Prenatal antidepressant exposure: clinical and preclinical findings

Abstract

Pharmacological treatment of any maternal illness during pregnancy warrants consideration of the consequences of the illness and/or medication for both the mother and unborn child. In the case of major depressive disorder, which affects up to 10-20% of pregnant women, the deleterious effects of untreated depression on the offspring can be profound and long lasting. Progress has been made in our understanding of the mechanism(s) of action of antidepressants, fetal exposure to these medications, and serotonin's role in development. New technologies and careful study designs have enabled the accurate sampling of maternal serum, breast milk, umbilical cord serum, and infant serum psychotropic medication concentrations to characterize the magnitude of placental transfer and exposure through human breast milk. Despite this progress, the extant clinical literature is largely composed of case series, population-based patient registry data that are reliant on nonobjective means and retrospective recall to determine both medication and maternal depression exposure, and limited inclusion of suitable control groups for maternal depression. Conclusions drawn from such studies often fail to incorporate embryology/neurotransmitter ontogeny, appropriate gestational windows, or a critical discussion of statistically versus clinically significant. Similarly, preclinical studies have predominantly relied on dosing models, leading to exposures that may not be clinically relevant. The elucidation of a defined teratological effect or mechanism, if any, has yet to be conclusively demonstrated. The extant literature indicates that, in many cases, the benefits of antidepressant use during pregnancy for a depressed pregnant woman may outweigh potential risks.

Fig. 1.

Comparison of human and rat pharmacokinetics of the antidepressant escitalopram during pregnancy. Based on the published half-life of escitalopram and observed peak and trough serum concentrations observed in humans and rats. Theoretical serum sampling of escitalopram after single injections (10 mg/kg free base) during pregnancy in rats would yield a peak bolus concentration of approximately 300 ng/ml followed by rapid clearance. The clinically observed range of escitalopram in human women with no attention paid to time of sampling reveals peak serum concentrations of ∼65 ng/ml and trough serum concentrations of ∼17 ng/ml.

Fig. 2.

Representative autoradiographs of in utero exposure to SRIs. Representative autoradiographs of escitalopram (ESCIT), fluoxetine (fluoxetine), paroxetine (PAROX), sertraline (SRT), and venlafaxine (VEN), including representative pregnant dams exposed to VEN during pregnancy. Each treatment group had its own vehicle run in the same assay, but one series is shown for reference. Total binding representative images are displayed for comparison. Dense patches of total binding in the somatosensory cortex are consistent with previous studies investigating SERT binding during the early postnatal period (D'Amato et al., 1987; Kelly et al., 2002). PNC, postnatal clearance. Adapted from Capello et al. (2011).

Fig. 3.

Use of antidepressants during pregnancy: 1996–2005. The line with diamonds indicates any antidepressant use, the line with squares indicates SSRI use, the line with triangles indicates tricyclic antidepressant use, the line with crosses indicates tetracyclic antidepressant use, the line with asterisks indicates monoamine oxidase inhibitor use, and the line with circles indicates other miscellaneous antidepressant use. Less than 0.1% of pregnant women were exposed to tetracyclic antidepressants and MAO inhibitors. The pregnancy period is considered to be the period from 1 to 270 days before delivery, with three 90-day trimesters: first trimester incorporates the period from 181 to 270 days before delivery; second trimester incorporates the period from 91 to 180 days before delivery; third trimester incorporates the period from 1 to 90 days before delivery. Data for 2005 are not available for 1 of the 7 sites included in the analyses. Antidepressant use in the seven health plans for the period 1996–2000 were calculated using data from an earlier CERT study by Andrade et al. (2008) that evaluated medication use during pregnancy using similar methods (definitions and measures) as the present study. Adapted from Andrade et al. (2008).

Fig. 4.

Kaplan-Meier curves illustrating the time to relapse after discontinuation of antidepressants during pregnancy. Adapted from Cohen et al. (2006).

Fig. 5.

Percentage of pregnant women taking prescription drugs arranged by the Food and Drug Administration-labeling categories between 1996 and 2000 in the United States. Category A represents drugs that have well-controlled and adequate human and animal studies that show a low risk to the fetus. Category B drugs are classified as having animal studies that do not show a major risk to the fetus and the absence of well-controlled and adequate human studies. In Category C, a drug during pregnancy has an adverse effect in animal studies but there is an absence of well-controlled and adequate human studies. Category D drugs have a clear adverse effect in human and animal studies but the benefit to the pregnant woman may outweigh the risk. Category X drugs have a clear adverse effect in human and animal studies, and the benefit to the pregnant woman does not outweigh the risk to the fetus (Food and Drug Administration, 2011). Data adapted from (Andrade et al., 2004).

Fig. 6.

Teratological relevance of animal studies versus clinical relevance of human studies. The majority of human studies investigating prenatal antidepressant exposure compare medicated and depressed pregnant women to unmedicated and nondepressed control groups to investigated clinical outcomes. The majority of animal studies investigating prenatal antidepressant exposure compare a medicated animal to an unmedicated animal to determine teratological consequences.