Antidepressant
PREGNANCY RECOMMENDATION: Limited Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The animal and most of the human data suggest low risk. Although increased rates of heart defects were reported in two studies, this outcome has not been confirmed by other studies. One study found a strong association between bupropion use in pregnancy and attention deficit/hyperactivity disorder (ADHD) in offspring, but cigarette smoking was a potential confounder. Additional research is required to clarify this risk. If a woman requires bupropion, she should be informed of the potential risks, but the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Bupropion is a unique antidepressant of the aminoketone class that differs from other antidepressants in that it does not inhibit monoamine oxidase and does not alter the reuptake of norepinephrine or serotonin. Anticholinergic effects are much less frequent and less severe than those observed with other antidepressants. The drug is extensively metabolized with three active metabolites, but the antidepressant activity has not been fully characterized. Plasma protein binding of bupropion and one metabolite is 84%, whereas the binding of a second active metabolite is about half that of bupropion. The elimination half-lives of the three active metabolites range from 20 to 37 hours (1).
Reproduction studies in rats and rabbits at doses up to about 7–11 times the maximum recommended human dose based on BSA (MRHD) revealed no clear evidence of impaired fertility or fetal harm. However, in rabbits, a slight increase in the incidence of fetal malformations and a reduction in fetal weight was observed at doses ≥MRHD (2).
Bupropion caused an increase in nodular proliferative lesions of the liver in rats, but not mice, in lifetime carcinogenicity studies. No increase in malignant tumors of the liver or other organs was observed in either species. Bupropion was mutagenic in one test. In rats, a dose about 11 times the MRHD caused chromosomal aberrations (2).
Consistent with its molecular weight (about 240 for the free base), bupropion crosses the human placenta. In a 2010 report, healthy term placentas were used to determine the transplacental transfer and metabolism of bupropion (3). Following a 4-hour infusion, the amounts of bupropion in the maternal and fetal circulations and in the placenta were 32%, 20%, and 48%, respectively. The amount retained by the placenta was metabolized to threohydrobupropion, one of the active metabolites. The ratio of metabolite to parent compound in the three sites was 0.08, 0.07, and 0.06, respectively (3). In a second report from these investigators, it was found that the placenta metabolized bupropion to all three active metabolites (4). Human placental 11β-hydroxysteroid dehydrogenase was the primary enzyme involved, but CYP2B6 also had activity. Significantly higher amounts of the three active metabolites were measured in the placentas of women who smoked ≥20 cigarettes/day compared with those who smoked ≤10 cigarettes/day and nonsmokers (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, three newborns had been exposed to bupropion during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (none expected).
A prospective comparative study in 136 women exposed to bupropion (for depression or smoking cessation) was published in 2005 (5). The pregnancy outcomes of 105 live births included no major malformations, mean birth weight of 3450 g, mean gestational age of 40 weeks, 20 spontaneous abortions (SABs), 10 elective abortions (EABs), and 1 stillbirth. There also was one neonatal death after delivery at 22 weeks because of abruptio placenta. Compared with nonteratogen-exposed controls, only the number of SABs (14.7% vs. 4.5%; p = 0.009) and EABs (7.4% vs. 0.75%; p = 0.015) were significantly increased. In a subanalysis, there were no significant differences when women taking bupropion for depression (N = 91) were compared with a group using other antidepressants and a nonteratogen exposed group (5).
A 2005 meta-analysis of seven prospective comparative cohort studies involving 1774 patients was conducted to quantify the relationship between seven newer antidepressants and major malformations (6). The antidepressants were bupropion, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, and trazodone. There was no statistical increase in the risk of major birth defects above the baseline of 1%–3% in the general population for the individual or combined studies (6).
The final report of the Bupropion Pregnancy Registry, covering the period September 1, 1997, through March 31, 2008, was issued in August 2008 (7). The Registry was closed to new enrollments on November 1, 2007. The Registry prospectively (before the pregnancy outcome was known) enrolled 1597 pregnancies exposed to bupropion. Among these cases, 31 were still pregnant, 572 were lost to follow-up, and there were 1005 known outcomes (includes 9 sets of twins and 1 set of triplets). The number of outcomes involving earliest exposure in the 1st, 2nd, or 3rd trimester were 806, 147, and 52, respectively. The outcomes of those with earliest exposure in the 1st trimester included 651 live births without defects, 96 SABs, 33 EABs, and 2 fetal deaths, and outcomes with defects included 18 live births, 5 EABs, and 1 fetal death. For earliest exposure in the 2nd trimester, outcomes without reported defects were 142 live births, 1 SAB, and 1 EAB, and outcomes with defects 3 live births. Among exposures in the 3rd trimester, there were no defects in 51 live births and 1 fetal death. After excluding EABs and fetal deaths without known defects and all SABs, the proportion of birth defects with earliest exposure in the 1st trimester was 3.6% (95% confidence interval [CI] 2.3–5.3). The proportion of birth defects with earliest exposure in the 2nd trimester was 2.1% (95% CI 0.5–6.4) (7).
There were 28 outcomes, 25 with earliest exposure in the 1st trimester, with birth defects reported retrospectively (after the pregnancy outcome was known) (7). Although retrospective reports are usually biased, reporting adverse outcomes and not normal infants, nine of the defects involved the heart and great vessels. The Registry has noted the increased number of cardiac defects in the prospective and retrospective groups. However, the relatively small sample size, the potential bias from the large percentage of cases lost to follow-up, and the incomplete descriptions of the defects prevented determining if the data reflect a potential drug effect on the developing cardiovascular system (7).
Required statement: Committee consensus. After reviewing the 1005 prospectively reported pregnancy outcomes, the Bupropion Pregnancy Registry Advisory Committee concludes the Registry has successfully met its primary purpose which was to exclude a major teratogenic effect in pregnancies inadvertently or intentionally exposed to any formulation of bupropion. The Registry was not designed to exclude an increase in the risk of specific defects (5).
A study published in 2007 was conducted to determine if bupropion exposure in the 1st trimester was associated with congenital malformations (8). Using data collected in 1995–2004, the prevalence of structural defects in 1213 infants exposed to bupropion in the 1st trimester was compared with 4743 infants exposed to other antidepressants and to 1049 infants exposed to bupropion after the 1st trimester. For all congenital anomalies, the prevalence in the 1st trimester bupropion group was 23.1/1000 infants, adjusted odds ratio (AOR) 0.95 (95% CI 0.62–1.45) and 1.00 (95% CI 0.57–1.73) in comparison to other antidepressants (prevalence 23.2/1000) and bupropion exposure after the 1st trimester (prevalence 21.9/1000), respectively. For cardiovascular anomalies, the prevalence for 1st trimester bupropion exposure was 10.7/1000, AOR 0.97 (95% CI 0.52–1.80) and 1.07 (95% CI 0.48–2.40) compared with other antidepressants (prevalence 10.8/1000) and bupropion exposure after the 1st trimester (prevalence 9.5/1000), respectively. The results did not support a hypothesis of a teratogenic effect of 1st trimester exposure to bupropion (8).
A prospective cohort study evaluated a large group of pregnancies exposed to antidepressants in the 1st trimester to determine if there was an association with major malformations (9). The patient population came from the Motherisk database and involved 928 cases that met their criteria. The 928 matched (for age, smoking, and alcohol use) controls were pregnancies not exposed to antidepressants or known teratogens. In addition to the 113 bupropion cases, the other cases were 184 citalopram, 21 escitalopram, 61 fluoxetine, 52 fluvoxamine, 68 mirtazapine, 39 nefazodone, 148 paroxetine, 61 sertraline, 17 trazodone, and 154 venlafaxine. In the antidepressant group, there were 24 (2.5%) major defects compared with 25 (2.6%) in controls (odds ratio [OR] 0.9, 95% CI 0.5–1.61). There were no major defects in the pregnancies exposed to bupropion, escitalopram, or trazodone (9).
A National Birth Defects Prevention Study to determine if bupropion was associated with congenital heart defects was published in 2010 (10). The retrospective case–control study compared 6853 infants with major heart defects with 5869 control infants. Bupropion exposure was defined as any reported use between 1 month before and 3 months after conception. Case infants were more likely to have left outflow tract defects than control infants (OR 2.6, 95% CI 1.2–5.7). The authors noted that additional studies were required to confirm their results (10).
Another study published in 2010 found a significant association between bupropion use in pregnancy and ADHD in offspring (11). A claims-based dataset was used to identify 431 (1.13%) children, from 38,074 families, who had a diagnosis or treatment for ADHD at or before 5 years of age. The average maternal age at delivery was 31 years. Maternal age was not associated with ADHD in offspring, but male children were more likely to have ADHD (OR 2.79, p <0.001). Significant associations were found between the presence of ADHD in children and a diagnosis of ADHD in the mother (OR 4.15, p <0.001) or father (OR 3.54, p <0.001). This finding was consistent with the known strong inheritance of the disorder. Significant associations with ADHD in offspring were also found for the mother, but not the father, for diagnosis of bipolar disorder (OR 5.08, p <0.001), psychotic disorder (OR 4.05, p = 0.02), or depression (OR 2.58, p <0.001). Exposure to bupropion, especially in the 2nd trimester (OR 14.66, p <0.001) was associated with ADHD in children, but selective serotonin reuptake inhibitors (SSRIs) were not (OR 0.91, p = 0.74). Because cigarette smoking during pregnancy has been related to ADHD (see also Cigarette Smoking) and bupropion is used in smoking cessation programs, the author noted that this was a potential confounder. Women taking bupropion before or after pregnancy did not have a higher risk for having children with ADHD (11).
BREASTFEEDING SUMMARY
Bupropion is excreted into breast milk. A 37-year-old lactating woman was treated with 100 mg of bupropion 3 times daily (12). She was nursing her 14-month-old infant twice daily at times corresponding to 9.5 and 7.5 hours after a dose. Peak milk concentrations of bupropion occurred 2 hours after a 100-mg dose with a value of 0.189 mcg/mL, but the peak plasma level measured, 0.072 mcg/mL, occurred at 1 hour. The milk:plasma (M:P) ratios at 0, 1, 2, 4, and 6 hours after a dose were 7.37, 2.49, 4.31, 8.72, and 6.24, respectively. Two metabolites, hydroxybupropion and threohydrobupropion, were also measured with peak concentrations of both occurring at 2 hours in milk and plasma. The milk concentration ranges for the two metabolites were milk levels 0.093–0.132 and 0.366–0.443 mcg/mL, respectively, whereas the M:P ratios were 0.09–0.11 and 1.23–1.57, respectively. The levels of a third metabolite, erythrohydrobupropion, were too low to be measured in breast milk (test sensitivity 0.02 mcg/mL). No adverse effects were observed in the infant nor was any drug or metabolite found in his plasma, an indication that accumulation had not occurred (12).
Two breastfeeding mothers, one at 15 weeks after birth and the other at 29 weeks, were being treated with bupropion, 75 mg twice daily and sustained release (SR) 150 mg daily, respectively (13). The drug was at steady state in both mothers. Neither bupropion nor its metabolite (hydroxybupropion) was detectable in the infants. No adverse effects were observed in the infants (13).
A 2004 report described the excretion of bupropion and its three active metabolites into breast milk in 10 mothers an average 12.5 months after birth (14). The average weight of the mothers was 59.4 kg. All had stopped breastfeeding and none had taken bupropion before the study. The dose during the study was SR 150 mg/day for 3 days, then SR 300 mg/day for 4 days, and samples were collected on day 7. Milk samples were collected with an electric breast pump. The calculated average bupropion dose in milk, based on 150 mL/kg/day, was 6.75 mcg/kg/day or 0.14% of the mother’s weight-adjusted dose. The average M:P ratios of bupropion and the three active metabolites (hydroxybupropion, erythrohydrobupropion, and threohydrobupropion) were 2.8, 0.1, 0.9, and 1.2, respectively. The estimated daily infant doses of the metabolites were 15.75, 10.80, and 68.85 mcg/kg/day, respectively (14).
Seizures were reported in a 6-month-old breastfeeding infant whose mother had just started SR bupropion 150 mg/day (15). The 31-year-old mother, a pediatrician, had taken the agent for depression before pregnancy but had discontinued it before conception. She continued off the drug throughout pregnancy and while nursing her female infant. At 6 months postpartum, she restarted bupropion because of increasing depression. She had taken two doses, about 36 hours apart, when about 72 hours after the first dose she observed the infant arching her back, rolling her eyes, and smacking her lips for about 10–15 seconds. The mother thought the infant was having a seizure. Following this event, the mother observed a 5–10 minute postictal state that included staring and nonresponsiveness. Later examination of the infant at a specialty pediatric seizure clinic revealed a normal physical examination and laboratory tests, as well as an unremarkable electroencephalogram. Neither infant nor maternal bupropion levels were obtained. The mother stopped the drug and continued to nurse with no further seizure activity noted over the next 6 weeks. Because rare seizures have occurred in adults taking the antidepressant, the seizures were attributed to the drug (15).
A 2009 report described bupropion concentrations, but not of metabolites, in the breast milk, serum, and urine of four nursing mothers taking SR 150–300 mg/day at steady state (16). The samples were collected a mean 13 days after birth. The mean peak and trough milk concentrations were 64.1 and 9.2 ng/mL, respectively, whereas the mean M:P ratio was 1.3. Infant serum levels were not checked. In two infants, urine levels of bupropion were not detected (<10 ng/mL) but, in a third infant, born 5.5 weeks prematurely, the bupropion concentration was 41.0 ng/mL. The mean infant dose as a percentage of the mother’s weight-adjusted dose was 5.7% (16).
The elevated (>1) M:P ratios for bupropion in the three studies above are consistent with the accumulation in milk observed with weak bases (i.e., ion-trapping). A 1996 review of antidepressant treatment during breastfeeding found no information that bupropion exposure during nursing resulted in quantifiable amounts in an infant or that the exposure caused adverse effects (17). The case above that observed seizures may or may not have been related to bupropion. The reported experience in breastfeeding mothers taking bupropion is too limited to determine the relationship. Nevertheless, nursing mothers and their caregivers should be aware of this possible complication. The American Academy of Pediatrics classifies bupropion as a drug whose effect on the nursing infant is unknown but may be of concern (18).
References
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