Antidepressants and Pregnancy

By Lucy J. Puryear, MD

Depression occurs most commonly in women during the reproductive years, ages 22-45. The treatment of depression during pregnancy raises difficult issues. Many women and/or physicians are reluctant to use antidepressant medications during pregnancy; however, untreated depression may also have deleterious consequences for the fetus. As such, withholding antidepressant medication during pregnancy may not be the safest option in many circumstances. Fortunately, some antidepressant medications are considered relatively safe in pregnancy, although a thorough evaluation of the risk:benefit ratio is prudent.

If the mother is experiencing only mild depressive symptoms, psychotherapy alone may be useful.1,2 In this situation, the patient exhibits no impairment in day-to-day functioning and has no accompanying thoughts of death. Psychotherapy alone is particularly indicated if there is no past history of more severe depression. Major depression, or clinical depression, is characterized by decreased energy, anhedonia (loss of interest in usual activities), tearfulness, excessive guilt, altered sleep and appetite, and suicidal thoughts or thoughts of death. In these cases, initiation of antidepressant medication may be necessary. Additionally, many women become pregnant while taking antidepressants, thereby raising the question of medication discontinuation.

If the woman has a history of recurrent, moderate-to-severe episodes of major depression, it is generally unwise to stop medication because the risk of recurrence is high. If there have been previous suicide attempts or hospitalizations, then antidepressants will need to be continued throughout the pregnancy and into the postpartum period. In these circumstances a choice needs to be made whether to remain on the current effective medication or to change to one with the most safety data. This is a decision best made in collaboration with the prospective parents.

Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, is arguably the safest antidepressant during pregnancy. The manufacturer (Eli Lilly and Company) has a large database of women who have taken fluoxetine while pregnant without adverse fetal outcomes.3,4 In a 1993 study of 128 women taking fluoxetine during pregnancy, there was no increase in congenital anomalies or perinatal complications compared to women taking nortriptyline, a tricyclic antidepressant.3 The only study to date with a possible negative outcome is a study of 228 women who were exposed to fluoxetine in the first or second trimesters only vs. those who took the medication throughout the entire pregnancy.5 Although this study suggests that exposure in the last trimester of pregnancy may be problematic, there were many other maternal variables not controlled for that may have affected outcome. Maternal age was higher in the fluoxetine-treated group, and depressive illness was not present in the control group. This is an important confound because untreated depression, in and of itself, may be associated with more neonatal complications.

There are few data regarding exposure to antidepressants and long-term behavioral outcome. One of the few studies published recently found no long-term effects on IQ, speech, or behavior in 55 children up to the age of 8 who had been exposed to fluoxetine in utero.9 Although this information is preliminary, it appears that there are no long-term complications to children whose mothers have taken fluoxetine. There are no long-term behavioral outcome data about other antidepressants.

Several newer serotonergic medications are also available, although there are fewer data regarding their use during pregnancy. A recent retrospective study found no teratogenic effects following exposure to sertraline, paroxetine, and fluvoxamine.6 These preliminary data are encouraging, but the sample included only 267 women in total, which is substantially less than the combined fluoxetine data. Among the older antidepressants, nortriptyline remains a reasonable choice if the serotonin reuptake inhibitors cannot be tolerated due to side effects or if the patient is unresponsive to SSRIs. Older data suggested that the tricyclic antidepressants may have been associated with limb deformities; however, newer evidence does not support this finding.7,8 The advantage of nortriptyline is its therapeutic window of 50 to 150 ng/mL, which allows for the use of blood levels to guide dosing.

There is currently no database available on the use of bupropion, nefazodone, mirtazepine, or venlafaxine during pregnancy. Use of these agents must be undertaken with caution in pregnancy until human data are available. The Physician’s Desk Reference pregnancy category has created some confusion. Although the SSRIs are listed as Class C drugs and bupropion as Class B, the difference between these two classifications has no clinical use. Class B means that animal studies show no risk or show some risk but there are no well-controlled studies in animals or women. Class C means animal studies may show adverse risk but there are no well-controlled studies in women. These distinctions are not helpful when trying to ascertain safety for human use during pregnancy.

In addition, many more women are choosing to breastfeed. Data to date indicate that nortriptyline, clomipramine, sertraline, and fluoxetine are excreted in small quantities and the amount the infant receives is negligible.10,11 An elegant study assessing the amount of sertraline excreted in breast milk and analyzing infant exposure has shown sertraline and the metabolite desmethylsertraline to be minimally detectable in the infant. On the basis of these data, if the mother becomes depressed in the postpartum period and wishes to breastfeed, sertraline is currently a first-line treatment. However, if the mother has been treated during pregnancy with fluoxetine, many clinicians will continue to use this medication during the postpartum period and allow the mother to breastfeed.12

In summary, depression during pregnancy can be safely treated with minimal risk to both the fetus and the mother. A careful psychiatric history is imperative. If medication can be avoided, then this is obviously the first choice. However, women have increased risks for depressive illness that often coincide with reproductive events. Antidepressant treatment is often necessary to insure a good outcome for all concerned.

References

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2. Spinelli MG. Am J Psychiatry 1997;154(7):1028-1030.

3. Pastuszak A, et al. JAMA 1993;269(17):2246-2248.

4. Goldstein DJ, et al. Obstet Gynecol 1997;89(5 Pt 1): 713-718.

5. Chambers CD, et al. N Engl J Med 1996;335(14):1010-1015.

6. Kulin NA, et al. JAMA 1998;279(8):609-610.

7. Altshuler LL, et al. Am J Psychiatry 1996; 153(5): 592-606.

8. Lewis-Hall FC, et al. J Womens Health 1997;6(3): 337-343.

9. Nulman I, et al. N Engl J Med 1997; 336(4):258-262.

10. Stowe ZN, et al. Am J Psychiatry 1997;154(9):1255-1260.

11. Llewellyn A, Stowe ZN. J Clin Psychiatry 1998;59 (Suppl 2):41-52.

12. Taddio A, et al. J Clin Pharmacol 1996;36(1):42-47.