TERATOLOGY 46:447-454 (1992)
Congenital Heart Disease in the Offspring and Maternal Habits and Home Exposures During Pregnancy JORMA TIKKANEN AND OLLI P. HEINONEN National Agency for Welfare and Health (J.T.),National Public Health Institute (O.P.H.), Helsinki, Finland
ABSTRACT
To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982-1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre-tested questionnaire. Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%)as controls (14.6%).Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures t o disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups. Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, C19, = 1.4-5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%)than among the control group (22.0%).However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2,95%confidence interval 0.9-1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis. It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart. 0 1992 Wiley-Liss, Inc.
Despite the importance of congenital heart disease as a cause of infant mortality and disability, the etiology of this anomaly remains almost totally unknown. One recent estimate suggests that known risk factors for congenital heart disease explain only 10 per cent of the etiology (Tikkanen, '86). Some environmental factors, such as thalidomide (Lenz, '62) and rubella virus, are classical causes of congenital heart disease (Higgins, '65). Maternal alcohol consumption during early pregnancy seems to increase the risk (Hanson et al., '76; Tikkanen and Heinonen, '91b), while maternal lithium therapy during the first trimester can
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1992 WILEY-LISS, INC.
cause a special type of cardiac malformation, Ebstein's anomaly (Nora et a]., '74). There have been few studies on maternal habits such as drug consumption and home exposures during early pregnancy on the risk of congenital heart disease in the offspring. Some reports have suggested that maternal hormone therapy (Heinonen et al., '77a) as well as anticonvulsant (Anderson, '76) and salicylate (McNiel, '73) intakes could cause cardiovascular malformations.
Received October 31, 1991, accepted June 26, 1992
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According to a recent literature review (Ferencz and Villasenor, '91) of occupational, home, and other environmental factors in cardiovascular malformations, solvents, pesticides, and lead among others have been suspected of damaging the developing fetal heart. Attention has also been focused on maternal diseases (Tikkanen and Heinonen, '92a), and special exposures during pregnancy, such as examinations by X-ray (Tikkanen and Heinonen, '91b) and ultrasound (Tikkanen, '86). Although understanding of the origins of cardiovascular malformations is increasing only very slowly, the accumulated literature does suggest that a large proportion maternal habits and environmental exposures are probably not harmful to the fetal heart. Some reports have observed, for instance, that maternal coffee, tea, and cola consumption, and use of deodorants or hair sprays during early pregnancy are not associated with the risk of congenital heart disease in the offspring (Tikkanen, '86; Tikkanen and Heinonen, '91b). Studies also indicate that maternal smoking or exposure to passive smoking during early pregnancy a t home or a t work are not connected with the risk of congenital heart disease in the offspring (Heinonen, '76; Tikkanen, '86; Tikkanen and Heinonen, '91b). Neither does maternal exposure to video display terminals during early pregnancy seem to increase this risk (Tikkanen and Heinonen, '91b). Moreover, certain factors which can cause maternal hyperthermia during pregnancy, such as sauna bathing or high maternal workplace or environmental temperature, seem not to be associated with the risk of cardiovascular malformations in the offspring (Tikkanen and Heinonen, '91c). In the modern Western world, many pregnant women are exposed to a number of chemical and physical factors which, according to animal studies, may have a teratogenic effect on the developing fetal heart. For this reason an investigation into the etiology of congenital heart disease was started in Finland in 1981 (Tikkanen, '86; Tikkanen and Heinonen, '90, '91b, '92a,b). The present report concerns part of this large project. The purpose of this particular study was to investigate maternal habits and home exposures during pregnancy as possible risks for congenital heart disease in the offspring.
MATERIALS AND METHODS
As the formation of the case and control groups and the interview of the mothers have been detailed in earlier reports (Tikkanen and Heinonen, '90, '92a,b), only a summary of the materials and methods is presented here. Cardiovascular malformations The cases were selected from all 133,000 live and stillbirths in Finland during 1982 and 1983. Infants with cardiovascular malformations were identified independently from the Finnish Register of Congenital Malformations or the Children's Cardiac Register. Pediatricians, especially pediatric cardiologists, send their notifications of cardiovascular malformations to these registers. One third (31%) of the malformations were reported only to the former registry, one third (34%) only to the latter, and one third (35%) to both. In both registers cardiovascular anomalies detected during the first year of life had been diagnosed by echocardiography, cardiac catheterization, surgery, or autopsy. Twenty-six of the children were stillborn and their diagnoses based on autopsy findings. In 59% of the cases, diagnosis had been made during the first month of life, in 15% during the second month, and in 26% after the second month but before the age of 1 year. Between 1 January 1982 and 30 April 1984,553 infants with congenital heart disease born in 1982-1983 had been reported. Twenty-three of these children were excluded because the diagnosis of cardiovascular malformation was made solely on the basis of a clinical examination and not confirmed by cardiac catheterization, echocardiography, cardiac surgery, or autopsy. Sixty-three cases with chromosomal anomalies (e.g., Down's syndrome, trisomy 18,13, or a known genetic syndrome) or extracardiac anomalies were also deleted from the study. Mothers of 61 infants refused to participate in the interview. All these exclusions thus reduced our numbers from 553 cases to 406 infants with a total of 583 cardiovascular malformations. Every cardiovascular anomaly was checked by a professor of pediatric cardiology against the hospital records. Moreover, the same professor had personally examined the cardiac status of approximately 50% of all the case infants at the Helsinki Central Hospital.
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
Common cardiovascular malformations in this data were ventricular septal defect (n = 150), patent ductus arteriosus (n = go), coarctation of the aorta (n = 50), atrial septal defect (n = 50), transposition of the great arteries (n = 361, hypoplastic left ventricle (n = 34),tetralogy of Fallot (n = 23), and truncus arteriosus (n = 14). Rarer cardiovascular malformations included pulmonary atresia (n = 111, total anomalous pulmonary venous drainage (n = 91, pulmonary stenosis (valvular) (n = 51, aortic stenosis (n = 31, and tricuspid atresia (n = 2). All the cardiovascular malformations were classified using a method for the epidemiological study of congenital heart disease (Tikkanen, '86). This approach makes it possible to investigate causes of cardiovascular malformations by taking into account the embryologic nature of the defects. This classification, which has also been recently described elsewhere (Heinonen, '76; Tikkanen and Heinonen, '91b), has six categories: ventricular septal defect (VSD, n = 150), conus arteriosus (CAS, n = 901, atrial septal defect (ASD, n = 50), hypoplastic left ventricle (LHHS, n = 341, endocardial cushion defect (ECD, n = 22), and other n = 237). defects (0, According to this classification only ventricular septal defects comprised the VSD category and only atrial septal defects made up the ASD group. The conus arteriosus category (CAS) included the following cardiac defects: tetralogy of Fallot, transposition of the great arteries, truncus arteriosus, double outlet right ventricle, aorto-pulmonic window, and pulmonic valve atresia. Left ventricular hypoplasia, aortal valve atresia, mitral stenosis, and mitral atresia were all classified under the LHHS category. Atrial septal defect (primary) and atrioventricular canal joined the ECD group.
Controls The controls were randomly selected from all deliveries in Finland during 1982-1983 (approximately 133,000).For each year, 400 non-malformed infants were selected from 52 hospitals on the basis of their frequency of deliveries in 1981. On randomly chosen dates, the first infant born who was free of anomaly in every organ was selected for inclusion in the study. Forty-four (5.5%) of the mothers thus selected could not be contacted or refused to
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participate. Thus the final group consisted of 756 infants.
Interview of the mother All the mothers were interviewed a t maternity welfare centers by a midwife using a structured questionnaire. The mothers of affected and normal infants were interviewed approximately 92 days (range 14-147) and 96 days (range 21-1541, respectively, after delivery, and the interview lasted approximately 1 hour. In the first part of the interview the mothers were asked about drug consumption during the first trimester of pregnancy. First came general questions on their drug consumption, medications used in some common diseases, and those most frequently taken during pregnancy in Finland. However, only the intakes of acetylsalicylic acid, diazepam and contraceptive pills were analyzed for this report. Maternal exposures a t home formed the second part of the interview. First the mother was asked to describe her domestic tasks during the first trimester of pregnancy. Following structured rules, the interviewer sought details on exposure to chemicals or physical factors. The following exposures were noted: organic solvents, dyes, lacquers, paints, glues, disinfectants, plastic raw materials, wood preservatives, pesticides, dusts, and microwave ovens. If the mother reported any exposure to specific physical or chemical factors, the interviewer noted the frequency of exposure (regular or occasional). The third part of the interview contained questions on disorders in the family and selected habits of the mothers during pregnancy. In this section the mothers were asked about cardiovascular malformation or similar disorders in family members and their own symptoms during the first trimester of pregnancy. The interview also sought details on maternal smoking, coffee, tea, and alcohol consumption, as well a s use of deodorants and other chemicals. Statistical methods In cross-tabulation of the data, odds ratios and their 95%confidence intervals were calculated to test the hypothesis that casemother characteristics or exposures somehow differed from those of control mothers. A logistic regression analysis was applied to the data to evaluate whether the associ-
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TABLE 1 . Selected maternal diseases or conditions during previous pregnancies Cases (n : 406) Disease or condition Miscarriage 1 2 2 Induced abortion Premature birth Stillbirth Extrauterine eravid
%
Controls (n= 756) 9%
Odds ratio and 95%confidence interval
10.4 5.2 12.3 3.6 0.5 0.5
12.5 2.0 11.7 2.4 0.6 0.7
0.8 10.5-1.21 . 2.7 (1.4-5.3) 1.1 (0.8-1.6) 1.6 (0.8-3.2) 0.9 (0.2-4.9) 0.7 (0.2-3.8)
Y
ation between maternal ultrasound examination during the first trimester and the risk of congenital heart disease in the offspring was related to the risk of miscarriage during early pregnancy. Maternal ultrasound examination and the risk of miscarriage were dichotomized (yeslno) and included in the analysis. The analysis was performed using the BMDP program. The adjusted relative odds ratios and their 95% confidence intervals were computed from the estimates of model parameters and their standard errors (Lemeshow and Hosmer Jr., '84). RESULTS
Maternal diseases, contraception, and ultrasound examination Table 1lists selected maternal diseases or conditions during previous pregnancies. Having had several miscarriages during earlier pregnancies was more prevalent among cases than controls. Other conditions such as induced abortion, previous stillbirth, or extrauterine gravid seemed not to predict the birth of an infant with a cardiovascular anomaly (Table 1).No significant differences in any of these factors were found between any of the ontogenetic defect groups (VSD, CAS, ASD, ECD, LHHS, and 0) and the controls. Table 2 presents the maternal use of contraceptive methods a t the time of conception. Interrupted coitus was more prevalent among the cases than the control group. Methods such as chemical foam or IUD were equally prevalent in the two groups. Intakes of neither mini-pills nor other contraceptive pills were associated with the risk of congenital heart disease in the offspring (Table 2). Neither were there significant differences in these factors between any of the ontogenetic groups (VSD, CAS, ASD, LHHS, ECD, and 0) and the controls. Maternal ultrasound examination during
the first 16 weeks of pregnancy had been performed more often among the case group (28.3%) than among the controls (22.0%) (Table 3). This was true for all of the ontogenetic groups of congenital heart disease, as follows: VSD (33.0%),CAS (26.7%),ASD (28.0%),LHHS(26.5%),ECD(27.3%),andO (26.6%). Habits and home exposures Maternal overall drug consumption during the first trimester of pregnancy was as prevalent among case mothers (13.3%) as controls (14.6%)(Table 4).Maternal intake of acetylsalicylic acid such as AspirinR was as common in the case (8.0%) and control groups (5.8%).This also held for the specific groups of cardiovascular malformations such as VSD (8.0%), CAS (5.8%), ASD (2.0%),LHHS (5.9%), and 0 (7.6%), except for the ECD grou where 18.2% of mothers had used AspirinP; during the first trimester. Few mothers consumed diazepam during early pregnancy (Table 4).The intake of diazepam was as prevalent among cases and controls, and no differences were found between any of the ontogenetic groups of congenital heart disease and the control group. Use of sweetening agents in coffee was as prevalent among case mothers (3.7%) as controls (3.8%),and no respective differences between the groups were found in tea (6.117.0%) or cocoa (3.8/3.2%) consumption (Table 4).No differences were found in the use of sweetening agents between any of the ontogenetic groups of congenital heart disease and the control group. Table 5 presents maternal exposures to chemical and physical factors at home during the first trimester. All of the recorded chemical and physical exposures during the first trimester were equally prevalent among case and control mothers. No differences were found in, e.g., exposures to wash-
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
TABLE 2. Maternal
use of
Contraceptive method being used at conception Interrupted coitus “Safe” days Mechanical (condom, pessary) Chemical (foam) Both mechanical and chemical IUD Contraceptive mini pills Other contraceptive pill No contraception All
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contraception at the time of conception’ Cases Controls Odds ratio and (n = 5721 in = 1,050) 95% confidence % % interval 1.4 0.4 3.7 (1.1-12) 1.0 0.4 2.6 (0.5-4.0) 7.9 9.3 0.8 (0.6-1.1) 0.3 0.4 0.9 (0.1-4.9) 0.5 0.8 0.7 (0.2-2.6) 5.4 0.9 (0.6-1.4) 4.9 0.9 0.5 1.8 (0.5-6.2) 3.1 3.3 1.0 (0.6-1.8) 80.0 79.5 1.0 (0.8-1.3) 100.0 100.0 -
‘These data on contraception were only available on the basis of the 3-year period 1982-1984.
TABLE 3. Maternal exposure to ultrasound examination during the first trimester of pregnancy Cases Controls Odds ratio and Ultrasound (n = 406) (n = 754) 95% confidence examination % % interval 22.0 28.3 Yes 1.4 (0.8-2.51 78.0 73.7 No 100.0 100.0 All
TABLE 4. Maternal drug cunsumption during the first trimester of pregnancy Cases (n -406) Intake Overall drug consumption Intake of AspirinR Intake of diazepam Use of sweetening agents in coffee Use of sweetening agents in tea Use of sweetening agents in cocoa
ing substances, dyes, lacquers or paints, pesticides, or microwave ovens, and none were evident between the controls and any of the ontogenetic groups (VSD, CAS, ASD, ECD, LHHS, and 0).
Logistic regression analysis In order to test whether the association between ultrasound examination and the risk of congenital heart disease in the offspring was confounded by the threat of miscarriage during the first trimester a logistic regression analysis was performed. Maternal ultrasound examination and threatened miscarriage during the first trimester of pregnancy were dichotomized (yesino) and included in regression analyses of all the cardiovascular malformations. Maternal ultrasound examination during the first trimester of pregnancy showed an adjusted odds ratio of 1.2 (95% confidence interval 0.9-1.7), and the threat of miscar-
Controls (n = 756)
%
%
13.3 8.0 0.5 3.7 6.1 3.8
14.6 5.8 1.1 3.8 7.0 3.2
Odds ratio and 95% confidence interval 0.9 (0.5-1.8) 1.4 (0.5-3.6) 0.5 (0.02-101 1.0 (0.3-3.41 0.9 (0.3-2.3‘1 1.2 (0.3-4.31
riage an odds ratio of 1.2 (95% confidence interval 0.6 -2.4). In logistic regression analysis of the VSD group, maternal exposure to ultrasound examination showed a relative odds ratio of 1.6 (95% confidence interval 1.0-3.7). The odds ratio of threatened miscarriage during the first trimester did not differ significantly from unity. DISCUSSION
About 14% of the mothers in this data consumed a t least one drug during the first trimester of pregnancy. The intake of drugs during early pregnancy is hazardous because they are responsible for 1.5 per cent of all congenital anomalies, and most drugs have not been tested in humans (Tikkanen, ’86). We investigated in the present survey the intakes of contraceptive pills, acetosalicylic acid, and diazepam, because these substances have been suspected of damaging
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J. TIKKANEN AND O.P. HEINONEN TABLE 5. Maternal exposure to chemical and physical factors at home during the first trimester of pregnancy Cases Controls Odds ratio and (n= 756) 95% confidence (n = 406) % % interval Exposure category Washing substances and disinfectants Occasional 28.9 25.9 1.2 (0.9-1.5) 38.1 36.7 1.1 (0.8-1.4) Regular Dyes,lacquers, paints Occasional 10.3 10.1 1.0 (0.7-1.5) 0.2 0.0 Regular Organic solvents 4.9 4.0 1.3 (0.7-2.3) Occasional Regular 0.5 0.5 0.9 (0.2-5.0) Pesticides Occasional 2.9 2.0 1.5 (0.7-3.2) Regular 0.2 0.0 Mineral oil products 1.7 2.1 Occasional 0.8 (0.3-2.0) 0.2 0.1 1.9 (0.1-30) Regular Wood preservatives 2.0 1.6 1.2 (0.5-3.0) Occasional 0.2 0.0 Regular Plastic raw materials 0.2 0.3 0.9 (0.08-10) Occasional 0.0 0.3 Regular Glues Occasional 4.6 5.3 0.9 (0.5-1.6) Regular 0.5 0.3 1.9 (0.7-5.2) Microwave ovens 0.7 0.9 0.8 (0.2-3.1) Occasional 0.5 0.3 1.9 (0.3-14) Regular Textile dusts 11.3 13.0 0.9 (0.6-1.3) Occasional 7.6 8.0 1.0 (0.6-1.6) Regular Other dusts Occasional 11.9 12.3 1.0 (0.7-1.4) 6.7 7.5 0.9 (0.6-1.4) Regular
the fetal heart. They are also in common use in Finland, so both mothers as well as interviewers recognized these preparations in the interview, which probably increased the reliability of the drug-related answers. Several earlier reports have suggested that synthetic estrogens, progesterones, and contraceptive pills may disturb the normal cardiovascular development of the fetus. The use of contraceptive pills was therefore investigated in this study. Maternal exposure to contraceptive pills during the period of cardiogenesis occurred in 23 out of 572 congenital heart patients (4.0%) compared with 40 out of 1,050 controls (3.8%))suggesting no association between these factors. This negative finding is in line with some other investigations (Matsunaga and Shiota, '79; Ferencz et al., '80). Therefore we consider that earlier findings of positive associations between maternal intake of hormones and cardiovascular malformations in the offspring may be because many compli-
cations of pregnancy were treated with hormonal therapy. Because congenital heart disease of the fetus is associated, e.g., with the risk of miscarriage, maternal hormonal therapy may have been falsely regarded as a cause of congenital heart disease. The teratogenic properties of salicylates were first demonstrated by Joseph J. Warkany and co-workers (Warkany, '71). Because animal experiments have shown that salicylate teratogenicity can be enhanced by the maternal physiological state and that salicylates cross the human placenta (McNiel, '73)) the possibility exists that large doses of aspirin or other salicylates may be teratogenic in humans. Therefore in this study a commonly used salicylate, AspirinR, was investigated. No association between maternal intake of Aspirin and congenital heart disease was found, in agreement with Heinonen et al. ('77b) among others. However, when comparing the results of this investigation with other studies (e.g., Heino-
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
nen et al., '77a,b) the differences in study design (e.g., sample size and choice of controls) should be kept in mind. Moreover, the limited power of teratoepidemiological casecontrol studies like this should be considered. This is particularly true for effects of rare exposures such as maternal drug consumption. Therefore, conclusions about the negative findings of this investigation must be drawn very carefully. In this survey some maternal conditions during previous pregnancies were investigated to evaluate their power to predict the birth of a n infant with congenital heart disease. Of these factors, induced abortion, premature birth, stillbirth, and extrauterine gravid were not associated with the risk of congenital heart disease in the offspring during the next pregnancy. In contrast, several miscarriages in earlier pregnancies did seem to associate with the risk of congenital heart disease in the subsequent offspring. In the 1980s a public debate over the safety of ultrasound examination during early pregnancy was initiated in Finland. One question dealing with this was therefore included in the study questionnaire. According to this data, ultrasound examination had been performed more often among the case group than the control group. U1trasound examination during the first trimester was not, however, responsible for cardiovascular malformations: logistic regression analysis showed that the threat of miscarriage during early pregnancy was in fact the confounding factor explaining the association between ultrasound examination and the risk of congenital heart disease. It is thus good to keep in mind that fetuses with congenital heart disease may exert complications of pregnancy which lead to investigation by ultrasound (Tikkanen and Heinonen, '91a). During the past few decades many common environmental factors, such as sauna bathing or exposure to microwave ovens a t home, have been suspected of damaging the developing fetus. Despite these suspicions, most teratoepidemiological studies have focused on possible teratogenic hazards only at mothers' workplaces. For this reason we investigated domestic maternal exposures as widely as possible. None of these, e.g., exposure to disinfectants, dyes, lacquers, paints, or microwave ovens, were associated with the risk of congenital heart disease. Therefore we conclude that these chemical
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or physical factors probably do not have a teratogenic effect on the fetal heart a t usual levels of exposure. These study results need to be interpreted with some caution, since information of this type gathered from mothers post partum does not come with the highest degree of reliability. A mother of a malformed infant may scrutinize her memory for all possible causes, while the mother of a healthy child has less incentive t o recall such events from early pregnancy. To this extent, differences between case and control groups may be a function of maternal memory bias. On the other hand, i t is not reasonable to assume that the reporting of similar exposures by the two groups, e.g., to pesticides or microwave ovens at home, was due to systematically poor recall by mothers of the malformed infants. I n this data 61 mothers of malformed infants refused to participate in the interview. It seemed that these infants had a more severe cardiac defect than babies whose mothers took part in the interview. This phenomenon probably has a psychological basis. It is likely t h a t the mothers of severely malformed infants are still in the shock stage soon after delivery, and thus unable to face such interviews. The mothers of milder cases tended to react in a n opposite manner. Because their children could probably be operated on to become healthy, the mothers wanted more information on causes of cardiovascular defects and were willing to take part in the interview. However, from the viewpoints of etiological study of congenital heart disease, a s well as genetic counselling, it would be very important for mothers of severe malformed infants to be interviewed. The interview of the mothers included some other potential sources of error. The interviews were performed among the control group a little later after delivery than among the case group. However, the range between delivery and interview was similar in the case and control groups. Possible biases due to the use of many interviewers should also be considered. Nevertheless, the interviews were performed by experienced and well-educated midwives using structured and pre-tested questionnaires (Tikkanen, '861, which probably increased the reliability of the interviews. Other possible biases in teratoepidemiological studies should also be kept in mind
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when considering the findings of this investigation. These include power problems, chance associations, and possible influences of confounding factors (Tikkanen and Heinonen, '90, '91a, '9lb). The birth of a malformed infant causes a great deal of human suffering and places considerable demands on mothers as well as other family members for many years. One significant potential of epidemiological case-control study findings such as these is thus their ability to reduce or eliminate guilt feelings in mothers of malformed infants. For this reason we regard the negative role of certain maternal habits or home exposures in the genesis of cardiovascular malformations to be important new information. LITERATURE CITED Anderson. R.C. (1976) Cardiac defects in children of mothers receiving anticonvulsant therapy during pregnancy. J . Pediatr., 89:318-319. Ferencz, C., G.M. Metanoski, and P.D. Wilson (1980) Maternal hormone therapy and congenital heart disease. Teratology, 21r225-239. Ferencz, C., and A.C. Villaseiior (1991) Epidemiology of cardiovascular malformations: The state of the art. Cardiol Young, 1.264-284. Hanson, J.W., K.L. Jones, and D.W. Smith (1976) Fetal alcohol syndrome: Experience with 41 patients. JAMA, 235t1458-1460. Heinonen, O.P. (1976) Risk factors for congenital heart disease: A prospective study. In: Birth Defects: Risks and Consequences, S. Kelly, E.B. Hook, D.T. Janerich, and J.H. Porter, eds. Academic Press, New York, pp. 221-264. Heinonen, O.P., D. Slone, and R.R. Monson (1977aj Cardiovascular birth defects and antenatal exposure to female sex hormones. N. Engl. J. ,Med., 29667-70.
Heinonen, O.P., D. Slone, and S. Shapiro (1977bj Birth Defects and Drugs in Pregnancy. Publishing Sciences Group, Inc., Littleton, Massachusetts. Higgins, I.T.T. (1965) The epidemiology of congenital heart disease. J . Chron. Dis., 18:699-721. Lemeshow, S., and D.W. Hosmer Jr. (1984) Estimating odds ratios with categorically scaled covariates in multiple logistic regression analysis. Am. J. Epidemiol., 119:147-151. Lenz, W. (1962) Thalidomide and congenital abnormalities. Lancet, 1t45. Matsunaga, E., and Shiota, K. (1979) Threatened abortion, hormone therapy and malformed embryos. Teratology, 20~469-479. McNiel, J.R. (1973) The possible teratogenic effect of salicylates on the developing fetus: Brief summaries of eight suggestive cases. Clin. Pediatr., 12:347-350. Nora, J.J., A.H. Nora, and W.H. Toews (1974) Lithium, Ebstein's anomaly, and other congenital heart defects. Lancet, 11.594-595. Tikkanen, J . (1986) Risk factors for congenital heart disease. Thesis. Health services research by the National Board of Health in Finland. Helsinki. Tikkanen, J., and O.P. Heinonen (1990) Risk factors for cardiovascular malformations in Finland. Eur. J. Epidemiol., 4:348-356. Tikkanen, J., and O.P. Heinonen (1991a) Risk factors for ventricular septa1 defect in Finland. Public Health, 105:99-112. Tikkanen, J., and O.P. Heinonen (1991b) Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology, 43~591-600. Tikkanen, J., and O.P. Heinonen (1991~) Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur. J. Epidemiol., 7: 628-635. Tikkanen, J., and O.P. Heinonen (1992a) Maternal diseases and environmental exposures during pregnancy and congenital heart disease in the offspring. Int. J. Occup. Med. Toxicol., 1 t17-32. Tikkanen, J., and O.P. Heinonen (199213) Risk factors for conal malformations of the heart. Eur. J . Epidemiol., 8t48-57. Warkany, J. (1971) Congenital Malformations. Chicago, Year Book, Medical Publishers.
Congenital Heart Disease in the Offspring and Maternal Habits and Home Exposures During Pregnancy JORMA TIKKANEN AND OLLI P. HEINONEN National Agency for Welfare and Health (J.T.),National Public Health Institute (O.P.H.), Helsinki, Finland
ABSTRACT
To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982-1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre-tested questionnaire. Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%)as controls (14.6%).Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures t o disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups. Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, C19, = 1.4-5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%)than among the control group (22.0%).However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2,95%confidence interval 0.9-1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis. It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart. 0 1992 Wiley-Liss, Inc.
Despite the importance of congenital heart disease as a cause of infant mortality and disability, the etiology of this anomaly remains almost totally unknown. One recent estimate suggests that known risk factors for congenital heart disease explain only 10 per cent of the etiology (Tikkanen, '86). Some environmental factors, such as thalidomide (Lenz, '62) and rubella virus, are classical causes of congenital heart disease (Higgins, '65). Maternal alcohol consumption during early pregnancy seems to increase the risk (Hanson et al., '76; Tikkanen and Heinonen, '91b), while maternal lithium therapy during the first trimester can
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1992 WILEY-LISS, INC.
cause a special type of cardiac malformation, Ebstein's anomaly (Nora et a]., '74). There have been few studies on maternal habits such as drug consumption and home exposures during early pregnancy on the risk of congenital heart disease in the offspring. Some reports have suggested that maternal hormone therapy (Heinonen et al., '77a) as well as anticonvulsant (Anderson, '76) and salicylate (McNiel, '73) intakes could cause cardiovascular malformations.
Received October 31, 1991, accepted June 26, 1992
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According to a recent literature review (Ferencz and Villasenor, '91) of occupational, home, and other environmental factors in cardiovascular malformations, solvents, pesticides, and lead among others have been suspected of damaging the developing fetal heart. Attention has also been focused on maternal diseases (Tikkanen and Heinonen, '92a), and special exposures during pregnancy, such as examinations by X-ray (Tikkanen and Heinonen, '91b) and ultrasound (Tikkanen, '86). Although understanding of the origins of cardiovascular malformations is increasing only very slowly, the accumulated literature does suggest that a large proportion maternal habits and environmental exposures are probably not harmful to the fetal heart. Some reports have observed, for instance, that maternal coffee, tea, and cola consumption, and use of deodorants or hair sprays during early pregnancy are not associated with the risk of congenital heart disease in the offspring (Tikkanen, '86; Tikkanen and Heinonen, '91b). Studies also indicate that maternal smoking or exposure to passive smoking during early pregnancy a t home or a t work are not connected with the risk of congenital heart disease in the offspring (Heinonen, '76; Tikkanen, '86; Tikkanen and Heinonen, '91b). Neither does maternal exposure to video display terminals during early pregnancy seem to increase this risk (Tikkanen and Heinonen, '91b). Moreover, certain factors which can cause maternal hyperthermia during pregnancy, such as sauna bathing or high maternal workplace or environmental temperature, seem not to be associated with the risk of cardiovascular malformations in the offspring (Tikkanen and Heinonen, '91c). In the modern Western world, many pregnant women are exposed to a number of chemical and physical factors which, according to animal studies, may have a teratogenic effect on the developing fetal heart. For this reason an investigation into the etiology of congenital heart disease was started in Finland in 1981 (Tikkanen, '86; Tikkanen and Heinonen, '90, '91b, '92a,b). The present report concerns part of this large project. The purpose of this particular study was to investigate maternal habits and home exposures during pregnancy as possible risks for congenital heart disease in the offspring.
MATERIALS AND METHODS
As the formation of the case and control groups and the interview of the mothers have been detailed in earlier reports (Tikkanen and Heinonen, '90, '92a,b), only a summary of the materials and methods is presented here. Cardiovascular malformations The cases were selected from all 133,000 live and stillbirths in Finland during 1982 and 1983. Infants with cardiovascular malformations were identified independently from the Finnish Register of Congenital Malformations or the Children's Cardiac Register. Pediatricians, especially pediatric cardiologists, send their notifications of cardiovascular malformations to these registers. One third (31%) of the malformations were reported only to the former registry, one third (34%) only to the latter, and one third (35%) to both. In both registers cardiovascular anomalies detected during the first year of life had been diagnosed by echocardiography, cardiac catheterization, surgery, or autopsy. Twenty-six of the children were stillborn and their diagnoses based on autopsy findings. In 59% of the cases, diagnosis had been made during the first month of life, in 15% during the second month, and in 26% after the second month but before the age of 1 year. Between 1 January 1982 and 30 April 1984,553 infants with congenital heart disease born in 1982-1983 had been reported. Twenty-three of these children were excluded because the diagnosis of cardiovascular malformation was made solely on the basis of a clinical examination and not confirmed by cardiac catheterization, echocardiography, cardiac surgery, or autopsy. Sixty-three cases with chromosomal anomalies (e.g., Down's syndrome, trisomy 18,13, or a known genetic syndrome) or extracardiac anomalies were also deleted from the study. Mothers of 61 infants refused to participate in the interview. All these exclusions thus reduced our numbers from 553 cases to 406 infants with a total of 583 cardiovascular malformations. Every cardiovascular anomaly was checked by a professor of pediatric cardiology against the hospital records. Moreover, the same professor had personally examined the cardiac status of approximately 50% of all the case infants at the Helsinki Central Hospital.
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
Common cardiovascular malformations in this data were ventricular septal defect (n = 150), patent ductus arteriosus (n = go), coarctation of the aorta (n = 50), atrial septal defect (n = 50), transposition of the great arteries (n = 361, hypoplastic left ventricle (n = 34),tetralogy of Fallot (n = 23), and truncus arteriosus (n = 14). Rarer cardiovascular malformations included pulmonary atresia (n = 111, total anomalous pulmonary venous drainage (n = 91, pulmonary stenosis (valvular) (n = 51, aortic stenosis (n = 31, and tricuspid atresia (n = 2). All the cardiovascular malformations were classified using a method for the epidemiological study of congenital heart disease (Tikkanen, '86). This approach makes it possible to investigate causes of cardiovascular malformations by taking into account the embryologic nature of the defects. This classification, which has also been recently described elsewhere (Heinonen, '76; Tikkanen and Heinonen, '91b), has six categories: ventricular septal defect (VSD, n = 150), conus arteriosus (CAS, n = 901, atrial septal defect (ASD, n = 50), hypoplastic left ventricle (LHHS, n = 341, endocardial cushion defect (ECD, n = 22), and other n = 237). defects (0, According to this classification only ventricular septal defects comprised the VSD category and only atrial septal defects made up the ASD group. The conus arteriosus category (CAS) included the following cardiac defects: tetralogy of Fallot, transposition of the great arteries, truncus arteriosus, double outlet right ventricle, aorto-pulmonic window, and pulmonic valve atresia. Left ventricular hypoplasia, aortal valve atresia, mitral stenosis, and mitral atresia were all classified under the LHHS category. Atrial septal defect (primary) and atrioventricular canal joined the ECD group.
Controls The controls were randomly selected from all deliveries in Finland during 1982-1983 (approximately 133,000).For each year, 400 non-malformed infants were selected from 52 hospitals on the basis of their frequency of deliveries in 1981. On randomly chosen dates, the first infant born who was free of anomaly in every organ was selected for inclusion in the study. Forty-four (5.5%) of the mothers thus selected could not be contacted or refused to
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participate. Thus the final group consisted of 756 infants.
Interview of the mother All the mothers were interviewed a t maternity welfare centers by a midwife using a structured questionnaire. The mothers of affected and normal infants were interviewed approximately 92 days (range 14-147) and 96 days (range 21-1541, respectively, after delivery, and the interview lasted approximately 1 hour. In the first part of the interview the mothers were asked about drug consumption during the first trimester of pregnancy. First came general questions on their drug consumption, medications used in some common diseases, and those most frequently taken during pregnancy in Finland. However, only the intakes of acetylsalicylic acid, diazepam and contraceptive pills were analyzed for this report. Maternal exposures a t home formed the second part of the interview. First the mother was asked to describe her domestic tasks during the first trimester of pregnancy. Following structured rules, the interviewer sought details on exposure to chemicals or physical factors. The following exposures were noted: organic solvents, dyes, lacquers, paints, glues, disinfectants, plastic raw materials, wood preservatives, pesticides, dusts, and microwave ovens. If the mother reported any exposure to specific physical or chemical factors, the interviewer noted the frequency of exposure (regular or occasional). The third part of the interview contained questions on disorders in the family and selected habits of the mothers during pregnancy. In this section the mothers were asked about cardiovascular malformation or similar disorders in family members and their own symptoms during the first trimester of pregnancy. The interview also sought details on maternal smoking, coffee, tea, and alcohol consumption, as well a s use of deodorants and other chemicals. Statistical methods In cross-tabulation of the data, odds ratios and their 95%confidence intervals were calculated to test the hypothesis that casemother characteristics or exposures somehow differed from those of control mothers. A logistic regression analysis was applied to the data to evaluate whether the associ-
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TABLE 1 . Selected maternal diseases or conditions during previous pregnancies Cases (n : 406) Disease or condition Miscarriage 1 2 2 Induced abortion Premature birth Stillbirth Extrauterine eravid
%
Controls (n= 756) 9%
Odds ratio and 95%confidence interval
10.4 5.2 12.3 3.6 0.5 0.5
12.5 2.0 11.7 2.4 0.6 0.7
0.8 10.5-1.21 . 2.7 (1.4-5.3) 1.1 (0.8-1.6) 1.6 (0.8-3.2) 0.9 (0.2-4.9) 0.7 (0.2-3.8)
Y
ation between maternal ultrasound examination during the first trimester and the risk of congenital heart disease in the offspring was related to the risk of miscarriage during early pregnancy. Maternal ultrasound examination and the risk of miscarriage were dichotomized (yeslno) and included in the analysis. The analysis was performed using the BMDP program. The adjusted relative odds ratios and their 95% confidence intervals were computed from the estimates of model parameters and their standard errors (Lemeshow and Hosmer Jr., '84). RESULTS
Maternal diseases, contraception, and ultrasound examination Table 1lists selected maternal diseases or conditions during previous pregnancies. Having had several miscarriages during earlier pregnancies was more prevalent among cases than controls. Other conditions such as induced abortion, previous stillbirth, or extrauterine gravid seemed not to predict the birth of an infant with a cardiovascular anomaly (Table 1).No significant differences in any of these factors were found between any of the ontogenetic defect groups (VSD, CAS, ASD, ECD, LHHS, and 0) and the controls. Table 2 presents the maternal use of contraceptive methods a t the time of conception. Interrupted coitus was more prevalent among the cases than the control group. Methods such as chemical foam or IUD were equally prevalent in the two groups. Intakes of neither mini-pills nor other contraceptive pills were associated with the risk of congenital heart disease in the offspring (Table 2). Neither were there significant differences in these factors between any of the ontogenetic groups (VSD, CAS, ASD, LHHS, ECD, and 0) and the controls. Maternal ultrasound examination during
the first 16 weeks of pregnancy had been performed more often among the case group (28.3%) than among the controls (22.0%) (Table 3). This was true for all of the ontogenetic groups of congenital heart disease, as follows: VSD (33.0%),CAS (26.7%),ASD (28.0%),LHHS(26.5%),ECD(27.3%),andO (26.6%). Habits and home exposures Maternal overall drug consumption during the first trimester of pregnancy was as prevalent among case mothers (13.3%) as controls (14.6%)(Table 4).Maternal intake of acetylsalicylic acid such as AspirinR was as common in the case (8.0%) and control groups (5.8%).This also held for the specific groups of cardiovascular malformations such as VSD (8.0%), CAS (5.8%), ASD (2.0%),LHHS (5.9%), and 0 (7.6%), except for the ECD grou where 18.2% of mothers had used AspirinP; during the first trimester. Few mothers consumed diazepam during early pregnancy (Table 4).The intake of diazepam was as prevalent among cases and controls, and no differences were found between any of the ontogenetic groups of congenital heart disease and the control group. Use of sweetening agents in coffee was as prevalent among case mothers (3.7%) as controls (3.8%),and no respective differences between the groups were found in tea (6.117.0%) or cocoa (3.8/3.2%) consumption (Table 4).No differences were found in the use of sweetening agents between any of the ontogenetic groups of congenital heart disease and the control group. Table 5 presents maternal exposures to chemical and physical factors at home during the first trimester. All of the recorded chemical and physical exposures during the first trimester were equally prevalent among case and control mothers. No differences were found in, e.g., exposures to wash-
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
TABLE 2. Maternal
use of
Contraceptive method being used at conception Interrupted coitus “Safe” days Mechanical (condom, pessary) Chemical (foam) Both mechanical and chemical IUD Contraceptive mini pills Other contraceptive pill No contraception All
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contraception at the time of conception’ Cases Controls Odds ratio and (n = 5721 in = 1,050) 95% confidence % % interval 1.4 0.4 3.7 (1.1-12) 1.0 0.4 2.6 (0.5-4.0) 7.9 9.3 0.8 (0.6-1.1) 0.3 0.4 0.9 (0.1-4.9) 0.5 0.8 0.7 (0.2-2.6) 5.4 0.9 (0.6-1.4) 4.9 0.9 0.5 1.8 (0.5-6.2) 3.1 3.3 1.0 (0.6-1.8) 80.0 79.5 1.0 (0.8-1.3) 100.0 100.0 -
‘These data on contraception were only available on the basis of the 3-year period 1982-1984.
TABLE 3. Maternal exposure to ultrasound examination during the first trimester of pregnancy Cases Controls Odds ratio and Ultrasound (n = 406) (n = 754) 95% confidence examination % % interval 22.0 28.3 Yes 1.4 (0.8-2.51 78.0 73.7 No 100.0 100.0 All
TABLE 4. Maternal drug cunsumption during the first trimester of pregnancy Cases (n -406) Intake Overall drug consumption Intake of AspirinR Intake of diazepam Use of sweetening agents in coffee Use of sweetening agents in tea Use of sweetening agents in cocoa
ing substances, dyes, lacquers or paints, pesticides, or microwave ovens, and none were evident between the controls and any of the ontogenetic groups (VSD, CAS, ASD, ECD, LHHS, and 0).
Logistic regression analysis In order to test whether the association between ultrasound examination and the risk of congenital heart disease in the offspring was confounded by the threat of miscarriage during the first trimester a logistic regression analysis was performed. Maternal ultrasound examination and threatened miscarriage during the first trimester of pregnancy were dichotomized (yesino) and included in regression analyses of all the cardiovascular malformations. Maternal ultrasound examination during the first trimester of pregnancy showed an adjusted odds ratio of 1.2 (95% confidence interval 0.9-1.7), and the threat of miscar-
Controls (n = 756)
%
%
13.3 8.0 0.5 3.7 6.1 3.8
14.6 5.8 1.1 3.8 7.0 3.2
Odds ratio and 95% confidence interval 0.9 (0.5-1.8) 1.4 (0.5-3.6) 0.5 (0.02-101 1.0 (0.3-3.41 0.9 (0.3-2.3‘1 1.2 (0.3-4.31
riage an odds ratio of 1.2 (95% confidence interval 0.6 -2.4). In logistic regression analysis of the VSD group, maternal exposure to ultrasound examination showed a relative odds ratio of 1.6 (95% confidence interval 1.0-3.7). The odds ratio of threatened miscarriage during the first trimester did not differ significantly from unity. DISCUSSION
About 14% of the mothers in this data consumed a t least one drug during the first trimester of pregnancy. The intake of drugs during early pregnancy is hazardous because they are responsible for 1.5 per cent of all congenital anomalies, and most drugs have not been tested in humans (Tikkanen, ’86). We investigated in the present survey the intakes of contraceptive pills, acetosalicylic acid, and diazepam, because these substances have been suspected of damaging
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J. TIKKANEN AND O.P. HEINONEN TABLE 5. Maternal exposure to chemical and physical factors at home during the first trimester of pregnancy Cases Controls Odds ratio and (n= 756) 95% confidence (n = 406) % % interval Exposure category Washing substances and disinfectants Occasional 28.9 25.9 1.2 (0.9-1.5) 38.1 36.7 1.1 (0.8-1.4) Regular Dyes,lacquers, paints Occasional 10.3 10.1 1.0 (0.7-1.5) 0.2 0.0 Regular Organic solvents 4.9 4.0 1.3 (0.7-2.3) Occasional Regular 0.5 0.5 0.9 (0.2-5.0) Pesticides Occasional 2.9 2.0 1.5 (0.7-3.2) Regular 0.2 0.0 Mineral oil products 1.7 2.1 Occasional 0.8 (0.3-2.0) 0.2 0.1 1.9 (0.1-30) Regular Wood preservatives 2.0 1.6 1.2 (0.5-3.0) Occasional 0.2 0.0 Regular Plastic raw materials 0.2 0.3 0.9 (0.08-10) Occasional 0.0 0.3 Regular Glues Occasional 4.6 5.3 0.9 (0.5-1.6) Regular 0.5 0.3 1.9 (0.7-5.2) Microwave ovens 0.7 0.9 0.8 (0.2-3.1) Occasional 0.5 0.3 1.9 (0.3-14) Regular Textile dusts 11.3 13.0 0.9 (0.6-1.3) Occasional 7.6 8.0 1.0 (0.6-1.6) Regular Other dusts Occasional 11.9 12.3 1.0 (0.7-1.4) 6.7 7.5 0.9 (0.6-1.4) Regular
the fetal heart. They are also in common use in Finland, so both mothers as well as interviewers recognized these preparations in the interview, which probably increased the reliability of the drug-related answers. Several earlier reports have suggested that synthetic estrogens, progesterones, and contraceptive pills may disturb the normal cardiovascular development of the fetus. The use of contraceptive pills was therefore investigated in this study. Maternal exposure to contraceptive pills during the period of cardiogenesis occurred in 23 out of 572 congenital heart patients (4.0%) compared with 40 out of 1,050 controls (3.8%))suggesting no association between these factors. This negative finding is in line with some other investigations (Matsunaga and Shiota, '79; Ferencz et al., '80). Therefore we consider that earlier findings of positive associations between maternal intake of hormones and cardiovascular malformations in the offspring may be because many compli-
cations of pregnancy were treated with hormonal therapy. Because congenital heart disease of the fetus is associated, e.g., with the risk of miscarriage, maternal hormonal therapy may have been falsely regarded as a cause of congenital heart disease. The teratogenic properties of salicylates were first demonstrated by Joseph J. Warkany and co-workers (Warkany, '71). Because animal experiments have shown that salicylate teratogenicity can be enhanced by the maternal physiological state and that salicylates cross the human placenta (McNiel, '73)) the possibility exists that large doses of aspirin or other salicylates may be teratogenic in humans. Therefore in this study a commonly used salicylate, AspirinR, was investigated. No association between maternal intake of Aspirin and congenital heart disease was found, in agreement with Heinonen et al. ('77b) among others. However, when comparing the results of this investigation with other studies (e.g., Heino-
CARDIOVASCULAR MALFORMATIONS AND ENVIRONMENTAL EXPOSURES
nen et al., '77a,b) the differences in study design (e.g., sample size and choice of controls) should be kept in mind. Moreover, the limited power of teratoepidemiological casecontrol studies like this should be considered. This is particularly true for effects of rare exposures such as maternal drug consumption. Therefore, conclusions about the negative findings of this investigation must be drawn very carefully. In this survey some maternal conditions during previous pregnancies were investigated to evaluate their power to predict the birth of a n infant with congenital heart disease. Of these factors, induced abortion, premature birth, stillbirth, and extrauterine gravid were not associated with the risk of congenital heart disease in the offspring during the next pregnancy. In contrast, several miscarriages in earlier pregnancies did seem to associate with the risk of congenital heart disease in the subsequent offspring. In the 1980s a public debate over the safety of ultrasound examination during early pregnancy was initiated in Finland. One question dealing with this was therefore included in the study questionnaire. According to this data, ultrasound examination had been performed more often among the case group than the control group. U1trasound examination during the first trimester was not, however, responsible for cardiovascular malformations: logistic regression analysis showed that the threat of miscarriage during early pregnancy was in fact the confounding factor explaining the association between ultrasound examination and the risk of congenital heart disease. It is thus good to keep in mind that fetuses with congenital heart disease may exert complications of pregnancy which lead to investigation by ultrasound (Tikkanen and Heinonen, '91a). During the past few decades many common environmental factors, such as sauna bathing or exposure to microwave ovens a t home, have been suspected of damaging the developing fetus. Despite these suspicions, most teratoepidemiological studies have focused on possible teratogenic hazards only at mothers' workplaces. For this reason we investigated domestic maternal exposures as widely as possible. None of these, e.g., exposure to disinfectants, dyes, lacquers, paints, or microwave ovens, were associated with the risk of congenital heart disease. Therefore we conclude that these chemical
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or physical factors probably do not have a teratogenic effect on the fetal heart a t usual levels of exposure. These study results need to be interpreted with some caution, since information of this type gathered from mothers post partum does not come with the highest degree of reliability. A mother of a malformed infant may scrutinize her memory for all possible causes, while the mother of a healthy child has less incentive t o recall such events from early pregnancy. To this extent, differences between case and control groups may be a function of maternal memory bias. On the other hand, i t is not reasonable to assume that the reporting of similar exposures by the two groups, e.g., to pesticides or microwave ovens at home, was due to systematically poor recall by mothers of the malformed infants. I n this data 61 mothers of malformed infants refused to participate in the interview. It seemed that these infants had a more severe cardiac defect than babies whose mothers took part in the interview. This phenomenon probably has a psychological basis. It is likely t h a t the mothers of severely malformed infants are still in the shock stage soon after delivery, and thus unable to face such interviews. The mothers of milder cases tended to react in a n opposite manner. Because their children could probably be operated on to become healthy, the mothers wanted more information on causes of cardiovascular defects and were willing to take part in the interview. However, from the viewpoints of etiological study of congenital heart disease, a s well as genetic counselling, it would be very important for mothers of severe malformed infants to be interviewed. The interview of the mothers included some other potential sources of error. The interviews were performed among the control group a little later after delivery than among the case group. However, the range between delivery and interview was similar in the case and control groups. Possible biases due to the use of many interviewers should also be considered. Nevertheless, the interviews were performed by experienced and well-educated midwives using structured and pre-tested questionnaires (Tikkanen, '861, which probably increased the reliability of the interviews. Other possible biases in teratoepidemiological studies should also be kept in mind
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when considering the findings of this investigation. These include power problems, chance associations, and possible influences of confounding factors (Tikkanen and Heinonen, '90, '91a, '9lb). The birth of a malformed infant causes a great deal of human suffering and places considerable demands on mothers as well as other family members for many years. One significant potential of epidemiological case-control study findings such as these is thus their ability to reduce or eliminate guilt feelings in mothers of malformed infants. For this reason we regard the negative role of certain maternal habits or home exposures in the genesis of cardiovascular malformations to be important new information. LITERATURE CITED Anderson. R.C. (1976) Cardiac defects in children of mothers receiving anticonvulsant therapy during pregnancy. J . Pediatr., 89:318-319. Ferencz, C., G.M. Metanoski, and P.D. Wilson (1980) Maternal hormone therapy and congenital heart disease. Teratology, 21r225-239. Ferencz, C., and A.C. Villaseiior (1991) Epidemiology of cardiovascular malformations: The state of the art. Cardiol Young, 1.264-284. Hanson, J.W., K.L. Jones, and D.W. Smith (1976) Fetal alcohol syndrome: Experience with 41 patients. JAMA, 235t1458-1460. Heinonen, O.P. (1976) Risk factors for congenital heart disease: A prospective study. In: Birth Defects: Risks and Consequences, S. Kelly, E.B. Hook, D.T. Janerich, and J.H. Porter, eds. Academic Press, New York, pp. 221-264. Heinonen, O.P., D. Slone, and R.R. Monson (1977aj Cardiovascular birth defects and antenatal exposure to female sex hormones. N. Engl. J. ,Med., 29667-70.
Heinonen, O.P., D. Slone, and S. Shapiro (1977bj Birth Defects and Drugs in Pregnancy. Publishing Sciences Group, Inc., Littleton, Massachusetts. Higgins, I.T.T. (1965) The epidemiology of congenital heart disease. J . Chron. Dis., 18:699-721. Lemeshow, S., and D.W. Hosmer Jr. (1984) Estimating odds ratios with categorically scaled covariates in multiple logistic regression analysis. Am. J. Epidemiol., 119:147-151. Lenz, W. (1962) Thalidomide and congenital abnormalities. Lancet, 1t45. Matsunaga, E., and Shiota, K. (1979) Threatened abortion, hormone therapy and malformed embryos. Teratology, 20~469-479. McNiel, J.R. (1973) The possible teratogenic effect of salicylates on the developing fetus: Brief summaries of eight suggestive cases. Clin. Pediatr., 12:347-350. Nora, J.J., A.H. Nora, and W.H. Toews (1974) Lithium, Ebstein's anomaly, and other congenital heart defects. Lancet, 11.594-595. Tikkanen, J . (1986) Risk factors for congenital heart disease. Thesis. Health services research by the National Board of Health in Finland. Helsinki. Tikkanen, J., and O.P. Heinonen (1990) Risk factors for cardiovascular malformations in Finland. Eur. J. Epidemiol., 4:348-356. Tikkanen, J., and O.P. Heinonen (1991a) Risk factors for ventricular septa1 defect in Finland. Public Health, 105:99-112. Tikkanen, J., and O.P. Heinonen (1991b) Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology, 43~591-600. Tikkanen, J., and O.P. Heinonen (1991~) Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur. J. Epidemiol., 7: 628-635. Tikkanen, J., and O.P. Heinonen (1992a) Maternal diseases and environmental exposures during pregnancy and congenital heart disease in the offspring. Int. J. Occup. Med. Toxicol., 1 t17-32. Tikkanen, J., and O.P. Heinonen (199213) Risk factors for conal malformations of the heart. Eur. J . Epidemiol., 8t48-57. Warkany, J. (1971) Congenital Malformations. Chicago, Year Book, Medical Publishers.
