SSRIs and Pregnancy: Putting the Risks Into Perspective

Mood disorders are common in women and typically emerge during the childbearing years.¹ While pregnancy has traditionally been considered a time of emotional well- being, recent data indicate that about 10% to 15% of women experience clinically significant depressive symptoms during pregnancy.^2-5 The risk is particularly high in women with recurrent major depression who discontinue antidepressant medication proximate to conception; 68% of those women experience a depressive relapse.⁶

The clinician faces certain challenges in making recommendations regarding treatment for depression during pregnancy. While psychotherapy is an attractive option, not all women respond to this intervention and many require pharmacotherapy. All antidepressant medications readily diffuse across the placenta, and no psychotropic drug has yet been approved by the FDA for use during pregnancy. Although data accumulated during the past 30 years suggest that certain medications, including SSRIs, may be used safely during pregnancy,^7,8 knowledge regarding the risks of prenatal exposure to psychotropic medications remains incomplete.

While most reports do not indicate that antidepressants increase the risk of miscarriage, several reports have suggested small increases in rates of spontaneous abortion among women treated with SSRIs during the first trimester of pregnancy.^9-13 In these individual reports, the observed differences have not reached statistical significance, and in all cases, reported rates of miscarriage in exposed women have never exceeded the rate of spontaneous abortions observed in the general population (12% to 15%). Findings from a recent meta-analysis that included 3567 women showed that the miscarriage rate was 1.43-fold higher in women who had been exposed to antidepressants than in those who had not (12.4% vs 8.7%, respectively).¹⁴ The authors concluded that while maternal exposure to antidepressants may be associated witha small increase in risk of miscarriage, depression itself also may be a contributing factor and that further studies are needed to clarify this issue.

The baseline incidence of major congenital malformations in newborns born in the United States is estimated to be between 2% and 3%. A teratogen is an agent that interferes with organ formation and that produces some type of organ malformation or dysfunction. Data on the overall teratogenicity of SSRIs come from relatively small prospective observational studies, larger international birth registries, and managed health care databases; these data have cumulatively supported the reproductive safety of fluoxetine(Drug information on fluoxetine) and certain other SSRIs.¹⁵

Although SSRIs share a common mechanism of action, their chemical structures are distinct; whether they have similar effects on pregnancy outcomes is not known. Of the antidepressants, fluoxetine is the best charac- terized with regard to its use during pregnancy; prospective studies complemented by postmarketing surveillance studies indicate no increase in risk of major congenital malformation in infants exposed to it.^9,15-18 Information regarding the reproductive safety of other SSRIs is accumulating but is more limited in terms of sample size.^15,19-21 In a recent meta-analysis that included 1774 antidepressant-exposed infants, first-trimester exposure to SSRIs was not associated with an increased risk of major malformations above the baseline level of 2% to 3%.²²

On the basis of these data, SSRIs are not generally thought to be major te- ratogens; however, concerns about the potential teratogenicity of SSRIs were first raised in 2005 when several studies suggested that paroxetine(Drug information on paroxetine) may be associated with a small increase in risk of congenital abnormalities. A preliminary analysis of data derived from an HMO-claims database demonstrated a 1.8-fold increase in overall risk of malformations in infants exposed to paroxetine and showed a trend toward increased risk of cardiovascular malformation (odds ratio [OR], 1.54).²³ Data from the Swedish Medical Birth Registry, which included 882 paroxetine-exposed children, demonstrated a 1.78-fold increased risk of cardiovascular malformation; the majority of these defects were ventricular or atrial septal defects. Infants exposed to other SSRIs did not have an increased risk of cardiac defects.²³

Two recent retrospective case-control studies evaluated the risks of early exposure to SSRIs.^24,25 Alwan and colleagues²⁴ analyzed data from the National Birth Defects Prevention study, comparing 9622 infants who had selected major birth defects with 4092 controls who had no defects. After delivery, the mothers of these infants were interviewed regarding drug exposures during pregnancy and other possible risk factors for major malformations. The investigators found an association between exposure to an SSRI during the first trimester and an increased risk of omphalocele (OR, 2.8). The strongest effect was observed with paroxetine, which accounted for 36% of all SSRI exposures and which was associated with an 8.1-fold increase in risk of omphalocele. SSRI exposure during the first trimester also was associated with craniosynostosis (OR, 2.5) and anencephaly (OR, 2.4).

Using a similar study design, researchers from the Slone Epidemiology Center at Boston University analyzed 9849 infants with identified birth defects and 5860 infants without such defects.²⁵ In contrast to the previous study, they found that overall use of SSRIs was not associated with significantly increased risks of craniosynostosis, omphalocele, or heart defects. However, when they looked for associations between the use of specific SSRIs and specific defects, they observed significant associations between first-trimester exposure to sertraline(Drug information on sertraline) and both omphalocele (OR, 5.7) and septal defects (OR, 2.0) and between exposure to paroxetine and right ventricular outflow tract obstruction defects (OR, 3.3).

This volley of conflicting reports has left many clinicians confused and uncertain about how to counsel their patients regarding the safety of SSRIs during pregnancy. For example, while earlier reports suggested a link between paroxetine and septal defects, the 2 most recent studies show no such association. While one of the case-control studies suggests that paroxetine may increase the risk of omphalocele, the other does not and, instead, links sertraline exposure to this defect. The differences in the results from the available studies and the diversity in the types of abnormalities reported make it difficult to definitively draw a causal link between SSRI exposure and any particular congenital abnormality.

While there is clearly a need for more thorough analysis of the existing data, taken together, these reports may signal an increase in risk of malformations in children exposed to SSRIs. However, it is important to put these risks into perspective. Even if we assume the associations from these case-control studies to be true, the absolute risk of malformations remains low. For example, an 8.1-fold increase in risk of omphalocele translates into an absolute risk of only 0.2% (approximately 2 of every 1000 births). Absolute risk is of far greater clinical value than relative risk and should be taken into consideration before patients are arbitrarily counseled to discontinue antidepressants during pregnancy.²⁶