Materials and Methods
The NBDPS is a large ongoing case-control study of 30 major structural malformations in the United States. The NBDPS is an approved activity of the institutional review boards of participating centers and the Centers for Disease Control and Prevention. For all subjects, informed consent was provided. Detailed study methods have been published. Briefly, data originate from the following sites, each of which is based on a population-based birth defect registry with active case ascertainment: Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Every year each participating site enrolls eligible cases of major malformations among liveborn infants, stillbirths, and pregnancy terminations, excluding cases of chromosomal or single-gene conditions. Control subjects without major malformations are selected randomly from birth certificates or birth hospital records from the same underlying population.
Eligible families are approached; after informed consent is obtained, mothers are interviewed by telephone with the use of a structured, computer-assisted questionnaire. Buccal samples are requested from baby, mother, and father.
Case selection, review, and classification
Diagnosis of congenital heart defects is confirmed by echocardiography, catheterization, surgery, or autopsy. Most diagnoses occurred in the first year of life, and all occurred by the second year of life (by protocol, maternal interviews are conducted by the child’s second birthday). A central team of clinicians with expertise in pediatric cardiology and genetics reviewed, coded, and classified the phenotypes, using a structured and published process. Briefly, each congenital heart defect was classified as simple, association, or complex. Simple defects are single, well-defined heart defects with a unifying diagnosis. Examples include isolated ventricular septal defects or tetralogy of Fallot. Associations are the combination of typically 2 heart defects that usually occur in isolation and do not constitute a well-defined single entity (for this reason, tetralogy of Fallot is considered simple and not an association). An example of association is the combination of perimembranous ventricular septal defect with secundum atrial septal defect. The complex category includes a small group of phenotypes with multiple structural cardiac findings that can occur in heterotaxy or certain single ventricle phenotypes.
To improve case homogeneity, this analysis focused on those congenital heart defects that were classified as simple, in addition to selected associations and heterotaxy. Association phenotypes included (1) left ventricular outflow tract obstruction associations (coarctation of the aorta plus either aortic stenosis, ventricular septal defect or atrial septal defect), (2) right ventricular outflow tract obstruction association (pulmonary valve stenosis plus ventricular septal defect or atrial septal defect), and (3) septal association (ventricular septal defect plus atrial septal defect). Septal defects in these associations do not include primum atrial septal defects and inlet or supracristal ventricular septal defects because these are considered part of other groups: primum atrial septal defects and inlet ventricular septal defects are included with atrioventricular septal defects and supracristal ventricular septal defects are included with outflow tract/conotruncal malformations. Finally, each case was also classified as isolated or nonisolated, depending on the presence of major unrelated extracardiac malformations. Because of the high prevalence of muscular ventricular septal defects and ventricular septal defects “not otherwise specified,” these defects were eligible only in the initial years of the study (California, Georgia, Iowa, Massachusetts, New York, and Texas before Oct. 1, 1998; Arkansas and New Jersey before Jan. 1, 1999).
Exposure assessment
Overall participation in the interview in NBDPS was 69% among case mothers and 66% among control mothers. Maternal interviews, in English or Spanish, were performed by telephone with a standardized, computer-based questionnaire, no earlier than 6 weeks and not later than 24 months after the infant’s estimated date of delivery. For febrile illnesses, variables were based on several questions on type of illnesses (respiratory illnesses, pelvic inflammatory disease, urinary tract infections, and others) and their timing, duration, presence of fever (fever duration and peak value), and associated use of medication. When the exposure was uncertain (eg, mothers reported a febrile illness but was unsure of the month or reported a respiratory illness but was unsure of fever), these data were excluded from the analysis to minimize exposure misclassification.
Exclusions and inclusions
We included deliveries with estimated due dates from 1997-2005. Interviews were completed with 8134 mothers of babies with a major eligible congenital heart defect and 6807 control mothers on average by 12 months from the date of delivery for case mothers and 9 months for control mothers. We excluded all case and control mothers with reported type 1 or type 2 pregestational diabetes mellitus (231) because of the strong teratogenic risk of this condition. The final analysis included data from 7020 case mothers and 6746 control mothers.
Statistical methods
Effect estimates were generated by logistic modeling (SAS Corporation, Cary, NC) and are presented as odds ratio (OR) with 95% confidence intervals (CIs). CIs are presented in preference to probability values because confidence intervals convey more information. We used as reference the stratum with no reported fever or infection during the first trimester; estimates were produced separately for first-trimester illnesses with fever and without fever (2 mutually exclusive groups) to investigate the relative contribution of fever and the underlying illnesses to overall disease risk. Covariates in the logistic model were selected based on case-control differences and evidence from the published literature regarding risk factors for congenital heart defects. The same covariate set was used throughout the analyses. Covariates that were retained in final models included maternal age (single year as a continuous variable); maternal race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other); maternal cigarette smoking during the first trimester (yes, no); maternal alcohol consumption during the first trimester (yes, no); maternal education (≤12 years, >12 years); prepregnancy body mass index (continuous); history of seizures (yes, no); time to interview (≤1 year, >1 year); and family history of a first-degree relative with a major congenital heart defect (yes, no). Parity and gestational diabetes mellitus did not modify the risk estimates appreciably and were not included. Periconceptional multivitamin use was defined as regular use (at least 3 times weekly) from 1 month before conception through the end of the first trimester. This variable was used as a stratification variable to investigate its role as an effect modifier. To do so, we constructed 3 strata: (1) vitamin users, without reported fever or illness (the common reference group); (2) vitamin nonusers, with reported febrile illness; and (3) vitamin users, with reported febrile illness. ORs were then generated by contrasting group 2 vs group 1, and group 3 vs group 1. In the analysis by fever severity, we defined high fevers as fever ≥102°F and fevers of long duration as reported to have lasted ≥24 hours. In the analysis by use of antipyretics, we evaluated the use of nonsteroidal antiinflammatory drugs, which included paracetamol, acetylsalicylic acid, and paracetamol during the first trimester. Because of the analytic structure of the data, the use of antipyretics could be established for the time period of interest but not directly linked to the individual episode of febrile illness.
Results
The study ( Table 1 ) included 7020 mothers of babies with major congenital heart defects (cases) and 6746 mothers of babies without birth defects (control subjects). Overall, the heart defect was isolated (ie, without additional extracardiac defects) in 84% of cases, but with some variability between heart defect types (eg, between conotruncal defects). Case and control mothers were similar in many characteristics, although case-mothers were slightly more likely to be overweight or obese and to report first-trimester smoking and a family history of heart defects ( Table 2 ).
| Type of heart defect | Total, n | Isolated, n (%) a |
|---|---|---|
| Heterotaxy | 200 | 0 |
| Conotruncal defects | 1227 | 1036 (84.4) |
| Tetralogy of Fallot | 663 | 529 (79.8) |
| d-Transposition of the great arteries | 376 | 357 (94.9) |
| Atrioventricular septal defect | 109 | 94 (86.2) |
| Total anomalous pulmonary venous return | 156 | 145 (92.9) |
| Left ventricular outflow tract obstructions | 1188 | 1055 (88.8) |
| Hypoplastic left heart | 350 | 322 (92.0) |
| Coarctation of the aorta | 362 | 314 (86.7) |
| Aortic stenosis | 188 | 178 (94.7) |
| Left ventricular outflow tract obstruction associations, all | 275 | 230 (83.6) |
| Right ventricular outflow tract obstructions | 1075 | 990 (92.1) |
| Pulmonary atresia | 102 | 96 (94.1) |
| Pulmonic valve stenosis | 622 | 593 (95.3) |
| Right ventricular outflow tract obstruction association | 233 | 197 (84.5) |
| Septal defects | 3065 | 2553 (83.3) |
| Ventricular septal defect, perimembranous | 1011 | 893 (88.3) |
| Ventricular septal defect, muscular | 164 | 147 (89.6) |
| Atrial septal defect, secundum | 974 | 780 (80.1) |
| Atrial septal defect, not otherwise specified | 334 | 275 (82.3) |
| Septal associations | 537 | 426 (79.3) |
| Total | 7020 | 5873 (83.7) |
| Characteristic | Cases, n (%) a , b | Control subjects, n (%) a , c |
|---|---|---|
| Maternal education, y | ||
| <High school (<12 y) | 1202 (17) | 1114 (17) |
| High school (12 y) | 1792 (26) | 1635 (24) |
| >High school (>12 y) | 3905 (56) | 3889 (58) |
| Race/ethnicity | ||
| Non-Hispanic white | 4102 (58) | 3993 (59) |
| Non-Hispanic black | 807 (12) | 765 (11) |
| Hispanic | 1577 (22) | 1489 (22) |
| Other | 517 (7) | 470 (7) |
| Maternal smoking, first trimester | ||
| No | 5674 (81) | 5548 (82) |
| Yes | 1242 (18) | 1110 (16) |
| Maternal alcohol use, first trimester | ||
| No | 5403 (77) | 5098 (76) |
| Yes | 1480 (21) | 1529 (23) |
| Folic acid supplement use, first trimester | ||
| No | 952 (14) | 852 (13) |
| Yes | 5875 (84) | 5733 (85) |
| Body mass index, kg/m 2 | ||
| Underweight (<18.5) | 369 (5) | 360 (5) |
| Normal weight (18.5−<25) | 3460 (49) | 3620 (54) |
| Overweight (25−<30) | 1593 (23) | 1447 (21) |
| Obesity (≥30) | 1292 (18) | 1036 (15) |
| Family history of heart defects | ||
| Yes | 239 (3) | 83 (1) |
| No | 6781 (97) | 6683 (98) |
a Percentages may not add to 100% because of rounding and missing values
A first-trimester febrile illness was reported by 7.4% (1 in 13) control mothers and by 8.1% of case mothers ( Table 3 ). The phenotypes more strongly associated overall with febrile illness were heterotaxy, aortic stenosis, right ventricular outflow tract obstructions (RVOTO), and septal associations. ORs, when elevated, were modestly so (<2) with many confidence intervals including unity. Further analyses identified a more complex pattern of associations. Febrile illnesses were associated with generally higher ORs compared with nonfebrile illnesses. Examples include heterotaxy (OR, 1.7 for febrile illness vs 0.8 for non-febrile illness), aortic stenosis (OR, 1.8 vs 1.1), RVOTO (OR, 1.3 vs 0.9), and RVOTO associations (OR, 1.8 vs 1.0). Isolated cases seemed to drive the overall risk estimates ( Table 4 ). Regarding the source of febrile illness, the strongest associations with heart defect risk were found for urinary tract infections and pelvic inflammatory disease ( Figure 2 ); for these infections, 10 associations had ORs >2 compared with none for respiratory illnesses ( Table 3 ). Because respiratory illnesses were by far the most common source of fever, which accounted for 91% (456/501) of all febrile illnesses among control subjects, the overall association of fever with heart defects was weak.
| Group | All, n | Febrile illness a | Febrile urinary tract infection or pelvic inflammatory disease | Febrile respiratory infections | Nonfebrile illness b | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Exposed, n | Adjusted OR | 95% CI | Exposed, n | Adjusted OR | 95% CI | Exposed, n | Adjusted OR | 95% CI | Exposed, n | Adjusted OR | 95% CI | ||
| Control subjects | 6746 | 501 | 1.0 | Reference | 24 | 1.0 | Reference | 456 | 1.0 | Reference | 1022 | 1.0 | Reference |
| Total cases | 7020 | 572 | 1.14 | 1.00–1.30 | 48 | 1.73 | 1.03–2.92 | 493 | 1.09 | 0.94–1.25 | 1039 | 1.05 | 0.95–1.16 |
| Heterotaxy | 200 | 24 | 1.71 | 1.07–2.74 | 3 | 2.61 | 0.59–11.51 | 20 | 1.66 | 1.00–2.74 | 23 | 0.78 | 0.49–1.26 |
| Tetralogy of Fallot | 663 | 49 | 1.11 | 0.80 – 1.53 | 6 | 2.55 | 0.94–6.92 | 37 | 0.93 | 0.65–1.33 | 102 | 1.15 | 0.90 – 1.45 |
| d-Transposition of great arteries | 376 | 31 | 1.23 | 0.83 – 1.81 | 1 | 0.84 | 0.11–6.31 | 28 | 1.23 | 0.81–1.85 | 58 | 1.07 | 0.79 – 1.46 |
| Atrioventricular septal defect | 109 | 4 | 0.57 | 0.21 – 1.60 | 0 | — | — | 4 | 0.64 | 0.23–1.80 | 22 | 1.46 | 0.88 – 2.43 |
| Total anomalous pulmonary venous return | 156 | 22 | 0.72 | 0.34 – 1.49 | 2 | 3.38 | 0.76–15.12 | 6 | 0.60 | 0.26–1.40 | 8 | 0.85 | 0.52 – 1.41 |
| Hypoplastic left heart syndrome | 350 | 31 | 1.25 | 0.83 – 1.88 | 1 | 1.01 | 0.13–7.64 | 27 | 1.17 | 0.76–1.81 | 49 | 0.96 | 0.69 – 1.33 |
| Coarctation of the aorta | 362 | 26 | 0.98 | 0.63 – 1.54 | 3 | 2.94 | 0.84–10.2 | 22 | 0.88 | 0.54–1.44 | 53 | 1.10 | 0.80 – 1.51 |
| Aortic stenosis | 188 | 27 | 1.78 | 1.09–2.90 | 1 | 1.76 | 0.24–13.1 | 25 | 1.87 | 1.13–3.09 | 26 | 1.06 | 0.68 – 1.66 |
| Left ventricular outflow tract obstruction association c | 275 | 24 | 1.20 | 0.77 – 1.88 | 2 | 2.49 | 0.57–10.9 | 20 | 1.10 | 0.68–1.78 | 36 | 0.84 | 0.58 – 1.24 |
| Pulmonary atresia | 102 | 9 | 1.19 | 0.58 – 2.41 | 0 | — | — | 8 | 1.17 | 0.55–2.47 | 14 | 0.83 | 0.46 – 1.52 |
| Pulmonic valve stenosis | 622 | 56 | 1.3 | 0.95 – 1.78 | 7 | 4.29 | 1.77–10.4 | 47 | 1.18 | 0.84–1.66 | 80 | 0.92 | 0.71 – 1.19 |
| Right ventricular outflow tract obstruction association d | 233 | 25 | 1.77 | 1.13–2.78 | 4 | 4.32 | 1.37–13.6 | 21 | 1.67 | 1.03–2.71 | 31 | 1.03 | 0.68 – 1.5 |
| Ventricular septal defect, perimembranous | 1011 | 82 | 1.16 | 0.90 – 1.51 | 1 | 0.00 | 0.00–0.00 | 80 | 1.26 | 0.97–1.65 | 168 | 1.20 | 0.99 – 1.45 |
| Ventricular septal defect, muscular | 164 | 12 | 0.78 | 0.40 – 1.54 | 1 | 1.06 | 0.10–11.20 | 10 | 0.71 | 0.34–1.46 | 24 | 0.98 | 0.59 – 1.63 |
| Atrial septal defect, secundum | 974 | 63 | 0.91 | 0.68 – 1.21 | 7 | 1.79 | 0.74–4.33 | 52 | 0.82 | 0.60–1.13 | 145 | 1.01 | 0.83 – 1.24 |
| Atrial septal defect, not otherwise specified | 334 | 19 | 0.84 | 0.51 – 1.38 | 2 | 1.76 | 0.40–7.82 | 16 | 0.77 | 0.45–1.33 | 58 | 1.20 | 0.87 – 1.65 |
| Septal association e | 537 | 51 | 1.41 | 1.03–1.95 | 6 | 3.70 | 1.44-9.50 | 42 | 1.28 | 0.90–1.81 | 73 | 0.92 | 0.69 – 1.22 |
a Respiratory, urinary tract, pelvic inflammatory, other, and multiple
b Same as “footnote a,” but without fever
c Include coarctation of the aorta + aortic stenosis; coarctation of the aorta + ventricular septal defect; coarctation of the aorta + ventricular septal defect + atrial septal defect
d Include pulmonary valve stenosis + ventricular septal defect and pulmonary valve stenosis + atrial septal defect
| Group | Isolated (no extracardiac malformations) | Nonisolated (with extracardiac malformations | ||||||
|---|---|---|---|---|---|---|---|---|
| All, n | Exposed, n (%) | Adjusted OR | 95% CI | All, n | Exposed, n (%) | Adjusted OR | 95% CI | |
| Control subjects | 6746 | 501 (7.4) | 1.00 | Reference | 1.00 | Reference | ||
| All heart defects combined | 5873 | 473 (8.1) | 1.13 | 0.99–1.31 | 1147 | 99 (8.6) | 1.21 | 0.95–1.54 |
| Heterotaxy | — | — | — | — | 200 | 24 (12.0) | 1.71 | 1.07–2.74 |
| Conotruncal defects | 1036 | 83 (8.0) | 1.26 | 0.98–1.62 | 191 | 14 (7.3) | 0.94 | 0.51–1.72 |
| Tetralogy of Fallot | 529 | 41 (7.8) | 1.24 | 0.88–1.75 | 134 | 8 (6.0) | 0.67 | 0.29–1.56 |
| d-transposition of the great arteries | 357 | 30 (8.4) | 1.26 | 0.85–1.88 | 19 | 1 (5.3) | 0.66 | 0.08–5.14 |
| Atrioventricular septal defect | 94 | 2 (2.1) | 0.32 | 0.08–1.35 | 15 | 2 (13.3) | 2.24 | 0.47–10.6 |
| Total anomalous pulmonary venous return | 145 | 8 (5.5) | 0.77 | 0.37–1.61 | 11 | 0 | — | |
| Left ventricular outflow tract obstructions | 1055 | 96 (9.1) | 1.23 | 0.96–1.58 | 133 | 13 (9.8) | 1.28 | 0.69–2.38 |
| Hypoplastic left heart | 322 | 28 (8.7) | 1.24 | 0.81–1.91 | 28 | 3 (10.7) | 1.49 | 0.44–5.19 |
| Coarctation of the aorta | 314 | 23 (7.3) | 0.99 | 0.61–1.60 | 48 | 3 (6.3) | 0.92 | 0.28–3.07 |
| Aortic stenosis | 178 | 26 (14.6) | 1.91 | 1.18–3.17 | 10 | 1 (10.0) | 0.00 | 0.00–0.00 |
| Left ventricular outflow tract obstruction association | 230 | 18 (7.8) | 1.06 | 0.64–1.76 | 45 | 6 (13.3) | 2.01 | 0.81–4.99 |
| Right ventricular outflow tract obstructions | 990 | 93 (9.4) | 1.35 | 1.05–1.73 | 85 | 7 (8.2) | 1.25 | 0.56–2.80 |
| Pulmonary atresia | 96 | 9 (9.4) | 1.26 | 0.62–2.59 | 6 | 0 | — | |
| Pulmonic valve stenosis | 593 | 56 (9.4) | 1.38 | 1.01–1.89 | 29 | 0 | — | |
| Right ventricular outflow tract obstructions association | 197 | 19 (9.6) | 1.56 | 0.93–2.59 | 36 | 6 (16.7) | 3.21 | 1.19–7.98 |
| Septal defects | 2553 | 191 (7.5) | 1.06 | 0.89–1.28 | 512 | 39 (7.6) | 1.10 | 0.77–1.58 |
| Ventricular septal defect, perimembranous | 893 | 75 (8.4) | 1.21 | 0.91–1.57 | 118 | 7 (5.9) | 0.91 | 0.41–2.01 |
| Ventricular septal defect, muscular | 147 | 12 (8.2) | 0.87 | 0.44–1.72 | 17 | 0 | — | |
| Atrial septal defect, secundum | 780 | 49 (6.3) | 0.88 | 0.64–1.22 | 194 | 14 (7.2) | 0.98 | 0.55–1.77 |
| Atrial septal defect, not otherwise specified | 275 | 15 (5.5) | 0.77 | 0.44–1.35 | 59 | 4 (6.8) | 1.21 | 0.42–3.48 |
| Septal association | 426 | 37 (8.7) | 1.31 | 0.91–1.89 | 111 | 14 (12.6) | 1.83 | 0.99–3.38 |
To assess for possible associations with severity, we reanalyzed the data by magnitude and duration of the fever. Restricting the analysis to higher fevers (≥102°F) did not change the overall risk for heart defects (OR, 1.01; 95% CI, 0.81–1.26, based on 162 and 156 exposed cases and control subjects, respectively). Similarly, fevers of longer duration (≥24 hours) were not associated with higher risks (data not shown).
Because of sample size, stratification by antipyretic use during the periconceptional period was possible for all heart defects combined and not for individual heart defect types ( Table 5 ). The pattern was suggestive of a possible mitigating role of antipyretic use, which was driven by febrile illnesses associated with urinary tract infection/pelvic inflammatory disease; however, sparse data limited the precision of the risk estimates.
| Fever | Antipyretics | All febrile illnesses | Respiratory fever | Urinary tract infection/pelvic inflammatory disease fever | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cases, n | Control subjects, n | OR (95%CI) | Cases, n | Control subjects, n | OR (95% CI) | Cases, n | Control subjects, n | OR (95% CI) | ||
| Yes | Yes | 577 | 515 | 1.06 (0.92–1.22) | 447 | 430 | 0.98 (0.79–1.07) | 55 | 40 | 1.30 (0.86–1.97) |
| Yes | No | 61 | 37 | 1.56 (1.03–2.36) | 40 | 35 | 1.08 (0.68–1.71) | 7 | 0 | Infinity a |
| No | Yes | 4930 | 4815 | 0.97 (0.89–1.06) | 4930 | 4815 | 0.97 (0.88–1.06) | 4930 | 4815 | 0.97 (0.88–1.06) |
| No | No | 1253 | 1183 | 1.00 (Reference) | 1253 | 1183 | 1.00 (Reference) | 1253 | 1183 | 1.00 |
| T otals | 6821 | 6550 | 6670 | 6463 | 6245 | 6039 | ||||
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