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Trazodone is a phenylpiperazine antidepressant. At high dosages in some animal species, it is fetal-toxic and teratogenic. There have been no postmarketing reports of human fetal abnormalities associated with this drug (1). A surveillance study of Michigan Medicaid recipients found that, of 100 newborns exposed to trazodone during the first trimester, 1 had major malformation (F Rosa, personal communication, 1993). Nefazodone is a phenylpiperazine antidepressant directly related to trazodone. At high dosages in some animal species, it was fetal-toxic but not teratogenic. There have been no postmarketing reports of human fetal abnormalities associated with this drug (2). A manufacturer’s report of 84 cases of exposure in pregnancy listed 48 outcomes, including 2 babies with renal abnormalities. In these 2 cases, there were no details regarding the time of exposure during pregnancy. In 38 of the pregnancies, the mother took the drug in the first trimester (Bristol-Myers Squibb, personal communication, 2001). A literature search did not uncover any human prospective controlled studies on the use of these drugs during pregnancy. A significant number of women of child-bearing age suffer from depression. Coupled with the fact that at least 50% of pregnancies are unplanned (3), it is likely that some women will use trazodone or nefazodone in early pregnancy. We have found that some women have chosen to abort a wanted pregnancy because they lack information on the safety of a particular drug (4). In another study we showed that, owing to misinformation coupled with fear, several women elected to abruptly discontinue needed antidepressants after pregnancy was diagnosed (5). This fear of taking drugs during pregnancy persists, despite the fact that several antidepressants have not been found to be harmful. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) (6–10). A British study documented that research on maternal depression during pregnancy has been relatively neglected in favour of studies of postnatal depression, even though maternal depression is more prevalent, and approximately 25% of postpartum depressions actually began during pregnancy (11). The American Psychiatric Association Committee on Research on Psychiatric Treatments identified treatment of major depression during pregnancy as a priority clinical- management area. Based on this recommendation, a position paper was published on risk–benefit decision making for treatment of depression during pregnancy. The authors concluded that no evidence existed to implicate antidepressants as a cause of harm to an unborn baby and that pregnant women should be treated, provided that the benefits and possible risks are well explained to them (12). Another recent study found that untreated depression during pregnancy can have deleterious effects on peripartum and neonatal outcomes, including more caesarean sections and more admissions to neonatal intensive care units (13). With this in mind, and given the probability that more women will be treated pharmacologically for depression during pregnancy, it is of the utmost importance to study the fetal safety of all antidepressants, so that women can choose an antidepressant that is both safe and effective. Our primary objective was to ascertain whether trazodone or nefazodone increased the baseline risk of 1% to 3% for major malformations. Secondary objectives included possible effects on spontaneous and therapeutic abortions, gestational age, and birth weight. Patients and MethodsThe Motherisk Program and the other participating centres are counselling services for pregnant and lactating women and their health professionals. These centres provide information on the safety or risk of drugs, chemicals, radiation treatment, and infectious diseases. For this study, we attempted to follow up all women who had called each service requesting information about the safety of trazodone or nefazodone during the first trimester of their pregnancy and to ascertain the outcome of their pregnancies. Upon successful contact, we used a structured questionnaire to obtain a history of drug exposure and pregnancy outcome, along with other endpoints of interest. Exposure history included the medical indication for drug use, dosage, frequency of administration, and timing of exposure, as well as maternal demographics and obstetrical history. At follow-up, we questioned women regarding the course of their pregnancy, the health of their child, and the specific details of their exposure to trazodone or nefazodone and any concomitant drugs or other exposures. Outcomes were confirmed by a letter asking the child’s primary care physician to corroborate the mother’s information. The primary outcome of interest was the incidence of major malformations, which were defined as the presence of any anomaly with an adverse effect on either the function or the social acceptability of the child (14). Secondary outcomes included the rates of spontaneous or therapeutic abortions, livebirths and stillbirths, gestational age at birth, and birth weight. Exposure was defined as occurring during organogenesis if the drug was consumed between the fourth and fourteenth week of gestation. We used 2 groups of women to compare the endpoints, with data collected in the same fashion. These groups were 1) disease-matched women suffering from depression but taking other nonteratogenic antidepressants and 2) women exposed to other nonteratogenic drugs (specifically, sumatriptin [15], dextromethorphan [16], diclectin [17], and clarithromycin [18]). They were also compared for age, smoking, and alcohol use and matched for time of call, because reported spontaneous abortions rates are probably higher when women call earlier in pregnancy. Most women were followed up between 4 and 6 months after their expected confinement date. Outcomes of interest were compared among the study and comparison groups with the chi-square, Fisher’s exact, and analysis of variance (ANOVA) statistical tests. We received oral consent from each participant after the study was fully explained over the telephone. Our hospital research ethics board approved the study. ResultsWe were able to ascertain the outcomes of 147 pregnancies from 5 different centres located in Toronto, Ontario; Farmington, Connecticut; Milan, Italy; London, Ontario; and Detroit, Michigan. All the women used the drugs during the first trimester, with 52 (35%) using the drug throughout their pregnancies. There were no significant differences in the maternal characteristics of the exposed and comparison groups, with the exception that the trazodone or nefazodone group combined with the other antidepressants group had more smokers: 21% vs 8.2% (P = 0.015). However, most of these women had reduced the number of cigarettes smoked during their pregnancies, with only 4 women in the antidepressant groups smoking in excess of 20 cigarettes daily. There were no differences in any outcome measures for smokers, compared with nonsmokers, including the rates of spontaneous abortions and mean birth weights. There were 121 (82.4%) live births, 20 (13:6%) spontaneous abortions, and
6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major
malformations. The mean birth weight was 3288 g (SD 708). Among the 3 groups,
pregnancy outcome (including rates of preterm delivery) did not differ,
except that there were more spontaneous abortions in both antidepressant
groups. However, this difference did not reach statistical significance
(Table 1). There were 2 major malformations in the exposed group; in the
other antidepressant group, there were 3 major malformations. There were
4 major malformations in the nonteratogen group (Table 2).
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