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A Multicentre Prospective Controlled Study to Determine the Safety of Trazodone and Nefazodone Use During Pregnancy
Discussion
To our knowledge, this is the first prospective controlled study examining
the risk or safety of trazodone or nefazodone use during pregnancy with
all women exposed during the first trimester and 35% exposed throughout
the pregnancy. However, it must be noted that this study did not attempt
to evaluate potential neurobehavioural effects of these drugs.
The only difference among the groups was in the rate of spontaneous abortions,
which was higher in both the exposed group and in the other antidepressant
group (13.4% and 11.2%, respectively, compared with 8% in the nonteratogen
group) (Table 1). To date, this increase in the rate of spontaneous abortion
has been reported in 3 studies from our group. In our study of fluoxetine,
the rate was 13.5% in the exposed group, 12% in the tricyclic group, and
7% in the Motherisk general population group (6). With the newer SSRIs,
the rate in the exposed group, compared with the general Motherisk population,
was 12% vs 7% (7). Finally in our most recent antidepressant study (of
venlafaxine) there was a 12% spontaneous abortion rate in the antidepressant
groups, compared with 7% in the Motherisk general population group (10).
A European teratology information group also published a study on pregnancy
outcomes for 6 different antidepressants. In that cohort, the rates of
spontaneous abortions ranged from 10.6% to 13.2%; however, there was no
comparison group (19). In addition, Eli Lilly has published a report of
their fluoxetine pregnancy registry comprising 796 spontaneous reports
of pregnancy outcomes, including 110 (13.8%) spontaneous abortions (20).
Despite the reports of higher spontaneous abortion rates, it must be noted
that the results did not reach statistical significance in any of these
studies. Further, they were in the expected range of up to 15% in the general
population.
The results continue to raise the question whether there may be a possible
causative association between depression and an increase in spontaneous
abortion rates—a reason for our selecting as one of our comparison groups
a disease-matched group of women also suffering from depression. It is
also possible that, in some cases, a woman who is treated for depression
may decide to terminate her pregnancy but choose to report it as a miscarriage,
owing to guilt about her decision.
Women who have been diagnosed with depression prior to becoming pregnant
should weigh the benefits and risks carefully with their physician before
deciding whether to continue or discontinue an antidepressant during pregnancy.
If they do decide to discontinue, the medication should be tapered off
slowly to avoid abrupt discontinuation syndrome. Increasing evidenced-based
information should reassure women and their health professionals that the
benefits of taking an anti- depressant in pregnancy can largely outweigh
any unproven risks. In fact, failure to treat depression during pregnancy
can have significant negative ramifications for both the mother and child.
For example, a mother with severe depression may not be able to carry out
her maternal duties in an optimal fashion and could have difficulty bonding
with her child (21,22). A recent study also found that depression and anxiety
in early pregnancy are associated with a risk for subsequent preeclampsia
(23).
Although several recent case reports have documented hepatotoxicity associated
with the use of nefazodone (24), this adverse effect was not reported by
any of the women in our study.
A limitation of this study is the sample size, which is small for statistical
purposes, and has only an 80% power to detect a fourfold increase in the
rate of malformations, with an alpha of 0.05. Approximately 800 cases in
each group would be required to detect a twofold risk of relatively common
malformations, and thousands of cases would be required to detect rare
defects.
In this cohort of women exposed to trazodone or nefazodone during pregnancy,
all of whom took these antidepressants during the first trimester, the
results do not suggest a risk for major malformations above the baseline
rate of 1% to 3%. This evidence-based information can help women and their
health professionals when they are deciding whether to treat depression
with these particular drugs during pregnancy.
Funding Support
This article was supported by an unrestricted educational grant from Bristol-Myers
Squibb.
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Manuscript received March 2002, revised, and accepted May 2002.
1. Assistant Director, The Motherisk Program, Toronto, Ontario.
2. Masters Student, The Motherisk Program, Toronto, Ontario.
3. Coordinator, Pregnancy Riskline, Farmington, Connecticut.
4. Mario Negri Institute, Milan, Italy.
5. Director, The FRAME Program, London, Ontario.
6. Director, Michigan Teratogen Information Service, Detroit, Michigan.
7. Director,The Motherisk Program, Toronto, Ontario.
Address for Correspondence: A Einarson, The Motherisk Program, Division
of Clinical Pharmacology, The Hospital for Sick Children, 555 University
Avenue Toronto, ON M5G 1X8
e-mail: einarson@sickkids.on.ca
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