% (18/41) and pathological caryotype was found in 46,3% (19/41), in four cases there was seen a genetic syndrome shortly after birth. In general, genetic pathology both prenatally and postnatally was 10,2% (23/ 225). It can be seen in Table 8. Comparing the incidence of heart pathologies in mother at the age under 35 years, with that of mother from 35 years, it was
  • 22. found that the older are the mother, the greater probability for the development of a fetal heart pathology OR (odds ratio)= 3,40 (95% confidence interval from 1,13 to 10,06). Distribution in these age groups was tested by Fisher's chi square test and by using Yates correction, it was found that this distribution is statistically confident variable (c2 - 4,94, p = 0,026). Table 8. Prevalence of genetic pathology (n=225) Nr. Genetic pathology N % 95% TI Lo. Up. 1. trisomyl8 8 3,6% 1,8% 6,9% 2. trisomy 21 7 3,1% 1,5% 6,3% 3. trisomyB 2 0,9% 0,2% 3,2% 4. 22qll deletion 1 0,4% 0,1% 2,5% 5. 47+M I 0,4% 0,1% 2,5% 6. Syndromes: - Dandy Walker 1 0,4% 0,1% 2,5% - Goldenhar 1 0,4% 0,1% 2,5% - Ivemark 1 0,4% 0,1% 2,5% - Cornelia de Lange 1 0,4% 0,1% 2,5% 7. Normal caryotype 18 8,0% 5,1% 12,3% Nonstructural heart pathologies In 3,2% (2/62) cases aortic valve regurgitation was described by dopplerography during pregnancy as little expressed or moderately expressed and not correlating to structural heart pathology. In one of these cases the first- degree relatives had congenital heart disease in the family history. There are no data of pregnancy termination or need for treatment because of the heart disease after birth. Potential stenosis of aortal valve - abnormal spectral Doppler measurements in the ascending aorta were seen in 3,2% (2/62) cases, however, in both cases after birth the echocardiographic examination was without any pathological finding and specific therapy was not needed. Hemodynamic disorders, which are characterized by pathological Doppler measurements at ductus arteriosus and ductus venosus level in 12,9% (8/62) cases. Diaphragmatic hernia in 62,5% (5/8) cases, cysts in lung tissues in 12,5% (1/ 8), oligohydramnios 12,5% (1/8) in a 37-years old mother and fetus grows retardation 12,5% (1/8) where a mother is an active smoker. Pregnancy was terminated in one case where a fetus was diagnosed diaphragmatic hernia.
  • 23. Hypertrophic cardiomyopathy was seen in 9,7% (6/62) cases. In two of them, the etiological factor - feto-fetal transfusion, in one case intrauterine virus infection (cytomegalo, herpes simplex). An early neonate death was in one case in a 38 years old woman whose fetus had hypertrophic cardiomyopathy in combination with intestinal pathology. Pregnancy was terminated in 83,3% (5/6). Dilatation cardiomyopathy (DCMP) in utero was found in fetus in 8 cases from 62 (12,9%), figure 2. Table 9. Correlation of dilatation cardiomyopathy with codiagnosis, prena- tally diagnosed genetic pathology, family or maternal risk factor and outcome. Abbreviations: TOP - teermination of pregnancy; ND - no data * maternal cytomegalo virus infection Left superior veina cava is diagnosed in 1,6% (1/62) cases, this finding can be explained as an anatomical specificity if it does not combine with a structural heart pathology as it is in this case. Mitral valve regurgitation (MVR) has been found in this study in 9,7% (6/62) cases. In this group of heart diseases there are no data of pregnancy termination or any specific heart disease treatment. Tricuspid valve regurgitation, which Doppler during pregnancy had been defined as moderate or severe and did not correlate with structural heart pathology, were included into this study. In total, in 13 (21 %/62) cases isolated tricuspid valve regurgitation was diagnosed. There are no data on of pregnancy termination or the necessary treatment due to heart disease after birth.
  • 24. Situs inversus without heart pathology was seen in one case. No other organ pathologies were diagnosed either. The existing findings can be considered as anatomical specificity. The baby after birth is not under observation of a paediatric cardiologist. Figure 2. The 31st gestation week. Cross-section, four-chamber view. Typical cardiomegaly, pericardia! effusion in a case of dilatation cardiomyopathy. Pericardia) effusion (>2 mm) was seen in 17,7% (11/62) cases of non-structural heart pathologies. The reason for this finding in 9,0% (1/11) cases can be considered as multiple development anomalies, hydronephrosis 9,0% (1/11). Codiagnosis - polyhydramnios 27,2% (3/11) and oligohydramnios 9,0% (1/ II), the caryotype during pregnancy was determined in two cases; its result was pathological in one - 21 chromosome trisomy. In three cases the maternal age was over 35 years, in one case - over forty where the fetus was diagnosed trisomy 2land poyhydramnios. Formation - suspicion to possible neoplasm in this study was in 6,4% (4/62) cases. Extracardiac formation in the lung was found in the third trimester in one case and since it did not produce any hemodynamic problems and was
  • 25. connected with lung tissues, there was no need for a paediatric cardiologist's care. In one case both prenatally and postnatally were found a rudimentary formation in the right atrium, which did not cause hemodynamic disorders and the case is still under a paediatric cardiologists' care. Rudimentary formation postnataily was confirmed also in the right ventricle. The only tumour — rhabdomyosarcoma in the right ventricle was found in one case in the 32nd gestation week which resulted in fetus mortus. Heart rhythm disorders. Such were 25,8% (58/225) cases. Up to the 22nd gestation week (including) such disorders manifested in 27,6% (16/58) cases, however after the 30th gestation week - 53.4% (31/58). In 12,1% (7/58), mothers are older than 35 years. In 8,6% (5/58) cases fetal arrhythmia correlate with oligohydramnios (I), polyhydramnios (1), fetal growth retardation (2) and hemodynamic disorders - pathological dopplerographic finding ductus venosus and ductus arteriosus. In two cases the caryotype for a fetus was defined due to suspicion for a possible genetic pathology (mother's age, changed alfa-fetoprotein level), from them in one case - the 21 st chromosome trisomy. Heart pathology in a mother - 1,7% (I), herpes simplex 1,7% (1) and cytomegalovirus 1,7% (1) infection during pregnancy. Premature contractions 84,5% (49/58). Basically functional arrhythmia which were manifested after the 30th gestation week, from them in 96% cases there was no need for a specific therapy either prenatally, or postnatally. The reason for extrasystoles in 6.9% (4/58) cases can be considered extracardiac fetal problems, such as oligohydramnios, polyhydramnios, hemodynamic disorders and fetus growth retardation. However, in one case (1,7%) where the mothers age was over 35 years, the fetus was found 21 chromosome trisomy up to the 22nd gestation week in diagnostic amniocentesis and pregnancy was interrupted. Extra beats was combined with a structural heart pathology, such as TGA, AVSD and complex heart diseases in 5,3% (12/225) cases. Supraventricular tachycardia in 3,4% (2/58) cases appeared after the 35th gestation week. Due to hemodynamic disorders, pregnancies were interrupted by operative labour. Both fetuses were successfully treated postnatally by using antiarrhythmics therapy. Sustained bradycardia (<100x') 5,2% (3/58). Complications during pregnancy were not found in an either case, arrhythmias were not seen after birth. Tachycardia >170-180 times per minute with a tendency to remain for several minutes was observed in 3,4% (2/58) cases. The reason may be the fetus growth
  • 26. retardation in one case and in the second - cytomegalovirus infection. In both cases no specific drug therapy for the treatment of heart rhythm disorders was not applied, they spontaneously disappeared. Congenital complete atrioventricular block was seen in one (1,7%) case in the 22nd gestation week, one of the most complex cases in the group of heart rhythm disorders. Operative labour in the 36th gestation week, a successful permanent epicardial paccemecer system implantation on the 5th day of birth. Structural heart pathologies. Structural heart pathology group 45,7% (105/225). This group was divided into: 1) heart diseases which can be diagnosed in a four-chamber view; 2) pathologies of great arteries. Atrioventricular septal defect (AVSD) as an isolated pathology was diagnosed in 7,6% (8/105) cases. Changes in chromosome number were found in 75% (6/8) cases. Pregnancy was interrupted in 62,5% (5/8). Suspicion to heart disease and the diagnosis verification at the Latvian State Children's Cardiology Centre only after 30 gestation weeks is in 37,5% (3/8) cases, from them in two cases (66,7%) -chromosomal pathology (Down syndrome and Edwards syndrome). Unfavourable outcome in the first week - exitus letalis in one case (33,3%). Table 10. AVSD correlation with codiagnosis, caryotype and outcome. Diagnosis Codiagnosis Caryotype Outcome (number) prenatally prenatally AVSD (I) IUGR 47 XX+18 TOP AVSD(l) IUGR TOP AVSD(l) MDA 47 XX +21 TOP AVSD(l) Polyhydranmios ND AVSD (1) Hydrothorax 47+M TOP AVSD (1) Diaphragmatic hernia 47XY+18 EL AVSD(l) -- 47 XX+21 TOP AVSD(l) -- 47XY+21 PCo Abbreviations: EL - exitus letalis after birth; IUGR-intrauterine growth retardation; TOP - termination of pre gnancy; MDA- multiple development anomalies; PCo PCo - under paediatric cardiologist's observation. ASDI in this study was diagnosed in ]% (1/105) cases in a41-years old mother in 20th gestation week, pregnancy was terminated, taking into account 13 chromosome trisomy (Patau's syndrome)as a result of amniocentesis. Aortic valve stenosis in the study was diagnosed in 1% (1/105) cases. During
  • 27. 29 gestation weeks there were indications to a trivial aortic valve stenosis which was progressing till the end of pregnancy. The newborn after birth was not hospitalized in the Latvian State Children's Cardiology Centre and died on the fifth day after birth due to a severe aortic valve stenosis. Double outlet right ventricle makes 2,9% (3/105) from structural heart pathology group, 66,7% (2/3) pregnancies are interrupted. In one case a father's age might have been the etiological factor (67 years), in the second case Ivemark syndrome was seen after birth. Ebstein's anomaly was seen in 1,9% (2/105), a grave form in both cases, recognized in the iast trimester. In one case - fetal hydrops and early neonatal's death. In the second case - pulmonary artery hypoplasia, the infant after birth was under paediatric cardiologist's observation. Hypoplastic left heart syndrome. One of the most commoonly diagnosed heart diseases in utero, including, four-chamber view. In the Latvian Sate Children's Cardiology Centre 14 such cases have been diagnosed, 13,3% of the total number of structural heart pathologies. Codiagnosis: fetal growth retardation (1), congenital heart disease in the first degree relative (1), maternal exposure to psychotrophic drugs in one case. Termination of pregnancy occurred in 57,1% (8/14) cases, 35.7% (5/14) - an early neonatal death and operative therapy in the first days after birth with a postoperative exitus letalis in 7,1% (1/14) cases. Complex heart disease (includes more than three malformations) is seen in 4,8% (5/105) cases. Fetal growth retardation is seen in one of them. Termination of pregnancy in 60% (3/5). Two cases are still under paediatric cardiologist observation. Genetic pathology - Goldenhar syndrome in one case was diagnosed after birth. Tetralogy of Fallot was diagnosed in 4,8% (5/105). As a codiagnosis for this heart pathology there is oligohydramnios (1), diaphragmatic hernia (1) and fetal hydrops (1). The caryotype prenatally was determined in 40% (2/5), from them trisomy 18, diaphragmatic hernia ultrasonographically and pregnancy was terminated (I). In total, termination of pregnancy in this group occurred in 40%, including one where a sibling had hypoplastic left heart syndrome. Neonatal death after birth was in 20%( I /5) cases where the existing heart disease was complicated by fetal hydrops. Tricuspid valve atresia - 1,9% (2/105) cases. The caryotype was determined in one case, however, despite its normal result, pregnancy was chosen to interrupt because of a poor postnatal prognosis. Another case from this heart disease group was diagnosed after 30th gestation week and it is still under a children cardiologist's care. Tricuspid valve dysplasia. One of the most severe heart diseases during
  • 28. pregnancy which make up to 4,8% (5/105). The caryotype was diagnosed in 60% (3/5) cases, pathologic reponse was in one of them - 21 chromosome trisomy in a mother aged over 35 years. Pregnancy was terminated in 80% (4/ 5) cases. Fetus mortus in one case. Tricusp and pulmonary valve stenosis - 1% (1/105). This heart disease is combined with hydronephrosis and is diagnosed only in the last trimester and ends with an early neaonatal death. Ventricular septal defect (VSD) - 16,2% (17/105). Genetic pathology was found in 35,3% (6/17), including prenatally 18 chromosome trisomy in 4 cases, a fetus with multiple developmental anomalies in a 44 years old mother as one of the cases. Table 11. It demonstrates the correlation of ventricular septal defect with codiagnosis, genetic pathology and outcome. Diagnosis Codiagnosis Caryotype Genetic Outcome Abbreviations: EL - exitus letalis after birth, TOP- termination of pregnancy, MDA- multiple development anomalies PCo - under paediatric cardiologist's observation. Muscular ventricular septal defect structural heart pathology which does not cause any hemodynamic disorders. In this study - 29,5% (31 /105). Prenataly the caryotype is defined in 2 cases (6,4%), one with a pathological result. As a relative or doubtful risk factor might be donor's egg cell (after 1VF procedure) in a 50 years old mother. In two cases, despite an insignificant muscular VSD prenataly, a long-term hospital treatment under a cardiologist's observation was needed. In one of them - a heart operation under cardiopulmonary bypass at the age of three months due to a tumour (myxoma) in the right atrium, and in
  • 29. another case also at the age of three months due to a viral etiology secondary dilatation cardiomyopathy. Transposition of great arteries was found prenatally in 2,9% (3/105) cases. 33,3% (1/3) were diagnosed up to the 22nd gestation week. 66,7% (2/3) -operated on in the first days of life. Early neonatal death (1), post operative exitus letalis (1). Good late post operative result in 1 case: twin pregnancy in a 44 years old mother, in the 27th gestation week one of the twins was found TGA. In this case the caryotype (normal result) was defined prior to 16th gestation week. The neonate had successful "switch" procedure in first day of life. Coarction of aorta 1% (1/105) increased spectral Doppler in a fetus in 32nd gestation week of a mother with diabetes mellitus. In all examinations the abnormal Doppler measurements in the descending aorta were prevailing, which normalized after birth and no specific treatment was needed. Anomalous coronary arteries - suspicion to a left coronary artery fistula in a fetus in 37th gestation week persisted in I % (1/105) cases. After birth no specific treatment was applied. Pulmonary artery valve stenosis - 1% (1/105) cases. In the family history of a 21 years old mother in 32nd gestation week - rubella infection in the first trimester. The baby after birth is still under paediatric cardiologists' observation. Truncus arteriosus coiminis (TAC) was diagnosed in this study in 3.8% cases (4/105) of structural heart pathologies. This heart disease can be diagnosed also in four-chamber view. Only in one case from these four truncus arteriousus communis prenatally diagnosed heart diseases it was diagnosed by 22nd gestation week. Pregnancy was continued; it ended with a pre-term labour and exitus letalis. Table 12. It demonstrates TAC correlation with maternal and family risk factors, caryotype and outcome. Diagnosis Family/maternal risk factors Caryotype Outcome (number) TAC (2) _ _ EL TAC Maternal exposure to alcohol -- OP* /PCo TAC CHD previus child 22ql 1 deletion ** PCo Abbreviations: EL- exitus letalis after birth, OP - operated, PCo - under paediatric cardiologist's observation; *after birth there is pulmonary artresia with a ventricular septal defect, operated
  • 30. at neonatal age; **22 q 11 chromosome deletion is found in mother and two babies, both with a congenital heart disease - conotruncal anomaly. In conclusion: termination of pregnancy occurred in 18,7% (42/225) cases, exitus letalis - 4,4% (10/225) at an early neonatal period, fetus mortus 0,4% (1 /225), heart operations in a neonatal period 1,8% (4/225), normal fetus heart after birth has been found in 22,2% (50/225) which make up a group of heart rhythm disorders, and about 53 % (118/225) remain paediatric cardiologist care. The number of structural heart diseases diagnosed in a four-chamber view was greatly prevalent (89,5%, 94/105) over those, which were diagnosed by examining great arteries (10,5%, 11/105). Within five years while doing 2445 fetal echocardiogramms, false negative results were found in 0,2% (4/2445) cases, from them - subaortal ventricular septal defects (2), later they were successfully operated, and valvular pulmonary artery stenosis (2), which was manifested only after birth, while doing a fetus echocardiogramm not seen in 19 gestation weeks, which was retrospectivelly proved also by a video-recorded examination. No severe or combined heart pathologies are included in this group. There are no data on false positive results. DISCUSSION OF RESULTS Prenatal diagnostics of congenital heart diseases occupies a significant role in children cardiology [Allan L.D. et al., 2002; Buskens E. et al., 1996; Hsien C. etal., 1996; Gembruch U., 1997; Meberg A.,2002, Sharland al., 1992]. Taking into account a high mortality rate from congenital pathologies not only in the whole world, Latvia including [Zīdere V., et al., 2003], timely diagnostics of congenital heart diseases pathologies ensures a provision of professional and qualitative care at an early neonatal period, as well as reduces infant mortality [Hafner E. et al., 1998]. Early diagnostics of pathologies gives a chance to the family decide whether to continue pregnancy or to interrupt it, if the existing heart pathology is fatal or its treatment possibilities are limited and prognosis for a good life quality is doubtful [Allan L.D., 2000; Menahem S. et al., 2003]. Considering the high neonatal and infant mortality (9.9%0, 2002) in Latvia, including congenital anomalies (3,0%0,2002) and congenital heart pathologies (0,9%0,2002) (Year-Book of Health Care Statistics in Latvia, 2002, p.35-37), proper and timely medical care improves the quality of medical care and the demographic situation in the country. AEPC fetal working group recommendations says that in order to diagnose
  • 31. and make the diagnosis precise, its perinatal diagnosis, fetus echocardiography has to be done by a paediatric cardiologist, preferably at a children cardiology centre. In the countries where prenatal cardiology centres are not established, fetal heart examination is done by gynaecologists and even midwives [Berghella V. et al., 2001; Eurenius K. et al., 1999; Skansky M. et al., 2000], but such a system is not considered as optimal. Taking into consideration Latvia's geographical situation, its comparatively small territory and the population rate, there is an opportunity for the first time to develop an ideal AEPC recommended model in Latvia. Leading world specialists in fetal cardiology keep discussing about a series of indications for fetus echocardiography, such as mother's age, diabetes at pregnancy, echogenic cardiac focus, alcoholism [Allan L.D. et al., 2000; Cooper M.J. et al., 1995; Dildy G.A. et al., 1996; Huggon I.C. et al., 2001; Jeanty P., 1996], However, organizing medical care in Latvia in this field for the first time and analyzing the situation in total, we can draw conclusions that, taking into account the fact that paediatric cardiology and especially fetal cardiology is a very new medical branch, comparing it to the Western countries, and gynaecologists and obstetricians having a comparatively short experience, it would be worth to take into account also relative indications of fetal heart disease in order to improve mother and child health care system in Latvia. Comparing the situation with the first year experience in prenatal cardiology, the total number of fetal echocardiogramms has considerably increased from 135 in the first year (1998) to 765 in thefifthyear (2002). Consequently, the number of diagnosed pathologies has increased as well, from 4 (1998) to 44 (2002). The data mentioned characterize not only paediatric cardiologists' work in fetal cardiology but also a successful work done by gynaecologists-obstetricians and geneticians in this field, which, in its turn, indisputably improves health care in Latvia. Comparing it with results of experienced specialists, and analysing our 2445 fetal echocardiogramms, 225 (9,2%) examinations are of pathological findings, these data can be considered satisfactory or even good, comparing them in absolute numbers, e.g., M. Eronen study (1997) at the Children's hospital, University of Helsinki - twelve years' experience - 422 echocardiogramms with 193 (46%) pathological findings (Table 14). Undoubtedly a much greater experience is in the countries of longstanding traditions in fetal cardiology, for example, Guy's hospital in London [LD Allan et al.,2000; Buskens E. Et al., 1996]. Other factors are also of importance, such as, population rate, pregnancy rate, financial resources allocated for the development of this field- Comparing the study data of the Latvian State Children Cardiology Centre with those of other countries, 46,7% of pathological
  • 32. examinations consist of structural heart pathologies, 27,6% - non-structural heart pathologies, 25,8% - heart rhythm disorders. The data of comparative studies by D.H. Brick and L.D. Allan (2000) (Table 13) give the evidence that the number of prenatally diagnosed heart diseases increases if the number of fetal echocardiograms increases in those cases when extracardiac pathologies get diagnosed in routine obstetric ultrasonographies. In the publication mentioned, there are compared study results from Italy, London (1980-1992), the United Kingdom, New York (1993-1999) and Yale, the USA. In the New York study by D.H. Brick, the gestation time from 15-42 week (on average 26), similarly to the data of Italy, London and also Latvia. It is worth mentioning, that 43% heart pathologies in Italy and Yale, but 68% in London study, were diagnosed by 24th gestation week. By the way, in a lot of countries this time is 24 gestation weeks - the time for legal pregnancy interruption according to medical indications and the time when diagnosis of heart pathologies is considered to be timely (in Latvia - 22 gestation weeks). High data of London study can be explained by the fact that in the UK there is a very well organized fetal routine ultrasonographic examination in between 18 to 20 gestation week in the whole country, just opposite to the USA where this medical service is not organized in a system and is administered only in case of diagnosing a heart disease. In Latvia in 31,2% cases the heart pathology was found by 22nd gestation week including. In Yale study 32% extracardiac, 28% chromosomal anomalies were diagnosed, while in New York study - 16% extracardiac and 9% chromosomal pathologies were diagnosed. London and Italian study -17% chromosomal pathologies, from them 17% cases showed extracardiac anomalies. In our study chromosomal pathology during pregnancy was diagnosed in 8% (19/225) cases, from them 14% - extracardiac anomalies, postnatally in 4 other cases a genetic syndrome was diagnosed, in total - 10,3%. Extracardiac pathology 25,3% (57/225) and positive family and mother's history in 7,6% cases. Table 13. Characteristics of comparative study. London New York Yale Italy Latvia 1980-1992 1993-1999 1998-2003IV Extracard iacanomalies ND 16% 32% 17% 25,3% Chromosomal anomalies 17% 9% 28% 17,5% 10,3% Diagnosis prior to 24 gest.week 68% 46% ND 43% 31,2%* Termination of pregnancy 55% 24% 45% 29% 18,7% First diagnoses at average gest.week 26 26 -26 -26 28 ND-no data; * in Latvia study up to 22 gestation week
  • 33. Analyzing study data and the experience of clinics in different countries [Allan L.D., 2000; Brick H.D. et al, 2002; Gill H.K. et al., 2003], including the previously mentioned as well, pregnancies were terminated from 24% to 55% and even 60% cases. This undeoubtedly correlates to the gestation time at which the heart pathology has been diagnosed. Studies show that the earlier an anomaly gets diagnosed, the greater is the rate of interrupted pregnancies. In the Latvian study 18,7% pregnancies were interrupted where fetal heart pathologies were diagnosed. It can be explained by the fact that the time limit for legal pregnancy termination is precocious (22 gestation weeks) to the compared studies (24 gestation weeks), and also slightly lower is the number of early diagnosed pathologies. The tendency for pregnancy termination remains despite the rapid development of pediatric cardiology and cardiosurgery in the last ten years, which might be due to insufficient retrospective data and experience of management of severe heart diseases because in many congenital heart diseases the treatment methods used are comparatively new and there are no studies of further results, as well as in severe, combined heart pathology cases. Despite possibilities for surgical correction, parents are still not sure of a chance to provide their expected child a good life quality [Allan L.D., 2000]. By analyzing the incidence of diagnosed pathologies in detail, the majority of studies were found to be alike. Among the prenatally diagnosed structural heart diseases in a four-chamber view [Brick al., 2002; Eronen M., 1997; Gill al., 2003; Levi S.,1998; Paladini al., 2002; Skansky M. et al, 2000] most commonly are AVSD, HLHS, tetralogy of Fallot, VSD, followed by mitral valve atresia, TGA, DORV and others. The study of State Children's Cardiology Centre is slightly different, the first to be mentioned are VSD, muscular VSD, HLHS, tetralogy of Fallot, complex heart disease and others. Studies unequivocally prove that a complete heart examination in routine fetus investigation may yield maximum results and by adding great arteries views to traditionaliy used four chamber position, the diagnostics of combined, severe heart diagnosis increases from 60% to 90% [Allan L.D., 2000; Carvalho al.,2002; Wong al., 2003; Hess al., 1998; Levi al.,1998].
  • 34. Table 14. demonstrates our study results in comparison to that of M. Eronen (1997) at the Children's hospital, University of Helsinki. * only in a structural pathology group ** termination of pregnancy, fetus mortus, early neonatal death CONCLUSIONS 1.Fetal heart pathology is a common fetal anomaly in Latvia which can be diagnosed during pregnancy. 2.By increase of total fetal echocardiogram rate, there is an increase of diagnosed pathologies from 3% in the first year when starting prenatal cardiology till 8,6% in the fifth. 3.Paediatric cardiologist with an extra training in prenatal cardiology, by using now available medical equipment, provides the verification of an early heart pathology in Latvia starting with the 15th gestation week. 4.Using up-to-date echocardiographic equipment, the Latvian State Children Cardiology Centre is able to diagnose wide spectre congenital heart anomalies. 5.Fetal heart pathology in Latvia is very often combined with extracardiac (25,3%) and genetic pathology (10,3%), as well as the risk for a genetic pathology and a heart disease in a fetus increases in mothers over 35 years - 23,3% (p=0,026). 6.The study proves that severe, combined heart pathologies are diagnosed comparatively late and the medial gestation time at which the heart pathologies in a fetus are diagnosed for the first time is later in time (28 gestation week) as compared to the studies in clinics with longstanding experience (26 gestation week). 7.In our study a fetal heart pathology was diagnosed in 31 % up to 22nd gestation week which is the legal time for interrupting of pregnancy in Latvia. 8.Timely diagnostics of fetal heart malformations in severe cases of poor life
  • 35. prognosis allows the family to choose whether to continue pregnancy or terminate it. In our study - if severe heart diseases are diagnosed timely, the family decides not to continue pregnancy. 9.Comparing results of our first study in Latvia with those of developed countries in Europe and the USA which have long-term experience with diagnosed heart pathologies, no statistically confident differences have been found. 10. Doing a research within one country, there were worked out recommendations for fetal heart ultrasonographic examination adapted for Latvia. Working out and implementing the recommendations for fetal heart ultrasonographic examination in a doctor's practice, considering the perinatal care situation in Latvia, as well as teaching gynaecologists and obstetricians in this field, the results in prenatal and postnatal children cardiology have greatly improved. PRACTICAL RECOMMENDATIONS 1.Organizing perinatal care, it is important to envisage the time and to provide the technical opportunities in order in each fetal ultrasonographic examination the gynaecologist could pay a special attention to fetal heart examination, great arteries vessels including. 2.To improve the diagnostic level of fetal heart pathologies, it is important to examine at least one fetal ultrasonographic examination in the period from 18- 20th gestation week, but in a high risk pregnancy case starting already from 15-16 gestation week. 3.When examining a fetal heart in routine obstetric ultrasonography, one should choose an adequate programme (fetal heart) and 5 or 3 MHz transducer, majority of which are offered by contemporary equipment. 4.By diagnosing a cardiac or any other extracardiac fetal pathology, it is necessary to have a paediatric cardiologist's consultation. 5.Taking into account a rather small territory of Latvia and its unfavourable demographic situation - low birth rate and high perinatal mortality, and in order to preserve a high fetal echocardiographic quality and to ensure an adequate medical help, in case of a congenital heart risk, the fetal heart specialized examination has to be done at children cardiology centres. 6.In case of heart pathology, if pregnancy time permits, it is worth doing a caryotype analysis which would certainly help prognose both prenatal and postnatal outcome. 1. Diagnostics of prenatal heart pathologies, including heart and genetic ones, helps the family and doctors choose the further treatment tactics and organize
  • 36. 2. it correctly, at the same time the medical institutions can plan for medical resources timely and purposefully. 8. A fetus with a congenital heart pathology can be delivered in a medical institution which has a close collaboration with a children cardiology centre to optimize an instant help in each diagnostic category. 9.The information on a possible fetal heart specific examination and echocardiography has to be available to each family in order to have a possibility to choose it, even if there are no specific indications or heart pathology risk. This is a significant psychological aspect during pregnancy - confidence in having a healthy child. 10. In perspective, striving for an ideal mother and child health care in Latvia, it would be necessary to provide fetal echochardiography in each pregnancy and done by a paediatric cardiologist trained in fetal cardiology.