Eur, J. Epidemiol. 0392-2990
EUROPEAN
September 1989, p. 382-391
Vol. 5, No. 3
JOURNAL
OF EPIDEMIOLOGY
RISK FACTORS IN CONGENITAL HEART DISEASE C. STOLL 1, Y. ALEMBIK, M.P. ROTH, B. DOTT and B. DE GEETER Institut de Pudriculture, - Centre Hospitalo-Universitaire 23 Rue de la Porte de l'H@ital, 67091 Strasbourg Cedex, France.
Key words: Congenital heart disease - Epidemiology - Congenital heart malformations Congenital malformations - Birth defects
Risk factors were studied in 801 children with congenital heart disease (CHD) coming from 105,374 consecutive births of known outcome. The incidence of CHD was 7.60 %0. Diagnosis was performed in 66.5% of the cases during the perinatal period. Two-hundred-fifty seven of the cases also had at least one non-cardiac malformation (multiply malformed). Ninety-two cardiac infants (11.47%) had recognized chromosomal and non-chromosomal syndromes. The most frequent noncardiac malformations were renal, digestive and limb anomalies. For each case a control was studied. The following features were screened: sex ratio, parity and previous pregnancies, parental age, residency, education, ethnic origin, lenght, head circumference and weight at birth, genetic and environmental factors. Odds ratio values were calculated for the risk factors. Weight, length and head circumference at birth of cardiac infants were less than those of controls. The weight of placenta was also lower than in controls. The pregnancy with CHD was more often complicated by hydramnios and threatened abortions, except in infants with isolated CHD. Oliogoamnios was more frequent in pregnancies producing multiply malformed infants and those with recognized syndromes with CHD. One out of four children with CHD had an extracardiac malformation, which is ten times the rate of incidence of malformation in our population. The incidence of CHD in first degree relatives of these infants was 3.0%. These first degree relatives also had more non-cardiac malformations than did those of the controls.
INTRODUCTION
Congenital heart defects (CHD) are the most c o m m o n o f all birth defects (23). The etiologies of C H D are heterogeneous and include chromosomal, and Mendelian factors, specific teratogenic factors (such as rubella, thalidomide and alcohol) and multifactorial causes. Since only a small proportion o f cardiac malformations are attributable to chromosomal or Mendelian disorders, multifactorial determination involving both genetic and environmental factors has been suggested in most cases (18). Although the multifactorial nature of C H D has long been recognized, the risks for C H D have most often been studied in clinical series with biased 1 Corresponding author.
ascertainment. Given the difficulties associated with precise clinical cardiac diagnoses, the relative rarity of CHD and the natural history of many o f these anomalies, it is not surprising that previous studies have been associated with various short-comings, i.e., absence o f specific lesion diagnosis, experience limited to a single hospital or data restricted to autopsied patients. The present study provides rates by specific lesions for total births (still births, live births, and interruption of pregnancy after prenatal diagnosis) among 105,374 consecutive pregnancies in one small region. In equating period prevalence with incidence, the assumption is made that the rate of C H D in abortions is zero, which is certainly not true (17). Complete ascertainment of infants with C H D in a defined geographic area provides an opportunity
382
Vol. 5, 1989
Risk factors in congenitalheart disease
obtained through the pediatric cardiologist and the physician in charge of the infant's care. For each case, an initial report and a follow-up report at one year of age were prepared using the material collected. For each case a control was studied. The control was a normal child of the same sex born after the case in the same maternity hospital. To determine sex ratios, the normal newborn population was used as a control group. For seasonality studies the monthly occurrences of all normal births from 1979 to 1986 were chosen as control rates. Statistical comparison was made by the x2test with Yates's correction for the characteristic under study in cases and controls and by the Student's test for comparison of means. Multiple linear regression and the spectra procedure (9, 25, 26) were used for seasonality studies. Odds ratio values were calculated according to the SAS procedure (25, 26).
to study the epidemiology and the risk factors of CHD. MATERIAL AND METHODS
The malformations for this study came from 105,374 consecutive births of known outcome, including 725 stillborn babies. The newborns of 11 hospitals were examined from January 1, 1979, to December 31, 1986. The region of investigation was the city of Strasbourg, France (an urban area) and the area defined by the "Departement du Bas-Rhin" in which Strasbourg is situated (a rural area). All newborns were registered within the first 8 postpartum days, as were all fetuses with a minimum age of 26 weeks. No delivery took place at home in the area under study. Each month all eleven maternity hospitals in the study area were visited by a doctor. Consultant neonatologists and pediatricians were interviewed concerning the CHD cases among births in the maternity units or in infants admitted to the neonatal units. These interviews constituted the main source of information. Similarly, visiting doctors were also interviewed in order to identify mild cases (cardiac murmurs) which do not require treatment or transfer to a neonatal unit. All autopsy reports of fetuses and dead infants in the study area were investigated for CHD. The only consultant pediatric cardiologist in the study area reports his patients. Admissions to the university pediatric cardiology unit were also checked for eligible cases. Finally, all hospital and private pediatricians and well-baby clinic staff members in the study area were informed about the study and asked to report all cases of CHD they detected. When a suspected or confirmed case was reported, information was obtained from all available records: prenatal consultation records, maternity files, neonatal unit files, autopsy reports, out-patient clinic files, pediatric cardiology and surgery files. For each case and for each control, detailed medical, environmental, socio-demographic and familial information were obtained, following the criteria previously described (23, 24). In this study teratogenic exposure was considered only when it occurred during the first trimester of pregnancy. Cigarette smoking was considered only in women smoking at least 5 cigarettes per day. All data were entered according to a standard format into a computer system. A karyotype was requested for all stillborns, all cases with clinically suspected chromosomal syndromes and all multiply malformed infants with at least three major malformations (23). "Cardiac infants" were defined as infants less than 1 year old with structural cardiac abnormalities confirmed by echocardiography, cardiac catheterization, surgery or autopsy. All anatomic cardiac lesions were coded according to the International Society of Cardiology classification (13). For each case, follow-up information was
RESULTS
During the eight-year study period, 801 cases of C.H.D. were detected out of a total of 105,374 births in the "departement du Bas-Rhin', representing an incidence of 7.60%. Autopsy findings were used for 135 infants (16.9%), 518 other children had undergone echocardiography without cardiac catheterization (62.7%) and all other patients had been studied by cardiac catheterization (18.4%). The number of cases by year were: 75 in 1979, 60 in 1980, 80 in 1981, 96 in 1982, 108 in 1983, 121 in 1984, 125 in 1985, 136 in 1986. The distribution of specific forms of CHD is shown in Table 1. Of the 801 cases, 757 were live births (94.50%), 25 were still births (3.12%) and in 19 (2.37%) pregnancies had been interrupted after prenatal diagnosis of malformations. Autopsies were performed on all still births and in 110 of the 127 infants who died after birth (86.6%). Diagnosis was made at birth in 197 cases (24.6%) and during the first week of life in 336 (41.9%) cases, for a total of 533 cases diagnosed during the perinatal period (66.5%). Ninety cases were diagnosed during the first month of life (11.2%), 134 between 1 month and I year of age (16.7%), and 44 cases were diagnosed prenatally (5.5%). The prevalence of C.H.D. with and without non-cardiac malformations is shown in Table 2. Five hundred ninety five cases (74.28O/o) had only cardiac malformations (isolated C.H.D.), and 92 (11.47%) also had recognized chromosomal and nonchromosomal syndromes. Excluding these latter syndromes, 114 cases (14.23%) had at least one extracardiac anomaly (multiply malformed) (Table 2) and 66 had 3 or more anomalies. The non-cardiac malformations are represented in Table 3. Only one cardiac malformation was present in 75.7% of the patients while 13.9% had two and 5.6% had three cardiac lesions. The sex ratio for CHD in general was 425 M : 376 F - 1.13 (controls 1.06 : non significant (NS)). Sex ratios were 1.12 for isolated CHD, 1.09 for multiple
383
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Eur. J. Epidemiol.
TABLE 1 . - Distribution and incidence o f cardiac malformations in all cardiac infants, in those with isolated congenital heart disease (CHD) and in cardiac infants with non-cardiac malformations. All cardiac infants Type
Isolated CHD
Cardiac + non-cfardiac malformations Recognized syndromes
No (%) of total cases
Incidence (%o)
No (%)
Multiple malformations
VSD
393 (38.7)
3.72
301 (40.8)
60 (33.3)
31 (34.0)
6 (26.0)
ASD II
137 (13.5)
1.30
97 (13.1)
32 (17.7)
8 (8.7)
2 (8.6)
PDA
73 (7.2)
0.69
46 (6.2)
19 (10.5)
6 (6.5)
3 (13.0)
CoA
51 (5.0)
0.48
37 (5.0)
7 (3.8)
5 (5.4)
2 (8.6)
PS
71 (7.0)
0.67
70 (9.4)
10 (5.5)
4 (4.3)
0
AS
33 (3.2)
0.29
29 (3.9)
3 (1.6)
0
1 (4.3)
TGA
46 (4.5)
0.43
40 (5.4)
5 (2.7)
0
1 (4.3)
TOF
23 (2.2)
0.21
16 (2.1)
7 (3.8)
4 (4.3)
0
AVCD
34 (3.3)
0.32
9 (1.2)
1 (0.5)
24 (26.3)
0
Chromosomal Non-chromosomal No (%) No (%)
SV
28 (2.7)
0.26
19 (2.5)
6 (3.3)
2 (2.1)
1 (4.3)
TA
14 (1.3)
0.13
8 (1.0)
5 (2.7)
1 (1.0)
0
LHH
31 (3.0)
0.29
26 (3.5)
3 (1.6)
0
2 (8.6)
0.03
4 (0.5)
0
0
0
5 (0.6)
4 (2.2)
0
2 (8.6)
6 (6.5)
3 (13.0)
Ebstein
4 (0.04)
Dextrocardia
11 (1.0)
0.10
Complex CHD
79 (7.8)
0.74
VSD = ventricular septal defect; ASD = atrial septal defect; PDA = patent ductus arteriosus; CoA = coarctation of aorta; PS = pulmonary stenosis; AS = aortic stenosis; TGA = transposition of great arteries; TOF = tetralogy ofFallot; AVCD = atrial-ventricular canal defect; SV = single ventricle; TA = tricuspid atresia; LHH = left heart hypoplasia; complex CHD = complex cardiopathies.
malformations, 1.08 for recognized syndromes, 1.09 for ventricular septal defect and 0.81 for atrial septal defect. Parity and previous pregnancies: Most o f the women were pregnant for the first time (45.9%), while 29.9% had had one previous pregnancy (controls 46.0% and 32.7%-NS). One previous spontaneous abortion was reported by 13.8%, and 3.0% reported two such events (controls 19.2% and 2.7%: NS). Ten women reported a previous interruption for another malformation (1.2%). One previous still birth was reported by 18 women (2.2%) and 1 reported two previous still births (0.1%) (controls 0.9, 1.8 and 0%: N.S.) Parental age: Mean maternal age was 26.5 years, and mean paternal age was 29.5 years. W h e n mothers o f Down's syndrome infants were excluded, the mean
TABLE 2. - Prevalence of congenital heart disease (CHD) with and without non-cardiac anomalies.
No
%
Prevalence per 10,000 births
Isolated CHD
595
74.28
56.46
CHD with non-cardiac anomalies - chromosomal abnormalities (Down's syndrome) - recognized non-chromosomal syndromes - multiple malformations
206 25.71 72 8.98 (45) (5.61) 20 2.49
19.54 6.83 (4.27) 1.89
114
10.81
Total
801
14.23
76.01 3 8 4
vol. 5, 1989
Risk factors in congenital heart disease
TABLE 3. - Non-cardiac malformations associated with CHD. Multiple malformations
Chromosomal
Total
Type No Limb-defects polydactyly club foot reduction defects other
30
Other musculo-skeletal spine rib and sternum diaphragmatic hernia
16
Digestive system anal atresia and stenosis malrotation tracheo-esophageal fistula pyloric stenosis duodenal stenosis other
37
Renal anomalies ureteral anomalies unilateral agenesia bilateral agenesia hydronephrosis cystic kidney reflux other
45
CNS hydrocephaly arhinencephaly agenesia of corpus collosum spina bifida anencephaly
22
Eye cataract coloboma microphthalmia
%
No
%
No
%
13.7
7
12.2
37
13.4
8 8 6 8
3 1 3 7.3
16.9
54
1 9 2
24.5
14
59
4 1
1 6 8
14.0
30
1 6 1
8
3.6
3
4 3 1
21.4
17 8 4 9 4 4 13
2
10.0
19.6
10 18 6 3 4 13
1 4 20.6
6.9
6 4 9 29.8
17
11 7 2 1 1
11
19
2
13 7 4 7 4 3 7
Genital defects hypospadias internal female genitalia
5.2 1
9 9 4 3 3 9
25
10.9
12 13 3 1 1 5.2
11
4.0
4 4 3
1 2
11.4
25
9 4 4 8
9.0
9 4 4 8 5.0
11
5 6
4.0
5 6
Cleft lip palate
7
3.2
Miscellaneous
17
7.7
Total
3
5 4 7
Ear, face and neck ear anomaly facial dysmorphia hypertelorism other
11 9 6 11
218
8.7
57 385
12
4.3
17
6.1
275
Stoll C. et aL
Eur. J. Epidemiol.
maternal age was 26.1 years. Controls: mean maternal age 26.0 yrs., mean paternal age 29.2 yrs.: (NS). Residency: Three hundred sixty two mothers were residents of urban areas (45.2%) and 439 lived in rural areas (54.8%) (controls 45.0 and 55.0%: NS). Education: Five hundred forty three mothers had not attended high school (67.8%), 193 had attended high school or college (24.0%), 41 were university students (5.1%) and 24 attended technical schools 43.0%). Controls (66.9%, 27.60/0, 3.7% and 2.0%: NS). Ethnic origin: Forty-three mothers were black (5.4%), 44 oriental (5.5%) and 714 caucasian (89.1%). (Controls 6.3%, 6.7% and 86.8%: NS). Lenght, head circumference and weight at birth: At birth the mean weight of all children with CHD was 3.080 g (controls 3,297, p < 0.01); the mean lenght was 48.3 cm (controls 49.4 era, p < 0.01) and the mean head circumference was 34.0 cm (controls 34.6, p < 0.01). For multiply malformed infants with CHD, mean birth weight was 2693 g, mean birth lenght 46.2 cm and mean birth head circumference, 33.1 cm. In contrast those measurements for children with isolated CHD were respectively 3,118 g (p < 0.01), 49.0 cm (p < 0.01) and 34.2 cm (p < 0.01). Lenght of gestation was less than 26 weeks in 3.8% of the CHD cases, from 27 to 32 weeks in 4.6%, from 33 to 36 weeks in 11.7% and 37 weeks or more in 79.8% of the cases (controls 3.4%; 4.7%; 13.4%; 78.4%; NS). Mean lenghts of gestation for multiply malformed infants and for those with isolated CHD, were 35.2 weeks and 37.7 weeks respectively (p < 0.05). Analysis of.weight, lenght and head circumference at birth and weight of placenta was performed after standardization for sex and gestational age in cardiac
infants with isolated CHD, those with multiple malformations and those with recognized syndromes (Table 4). No statistical difference was found for these variables between controls and isolated CHD cases. In multiply malformed infants and those with recognized syndromes born after 36 weeks of gestation, birthweight was lower than that of controls. Birthlenght in infants with recognized syndromes born after 36 weeks of gestation was also lower than that of controls. Head circumferences of multiply malformed male infants born between 36 and 38 weeks of gestation and in male infants with recognized syndromes born after 38 weeks of gestation were also lower, as was the weight of the placenta in females with recognised syndromes born between 36 and 38 weeks of gestation.
Factors associated with CHD: a) Genetic factors Consanguinity ofparents: There were nine cases of parental consanguinity among CHD cases (1.1°/0): two cousins once removed and seven cousins twice removed (controls 1.1.0/0). Inheritance: An inherited Mendelian condition was present in 16 cases. Recognized non-chromosomal syndromes: Twenty infants had non-chromosomal syndromes: 1 achondroplasia, 1 albinism, 1 Meckel's syndrome, 1 Ivermark's syndrome, 1 male pseudohermaphroditism, 2 Apert-Crouzon, 2 osteopetrosis, 1 FreemanSheldon's syndrome, 1 Aicardi's syndrome, 1 osteogenesis imperfecta, 1 Holt-Oram's syndrome, 1 Klippel-Trenaunay-Weber, 2 Carpenter's syndrome, 1
TABLE 4. - Weight, length and head circumference at birth by sex and gestational age for cardiac infants with isolated CHD, with multiple anomalies and with recognized syndromes (including chromosomal syndromes) by gestational age (NS = non significant, * = p < 0.05, ** = p < 0.01). Gestational age in weeks Isolated CHD < 36
3 6 - 38
Multiple malformations > 38
< 36
3 6 - 38
2396 NS 3074 NS 3458 NS 2209 NS 2697 * 1946 NS 2712 NS 3310 NS 1859 NS 2538" 2099 NS 2899 NS 3393 NS 2041NS 2648"
> 38
Syndromes < 36
36 - 38
> 38
Birthweight (g)
male female all
Birthweight (cm)
male female all
44NS 44NS 44NS
48.9NS 47.5 NS 48.2 NS
50.4NS 49.7NS 50.1NS
44.1NS 42.0NS 43.0 NS
47.1NS 46.6NS 47.0NS
49.3 NS 48.3 NS 48.8"
46.2NS 45.6NS 45.9NS
45.8" 46.8" 46.4"
46.7"* 47.2" 47.0"*
Head circumference (cm)
male female all
31.6NS 31.3 NS 31.4 NS
33.9NS 33.1NS 33.5 NS
35.1NS 34.4NS 34.8 NS
32.0 NS 30.1NS 31.0NS
33.5" 32.7 NS 33.1NS
34.6 NS 33.3 NS 34.0"
33.2 NS 33.0 NS 33.1NS
32.5 NS 32.1NS 32.3 NS
33.6"* 34.0 NS 33.7"*
Weight of placenta (g)
male female all
506NS 430 NS 457 NS
551NS 615 NS 582 NS
594NS 627 NS 608 NS
467NS 372 NS 409 NS
490NS 451 NS 477 NS
485NS 483 NS 484 NS
438NS 406 NS 422 NS
448NS 381 * 419 NS
447NS 578 NS 502 NS
386
3306 NS 2603 NS 3024 NS 2756 ** 3062 NS 2510 NS 2557 * 2818 * 3184" 2556NS 2776 NS 2785"*
Vol. 5, 1989
Risk factors in congenital heart disease
Ellis van Creveld's syndrome, 1 Noonan's syndrome, 2 VATER association. Cytogenetics: Karyotypes were obtained in 153 cases (19.1%). Of these, 81 were normal. Among the others there were 45 of cases of Down's syndrome, 7 of trisomy 13, 15 of trisomy 18, 1 of Turner's syndrome, one of the 5p- syndrome, one of 4psyndrome, one of d e r t (3; 7) (p26; q21) and one of trisomy 16. Twenty-one of the 45 infants with Down's syndrome had atrial-ventricular canals (46.7%), 15 had ventricular septal defects (33.3%), 4 had patent ductus arteriosus (8.9%) and 2 had coarctation of the aorta (4.4%). The remaining three were respectively affected by atrial septal defect, tetralogy of Fallot and single ventricle (2.2%). Occurrence in twins: Among our 801 index patients, 20 were twins and two were triplets (2.8%) (controls 3.6°/o). Each had an unaffected twin sibling. Two moters, 7 fathers and 15 siblings had the same CHD as the proband (3.0%). Forty nine firstdegree relatives had other malformations (6.1%) (controls: 3.2%, p < 0.01) and 28 second-degree relatives had CHDs: 20 on the maternal side, 8 on the paternal side.
b) Environmental factors One hundred eighty five mothers were smokers (23.00/0) (controls 21.6%: NS). The number of mothers not exposed during work (unemployed, housewife, clerk, professional and managerial) was 617 (77.0%). Exposed (unskilled, semiskilled and skilled workers) were 184 (23.0%): 81 (10.1%) were working in industrial plants, 41 (5.1%) were nurses or M.D. or had paramedical work, 36 (4.5%) were cleaners, 4 were hairdressers and the 22 other had miscellaneous exposing work (controls non exposed 74.7%, exposed 25.2%: NS). Four hundred twenty seven (53.30/0) of the fathers were exposed during work: 329 (41.0°/0) in industrial plants, 26 (3.2%) in health related occupations, 9 (1.1%) in cleaning, the others in miscellaneous occupations (controls 53.1%: N.S.). Seasonality: Rates of CHD by month of conception for the eight study years are shown in figure 1. No statistically significant seasonal variation in the birth prevalence could be demonstrated compared to the monthly occurrence of all normal births. Pregnancy: Seventeen pregnancies had occurred after treatment for infertility and 4 after insemination with donor sperm. Oral contraceptives had been used by 8.2% of the mothers during the 3 months before pregnancy, while 3.6% had used an intrauterine device (IUD) (controls 10.4% and 2.4%: N.S.). During the pregnancy in question, 13.1% of the women had threatened abortions, 6.1% had had hydramnios and 4.1% oligoamnios (controls 4.3%, p < 0.01; 1.30/0, p < 0.001; 0.80/0, p < 0.001). Isolated CHD, CHD associated with other noncardiac defects (multiply malformed), CHD with recognized syndromes and VSD and ASD, the most
"RATE
1,6 1.4
1.2 1.@ 9.8
0,6:
l,i, ;i
,v
o.4~ '.I';i o.2~ ~.~ . . . . .
.
:,. '
i
12
. . . . .
i
24
. . . . .
i
. . . . .
36
i
. . . . .
48
:
r
.
60
.
.
.
.
72
.
.
.
.
.
84
96
months
all cardiac infants. isolated cardiac heart disease.
Figure 1- Monthly rates of congenital heart disease by month of conception.
frequent CHD types, were considered separately and compared to controls. No statistically significant differences from control values were found for weight, length or head circumference at birth or for the weight of placenta in any of the categories studied. Threatened abortions and hydramnios were statistically more frequent than in controls in all categories except isolated CHD. Oligoamnios was more common, with respect to controls, in pregnancies producing infants with recognized syndromes or multiple malformations. Maternal pathology included diabetes in 4.1% of the mothers, epilepsy in 0.4% and arterial hypertension in 8.9% (controls 2.1%: NS, 0.4%: NS, 3.4: NS). During pregnancy 3.6% had had X-rays, 7.5% fever and 6.4% "flu" (controls 3.3%: NS, 8.1%: NS, 6.9%: NS), while 3.1% had consumed alcohol and 8.2% had taken medication (controls 11.9%: NS): antibiotics (2.9%), antispasmodics (1.8%), estrogen (1.8%). For 5.1% of the women, prenatal diagnosis had been performed because of maternal age (controls 4.7%: NS). Risk factors were studied for CHD as a whole, for isolated CHD, for CHD in multiply malformed infants, for CHD associated with recognized syndromes and for the most frequent CHD types (VSD and ASD). The results are shown in Table 5. As can be seen, odds ratios were not significant. Maternal age was higher than that of controls in cases of recognized syndromes, but Down's syndromes are included in this category. If Down's syndromes are excluded, no difference in maternal age could be found (Table 5).
387
DISCUSSION
Congenital heart defects are among the most difficult groups of malformations to ascertain
Stoll C. et al.
Eur. J. Epidemiol.
TABLE 5. - Odds ratios for risk factors for infants with isolated CHD, with non-cardiac malformations (multiple malformations), with recognized syndromes, with VSD (ventricular septal defect) and with ASD (atrial septal defect) (C.L. = confidence limits. None of the odd ratio values was significant).
Isolated CHD
Multiple malform,
Recognized syndromes
Odds
C.L.
Odds
C.L.
Odds
C.L.
Diabetes
1.3
0.38-4.5
2.54
0.63-10.1
1.03
Epilepsy
0.41
0.03-4.5
1.04
0.06-16.8
1.01
X-rays
0.94
0.10-0.99 0 . 8 3 0.31- 1.15 0 . 9 9
Hypertension
0.62
0.32-1.2
Fever
0.84
0.29-0.94 0 . 9 3 0.22- 1.06 0 . 9 1
0.71
0'.29- 1.7
0.82
VSD
ASD
Odds
C.L.
Odds
C.L.
0.99-1.06
1.4
0.4 -5.27
1.64
0.38-7.09
0.99-1.03
0.6
0.05-7.03
1.01
0.99-1.03
0.23-1.21
0.64
0.32-1.21
0.82
0.11-1.35
0.24-1.23
0.61
0.31-1.23
0.21-1.44 0 . 5 7
0.43
0.16-1.13
0.42-0.86 0 . 7 6
0.18-1.29
Flu
0.47
0.20-1.08 0 . 8 5 0.30- 2.3
0.7
0.2 -2.43
0.19-1.14 0 . 7 3
0.26-2.03
Medication
0.65
0.07-0.72 0 . 6 2 0.23- 0.81
0.72
0.13-0.95 0 . 6 5
0.07-1.33
0.83
0.24-1.34
Cigarettes
0.88
0.38-0.99 0 . 9 7 0.56- 1.6
0.9
0.48-1.55
1.6
0.4-1.97
0.71
0.42-1.19
1.55 1.44
0.91-2.65 0.83-2.47
1.53 1.7
0.7 -3.32 0.8 -3.56
1.68 1.45
0.96-2.95 0.83-2.53
1.29 1.55
0.67-2.52 0.82-2.91
Occupational exposure
mother father
1.72 1.58
1.01- 4.4 0.82- 3.03
0.47
Maternal age
0.86
0.56-1.34 0 . 7 2 0.42- 1.25 2 . 4 8
0.26-2.25
0.8
0.5 -1.27
1.01
0.59-1.72
Patemal age
0.74
0.47-1.17 0 . 7 0 0.40- 1.24 0.55
0.3 -1.01
0.7
0.4-1.18
0.61
0.38-1.06
accurately (2, 6, 15, 16). A number of affected infants have no symptoms or signs of CHD at birth or in the first months or years of life. Non-structural heart disease may also mimic anatomical CHD. Some diagnoses made in early infancy may require revision after full investigation during follow-up. Comparison of studies on CHD is difficult for several reasons. The first is that definitions and classifications vary from study to study. The second is the difficulty in knowing the proportion of cases diagnosed by conclusive techniques and considering the proportion of cases actually identified. The duration of follow-up is crucial (12). Our study involves a well-defined population in which all cases are referred to the Registry of Congenital Malformations and followed until one year of age for this study. The cases are reported by several sources, which minimizes the number of cases not ascertained. All patient follow-up is carried out by the same pediatric cardiologist, in close collaboration with the Registry of Congenital Malformations, thus eliminating the problem of variation in diagnostic criteria. The methods used for recording risk factors were identical for cases and controls to avoid the bias of differential recording between these two categories of subjects. The incidence of detected CHD was 7.60%0. This figure is in accord with the findings of the few recent surveys of this type (7). Compared with these surveys, the occurrences of severe morphologic abnormalities, such as transposition of great arteries, tetralogy of Fallot, coarctation of the aorta, pulmonary stenosis, aortic stenosis and patent ductus arteriosus, were 388
similar but higher for atrial septal defect and ventricular septal defects. The overall incidence of CHD has increased since 1982 according to the findings of Grabitz et al. (10). The increase in frequency observed in our study was probably not the result of a real increase in the incidence of CHD but rather the consequence of improved ascertainment due to systematic use of echocardiography since 1982. From 1982 on, all children with cardiac murmurs have undergone echocardiography. The increase in CHD was present and similar for all different cardiac lesions. The incidence in urban and rural areas was the same. Among our CHD infants, the prevalence of chromosomal abnormalities was higher than that found in the study by Ferencz et al. (8): 6.83 vs 5.1. Chromosomal abnormalities were 100 times more frequent in CHD infants with respect to controls and expected population rates (11). The prevalence of Down's syndrome in our study is similar to that reported by Ferencz et al. (8). However, our prevalences of CHD in general and of isolated CHD are almost twice those reported by these investigators (8). Ferencz et al. (8) say that full ascertainment of the live-born resident case population is made in the area under study. If this is true, as we have only 25 stillborn out of our 801 cases, we must admit that prevalence of CHD is higher in our region than in the BaltimoreWashington region. The prevalence of multiple malformed is three times higher in our study than in the study of Ferencz et al. (8): 10.8 v. 3.4% (Table 2), the percentage of the multiple malformed is 14.2 in our study compared to 8.4 in the study of Ferencz et al. ( 8 ) . The prevalences of recognized non-
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chromosomal syndromes are the same in both studies (2.0 and 1.89%o). The differences in the prevalence of isolated CHD and of multiple malformations with CHD must reflect the different ascertainment systems used in the two studies: Ferencz et al. (8) employed regional pediatric cardiology referral centers and 53 hospitals serving the study area while our survey was registry based. We found a percentage of CHD infants with non-cardiac anomalies of 25.7, slightly higher than that reported by Kenna et al. (15) (20%). Our study failed to demonstrate a consistent seasonal variation in the incidence of all the congenital heart lesions or of the most important ones. As in the other studies of CHD (see 15), infants with CHD in our study had lower birth weights and lengths and smaller head circumferences than controls. Placental weight, which has not been evaluated in previous studies, was found to be lower in CHD cases than in controls. In our study, CHD was not found to be associated with shorter gestation as it was in the Liverpool study (15). Therefore it seems unlikely that CHD is directly related to poor intrauterine growth (15) as our study demonstrated that patients with isolated CHD have no intrauterine growth retardation. Our data showed that gestational age and sex could be correlated with intrauterine growth and weight of placenta (Table 4). The sex ratio for all CHD is greater than unity (M/F = 1.13) which is similar to control ratio (1.06). The ratio does not vary from lesion to lesion or from category to category in our data. Maternal age was slightly higher in CHD patients than in the control population (mean maternal age 26.5 versus 26.0) but the difference is not significant. When Down's syndrome infants are excluded, the proportion of mothers aged 30 or more is similar in patients and in controls. Mean paternal age was also slightly higher in CHD patients than in the controls (29.5 years versus 29.2), but again the difference is not significant. The parity distribution showed no difference between patients with CHD and controls. The reproductive histories do not differ statistically from those of controls. Maternal diabetes, epilepsy, hypertension and fever during pregnancy was no more common among CHD infants than among controls, but hydramnios and threatened abortions were much more frequent in all categories of cardiac infants studied with the exception of isolated CHD (p < 0.001). Oligoamnios was more common in pregnancies producing multiply malformed cardiac infants and children with CHD and recognized syndromes. Maternal epilepsy and diabetes are known risk factors for CHD. In our study 4.1% of the mothers were diabetics as opposed to only 2.10/0of the controls' mothers. The difference is not statistically significant. In the study by Briard et al. (3), 1.3% of the mothers of children with CHD were diabetic vs. 0.6% in controls.
We did not found more epileptic mothers among cardiac infants than among control infants. Briard's group (3) reported that from 0.3-1.9% of the mothers of cardiac infants took antiepileptic drugs, depending on the type of the CHD studied. Mitchell et al. (16) found epilepsy in 1.4% of the mothers of cardiac infants. The prevalence of Down's syndrome in this series was quite similar to that reported by Ferencz et al. (8) (4.2 vs. 3.9). The association of CHD with trisomy 21 was present in 5.6% of our cardiac infants. This figure is similar to that found in the Liverpool study (15) (50/0). The most common cardiac defects in infants with Down's syndrome were atrial-ventricular canal defect (AVCD), which was present in 46.7o/0 of the cases, and ventricular septal defect (VSD) found in 33.30/o. Pernot et al. (22) reported that 55°/0 of the 452 trisomic 21 children they evaluated had AVCD and 20% had VSD. In another study (21) these percentages were respectively 42.7 and 33. Our results are similar to those of these two studies. Diagnosis was performed at birth or during the first week of life in 61.1°/0 of the cases~ Prenatal diagnosis was made in only 5.4% of the cases. When performed, prenatal diagnosis was made late in pregnancy, usually after 32 weeks. Congenital defects outside the cardiovascular system were recorded in 206 infants with CHD (25.7°/0), which is almost 10 times the chance expectation for our registry (24). The most frequent were musculo-skeletal, gastro-intestinal, renal-urinary and central nervous anomalies. Extra-cardiac malformations were 3 times more frequent in our patients than in those of Kramer et al. (16), who studied 881 children with CHD. We observed more digestive system anomalies, more renal malformations and more cleft lip and/or palate than Kramer (19.6 vs. 1.0%, 21.4 vs. 0.90/0 and 3.2 vs. 1.0%). In another study, only 130/0 of the children with CHD had extra-cardiac defects (14). Although these studies were not registry based, the difference is striking. A paper on extracardiac malformations, based on our material, is under preparation. The various kind of associated defects were detailed in the results section (the association with Down's syndrome being well known was excluded, 5.6% of infants with CHD had trisomy 21). In children with CHD the incidence of extra-cardiac anomalies, with the exception of oral clefts, was greater than that in our general population (23). The incidences of digestive, renal and central nervous system anomalies were three times those of our population (23). There was no increase in parental consanguinity in our CHD patients. Occurrence of CHD in twins was not increased: 3.0% (5.3% in a study by Calzolari et al. (4) on hypospadias). No cotwin had a CHD. When performed the karyotypes were normal in all cases except those involving Down's syndrome or other trisomies. Only one Turner's syndrome was detected. The incidence of CHD in first-degree relatives of
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Eur. J. Epidemiol.
8. Ferencz C., Rubin J.D., Mc Carter R.J., Bougham J.A., Wilson P.D., Brenner J.J., Neil C.A., Perry L.W., • Hepner S.L and Downing J.W. (1987): Cardiac and non cardiac malformations: observation in a population based study. - Teratology 35: 367-378.
C H D infants was 3.1%, which is four times the incidence in our general population. K e n n a et al. (15) found the same lesion in five sibships and a lesion of the same group (left to right shunt) in five other sibships. Campbell (5) also found the incidence o f C H D in sibs to be about twice that expected. Nora (19) reached the same conclusion. It can, therefore, be concluded that the risk o f C H D in siblings of a C H D infant is two to three times greater than that o f the general population. The affected sibling is m u c h m o r e likely to have the same heart lesion than a different one (1). Genetic counseling must be given to the family and prenatal diagnosis proposed (echocardiography). In our study no preferential maternal transmission was noted. Only one m o t h e r had the same form o f C H D as the proband. Therefore, the question o f cytoplasmic inheritance raised by Nora (20) cannot be confirmed by our data. In our study, first-degree relatives o f C H D infants also had m o r e non-cardiac malformations than those o f the controls: 6.1% vs. 3.2%. This finding has important implications for genetic counseling.
9. Fuller W.A. (1986): Introduction to statistical time series. - John Wiley, ed., New York. 10. Grabitz R.G., Joffres M.R. and Collins-Nakai R.L. (1988): Congenital heart disease: incidence in the first year of life. The Alberta Heritage Pediatric Cardiology Program. - Am. J. Epidemiol. 128: 381388. 11. Grouchy de J. and Turleau C. (1982): Atlas des maladies chromosomiques. L'Expansion Scientifique, Paris, 2~me 6d. 12. Hoffman J.I.E. and Christianson R. (1978): Congenital heart disease in a cohort of 19,502 births with long term follow-up. - Amer. J. Cardiol. 42: 641-647. 13. International Society of Cardiology Classification of Heart disease in Childhood. VR. B. Offset drukkerij, Groningen, 1970. 14. Jaiyesimi F. and Antia A.K (1979): Extracardiac defects in children with congenital heart disease. Brit. Heart J. 42: 475-479.
Acknowledgement This study was supported by grant CRE 84-8022 from the INSERM.
15. Kenna A.P., Smithells R. W. and Fielding D. W. (1975): Congenital heart disease in Liverpool: 1960-1969. Quart. J. Med. 44: 17-44.
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17. Mitchell S.C., Korones S.B. and Berendes H. W. (1971): Congenital heart disease in 56,109 births. Circulation 43: 323-332. (1968): Multifactorial inheritance 18. Nora J.J. hypothesis for the etiology of congenital heart disease: The genetic environmental interaction. Circulation 18: 604-617. 19. Nora J.J. and Nora A.H. (1978): Genetics and counseling in cardiovascular disease. - Charles C. Thomas, Edit., Springfield, 227p. 20. Nora J.J. and Nora A.H. (1987): Maternal transmission of congenital heart disease: new recurrence risk figures and the question of cytoplasmic inheritance and vulnerability to teratogens. - Am. J. cardiol. 59: 459-463. 21. Normand J., Sassolas E, Bozio A., Jocteur-Monrozier D. and Andrk M. (1981): Les cardiopathies de la trisomie 21. - Arch. Mal. Coeur 74: 1427-1436. 22. Pernot C., Dupuis C., Worms A.M., Blanc B. and Steppe M. (1982): Les cardiopathies de la trisomie 21. Etude de 452 observations. - M6d. et Hyg. 40: 589594. '
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