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OBSTETRICS REPORT

Treating Depression During Pregnancy: Update on Selective Serotonin Reuptake Inhibitors

David E. Abel, MD

Pharmacotherapy for depression during pregnancy has always been a matter of weighing the fetal risks of medication use against the maternal risks of untreated mental illness. In the case of selective serotonin reuptake inhibitors (SSRIs), recent government rulings and research results, including a well-publicized 2007 study in the New England Journal of Medicine, do not always agree about the risk/benefit profile.

The treatment of depression during pregnancy, and in particular the use of SSRIs, has received a great deal of attention since the advent of these medications. As depression is a common finding among women of childbearing age, it is important for the clinician to understand the issues surrounding the use of SSRIs in the pregnant patient. Of special concern is the question of a relationship between SSRI use and congenital anomalies, neonatal withdrawal, and other adverse perinatal outcomes. The recent decision by the FDA to change the pregnancy category of paroxetine from C (potential may exist for adverse fetal effects, but benefits may outweigh risks) to D (adverse fetal effects have been demonstrated, but benefits may outweigh risks) has only added to the controversy.1 The purpose of this article is to enhance the health care provider’s ability to effectively counsel patients regarding the use of SSRIs during pregnancy.

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EPIDEMIOLOGY

The incidence of depression (minor and major) during pregnancy and/or the postpartum period is approximately 10%.2,3 A woman has a 10% to 25% risk of being diagnosed with a major depressive disorder at some point in her life, with the greatest risk occurring during the childbearing years.4 These prevalence rates are comparable among different countries. Approximately 3% to 5% of women experience major depression during pregnancy.5 If untreated, 50% of these women will experience a postpartum exacerbation, which can confer a risk of attempted suicide of up to 15%.6 Thus, the importance of recognizing and treating depression during pregnancy cannot be understated.

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CONGENITAL ANOMALIES

Patients are often concerned about potential teratogenicity that may be associated with SSRI use. In fact, there are more data indicating a lack of teratogenic risk with SSRIs compared with other common medications used during pregnancy. The FDA has assigned most anti-depressants a pregnancy category rating of C, implying minimal availability of human data such that risk cannot be excluded with certainty. With regard to specific SSRIs, sertraline is classified as category B, and cumulative data including 4 prospective studies involving approximately 1,100 pregnant women demonstrated no teratogenic effects with the use of fluoxetine in the first trimester.7-10 Two studies looking at citalopram found no increase in congenital anomalies above the baseline risk.11,12 Similar results were also found with sertraline and paroxetine.13 A list of commonly used SSRIs and their pregnancy category ratings is presented in Table 1.

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TABLE 1. Pregnancy Classification of Selective Serotonin Reuptake Inhibitors

In December 2005 the FDA changed the pregnancy category of paroxetine from C to D based on the finding of a moderate (1.5- to 2-fold) increase in the rate of cardiovascular malformations (ie, atrial and ventricular septal defects) among infants exposed during the first trimester.1 These data were derived from a Swedish registry and a US insurance-claims database. Data derived from these sources should be interpreted with caution as there may be methodologic limitations. An ACOG Committee Opinion published in December 2006 does not specifically state that paroxetine is absolutely contraindicated during pregnancy but advises that its use preconceptionally or during gestation should be avoided if possible.2 Notably, the opinion adds that the benefits of paroxetine therapy in a given pregnant patient may outweigh the potential risks. In contrast to the data suggesting an association between paroxetine exposure and congenital heart defects, a recent study refuted this association.14 Over 3,000 first-trimester exposures were ascertained from 8 teratology information services (the largest number of cases thus far reported for paroxetine exposure). The authors did not find an increased risk of congenital cardiovascular defects with first-trimester paroxetine exposure.

Another concern regarding the use of SSRIs during pregnancy was raised by a case-control study that identified an increased (6.1-fold) risk of persistent pulmonary hypertension (PPHN) in newborns exposed to SSRIs after 20 weeks’ gestation.15 The incidence of PPHN in the general population is 1 to 2 per 1,000 live births, with a mortality rate of 10% to 20%. The authors suggested that serotonin’s vasoconstrictive properties and mitogenic effects on pulmonary smooth-muscle cells may explain this phenomenon. A 6.1-fold increase in the risk of PPHN translates into 6 to 12 cases per 1,000 births—a relatively small absolute risk. An even smaller risk of PPHN was noted in a more recent case-control study using data from the Swedish Medical Birth Register.16 Exposures to many different SSRIs were included, and only a 2.4-fold increased risk of PPHN was noted with exposure after 34 weeks’ gestation. In contrast to the above 2 studies, a recent study examined the prevalence of PPHN in infants whose mothers were exposed to SSRIs in the third trimester.17 In this retrospective study, no difference in the prevalence of PPHN was noted when compared to nonexposed infants. Limitations of this study include a small number of PPHN cases and inherent bias when analyzing data obtained from several health plan databases.

Two large case-control studies published in the same issue of the New England Journal of Medicine examined a possible link between SSRI use during pregnancy and congenital anomalies.18,19 In the first study, Alwan et al retrospectively looked at first-trimester SSRI exposure in more than 9,600 infants with major birth defects.18 The controls were a random selection of approximately 4,000 live-born infants without any major anomalies. The authors found no significant association between first-trimester SSRI exposure and congenital heart defects or most other major birth defects. A group of anomalies comprising anencephaly, omphalocele, and craniosynostosis did appear to be associated with SSRI use (ie, paroxetine, citalopram), but the authors noted that the absolute risks were small.

The second study—another large, population-based analysis—examined the association between first-trimester SSRI exposure and congenital anomalies in more than 9,800 infants with birth defects.19 These authors found no significant association with craniosynostosis; omphalocele was significantly associated with sertraline use based on 3 exposures. Furthermore, no increased risk of congenital heart defects was noted. As in the Alwan et al study, there was a significant association between paroxetine use and right ventricular outflow obstruction (6 exposures).18 Sertraline use was associated with septal defects (13 exposures). Overall, it cannot be definitively concluded that the use of SSRIs during pregnancy poses a significant teratogenic risk based on the findings to date.

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POOR NEONATAL ADAPTATION

A constellation of neonatal symptoms has been associated with antidepressant use near term, comprising poor neonatal adaptation (PNA).20 Table 2 lists some of the features suggestive of PNA. This cluster of findings has also been called neonatal withdrawal or neonatal abstinence syndrome. These symptoms are usually self-limiting and benign. To date, there have been no reports of serious complications or mortality from PNA. It is unclear whether PNA is a withdrawal phenomenon or possibly reflects serotonin toxicity. A review of the literature concluded that this “neonatal behavioral syndrome” can be managed with supportive care.21 In a large, population-based study including all infants with reported prolonged SSRI exposure, the rate of PNA was 30%, and the authors recommend postnatal monitoring for 48 hours.22 It is difficult to compare the data on PNA due to methodologic differences, varying definitions of the condition, and inadequate control groups.

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TABLE 2. Signs and Symptoms of Poor Neonatal Adaptation

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OTHER ADVERSE PERINATAL OUTCOMES

There are conflicting data with regard to outcomes such as preterm birth and low birth weight in infants exposed to SSRIs in utero. One retrospective cohort study looked at 972 pregnant patients who had been given at least one SSRI prescription in the year before delivery.23 An increased risk of low birth weight, preterm birth, fetal death, and seizures was noted. However, the control subjects were not depressed, leading some to speculate that exposure to depression rather than to SSRIs may have contributed to the adverse outcomes. Depression that is not treated during pregnancy may increase the risk of substance abuse, low weight gain, and sexually transmitted infections.2

One study that offers a different perspective on the treatment of depression during pregnancy looked at the effects of discontinuing treatment.24 In this prospective longitudinal study, 68% of patients who discontinued medication experienced a relapse, compared with a 26% relapse rate in women who maintained medication use throughout pregnancy. The risk of relapse was increased in those with a long history of depression and/or a history of recurrent relapses.

A recent study was the first to examine the possible association between SSRI exposure beyond the first trimester and the risk of gestational hypertension and preeclampsia.25 The data analyzed were from the Slone Epidemiology Center Birth Defects Study. The risk of gestational hypertension and preeclampsia was greater in those patients who continued treatment beyond the first trimester (an approximate 15% risk or 4.9-fold increase compared to nonexposures). The authors acknowledge the inability to distinguish the medication from the mood disorder itself as the possible cause for this increased risk.

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CONCLUSIONS

As stated in the ACOG Committee Opinion,2 the treatment of depression during pregnancy must be individualized. It is important for the clinician to educate the patient about all of the relevant issues so she can make an informed choice, and this counseling should be carefully documented. The risks of discontinuing treatment may have consequences that outweigh the small potential risks of treatment. For some patients other medications (eg, tricyclic antidepressants, bupropion, venlafaxine) may be reasonable alternatives. Tapering or discontinuing SSRIs is controversial and probably should be avoided to minimize the risk of postpartum depression. A collaborative approach involving a psychiatrist and other mental health professionals is strongly advised.

The author reports no actual or potential conflicts of interest in relation to this article.

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David E. Abel, MD, is a specialist in Maternal-Fetal Medicine, Northwest Perinatal Center, Portland, OR.

References

1. US Food and Drug Administration. Public Health Advisory on Paroxetine. www.fda.gov/cder/drug/advisory/paroxetine200512.htm. Published December 8, 2005. Accessed August 6, 2007.
2. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy. Obstet Gynecol. 2006;108(6):1601-1603.
3. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol. 2005;106(5 pt 1):1071-1083.
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