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Antidepressants During Pregnancy: Treating the Condition While Acknowledging the Risks

Decisions about treating depression during pregnancy must be individualized.

Women are at higher risk than men for developing depression, and this increased risk is particularly apparent during the childbearing years.^1,2 Thus, if you are a clinician whose clientele includes women in their reproductive years, chances are that some of your patients will experience new-onset or recurrent depressive episodes while pregnant or will become pregnant while using an antidepressant.

Pregnancy does not confer protection against depression. Results of a recent prospective study of pregnant women who were taking antidepressants at or near the time of conception demonstrated that women who opted to discontinue treatment during pregnancy were five times more likely to relapse than were those who stayed on treatment (Journal Watch Women’s Health Apr 4 2006).³ Given that treating depression during pregnancy is such an important issue, how can we handle the uncertainty (as well as the stigma) involving antidepressants and reproductive safety? Much of the existing confusion derives from the complexity of evaluating absolute versus relative risks for both infant and mother and the difficulty in balancing these risks.⁴

RISKS ASSOCIATED WITH UNTREATED DEPRESSION — IS NOT TREATING AN OPTION?

Despite the cautionary remarks commonly made by most regulatory agencies and medical societies about the use of psychotropic medications during pregnancy, considerable data supporting the efficacy and reproductive safety of antidepressants have accrued.⁵ Conversely, evidence suggests that untreated depression has negative consequences for both mother and child. Depression during late pregnancy is associated with poor obstetric and neonatal outcomes, including increased risks for cesarean and instrumental vaginal deliveries, intrauterine growth retardation, and premature delivery.^6,7 The impact of untreated depression during pregnancy is not limited to perinatal adverse outcomes. The authors of a prospective study of mother–child pairs suggested that uncontrolled maternal depression during and after pregnancy might adversely affect the child’s IQ and language development and showed that such adverse effects were not associated with the use of antidepressants (Journal Watch Women’s Health Dec 17 2002).⁸

DECONSTRUCTING THE MYTHS: THE SAFETY AND EFFICACY OF ANTIDEPRESSANTS DURING PREGNANCY

Notwithstanding the accumulating evidence about the consequences of untreated depression, many clinicians and their patients remain extremely reluctant to prescribe or use antidepressant medications when depression is first diagnosed during pregnancy. Moreover, in women who already were taking antidepressants before conceiving, their medication doses might be decreased once pregnancy has been documented. This practice could result in exposure of the fetus to a relapse of maternal depression as well as to the psychotropic agent.

Which antidepressant agents are safest and most efficacious for use during pregnancy is a commonly asked question. A recent meta-analysis included seven prospective studies of the teratogenic risks associated with first-trimester exposures to antidepressants that have entered the market since 1980 (such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors). The incidence of malformations in infants exposed prenatally to fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), venlafaxine (Effexor), nefazodone (Serzone), trazodone (Desyrel), or bupropion (Wellbutrin) was compared to that of nonexposed infants. The composite sample size (n = 1774) was sufficient to rule out any increased risk for major malformations with prenatal exposure to these antidepressants as a group compared to the baseline rate of 1% to 3% found in the general population.⁵

A recent comprehensive review includes data from animal and human studies of exposure to various SSRIs, the most widely used antidepressants, during pregnancy⁹. The results of animal studies suggest that only high doses of SSRIs are teratogenic. Published data from studies involving more than 2600 women do not indicate an increased risk for major malformations when any SSRI is given in therapeutic doses during pregnancy.

Because available data are insufficient to support a clinical recommendation as to which SSRI is the safest to use during pregnancy, switching from an ongoing, successful treatment to a different antidepressant is generally not recommended — particularly when the clinical response of the patient to the alternative medication is unknown.

REMAINING QUESTIONS

The decision to prescribe an antidepressant to a pregnant woman remains far from risk free. First, we need more studies characterizing the long-term developmental impact of prenatal antidepressant exposure. Second, the existing studies are limited with respect to their power to assess relative risk for minor malformations. The authors of another recent meta-analysis pointed out an increased risk for spontaneous abortions among antidepressant users despite the fact that the effect of the illness itself could not be excluded.¹⁰

Other concerns regarding the use of antidepressants during pregnancy include the occurrence of withdrawal symptoms in the newborn and an increased risk for persistent pulmonary hypertension of the newborn (PPHN) associated with exposure to SSRIs late in gestation.¹¹ The symptoms attributed to neonatal withdrawal include increased muscle tone, irritability, jitteriness, hypothermia, and respiratory distress. The condition usually does not pose any threat to the infant and resolves completely during the first several postnatal hours or few days. Most of these symptoms are also clinical characteristics of serotonin toxicity in adults who use SSRIs, raising the question of whether this phenomenon reflects neonatal overreactivity to serotonin.

PPHN requires serious consideration, as this condition is associated with significant infant mortality and morbidity. In a case-control study, investigators assessed 377 women whose infants had PPHN. Exposure to an SSRI after the 20th week of gestation resulted in a sixfold increased risk for PPHN compared with nonexposure (Journal Watch Women’s Health Apr 4 2006).¹¹ The absolute risk is small (about 6 to 12 cases per 1000 women), but these findings should be taken into consideration when deciding whether an SSRI should be maintained throughout pregnancy. Furthermore, clinicians should carefully consider the risk-benefit ratio before prescribing an SSRI to an asymptomatic woman during the third trimester as a way to minimize the risk for postnatal depression.

CONCLUSION

In summary, clinicians should bear in mind the mounting evidence about the adverse effects of uncontrolled depression during pregnancy. However, decisions about management must be individualized with input from patients and their partners and should be guided by life history of depression (number and severity of episodes), prior occurrence of depression during pregnancy or postpartum, and severity of symptoms at the time of conception and throughout the pregnancy. With these factors in mind, close monitoring by a psychiatrist should be considered for patients who opt to discontinue medication immediately before or during pregnancy.

— Claudio N. Soares, MD, PhD

Dr. Soares is Associate Professor of Psychiatry and Behavioral Neurosciences, and Director, Women’s Health Concerns Clinic, McMaster University, Hamilton, Ontario, Canada. He is a consultant for Forest, GlaxoSmithKline, Sepracor, and Wyeth; is on the speaker’s bureau for GlaxoSmithKline, Lundbeck, and Wyeth; and receives grant support from NARSAD, NIMH, and Eli Lilly.

Published in Journal Watch Women's Health April 26, 2007

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8. Nulman I et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry 2002 Nov; 159:1889-95.

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11. Chambers CD et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006 Feb 9; 354:579-87.

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Reader Remarks:

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• Wellbutrin, Neurontin, Seroquel and Lithium
  Faith Cardenas, 5 Aug 2009 10:44 AM EST
  Mulitple meds during pregnancy, I am disabled due to diaganosis and probably carrying twins.