Maternal use of bupropion and risk for congenital heart defects

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OBSTETRICS
Maternal use of bupropion and risk
for congenital heart defects
Sura Alwan, MSc; Jennita Reefhuis, PhD; Lorenzo D. Botto, MD; Sonja A. Rasmussen, MD, MS;
Adolfo Correa, MD, MPH; Jan M. Friedman, MD, PhD; and the National Birth Defects Prevention Study
OBJECTIVE: We sought to determine if maternal bupropion treatment in
fants (adjusted odds ratio, 2.6; 95% confidence interval, 1.2–5.7; P ϭ early pregnancy is associated with congenital heart defects in the infant.
STUDY DESIGN: We conducted a retrospective case-control study of
CONCLUSION: We identified a positive association between early preg-
birth defects risk factors. Data on 6853 infants with major heart defects nancy bupropion use and left outflow tract heart defects; however, the were compared with 5869 control infants born in 1997–2004. Bupro- magnitude of the observed increased risk was small. Nevertheless, fur- pion exposure was defined as any reported use between 1 month be- ther studies are needed to confirm these results.
RESULTS: Mothers of infants with left outflow tract heart defects were
Key words: birth defects, bupropion exposure, congenital heart more likely to have reported taking bupropion than mothers of control in- Cite this article as: Alwan S, Reefhuis J, Botto LD, et al. Maternal use of bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010;202:x.ex-x.ex.
Bupropionisanaminoketonethatis they become It is, therefore, registry. These included 651 live births
without birth defects, 18 live births with birth defects, 1 fetal death with a birth market. It is a weak inhibitor of neuronal lead to incomplete or biased reporting of ital anomalies had been reported in 24 of in the first trimester and reported to the time after birth, and the registry did notcollect data on a comparison group. Theregistry also received retrospective noti- From the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada (Ms Alwan and Dr Friedman); the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, 28 retrospectively reported birth defects GA (Drs Reefhuis, Rasmussen, and Correa); and the Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT (Dr Botto).
Presented at the 49th Annual Meeting of the Teratology Society in Rio Grande, Puerto Rico, June27–July 1, 2009, and at the 25th International Conference of Pharmacoepidemiology and Therapeutic Risk Management in Providence, Rhode Island, August 16-19, 2009.
Received Oct. 9, 2009; revised Dec. 10, 2009; accepted Feb. 8, 2010.
Reprints: Jennita Reefhuis, PhD, National Center on Birth Defects and Developmental Disabilities, the possibility of an association between Centers for Disease Control and Prevention, 1600 Clifton Rd., MS E-86, Atlanta, GA 30333.
nancy and congenital heart defects in the The National Birth Defects Prevention Study is funded by the Centers for Disease Control and turer to undertake a retrospective cohort The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
0002-9378/$36.00 • 2010 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2010.02.015 MONTH 2010 American Journal of Obstetrics & Gynecology
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Fisher’s exact confidence limits were cal- infants in each birth defect category was nal age (Ͻ35, Ն35 years), maternal race sure status by clinical geneticists. In ad- posure status by a team of experts in pe- heart defects, and each case was assigned sure in early pregnancy is associated with Ն1 selected category of congenital heart types of heart defects were included in family income (Ͻ$20,000, Ն$20,000),defects in the infant. We also carried out fancy, very rare, often related to preterm heart, or heart defects that were associ- the logistic regression if their removal re- ATERIALS AND METHODS
cluded in the final models for all defects.
genetic risk factors for Ͼ30 selected cat- type 1 or 2 diabetes (304 case and 32 con- justed analyses because of the strong as- sociation of diabetes with birth defects.
born on or after Oct. 1, 1997, who had an met the inclusion criterion of at least 3 live births (all participating sites), fetal deaths Ͼ20 weeks’ gestation (Arkansas, not they took any of a list of medications, Carolina, Texas, and Utah), or electively 12,383 case infants (including 6853 diag- nosed with at least 1 of the selected heart during their pregnancy were excluded.
hospital or vital records. Only 1 case or son ␹2 tests, and odds ratios (ORs) and 1.e2 American Journal of Obstetrics & Gynecology MONTH 2010
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sented in Mothers of case infantswere significantly more likely to be older, TABLE 1
Characteristics of mothers of case and control infants,
National Birth Defects Prevention Study 1997–2004
early in pregnancy, and have a lowerfamily income compared with mothers Bupropion
of control infants. Other characteristics, Mothers of
Mothers of
such as having type 1 or 2 diabetes prior case infants
control infants
to pregnancy, a multiple pregnancy, or at Characteristic
(n ؍ 12,383), n (%)
(n ؍ 5869), n (%)
␹2 P value
least 1 previous live birth were more fre- (which fell within 4 major categories) in- Maternal smoking in the period of 1 mo before to 3 mo after conception a left outflow tract heart defect in the in- 1.2–5.7). The main diagnoses assigned to Maternal alcohol intake in the period of 1 mo before to 3 mo after conception the aorta in 5 cases (1 of which also had features of a hypoplastic left heart vari- ant), hypoplastic left heart syndrome in 3 cases, and aortic stenosis in 2 cases. Out of the 10 exposed cases with left outflow tract defects, 7 were isolated cardiovas- cular defects, 2 also had multiple noncar- of the cervical facial region; A, Arterial defects, aortic coarctation and other aor- Alwan. Bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010. tic abnormalities; E, Eye Mothers of all 10 cases reported takingWellbutrin. None of these 10 mothers MONTH 2010 American Journal of Obstetrics & Gynecology
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Characteristics of mothers of case and control infants, National
Birth Defects Prevention Study 1997–2004 (continued)
Bupropion
Mothers of
Mothers of
case infants
control infants
sociations of any congenital heart defect Characteristic
(n ؍ 12,383), n (%)
(n ؍ 5869), n (%)
␹2 P value
1.4; 95% CI, 0.8 –2.5; n ϭ 34). Likewise, a Use at any time between 1 month before and 1 month after conception; b Exposure to bupropion was defined as reported use at any time between 1 month before to 3 months after conception—women were considered not to have been exposed if theydid not take an antidepressant at any time from 3 months before conception and through the end of pregnancy.
Alwan. Bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010. A relatively large number of cases withcongenital heart defects among mothers the other) in the first trimester. Limiting though 2 also reported use of other anti- genesis is most likely to be susceptible to in 1 case and fluoxetine and sertraline in ence group was available to permitstatistical assessment of this observation,these results raised concern that mater- Associations of maternal bupropion use among infants
with various categories of heart defects, National
creased risk of congenital heart defects.
Birth Defects Prevention Study 1997–2004
Adjusted
case-control study to test this hypothesis.
Crude analysisa
analysisb
Heart defect (n)
Exposed (n)
OR (95% CI)
OR (95% CI)
tract heart defects but not among infants All groups of heart defects in NBDPS (6853) propion exposure and the risk for several .
ASD, atrial septal defects; CI, confidence interval; NBDPS, National Birth Defects Prevention Study; nos, not otherwise specified; OR, odds ratio; VSD, ventricular septal defects.
a Fisher’s exact CI; b Adjusted for maternal race, obesity, smoking, and family income— cases and controls with preexisting type 1 or 2 diabetes in the mother were excluded.
Alwan. Bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010. 1.e4 American Journal of Obstetrics & Gynecology MONTH 2010
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TABLE 3
Associations of maternal bupropion use among infants with various categories of birth
defects not involving the heart, National Birth Defects Prevention Study 1997–2004
Crude analysisa
Adjusted
analysisb
Controlsc
No. of exposed
Birth defect (n)
(no. exposed)
OR (95% CI)
OR (95% CI)
Hypospadias, second or third degree (1147) .
CI, confidence interval; OR, odds ratio.
a Fisher’s exact CI; b Adjusted for maternal race, obesity, smoking, and family income— cases and controls with preexisting type 1 or 2 diabetes in the mother were excluded; c Number of controls is different for oral clefts and hypospadias, because data on oral clefts from Utah in 2003 were not available and only male control infants were included for infants with hypospadias.
Alwan. Bupropion and risk for congenital heart defects. Am J Obstet Gynecol 2010. pressants during the first trimester in the ranted before inferences about a possible heart defects, which are estimated to ac- sibility that the association we observed with left outflow tract heart defects is ac- of confidence. Even if there were a 2-fold tually related to depression, rather than increased risk for left outflow tract heart defects, the absolute risk of a cardiovas- 1.0 –10.6), a value similar to that ob- ever, the fact that previous studies of ma- during the first trimester would be low.
Based on an estimated prevalence for left defects was not reported for any of the 10 pion early in pregnancy in our study. Fa- were unable to evaluate a potential dose- defects has been suggested in the litera- bupropion treatment of 2.1/1000 births.
in their etiology. Of course, this does not other sources, so the influence of recall bias on the results is difficult to assess.
factors as well in a complex and probably propion prescriptions in the first trimes- cleft lip with or without cleft palate, cleft palate alone, second- or third-degree hy- the first trimester. Five of the 13 infants left outflow tract heart defects suggests a possible doubling of risk over baseline if with other major birth defects in the ret- MONTH 2010 American Journal of Obstetrics & Gynecology
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ACKNOWLEDGMENTS
12. Frieden IJ, Reese V, Cohen D. PHACE syn-
We are grateful to all of the families participating drome: the association of posterior fossa brainmalformations, hemangiomas, arterial anoma- in the NBDPS and to all NBDPS investigators.
Coding of drug information in the NBDPS uti- lies, coarctation of the aorta and cardiac de- lized the Slone Drug Dictionary, under license fects, and eye abnormalities. Arch Dermatol from the Slone Epidemiology Center at Boston 13. Alwan S, Reefhuis J, Rasmussen SA, Olney
RS, Friedman JM; National Birth Defects Pre-
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