Antidepressant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The animal and limited human data suggest that the risk for major malformations in the embryo is low. Studies for other aspects of developmental toxicity in the embryo–fetus, however, have not been conducted.
FETAL RISK SUMMARY
Trazodone is an antidepressant. At high doses in some animal species, trazodone is fetal toxic and teratogenic. However, others have reported no teratogenicity in rats and rabbits (1).
One manufacturer has received several anecdotal descriptions concerning the use of trazodone in pregnancy (T. Donosky, personal communication, Mead Johnson Pharmaceutical Division, 1987). Included in these was a report of an infant born with an undefined birth defect after in utero exposure to the antidepressant. Another report described a normal infant exposed throughout gestation beginning with the 5th week. No confirmatory follow-up information was available for either of these cases. A third case from the manufacturer’s files involved a woman who took trazodone, 50–100 mg/day, during the first 3 weeks of pregnancy and eventually delivered a normal infant. Finally, a woman was treated with trazodone for 8 days, at which time the drug was discontinued because of a positive pregnancy test. A spontaneous abortion occurred approximately 1.5 months later. No cause and effect relationship can be inferred between trazodone and any of the above adverse outcomes.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 100 newborns had been exposed to trazodone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (1%) major birth defect was observed (four expected), but details are not available. No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A prospective multicenter study evaluated the effects of lithium exposure during the 1st trimester in 148 women (2). One of the pregnancies was terminated at 16 weeks’ gestation because of a fetus with the rare congenital heart defect, Ebstein’s anomaly. The fetus had been exposed to lithium, trazodone, fluoxetine, and L-thyroxine during the 1st trimester. The defect was attributed to lithium exposure.
In a 1996 descriptive case series, the European Network of the Teratology Information Services (ENTIS) prospectively examined the outcomes of 689 pregnancies exposed to antidepressants (3). Multiple drug therapy occurred in about two-thirds of the mothers. Trazodone was used in 13 pregnancies. The outcomes of these pregnancies were two elective abortions, eight normal newborns (includes one premature infant), and three normal infants who died after birth (after difficult delivery; twins delivered at 27 weeks’; multiple other drugs) (3).
A 2003 prospective controlled study described the outcomes of 147 pregnancies exposed in the 1st trimester (52 used the drugs throughout gestation) to either trazodone or nefazodone, a closely related antidepressant (4). The data were gathered from five teratology information services in Canada (two sites), the United States (two sites), and Italy. The outcomes were compared with two control groups (one exposed to other antidepressants and one exposed to nonteratogens). There were no significant differences between the three groups in terms of spontaneous abortions, elective abortions, stillbirths, major malformations, gestational age at birth, or birth weights. In the study group, there were two (1.4%) major malformations: neural tube defect and Hirschsprung disease (4).
A 2005 meta-analysis of seven prospective comparative cohort studies involving 1774 patients was conducted to quantify the relationship between 7 newer antidepressants and major malformations (5). 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 (5).
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 (6). 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 17 trazodone cases, the other cases were 113 bupropion, 184 citalopram, 21 escitalopram, 61 fluoxetine, 52 fluvoxamine, 68 mirtazapine, 49 nefazodone, 148 paroxetine, 61 sertraline, and 154 venlafaxine. In the antidepressant group, there were 24 (2.5%) major defects compared with 25 (2.6%) in controls (odds ratio 0.9, 95% CI 0.5–1.61). There were no major defects in the pregnancies exposed to bupropion, escitalopram, or trazodone (6).
BREASTFEEDING SUMMARY
Trazodone is excreted into human milk. Six healthy lactating women, 3–8 months postpartum, were given a single 50-mg oral dose of trazodone after an overnight fast (7). Simultaneous serum and milk samples were collected at various times ≤30 hours after ingestion. The infants of the mothers were not allowed to breastfeed during the first 4 hours after the dose. The mean milk:plasma ratio, based on AUC for the two fluids, was 0.142. Based on 500 mL of milk consumed during a 12-hour interval, the infants would have received a trazodone dose of 0.005 mg/kg. This study was unable to include a potentially active metabolite, 1-m-chlorophenylpiperazine, in the analysis (7).
A 2006 report described six women taking quetiapine and other psychotropic agents during breastfeeding (8). One woman was treated with trazodone, quetiapine, and venlafaxine throughout gestation. Details of the pregnancy or its outcome were not provided. At 6.5 weeks postpartum, milk samples were obtained for analysis after doses of 75 mg for each drug (timing of samples and daily doses were not specified). Quetiapine was not detected (<30 nmol/L), but the milk levels of trazodone and venlafaxine were 108 and 371 nmol/L, respectively. The estimated infant daily doses for all three drugs were <0.01 mg/kg/day. In addition, the infant’s behavior was assessed using the Bayley Scales of Infant Development, Second Edition, that suggested normal development (8).
Although the amount of trazodone in milk is very small, the American Academy of Pediatrics classifies trazodone as a drug for which the effect on nursing infants is unknown but may be of concern (9).
References
1.Schardein JL. Psychotropic drugs. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:252.
2.Jacobson SJ, Jones K, Johnson K, Ceolin L, Kaur P, Sahn D, Donnenfeld AE, Rieder M, Santelli R, Smythe J, Pastuszak A, Einarson T, Koren G. Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 1992;339:530–3.
3.McElhatton PR, Garbis HM, Elefant E, Vial T, Bellemin B, Mastroiacovo P, Arnon J, Rodriguez-Pinilla E, Schaefer C, Pexieder T, Merlob P, Dal Verme S. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol 1996;10:285–94.
4.Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003;48:106–9.
5.Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14:823–7.
6.Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry 2009;54:242–6.
7.Verbeeck RK, Ross SG, McKenna EA. Excretion of trazodone in breast milk. Br J Clin Pharmacol 1986;22:367–70.
8.Misri S, Corral M, Wardrop AA, Kendrick K. Quetiapine augmentation in lactation. A series of case reports. J Clin Psychopharm 2006;26:508–11.
9.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.