GSK Medicine: Study Number: Title: Rationale: Study Period: Objectives: Indication: Study Investigators/Centers: Data Source:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Bupropion Study Number:WWE Title: EPIDEMIOLOGY STUDY: First Trimester Exposure to Bupropion in Relation to the Risk of Cardiac Defects Rationale: Bupropion is a unique drug that is used both to treat depression and as an aid in smoking cessation. In 2008, the final report from the GlaxoSmithKline Bupropion Pregnancy Registry described 24 congenital malformations among the 675 women exposed to bupropion in the first trimester of pregnancy, which is the period that is relevant for the development of most birth defects. Of these, 9 had congenital heart disease of varying severity, including a number of infants with ventricular septal defects (VSDs); of note, 2 of these 9 had coarctation of the aorta. While the number of affected infants was small, the distribution of defects appeared unusual; although cardiac malformations occur in the general population at a frequency of approximately 1%, coarctation is quite rare, occurring in only about 6 per 10,000 births. More recently, an analysis of data from the Centers for Disease Control and Prevention s case-control National Birth Defects Prevention Study (NBDPS), found no association with non-muscular VSDs but reported an increased risk of left outflow tract heart defects, a subgroup of cardiac malformations that includes coarctation of the aorta and hypoplastic left heart syndrome (Alwan et al, 2010). At the request of GlaxoSmithKline, an analysis of data from the Slone Epidemiology Center (SEC) Birth Defects Study (BDS) was undertaken. Study Period: 15 July 2011 to 11 July 2012 Objectives: The outcomes of primary interest were those evaluated for association with bupropion in recent studies. Specifically, these were certain cardiac defects including VSD and left outflow tract heart defects considered as a group: coarctation of the aorta, and hypoplastic left heart syndrome. Secondary analyses assessed possible risks related to other heart defect classes where numbers were sufficient. Indication: All bupropion exposures independent of indication. Study Investigators/Centers: Slone Epidemiology Center at Boston University Data Source: The BDS is a multi-center program of case-control surveillance for birth defects that has been in operation since It provides a resource both for the identification of previously unsuspected associations and for the testing of hypotheses regarding medications and other environmental agents. Study Design: Case-control Study Population:Infants with any of a wide range of malformations are identified at study centers that include the areas surrounding Boston, Philadelphia, Toronto (through 2003), and San Diego (since 2000), as well as a portion of New York State (since 2004) and the entire state of Massachusetts (since 1998). Research staff in Philadelphia, Toronto, and San Diego identified malformed subjects by reviewing hospital admission and discharge lists. Malformed subjects in New York and, since 1998, in Massachusetts, were identified from state-wide birth-defect registries. Infants with isolated minor defects were excluded; for example, accessory nipple, dislocatable hip, low set ears, and skin tag were all excluded, as were minor isolated cardiac defects such as heart murmur, patent ductus arteriosus in premature infants and patent foramen ovale in premature infants. Information gathered on each subject includes name, address, telephone number, diagnostic information, and date of birth. Beginning in 1992, the BDS also systematically enrolled mothers of non-malformed infants; initially these infants were identified exclusively at study hospitals, but in 1998, BDS further enhanced inclusion of normal newborns by enrolling a population-based random sample of newborns in Massachusetts. The current analysis was restricted to women interviewed after February, 1993, the date that corresponds to implementation of a new version of the questionnaire, and includes interviews through December These dates correspond approximately to dates of last menstrual period (LMP) of Study Exposures, Outcomes: The interview was conducted by trained nurses unaware of study hypotheses. The interview, lasted minutes, addressed demographic, reproductive, and medical factors; health behaviors such as cigarette smoking, alcohol, and caffeine consumption; occupational exposures; and dietary intake. It also collected detailed data on all medications (prescription, over-the-counter, vaccines, vitamins/minerals, and herbal products) used anytime from two months prior to conception through the pregnancy. Information on drug exposures was obtained via a series of questions increasing in specificity. Women were first asked about any of a list of illnesses that they may have experienced during pregnancy and about any medications they may have used to treat those conditions. This was followed by a list of conditions other than these illnesses that may trigger drug use. Relevant to the present analysis, anxiety, depression, other psychological conditions, and to help stop smoking were included in these lists. The women were then asked about specific medications by name. This list included: Prozac, Zoloft, Paxil, Effexor, Elavil, Celexa, Luvox, Lexapro, Wellbutrin, and Zyban. 1

2 The etiologically relevant time period for the defects under study is the first trimester, and for this analysis exposures occurring between 28 days prior to the LMP through the fourth lunar month (LM) were included. Whereas bupropion, whether used as an antidepressant or for smoking cessation, is the focus of this analysis, the effects of other antidepressants were also considered to assess confounding by indication. Seven non-mutually exclusive exposure groups, all relating to first trimester exposure only, were created: 1) Any exposure to bupropion in the first trimester ( any bupropion ). 2) Exposure to bupropion alone among antidepressants ( bupropion alone ) 3) Exposure to bupropion in combination with another antidepressant ( bupropion and other ) 4) Exposure to an antidepressant other than bupropion ( any other antidepressant ) 5) Exposure to an SSRI antidepressant with or without other antidepressants ( SSRI ) 6) Exposure to tricyclic antidepressants with or without other antidepressants ( TCA ) 7) Exposure to an antidepressant other than bupropion, an SSRI, or a TCA ( other antidepressant ) The reference group for all exposure groups was the same in all analyses: women who had no exposure to any antidepressant at any time from 56 days prior to LMP through the end of pregnancy. The no exposure definition included an additional 28 days (28-56 days prior to LMP) to avoid potential misclassification and to insure that women with depression treated immediately prior to pregnancy were excluded. Women with exposure to any antidepressant outside of the first trimester window and women who reported a drug not classified as an antidepressant for the indication depression were excluded from all analyses (205 and 47 women respectively). Data Analysis Methods: Data were analyzed using SAS version 9.2. Odds ratios and 95% confidence intervals (CI) were calculated separately for each exposure and outcome. When there were fewer than 5 exposed cases, exact confidence intervals were calculated. To assess confounding, the following potential risk factors were evaluated: maternal age; maternal race; maternal education; LMP year; study center; smoking history; alcohol consumption; family history of any birth defect; family history of any cardiac defect in a first degree relative; pre-pregnant body mass index (BMI); gravidity; history of seizures, diabetes mellitus, or hypertension; infertility; and periconceptional folic acid use. Each factor was evaluated for the effect on the crude association and a final model was constructed for each outcome group. All factors that changed the effect estimate by 10% or more were included in the model. If fewer than two factors met this condition, the two factors that had the greatest effect were included in the model. Limitations: It is important that testing of these possible signals include assessment of factors that may act as potential confounders or risk modifiers. Factors that will be considered in the analyses include: sociodemographic characteristics, alcohol consumption, smoking, caffeine consumption, and use of other medications, including both prescription and over-the-counter drugs. Because patterns of smoking, alcohol, and caffeine consumption may change once a pregnancy is recognized, data are collected on these factors both before and after the date a woman recognizes her pregnancy and consider the pattern in effect at the etiologically relevant time considered. This information is gathered using a set of questions that elicit exposure (reported as amount, e.g. number of cigarettes) in the two months preceding the LMP, after the woman knew she was pregnant, and the date of the change in pattern. Women may report any number of changes in pattern. For alcohol consumption, we also obtain the type of alcohol consumed (wine, beer, liquor), and the maximum number of drinks consumed on any single day are also obtained. A major consideration in assessing effects of bupropion in pregnancy is the possibility that the effects observed are due not to the medication but to the condition for which the medication was prescribed. In the case of bupropion, these indications include depression and smoking cessation. Study Results: No statistically significant increase of left outflow tract heart defects with maternal bupropion use (n=2; adjusted OR= 0.4; 95% CI 0.1, 1.6). However, a statistically significant association was observed for ventricular septal defects (n=17; adjusted OR=2.5; 95% CI 1.3, 5.0) following the use of bupropion alone during the first trimester. 2

3 Demographics/Baseline Characteristics Total N Study Group Cases 2,734 infants with VSD, 1,233 with any left-sided cardiac defect, 476 with coarctation of the aorta, 286 with hypoplastic left heart syndrome, and 3,184 with other cardiac defects. Comparison Group Controls 8,611 nonmalformed infants 3

4 Primary and Secondary Outcome(s) Table 1. Ventricular Septal Defect in Relation to First Trimester Bupropion Use. Slone Epidemiology Center Birth Defects Study, VSD (n=2,704) Any Antidepressant 133 (4.9) 1.2 (0.9, 1.4) 1.3 (1.0, 1.6) a Any Bupropion 23 (0.9) 1.9 (1.1, 3.2) 1.6 (1.0, 2.8) b Bupropion Alone 17 (0.7) 2.9 (1.5, 5.5) 2.5 (1.3, 5.0) b Bupropion in Combination 6 (0.2) 1.0 (0.4, 2.4) 0.9 (0.4, 2.2) c Any Other Antidepressant 116 (4.3) 1.1 (0.9, 1.3) 1.2 (0.9, 1.5) a SSRI 102 (3.8) 1.1 (0.9, 1.4) 1.3 (1.0, 1.6) a TCA 8 (0.3) 0.8 (0.4, 1.7) 0.8 (0.4, 1.8) b Other Antidepressant 15 (0.6) 0.98 (0.6, 1.8) 0.9 (0.5, 1.6) d a Study center and race b Study center and family history of birth defects c Family history of birth defects and race d Family history of birth defects and BMI 4

5 Table 2. Left-Sided Cardiac Defects in Relation to First Trimester Bupropion Use. Left-Sided Defects (n=1,220) Any Antidepressant 61 (5.0) 1.2 (0.9, 1.6) 1.4 (1.1, 1.9) a Any Bupropion 2 (0.2) 0.7 (0.0, 1.4) 0.4 (0.1, 1.6) b * Bupropion Alone 1 (0.1) 0.4 (0.0, 2.4) 0.5 (0.1, 3.4) a * Bupropion in Combination 1 (0.1) 0.4 (0.0, 2.3) 0.3 (0.0, 2.0) b Any Other Antidepressant 60 (4.9) 1.2 (0.9, 1.6) 1.4 (1.1, 1.9) a SSRI 48 (4.0) 1.2 (0.9, 1.6) 1.4 (1.0, 1.9) a TCA 3 (0.3) 0.7 (0.1, 2.1) 0.7 (0.2, 2.3) c* Other Antidepressant 14 (1.2) 2.0 (1.1, 3.7) 2.0 (1.1, 3.8) d b LMP year and family history of birth defects c LMP year, family history of birth defects, and study center d Study center and family history of birth defects 5

6 Table 3. Coarctation of the Aorta in Relation to First Trimester Bupropion Use. Coarctation of the Aorta (n=471) Any Antidepressant 29 (6.2) 1.5 (1.0, 2.2) 1.9 (1.3, 2.8) a Any Bupropion 0 (0) Bupropion Alone 0 (0) Bupropion in Combination 0 (0) Any Other Antidepressant 29 (6.2) 1.5 (1.0, 2.3) 2.0 (1.3, 2.9) a SSRI 22 (4.7) 1.4 (0.9, 2.2) 1.8 (1.2, 2.9) a TCA 2 (0.5) 1.2 (0.1, 4.6) 1.3 (0.3, 5.5) b * Other Antidepressant 6 (1.3) 2.3 (1.0, 5.4) 2.9 (1.3, 6.8) a b LMP year, family history of birth defects, and study center 6

7 Table 4. Hypoplastic Left Heart Syndrome in Relation to First Trimester Bupropion Use. Hypoplastic Left Heart Syndrome (n=281) Any Antidepressant 10 (3.6) 0.8 (0.4, 1.6) 1.0 (0.5, 2.0) a Any Bupropion 1 (0.4) 0.8 (0.0, 4.6) 0.8 (0.0, 4.6) b Bupropion Alone 1 (0.4) 1.6 (0.0, 10.1) 2.0 (0.3, 15.3) a * Bupropion in Combination 0 (0) Any Other Antidepressant 9 (3.2) 0.8 (0.5, 1.6) 1.0 (0.5, 1.9) a SSRI 8 (2.9) 0.8 (0.4, 1.7) 1.1 (0.5, 2.2) a TCA 1 (0.4) 1.0 (0.0, 5.7) 0.9 (0.1, 7.1) c * Other Antidepressant 1 (0.4) 0.6 (0.0, 3.7) 0.6 (0.1, 4.5) d * b LMP year and family history of birth defects c LMP year, family history of birth defects, and study center d Family history of birth defects and mother s age 7

8 Table 5. Conotruncal and Major Arch Anomalies in Relation to First Trimester Bupropion Use Conotruncal / Major Arch Anomalies (n=1,424) Any Antidepressant 78 (5.5) 1.3 (1.0, 1.7) 1.6 (1.2, 2.0) a Any Bupropion 8 (0.6) 1.3 (0.6, 2.7) 1.4 (0.6, 3.0) b Bupropion Alone 6 (0.4) 1.9 (0.8, 4.9) 2.3 (0.9, 5.8) a Bupropion in Combination 2 (0.1) 0.6 (0.1, 2.5) 0.6 (0.1, 2.6) c * Any Other Antidepressant 72 (5.1) 1.3 (1.0, 1.6) 1.5 (1.2, 2.0) a SSRI 61 (4.3) 1.3 (1.0, 1.7) 1.6 (1.2, 2.1) a TCA 5 (0.4) 1.0 (0.4, 2.5) 1.05 (0.4, 2.7) d Other Antidepressant 9 (0.7) 1.1 (0.6, 2.3) 1.1 (0.6, 2.3) b c LMP year and family history of birth defects d LMP year, family history of birth defects, and study center b LMP year and smoking history 8

9 Table 6. Atrial Septal Defects in Relation to First Trimester Bupropion Use. Atrial Septal Defects (n=1,142) Any Antidepressant 53 (4.6) 1.1 (0.8, 1.5) 1.2 (0.9, 1.7) a Any Bupropion 3 (0.3) 0.6 (0.1, 1.9) 0.7 (0.2, 2.2) a * Bupropion Alone 2 (0.2) 0.8 (0.1, 3.3) 1.1 (0.2, 4.6) a * Bupropion in Combination 1 (0.1) 0.4 (0.0, 2.4) 0.4 (0.1, 2.7) b * Any Other Antidepressant 51 (4.5) 1.1 (0.8, 1.5) 1.2 (0.9, 1.7) a SSRI 42 (3.7) 1.1 (0.8, 1.5) 1.3 (0.9, 1.8) a TCA 6 (0.5) 1.4 (0.6, 3.4) 1.5 (0.6, 3.6) c Other Antidepressant 10 (0.9) 1.5 (0.8, 3.1) 1.3 (0.6, 2.3) d b LMP year and family history of birth defects c Study center and family history of birth defects d BMI and alcohol use 9

10 Table 7. Right-Sided Cardiac Defects in Relation to First Trimester Bupropion Use. Right-Sided Defects (n=1,042) Any Antidepressant 58 (5.6) 1.3 (1.0, 1.7) 1.6 (1.2, 2.1) a Any Bupropion 4 (0.4) 0.9 (0.2, 2.4) 1.0 (0.4, 2.9) a * Bupropion Alone 4 (0.4) 1.8 (0.4, 5.3) 2.2 (0.7, 6.6) a Bupropion in Combination 0 (0) Any Other Antidepressant 54 (5.2) 1.3 (1.0, 1.7) 1.6 (1.2, 2.1) a SSRI 47 (4.6) 1.4 (1.0, 1.9) 1.7 (1.2, 2.3) a TCA 3 (0.3) 0.8 (0.2, 2.5) 0.9 (0.3, 3.1) a * Other Antidepressant 8 (0.8) 1.4 (0.7, 2.9) 1.3 (0.6, 3.0) b b Study center and alcohol use 10

11 Table 8. AV Canal Defects in Relation to First Trimester Bupropion Use. No. Exposed (%) Crude Adjusted AV Canal Defects (n=521) Any Antidepressant 25 (4.8) 1.1 (0.7, 1.7) 1.3 (0.8, 1.9) a Any Bupropion 2 (0.4) 0.9 (0.1, 3.3) 0.9 (0.2, 3.6) b * Bupropion Alone 2 (0.4) 1.8 (0.2, 7.3) 2.0 (0.5, 8.8) c * Bupropion in Combination 0 (0) Any Other Antidepressant 23 (4.4) 1.1 (0.7, 1.7) 1.2 (0.8, 1.9) a SSRI 19 (3.7) 1.1 (0.7, 1.8) 1.3 (0.8, 2.0) a TCA 1 (0.2) 0.5 (0.0, 3.1) 0.7 (0.1, 4.8) a * Other Antidepressant 6 (1.2) 2.0 (0.9, 4.8) 1.9 (0.8, 4.5) d b LMP year and gravidity c LMP year, study center, and gravidity d LMP year and BMI 11

12 Conclusion: An elevated risk for VSD was observed for bupropion alone (OR=2.54, 95% CI 1.3, 5.0). It is unclear why an elevated risk for bupropion taken in combination with other antidepressants was not observed. The OR for bupropion alone in relation to hypoplastic left heart syndrome was also elevated (2.0), but this was based on only one exposed case and thus the confidence interval was large (0.3,15.3). There was no suggestion of increased risk for leftsided defects as a group, although there were only two bupropion-exposed cases. There were no exposed cases of coarctation of the aorta, whereas the expected, based on an exposure rate of 0.5% would have been 2 or 3. It is of note that use of antidepressants other than bupropion was associated with left-sided defects. This association was entirely due to an increased risk related to coarctation of the aorta. In secondary analyses, four other cardiac subgroups that had sufficient numbers of cases to permit analysis were considered. Among these, elevated ORs for bupropion were observed for right-sided defects (OR=2.2, based on 4 exposed cases) and for AV canal defects (2.0, based on 2 exposed cases), although for both the 95% confidence interval included 1.0 Several possible explanations for these results were considered including the possibility of confounding and other types of bias. With respect to confounding, a wide range of factors that are known to be or may be related to both exposure and outcome, including cigarette smoking, folic acid supplementation, and family history of cardiac defects were considered individually and did not change the effect estimate. Because there were few exposed cases in each outcome group, there was limited ability to consider multiple factors simultaneously. However, models were constructed that included at least two factors with the greatest impact on the odds ratio. The possibility of confounding by unmeasured factors remains a possibility. Recall bias, which would result if mothers of malformed infants search their memories more carefully and therefore more completely report exposures than mothers of nonmalformed infants, is an unlikely explanation for the observed increases in risk because these increases were restricted to specific antidepressants and specific outcomes. If recall bias accounted for these results, increased risks for many antidepressants in relation to many outcomes would be expected. Selection bias must also be considered. A particular concern in studies of birth defects is potential detection bias; in the case of antidepressants, it seems plausible that infants of anxious and/or depressed mothers might be scrutinized more carefully because of concerns on the part of the mother, physician, or nursing staff, and birth defects would thus be found or reported more frequently. However, for the severe defects considered in this analysis, such bias is unlikely because these will almost certainly be detected regardless of exposure status. While VSDs might in fact be differentially identified as a result of more careful examination, if that were the case, the expectation would be to see this association with other antidepressants as well as bupropion. It is of interest that in all of the comparisons, risk estimates for bupropion alone were higher than those observed for bupropion in combination with other antidepressants. These differences were often based on small numbers and were all statistically unstable. While chance can never be excluded, the consistency of this pattern is noteworthy. It was not explained by higher doses or differences in gestational timing in the bupropion-alone group. Another possible explanation for this phenomenon might be that women treated with bupropion alone are different in ways that are associated with an increased risk of cardiac defects. However, this scenario is highly unlikely, based on how antidepressants are prescribed. Thus there is no plausible explanation other than chance for this pattern. In summary, although the cardiac classification was very similar to that used by Alwan et al, a similarly increased risk for left-sided defects was not observed. The observed OR was below 1, based on two exposed cases and the confidence interval was wide, though it is of note that the upper bound excluded 3.5. For hypoplastic left heart syndrome there was 1 bupropion-exposed case resulting in an estimate that, while not markedly elevated, was too unstable to permit interpretation. For coarctation, the absence of exposed cases precluded risk estimation but it is noteworthy that 2-3 cases would have been expected. Based on larger numbers of exposed cases, an increased risk for VSD associated with first trimester bupropion use was found. As noted, Alwan et al did not observed an increased risk for VSD, but they excluded muscular VSDs, one of the more common types of VSD, from their study; however, this exclusion does not account for the differences between the current findings and theirs, since in the current study odds ratios were elevated for both muscular and non- muscular VSDs. References: Alwan S, Reefhuis J, Botto LD, Rasmussen SA, Correa A, Friedman JM. Maternal Use of Bupropion and Risk for Congenital Heart Defects. Am J Obstet Gynecol 2010;203:52.e1-6 12