Objective
We sought to determine if maternal bupropion treatment in early pregnancy is associated with congenital heart defects in the infant.
Study Design
We conducted a retrospective case-control study of birth defects risk factors. Data on 6853 infants with major heart defects were compared with 5869 control infants born in 1997–2004. Bupropion exposure was defined as any reported use between 1 month before and 3 months after conception.
Results
Mothers of infants with left outflow tract heart defects were more likely to have reported taking bupropion than mothers of control infants (adjusted odds ratio, 2.6; 95% confidence interval, 1.2–5.7; P = .01).
Conclusion
We identified a positive association between early pregnancy bupropion use and left outflow tract heart defects; however, the magnitude of the observed increased risk was small. Nevertheless, further studies are needed to confirm these results.
Bupropion is an aminoketone that is structurally and chemically different from other antidepressants on the market. It is a weak inhibitor of neuronal uptake of dopamine, norepinephrine, and serotonin and does not inhibit monoamine oxidase. Bupropion was first marketed as an oral antidepressant (Wellbutrin; GlaxoSmithKline, London, UK) and was subsequently developed as a nonnicotine aid to smoking cessation (Zyban; GlaxoSmithKline). Major depression among women of reproductive age is common, and women who smoke are encouraged to stop doing so when they become pregnant. It is, therefore, not surprising that some women are treated with bupropion early in pregnancy. Nevertheless, available data on the safety of such treatment in human pregnancy are limited.
The manufacturer, GlaxoSmithKline, established a Bupropion Pregnancy Registry in 1997 to follow up the outcomes of pregnancies in which women took this drug. By the end of March 2008, congenital anomalies had been reported in 24 of 675 (3.6%) infants of women identified prospectively to have taken bupropion in the first trimester and reported to the registry. These included 651 live births without birth defects, 18 live births with birth defects, 1 fetal death with a birth defect, and 5 induced abortions with birth defects. Congenital heart defects were observed in 9 (1.3%) of these infants. The registry used voluntary recruitment and reporting, which may lead to incomplete or biased reporting of pregnancies or outcomes. Most outcome reports were from clinicians who cared for the mother during her pregnancy and who may only have had information on birth defects diagnosed within a short time after birth, and the registry did not collect data on a comparison group. The registry also received retrospective notification of bupropion-exposed pregnancies after their outcomes were known. Of 28 retrospectively reported birth defects with maternal bupropion exposure (including 25 involving first-trimester exposure), there were 12 reports of congenital heart defects.
These findings raised concern about the possibility of an association between maternal bupropion use early in pregnancy and congenital heart defects in the infant, which prompted the manufacturer to undertake a retrospective cohort study of claims records of a large managed care database. That study did not find an association with cardiovascular defects among infants of women who had received prescriptions for bupropion during the first trimester of pregnancy when compared with infants whose mothers had received prescriptions for other antidepressants during pregnancy or infants whose mothers received bupropion prescriptions outside the first trimester.
We used data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study, to determine if maternal bupropion exposure in early pregnancy is associated with ≥1 selected category of congenital heart defects in the infant. We also carried out an exploratory analysis to compare the prevalence of maternal bupropion use among the mothers of infants with 6 categories of noncardiac defects.
Materials and Methods
The NBDPS is an ongoing, multisite case-control study of environmental and genetic risk factors for >30 selected categories of major birth defects. Case infants were ascertained by population-based birth defects surveillance systems at 10 study sites (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah). We used data on infants born on or after Oct. 1, 1997, who had an estimated date of delivery on or before Dec. 31, 2004. Case infants were either live births (all participating sites), fetal deaths >20 weeks’ gestation (Arkansas, California, Georgia, Iowa, Massachusetts, New York [since 2000], North Carolina, Texas, and Utah), or electively terminated pregnancies with reliably ascertained defects (Arkansas, California, Georgia, Iowa, New York [since 2000], North Carolina, Texas, and Utah). Infants with recognized or strongly suspected chromosomal abnormalities or single-gene conditions were excluded from the study. Control infants were liveborn with no major birth defects, randomly selected from the same geographical populations using either birth hospital or vital records. Only 1 case or control infant was included from each multifetal pregnancy. This study received institutional review board approval at all participating sites.
To confirm eligibility, information on infants in each birth defect category was reviewed without knowledge of exposure status by clinical geneticists. In addition, case infants with heart defects were reviewed without knowledge of exposure status by a team of experts in pediatric cardiology and epidemiology of heart defects, and each case was assigned to 1 of 33 cardiac diagnostic subcategories, each of which was in turn placed into ≥1 of 9 major categories. Not all types of heart defects were included in the NBDPS; those that were excluded were either not well ascertained in infancy, very rare, often related to preterm delivery (patent ductus arteriosus, patent foramen ovale), vascular defects that are not true malformations of the heart, or heart defects that were associated with chromosomal abnormalities. The proportion of infants with various categories of heart defects does not reflect their relative population frequencies, because some infants with more common defects were excluded.
Extensive information regarding demographics and pregnancy exposures was collected by standardized telephone interviews with mothers of case or control infants. The interviews were conducted in English or Spanish 6 weeks to 2 years after the estimated date of delivery. Infants with incomplete maternal interviews were excluded. Mothers were asked during the interview whether or not they took any of a list of medications, including Wellbutrin and Zyban. Exposure was defined as reported use of bupropion anytime between 1 month before and 3 months after conception. Women were considered unexposed if they did not use any antidepressant at any time during pregnancy. Mothers who reported having depression but who did not report use of an antidepressant during their pregnancy were excluded. Only heart defects or other birth defect categories that had at least 3 cases exposed to bupropion in the period from 1 month before to 3 months after conception were analyzed in the study.
Crude analyses were done using Pearson χ 2 tests, and odds ratios (ORs) and Fisher’s exact confidence limits were calculated with software (SPSS 11.0; SPSS, Inc, Chicago, IL). The following potential confounders were evaluated: maternal age (<35, ≥35 years), maternal race (non-Hispanic white, other), maternal education (≤12 years, >12 years), maternal obesity before pregnancy (body mass index <30 kg/m 2 , ≥30 kg/m 2 ), maternal smoking and alcohol use from 1 month before to 3 months after conception, use of a dietary supplement containing folic acid from 1 month before to 1 month after conception, annual family income (<$20,000, ≥$20,000), plurality (singleton, twins and above), and parity (no previous live births, ≥1 live birth). Potential confounders were first evaluated for association with bupropion exposure and with the birth defects categories and were excluded from the logistic regression if their removal resulted in a change in risk estimate of <10%. All confounders retained in the model for any of the defects were included in the final models for all defects. Infants of women with pregestational type 1 or 2 diabetes (304 case and 32 control mothers) were excluded from adjusted analyses because of the strong association of diabetes with birth defects.
Results
Four major categories of heart defects and 6 other categories of birth defects met the inclusion criterion of at least 3 cases exposed to bupropion in the period between 1 month before and 3 months after conception. Of 18,534 case and control mothers available for study, we excluded 276 mothers who did not complete their interviews and 6 mothers who reported depression but did not report use of any antidepressant. A total of 12,383 case infants (including 6853 diagnosed with at least 1 of the selected heart defects and 5763 diagnosed with at least 1 of the 6 categories of noncardiac defects studied) and 5869 control infants were analyzed. Among all case and control mothers, 90 (0.5%) reported use of bupropion in the 1 month before to 3 months after conception.
Characteristics of case and control mothers included in the study are presented in Table 1 . Mothers of case infants were significantly more likely to be older, have a higher education, be obese, smoke early in pregnancy, and have a lower family income compared with mothers of control infants. Other characteristics, such as having type 1 or 2 diabetes prior to pregnancy, a multiple pregnancy, or at least 1 previous live birth were more frequently reported among mothers of case infants than among mothers of control infants. Pregnancy intention, on the other hand, was reported more frequently among mothers of control infants.
| Characteristic | Bupropion | χ 2 P value | |
|---|---|---|---|
| Mothers of case infants (n = 12,383), n (%) | Mothers of control infants (n = 5869), n (%) | ||
| Maternal race/ethnicity | |||
| Non-Hispanic white | 7481 (60.6) | 3525 (60.3) | .35 |
| Other | 4868 (39.4) | 2323 (39.7) | |
| Maternal age | |||
| <35 y | 10,489 (84.7) | 5051 (86.1) | .01 |
| ≥35 y | 1894 (15.3) | 818 (13.9) | |
| Maternal education | |||
| ≤12 y | 5546 (44.8) | 2457 (41.9) | < .001 |
| >12 y | 6826 (55.2) | 3402 (58.1) | |
| Maternal prepregnancy BMI | |||
| Not obese (BMI <30 kg/m 2 ) | 9685 (81.3) | 4738 (84.1) | < .001 |
| Obese (BMI ≥30 kg/m 2 ) | 2223 (18.7) | 898 (15.9) | |
| Maternal smoking in the period of 1 mo before to 3 mo after conception | |||
| 0/d | 9687 (78.3) | 4745 (80.9) | < .001 |
| 1–14/d | 1861 (15.0) | 782 (13.3) | |
| ≥15/d | 826 (6.7) | 337 (5.7) | |
| Annual family income | |||
| <$20,000 | 3845 (33.9) | 1679 (32.0) | .01 |
| ≥$20,000 | 7507 (66.1) | 3574 (68.0) | |
| Type 1 or 2 diabetes prior to pregnancy | |||
| No | 11,125 (97.3) | 5464 (99.4) | < .001 |
| Yes | 304 (2.7) | 32 (0.6) | |
| Maternal alcohol intake in the period of 1 mo before to 3 mo after conception | |||
| No | 7746 (62.9) | 3677 (63.0) | .47 |
| Yes | 4572 (37.1) | 2164 (37.0) | |
| Maternal folic acid intake a | |||
| No | 6124 (49.5) | 2883 (49.1) | .34 |
| Yes | 6259 (50.5) | 2986 (50.9) | |
| Plurality | |||
| Singleton | 11,593 (93.7) | 5689 (97.0) | < .001 |
| Multiple | 775 (6.3) | 174 (3.0) | |
| Parity | |||
| No previous live births | 5344 (43.2) | 2352 (40.1) | < .001 |
| ≥1 previous live birth | 7034 (56.8) | 3514 (59.9) | |
| Pregnancy intended | |||
| No | 4448 (43.4) | 1933 (40.7) | .001 |
| Yes | 5800 (56.6) | 2821 (59.3) | |
| Exposure to bupropion b | |||
| No | 11,733 (99.5) | 5626 (99.5) | .27 |
| Yes | 64 (0.5) | 26 (0.5) | |
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