New antidepressants in pregnancy

Adrienne Einarson, RN Gideon Koren, MD, FRCPC

February 2004

Many women of childbearing age suffer from depression and, because at least 50% of pregnancies are unplanned,¹ some women are exposed to antidepressants early in pregnancy. In a previous study we showed that misinformation and fear of teratogenicity led many women to abruptly discontinue needed antidepressants after pregnancy was diagnosed.² Today, physicians feel comfortable prescribing selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine, because these drugs have been available for many years and a large body of evidence documents their safety during pregnancy.^3-6 Physicians continue to be concerned, however, about the newer antidepressants.

Several studies have documented how important it is to treat depression during pregnancy. A British study showed that depression during pregnancy has been relatively neglected compared with postpartum depression, even though it is more prevalent and approximately 25% of postpartum depressions actually begin during pregnancy.⁷

The American Psychiatric Association?s Committee on Research on Psychiatric Treatments identified treatment of major depression during pregnancy as a priority in clinical management. Based on this, a position paper was published on risk-benefit decision making for such treatment.⁸ The authors concluded there was no evidence that antidepressants caused harm to unborn babies and that pregnant women should be treated as long as benefits and possible risks are well explained to them. A recent survey of 3472 pregnant women in the United States revealed that one in five had symptoms of depression, but few (24%) actually received treatment during pregnancy.⁹

In the 1990s, newer non?SSRI antidepressants were introduced and were used by women who became pregnant while taking them. Motherisk has been studying these newer drugs and has published the only study currently available on the safety of venlafaxine, a phenethylamine bicyclic derivative chemically unrelated to other antidepressants.¹⁰ We followed 150 women who had all been exposed to venlafaxine in the first trimester (35 [23%] were exposed throughout pregnancy) and compared them with two control groups. In the venlafaxine group, there were 125 live births, 18 spontaneous abortions, seven therapeutic abortions, and two major malformations. There were no statistically significant differences among groups for any of the end points examined.

We also published the only study examining the fetal safety of trazodone and nefazodone, both phenylpiperazine antidepressants structurally unrelated to other antidepressants.¹¹ Among 147 women, there were 121 live births (two babies had major malformations), 20 spontaneous abortions, and six therapeutic abortions. In all cases, exposure occurred during the first trimester (52 [35%] were exposed throughout pregnancy). There were no statistically significant differences among the three groups in any end points examined. Trazodone has actually been on the market for many years, but, since it is structurally similar to nefazodone and there have been no studies on its safety during pregnancy, we decided to include both drugs in our study.

Bupropion, an antidepressant of the amino-ketone class, is indicated for two conditions: depression and smoking cessation. To date, no studies have been published of its effect on human pregnancy. The manufacturer has a registry in which the outcomes of 266 pregnancies of women exposed during the first trimester are documented. There appeared to be no increased risk of major malformations. There was, however, no comparison group. At Motherisk, we are currently enrolling pregnant women and women planning pregnancy who have been exposed to bupropion along with comparison groups matched for smoking and depression.

Mirtazepine, a tetracyclic antidepressant that enhances noradrenergic and specific serotonergic transmission, has been available in Canada since 2001. There is no information on its safety during pregnancy, but animal studies revealed no adverse effects on reproduction, and there have been no reports of adverse effects in babies of mothers who took it during pregnancy. Motherisk is studying this drug also. If you have patients taking either bupropion or mirtazapine, please ask them to get in touch with the Motherisk Program at (416) 813-6780 or 1-800-670-6126.

If women do not respond to or suffer adverse effects from SSRIs and require antidepressants, available information suggests the newer anti-depressants are safe. This evidence-based information should help patients and their physicians work out a risk-benefit ratio and make an informed decision about treatment. Pregnant women with depression should be treated appropriately to ensure that they are in optimal mental health to interact and bond with their babies.

References

1. Martin JA, Park MM, Sutton PD. Births: preliminary data for 2001. Natl Vital Stat Rep 2002;50(10):1-20.
2. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs due to fears of teratogenic risk and the impact of counseling. J Psychiatry Neurosci 2001;26(1):44-89.
3. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Donnenfeld A, et al. Pregnancy outcome following first trimester exposure to fluoxetine. JAMA 1993;269:2246-8.
4. Kulin N, Pastuszak A, Sage S, Schick-Boschetto B, Spivey G, Feldkamp M, et al. Pregnancy outcome following maternal use of the new serotonin reuptake inhibitors: a prospective multicenter study. JAMA 1998;279:609-10.
5. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-5.
6. Nulman I, Rovet J, Stewart DE, Wolpin J, Gardener HA, Theis J, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336:258-62.
7. Evans J, Heron J, Francomb H, Oke S, Golding J. Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001;323:257-60.
8. Wisner K, Zarin D, Appelbaum P, Gelenberg A, Leonard H, Frank E. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry 2000;157:1933-40.
9. Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health. In press.
10. Einarson A, Fatoye B, Sarkar M, Lavigne L, Brochu J, Chambers C, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicentre prospective controlled study. Am J Psychiatry 2001;158:1728-30.
11. Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003;48(2):106-10.

Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Ms Einarson is a member and Dr Koren is Director of the Motherisk Program. Dr Koren, a Senior Scientist at the Canadian Institutes for Health Research, is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and, in part, by a grant from the Canadian Institutes for Health Research.

Copyright Canadian Family Physician 2004;50:227-9.