Maternal Obesity and Infant Heart Defects

Maternal Obesity and Infant Heart Defects Marie I. Cedergren* and Bengt A.J. Källén Abstract CEDERGREN, MARIE I. AND BENGT A.J. KÄLLÉN. Maternal obesity and infant heart defects. Obes Res. 2003; 11:1065 1071. Objective: This study determined whether obese women have an increased risk of cardiovascular defects in their offspring compared with average weight women. Research Methods and Procedures: In a case-control study, prospectively collected information was obtained from Swedish medical health registers. The study included 6801 women who had infants with a cardiovascular defect and, as controls, all delivered women (N 812,457) during the study period (1992 to 2001). Infants with chromosomal anomalies or whose mothers had pre-existing diabetes were excluded. Obesity was defined as BMI 29 kg/m 2, and morbid obesity was defined as BMI 35 kg/m 2. Comparisons were made with average weight women (BMI 19.8 to 26 kg/m 2 ). Results: In the group of obese mothers, there was an increased risk for cardiovascular defects compared with the average weight mothers [adjusted odds ratio (OR) 1.18; 95% CI, 1.09 to 1.27], which was slightly more pronounced for the severe types of cardiovascular defects (adjusted OR 1.23; 95% CI, 1.05 to 1.44). With morbid obesity, the OR for cardiovascular defects was 1.40 (95% CI, 1.22 to 1.64), and for severe cardiovascular defects, the OR was 1.69 (95% CI, 1.27 to 2.26). There was an increased risk for all specific defects studied among the obese women, but only ventricular septal defects and atrial septal defects reached statistical significance. Discussion: In this sample, a positive association was found between maternal obesity in early pregnancy and congenital heart defects in the offspring. A suggested explanation is undetected type 2 diabetes in early pregnancy, but other explanations may exist. Received for review November 4, 2002. Accepted in final form June 24, 2003. *Division of Obstetrics and Gynaecology, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden and Tornblad Institute, University of Lund, Lund, Sweden. Address correspondence to Dr. Marie Cedergren, Dept. Ob/Gyne, University Hospital, SE-581 85 Linköping, Sweden. E-mail: marie.cedergren@lio.se Copyright 2003 NAASO Key words: BMI, congenital malformations, pregnancy outcome Introduction Maternal obesity seems to be associated with the development of neural tube defects in the offspring (1 4). Whether the same association exists between maternal obesity and infant congenital heart defects is still unclear (2,5 10). Even a weak association is important to detect because of the increasing population of obese women of childbearing age. In Sweden, the prevalence of overweight women during the fertile period doubled between 1980 and 1997 (11). Congenital cardiovascular defects are among the most common major birth defects. The total prevalence at birth of cardiovascular defects is estimated at 7 to 9 per 1000 births (12,13). A few agents and maternal conditions are confirmed as cardiac teratogens, e.g., maternal rubella infection, maternal diabetes, alcoholism, anticonvulsants and/or maternal epileptic disease, thalidomide, and retinoids (14). Only a small proportion of congenital heart defects is caused by known teratogenic agents (2%); the remaining, except those of chromosomal origin (8%), are still unrelated to specific exposures (15). The objective of this study was to thoroughly assess, in a large prospective data set from Swedish medical health registries, whether maternal obesity, defined as BMI 29 kg/m 2, was associated with an increased risk of overall and specific infant cardiovascular defects. Research Methods and Procedures Study Population and Exposure Assessment The study population consisted of 982,867 infants born in Sweden January 1, 1992 through December 31, 2001. In 812,457 (83%), information on maternal height and maternal weight in early pregnancy was available, and there was no known pre-existing maternal diabetes. Pre-existing maternal diabetes was identified from diagnoses given to the woman at delivery. Women with gestational diabetes in the current or previous pregnancies were not excluded. OBESITY RESEARCH Vol. 11 No. 9 September 2003 1065

The infants were identified using the Swedish Medical Birth Registry (16). Medical data on almost all (98% to 99%) infants born in Sweden are listed in the register, which also includes stillbirths after 28 complete weeks of gestation. The register contains a large number of items concerning pregnancy, delivery, and pediatric neonatal examination. It is based on copies of the standardized medical record forms completed at the maternity health care centers, at the delivery units, and at the pediatric examination of the newborn. The system is identical throughout the country. Maternal weight and height were ascertained at the first visit at the maternity health care center and directly recorded by the midwife in the standardized form. Ninety percent of the women attended the antenatal clinic for the first time during the first trimester. BMI (kg/m 2 ) was calculated from these data. Women were grouped in five categories of BMI: underweight ( 19.8 kg/m 2 ), average weight (19.8 to 26 kg/m 2 ), overweight (26.1 to 29 kg/m 2 ), obese ( 29 kg/m 2 ), and morbidly obese ( 35 kg/m 2 ). The fifth category is thus part of the fourth. Identification and Classification of Cases with Congenital Heart Defects Infants with a congenital cardiovascular defect were identified from three sources: International Classification of Disease (ICD) 1 codes recorded in the Swedish Medical Birth Registry, ICD codes in the Swedish Registry of Congenital Malformations (17), and International Society of Cardiology (ISC) codes in the Swedish Child Cardiology Register (12). Thus, all three registers gave cardiac diagnoses. The Medical Birth Register and the Register of Congenital Malformations both refer to the neonatal period, and diagnoses are often unspecific or preliminary, whereas the Cardiology Register catches cases up to the age of 1 year and contains detailed cardiac diagnoses from echocardiography, catheterization, operation, or autopsy. In most instances, the diagnoses agreed among the three registers (but cases were often not recorded in all three registers). When discrepancies existed, the Cardiology Register diagnoses were regarded as the most reliable ones. The various sources were linked using the personal identification numbers of mothers and/or infants. These numbers are given to each person living in Sweden and are extensively used in society, including for all health care. A file was built up, cleaning the available information with a final, best possible diagnosis of cardiovascular defects for each infant, according to the register data quality mentioned above. Primary outcome was any congenital cardiovascular defect reported to any one of the above-described registers, except patent ductus arteriosus in preterm infants ( 2500 g) 1 Nonstandard abbreviations: ICD, International Classification of Disease; OR, odds ratio. Table 1. Cardiovascular defect diagnoses (isolated or nonisolated) with number of infants with each diagnosis Cardiac diagnosis Number of diagnosis Severe defects Hypoplastic left heart syndrome 166 Single ventricle 78 Tricuspidal atresia 36 Common truncus 226 Pulmonary atresia 26 D-transposition 164 Double outlet right ventricle 17 Endocardial cushion defect 905 Total abnormal pulmonary vein return 18 Tetralogy of Fallot 223 Ebstein s anomaly 26 Mild defects Ventricular septal defect 2676 Atrial septal defect 639 Coarctation of aorta 117 Corrected transposition 3 Pulmonary valve stenosis 68 Patent ductus (term infant) 107 Other specified defect, mainly valve anomalies 562 Unspecified defect 1443 The sum of the number of diagnoses exceeds the total number of infants because one infant can have more than one cardiovascular diagnosis. Mild defects are tabulated only in the absence of severe defects. and single umbilical artery. All infants who also had a major noncardiovascular malformation were identified from the ICD codes in the above-described registers. Minor and variable conditions like preauricular tags, undescended testicle, unstable hip, and nevus were not included. The congenital heart defects were classified as follows: 1. Isolated, if the cardiac diagnosis was the only major congenital defect present. 2. Nonisolated, if there were major noncardiovascular malformations present but no known chromosome anomaly. 3. Chromosomal, if the cardiac defect was part of a known chromosomal abnormality. The cardiac defects were divided into groups of severe and mild forms according to a recent study (18,19). Table 1 1066 OBESITY RESEARCH Vol. 11 No. 9 September 2003

lists the types of cardiac defects included in the two groups. Mild cardiac defects were counted only when no severe defect was present. A third group consisted of unspecified cardiac defects (Table 1), which were identified by the ICD codes 746.9 or Q24.9 in the absence of any other cardiac defect diagnosis. When two or more different severe cardiac defects occurred at the same time, the defect was classified as complex. Confounding Maternal age, parity, smoking, and year of birth were thought to be potential confounding factors and were included as covariates in the adjusted analyses. Statistical Analyses Frequency distributions were compared using 2 statistics. Odds ratios (ORs) were determined using Mantel- Haenszel technique for adjusted rates (20). Estimates of 95% CI were made with a test-based method (21). When two stratified ORs were compared, z tests were performed based on the variances obtained from the stratified analyses. Results Maternal BMI was calculated for 83% of all births registered during the study period. A total of 8947 infants with cardiovascular defects were identified during the observation period (9.1 per 1000 births). Among them, mothers of 7379 infants (82%) had information that enabled the calculation of BMI. A chromosomal abnormality (n 491) or maternal pre-existing diabetes (mainly type 1; n 87) was present in 578 cases (7.8%). Of 6801 remaining infants, 5714 (84%) had an isolated cardiovascular defect. Complex types occurred in 5.5% (N 371). The case mothers were compared with all delivered women with respect to maternal age, parity, and maternal smoking in early pregnancy (Table 2). The distribution of maternal age, parity, and smoking in early pregnancy was similar for both groups. Adjustment for these factors and the year of birth did not change the ORs noticeably; only adjusted ORs will be presented. The observed prevalence of obesity (BMI 29 kg/m 2 ) was 10.6% in the control group and 12.1% in the case group. The corresponding prevalence of overweight, if the cut-off level is BMI 26 kg/m 2, was 23.3% among controls and 25.0% among cases. Morbid obesity was slightly more common in the case group (2.7%) compared with the control group (2.0%). Table 3 shows the distribution of some groups of cardiac defects according to maternal BMI. There is no significant difference in the BMI distribution among mothers of infants with specified and with unspecified cardiovascular defects ( 2 2.93 at 4 df, p 0.57). Table 2. Characteristics of mothers of infants with cardiovascular defects (isolated or nonisolated) and of all delivered women Maternal characteristics Case mothers (n 6801) All delivered women (n 812,457) N Percent N Percent Maternal age 20 152 2.2 16,509 2.0 20 to 24 1,194 17.6 139,356 17.2 25 to 29 2,492 36.6 299,711 36.9 30 to 34 1,930 28.4 243,484 30.0 35 to 39 871 12.8 96,132 11.8 40 162 2.4 17,265 2.1 Parity 1 2,849 41.9 333,678 41.1 2 2,362 34.7 295,217 36.3 3 1,089 16.0 124,931 15.4 4 501 7.4 58,631 7.2 Maternal smoking Unknown 174 2.6 19,832 2.2 No smoking 5,585 82.1 664,066 81.7 Smoking 1,042 15.3 128,559 15.8 Table 4 shows the risk of cardiovascular defects by class of BMI. Average weight (BMI 19.8 to 26 kg/m 2 ) was used as a reference. In the overweight group (BMI 26.1 to 29 kg/m 2 ), the risk is slightly above one for all defects as well as for isolated and nonisolated defects separately, although statistical significance was not reached. In the group of obese (BMI 29 kg/m 2 ) mothers, there is an overall statistically significant increased risk for cardiovascular defects, except for complex ones, but the number is low in that group (N 45), except for unspecified defects. In the subgroup of morbid obesity, BMI 35 kg/ m 2, the ORs are still higher and reach statistical significance also in the complex group. Because of the small numbers, this subgroup was not presented for specific cardiac defects. The proportional attributable risk of cardiovascular defects caused by maternal obesity (BMI 29 kg/m 2 ) is [(1.18 1)/1.18] 0.15. In the general population of delivered women in Sweden, 10.6% are obese; thus, the population attributable fraction of cardiac defect is 0.15 10.6% 1.6. For some specific types of cardiovascular defects where numbers were reasonably large, separate analyses were performed (Table 4). There was an increased risk for all specific cardiac defects studied, but the only ones reaching statistical significance were ventricular septal defects and OBESITY RESEARCH Vol. 11 No. 9 September 2003 1067

Table 3. Distribution of BMI among all delivered women and women with infants with cardiovascular defects, according to cardiovascular defect type BMI (kg/m 2 ) Group of women <19.8 19.8 to 26 26.1 to 29 29.1 to 35 >35 Total All delivered women 82,193 540,853 103,378 69,728 16,305 812,457 All cardiovascular defects 627 4474 874 640 186 6801 Isolated cardiovascular defects 524 3778 728 537 147 5714 Nonisolated cardiovascular defects 103 696 146 103 39 1087 Severe cardiovascular defects 132 983 179 140 48 1482 Among them, complex 36 251 39 33 12 371 Mild cardiovascular defects 362 2533 504 370 107 3876 All specified cardiovascular defects 494 3516 683 510 155 5358 Unspecified cardiovascular defects 133 958 191 130 31 1443 Hypoplastic left heart syndrome 13 103 27 17 6 166 D-transposition 10 110 17 20 7 164 Endocardial cushion defect 78 608 108 86 25 905 Tetralogy of Fallot 28 148 21 16 10 223 Ventricular septal defect 248 1782 326 256 64 2676 Atrial septal defect 54 403 89 66 27 639 Coarctation of aorta 10 71 19 13 4 117 Mild cardiovascular defects (see Table 1) only in the absence of a severe defect. When not otherwise specified, isolated and nonisolated defects are treated together. atrial septal defects. There was no statistically significant difference between the highest OR for D-transposition (1.48) and the lowest OR for tetralogy of Fallot (1.07; z 0.99, p 0.24). Underweight (BMI 19.8 kg/m 2 ) seemed to be protective for isolated cardiovascular defects (Table 4). The risk among the underweight women was slightly below unity in all subgroups, although the findings could be random. The pattern of lower ORs among underweight women was consistent across the specific defect subgroups evaluated, except for tetralogy of Fallot (OR 1.26; 95% CI, 0.42 to 3.76). CIs become wide in the analysis of specific subgroups of cardiovascular defects and include unity. Discussion We observed a positive association between maternal obesity (BMI 29 kg/m 2 ) in early pregnancy and congenital heart defects in the offspring. This association has been pointed out in other studies, although low numbers of cases limited their statistical power. A case-control study from Germany reported elevated ORs among women with BMI 30 kg/m 2 for transposition of the great arteries and truncus arteriosus, but no increased risk was found for any cardiovascular defect (7). A recent study concluded that obese African-American women were more likely to have infants with a cardiac anomaly (OR 6.5; 95% CI, 1.2 to 34.9); this finding was based on seven cases of cardiac malformations, and chromosomal anomalies were not excluded (8). Watkins and Botto found that overweight women (BMI 26 kg/m 2 ) were more likely to have a child with a major isolated heart defect (OR 1.36; 95% CI, 0.95 to 1.93; N 66) than women with BMI 19.9 to 22.7 kg/m 2 (6). In a study from California (10), no effect of BMI was seen at conotruncal defects, but numbers were low. The percentage of women with a BMI 29 kg/m 2 were the same (9%) among case and control mothers. Our study can be seen as a large case-control study based on 6801 mothers giving birth to an infant with a congenital heart defect. The completeness of ascertainment of the infants with congenital cardiovascular defects is probably high. We used three Swedish medical health registers as sources of information, and the best possible diagnosis for each infant was identified. Infants with chromosomal anomalies and infants of mothers with diabetes were excluded from the analysis because of known associations with cardiovascular malformations. The advantage of register studies is the large number of individuals, which gives high statistical power and makes it possible also to demonstrate 1068 OBESITY RESEARCH Vol. 11 No. 9 September 2003

Table 4. Adjusted OR for each BMI class to have an infant with a cardiovascular defect using BMI class 19.8 to 26 kg/m 2 as a reference (1.00) Group of cardiovascular defects BMI < 19.8 BMI 26.1 to 29 kg/m 2 kg/m 2 BMI > 29 kg/m 2 BMI > 35 kg/m 2 OR 95% CI OR 95% CI OR 95% CI OR 95% CI All defects 0.92 0.84 to 1.00 1.03 0.96 to 1.11 1.18 1.09 to 1.27 1.41 1.22 to 1.64 Isolated defects 0.90 0.82 to 0.99 1.02 0.94 to 1.10 1.17 1.07 to 1.27 1.34 1.14 to 1.58 Nonisolated defects 1.00 0.76 to 1.31 1.09 0.91 to 1.30 1.25 1.04 to 1.50 1.80 1.30 to 2.49 Severe defects 0.89 0.70 to 1.12 0.95 0.81 to 1.12 1.23 1.05 to 1.44 1.69 1.27 to 2.26 Complex severe defects 0.97 0.68 to 1.38 0.84 0.60 to 1.18 1.21 0.88 to 1.67 1.78 1.00 to 3.16 Mild defects 0.89 0.79 to 0.99 1.06 0.97 to 1.15 1.15 1.04 to 1.27 1.40 1.18 to 1.68 Unspecified defects 0.86 0.69 to 1.07 1.08 0.93 to 1.27 1.15 0.98 to 1.37 1.22 0.85 to 1.75 Hypoplastic left heart syndrome 0.83 0.23 to 2.95 1.34 0.87 to 2.06 1.41 0.90 to 2.21 D-transposition 0.63 0.15 to 2.61 0.77 0.45 to 1.30 1.48 0.97 to 2.27 Endocardial cushion defect 0.85 0.61 to 1.18 0.95 0.77 to 1.17 1.21 0.99 to 1.49 Tetralogy of Fallot 1.26 0.42 to 3.76 0.73 0.46 to 1.15 1.07 0.70 to 1.64 Ventricular septal defect 0.92 0.79 to 1.06 0.96 0.85 to 1.08 1.14 1.01 to 1.28 Atrial septal defect 0.91 0.59 to 1.40 1.12 0.89 to 1.40 1.37 1.09 to 1.72 Coarctation of aorta 0.95 0.14 to 6.27 1.39 0.84 to 2.30 1.47 0.88 to 2.46 weak effects on reproductive outcome. The drawback is the sometimes low validity of infant cardiac diagnosis, despite the use of multiple sources. Within the group of unspecified cardiovascular defects, a substantial proportion of infants probably did not have such a defect (12). A dilution of the material with healthy infants will bias the observed risk estimates toward unity. In Table 4, there is a tendency for lower ORs at high BMI for unspecified defects than for the other groups. Exposure information (weight and height) was recorded in early pregnancy and, therefore, was prospective with regard to the identification of congenital cardiac defects. Recall bias was thus avoided. Some effect on the weight measurement will exist according to when during the first trimester the woman attended the antenatal clinic, but it is unlikely that this will covary with the risk for a cardiac defect. Theoretically, maternal alcoholism may result in late attendance, but quantitatively, this is a small error because maternal alcoholism is rare among pregnant women in Sweden; in addition, in order to have a confounding effect, there would need to be an association between alcoholism and obesity. A number of potential confounding factors associated with maternal obesity, such as maternal age, parity, and smoking in early pregnancy, were adjusted for in this study, but they changed the OR estimates little. A putative confounding factor, not stratified for in this study, is socioeconomic level, which could have affected the result, but smoking during pregnancy is strongly correlated with socioeconomic level in Sweden. Maternal education can be used as a proxy for socioeconomic conditions it does not covary with the risk for a cardiovascular defect in Sweden. Information on maternal education is available only up to 1996; for the period 1992 to 1995, we found no correlation between maternal educational level and the risk for a cardiac defect (M.I. Cedergren and B.A.J. Källén, unpublished information). Another problem concerning studies in this field is the definition of obesity. Different thresholds or cut-off values for defining obesity were used in different studies, which makes it difficult to compare risk estimates. We found a slightly increased risk for infant cardiovascular defects of any type in the overweight group (BMI 26.1 to 29 kg/m 2 ), although the finding could be random, whereas maternal obesity (BMI 29 kg/m 2 ) was significantly associated with cardiovascular defects in the offspring. This association was even more pronounced among the morbidly obese (BMI 35 kg/m 2 ). These findings indicate the necessity of dividing the group of women with excess weight into not only overweight, but also obese and morbidly obese (BMI 35 kg/m 2 ), categories when conducting further studies. An epidemic of obesity is a current issue in Sweden as well as in other developed countries, especially in the United States (22). In our sample, 10.6% of the control mothers had a BMI 29 kg/m 2, which is in accordance with a recent survey in Sweden (11). That study reported the prevalence of overweight (BMI 25 kg/m 2 )to OBESITY RESEARCH Vol. 11 No. 9 September 2003 1069

be 41.6% in Swedish women, which is higher than in our pregnant women, where 23% had a BMI 26 kg/m 2. The observed increased risk among obese women seems to be similar for isolated and nonisolated cardiovascular defects in infants. There is no major difference in the risk estimates whether the defect is severe or mild. This finding speaks toward an overall excess risk for cardiovascular defects associated with maternal obesity. Among specific cardiovascular defects, there appeared to be an increased risk of ventricular septal defects and atrial septal defects. Despite the large number of subjects, no statistically significant association could be found between maternal obesity and hypoplastic left heart syndrome, transposition, endocardial cushion defect, tetralogy of Fallot, or coarctation of aorta, although ORs were increased. Even larger groups of these specific cardiac defects are needed to evaluate this indicated association. Whatever the underlying mechanism for the observed association between maternal obesity and infant cardiovascular defect is, it affects fetal heart development in early pregnancy. The critical period for most defects occurs 14 to 60 days after conception. A likely explanation is undetected type 2 diabetes, because obese women, in the absence of overt diabetes, have been found to have an impaired glucose metabolism (23), which may be associated with an increased risk of congenital heart disease (24,25). Another possible explanation for the association between obesity and cardiovascular defects could be improper nutrition. It has been suggested that lack of folic acid could increase the risk of a cardiovascular defect (26,27), but data on folic acid supplementation in Sweden gave no support for such an association (28). The observed association between maternal obesity and cardiovascular defects in the offspring is of importance from various points of view. Congenital cardiovascular defects contribute to increased morbidity and mortality during childhood, and little is known about putative preventive mechanisms. Overweight or obesity among women of childbearing age is associated with a number of complications, especially later in life. Pregnancy is a life event when women may be more inclined to behavioral changes. It is possible that appropriate counseling and management during pregnancy for the obese women could reduce the gestational weight gain, improve perinatal outcome, and also contribute to persistent behavioral changes concerning nutrition and physical exercise. Acknowledgments Östergötland County Council (M.C.) and a grant from K. and A. Wallenberg s foundation (B.K.) supported this study. We thank the National Board of Health and Social Welfare, Stockholm, for access to the health registers. References 1. Källén K. Maternal smoking, body mass index, and neural tube defects. Am J Epidemiol. 1998;147:1103 11. 2. Waller DK, Mills JL, Simpson JL, et al. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol. 1994;170:541 8. 3. Shaw GM, Velie EM, Schaffer D. Risk of neural tube defectaffected pregnancies among obese women. JAMA. 1996;275: 1093 6. 4. Werler MM. Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. JAMA. 1996; 275:1089 92. 5. Moore LL, Singer MR, Bradlee ML, Rothman KJ, Milunsky A. A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology. 2000;11:689 94. 6. Watkins ML, Botto LD. Maternal prepregnancy weight and congenital heart defects in offspring. Epidemiology. 2001;12: 439 46. 7. Queisser-Luft A, Kienger-Baum D, Menger H, Stolz G, Schlaefer K, Merz E. Does maternal obesity increase the risk of fetal abnormalities? Analysis of 20,248 newborn infants of the Mainz Birth Register for detecting congenital abnormalities. Ultraschall Med. 1998;19:40 4. 8. Mikhail LN, Walker CK, Mittendorf R. Association between maternal obesity and fetal cardiac malformations in African Americans. J Natl Med Assoc. 2002;94:695 700. 9. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformations a study based on prospectively collected data. Scand J Work Environ Health. 2002;28: 12 7. 10. Shaw GM, Todoroff K, Schaffer DM, Selvin S. Maternal height and prepregnancy body mass index as risk factors for selected congenital anomalies. Paediatr Perinat Epidemiol. 2000;14:234 9. 11. Lissner L, Johansson SE, Qvist J, Rossner S, Wolk A. Social mapping of the obesity epidemic in Sweden. Int J Obes Relat Metab Disord. 2000;24:801 5. 12. Carlgren LE, Ericson A, Källén B. Monitoring of congenital cardiac defects. Pediatr Cardiol. 1987;8:247 56. 13. Hanna EJ, Nevin NC, Nelson J. Genetic study of congenital heart defects in Northern Ireland (1974 1978). J Med Genet. 1994;31:853 63. 14. Bruyere HJ Jr, Kargas SA, Levy JM. The causes and underlying developmental mechanism of congenital cardiovascular malformations: a critical review. Am J Med Genet Suppl. 1987;3:411 31. 15. Nora JJ, Nora AH. The evolution of specific genetic and environmental counselling in congenital heart diseases. Circulation. 1978;57:205 13. 16. Cnattingius S, Ericson A, Gunnarskog J, Källén B. A quality study of a medical birth registry. Scand J Soc Med. 1990;18:143 8. 17. Källén B, Winberg J. A Swedish register of congenital malformations. Experience with continuous registration during 2 years with special reference to multiple malformations. Pediatrics. 1968;41:765 76. 1070 OBESITY RESEARCH Vol. 11 No. 9 September 2003

18. Pradat P, Francannet C, Harris JA, Robert E. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr Cardiol. 2003;24:195 221. 19. Harris JA, Francannet C, Pradat P, Robert E. The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations. Pediatr Cardiol. 2003;24:222 35. 20. Mantel N, Haenszel W. Statistical aspects of the analyses of data from retrospective studies of disease. J Nat Cancer Inst. 1959;22:719 48. 21. Miettinen OS. Simple interval estimation of risk ratio. Am J Epidemiol. 1974;100:515 6. 22. Mokdad AH, Serdula MK. The spread of the obesity epidemic in the United States. JAMA. 1999;282:1519 22. 23. Scheen AJ, Paquot N, Lethiexhe MR, Paolisso G, Castillo MJ, Lefebvre PJ. Glucose metabolism in obese subjects: lessons from OGTT, IVGTT and clamp studies. Int J Obes Relat Metab Disord. 1995;19:S14 S20. 24. Towner D, Kjos SL, Leung B, et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care. 1995;18:1446 51. 25. Åberg A, Westbom L, Källén B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev. 2001;61:85 95. 26. Scanlon KS, Ferencz C, Loffredo CA, et al. Preconceptional folate intake and malformations of the cardiac outflow tract. Epidemiology. 1998;9:95 8. 27. Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal multivitamin use. Am J Epidemiol. 2000;151:878 84. 28. Källén AJB, Otterblad Olausson P. Use of folic acid and delivery outcome: a prospective study. Reprod Toxicol. 2002; 16:327 32. OBESITY RESEARCH Vol. 11 No. 9 September 2003 1071