Eur. J. Epidemiol. 0392-2990 November 1992, p. 789-796

EUROPEAN

•Vol- 8, No. 6

JOURNAL OF

EPIDEMIOLOGY

A CASE-CONTROL STUDY OF MAJOR CONGENITAL HEART DEFECTS IN SWEDEN - 1981-1986 P. PRADAT *Department o f Embryology - University o f L u n d - Biskopsgatan 7 - S-223 62 - L u n d - Sweden.

Keywords: Congenital heart defect - Case-control study - Diabetes - Epilepsy - Abortion This paper reports the results of a case-control study of major congenital heart defects (CHD) in Sweden. During the period 1981-1986, 1,324 such cases were identified and 2,648 controls were selected. Some common maternal characteristics and exposures were studied using information from prospectively collected data. Possible associations with CHD were found for previous perinatal death, maternal diabetes, epilepsy, hydramnios and disproportion between fetus and pelvis. More specific associations were observed between previous spontaneous abortion, epilepsy, hydrarnnios and truncus anomalies and between diabetes and septal anomalies. However, no associations were found with involuntary childlessness, contraceptive use, or smoking.

INTRODUCTION

Congenital heart defects (CHD) are among the most frequent of all major malformations of the newborn infant. Estimates of the prevalence at birth vary widely in the literature, mainly due to different inclusion criteria, but major heart defects seem to occur at a rate of 2.8 per 1,000 births (27). In approximately 90% of all cases, the origin of the defect remains unknown (30). Cardiac defects are thought to be the result of an interaction of genetic and environmental factors (26), a so-called multifactorial etiology (7, 21). Many studies have tried to demonstrate possible relationships between CHD and maternal exposures but conflicting results were often obtained. The relation between aspirin use and CHD is an example of such differences (37, 40). Other studies have concentrated on the possible effect of some occupational exposures on the prevalence of CHD (31, 33-35), or on the effect of prenatal exposure

to exogenous sex hormones (12, 16, 24, 39). The association between diabetes mellitus and CHD has also been studied (15, 25, 28) and transposition of the great arteries and septal defects have been reported as the major types of defects. Maternal epilepsy and use of anticonvulsant drugs is followed by an increased risk of major congenital malformations in the offspring, including congenital heart defects (1, 4). After classification of the defects into subgroups, we investigated the possible relationship between cardiovascular malformations and some maternal characteristics. Data on the latter were collected prospectively during pregnancy (for early events) or at delivery (for late events). Few previous prospective studies on etiological factors in the origin of congenital heart defects are available. In the prospective Boston Collaborative Perinatal Project, an association between sex steroid use during early pregnancy and congenital heart defects was reported (9) but the actual findings have been criticised (38).

Abbreviations: ASD, atrial septal defect; CHD, congenital heart defect; CI, confidence interval; CoA, coarctation of the aorta;

DORV, double outlet right ventricle; ECD, endocardial cushion defect; HLHS, hypoplastic left heart syndrome; IUD, intrauterine device; LMP, last menstrual period; OC, oral contraceptive; OR, odds ratio; PDA, patent ductus arteriosus; TGV, transposition of the great vessels; VSD, ventdcular septal defect.

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MATERIALS AND METHODS

Cases: As described in a previous paper (27), the cases were infants born in Sweden during the period 19811986 presenting with a major CHD, usually diagnosed by echocardiography, cardiac catheterization, at operation, or at autopsy. These infants were identified from two Swedish registries: the Registry of Congenital Malformations (14) and the Child Cardiology Registry (2). Cases with a known chromosomal anomaly have been excluded from the study*. Table 1 lists the nine groups of heart defects analyzed with the number of cases in each group. The total number of cases was 1,324. TABLE 1. - The nine subgroups of heart defects analyzed in the case-control study (27) and the number of infants in each group. Heart defect Truncus anomalies Septum anomalies Mitral valve anomalies Tricuspidal valve anomalies HLHS ECD Artery malformations (except CoA) CoA Other malformations Total n u m b e r of diagnoses* Total n u m b e r of infants

Number of cases ' Percentage 585 385 26 52 119 74 121 190 156

week 10-12). During 1982, questions concerning previous abortions, maternal smoking, use of oral contraceptives (OC), intrauterine devices (IUD), and involuntary childlessness were included in the registry. Records on infants born before this date thus lack this information in the registry and information is available on only 1,108 cases and their controls. Exposure information was based on ICD codes (Swedish revision of ICD-8, that contains a fifth digit). Exposure definitions were as follows: presence of at least one previous spontaneous abortion or perinatal death; involuntary childlessness of at least one year; threatened abortion (ICD code 632,3 or 632,9); smoking (at least one cigarette per day); diabetes (ICD code 250); epilepsy (ICD code 345); thyroid disease (ICD code between 240 and 246, inclusive); toxicosis (ICD code between 637,0 and 637,9 excluding only albuminuria, hypertonia and oedema, or ICD code 661,2); hydramnios (ICD code 634,4 or 661,4); disproportion between fetus and pelvis (ICD code between 654,0 and 656,9, inclusive). Statistical method: Odds ratios with 95% confidence intervals (CI) were calculated from the triplets using McNemar's test (19) and Miettinen's approximation (20). When numbers were low, an approximation to a binomial distribution was made instead. For smoking, one of the controls in a triplet sometimes lacked information. For this exposure, pairs (one case, one control) were also taken into account and the odds ratios were calculated using Mantel-Haenszel estimate (18). This explains why the total number of controls is less than twice the number of cases for this exposure.

34.3 22.5 1.5 3.0 7.0 4.3 7.1 11.1 9.1

1708 1324

* = The total number of diagnoses exceeds the total number of infants as a single infant may have more than one diagnosis.

Controls: For each case, two controls were selected from the Medical Birth Registry (3). Controls were randomly selected within the same 5-year maternal age group, year of birth, and hospital of birth as the case. The selection criterium was the absence of CHD diagnosis (ICD code 746 or 747) - infants with other congenital defects, perinatal deaths, or low birthweight were accepted as controls. Maternal characteristics: Characteristics of the case and control mothers were obtained from the Medical Birth Registry. The case records were linked with the Medical Birth Registry using the unique identification number each Swedish citizen receives soon after birth. Fifteen characteristics were studied (Table 2). Data are based on information recorded prospectively and routinely in the Medical Birth Registry at the In'st visit of the woman to the maternity health service (usually

The possible effects of the exposures were first investigated for all CHD and then for each of the nine subgroups of CHD. Sometimes, further analysis was made after exclusion of infants with associated noncardiac malformations. RESULTS

Table 2 gives the number of cases and controls and the odds ratios with their 95% confidence interval for each maternal characteristic. The total number of infants was 1,324, of whom 59 had an associated noncardiac malformation. The total number of births during the period was 573,422. Previous abortions No association appeared between previous induced abortions and CHD. It can be seen from Table 2 that a similar percentage of exposed women was found in both groups (OR = 1.15, 95% CI: 0.92-1.45). No correlation appeared between the presence of at least one previous spontaneous abortion and any CHD (OR = 1.22, 95% CI: 0.97-1.53) but a significant

*Among 183 infants with chromosomal anomalies, 155 had Down's syndrome, 12 were trisomy 18, 3 were trisomy 13 and one had a sex chromosomal anomaly; the remaining 12 had other chromosomal anomalies.

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Case-control study of congenital heart defects

T A B L E 2. - List of maternal exposures investigated in the case-control study with the n u m b e r o f cases and controls. For each exposure, an odds ratio with its 95% confidence interval (95% CI) is also given. The n u m b e r of cases and controls varies between the different exposures because data on some exposures were not available for the whole period. Cases

Controls Odds ratio

Previous induced abortion Previous spontaneous abortion Previous perinatal death Involuntary childlessness OC (3 months before LMP) 1 OC (during first trimester) IUD (3 months before LMP) Threatened abortion 2 Any smoking Any smoking (perinat. death only) Diabetes 2 Epilepsy2 Thyroid disease2 Toxicosis2 Hydramnios 2 Disproportion between fetus and pelvis2

No

%

No

%

141/1108 147/1108 35/1324 69/1108 35/1108 9/1108 21/1108 19/1324 240/ 761 31/ 113 22/1324 9/1324 3/1324 53/1324 24/1324 86/1324

12.7 13.3 2.64 6.23 3.16 0.81 1.90 1.44 31.5 27.4 1.66 0.68 0.23 4.0 1.81 6.50

250/2216 249/2216 37/2648 130/2216 57/2216 18/2216 58/2216 30/2648 466/1422 63/ 213 17/2648 0/2648 1/2648 88/2648 6/2648 125/2648

11.3 11.2 1.40 5.87 2.57 0.81 2.62 1.13 32.8 29.6 0.64 0 0.04 3.32 0.23 4.72

1.15 1.22 1.89 1.07 1.25 1 0.72 1.27 0.94 0.91 2.67 6 1.22 8 1.41

95% CI

0.92 0.97 1.20 0.79 0.80 0.44 0.71 0.78 0.56 1.43 3.95 0.48 0.86 3.76 1.06 -

1.45 1.53

2.99 1.45 1.93

1.19

2.28 1.14 1.48 4.99 315 1.73 17 1.87

= If the mother used oral contraceptives (OC) or IUD, the date of stopping the contraceptive is compared with the date of last menstrual period (LPM). 2 These diseases can be identified by the medical diagnoses given to the woman during pregnancy or at delivery. The diagnoses a r e coded (ICD-8) at the hospital. =

association was observed for the ninth group, "Other malformations". The proportions of exposed cases and exposed controls were 21/134 (15.7%) and 21/268 (7.8%), OR = 2.41, 95% CI: 1.22-4.77. Nine of the exposed cases had a total or partial anomalous lung vein drainage and six had systemic vein anomalies (three had absence of the proximal part of inferior vena cava and three had a persistent left superior vena cava). Table 3 gives the distribution o f the n u m b e r of previous spontaneous abortions among cases and controls. A heterogeneity appears between the groups. I f one considers as "exposed" infants whose mothers experienced at least two previous abortions, the difference becomes highly significant (OR = 2.06, 950/0 CI: 1.29-3.29) for all CHD. This effect was mainly due to truncus anomalies (OR = 3.88, 95% CI: 1.97-7.64). After exclusion o f triplets with a case or control with maternal diabetes, the difference between cases and controls decreased but remained significant (OR = 2.04, 950/0 CI: 1.26-3.28) and truncus anomalies still caused the main effect (OR = 3.70, 95% CI: 1.86-7.35). The difference between cases and controls was no longer significant when cases with truncus anomalies were excluded (OR = 1.18, 950/0 CI: 0.59-2.36). 791

Previous

perinatal

death

Table 2 shows a difference in the rate o f previous perinatal deaths between cases and controls if all C H D are considered (OR = 1.89, 95% CI: 1.20-2.99). This effect cannot be solely explained by one group of CHD, although a major part of exposed cases belong to the two first groups of CHD, that is, truncus anomalies (12 cases) and ASD-VSD (12 cases). The odds ratios in these two subgroups were 2.4 (95% CI: 0.95-6.20) and 1.6 (95% CI" 0.68-3.66), respectively. I f triplets with maternal diabetes were excluded, the difference between cases and controls decreased but remained significant (OR = 1.65, 95% CI: 1.00-2.71). I f cases with truncus anomalies or septal anomalies were exluded, the magnitude of the odds ratio did not change m u c h but was no longer significant (OR = 1.82, 95% CI: 0.69-4.72). Involuntary

childlessness

No association was found between involuntary childlessness and C H D (OR = 1.07, 95% CI: 0.79-1.45). Neither did a significant association appear if only involuntary childlessness of at least four years

Pradat P.

Eur. J. Epidemiol.

TABLE 3. - Distribution of the n u m b e r of previous spontaneous abortions among mothers of cases and controls.

Smoking in early pregnancy Table 2 shows that the percentage of smoking w o m e n was similar in cases and controls (OR = 0.94, 95% CI: 0.78-1.14). If cases are restricted to those that died perinatally, no significant difference is observed between cases and controls (OR = 0.91, 95°/0 CI: 0.56-1.48).

Number of previous spontaneous abortions 0 Cases Controls Odds ratio* 95% CI

961 1967

1

2

3

>4

110 26 5 6 211 28 7 3 1.22 2.06 2.31 4 0.97-1.53 1.29-3.29 0.97-5.50 0.85-24.7

Maternal diseases Table 2 shows that the percentage of w o m e n with a diagnosis of diabetes during pregnancy differed between cases and controls. For all CHD, the odds ratio was 2.67 (95% CI: 1.43-4.99). This difference can mainly be explained by the second group of C H D (ASD-VSD) which contains 10 of the 22 exposed cases. In this group, the odds ratio was 6.20 (95% CI: 1.97-19.5). The odds ratio was lower and no longer significant when the cases with ASD-VSD were excluded (OR = 1.85, 950/0 CI: 0.85-4.01). Nine other cases belonged to the group of truncus anomalies and the odds ratio was very high for this group, although the association was not significant (OR = 2.25, 95% CI: 0.89-5.71). I f this group was also excluded, the odds ratio decreased to 1.2 (95% CI: 0.19-6.17). A m o n g 10 infants that belonged to the ASD-VSD group, five had a VSD None, three had ASD and VSD and two had a diagnosis of cor bi/triloculare. Six of the nine cases of truncus anomalies were TGV. A significant difference also appeared between cases and controls when the mother had a diagnosis of epilepsy. W h e n all C H D were considered, 9 cases had an epileptic mother whereas no control had (lowest value of the CI was 3.95). Four of the nine exposed cases had a diagnosis o f t m n c u s anomaly and the odds ratio was highly significant in this group (lowest value of the CI was 1.32). A m o n g these four cases, two had a pulmonary valve anomaly (one of w h o m also had an aortic valve anomaly) and three had a diagnosis of aortic valve anomaly (one with a pulmonary valve anomaly and one with a mitral valve anomaly). Four

* = The odds ratios measure the risk at at least n previous spontaneous abortions (1 < n < 4). 95% CI = 95% confidence interval. -

duration was considered (OR = 1.20, 95% CI: 0.721.98). Table 4 gives the distribution of the "time to pregnancy" among cases and controls, defined as the time between stopping oral contraceptives or removal of I U D and the date of LMP. The distribution was very similar between cases and controls. Contraceptive use No significant association appeared between the use of oral contraceptives immediately before or after LMP and CHD. The odds ratio was 1.25 (95% CI: 0.801.93) when OC were used during three months before LMP and 1.0 when mothers continued OC use after LMP. N o r was there an association between the use of I U D and the presence of C H D (OR = 0.72 for all CHD, 95% CI: 0.44-1.19). Threatened abortion No association was found between threatened abortion during pregnancy and CHD. (OR = 1.27, 95% CI: 0.71-2.28).

TABLE 4. - Distribution of the "time to pregnancy" among mothers of cases and controls. "Time to pregnancy" is defined as the period between stopping oral contraceptives or I U D and the date of LMP. Time to pregnancy (months) 0

1

2

3

4

5

6

Cases

45

30

26

20

16

14

5

Controls

76

63

53

52

23

15

22

Odds ratio* 95% CI

0.82

0.91

0.93

0.53-1.27

0.62-1.34

0.62-1.40

* Odds ratio = crude odds ratio for a "time to pregnancy" of at

least

792

1.18 0.74-1.88

1.00 0.55-1.81

0.42 0.16-1.11

n months (1 < n < 6); 95% CI = 95% confidence interval.

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Vol. 8, 1992

other cases belong to the ASD-VSD group (lowest value of the CI was 1.32). Three had a diagnosis of VSD (one also had a CoA), and one had an ASD together with a pulmonary artery malformation. No significant association was found between thyroid disease and CHD, but the number of cases here is very small (OR = 6, 95% CI: 0.48-315). No relation between toxicosis during pregnancy and all CHD (OR = 1.22, 95% CI: 0.86-1.73) appeared whereas a significant effect could be observed for the group of septal anomalies (OR = 2.09, 95% CI: 1.094.01). This effect remained if triplets with maternal diabetes were excluded from the data (OR = 2.11, 95°/0 CI: 1.04-4.31). Among 16 "exposed" cases, eight had a VSD, three an ASD, three an ASD + VSD and two a cor bi/triloculare. If the effect oftoxicosis was examined for all CHD excluding septal anomalies, the odds ratio decreased from 1.22 to 0.98 (95°/0 CI: 0.64-1.51).

Hydramnios A strong association appeared between hydramnios and CHD (OR = 8 for all CHD, 95% CI: 3.76-17). The difference between cases and controls was significant for two groups of CHD: truncus anomalies (OR = 14, 95% CI: 3.22-127) and septal anomalies (OR = 4.7, 95% CI: 1.07-28). These associations remained when triplets with maternal diabetes were excluded (OR = 7.7 for all CHD, 95% CI: 3.57-16.5), and when cases with associated extracardiac malformations were also excluded (OR = 3.6, 95% CI: 1.08-13.7). In this latter case, however, only the association with trnncus anomalies remained significant (OR = 6, 95% CI: 1.07-61). Six of the nine exposed cases had a diagnosis of truncus anomaly. One had a common truncus, one a TGV, one a DORV, two a pulmonary valve anomaly and one an aortic valve anomaly. For septal anomalies, the odds ratio decreased to 2 (95% CI: 0.15-28), but numbers are very small.

Disproportion between fetus and pelvis An association was found between this characteristic and CHD (OR = 1.41, 95% CI: 1.06-1.87 for all CHD). If each group of CHD was studied, a relation appeared with HLHS (OR = 3.6, 95% CI: 1.0813.7). These results were not changed if triplets with hydramnios were excluded but decreased if cases with extracardiac malformations were removed. The odds ratio was then 1.19 for all CHD (95% CI: 0.85-1.66) and 3.2 for HLHS (95% CI: 0.92-12.4). If cases with HLHS were excluded, the odds ratio for all CHD was 1.07 (95% CI: 0.76-1.53).

DISCUSSION Only a few cardiac teratogens have been identified with certainty. Thalidomide and rubella are classical examples of such agents. When a

malformation has a multifactorial etiology, it is often difficult to detect possible associations between environmental factors and the defect. This may explain the wide diversity of the results in the literature. In most case-control studies, information on exposures is collected retrospectively, often by questionnaires sent to the mother after the birth of the infant. When collecting data in this way, recall bias may distort the results (13). In the Medical Birth Registry in Sweden ( 3 ) , data on maternal characteristics are collected at the first visit of the woman to the maternity health service (usually week 10-12). As far as we know, this study is the first large case-control study on CHD with prospectively collected exposure information. Another problem may arise when one is testing many different hypotheses. For example, when looking at the possible correlation between different exposures and CHD, one would expect to erroneously reject every 20th null hypothesis (if one is working with 95% confidence intervals). This can be called the multiple testing bias and the possibility of such an explanation should be kept in mind when the results are interpreted. In this study, fifteen exposures or characteristics of the mother were studied. A possible association was found between previous spontaneous abortions and one group of CHD (truncus anomalies). It also appears that the proportion of mothers that had at least two previous spontaneous abortions is increased in the case group. To see whether this result was explained by the inclusion of diabetic mothers (who present an increased risk for spontaneous abortions and peri~atal deaths), these were excluded. The association remained, which indicates that a true relation may exist between spontaneous abortions and CHD, and more specifically with truncus anomalies. In addition, the association between previous perinatal death and CHD remains if cases with maternal diabetes are excluded. Here again, a true association may exist. Possible effects of subfertility on the offspring are difficult to evaluate. In a study performed in Sweden, Ghazi et al. (8) found no increased rate of major malformations in infants born of subfertile women, except for a possible overrisk for the subgroup of women with at least four years of infertility. In the present study, no correlation between subfertility and CHD could be found, not even in the subgroup of women with at least four years of infertility. As mentioned in the Introduction, the possible effect of exposure to exogenous sex hormones has been widely discussed in the literature but results are controversial. Reviews of the teratogenicity of sexhormones have been published (26, 29). Several authors have reported an excess of transposition of the great vessels (TGV) among heart lesions associated with sex hormone use (12, 16, 22, 23), but other authors could not demonstrate any effect of sexhormone exposure (6, 39). In our study, exposure to

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exogenous sex-hormones was defined as the use of oral contraceptives (OC) within 3 months before LMP or during the first trimester of pregnancy. In neither of these was an association found. However, it should be underlined that in most studies dealing with sexhormone exposure, any sort of preparation is included. This may include hormone treatment for threatened abortions or maternal estrogen deficiency, pregnancy test, oral contraceptives, etc. In Sweden, sex hormones are practically not used for threatened abortion nor for pregnancy tests. The restriction to the use of oral contraceptives could explain the lack of association. It appears, therefore, that the use of OC before or during early pregnancy does not represent a risk for the mother to give birth to an infant with CHD. The main reason for sex hormone treatments during pregnancy is threatened abortion. In a society using such therapy, threatened abortion could appear as a confounder. To isolate the separate effect of threatened abortion, data from the present study could be used: no such effect on the risk of having an infant with CHD was found. Today it is generally accepted that maternal smoking during pregnancy is correlated with an increased risk of low birth weight and perinatal death. However, whether maternal smoking can induce congenital malformations is still unclear. In two recent studies (32, 33), Tikkanen and Heinonen found no correlation between maternal smoking and cardiovascular malformations. This is in contrast with previous results by Fedrick et al. (5) who found a 500/0 increase in the incidence of CHD in singleton babies of smoking mothers (7.3 per 1,000 births compared with 4.7 per 1,000 among infants of non-smoking mothers). The authors suggested that this correlation might be true for patent ductus arteriosus (PDA) and Fallot's tetralogy, but the number of cases was small. Furthermore, it doesn't appear that low birth weight infants were excluded from their study, which should be done because of the well-known correlations between low birth weight and maternal smoking and between low birth weight and PDA. In the present study, no correlation was found between smoking and CHD. In order to see whether smoking in pregnancy could lead to severe heart malformations or increase the risk of death due to a cardiac defect, the effect of smoking was also studied only in cases that died perinatally. No effect could be observed. Maternal smoking thus does not seem to represent a risk factor for the occurrence of CHD. The association between diabetes mellitus and congenital anomalies has been widely studied (25) and TGV and septal defects have been reported as the largest groups (15, 28). In the two latter studies the number of cases was small, however. In the present study, a strong correlation was found between maternal diabetes and infant CHD. No significant association remains when cases with ASD-VSD are excluded from the data, which indicates that a true association may exist between septal defects and maternal diabetes. It should be noticed that although

the correlation was not significant in this group, TGV constituted a major part of the defects (6 of 22). In our study, a strong association appears between maternal epilepsy and CHD, which agrees with previous literature (1, 4). Truncus and septal anomalies were found to be the most common defects. In a previous study, Weber et al. (36) noticed that the main defect was TGV. Although a true correlation seems to exist between maternal epilepsy and truncus and septal anomalies, further studies are needed to find out the importance of the maternal disease itself and specific drugs used. An association was observed between toxicosis and septal anomalies. This association may explain the slightly high odds ratio for all CHD. Because preeclampsia is a common obstetric complication in diabetic pregnancies (17), the possible effect of toxicosis was studied after exclusion of triplets with maternal diabetes. The association remained, however. Hydramnios is often associated with diabetic pregnancies (11, 17). Because of the well-known association between anencephaly or esophagus atresia and hydramnios, all cases with an associated extracardiac malformation were excluded. A strong association remains with the group of truncus anomalies. In a recent study, Hendricks et al. (10) found that cardiovascular malformations were the most common anomalies among fetuses of mothers that had a severe hydramnios during pregnancy. However, no detailed description of the defects was given. The observed association between CHD and disproportion between fetus and pelvis is difficult to explain and could well be random. Acknowledgements

This study was made possible by a grant from the Medical Faculty, University of Lund, Swden. REFERENCES

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5. Fedrick J., Alberman E.D. and Goldstein H. (t971): Possible teratogenic effect of cigarette smoking Nature 231: 529-530.

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