European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 1–6
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Association of certain chronic maternal diseases with the risk of specific congenital heart defects: a population-based study A. Vereczkey a,*, B. Gerencse´r b, A.E. Czeizel c, I. Szabo´ d a
Versys Clinics, Human Reproduction Institute, Budapest, Hungary Alfre´d Re´nyi Institute of Mathematics, Hungarian Academy of Sciences, Budapest, Hungary c Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary d Department of Obstetrics and Gynaecology, University of Pe´cs, Pe´cs, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 March 2014 Received in revised form 18 June 2014 Accepted 16 August 2014
Objective: Previous epidemiological studies have evaluated cases with all congenital heart defects (CHDs), rather than analysing different types of CHD. The objective of this study was to evaluate the possible association of certain chronic maternal diseases with the risk of different types of CHD, because the role of possible environmental factors in the origin of CHDs is unclear in the vast majority of patients. Study design: Different types of CHD, diagnosed after lethal outcome (autopsy report) or after surgical intervention (catheter or correction), were evaluated in order to estimate the possible role of chronic maternal diseases in their origin. This analysis was based on the rates of medically recorded chronic maternal diseases in 3562 live-born cases with CHDs, 38,151 population controls without any birth defects, and 16,602 malformed controls with other isolated congenital abnormalities, using the data set of the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities (1980–1996). Results: Maternal epilepsy treated with carbamazepine and migraine were found to be associated with higher risk of ventricular septal defect; panic disorders were associated with higher risk of hypoplastic left heart; type I diabetes mellitus was associated with higher risk of coarctation of the aorta; chronic hypertension was associated with higher risk of ventricular septal defect, common atrioventricular canal and common truncus; and paroxysmal supraventricular tachycardia was associated with higher risk of atrial septal defect secundum, common atrioventricular canal and ventricular septal defect. Conclusion: In conclusion, certain chronic maternal diseases were found to be associated with higher risk of specific CHDs. Appropriate treatment of these diseases may help to prevent these CHDs. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Congenital heart defects Epilepsy Migraine Diabetes mellitus Population-based case–control study
Introduction Congenital heart defects (CHDs) are the most common (4–50 per 1000 live-births) [1,2] and serious [3] structural birth defects (i.e. congenital abnormalities). The care of infants/children with CHDs has been revolutionised over recent decades [4], and progress in human genetics has resulted in better understanding of the genes associated with CHDs [5]. However, the role of possible environmental factors in the origin of CHDs is unclear in the vast majority of patients [6,7]. As such, this study aimed to investigate possible associations between chronic maternal diseases and the risk of CHDs.
* Corresponding author at: 1138 Budapest, Madara´sz Viktor utca 47-49, Hungary. Tel.: +36 1 3944 412; fax: +36 1 3944 412. E-mail addresses: [email protected], [email protected] (A. Vereczkey). http://dx.doi.org/10.1016/j.ejogrb.2014.08.022 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
CHDs have heterogeneous manifestations and origins [8]. The classification of CHDs used in the Baltimore-Washington Infant Study [9,10] was adopted in this study. Newborn infants affected with a single type of CHD, diagnosed by lethal outcome (autopsy report) and/or surgical intervention (catheter or correction), in the data set of the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA) [11] were included in this study. Materials and methods Study subjects Patients (i.e. cases with congenital abnormalities including CHDs in the HCCSCA) were selected from the Hungarian Congenital Abnormality Registry (HCAR) [12,13]. Reporting of cases with congenital abnormalities to the HCAR is mandatory for physicians, and autopsy is mandatory for all infant deaths; pathologists send a
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copy of the autopsy report to the HCAR if defects are identified. Approximately 90% of major congenital abnormalities were recorded on the HCAR [14]. Only those cases with congenital abnormalities who were reported to the HCAR during the first 3 months after birth were selected for the HCCSCA. In addition, cases with congenital abnormality syndromes caused by gene mutations or chromosomal aberrations with preconceptional origin were excluded. In the HCCSCA, controls were defined as newborn infants without congenital abnormalities, matched to cases by sex, birth week and district of parents’ residence. The source of these controls was the National Birth Registry of the Central Statistical Office for the HCCSCA. In general, two controls were matched to each case. Collection of exposure data and confounding factors An explanatory letter and an informed consent form were posted to the mothers of cases and controls immediately after their selection for the HCCSCA, and they were asked to supply their prenatal maternity logbook and all medical records concerning their diseases during the study pregnancy and their child’s congenital abnormality. These documents were returned within 4 weeks. Prenatal care is mandatory for pregnant women in Hungary, and women who do not attend for prenatal care do not receive a maternity grant or maternity leave. As such, nearly 100% of pregnant women attended for prenatal care, on average, seven times between 6 weeks of gestation and the end of pregnancy. Obstetricians in prenatal care are obliged to record pregnancy complications, maternal diseases and related medicinal products for women during pregnancy in the logbook. The mean standard deviation time between the end of pregnancy and return of the ‘information package’ (i.e. logbook, discharge summary and informed consent form) in the prepaid envelope was 3.5 2.1 and 5.2 2.9 months for cases and controls, respectively. Regional district nurses were asked to visit all case mothers who did not respond, and to evaluate the available medical documents. Unfortunately, the district nurses could only visit 200 non-respondent control mothers [15] and 600 respondent control mothers [16] in two validation studies because the ethics committee considered that this follow-up might be disturbing for the parents of healthy children. Data on chronic maternal diseases were available for 96.3% of cases (84.4% from postal replies and 11.9% from visits) and 83.0% of controls (81.3% from postal replies and 1.7% from visits). Signed informed consent forms were returned by 98% of mothers; names and addresses were deleted for the 2% of subjects who did not provide signed informed consent. The method of data collection was changed in 1997, but these data had not been validated at the time of this analysis. As such, this study is based on the 17-year dataset of the HCCSCA from 1980 to 1996. Study design of cases with CHDs In general, cases with congenital abnormalities were reported immediately after birth to the HCAR. Approximately 50% of cases with CHDs were reported as unspecified CHDs, because the exact diagnosis required further time-consuming examinations. The HCCSCA researchers were able to specify the type of CHD in a further 20% of cases by evaluation of the medical data of cases with congenital abnormalities 3.5 2.1 months after birth. For the remaining 30% of live-born cases without a specific CHD diagnosis, it was anticipated that they would have received care or surgical intervention at a paediatric cardiology institution; therefore, the HCCSCA researchers visited these cardiology in- and outpatient
clinics in 2008. Medical records were reviewed, and unspecified CHDs were changed to specific CHD diagnoses where possible. For cases with a diagnosis of CHD who were not found in the records of paediatric cardiology institutions, their mothers were contacted to clarify the fate and/or diagnosis in 2009 and 2010. Cases that could not be traced, cases without a specific CHD diagnosis, and cases whose mothers did not wish to participate were excluded from the study. Cases with multiple congenital abnormalities including CHDs were also excluded from the study. In addition, because some types of CHD have a wide spectrum of manifestations including spontaneous closure of ventricular or atrial septal defects, ductus arteriosus, etc., only cases with lethal outcomes (verified by autopsy record) or who had undergone surgical intervention (cardiac catheter diagnosis or correction) were included in the study. There were two control groups in this study: (i) the live-born population controls without any congenital abnormalities; and (ii) the live-born malformed controls with other isolated congenital abnormalities from the HCCSCA dataset. Statistical analysis of data GNU R 2.14, RStudio 0.97 version was used for statistical analysis. Associations between certain chronic maternal diseases
Reported CHD cases in HCAR, 1980–1996 15,206 ↘ ↙ Isolated Syndromic/mulple 2265 12,941 ↓ Reported during first 3 months aer birth in HCCSCA 9076 ↘ ↘ ↓ ↓ Non-respondent Undelivered ↓ 860 556 ↓ ↓ Visit at home ↓ ↙ ↓ ↘ Respondent Evaluated Refused collaboraon Unknown address 1080 71 265 7660 8740 ↙
↘ Checked in cardiology instuons 8103 ↙ ↘ ↙ Not found, maternal contact 1011 ↙ ↙ ↙ ↓ ↘ Found Collaboraon Refused No contact 7092 323 55 633
Misdiagnosis (syndromic, heart murmur, etc.) 637
7415 ↙ Excluded cases 2275 Not confirmed diagnosis 737 Spontaneous recovery 1383 Unspecified CHD 188 Death to other causes 12
↘ Confirmed diagnosis 5140 Diagnosis based on surgical documents or autopsy record 3838 (including 15 sllborn fetuses*) Ventricular septal defect 1661 (2*) Common ventricle complex 76 (1*) Atrioventricular canal defect 77 Atrial septal defect secundum 472 (1*) Patent ductus arteriosus 181 Conotruncal defects 598 (1*) Le-sided obstrucve defects 302 Right-sided obstrucve defects 200 Other isolated CHD 188 (1*) Other unspecified complex CHD 83 (9*)
Fig. 1. Flow of cases with congenital heart defects (CHDs) from the Hungarian Congenital Abnormality Registry (HCAR) to the Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSC).
A. Vereczkey et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 1–6
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Table 1 Number of cases with different types of congenital heart defects, population controls and malformed controls, and main sociodemographic characteristics of their mothers. Study groups
Abbreviation
Total n
Maternal (years)
age
Birth order
Mean
SD
Mean
Population controls Malformed controls Ventricular septal defect Single ventricle Atrial septal defect secundum Common atrioventricular canal Patent ductus arteriosus Common truncus Transposition of great arteries Tetralogy of Fallot Double outlet of right ventricle Conotruncal defects Atresia/stenosis of pulmonary valve Atresia/stenosis of tricuspid valve Ebstein’s anomaly Congenital abnormalities of pulmonary artery Right-sided obstructive defects Valvular aortic stenosis Hypoplastic left heart Coarctation of aorta Other congenital abnormalities of aorta Left-sided obstructive defects
PC MC VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
38,151 16,602 1659 75 471 77 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
25.4 25.4 25.6 25.9 26.0 26.4 25.7 25.1 26.0 25.2 26.6 25.7 25.8 25.0 24.3 26.3 26.0 24.8 25.9 25.9 26.4 25.8
4.9 5.2 5.2 5.7 5.8 5.4 5.2 4.2 5.0 5.3 4.3 5.1 5.2 4.1 7.6 5.9 5.6 4.5 5.4 5.6 6.1 5.4
1.7 1.8 1.9 1.9 2.1 2.1 2.0 2.0 1.9 1.8 2.0 1.9 1.9 1.7 1.6 2.1 2.0 1.9 1.8 2.0 1.9 1.9
Pregnancy order
Low SES
SD
Mean
SD
n
%
0.9 1.1 1.2 1.0 1.3 1.3 1.4 1.2 1.2 1.0 0.8 1.1 1.2 1.0 1.1 1.3 1.2 1.1 1.0 1.0 0.9 1.0
1.9 2.0 2.1 2.3 2.3 2.4 2.3 2.3 2.0 2.0 2.2 2.0 2.3 1.9 1.6 2.4 2.3 2.1 2.1 2.2 2.2 2.2
1.2 1.3 1.4 1.2 1.6 1.5 1.5 1.4 1.2 1.3 1.0 1.3 1.6 0.9 1.1 1.4 1.4 1.4 1.2 1.1 1.1 1.2
10,563 5932 594 26 165 33 77 17 99 73 8 197 29 3 1 34 67 20 20 35 28 103
27.7 35.7 36.4 36.1 36.3 42.9 44.0 39.5 32.8 33.8 33.3 33.7 40.3 23.1 14.3 31.8 33.7 35.7 27.4 31.3 51.9 34.9
(0.2) (0.2) (0.2) (0.4) (0.2) (0.3) (0.3) (0.3) (0.1) (0.2) (0.2) (0.1) (0.4) (0.2) (0.0) (0.3) (0.3) (0.2) (0.3) (0.2) (0.3) (0.3)
SES, socio-economic status; SD, standard deviation. Pregnancy order indicates the number of previous births and miscarriages. Low SES includes semi- and unskilled workers, housewives and unemployed.
and the risk of specific types of CHD [odds ratio (OR) with 95% confidence interval (CI)] were analysed using an unconditional logistic regression model in cases, population controls and malformed controls. Maternal age, birth order (parity) and low socio-economic status (based on the employment status of mothers) were considered as confounders [11]. Results The flow of cases and population controls in the HCCSCA is shown in Fig. 1. One hundred and eighty-eight cases with rare isolated CHDs and 83 cases with unspecified complex CHDs were excluded from the study. Thus, 3562 live-born cases with a specific type of CHD were included in this study. Table 1 shows the abbreviations for the CHDs. The population control group consisted of 38,151 live-born infants without any congenital abnormalities (1.8% of all live-births in Hungary), and the malformed control group consisted of 16,602 live-born infants with other isolated congenital abnormalities. The main sociodemographic data of mothers are also shown in Table 1 because these data (except pregnancy order) were used as confounders when calculating adjusted ORs. Of 125 chronic maternal diseases recorded in the HCCSCA, 30 were found to affect at least 35 (1%) pregnant women out of the 3562 cases (Table 2). In addition, 20 pregnant women with epilepsy and 25 pregnant women with cardiac dysrhythmias were evaluated in terms of their association with the risk of specific CHDs. Table 3 shows the number and percentage of cases of epilepsy and migraine in pregnant women. The prevalence of epilepsy was higher in the mothers of cases with ventricular septal defect (VSD) compared with the mothers of children in the population and malformed control groups. Of 14 epileptic mothers, seven received monotherapy [carbamazepine (n = 4), phenytoin (n = 2), valproate (n = 1] and seven received polytherapy (including carbamazepine in two women).
Table 2 Thirty of the 125 chronic diseases evaluated affected at least 35 pregnant women (i.e. 1%) out of the study population of 3562 cases. Four of these 30 diseases, plus epilepsy and cardiac dysrhythmias, were associated with higher risk for congenital heart defects (shown in bold type). Pregnancy complications such as gestational diabetes, hypertension and pre-eclampsia were excluded from this analysis. Chronic maternal diseases
n
%
Hypothyroidism Hyperthyroidism Diabetes mellitus Obesity Epilepsy Migraine Other headaches Depression Panic disorder Hypertension, essential Cardiac dysrhythmias Varicose veins in lower extremities Phlebitis/thrombophlebitis Haemorrhoids Hypotension, essential Otitis, chronic Allergic rhinitis (hay fever) Asthma (bronchial) Dyspepsia, includuing gastro-oesophageal reflux Gastric/duodenal ulcer Colitis ulcerosa Constipation, treated Cholelithiasis Glomerulonephritis Chronic kidney disease with secondary hypertension Nephrolithiasis Erosion of cervix Ovarian cyst Recurrent genital herpes Allergic urticaria Rheumatoid arthritis Lumbago
38 71 35 43 20 91 538 38 37 255 25 332 338 795 538 58 176 511 75 37 71 465 62 79 36 69 40 54 60 95 36 69
1.07 2.00 0.98 1.21 0.56 2.55 15.10 1.07 1.03 7.16 0.70 9.32 9.49 22.31 15.10 1.63 5.00 14.35 2.11 1.04 2.00 13.05 1.74 2.22 1.01 1.94 1.12 1.52 1.68 2.67 1.01 1.94
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Table 3 Prevalence rates of epilepsy and migraine in mothers of cases with various types of congenital heart defects (CHDs), mothers of population controls (PC) and mothers of malformed controls (MC). Study group
Population controls Malformed controls
Total
Epilepsy
n
n
%
38,151 16,602
90 64
0.2 0.4
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
14 1 3 0 0 0 1 0 0 1 1 0 0 0 1 0 0 0 0 0
0.8 1.3 0.6 0.0 0.0 0.0 0.3 0.0 0.0 0.2 1.4 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0
VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Comparison
Migraine
OR (95% CI)PC
OR (95% CI)MC Reference Reference
3.27 (1.77–5.59) 5.24 (0.29–24.25) 2.33 (0.57–6.33) 0.00 (0.00–Inf) 0.00 (0.00–133.2) 0.00 (0.00–Inf) 1.36 (0.08–6.16) 0.00 (0.00–25.63) 0.00 (0.00–Inf) 0.69 (0.04–3.12) 4.61 (0.26–21.81) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.77 (0.10–8.13) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–80.35) 0.00 (0.00–Inf) 0.00 (0.00–61.09)
2.19 (1.17–3.81) 3.84 (0.22–17.85) 1.61 (0.39–4.38) 0.00 (0.00–Inf) 0.00 (0.00–409.7) 0.00 (0.00–Inf) 0.92 (0.05–4.19) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.47 (0.03–2.15) 3.35 (0.19–15.94 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.16 (0.07–5.39) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf)
Comparison
n
%
713 391
1.9 2.4
53 4 9 4 1 1 4 5 0 10 0 0 0 3 3 1 3 1 2 7
3.2 5.3 1.9 5.1 0.6 2.3 1.3 2.3 0.0 1.7 0.0 0.0 0.0 2.8 1.5 1.8 3.9 0.9 3.5 2.3
OR (95% CI)PC
OR (95% CI)MC Reference Reference
1.72 (1.28–2.26) 2.92 (0.89–7.07) 1.01 (0.48–1.85) 2.74 (0.83–6.62) 0.29 (0.02–1.31) 1.22 (0.07–5.60) 0.69 (0.21–1.62) 1.23 (0.43–2.68) 0.00 (0.00–0.40) 0.89 (0.44–1.59) 0.00 (0.00–0.00) 0.00 (0.00–0.00) 0.00 (0.00–52.98) 1.51 (0.37–4.02) 0.80 (0.20–2.11) 0.96 (0.05–4.39) 1.12 (0.52–5.71) 0.47 (0.03–2.12) 1.96 (0.32–6.33) 1.25 (0.53–2.46)
1.35 (1.00–1.79) 2.26 (0.69–5.50) 0.80 (0.36–1.47) 2.13 (0.65–5.16) 0.23 (0.01–1.02) 0.98 (0.06–4.53) 0.53 (0.16–1.26) 0.97 (0.34–2.12) 0.00 (0.00–63.1) 0.70 (0.35–1.25) 0.00 (0.0–0.07) 0.00 (0.00–408.1) 0.00 (0.00–38.5) 1.18 (0.29–3.16) 0.62 (0.15–1.65) 0.79 (0.04–3.62) 1.67 (0.41–4.50) 0.37 (0.02–1.68) 1.51 (0.25–4.88) 0.99 (0.42–1.95)
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
Maternal diabetes was found to be associated with higher risk of coarctation of the aorta (COA) (Table 4). All pregnant women with type I diabetes mellitus were treated with insulin. Most pregnant women with type II diabetes mellitus were treated with dietary restriction and/or antidiabetic drugs; only two were treated with insulin. Of 35 cases with CHDs, 27 and eight had mothers with type I and type II diabetes mellitus, respectively, while of 229 controls, 88 and 141 had mothers with type I and type II diabetes mellitus, respectively. Thus, COA was found to be
Migraine was also found to be associated with VSD. There was no difference in the risk of VSD in the children of mothers who did and did not receive antimigraine drug treatment. Panic disorders were found to be associated with hypoplastic left heart (HLH) and other congenital abnormalities of the aorta (OCAA) (Table 4). However, this association was based on three cases with different OCAAs (bicuspid aortic valve, stenosis of aorta and interruption of aortic arch).
Table 4 Prevalence rates of panic disorders and diabetes mellitus in mothers of cases with various types of congenital heart defects, mothers of population controls (PC) and mothers of malformed controls (MC). Study group
Population controls Malformed controls VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Total
Panic disorders
Comparison
n
n
%
OR (95% CI)PC
38,151 16,602
196 157
0.5 0.9
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
8 2 4 0 2 1 3 3 1 8 1 0 0 1 2 0 5 1 3 9
0.5 2.6 0.8 0.0 1.1 2.3 1.0 1.4 4.2 1.3 1.4 0.0 0.0 0.9 1.0 0.0 6.6 0.9 5.3 3.0
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
Diabetes mellitus OR (95% CI)MC Reference Reference
0.85 (0.38–1.62) 4.61 (0.75–14.88) 1.49 (0.45–3.54) 0.00 (0.00–Inf) 1.88 (0.31–5.97) 3.87 (0.22–18.04) 1.82 (0.45–4.83) 2.55 (0.63–6.77) 8.45 (0.47–41.00) 2.50 (0.98–4.77) 2.44 (0.14–11.16) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.72 (0.10–7.81) 1.82 (0.30–5.77) 0.00 (0.00–Inf) 13.38 (4.64–30.54) 1.62 (0.09–7.31) 8.83 (2.12–24.52) 5.43 (2.55–10.15)
0.50 (0.23–0.96) 2.80 (0.46–9.03) 0.82 (0.25–1.97) 0.00 (0.00–13.82) 1.10 (0.18–3.49) 2.36 (0.13–11.01) 1.04 (0.25–2.75) 1.47 (0.36–3.91) 4.35 (0.24–21.01) 1.43 (0.64–2.74) 1.41 (0.08–6.44) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.90 (0.05–4.11) 1.00 (0.16–3.18) 0.00 (0.00–2.02) 7.66 (2.66–17.51) 0.93 (0.05–4.20) 5.37 (1.29–14.91) 3.20 (1.50–5.99)
Comparison
n
%
229 100
0.6 0.6
12 1 3 1 2 0 4 0 0 4 2 1 0 1 4 1 2 4 1 8
0.7 1.3 0.6 1.3 1.1 0.0 1.3 0.0 0.0 0.7 2.8 7.7 0.0 0.9 2.0 1.8 2.6 3.5 1.8 2.6
OR (95% CI)PC
OR (95% CI)MC Reference Reference
1.18 (0.62–2.02) 2.16 (0.12–9.85) 1.01 (0.25–2.69) 2.27 (0.13–10.34) 1.91 (0.31–6.05) 0.00 (0.00–40.52) 2.15 (0.66–5.12) 0.00 (0.00–0.00) 0.00 (0.00–164.3) 1.09 (0.34–2.58) 4.61 (0.75–14.93) 14.43 (0.79–74.3) 0.00 (0.00–Inf) 1.56 (0.09–7.11) 3.30 (0.98–7.93) 3.09 (0.17–14.36) 4.15 (0.68–13.45) 5.94 (1.80–14.47) 2.89 (0.16–13.40) 4.35 (1.94–8.39)
1.20 (0.62–2.10) 2.23 (0.13–10.3) 1.01 (0.25–2.72) 2.16 (0.12–9.93) 1.88 (0.31–6.02) 0.00 (0.00–25.9) 2.19 (0.67–5.28) 0.00 (0.00–5.25) 0.00 (0.00–Inf) 1.10 (0.34–2.65) 4.64 (0.75–15.2) 16.05 (0.87–84.3) 0.00 (0.00–nf) 1.50 (0.08–6.95) 3.29 (0.99–8.02) 3.33 (0.19–15.7) 4.34 (0.70–14.3) 6.11 (1.84–15.1) 3.03 (0.17–14.1) 4.56 (2.02–8.95)
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Table 5 Prevalence rates of chronic hypertension and cardiac dysrhythmias in mothers of cases with various types of congenital heart defects, mothers of population controls (PC) and mothers of malformed controls (MC). Study groups
Population controls Malformed controls VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Total
Hypertension
Comparison
n
n
OR (95% CI)PC
38,151 16,602
2224 947
5.8 5.7
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
122 5 24 10 16 6 15 15 0 36 7 1 2 11 21 2 6 6 7 21
7.4 6.6 5.1 12.7 8.8 13.6 4.9 6.8 0.0 6.0 9.7 7.7 28.6 10.2 10.5 3.6 7.9 5.3 12.3 7.0
%
OR (95% CI)MC Reference Reference
1.31 (1.08–1.58) 1.15 (0.40–2.58) 0.90 (0.58–1.33) 2.47 (1.19–4.60) 1.66 (0.95–2.69) 2.75 (1.04–6.06) 0.84 (0.48–1.36) 1.20 (0.68–1.96) 0.00 (0.00–0.01) 1.06 (0.74–1.46) 1.79 (0.75–3.66) 1.41 (0.08–7.16) 6.33 (0.89–30.24) 1.88 (0.95–3.37) 1.95 (1.20–3.00) 0.65 (0.11–2.09) 1.39 (0.54–2.95) 0.92 (0.36–1.93) 2.39 (0.98–4.95) 1.25 (0.77–1.90)
1.32 (1.08–1.60) 1.16 (0.41–2.62) 0.91 (0.58–1.35) 2.42 (1.16–4.51) 1.68 (0.96–2.73) 2.76 (1.04–6.11) 0.83 (0.47–1.35) 1.19 (0.67–1.96) 0.00 (0.00–0.13) 1.05 (0.73–1.46) 1.85 (0.77–3.79) 1.36 (0.07–6.98) 6.53 (0.92–31.14) 1.96 (0.98–3.52) 2.01 (1.24–3.11) 0.64 (0.11–2.08) 1.38 (0.53–2.93) 0.93 (0.36–1.95) 2.45 (0.98–5.10) 1.25 (0.77–1.91)
Cardiac dysrhythmias
Comparison
n
%
OR (95% CI)PC
156 72
0.4 0.4
12 0 8 4 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1
0.7 0.0 1.7 5.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.0 0.3
OR (95% CI)MC Reference Reference
1.77 (0.93–3.06) 0.00 (0.00–Inf) 4.22 (1.88–8.16) 12.73 (3.83–31.40) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–0.00) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–35.43) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 2.15 (0.12–9.76) 0.00 (0.00–Inf) 0.80 (0.05–3.59)
1.67 (0.86–2.96) 0.00 (0.00–Inf) 3.90 (1.72–7.70) 12.00 (3.58–30.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–94.03) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 2.03 (0.11–9.31) 0.00 (0.00–Inf) 0.75 (0.04–3.38)
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
associated with type I diabetes mellitus (OR 2.5, 95% 1.6–3.9) but not associated with type II diabetes mellitus (OR 1.0, 95% CI 0.6– 1.6). Chronic/essential hypertension in the mothers showed a weak association with VSD, common atrioventricular canal (CAVC), common truncus (CT) and right-sided obstructive defects (RSOD) (Table 5). Different antihypertensive drugs used for the treatment of these pregnant women were analysed separately. Only nifedipin showed a weak association with higher risk for RSOD; this drug was considered as a confounder in the calculation of adjusted ORs. Cardiac dysrhythmias were found to be associated with atrial septal defect secundum (ASD-II) and CAVC (Table 5). In the group of 25 cases, paroxysmal supraventricular tachycardia and extrasystolic arrhythmia were diagnosed in eight cases with ASD-II (8 and 0, respectively) and four cases with CAVC (3 and 1, respectively). All 12 cases with VSD had mothers with paroxysmal supraventricular tachycardia; thus, this cardiac dysrhythmia was also associated with higher risk for VSD (OR 1.92, 95% CI 1.8–3.64). Of 156 population controls, 151 had paroxysmal supraventricular tachycardia and five had extrasystolic arhythmia. Of 72 malformed controls, 71 had paroxysmal supraventricular tachycardia. During the evaluation of possible associations between chronic diseases and higher risk of specific CHDs, related drug treatments were also analysed, particularly in the second and third months of gestation. Carbamazepine showed an interaction with the teratogenic effect of epilepsy, and nifedipin was associated with maternal hypertension; other drugs were not considered as confounders in calculation of adjusted ORs for different CHDs. Comment This population-based study aimed to identify possible associations between chronic maternal diseases and the risk of specific types of CHD. Some previously known associations (epilepsy and type I diabetes mellitus) were confirmed. However, the study identified several new associations such as panic
disorders with HLH; chronic hypertension with VSD, CAVC and CT; and paroxysmal supraventricular tachycardia with ASD-II, CAVC and VSD. The characteristic syndromic pattern of congenital abnormalities in children born to epileptic pregnant women treated with antiepileptic drugs is well known [17,18]. However, the present findings indicate an association between VSD alone and maternal epilepsy treated with antiepileptic drugs. Of 14 epileptic pregnant women, four were treated with carbamazepine alone, and two epileptic pregnant women received carbamazepine as part of polytherapy. These findings are in agreement with two previous reports which indicated the role of carbamazepine in the origin of CHDs [18,19]. A possible association between migraine and VSD was observed in this study. However, the risk of CHDs did not differ between mothers with migraine who did and did not receive antimigraine drug treatments [20]. Panic disorders were found to be associated with higher risk of HLH. This finding needs further study. These pregnant women were mainly treated with benzodiazepines. The association between maternal diabetes mellitus and some types of CHD has been reported previously [10]. In general, children of diabetic mothers are at higher risk for multiple congenital abnormalities (‘diabetic embryopathy’) including CHD. This study found that the children of pregnant women with type I diabetes mellitus were at higher risk for isolated COA; a similar association was not found for the children of pregnant women with type II diabetes mellitus [21]. A possible association between maternal chronic/essential hypertension and higher risk of some types of CHD was found in this study. A previous Hungarian case–control study showed a weak association between chronic hypertension and related drug treatments and higher risk of CHDs (OR 1.3, 95% CI 1.0–1.5), but different types of CHD were not differentiated [22]. The present findings confirm the previously reported association between paroxysmal supraventricular tachycardia and higher
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risk of septal defects in the heart [23]. The multifactorial threshold model is the most plausible explanation for the origin of common isolated CHDs [24]. This study showed that polygenic predisposition in mothers may be associated with cardiac dysrhythmias, particularly paroxysmal supraventricular tachycardia, that may be detected by electrocardiograms [25]. Thus, cardiac dysrhythmias may indicate developmental disturbances in the septum as a subthreshold manifestation of septal defects in the mother. Other common maternal diseases were not found to be associated with higher risk for CHD, including eight pregnant women with deep thrombophlebitis who were treated with acenocoumarol (Syncumar). This study suggests that certain chronic maternal diseases are associated with increased risk for specific types of CHD, and these risks seem to be specific for certain types of CHD because similar risk was not found in the mothers of malformed controls. Appropriate treatment of these maternal diseases may help in the prevention of these types of CHD. Strengths of this study include the large population-based data set of the HCCSCA, which included 3562 live-born cases with CHDs, 38,151 live-born population controls without any congenital abnormalities and 16,602 live-born malformed controls with other isolated congenital abnormalities in the ethnically homogeneous Hungarian (Caucasian) population. The validity of CHD diagnoses was improved due to the follow-up of cases in cardiology institutes and personal contact with the mothers. The authors aimed to study cases with homogeneous types of CHD; therefore, cases with syndromic or unclassified multiple congenital abnormalities including CHDs were excluded from the study, and only those cases found to have a single type of CHD [after lethal outcome (verified by autopsy report) or after surgical intervention (catheter or correction)] were included in the study. A major strength of this study is that different types of CHD were analysed separately. The occurrence of chronic maternal diseases was recorded prospectively in the prenatal maternity logbook. The use of malformed controls enabled the authors to differentiate between the specific CHD risk and the general risk of congenital abnormalities. However, this study had some weaknesses. Only severe CHDs (i.e. the most serious manifestations of the given CHD entities) were included, so the results are not representative of the whole spectrum of CHDs. VSD (perimembranous and muscular types) was the most common type of CHD, and was confirmed by cardiac catheter or surgical correction. Some types of CHD occurred in very few infants, so the statistical power did not allow the authors to draw conclusions. The major bias of this study is connected with multiple testing, because 32 chronic maternal diseases and 17 types of CHD were analysed; as such, it is difficult to exclude the effect of chance. Another weakness of this study is that the dataset of the HCCSCA included cases and controls between 1980 and 1996; however, the possible effect of chronic maternal diseases has not altered, but related drug treatments have changed over time. Nowadays, the major diagnostic approach for the diagnosis of CHD is ultrasound scanning (echocardiography), but autopsy and surgical interventions may produce similar or better results. In conclusion, certain chronic maternal diseases (i.e. epilepsy treated with carbamazepine, migraine, panic disorders, type I diabetes mellitus, chronic hypertension, paroxysmal supraventricular tachycardia) were found to be associated with higher risk of specific types of CHD.
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. References [1] Hoffman JIE, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. J Am Heart J 2004;147:425–39. [2] Reller MD, Strickland MJ, Riehle-Colarusso F, Mahle MD, Correa A. Prevalence of congenital heart defects in Metropolitan Atlanta, 1998–2005. J Pediatr 2008;153:807–13. [3] Gilbao SM, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States 1999 to 2006. Circulation 2010;122:2254–63. [4] Fulton DR. Congenital heart diseases in children and adolescent. In: Fuster V, Walsh A, O’Rourke RA, Poole-Wilson P, editors. Hurst’s the heart. 12th ed., New York: McGraw Hill Medical; 2008. p. 1855–921. [5] Zaidi S, Choi M, Wakimoto H, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013;498:220–3. [6] Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115:2995– 3014. [7] Rasmussen SA, Erickson JD, Reef SE, Ross DS. Teratology: from science to birth defects prevention. Birth Defects Res A Clin Mol Teratol 2009;95:82–92. [8] Botto LD, Lin AE, Riekle-Colarusso T, Malik S, Correa A. Seeking cause: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A Clin Mol Teratol 2007;79:714–27. [9] Ferencz C, Loffredo CA, Rubin JD, Magee CA. Epidemiology of congenital heart diseases. The Baltimore-Washington Infant Study: 1981–1989. Mount Kisco, NY: Future Publ Co.; 1993. [10] Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD. Genetic and environmental risk factors of major cardiovascular malformations. The BaltimoreWashington Infant Study: 1981–1989. Armonk, NY: Future Publ Co.; 1997. [11] Czeizel AE, Rockenbauer M, Siffel Cs, Varga E. Description and mission evaluation of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. Teratology 2001;63:176–85. [12] Czeizel AE. The first 25 years of the Hungarian Congenital Abnormality Registry. Teratology 1997;55:299–305. [13] Czeizel AE, Me´tneki J, Be´res J. 50 years of the Hungarian Congenital Abnormality Registry. Congenit Anom 2013;54:22–9. [14] Czeizel AE, Into˝ dy Zs, Modell B. What proportion of congenital abnormalities can be prevented? Br Med J 1993;306:499–503. [15] Czeizel AE, Petik D, Vargha P. Validation studies of drug exposures in pregnant women. Pharmacoepid Drug Safety 2003;12:409–16. [16] Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191:790–4. [17] Holmes LB, Harvey EA, Couli BA. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–8. [18] Czeizel AE, Ba´nhidy F. Congenital abnormalities of children born to epileptic women treated with antiepileptic drugs in Hungary – a population-based study. Open Drug Safety J 2010;1:40–56. [19] Thomas SV, Ajaykumar B, Sindhu K, et al. Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr Cardiol 2008;29:604–8. [20] A´cs N, Ba´nhidy F, Puho´ E, Czeizel AE. Maternal severe migraine and risk of limb deficiencies. Birth Defects Res A Clin Mol Teratol 2006;76:592–601. [21] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes: a population-based case–control study. Congenit Anom 2010;50:115–21. [22] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Essential hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring – a population-based case control study. Hypertension Res 2011;34:257–63. [23] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Paroxysmal supraventricular tachycardia in pregnant women and birth outcomes of their children. Am J Med Genet 2010;150A:380–8. [24] Nora JJ. From generational studies to a multilevel genetic-environmental interaction. J Am Coll Cardiol 1994;23:1468–71. [25] Me´sza´ros M, Czeizel AE. ECG conduction disturbance in the first-degree relatives of children with ventricular septal defect. Hum Hered 1981;19: 298–301.
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Association of certain chronic maternal diseases with the risk of specific congenital heart defects: a population-based study A. Vereczkey a,*, B. Gerencse´r b, A.E. Czeizel c, I. Szabo´ d a
Versys Clinics, Human Reproduction Institute, Budapest, Hungary Alfre´d Re´nyi Institute of Mathematics, Hungarian Academy of Sciences, Budapest, Hungary c Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary d Department of Obstetrics and Gynaecology, University of Pe´cs, Pe´cs, Hungary b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 March 2014 Received in revised form 18 June 2014 Accepted 16 August 2014
Objective: Previous epidemiological studies have evaluated cases with all congenital heart defects (CHDs), rather than analysing different types of CHD. The objective of this study was to evaluate the possible association of certain chronic maternal diseases with the risk of different types of CHD, because the role of possible environmental factors in the origin of CHDs is unclear in the vast majority of patients. Study design: Different types of CHD, diagnosed after lethal outcome (autopsy report) or after surgical intervention (catheter or correction), were evaluated in order to estimate the possible role of chronic maternal diseases in their origin. This analysis was based on the rates of medically recorded chronic maternal diseases in 3562 live-born cases with CHDs, 38,151 population controls without any birth defects, and 16,602 malformed controls with other isolated congenital abnormalities, using the data set of the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities (1980–1996). Results: Maternal epilepsy treated with carbamazepine and migraine were found to be associated with higher risk of ventricular septal defect; panic disorders were associated with higher risk of hypoplastic left heart; type I diabetes mellitus was associated with higher risk of coarctation of the aorta; chronic hypertension was associated with higher risk of ventricular septal defect, common atrioventricular canal and common truncus; and paroxysmal supraventricular tachycardia was associated with higher risk of atrial septal defect secundum, common atrioventricular canal and ventricular septal defect. Conclusion: In conclusion, certain chronic maternal diseases were found to be associated with higher risk of specific CHDs. Appropriate treatment of these diseases may help to prevent these CHDs. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Congenital heart defects Epilepsy Migraine Diabetes mellitus Population-based case–control study
Introduction Congenital heart defects (CHDs) are the most common (4–50 per 1000 live-births) [1,2] and serious [3] structural birth defects (i.e. congenital abnormalities). The care of infants/children with CHDs has been revolutionised over recent decades [4], and progress in human genetics has resulted in better understanding of the genes associated with CHDs [5]. However, the role of possible environmental factors in the origin of CHDs is unclear in the vast majority of patients [6,7]. As such, this study aimed to investigate possible associations between chronic maternal diseases and the risk of CHDs.
* Corresponding author at: 1138 Budapest, Madara´sz Viktor utca 47-49, Hungary. Tel.: +36 1 3944 412; fax: +36 1 3944 412. E-mail addresses: [email protected], [email protected] (A. Vereczkey). http://dx.doi.org/10.1016/j.ejogrb.2014.08.022 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
CHDs have heterogeneous manifestations and origins [8]. The classification of CHDs used in the Baltimore-Washington Infant Study [9,10] was adopted in this study. Newborn infants affected with a single type of CHD, diagnosed by lethal outcome (autopsy report) and/or surgical intervention (catheter or correction), in the data set of the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA) [11] were included in this study. Materials and methods Study subjects Patients (i.e. cases with congenital abnormalities including CHDs in the HCCSCA) were selected from the Hungarian Congenital Abnormality Registry (HCAR) [12,13]. Reporting of cases with congenital abnormalities to the HCAR is mandatory for physicians, and autopsy is mandatory for all infant deaths; pathologists send a
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copy of the autopsy report to the HCAR if defects are identified. Approximately 90% of major congenital abnormalities were recorded on the HCAR [14]. Only those cases with congenital abnormalities who were reported to the HCAR during the first 3 months after birth were selected for the HCCSCA. In addition, cases with congenital abnormality syndromes caused by gene mutations or chromosomal aberrations with preconceptional origin were excluded. In the HCCSCA, controls were defined as newborn infants without congenital abnormalities, matched to cases by sex, birth week and district of parents’ residence. The source of these controls was the National Birth Registry of the Central Statistical Office for the HCCSCA. In general, two controls were matched to each case. Collection of exposure data and confounding factors An explanatory letter and an informed consent form were posted to the mothers of cases and controls immediately after their selection for the HCCSCA, and they were asked to supply their prenatal maternity logbook and all medical records concerning their diseases during the study pregnancy and their child’s congenital abnormality. These documents were returned within 4 weeks. Prenatal care is mandatory for pregnant women in Hungary, and women who do not attend for prenatal care do not receive a maternity grant or maternity leave. As such, nearly 100% of pregnant women attended for prenatal care, on average, seven times between 6 weeks of gestation and the end of pregnancy. Obstetricians in prenatal care are obliged to record pregnancy complications, maternal diseases and related medicinal products for women during pregnancy in the logbook. The mean standard deviation time between the end of pregnancy and return of the ‘information package’ (i.e. logbook, discharge summary and informed consent form) in the prepaid envelope was 3.5 2.1 and 5.2 2.9 months for cases and controls, respectively. Regional district nurses were asked to visit all case mothers who did not respond, and to evaluate the available medical documents. Unfortunately, the district nurses could only visit 200 non-respondent control mothers [15] and 600 respondent control mothers [16] in two validation studies because the ethics committee considered that this follow-up might be disturbing for the parents of healthy children. Data on chronic maternal diseases were available for 96.3% of cases (84.4% from postal replies and 11.9% from visits) and 83.0% of controls (81.3% from postal replies and 1.7% from visits). Signed informed consent forms were returned by 98% of mothers; names and addresses were deleted for the 2% of subjects who did not provide signed informed consent. The method of data collection was changed in 1997, but these data had not been validated at the time of this analysis. As such, this study is based on the 17-year dataset of the HCCSCA from 1980 to 1996. Study design of cases with CHDs In general, cases with congenital abnormalities were reported immediately after birth to the HCAR. Approximately 50% of cases with CHDs were reported as unspecified CHDs, because the exact diagnosis required further time-consuming examinations. The HCCSCA researchers were able to specify the type of CHD in a further 20% of cases by evaluation of the medical data of cases with congenital abnormalities 3.5 2.1 months after birth. For the remaining 30% of live-born cases without a specific CHD diagnosis, it was anticipated that they would have received care or surgical intervention at a paediatric cardiology institution; therefore, the HCCSCA researchers visited these cardiology in- and outpatient
clinics in 2008. Medical records were reviewed, and unspecified CHDs were changed to specific CHD diagnoses where possible. For cases with a diagnosis of CHD who were not found in the records of paediatric cardiology institutions, their mothers were contacted to clarify the fate and/or diagnosis in 2009 and 2010. Cases that could not be traced, cases without a specific CHD diagnosis, and cases whose mothers did not wish to participate were excluded from the study. Cases with multiple congenital abnormalities including CHDs were also excluded from the study. In addition, because some types of CHD have a wide spectrum of manifestations including spontaneous closure of ventricular or atrial septal defects, ductus arteriosus, etc., only cases with lethal outcomes (verified by autopsy record) or who had undergone surgical intervention (cardiac catheter diagnosis or correction) were included in the study. There were two control groups in this study: (i) the live-born population controls without any congenital abnormalities; and (ii) the live-born malformed controls with other isolated congenital abnormalities from the HCCSCA dataset. Statistical analysis of data GNU R 2.14, RStudio 0.97 version was used for statistical analysis. Associations between certain chronic maternal diseases
Reported CHD cases in HCAR, 1980–1996 15,206 ↘ ↙ Isolated Syndromic/mulple 2265 12,941 ↓ Reported during first 3 months aer birth in HCCSCA 9076 ↘ ↘ ↓ ↓ Non-respondent Undelivered ↓ 860 556 ↓ ↓ Visit at home ↓ ↙ ↓ ↘ Respondent Evaluated Refused collaboraon Unknown address 1080 71 265 7660 8740 ↙
↘ Checked in cardiology instuons 8103 ↙ ↘ ↙ Not found, maternal contact 1011 ↙ ↙ ↙ ↓ ↘ Found Collaboraon Refused No contact 7092 323 55 633
Misdiagnosis (syndromic, heart murmur, etc.) 637
7415 ↙ Excluded cases 2275 Not confirmed diagnosis 737 Spontaneous recovery 1383 Unspecified CHD 188 Death to other causes 12
↘ Confirmed diagnosis 5140 Diagnosis based on surgical documents or autopsy record 3838 (including 15 sllborn fetuses*) Ventricular septal defect 1661 (2*) Common ventricle complex 76 (1*) Atrioventricular canal defect 77 Atrial septal defect secundum 472 (1*) Patent ductus arteriosus 181 Conotruncal defects 598 (1*) Le-sided obstrucve defects 302 Right-sided obstrucve defects 200 Other isolated CHD 188 (1*) Other unspecified complex CHD 83 (9*)
Fig. 1. Flow of cases with congenital heart defects (CHDs) from the Hungarian Congenital Abnormality Registry (HCAR) to the Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSC).
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Table 1 Number of cases with different types of congenital heart defects, population controls and malformed controls, and main sociodemographic characteristics of their mothers. Study groups
Abbreviation
Total n
Maternal (years)
age
Birth order
Mean
SD
Mean
Population controls Malformed controls Ventricular septal defect Single ventricle Atrial septal defect secundum Common atrioventricular canal Patent ductus arteriosus Common truncus Transposition of great arteries Tetralogy of Fallot Double outlet of right ventricle Conotruncal defects Atresia/stenosis of pulmonary valve Atresia/stenosis of tricuspid valve Ebstein’s anomaly Congenital abnormalities of pulmonary artery Right-sided obstructive defects Valvular aortic stenosis Hypoplastic left heart Coarctation of aorta Other congenital abnormalities of aorta Left-sided obstructive defects
PC MC VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
38,151 16,602 1659 75 471 77 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
25.4 25.4 25.6 25.9 26.0 26.4 25.7 25.1 26.0 25.2 26.6 25.7 25.8 25.0 24.3 26.3 26.0 24.8 25.9 25.9 26.4 25.8
4.9 5.2 5.2 5.7 5.8 5.4 5.2 4.2 5.0 5.3 4.3 5.1 5.2 4.1 7.6 5.9 5.6 4.5 5.4 5.6 6.1 5.4
1.7 1.8 1.9 1.9 2.1 2.1 2.0 2.0 1.9 1.8 2.0 1.9 1.9 1.7 1.6 2.1 2.0 1.9 1.8 2.0 1.9 1.9
Pregnancy order
Low SES
SD
Mean
SD
n
%
0.9 1.1 1.2 1.0 1.3 1.3 1.4 1.2 1.2 1.0 0.8 1.1 1.2 1.0 1.1 1.3 1.2 1.1 1.0 1.0 0.9 1.0
1.9 2.0 2.1 2.3 2.3 2.4 2.3 2.3 2.0 2.0 2.2 2.0 2.3 1.9 1.6 2.4 2.3 2.1 2.1 2.2 2.2 2.2
1.2 1.3 1.4 1.2 1.6 1.5 1.5 1.4 1.2 1.3 1.0 1.3 1.6 0.9 1.1 1.4 1.4 1.4 1.2 1.1 1.1 1.2
10,563 5932 594 26 165 33 77 17 99 73 8 197 29 3 1 34 67 20 20 35 28 103
27.7 35.7 36.4 36.1 36.3 42.9 44.0 39.5 32.8 33.8 33.3 33.7 40.3 23.1 14.3 31.8 33.7 35.7 27.4 31.3 51.9 34.9
(0.2) (0.2) (0.2) (0.4) (0.2) (0.3) (0.3) (0.3) (0.1) (0.2) (0.2) (0.1) (0.4) (0.2) (0.0) (0.3) (0.3) (0.2) (0.3) (0.2) (0.3) (0.3)
SES, socio-economic status; SD, standard deviation. Pregnancy order indicates the number of previous births and miscarriages. Low SES includes semi- and unskilled workers, housewives and unemployed.
and the risk of specific types of CHD [odds ratio (OR) with 95% confidence interval (CI)] were analysed using an unconditional logistic regression model in cases, population controls and malformed controls. Maternal age, birth order (parity) and low socio-economic status (based on the employment status of mothers) were considered as confounders [11]. Results The flow of cases and population controls in the HCCSCA is shown in Fig. 1. One hundred and eighty-eight cases with rare isolated CHDs and 83 cases with unspecified complex CHDs were excluded from the study. Thus, 3562 live-born cases with a specific type of CHD were included in this study. Table 1 shows the abbreviations for the CHDs. The population control group consisted of 38,151 live-born infants without any congenital abnormalities (1.8% of all live-births in Hungary), and the malformed control group consisted of 16,602 live-born infants with other isolated congenital abnormalities. The main sociodemographic data of mothers are also shown in Table 1 because these data (except pregnancy order) were used as confounders when calculating adjusted ORs. Of 125 chronic maternal diseases recorded in the HCCSCA, 30 were found to affect at least 35 (1%) pregnant women out of the 3562 cases (Table 2). In addition, 20 pregnant women with epilepsy and 25 pregnant women with cardiac dysrhythmias were evaluated in terms of their association with the risk of specific CHDs. Table 3 shows the number and percentage of cases of epilepsy and migraine in pregnant women. The prevalence of epilepsy was higher in the mothers of cases with ventricular septal defect (VSD) compared with the mothers of children in the population and malformed control groups. Of 14 epileptic mothers, seven received monotherapy [carbamazepine (n = 4), phenytoin (n = 2), valproate (n = 1] and seven received polytherapy (including carbamazepine in two women).
Table 2 Thirty of the 125 chronic diseases evaluated affected at least 35 pregnant women (i.e. 1%) out of the study population of 3562 cases. Four of these 30 diseases, plus epilepsy and cardiac dysrhythmias, were associated with higher risk for congenital heart defects (shown in bold type). Pregnancy complications such as gestational diabetes, hypertension and pre-eclampsia were excluded from this analysis. Chronic maternal diseases
n
%
Hypothyroidism Hyperthyroidism Diabetes mellitus Obesity Epilepsy Migraine Other headaches Depression Panic disorder Hypertension, essential Cardiac dysrhythmias Varicose veins in lower extremities Phlebitis/thrombophlebitis Haemorrhoids Hypotension, essential Otitis, chronic Allergic rhinitis (hay fever) Asthma (bronchial) Dyspepsia, includuing gastro-oesophageal reflux Gastric/duodenal ulcer Colitis ulcerosa Constipation, treated Cholelithiasis Glomerulonephritis Chronic kidney disease with secondary hypertension Nephrolithiasis Erosion of cervix Ovarian cyst Recurrent genital herpes Allergic urticaria Rheumatoid arthritis Lumbago
38 71 35 43 20 91 538 38 37 255 25 332 338 795 538 58 176 511 75 37 71 465 62 79 36 69 40 54 60 95 36 69
1.07 2.00 0.98 1.21 0.56 2.55 15.10 1.07 1.03 7.16 0.70 9.32 9.49 22.31 15.10 1.63 5.00 14.35 2.11 1.04 2.00 13.05 1.74 2.22 1.01 1.94 1.12 1.52 1.68 2.67 1.01 1.94
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Table 3 Prevalence rates of epilepsy and migraine in mothers of cases with various types of congenital heart defects (CHDs), mothers of population controls (PC) and mothers of malformed controls (MC). Study group
Population controls Malformed controls
Total
Epilepsy
n
n
%
38,151 16,602
90 64
0.2 0.4
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
14 1 3 0 0 0 1 0 0 1 1 0 0 0 1 0 0 0 0 0
0.8 1.3 0.6 0.0 0.0 0.0 0.3 0.0 0.0 0.2 1.4 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0
VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Comparison
Migraine
OR (95% CI)PC
OR (95% CI)MC Reference Reference
3.27 (1.77–5.59) 5.24 (0.29–24.25) 2.33 (0.57–6.33) 0.00 (0.00–Inf) 0.00 (0.00–133.2) 0.00 (0.00–Inf) 1.36 (0.08–6.16) 0.00 (0.00–25.63) 0.00 (0.00–Inf) 0.69 (0.04–3.12) 4.61 (0.26–21.81) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.77 (0.10–8.13) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–80.35) 0.00 (0.00–Inf) 0.00 (0.00–61.09)
2.19 (1.17–3.81) 3.84 (0.22–17.85) 1.61 (0.39–4.38) 0.00 (0.00–Inf) 0.00 (0.00–409.7) 0.00 (0.00–Inf) 0.92 (0.05–4.19) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.47 (0.03–2.15) 3.35 (0.19–15.94 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.16 (0.07–5.39) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf)
Comparison
n
%
713 391
1.9 2.4
53 4 9 4 1 1 4 5 0 10 0 0 0 3 3 1 3 1 2 7
3.2 5.3 1.9 5.1 0.6 2.3 1.3 2.3 0.0 1.7 0.0 0.0 0.0 2.8 1.5 1.8 3.9 0.9 3.5 2.3
OR (95% CI)PC
OR (95% CI)MC Reference Reference
1.72 (1.28–2.26) 2.92 (0.89–7.07) 1.01 (0.48–1.85) 2.74 (0.83–6.62) 0.29 (0.02–1.31) 1.22 (0.07–5.60) 0.69 (0.21–1.62) 1.23 (0.43–2.68) 0.00 (0.00–0.40) 0.89 (0.44–1.59) 0.00 (0.00–0.00) 0.00 (0.00–0.00) 0.00 (0.00–52.98) 1.51 (0.37–4.02) 0.80 (0.20–2.11) 0.96 (0.05–4.39) 1.12 (0.52–5.71) 0.47 (0.03–2.12) 1.96 (0.32–6.33) 1.25 (0.53–2.46)
1.35 (1.00–1.79) 2.26 (0.69–5.50) 0.80 (0.36–1.47) 2.13 (0.65–5.16) 0.23 (0.01–1.02) 0.98 (0.06–4.53) 0.53 (0.16–1.26) 0.97 (0.34–2.12) 0.00 (0.00–63.1) 0.70 (0.35–1.25) 0.00 (0.0–0.07) 0.00 (0.00–408.1) 0.00 (0.00–38.5) 1.18 (0.29–3.16) 0.62 (0.15–1.65) 0.79 (0.04–3.62) 1.67 (0.41–4.50) 0.37 (0.02–1.68) 1.51 (0.25–4.88) 0.99 (0.42–1.95)
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
Maternal diabetes was found to be associated with higher risk of coarctation of the aorta (COA) (Table 4). All pregnant women with type I diabetes mellitus were treated with insulin. Most pregnant women with type II diabetes mellitus were treated with dietary restriction and/or antidiabetic drugs; only two were treated with insulin. Of 35 cases with CHDs, 27 and eight had mothers with type I and type II diabetes mellitus, respectively, while of 229 controls, 88 and 141 had mothers with type I and type II diabetes mellitus, respectively. Thus, COA was found to be
Migraine was also found to be associated with VSD. There was no difference in the risk of VSD in the children of mothers who did and did not receive antimigraine drug treatment. Panic disorders were found to be associated with hypoplastic left heart (HLH) and other congenital abnormalities of the aorta (OCAA) (Table 4). However, this association was based on three cases with different OCAAs (bicuspid aortic valve, stenosis of aorta and interruption of aortic arch).
Table 4 Prevalence rates of panic disorders and diabetes mellitus in mothers of cases with various types of congenital heart defects, mothers of population controls (PC) and mothers of malformed controls (MC). Study group
Population controls Malformed controls VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Total
Panic disorders
Comparison
n
n
%
OR (95% CI)PC
38,151 16,602
196 157
0.5 0.9
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
8 2 4 0 2 1 3 3 1 8 1 0 0 1 2 0 5 1 3 9
0.5 2.6 0.8 0.0 1.1 2.3 1.0 1.4 4.2 1.3 1.4 0.0 0.0 0.9 1.0 0.0 6.6 0.9 5.3 3.0
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
Diabetes mellitus OR (95% CI)MC Reference Reference
0.85 (0.38–1.62) 4.61 (0.75–14.88) 1.49 (0.45–3.54) 0.00 (0.00–Inf) 1.88 (0.31–5.97) 3.87 (0.22–18.04) 1.82 (0.45–4.83) 2.55 (0.63–6.77) 8.45 (0.47–41.00) 2.50 (0.98–4.77) 2.44 (0.14–11.16) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 1.72 (0.10–7.81) 1.82 (0.30–5.77) 0.00 (0.00–Inf) 13.38 (4.64–30.54) 1.62 (0.09–7.31) 8.83 (2.12–24.52) 5.43 (2.55–10.15)
0.50 (0.23–0.96) 2.80 (0.46–9.03) 0.82 (0.25–1.97) 0.00 (0.00–13.82) 1.10 (0.18–3.49) 2.36 (0.13–11.01) 1.04 (0.25–2.75) 1.47 (0.36–3.91) 4.35 (0.24–21.01) 1.43 (0.64–2.74) 1.41 (0.08–6.44) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.90 (0.05–4.11) 1.00 (0.16–3.18) 0.00 (0.00–2.02) 7.66 (2.66–17.51) 0.93 (0.05–4.20) 5.37 (1.29–14.91) 3.20 (1.50–5.99)
Comparison
n
%
229 100
0.6 0.6
12 1 3 1 2 0 4 0 0 4 2 1 0 1 4 1 2 4 1 8
0.7 1.3 0.6 1.3 1.1 0.0 1.3 0.0 0.0 0.7 2.8 7.7 0.0 0.9 2.0 1.8 2.6 3.5 1.8 2.6
OR (95% CI)PC
OR (95% CI)MC Reference Reference
1.18 (0.62–2.02) 2.16 (0.12–9.85) 1.01 (0.25–2.69) 2.27 (0.13–10.34) 1.91 (0.31–6.05) 0.00 (0.00–40.52) 2.15 (0.66–5.12) 0.00 (0.00–0.00) 0.00 (0.00–164.3) 1.09 (0.34–2.58) 4.61 (0.75–14.93) 14.43 (0.79–74.3) 0.00 (0.00–Inf) 1.56 (0.09–7.11) 3.30 (0.98–7.93) 3.09 (0.17–14.36) 4.15 (0.68–13.45) 5.94 (1.80–14.47) 2.89 (0.16–13.40) 4.35 (1.94–8.39)
1.20 (0.62–2.10) 2.23 (0.13–10.3) 1.01 (0.25–2.72) 2.16 (0.12–9.93) 1.88 (0.31–6.02) 0.00 (0.00–25.9) 2.19 (0.67–5.28) 0.00 (0.00–5.25) 0.00 (0.00–Inf) 1.10 (0.34–2.65) 4.64 (0.75–15.2) 16.05 (0.87–84.3) 0.00 (0.00–nf) 1.50 (0.08–6.95) 3.29 (0.99–8.02) 3.33 (0.19–15.7) 4.34 (0.70–14.3) 6.11 (1.84–15.1) 3.03 (0.17–14.1) 4.56 (2.02–8.95)
A. Vereczkey et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 1–6
5
Table 5 Prevalence rates of chronic hypertension and cardiac dysrhythmias in mothers of cases with various types of congenital heart defects, mothers of population controls (PC) and mothers of malformed controls (MC). Study groups
Population controls Malformed controls VSD SV ASD-II CAVC PDA CT TGA TF DORV CTD A/SPV A/STV EA CAPA RSOD VAS HLH COA OCAA LSOD
Total
Hypertension
Comparison
n
n
OR (95% CI)PC
38,151 16,602
2224 947
5.8 5.7
1659 76 471 79 181 44 307 222 24 597 72 13 7 108 200 56 76 113 57 302
122 5 24 10 16 6 15 15 0 36 7 1 2 11 21 2 6 6 7 21
7.4 6.6 5.1 12.7 8.8 13.6 4.9 6.8 0.0 6.0 9.7 7.7 28.6 10.2 10.5 3.6 7.9 5.3 12.3 7.0
%
OR (95% CI)MC Reference Reference
1.31 (1.08–1.58) 1.15 (0.40–2.58) 0.90 (0.58–1.33) 2.47 (1.19–4.60) 1.66 (0.95–2.69) 2.75 (1.04–6.06) 0.84 (0.48–1.36) 1.20 (0.68–1.96) 0.00 (0.00–0.01) 1.06 (0.74–1.46) 1.79 (0.75–3.66) 1.41 (0.08–7.16) 6.33 (0.89–30.24) 1.88 (0.95–3.37) 1.95 (1.20–3.00) 0.65 (0.11–2.09) 1.39 (0.54–2.95) 0.92 (0.36–1.93) 2.39 (0.98–4.95) 1.25 (0.77–1.90)
1.32 (1.08–1.60) 1.16 (0.41–2.62) 0.91 (0.58–1.35) 2.42 (1.16–4.51) 1.68 (0.96–2.73) 2.76 (1.04–6.11) 0.83 (0.47–1.35) 1.19 (0.67–1.96) 0.00 (0.00–0.13) 1.05 (0.73–1.46) 1.85 (0.77–3.79) 1.36 (0.07–6.98) 6.53 (0.92–31.14) 1.96 (0.98–3.52) 2.01 (1.24–3.11) 0.64 (0.11–2.08) 1.38 (0.53–2.93) 0.93 (0.36–1.95) 2.45 (0.98–5.10) 1.25 (0.77–1.91)
Cardiac dysrhythmias
Comparison
n
%
OR (95% CI)PC
156 72
0.4 0.4
12 0 8 4 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1
0.7 0.0 1.7 5.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.0 0.3
OR (95% CI)MC Reference Reference
1.77 (0.93–3.06) 0.00 (0.00–Inf) 4.22 (1.88–8.16) 12.73 (3.83–31.40) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–0.00) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–35.43) 0.00 (0.00–0.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 2.15 (0.12–9.76) 0.00 (0.00–Inf) 0.80 (0.05–3.59)
1.67 (0.86–2.96) 0.00 (0.00–Inf) 3.90 (1.72–7.70) 12.00 (3.58–30.00) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–94.03) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 0.00 (0.00–Inf) 2.03 (0.11–9.31) 0.00 (0.00–Inf) 0.75 (0.04–3.38)
OR, odds ratio; CI, confidence interval. Inf, infinity. See Table 1 for abbreviations of CHD types.
associated with type I diabetes mellitus (OR 2.5, 95% 1.6–3.9) but not associated with type II diabetes mellitus (OR 1.0, 95% CI 0.6– 1.6). Chronic/essential hypertension in the mothers showed a weak association with VSD, common atrioventricular canal (CAVC), common truncus (CT) and right-sided obstructive defects (RSOD) (Table 5). Different antihypertensive drugs used for the treatment of these pregnant women were analysed separately. Only nifedipin showed a weak association with higher risk for RSOD; this drug was considered as a confounder in the calculation of adjusted ORs. Cardiac dysrhythmias were found to be associated with atrial septal defect secundum (ASD-II) and CAVC (Table 5). In the group of 25 cases, paroxysmal supraventricular tachycardia and extrasystolic arrhythmia were diagnosed in eight cases with ASD-II (8 and 0, respectively) and four cases with CAVC (3 and 1, respectively). All 12 cases with VSD had mothers with paroxysmal supraventricular tachycardia; thus, this cardiac dysrhythmia was also associated with higher risk for VSD (OR 1.92, 95% CI 1.8–3.64). Of 156 population controls, 151 had paroxysmal supraventricular tachycardia and five had extrasystolic arhythmia. Of 72 malformed controls, 71 had paroxysmal supraventricular tachycardia. During the evaluation of possible associations between chronic diseases and higher risk of specific CHDs, related drug treatments were also analysed, particularly in the second and third months of gestation. Carbamazepine showed an interaction with the teratogenic effect of epilepsy, and nifedipin was associated with maternal hypertension; other drugs were not considered as confounders in calculation of adjusted ORs for different CHDs. Comment This population-based study aimed to identify possible associations between chronic maternal diseases and the risk of specific types of CHD. Some previously known associations (epilepsy and type I diabetes mellitus) were confirmed. However, the study identified several new associations such as panic
disorders with HLH; chronic hypertension with VSD, CAVC and CT; and paroxysmal supraventricular tachycardia with ASD-II, CAVC and VSD. The characteristic syndromic pattern of congenital abnormalities in children born to epileptic pregnant women treated with antiepileptic drugs is well known [17,18]. However, the present findings indicate an association between VSD alone and maternal epilepsy treated with antiepileptic drugs. Of 14 epileptic pregnant women, four were treated with carbamazepine alone, and two epileptic pregnant women received carbamazepine as part of polytherapy. These findings are in agreement with two previous reports which indicated the role of carbamazepine in the origin of CHDs [18,19]. A possible association between migraine and VSD was observed in this study. However, the risk of CHDs did not differ between mothers with migraine who did and did not receive antimigraine drug treatments [20]. Panic disorders were found to be associated with higher risk of HLH. This finding needs further study. These pregnant women were mainly treated with benzodiazepines. The association between maternal diabetes mellitus and some types of CHD has been reported previously [10]. In general, children of diabetic mothers are at higher risk for multiple congenital abnormalities (‘diabetic embryopathy’) including CHD. This study found that the children of pregnant women with type I diabetes mellitus were at higher risk for isolated COA; a similar association was not found for the children of pregnant women with type II diabetes mellitus [21]. A possible association between maternal chronic/essential hypertension and higher risk of some types of CHD was found in this study. A previous Hungarian case–control study showed a weak association between chronic hypertension and related drug treatments and higher risk of CHDs (OR 1.3, 95% CI 1.0–1.5), but different types of CHD were not differentiated [22]. The present findings confirm the previously reported association between paroxysmal supraventricular tachycardia and higher
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risk of septal defects in the heart [23]. The multifactorial threshold model is the most plausible explanation for the origin of common isolated CHDs [24]. This study showed that polygenic predisposition in mothers may be associated with cardiac dysrhythmias, particularly paroxysmal supraventricular tachycardia, that may be detected by electrocardiograms [25]. Thus, cardiac dysrhythmias may indicate developmental disturbances in the septum as a subthreshold manifestation of septal defects in the mother. Other common maternal diseases were not found to be associated with higher risk for CHD, including eight pregnant women with deep thrombophlebitis who were treated with acenocoumarol (Syncumar). This study suggests that certain chronic maternal diseases are associated with increased risk for specific types of CHD, and these risks seem to be specific for certain types of CHD because similar risk was not found in the mothers of malformed controls. Appropriate treatment of these maternal diseases may help in the prevention of these types of CHD. Strengths of this study include the large population-based data set of the HCCSCA, which included 3562 live-born cases with CHDs, 38,151 live-born population controls without any congenital abnormalities and 16,602 live-born malformed controls with other isolated congenital abnormalities in the ethnically homogeneous Hungarian (Caucasian) population. The validity of CHD diagnoses was improved due to the follow-up of cases in cardiology institutes and personal contact with the mothers. The authors aimed to study cases with homogeneous types of CHD; therefore, cases with syndromic or unclassified multiple congenital abnormalities including CHDs were excluded from the study, and only those cases found to have a single type of CHD [after lethal outcome (verified by autopsy report) or after surgical intervention (catheter or correction)] were included in the study. A major strength of this study is that different types of CHD were analysed separately. The occurrence of chronic maternal diseases was recorded prospectively in the prenatal maternity logbook. The use of malformed controls enabled the authors to differentiate between the specific CHD risk and the general risk of congenital abnormalities. However, this study had some weaknesses. Only severe CHDs (i.e. the most serious manifestations of the given CHD entities) were included, so the results are not representative of the whole spectrum of CHDs. VSD (perimembranous and muscular types) was the most common type of CHD, and was confirmed by cardiac catheter or surgical correction. Some types of CHD occurred in very few infants, so the statistical power did not allow the authors to draw conclusions. The major bias of this study is connected with multiple testing, because 32 chronic maternal diseases and 17 types of CHD were analysed; as such, it is difficult to exclude the effect of chance. Another weakness of this study is that the dataset of the HCCSCA included cases and controls between 1980 and 1996; however, the possible effect of chronic maternal diseases has not altered, but related drug treatments have changed over time. Nowadays, the major diagnostic approach for the diagnosis of CHD is ultrasound scanning (echocardiography), but autopsy and surgical interventions may produce similar or better results. In conclusion, certain chronic maternal diseases (i.e. epilepsy treated with carbamazepine, migraine, panic disorders, type I diabetes mellitus, chronic hypertension, paroxysmal supraventricular tachycardia) were found to be associated with higher risk of specific types of CHD.
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. References [1] Hoffman JIE, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. J Am Heart J 2004;147:425–39. [2] Reller MD, Strickland MJ, Riehle-Colarusso F, Mahle MD, Correa A. Prevalence of congenital heart defects in Metropolitan Atlanta, 1998–2005. J Pediatr 2008;153:807–13. [3] Gilbao SM, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States 1999 to 2006. Circulation 2010;122:2254–63. [4] Fulton DR. Congenital heart diseases in children and adolescent. In: Fuster V, Walsh A, O’Rourke RA, Poole-Wilson P, editors. Hurst’s the heart. 12th ed., New York: McGraw Hill Medical; 2008. p. 1855–921. [5] Zaidi S, Choi M, Wakimoto H, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 2013;498:220–3. [6] Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115:2995– 3014. [7] Rasmussen SA, Erickson JD, Reef SE, Ross DS. Teratology: from science to birth defects prevention. Birth Defects Res A Clin Mol Teratol 2009;95:82–92. [8] Botto LD, Lin AE, Riekle-Colarusso T, Malik S, Correa A. Seeking cause: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A Clin Mol Teratol 2007;79:714–27. [9] Ferencz C, Loffredo CA, Rubin JD, Magee CA. Epidemiology of congenital heart diseases. The Baltimore-Washington Infant Study: 1981–1989. Mount Kisco, NY: Future Publ Co.; 1993. [10] Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD. Genetic and environmental risk factors of major cardiovascular malformations. The BaltimoreWashington Infant Study: 1981–1989. Armonk, NY: Future Publ Co.; 1997. [11] Czeizel AE, Rockenbauer M, Siffel Cs, Varga E. Description and mission evaluation of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. Teratology 2001;63:176–85. [12] Czeizel AE. The first 25 years of the Hungarian Congenital Abnormality Registry. Teratology 1997;55:299–305. [13] Czeizel AE, Me´tneki J, Be´res J. 50 years of the Hungarian Congenital Abnormality Registry. Congenit Anom 2013;54:22–9. [14] Czeizel AE, Into˝ dy Zs, Modell B. What proportion of congenital abnormalities can be prevented? Br Med J 1993;306:499–503. [15] Czeizel AE, Petik D, Vargha P. Validation studies of drug exposures in pregnant women. Pharmacoepid Drug Safety 2003;12:409–16. [16] Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191:790–4. [17] Holmes LB, Harvey EA, Couli BA. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–8. [18] Czeizel AE, Ba´nhidy F. Congenital abnormalities of children born to epileptic women treated with antiepileptic drugs in Hungary – a population-based study. Open Drug Safety J 2010;1:40–56. [19] Thomas SV, Ajaykumar B, Sindhu K, et al. Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr Cardiol 2008;29:604–8. [20] A´cs N, Ba´nhidy F, Puho´ E, Czeizel AE. Maternal severe migraine and risk of limb deficiencies. Birth Defects Res A Clin Mol Teratol 2006;76:592–601. [21] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes: a population-based case–control study. Congenit Anom 2010;50:115–21. [22] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Essential hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring – a population-based case control study. Hypertension Res 2011;34:257–63. [23] Ba´nhidy F, A´cs N, Puho´ HE, Czeizel AE. Paroxysmal supraventricular tachycardia in pregnant women and birth outcomes of their children. Am J Med Genet 2010;150A:380–8. [24] Nora JJ. From generational studies to a multilevel genetic-environmental interaction. J Am Coll Cardiol 1994;23:1468–71. [25] Me´sza´ros M, Czeizel AE. ECG conduction disturbance in the first-degree relatives of children with ventricular septal defect. Hum Hered 1981;19: 298–301.
