Risk of Fetal Anomalies With Exposure to Selective Serotonin Reuptake Inhibitors
To the Editor. Kulin et al1 reported the first prospective study of pregnancy outcome following maternal use of the newer serotonin selective antidepressants. They describe a total of 267 drug exposures in the first trimester and report that 49 women continued to take a selective serotonin reuptake inhibitor (SSRI) throughout the pregnancy. However, they do not describe the extent of the SSRI exposure during these pregnancies. Sertraline, paroxetine, and fluvoxamine have relatively short elimination half-lives: the half-life of fluvoxamine is 15.6 hours2; paroxetine, 21.0 hours3; and sertraline, 26 hours,4 with its less active metabolite n-desmethylsertraline having a half-life of 62 to 104 hours. Thus, it is possible that women who discontinued use of medication shortly after missing a period may have washed out the drug and reduced fetal exposure to drug to less than 6 weeks. If this is the case, it would seem premature to comment on the teratogenic risk of exposure to these newer, shorter-acting SSRIs without a larger group of women who took these medications throughout the first trimester. In addition, what conclusion can be made regarding the reproductive safety of specific compounds such as fluvoxamine, paroxetine, and sertraline when these agents were combined to generate a sample size on which the risk estimates were based?
Lynn R. Grush, MD
Massachusetts General Hospital
1. Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279:8:609-610.
2. Luvox [package insert]. Scarborough, Ontario: Solvay Kingswood; 1991.
3. Paxil [package insert]. Mississauga, Ontario: SmithKline Beecham Pharmaceuticals; 1995.
4. Zoloft [package insert]. Kirkland, Quebec; Pfizer Pharmaceuticals; 1994.
Dr Grush is a member of the speakers bureau for Eli Lilly.
To the Editor. I congratulate Dr Kulin and colleagues1 for undertaking the daunting task of data collection from 9 teratology information centers. This is important information for practitioners who care for pregnant women with major depression. However, I have some concerns regarding the study design and conclusions.
Ascertainment of SSRI exposure comes from self-reporting by women to teratology centers. Although this seems to be a reasonable approach, this may represent a skewed population with a lesser degree of depression (and potentially decreased drug exposure). Severely depressed, hospitalized patients may lack either the energy or the degree of cognitive functioning needed to voluntarily call a teratology hotline. However, I have greater concern with the choice of the control group. Pregnant women with concerns of teratogen exposure (even if deemed nonsignificant at a later date) do not represent a "low-risk" control population. Indeed, the high risk of "major" anomalies (3.8%) in this control group confirms that conclusion. A more appropriate control group would be random selection of women from a low-risk or routine prenatal clinic. Another interesting control group would be women with major depression who are treated with tricyclic antidepressants since the choice for women with major depression for the study groups should be those taking an SSRI or a tricyclic, not an SSRI or no medication.
I am further concerned by the authors' conclusion. The 4.1% rate (9/222) of major malformations in the SSRI-exposed group is far greater than the background risk that would be expected for an average gravida (3% overall, with 1%-2% risk of major anomalies).2 Using the actual incidence of major anomalies in the SSRI group (4.1%) and the assumptions of 2%, 1.5%, or 1% incidence of major anomalies in the control group, a sample size of 1130 per group, 670 per group, or 420 per group would be required to show a significant difference (Sample Power, SPSS, Chicago, Ill). Therefore, the current sample size is not adequate to reach the conclusion.
I believe this study gives false reassurance regarding the safety of SSRI exposure during pregnancy. Until further studies fully evaluate these risks, SSRIs should be used judiciously for those pregnant women with major depression for which no other alternative is available.
Andrea G. Witlin, DO
University of Texas
1. Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279:609-610. MEDLINE
2. Simpson JL. Genetic counseling and prenatal diagnosis. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 3rd ed. New York, NY: Churchill Livingston; 1996:215-248.
In Reply. In response to Dr Grush's concern about the extent of SSRI exposure, all 267 women in the study took SSRIs during embryogenesis. All 3 drugs we studied interact with the same neurotransmitters, and it makes biological sense to combine them. With the availability of larger sample sizes in the future, it will be possible to achieve enough power for each drug separately.
Dr Witlin asserts that women who call teratogen information services represent those with milder forms of depression. This does not hold true based on our recent studies in which depression was quantified.1 Moreover, because the study aimed at assessing the effects of the drugs, milder depression, even if it exists, is not necessarily a "skew" but rather occurs in a group with fewer confounding factors.
With respect to the control group, we have ample evidence that this group, by their socioeconomic and medical characteristics, are clustered in the middle and upper classes and are a well-informed, low-risk group.2 Witlin's belief that 3.8% of major malformations reflects high risk does not agree with the available literature, where baseline risks range between 1% and 5%.3 Moreover, with a sample size of 250, there is no difference between 3.8% and 2%.
The suggestion to have a control group from a low-risk or routine prenatal clinic would compare apples with oranges. In contrast, women contacting teratogen information centers have a similar pattern of referrals and similar chance of recall and enrollment bias. More than 200 published studies with the Motherisk database have confirmed repeatedly that our control group well represents the characteristics of a low-risk control population.3
Unfortunately, the superficial approach of Witlin to baseline risk is a common cause for misinformation in the field of human teratology. We suggest that, rather than performing non–data driven comparisons, Witlin perform a confirmatory study to assess these questions.
Gideon Koren, MD
The Motherisk Clinic
The Hospital for Sick Children
1. Nulman I, Rovet J, Stewart D, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;336:258-262. MEDLINE
2. Koren G. Maternal-Fetal Toxicology; A Clinician's Guide. 2nd ed. New York, NY: Marcel Dekker; 1994.
3. Treating the mother–protecting the unborn. Available at: http://www.motherisk.org/ Accessed April 15, 1998.
Guidelines for Letters
Edited by Margaret A. Winker, MD, Senior Editor, and Phil B. Fontanarosa, MD, Senior Editor.
© 1998 American Medical Association. All rights reserved.