US Pharm. 2007;32(9):34-44.

A.S. is a 30-year-old woman who presents to your pharmacy for a refill of fluoxetine. While she is at the counter, she happens to mention that she and her husband would like to conceive a child, but she wonders if her fluoxetine should be stopped in the meantime to avoid any potential harm to the baby. When questioned, she states that she has been on fluoxetine for the past three years after suffering her second bout of major depression. She states that the fluoxetine has worked well for her, but she is concerned that it may harm the baby should she become pregnant. How should this patient be counseled?

Hormonal changes associated with a woman's reproductive cycle increase the lifetime risk for affective disorders.1 In the United States, one-year prevalence rates for major depressive disorder range from 7% to 13%, with peak prevalence between ages 25 and 44.2-4 Pregnancy and its associated hormonal changes increase the vulnerability for onset or reccurrence of depression.3,5 Those with a history of depression are at an increased risk for recurrence, continuation, or exacerbation of the disease state.3,6 Risk factors for depression during pregnancy include personal or family history of depression; personal history of childhood abuse, substance abuse, or tobacco smoking; inadequate social support; single parenthood; unplanned pregnancy; unemployment; and lower educational level.7-10

Diagnosis
Some somatic complaints of pregnancy may be difficult to differentiate from depression. Symptoms reported by patients may include less energy or fatigue, lack of interest in usual activities, difficulty concentrating, loss of appetite, insomnia, agitation, slowing of thought processes, and suicidal ideation. 11 Diagnosis of depression, whether in pregnant or nonpregnant women, follows the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.11 Patient reports of symptoms are used to aid diagnosis, and two questionnaires have been validated in the obstetrical population; these include the Edinburgh Postnatal Depression Score and the Beck Depression Inventory.12,13

Treatment
Once a diagnosis has been made, nonpharmacologic and pharmacologic interventions should be considered. Nonpharmacologic interventions include psychotherapy (individual and group) and bright light therapy. Bright light therapy has been found to be effective for seasonal affective disorder. The two most common psychotherapies include interpersonal therapy (focus on improving social interactions and coping skills) and cognitive behavioral therapy (focus on adjusting patients' self-detrimental thought processes).10 Interpersonal therapy has been shown to improve mood during pregnancy, but cognitive behavioral therapy has only been validated for postpartum depression.10,14

Pharmacologic interventions are widely used for depression and include antidepressants from various drug classes. Some examples include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepineph­ rine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). All available antidepressants are considered to be equally efficacious for uncomplicated depression, and the choice of agent depends on safety, side-effect profile, comorbidities, potential drug interactions, patient preference, and cost.15 Treatment goals should focus on remission of patient symptoms and restoration of function. Adequate patient follow-up and patient adherence are essential for optimal outcomes.

Antidepressant Safety
Two types of neonatal toxicity should be considered when evaluating drug therapy in pregnancy: embryotoxicity and teratogenicity. Teratogenicity typically occurs during the first trimester and involves major malformations to fetal organs or skeletal structures.16 Embryotoxicity is associated with fetal health defects and is typically associated with second- and third-trimester exposure.16 The vast majority of drugs, including antidepressants, cross the placenta and therefore have the potential for adverse consequences.

The FDA has assigned pregnancy safety ratings to medications based on human and animal data, but these ratings should be interpreted with caution. FDA pregnancy categories include A, B, C, D, and X. Category A indicates fetal risk has not been demonstrated in controlled trials; category B indicates no evidence of risk in humans despite risk observed in animal studies; category C means risk cannot be ruled out; category D indicates positive evidence of risk; and category X represents a contraindication for use in pregnancy, with risk outweighing any potential benefit. No currently available antidepressant has a rating of A or B. A list of antidepressant medications according to their respective pregnancy categories is available in Table 1.

SSRIs are common first-line agents for the treatment of depression, but concern about the safety of antidepressants has been raised over the past 10 years; deleterious neonatal health effects from late exposure to SSRIs have been reported. SRI-related neonatal syndrome (also referred to as poor neonatal adaptation) has been reported with SSRIs and SNRIs, with near-term exposure increasing the risk by two- to 10-fold.17 The mechanism of SRI-related neonatal syndrome is not well understood but is thought to be due to either SSRI withdrawal or toxicity.17 Common symptoms of this syndrome include tremor, jitteriness, feeding difficulties, irritability, agitation, rigidity, and respiratory distress. Other less frequent symptoms include seizures, excessive crying, hyperreflexia, and sleep disturbances. Symptoms are typically transient and self-limiting and may require intervention over several hours to several days.17

Persistent pulmonary hypertension has also been associated with SSRIs during late pregnancy, and spontaneous abortions have been a common finding in studies evaluating the use of antidepressants during pregnancy.16,18 The observed rates of spontaneous abortions in patients have been higher than those in the nonteratogen control groups, but differences have not been significant.16 Further evaluation would be useful to differentiate whether the increased risk is due to the antidepressant or the depression itself.16 Of newest concern are reports of cardiac malformations observed with first-trimester exposure to paroxetine. In December 2005, the FDA requested the addition of new warnings to the labeling of paroxetine and a change in the pregnancy category from C to D.

This article will review current information regarding the safety and toxicity of each class of antidepressants. It is important to note that due to ethical reasons, randomized, controlled trials cannot be done to evaluate the treatment of depression in pregnancy; therefore, the vast majority of data is extracted from case reports or cohort studies.

SSRIs: In the U.S., SSRIs are widely used for the treatment of depression. Fluoxetine was the first such agent on the market and, to date, has been the SSRI used most frequently among pregnant women. Until recently, prospective studies had provided reassurance that SSRI use in early pregnancy was not associated with an increase in major congenital malformations above what is expected for the general population. 19,20 However, in December 2005, the FDA issued new warnings concerning the risk of cardiac malformations from early exposure to paroxetine during pregnancy. Because of conflicting findings regarding the teratogenic risk of paroxetine in the first trimester, one study attempted to quantify the association between paroxetine and cardiac malformations and to evaluate whether there was a dose–response relationship. The study utilized the Medication and Pregnancy registry in Quebec, Canada, and comprised two nested, case-control studies that compared the prevalence of paroxetine use in the first trimester to the prevalence of other antidepressant exposures during the same time period.21 Of the 1,403 women who were included in the study, 101 infants had major congenital malformations and 24 had cardiac malformations.21 The use of paroxetine and other SSRIs did not increase the risk for cardiac malformations compared with other antidepressants.21 When the dose was evaluated, the risk of congenital malformations was increased for paroxetine at dosages greater than 25 mg daily (adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.19-4.17) as well as for cardiac malformations (adjusted OR, 3.07; 95% CI, 1.00-9.42).21 Based on this study, the risk of congenital and major cardiac malformations is increased when gestational exposure to paroxetine exceeds 25 mg per day during the first trimester. Additional studies are needed to further assess this relationship.

Since the new FDA warning, two large case-control studies have been conducted to evaluate the relationship between SSRIs during the first trimester of pregnancy and risk of congenital birth defects. The first study used data from the Slone Epidemiology Center Birth Defects Study.22 Analysis was restricted to women whose last menstrual cycle occurred between January 1, 1993, and December 31, 1994.22 Invited participants completed an interview within six months of delivery. First-trimester exposure to any SSRI as well as exposure to any non-SSRI antidepressant was evaluated, with adjustment for confounding factors. A total of 9,849 infants with malformations and 5,860 control infants were included. 22 When evaluated as a group, SSRIs did not significantly increase the risk for craniosynostosis (premature closing of the skull sutures), omphalocele (protrusion of intestines or other abdominal organs through an opening in the navel) or heart defects.22 When evaluated individually, sertraline increased the risk of septal defects (adjusted OR, 2.0; 95% CI, 1.2-4.0, based on 13 exposed subjects) and omphalocele (adjusted OR, 5.7; 95% CI, 1.6-20.7, based on three exposed subjects) and paroxetine increased the risk of right ventricular outflow tract obstruction defects (adjusted OR 3.3; 95% CI, 1.3-8.8, based on six exposed subjects).22 No significant association was observed between non-SSRI antidepressants and any specific birth defect.

The second study utilized data from the National Birth Defects Prevention Study.23 Analysis included infants who were born on or after October 1, 1997, and who had an estimated delivery date on or before December 31, 2002.23 Mothers of case and control infants were interviewed between six weeks and two years from time of estimated delivery.23 Exposure was defined as use of any SSRI one month before to three months after conception.23 Women who took non-SSRI antidepressants were included in the nonexposed group.23 Analyses were adjusted for confounding variables. In all, 9,622 case and 4,092 control infants were included with 2.4% of mothers of case infants and 2.1% of mothers of control infants reporting use of an SSRI.23 No significant association was noted between SSRI use in early pregnancy and the majority of birth defects assessed within the study. Three birth defects were significantly associated with maternal use of any SSRI during the first trimester, including craniosynostosis (adjusted OR, 2.5; 95% CI, 1.5-4.0, based on 24 exposed subjects), omphalocele (adjusted OR, 2.8; 95% CI, 1.3-5.7, based on 11 exposed subjects) and anencephaly (adjusted OR, 2.4; 95% CI, 1.1-5.1, based on nine exposed subjects).23 Selected SSRIs (fluoxetine, sertraline, and paroxetine) were individually evaluated with selected birth defects to assess for an association. While significant associations were detected, analyses were limited by the small number of exposed cases within each category of birth defects.23

While these case-control studies indicate that SSRIs, and potentially selected SSRIs, may increase the risk of specific birth defects, limitations of these studies should be kept in mind. Both studies performed multiple comparisons, and some of the observations could be due to chance. The potential for recall bias exists, since exposure was determined by maternal report.22,23 There is difficulty in separating maternal use of SSRIs from underlying depression as a cause, and there were limited numbers of exposed infants for each defect. 22,23 When taken in perspective, the absolute risk associated with SSRIs appears to be small in comparison with the baseline risk of birth defects that exists within pregnancy.22,23

Widespread use of SSRIs during pregnancy has also led to concerns regarding safety during the third trimester. One study evaluated the use of fluoxetine in 228 pregnant women during various trimesters, focusing on exposure to infants during the third trimester.24 When comparing late exposure to early exposure, the relative risk for admission to special care nurseries was 2.6 (95% CI, 1.1-6.9) and the adjusted relative risk of SRI-related neonatal syndrome was 8.7 (95% CI, 2.9-26.6).24 The following are limitations of the study: severity of depression was not controlled for, one-third of the women were taking other psychoactive medications, and more women in the third-trimester group were smokers.24 Another prospective study evaluated 55 neonates exposed to paroxetine in the third trimester.25 Twelve (21.8%) required prolonged hospitalization for neonatal complications. 23 When controlling for various factors, including maternal smoking and gestational age, the OR for respiratory distress was 9.53 (95% CI, 1.14-79.3), compared with a control group exposed to nonteratogenic medications.25 The authors noted in this study that all of the infants recovered after a brief intensive care stay and symptoms resolved within two weeks.

Several case reports describe symptoms consistent with either a serotonin toxicity or withdrawal effect, including irritability, jitteriness, agitation, restlessness, continuous crying, and feeding problems.20,26-29 In most cases, the onset of symptoms was usually within several days of delivery and resolved within one week.

Persistent pulmonary hypertension of the newborn (PPHN) is associated with significant morbidity and mortality and presents shortly after birth with severe respiratory failure requiring intubation and mechanical ventilation.30 The risk of PPHN was evaluated in a case-control study where 377 women who delivered infants with PPHN were recruited and matched to 836 controls whose infants did not have PPHN.18 For inclusion, the infants were to have a gestational age greater than 34 weeks, and no malformations could be present in the control group. Mothers of the two groups were contacted within six months of delivery to identify medications used during pregnancy, health history, and demographics. Antidepressants, specifically SSRIs, were found to significantly increase the risk of PPHN in late pregnancy (?20 weeks) with an adjusted OR of 6.1 (95% CI, 2.2-16.8).18 Use of other antidepressants was associated with a slightly lower risk of PPHN compared to SSRIs (adjusted OR, 3.2; 95% CI, 1.3-7.4).18 When placed in clinical context, 99% of women exposed to an SSRI during late pregnancy will deliver an infant unaffected by PPHN.18

Other perinatal complications that have been inconsistently reported include low Apgar scores, low birth weight, and prematurity.31-33 Unfortunately, limitations plague these studies, including lack of control for severity of depression and lack of an appropriate control group.

Questions regarding drug differences remain unresolved. It is possible that differences exist because of differences in their pharmacokinetic profiles. Studies that have evaluated the SSRIs have often evaluated the drugs as a class, and small sample sizes have not made subgroup analyses feasible.20

TCAs: First introduced in 1958, TCAs have been widely used for depression. With the advent of newer agents with a more favorable side-effect profile, such as SSRIs, the TCAs are no longer considered first line in the treatment of depression. Of the TCAs, nortriptyline and desipramine are preferred during pregnancy since they are associated with fewer anticholinergic side effects and are less likely to exacerbate orthostatic hypotension, which can be common in pregnancy.16

In the 1970s, case reports suggested that TCAs were associated with teratogenicity leading to fear of their use.16 Since then, several large case series have further evaluated this issue and failed to support those findings. One large case series examined the fetal outcome of 330 pregnancies exposed to TCAs; 97% of exposures occurred during the first trimester.34 The most common agents used were clomipramine, amitriptyline, and imipramine. The risk for major malformations was found to be no greater than the baseline risk of 1% to 3% in the general population.34 There was also no difference in the incidence of spontaneous abortions and fetal deaths. A study utilizing the data from the Swedish Medical Birth Registry examined medications used by women early in pregnancy in nearly 5,000 neonates with documented cardiac defects.35 Of those, 1,000 infants were found to have been exposed to TCAs, mostly clomipramine. When adjusted for confounders, an OR of 1.77 (95% CI, 1.07-2.91) was found for first-trimester use of TCAs (primarily clomipramine) and cardiac defects.35 Although a significant finding, no specific pattern of cardiac malformations was detected in neonates exposed to TCAs.35

SRI-related neonatal syndrome has been reported with TCAs and includes jitteriness, irritability, and less frequently, seizures.26,36 Symptoms secondary to rebound cholinergic hyperactivity have also been reported in neonates exposed to TCAs. 26,36 The potential for maternal toxicity due to their anticholinergic side effects and adverse neonatal health effects limit the role of TCAs in the treatment of depression in pregnancy.

MAOIs: Minimal data regarding the use of monoamine oxidase inhibitors in pregnancy exists due to their infrequent use in the treatment of depression. Limited data suggest that there is an increased risk of major malformations when used during pregnancy.16 Side effects and drug interactions with tyramine-containing food products that could lead to a hypertensive crisis has minimized the use of monoamine oxidase inhibitors within the general population. Given the above information, the use of monoamine oxidase inhibitors should not be used during pregnancy.

SNRIs: Two SNRIs used for the treatment of depression include duloxetine and venlafaxine. Literature regarding the safety of these agents during pregnancy is not as extensive as with the SSRIs, and only published literature regarding venlafaxine could be found. A prospective study by the Motherisk Program in Canada examined the safety of venlafaxine in 150 women who were exposed early in pregnancy (35 were exposed throughout pregnancy) and compared them to women exposed to SSRIs or known nonteratogens.37 Compared to either group, venlafaxine was not associated with an increased risk of major malformations, therapeutic abortions, or decrease in mean birth weights.37 The incidence of spontaneous abortions was higher in the venlafaxine and SSRI groups (12% and 10.7%, respectively) compared to the nonteratogen group (7%) but was not statistically significant.37

Other Antidepressants: Similar to the SNRIs, data regarding the safety of mirtazapine, bupropion, nefazodone, and trazodone in pregnancy is not extensive, with the risk of major congenital malformations as the primary outcome. A similar study conducted by the Motherisk Program evaluated the safety of mirtazapine in early pregnancy with two comparative groups: other antidepressants and nonteratogenic medications.38 In all, 104 pregnancy outcomes were evaluated with 25% of the women taking mirtazapine throughout pregnancy. Mirtazapine was not associated with an increased risk of major malformations above baseline but was linked with an increased risk of spontaneous abortions compared to the nonteratogen group, although this was not significantly different.38 The rate of preterm births (delivery prior to 37 weeks gestation) was found to be significantly higher in the mirtazapine group (10%) than in the nonteratogen group (2%).38

Bupropion, nefazodone, and trazodone have also been evaluated by the Motherrisk Program and utilized similar designs with two comparative groups: other antidepressants and nonteratogenic medications.39,40 Bupropion, nefazodone, and trazodone did not increase the risk of major malformations above baseline but were associated with an increased risk of spontaneous abortions compared to the nonteratogens.39,40 The increased risk of spontaneous abortions was not significantly different but is similar to that in other trials involving antidepressant use in pregnancy. The lack of a significant effect may be attributed to small sample sizes in the studies.

 

Depression and Pregnancy
Not only can medications affect the mother and fetus and have serious consequences, but depression can as well. Women with depression may present with a decreased appetite, which can lead to less weight gain throughout pregnancy.26 Pregnant women with depression may be more likely to smoke cigarettes or use alcohol, which can have negative consequences on the fetus. Severe depression can lead to poor self-care, poor prenatal care, and increased risk of suicide. 26 Preterm labor and low birth weight have also been linked with stress and anxiety in pregnant women.41

For women with a history of depression who are stabilized on antidepressants, there is often a concern about the continuation of antidepressants should they wish to become pregnant. Women may wish to discontinue the antidepressant to avoid harm to the infant and forego treatment for their depression. Due to concern about relapse of depression during pregnancy, Cohen et al. sought to examine the risk of relapse in women who discontinued their antidepressant compared to those who maintained treatment.42 The risk of relapse was also evaluated by each trimester. Two hundred and one women with depression were included and the overall depression relapse rate was 43%, with half occurring during the first trimester.42 Women who discontinued their antidepressant had a relapse rate of 68%, compared with a relapse rate of 26% among women who maintained their antidepressant.42 It was also noted that duration of illness (>5 years) and number of recurrent episodes (>4) was associated with a significant increase in the relapse of depression in pregnancy.42 The authors concluded that pregnancy does not protect against depression, and the risk of relapse needs to be considered when evaluating the continuation of antidepressants during pregnancy.

Conclusion

Depression is prevalent, and the highest incidence for onset in women is during the childbearing years. Risks and benefits must be weighed regarding the treatment of depression during pregnancy. Antidepressant therapy may have neonatal consequences but literature also supports maternal and fetal consequences of untreated depression. Therefore, each patient must individually decide in consultation with the patient's providers whether to initiate or continue therapy for depression in pregnancy. While antidepressants are considered relatively safe, further research is needed regarding the teratogenic and neonatal health effects and the role of newer antidepressants.

With respect to A.S.'s concerns about fluoxetine during pregnancy, you state that there are risks and benefits and that a discussion should take place between her and her health care provider. You inform A.S. that fluoxetine is one of the most extensively studied antidepressants during pregnancy. You proceed to tell her that this class of medications has been associated with congenital malformations, but the birth defects are rare and the absolute risk is small. You tell her that neonatal health effects from late-pregnancy exposure of fluoxetine have been reported with this class of medications. You also make her aware that untreated depression can have detrimental consequences on her health as well as the health of her baby. To help her make the most informed and appropriate decision, you recommend that she discuss all of her options with her psychiatrist and her gynecologist.

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