Ruta Nonacs, MD, PhD

Mood disorders are common in women and typically emerge during the childbearing years.

 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.

 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.

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,

 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.

 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).

 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 and certain other SSRIs.

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.

 Information regarding the reproductive safety of other SSRIs is accumulating but is more limited in terms of sample size.

 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%.

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 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).

 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.

Two recent retrospective case-control studies evaluated the risks of early exposure to SSRIs.

 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.

 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 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.

Multiple studies have suggested that exposure to SSRIs proximate to the time of delivery may be associated with poor perinatal outcomes. Using a variety of methodologies, studies have indicated that children who had been exposed to SSRIs in the third trimester are more likely to have had decreased gestational age, lower Apgar scores, and lower birth weight.

 However, many other studies have observed no differences between infants who had been exposed to SSRIs and those who had not.

 Thus, the clinical relevance of these findings is unclear. In general, the magnitude of the differences has been small. For example, the differences in Apgar scores between exposed and nonexposed infants have typically been less than 1 point and average Apgar scores in the exposed children have remained high (above 7); clinically, a score of 7 or greater suggests that the infant's condition is good to excellent.

In October 2005, the FDA ordered drug manufacturers to include warnings in the packaging inserts regarding the use of certain antidepressants during pregnancy. What prompted these label changes were postmarketing adverse event reports submitted to the FDA, as well as a number of controlled studies, suggesting a constellation of symptoms associated with third-trimester exposure to SSRIs. The symptoms most commonly reported include tremor, restlessness, jitteriness, increased muscle tone, increased crying, feeding difficulties, and respiratory distress.

 Whether these symptoms represent a direct effect of exposure to the antidepressant (ie, increased serotonergic activity) or a discontinuation syndrome is not yet clear. One report has suggested that neonatal symptoms may be more common in infants who had been exposed to agents with shorter half-lives, such as paroxetine.

 It should also be noted that infants born to mothers with untreated depression are at higher risk for adverse neonatal outcomes than those born to mothers who are not depressed, suggesting that it may be the underlying illness-rather than the medications used to treat the disorder-that is associated with poor neonatal outcomes.

While these reports have raised concerns regarding the use of SSRIs in pregnancy, it is important to put these findings into a larger context. Reassuringly, the vast majority of reported adverse events appear to be mild and relatively short-lived; they rarely require any type of medical intervention and typically resolve spontaneously within 1 to 4 days. Furthermore, there is no indication of longer-term problems in children who had been exposed to SSRIs.

A recent study linked SSRI use during late pregnancy to an increased risk of persistent pulmonary hypertension of the newborn (PPHN).

 PPHN is a cardiovascular syndrome that typically occurs in full-term infants and causes severe respiratory distress. Using a case-control design to evaluate risk factors for PPHN, investigators identified 377 infants with PPHN and a control group of 836 women and their infants. The use of an SSRI after the 20th week of gestation was significantly associated with PPHN (PPHN developed in 14 SSRI-exposed infants but in only 6 controls; adjusted OR, 6.1). Neither the use of SSRIs before the 20th week of gestation nor the use of other antidepressants any time during pregnancy was associated with PPHN. To date, this is the only study that reveals a link between SSRI exposure and the risk of PPHN.

It is difficult to reconcile these findings with other studies investigating neonatal outcomes in infants exposed to antidepressants in utero. There have been reports of respiratory distress (usually tachypnea or rapid breathing); however, the observed symptoms were relatively mild and transient and did not require specific medical intervention, suggesting that these cases were not PPHN, a more serious complication with significant morbidity. Nonetheless, these findings must be taken into consideration when deciding whether an SSRI should be used during pregnancy. While PPHN is a potentially serious complication, the absolute risk is still relatively small; the risk is estimated to be less than 1% in infants exposed to SSRIs.

Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, the CNS remains particularly vulnerable to toxic agents throughout pregnancy. However, insults that occur after neural tube closure produce changes in behavior and function as opposed to gross structural abnormalities. In a landmark study, Nulman and colleagues

 followed until preschool age a cohort of children who had been exposed to either tricyclic antidepressants (TCAs) (n = 80) or fluoxetine (n = 55) during pregnancy (most commonly during the first trimester), and compared these children with a cohort of children who had not been exposed to SSRIs (n = 84). Results indicated no significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level. A more recent report from the same group followed a cohort of children exposed to fluoxetine (n = 40) or TCAs (n = 47) for the 

 The authors concluded that their findings support the hypothesis that fluoxetine and TCAs are not behavioral teratogens.

 prospectively examined the relationship between prenatal antidepressant exposure and behavior in a group of 4-year-old children. In this study, outcomes were compared between children with prenatal exposure to SSRIs (n = 22) and children of healthy, non- depressed mothers with no medication exposure (n = 14). Levels of internalizing behaviors (eg, depression, anxiety, withdrawal), as reported by parents and other caregivers and as rated by a clinician, did not differ significantly between the children exposed to SSRIs and those without prenatal SSRI exposure. Similarly to the 2 previous studies from the Motherisk program, these findings support the hypothesis that in utero exposure to SSRIs has no long-term negative effects on the child. Although the studies are reassuring, these data are preliminary. Furthermore, it should be noted that effects of antidepressant exposure may appear later in a child's life. Clearly, further investigation into the long-term neurobehavioral effects of prenatal exposure to antidepressants is warranted.

While clinicians are appropriately concerned about the known and unknown risks associated with fetal exposure to psychiatric medications, the potential negative effect of untreated psychiatric illness on fetal well-being has frequently been overlooked. Depression not only increases the risk of self-injurious or suicidal behaviors in the mother but also may contribute to inadequate self-care and poor compliance with prenatal care. Women with depression often present with decreased appetite and consequently lower than expected weight gain in pregnancy, factors that have been associated with negative pregnancy outcomes.

 In addition, pregnant women with depression are more likely to smoke and to use alcohol or illicit drugs.

 Furthermore, current research suggests that maternal depression itself may adversely affect the developing fetus and may be associated with higher rates of preterm birth, lower birth weight, smaller head circumference, and lower Apgar scores.

Clinicians faced with the decision of whether to treat depression during pregnancy should weigh the risks and benefits of antidepressant use versus the risks of untreated psychiatric disorder. While there is a tendency to withdraw or withhold psychiatric medications, for many women this may not be the best option; treatment decisions must be made on a case-by-case basis. Ideally, decisions regarding treatment should be discussed before conception. In patients with less severe depression, it is appropriate to consider discontinuation of pharmacological therapy during pregnancy. In this setting, psychotherapy may be helpful and may eliminate the need for medications. In contrast, women who have a more recurrent or refractory depressive illness and who are at significant risk for relapse in the setting of medication discontinuation may decide that the safest option is to continue pharmacological treatment during pregnancy.

In choosing an antidepressant for use during pregnancy, the clinician should attempt to select a medication that has a well-characterized reproductive safety profile. Fluoxetine, with the most extensive literature supporting its reproductive safety, is a first-line choice. There is growing literature on the reproductive safety of the newer SSRIs. Although SSRIs are the antidepressants most commonly used in this setting, there are data that support the use of TCAs.

 While several studies outlined here suggest that there may be a small increase in the risk of certain malformations, it is felt that the absolute risk is low and that treatment is warranted when the risks of depression are thought to outweigh the risks associated with drug exposure.

Recent reports of adverse neonatal events in infants who had been exposed to SSRIs have led to changes in the package labeling of SSRIs, advising physicians to "carefully consider the potential risks and benefits of treatment" in patients and suggesting that clinicians consider tapering or discontinuing SSRIs late in the third trimester before labor and delivery. This approach may not be the most prudent, given that the women who most commonly take antidepressants during pregnancy are those who have histories of severe or recurrent depression and who have not been able to successfully taper their medications. In this situation, discontinuing antidepressant therapy proximate to delivery would probably place them at significant risk for relapse of depression.

While there may be a risk of neonatal symptoms associated with exposure to SSRIs near the time of delivery, it is important to note that these symptoms are generally mild and short-lived. Furthermore, there are no data to suggest that drug taper before delivery reduces the risk of the symptoms described in the newborn. Therefore, it is recommended that babies born to mothers taking SSRIsbe observed after delivery so that any neonatal symptomscan be recognized early and, if necessary, treated. Currently, affectedinfants are typically treated conservatively and may be admitted to a special care nursery for observation.

In a recent editorial, Michael F. Greene, MD, of the division of maternal and fetal medicine at Massachusetts General Hospital in Boston, noted that these newer-and often conflicting-studies clearly have made it more difficult to make decisions regarding the treatment of depression during pregnancy. He noted further that "patients and physicians alike would prefer it if there were clear lines separating risk and no risk and if all studies gave consistent results pointing in the same direction."

 While these more recent reports have raised concerns, the data, taken as a whole, are reassuring and indicate that the risks associated with SSRI exposure during pregnancy are low.

 Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. 

 O'Hara MW. Social support, life events, and depression during pregnancy and the puerperium. 

 Evans J, Heron J, Francomb H, et al. Cohort study of depressed mood during pregnancy and after childbirth. 

 Gotlib IH, Whiffen VE, Mount JH, et al. Prevalence rates and demographic characteristics associated with depression in pregnancy and the postpartum. 

 Flynn HA, Blow FC, Marcus SM. Rates and predictors of depression treatment among pregnant women in hospital-affiliated obstetrics practices. 

 Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. 

 Altshuler L, Cohen L, Moline ML, et al. The Expert Consensus Guidelines Series. Treatment of depression in women. 

 Ryan D, Milis L, Misri N. Depression during pregnancy. 

 Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). 

 Kulin N, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. 

 Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. 

 Einarson A, Bonari L, Voyer-Lavigne S, et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. 

 Djulus J, Koren G, Einarson TR, et al. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. 

 Hemels ME, Einarson A, Koren G, et al. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. 

 Hallberg P, Sjöblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. 

 Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. 

 Goldstein DJ. Effects of third trimester fluoxetine exposure on the newborn. 

Articles

Mood disorders are common in women and typically emerge during the childbearing years. 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.

Author | Ruta Nonacs, MD, PhD

Articles

SSRIs and Pregnancy: Putting the Risks Into Perspective