http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.918598

ORIGINAL ARTICLE

Birth outcomes of cases with conotruncal defects of heart – a population-based case-control study Attila Vereczkey1, Zsolt Ko´sa1, Melinda Csa´ky-Szunyogh2, Bala´zs Gerencse´r3, and Andrew E. Czeizel4 J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Mcgill University on 01/15/15 For personal use only.

1

Versys Clinics, Human Reproduction Institute, Budapest, Hungary, 2Hungarian Congenital Abnormality Registry, National Institute for Health Development, Budapest, Hungary, 3Alfre´d Re´nyi Institute of Mathematics, Hungarian Academy of Sciences, Budapest, Hungary, and 4Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary

Abstract

Keywords

Objective: The aim of this study was to evaluate the birth outcomes of cases with four types of conotruncal defects (CTDs), i.e. common truncus, transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle. Methods: Birth outcomes of 597 live-born cases with CTD and 38 151 population controls without any defects were compared in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities completed by socio-demographic variables of their mothers. Results: There was a male excess in cases with CTD (56.8%) with the same mean gestational age (39.4 versus 39.4 weeks) and preterm birth rate (8.2 versus 9.2%), but their mean birth weight was smaller (3077 versus 3276 g) with a high rate of low birthweight (14.6 versus 5.7%) compared to the birth outcomes of population controls. These data indicate intrauterine growth restriction of fetuses affected with transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle particularly in females, while there were a shorter mean gestational age and smaller mean birth weigh in cases with common truncus. Conclusions: In general CTD, except common truncus, had no effect for gestational age but associated with a high risk for intrauterine fetal growth restriction particularly in female cases.

Common truncus, congenital heart defects, double-outlet right ventricle, intrauterine growth restriction, male excess, transposition of great vessels, tetralogy of Fallot

Introduction Congenital heart defects (CHDs) represent the most common group of structural birth defects, i.e. congenital abnormalities (CAs). The birth prevalence of cases with CAs of heart and great vessels was between 4 and 50 per 1000 live-births in different studies because their occurrence depends on the age at examination, the sensitivity of the examination technique, the case definition and the types of CHDs included [1–6]. CHDs cannot be regarded as a single homogeneous CA-group because they have different manifestations, severity and etiology; thus, our study design was based on the differentiation of CHD-types according to the recently proposed classification of CHDs [7–10]. The evaluation of embryonic development of heart and great vessels helped to combine some previously clinically different CHD-entities into one pathogenetic group: the so-called conotruncal defects (CTDs) including common truncus, transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle. The aim

Address for correspondence: Andrew E. Czeizel, Foundation for the Community Control of Hereditary Diseases, 1026, Budapest, To¨ro¨kve´sz lejto00 32, Hungary. Tel/Fax: +36-1-3944 412. E-mail: czeizel@ interware.hu

History Received 6 March 2013 Accepted 23 April 2014 Published online 29 May 2014

of our study is to evaluate birth outcomes of cases with different CTD-types and the socio-demographic features of their mothers in the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) [11].

Methods Cases and population controls Cases with CA including CTD in the HCCSCA were selected from the Hungarian Congenital Abnormality Registry (HCAR) [12]. However, cases reported to the HCAR after the first three months of births or termination of pregnancies (23% of all cases, mainly mild CAs) and cases with CA-syndromes caused by gene mutations or chromosomal aberrations with preconception origin were excluded from the HCCSCA. The so-called population controls were defined as newborn infants without CA. Controls were selected from the National Birth Registry of the Central Statistical Office for the HCCSCA on the basis of case lists for each quarter of the years. In general, two population controls were matched to every case according to sex, birth week in the year when the case was born and district of parents’ residence. If population

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controls were twin, only one of these twin-pairs was selected randomly for the HCCSCA. A structured questionnaire with an explanatory letter and printed informed consent was mailed continuously to the address of mothers of cases and population controls immediately after their selection for the HCCSCA. The questionnaire requested information, among others, on maternal characteristics (socio-demographic data, history of previous pregnancies). In addition, mothers were requested to send us the prenatal maternity logbook, discharge summary of their deliveries and every medical record of their child’s CA. The mean ± S.D. time elapsed between the end of pregnancy and return of the ‘‘information package’’ (including logbook, discharge summary, questionnaire and signed informed consent) in our prepaid envelope was 3.5 ± 2.1 and 5.2 ± 2.9 months in cases and population controls, respectively. In addition, regional district nurses were asked to visit all non-respondent case mothers and to help them to fill-in the same questionnaire used in the HCCSCA and to evaluate the available medical documents. Unfortunately district nurses could visit only 200 non-respondent and 600 respondent population control mothers in two validation studies [13,14], because the ethics committee considered this follow-up to be disturbing for the parents of healthy children. Another validation study showed the low reliability of retrospective maternal self-reported information regarding smoking and alcohol drinking during the study pregnancy [15]. The number of smokers and alcohol drinkers during the study pregnancy, therefore, were evaluated only in those mothers, who were visited and questioned at home, but these data were completed on the basis of cross interview of family members living together, and finally the so-called family consensus was recorded. Three groups of drinking habit were differentiated: abstinent or occasional drinkers (less than one drink per week), regular drinkers (from one drink per week to daily one drink) and hard drinkers (more than one drink per day). The necessary information was available for 96.3% of cases (84.4% from replies and 11.9% from visits) and 83.0% of population controls (81.3% from replies and 1.7% from visits). The signed informed consent was sent back by 98% of mothers, the name and address were deleted in 2% of subjects without signed informed consent. The data of birth outcomes were based on the Notification Form of Cases with CA in the HCAR confirmed by the discharge summary of delivery and maternal information in the questionnaire. The birth outcomes of population controls were evaluated by the help of the latter two data sources. The gestational age was calculated from the first day of the last menstrual period. Maternal age and birth order (parity) were recorded in the HCAR but these variables were checked in the HCCSCA completed by pregnancy order, marital and employment status based on the prenatal maternity logbook and maternal questionnaire. The maternal employment is a good indicator of socioeconomic status in Hungary [16]. The method of data collection was changed in 1997 (since all case and control mothers are visited and questioned at home by regional nurses, but these data have not been

J Matern Fetal Neonatal Med, Early Online: 1–6

validated at the time of this analysis), and it explains here that only the 17 years’ datasets of the HCCSCA, 1980–1996 are evaluated. Study design of CTD We supposed that most survival cases with CHD were cared or had surgical intervention in the pediatric cardiologic institutions in Hungary, therefore one of us (M. Cs-Sz.) visited these cardiologic in- and outpatients clinics in 2008. Medical records were reviewed and the previous diagnosis of specified CHDs was checked (and corrected it if necessary) and the previous unspecified CHDs were modified to specified CHD-diagnoses. Some cases with CTD were not found in the records of cardiologic institutions; in these cases, we had a correspondence with mothers to clarify the status of their children in 2009 and 2010. However, (i) if these cases were not found, (ii) CTD-diagnosis was not specified, (iii) not confirmed, or (iv) mothers refused the collaboration, they were excluded from the study. CTDs represent the major anatomic phenotypes of outflow tract abnormalities, i.e. disturbances in the ventriculo-arterial portion of the ascending limb of the primitive S-shaped cardiac loop (the so-called conus or bulbus cordis), which will become septated by ridges derived from the endocardial cushions and by the aortico-pulmonary septum, respectively, to form the divided arterial outflow from the right and left ventricles and of the pulmonary artery and aorta [7–10]. At the evaluation of CTDs we had three selection steps: (I) Cases with syndromic CTD due to major mutant genes such as CA-syndromes (e.g. Holt-Oram) or chromosomal aberrations (e.g. Down syndrome) were excluded from the HCCSCA. Unidentified multiple CAs including CTD were also excluded in the study. (II) Only cases with well-defined diagnosis of four CTD-types were included to the study: (i) Truncus arteriosus communis (TAC) or common truncus is a CHD in which truncus arteriosus is not properly differentiated into the two great arteries. One large single artery receiving blood from both right and left ventricles has one semilunar valve and distributes blood to both systematic and pulmonary circulations. The pulmonary artery may arise either as a single vessel or as two separate vessels from the trunk. A ventricular septal defect is present in all cases. (ii) Transposition of great arteries (TGA) with or without ventricular defects and pulmonary or tricuspid atresia, the aorta arises from the right ventricle in the anterior position and the pulmonary artery from the left ventricle in a posterior position. This complete transposition creates two parallel circulations, this situation obviously is incompatible with life; thus, only surgical intervention can protect the life. Complete transposition of great vessels may exist with intact ventricular septum, with ventricular septal defect, with double-outlet right ventricle and with pulmonary/tricuspid atresia.

Conotruncal heart defects

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DOI: 10.3109/14767058.2014.918598

(iii) Tetralogy of Fallot (TOF), classically this CHD comprises of four components: large ventricular septal defect, an aorta overriding the ventricular septal defect, severe infundibular pulmonic stenosis (small pulmonary valve and pulmonary artery) or atresia and right ventricular hypertrophy. Thus, TOF is characterized by biventricular origin of the aorta above large ventricular septal defect. (iv) Double-outlet right ventricles (DORV). In this rare CHD (about 1% of cases with CHD), more than 50% of the semilunar valve orifices of both great arteries arise from the morphologic right ventricle. In most cases, the ventricles display a D loop, and the pulmonary arterial origin is normally positioned, arising from the conus above the right ventricle. The aorta also arises from the right ventricle above conal tissue. In most cases, the aortic origin is to the right (d-malposition) of the pulmonary arterial origin, with the two vessels in a side-by-side relationship. Rarely, the aortic origin is distinctly anterior to the pulmonary origin or the aorta arises to the left (l-malposition) of the pulmonary artery. (III) Finally, only lethal cases with autopsy report or survival cases with surgical correction were included in the study, thus the diagnosis of CTD cases had high validity. Statistical analysis The software GNU R 2.14, R-Studio version 0.97 (Alfre´d Re´nyi Institute of Mathematics, Hungarian Academy of Sciences, Budapest, Hungary) was used for the analysis of variables. First, frequency tables were made for the main birth outcomes of cases with CTD and population controls. Second, at the evaluation of quantitative birth outcomes of newborn infants (mean gestational age and birth weight) and age and pregnancy/birth order of mothers Student’s t-test was used while categorical variables of mothers as marital and employment status were analyzed by the Chi square test. At the evaluation of categorical birth outcomes, such as preterm birth and low birthweight, odds ratios (OR) with 95% confidence intervals (CI) were calculated in multivariable unconditional regression model at the comparison of cases and population controls.

Results Our population-based data set included 598 cases with CTD, only one TOF was diagnosed in stillborn male fetus; thus, only 597 live-born cases are evaluated in the study. The number of males was 339, thus the sex ratio: proportion of males was 56.8% in these cases. The sex ratio of the Hungarian newborn population was 51.3% during the study period. Of 597 cases, 44 (31; 70.5%) had TAC, 307 (169; 55.0%) were affected with TGA, 222 (127; 57.2%) had TOF and 24 (12; 50%) were recorded DORV. (In brackets the numbers of male cases with their sex ratio are shown.) Cases with TAC had obvious, cases with TGA and TOF had slight male predominance, while DORV cases did not differ from the expected sex ratio.

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These 597 cases had 902 matched controls and 38 151 population controls, the latter represented 1.8% of all Hungarian births between 1980 and 1996. The data of matched controls are not presented in the paper because they did not differ from the results of population controls. Among maternal variables (Table 1), first the total group of cases with CTD was analyzed. The mean maternal age was somewhat while the mean birth order was significantly higher due to the larger proportion of multiparous women in the mothers of cases than in the mothers of population control. There was no difference in mean pregnancy order (live- and stillbirths + miscarriages) between case and population control mothers, thus this finding is against the higher rate of miscarriages in the previous pregnancies of case mothers. The rate of unmarried mothers was similar between the study groups. However, there was a significant difference in the distribution of maternal employment status, because the proportion of low socio-economic status (semi- and unskilled workers, housewife) was larger in case mothers (34.0%) than in population control mothers (28.0%). The maternal variables of cases with different CTD-types were evaluated separately as well. The mean age (yr) was highest in the mothers of DORV (26.6) followed by the mothers of cases with TGA (25.9), TOF (25.3) and TAC (25.1). The mean birth order was highest: 2.0 in cases with DORV and TAC, and lowest: 1.8 in cases with TOF. The lower socioeconomic status was most obvious in the group of TAC (40.9%) compared to TGA (33.2%), TOF (33.8%), DORV (32.4%). The medically recorded live-birth outcomes in total group of cases with CTD are presented in Table 2. The number of twins was 12 among 597 cases (2.0%) while of 38 151 population controls, 410 (1.1%), thus the difference was near to the level of significance, OR with 95% CI: 1.88, 0.97–3.48). Table 1. Main variables of mothers of cases with CTD and population controls.

Variables Quantitative Maternal age 19 20–29 30– Mean, S.D. Birth order 1 2 or more Mean, S.D. Pregnancy order 1 2 or more Mean, S.D. Categorical Unmarried Employment status Professional Managerial Skilled worker Semi-skilled worker Unskilled worker Housewife Others

Case mothers (N ¼ 597) No.

%

Population control mothers (N ¼ 38 151) No.

% 23

48 426 123 25.7

8.0 71.4 20.6 5.0

261 336 1.9

43.7 56.3 1.1

234 363 2.0 No. 22

39.2 60.8 1.3 % 3.7

56 145 174 100 41 62 19

9.4 24.3 29.1 16.7 6.9 10.4 3.2

¼ 10.2 p ¼ 0.600 3277 8.6 27 602 72.3 7272 19.1 25.5 4.9 t ¼ 1.93 p ¼ 0.054 22 ¼ 3.79 p ¼ 0.052 18 209 47.7 19 942 52.3 1.7 1.0 t ¼ 4.42 p50.001 22 ¼ 3.08 p ¼ 0.079 16 320 42.8 21 831 57.2 1.9 1.2 t ¼ 1.87 p ¼ 0.062 No. % 1472 3.9 21 ¼ 0.05 p ¼ 0.83 26 ¼ 25.33 p50.001 4423 11.6 10 265 26.9 11 908 31.2 6161 16.1 2187 5.7 2354 6.2 853 2.2

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Table 2. Live-birth outcomes of cases with CTD and population controls, in addition live-birth outcomes according to the sex of cases and population controls (Preterm birth ¼ less than 37 weeks; postterm birth ¼ 42 or more weeks; low birthweight ¼ less than 2500 g; large birth weight ¼ 4500 or more grams). Live-birth outcomes Quantitative Gestational age (wk)* Birth weight (g)y Categorical Preterm birth* Postterm birth* Low birthweighty Large birthweighty

Population controls (N ¼ 38 151)

Cases (N ¼ 597) Mean

S.D.

Mean

S.D.



39.4 3077 No. 49 4 87 9

2.0 588 % 8.2 0.7 14.6 1.5

39.4 3276 No. 3496 151 2167 315

2.1 511 % 9.2 0.4 5.7 0.8

0.00 8.22 OR 0.89 1.75 2.83 1.84

p¼ 1.000 50.0001 95% CI 0.66–1.19 0.88–4.80 2.25–3.57 0.94–3.58

Female population controls (N ¼ 13 352)

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Live-birth outcomes Quantitative Gestational age (wk)* Birth weight (g)y Categorical Preterm birth* Low birthweighty

Female cases (N ¼ 258) Mean

S.D.

Mean

S.D.



39.2 2963 No. 17 42

2.0 538 % 6.6 16.3

39.3 3187 No. 1427 929

2.1 494 % 10.7 7.0

0.00 3.63 OR 0.59 2.60

p¼ 1.000 50.001 95% CI 0.36–0.97 1.86–3.64

Male population controls (N ¼ 24 799) Live-birth outcomes Quantitative Gestational age (wk)* Birth weight (g)y Categorical Preterm birth* Low birthweighty

Male cases (N ¼ 339) Mean

S.D.

Mean

S.D.



39.4 3164 No. 32 45

2.1 611 % 9.4 13.3

39.4 3323 No. 2069 1238

2.0 514 % 8.3 5.0

0.00 4.72 OR 1.15 2.91

p¼ 1.000 50.001 95% CI 0.79–1.65 2.12–4.01

*Adjusted for sex of cases/population controls, in addition for the age, parity (birth order) and employment status of mothers. yAdjusted for sex of cases/population controls, in addition to the age, parity (birth order), employment status of mothers and gestational age of newborns. Bold numbers show significant associations.

The mean gestational age was similar in cases and in population controls. However, the mean birth weight of cases was smaller with 199 g compared to population controls. These findings were in agreement with the similar rate of preterm births and 2.6-fold higher rate of low birthweight in cases than in population controls. The rate of preterm births without twins was 6.2% in cases and 8.1% in population controls (OR 95% CI: 0.79, 0.55–1.08). Thus, the major finding of this analysis is an obvious intrauterine fetal growth restriction of cases with CTD. The birth outcomes of cases with CTD were evaluated according to the sex as well (Table 2). The mean gestational age of male cases and male population controls was the same while it was 0.1 week shorter in female cases than in female population controls. However, the latter associated with a significantly lower rate of preterm birth in female cases. The mean birth weight was lower in females than in males both in the group of cases and population controls as in general. The difference in mean birth weight was larger in female cases (224 g) than in male cases (159 g) compared to their population controls. The rate of low birthweight was higher both in male cases and particularly female cases than in male and female population controls. Thus, these data indicate differences in the birth outcomes of female and male cases: both sexes had intrauterine growth restriction with a stronger effect in female cases, on the contrary of their shorter gestational age and lower rate of preterm birth.

We attempted to evaluate the birth outcomes of the four types of CTD separately compared to the data of population controls (Table 3). The distribution of 12 twins was the following: TAC 1 (2.3%), TGA 5 (1.6%), TOF 6 (2.7%), DORV 0. Cases with TAC showed a shorter mean gestational age and lower mean birth weight and these variables associated with a high rate of preterm birth and extremely high rate of low birthweight. These data indicate beyond shorter gestational age drastic intrauterine growth restriction. However, TAC was exceptional, because the mean gestational age of TGA, TOF and DORV did not differ from the mean gestational age of population controls in agreement with the somewhat lower rates of preterm births. The lower rate of preterm is noteworthy, because without twins it was 6.5% in cases with TGA and 3.6% in cases with TOF, and the latter was significantly lower. However, their mean birth weight was smaller and it associated with a higher rate of low birthweight. Thus, birth outcomes of TGA, TOF and DORV indicate intrauterine growth restriction. Only 58 case mothers were visited at home, 12 (20.7%) smoked cigarettes during the study pregnancy. The proportion of smokers was 19.8% in population control mothers. The rate of regular and hard drinkers together was 1.2% in the mothers of population controls, while five regular and two hard drinkers, together seven (12.1%) were revealed during the study pregnancy in the mothers of cases with CTD (OR with 95% CI: 10.8, 3.3–32.9).

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Table 3. Live-birth outcomes of cases with different types of CTD compared to the birth outcomes of population controls (see their data in Table 2).

Live-birth outcomes

Cases with TAC (N ¼ 44)

Comparison with population controls (N ¼ 38 151)

Study groups Quantitative

Mean

S.D.





Mean

S.D.





Gestational age (wk) Birth weight (g) Categorical Preterm birth* Low birthweighty

38.6 2919 No. 8 15

3.3 782 % 18.2 34.1

1.61 3.03 OR 2.2 8.6

0.115 0.004 95% CI 1.0–4.7 4.6–16.0

39.5 3,150 No. 25 36

1.9 586 % 8.1 11.7

0.92 3.76 OR 0.9 2.2

0.359 0.001 95% CI 0.6–1.3 1.6–3.1

Study groups

Cases with TOF (N ¼ 222)

Quantitative

Mean

S.D.





Mean

S.D.





Gestational age (wk)* Birth weight (g)y Categorical Preterm birth* Low birthweighty

39.3 2997 No. 14 32

1.9 535 % 6.3 14.4

0.78 7.77 OR 0.7 2.8

0.434 0.002 95% CI 0.4–1.1 1.9–4.1

39.4 3171 No. 2 4

2.0 563 % 8.3 16.7

0.00 0.91 OR 0.9 3.3

1.000 0.970 95% CI 0.2–3.8 1.1–9.7

Comparison with population controls (N ¼ 38 151)

Cases with TGA (N ¼ 307)

Cases with DORV (N ¼ 24)

Comparison with population controls (N ¼ 38 151)

Comparison with population controls (N ¼ 38 151)

*Adjusted for sex of cases/population controls, in addition for the age, parity (birth order) and employment status of mothers. yAdjusted for sex of cases/population controls, for the age, parity (birth order), employment status of mothers and gestational age of newborns. Bold numbers show significant associations.

Discussion The major findings of our study indicated male excess of cases with CTD, a characteristic difference in birth outcomes between TAC and TGA–TOF–DORV with obvious intrauterine fetal growth restriction; in addition, sex modified birth outcomes of cases with CTD: female cases had lower rate of preterm birth with higher rate of low birthweight. The male excess among cases with CTD found in our and other studies [9,17,18] is worth mentioning, because this supports the hypothesis of sex-modified threshold level in CTD polygenic system. An important finding of the study is that CTD, with the exception of TAC, had no effect for gestational age and rate of preterm birth. In fact, the latter was lower in cases with TGA– TOF–DORV than in population controls. However, CTD associates with an obvious risk for intrauterine fetal growth restriction. Thus, intrauterine life hemodynamic alterations due to CTD may affect size and growth patterns of the fetus [19]. However, our study showed first the sex difference in the birth outcomes of cases with different CDT-types, females had a stronger intrauterine growth restriction without shorter gestational age. The somewhat older mothers were found in our and another study [20], with a higher birth order and lower socioeconomic status in the mothers of our cases. Previously many studies showed an association between drinking habit of pregnant women and characteristic pattern (fetal alcohol syndrome/effect) of CAs including CHD as well in their children [21,22]. Tikkanen and Heinonen [23] found a much higher risk of conal CHD in the children of pregnant women with alcohol drinking during the first trimester of pregnancy. Our study confirmed it though it was based only on a subsample of our material; however, these data were collected through a cross interview of mothers and their close family members, excluding the very unreliable maternal selfreported information.

The strengths of our study are connected with the large population-based data set of the HCCSCA including 597 live-born cases with CTD and 38 151 population controls without CAs in the ethnically homogeneous Hungarian (Caucasian) population. The validity of CTD-diagnoses due to the follow-up of our cases in cardiologic institutions was good because finally only cases with precise diagnosis based on surgical description or autopsy records. Prenatal diagnosis of severe CHD fetuses was not introduced in Hungary during the study period. In addition, we did our best to work with CTD-types as homogeneously as possible, therefore, syndromic/unidentified multiple cases including CTD were excluded from the study. Birth outcomes of cases and population controls were medically recorded. However, there were some weaknesses of our study: (i) The rarity of some CTD-types creates difficulties in the evaluation of different anatomic subtypes, e.g. we were not able to differentiate the two subtypes of TGA on the basis of great artery relationship such as transpose (parallel) and normal (spiral) [9]. (ii) Lifestyle factors, such as smoking habit and alcohol drinking were known only in a subsample of mothers visited at home. In conclusion, our findings showed the male excess and intrauterine growth restriction of cases with CTD particularly in females, confirmed the role of regular/hard drinking in the origin of CTDs and some difference in the birth outcomes of TAC and TGA– TOF–DORV.

Acknowledgements This project was supported by the Hungarian Ege´szse´gu¨gyi Tudoma´nyos Tana´cs Pa´lya´zati Iroda´ja (Grant Office of Scientific Committee of Health Ministry) and Versys Clinics, Human Reproduction Institute, Budapest, Hungary. The authors thank Erika Varga for her help in the preparation of data set for statistical analysis.

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Declaration of interest The authors report no declarations of interest.

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Birth outcomes of cases with conotruncal defects of heart - a population-based case-control study.

The aim of this study was to evaluate the birth outcomes of cases with four types of conotruncal defects (CTDs), i.e. common truncus, transposition of...
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