Pregnancy and Lactation

One of the most challenging questions faced by patients and health care practitioners in family planning is whether to initiate or continue antidepressant therapy during conception, pregnancy, and the postpartum period. In exploring the risk-benefit analysis, one needs to consider the potential teratogenic risk of exposure of the antidepressant to the infants against the risks to the unborn children of women with untreated depression during pregnancy.

Newborns of women with depression have been shown to have a disproportionately higher risk of lower birth weight, preterm delivery, and small size for gestational age (Steer et al. 1992). Additionally, women with depression have higher rates of smoking and alcohol consumption, which represent further risks to pregnancy outcome (Zuckerman et al. 1989). Laboratory animal studies have demonstrated no significant effects of paroxetine in offspring of exposed pregnant mice in terms of early developmental tasks, locomotor and exploratory behavior, or cognition (Christensen et al. 2000; Coleman et al. 1999). In human studies, placental passage of paroxetine from mothers to developing infants was assessed by comparing maternal serum SRI concentrations with those found in cord blood at the time of delivery (Hendrick et al. 2003b). Paroxetine and sertraline had lower ratios of umbilical cord-maternal serum drug concentrations compared with citalopram and fluoxetine. Furthermore, unlike fluoxetine and sertraline, paroxetine cord blood concentrations did not correlate with maternal dosing, suggesting that an increase in maternal medication dose during pregnancy will not necessarily be accompanied by a comparable increase in fetal paroxetine exposure.

Clinical studies of paroxetine in the setting of pregnancy suggest that gestational exposure might have transient negative effects on newborn infants, particularly if the mother is treated during the third trimester. A prospective cohort study compared perinatal outcomes of 55 pregnant mothers treated with paroxetine, at various doses, during the third trimester with those of 27 mothers treated with paroxetine during one or both of the first two trimesters. A third sample was a control group of 27

expectant females treated with other medications classified as nonteratogenic. In this trial, Costei et al. (2002) found that third-trimester paroxetine exposure was associated with significant increases in neonatal distress (odds ratio = 9.53) compared with the other two groups. The most commonly observed forms of distress were characterized as respiratory distress and hypoglycemia. Results like these have stirred debate among neonatologists as to whether newborn distress attributed to SRIs is a manifestation of toxicity or of withdrawal (Stiskal 2005). Numerous case reports and case series have described transient neonatal symptoms following in utero exposure to SRI antidepressants, and these include (but are not limited to) tremor, hypertonicity, irritability, and poor feeding (Knoppert et al. 2006). Large trials correlating neonatal distress symptoms with infant serum drug levels, however, have not been performed thus far with paroxetine. Reduced or absent CYP2D6 isoenzyme activity associated with high paroxetine concentrations and hyperserotonergic states has been suggested as a putative mechanism for infant distress in many cases (Laine et al. 2004). Conversely, it has also been argued that in view of paroxetine's short half-life, neonatal distress is more likely to be caused by an SRI discontinuation effect (Stiskal 2006). The question is somewhat muddied by the fact that both hyper- and hyposerotonergic states can result in similar symptoms in newborns, such as restlessness and rigidity (Einarson and Koren 2006). The differential diagnosis between SRI neonatal withdrawal and serotonergic symptoms has important ramifications, given that withdrawal would be optimally treated with an SRI. In contrast, such treatment may endanger babies exhibiting serotonin toxicity.

Another significant clinical question is whether paroxetine is associated with teratogenicity. The results of an unpublished study conducted by GlaxoSmithKline (Paxil) led the FDA to warn that paroxetine may increase the risk of major congenital malformations. In a retrospective analysis of data from two U.S. managed-care insurance databases, pregnancy outcomes from a sample of 3,581 gravid mothers (ages 12-49 years) who were taking antidepressants were studied (see GlaxoSmithKline 2005). Of the 18 total medications compared, including other SRIs, SNRIs, TCAs, and newer drugs, only paroxetine had an increased risk of malformations that was significantly greater than that of other antidepressants (odds ratio = 2.20). Several organ systems, including the gastrointestinal, genitourinary, and central nervous systems, were affected in similar proportions. The most common cardiovascular anomalies were ventricular septal defects. The study did not include pregnant women without antidepressant exposure; however, the accepted prevalence of major congenital malformations for all births in the United States is roughly 3%, while the absolute rate observed among first-trimester paroxetine-exposed infants in this study was 4%. A 1% increase in absolute risk over baseline translates to a need for 100 pregnant women to take paroxetine during the first trimester before additional harm would come to 1 infant. Limitations of this study include its retrospective design, lack of controls, lack of clinical details about individual cases, and the fact that it represents a post hoc secondary analysis.

These data are contradicted by several other trials that might be considered more scientifically valid, given their prospective nature. In a cohort study, Kulin et al. (1998) compared rates of major congenital malformations in 237 pregnant women treated with paroxetine, fluvoxamine, or sertraline and found no significant differences among the medication groups compared with control groups. More recently, Hendrick et al. (2003a) followed a total of 138 pregnant females treated with paroxetine, fluoxetine, or sertraline and found that rates of neonatal complications and congenital malformations were lower (1.4%) than rates in the general population. There were no significant differences among individual antidepressants when compared with each other. In a postmarketing surveillance report, 137 pregnancies involving maternal exposure to paroxetine were cited, with no infant abnormalities noted (Inman et al. 1993). In spite of these more reassuring data, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice (2006) has recommended that paroxetine be avoided in women who are pregnant or planning to become pregnant.

Whether a woman decides to begin or continue paroxetine for the treatment of depression during pregnancy, the clinician is advised to monitor for relapse because one study demonstrated that higher doses are often needed, especially in the early third trimester, to effect or maintain disease remission (Hostetter et al. 2000). Another time of increased risk is the postpartum period, when women are at a threefold higher relative risk for depression compared with non-child-bearing women (Cox et al. 1993). It is estimated that 13% of women develop depression following childbirth (O'Hara and Swain 1996). Furthermore, children of women with postpartum depression suffer from a number of social and intellectual impairments thought to be associated with compromised mother-infant bonding (A. Stein et al. 1991). Consequently, postpartum depression represents a significant health risk to both mother and child, and treatment with antidepressants during this period is often necessary.

Balanced against the established hazards associated with postpartum depression is the potential risk of exposure to antidepressants by the nursing infant. Breast feeding has long been advocated by health care providers for improved mother-child interaction and for infant health. In women with postpartum depression, the decision to breast feed, therefore, presents a dilemma. The emerging data appear to allay the concern of the exposure of SRIs, including paroxetine, to infants through breast milk. Like other antidepressants, paroxetine is secreted into breast milk, with greater concentrations found in hindmilk than foremilk (Ohman et al. 1999; Stowe et al. 2000). In a prospective study involving 16 women with postpartum depression treated with paroxetine, the sera of nursing infants were analyzed for the presence of paroxetine at several time points following maternal administration of paroxetine. Paroxetine was undetectable in all infants (Stowe et al. 2000). The authors cautioned against interpreting the findings to suggest that there is no infant exposure to paroxetine through breast milk because it is indeed found in breast milk, albeit in very low concentrations. Nevertheless, in view of the undetectable concentrations in infant blood, the exposure appears to be minimal. Furthermore, no obvious alterations in infant behavior or temperament have been observed in the breast-fed children of women treated with paroxetine in the short term. These data suggest that the benefits of breast-feeding can be maintained in women treated with paroxetine with minimal apparent risk of exposure to the infant. This issue is described in considerable detail elsewhere in this textbook (see Chapter 64, "Psychopharmacology During Pregnancy and Lactation").

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