Antidepressant use in pregnancy: new concerns, old dilemmas

Mood disorders, such as depression, are common, especially among women who overall have a lifetime prevalence of major depressive disorder that is 70% higher than in males [1]. Furthermore, the lifetime prevalence rate among women in their childbearing years has been estimated to be as high as 21.3% [2]. Therefore, clinicians and their female patients must frequently take into consideration a woman’s potential to become pregnant, whether intentionally or unintentionally, when choosing among various options for the treatment of depression. The potential teratogenicity (negative consequences for the developing embryo or fetus) of any specific medication must be weighed against the potential maternal and fetal consequences of undertreating or not treating the underlying disease state. In addition, decisions regarding appropriate treatment in the latter part of pregnancy and during lactation must also consider the increased risk for mood disorder recurrence in the postpartum period [3,4]. In recent years, the availability and proven efficacy of a number of new psychotropic medications has offered many patients greater potential for symptom reduction and remission of their mood disorders. However, with the advent of these treatment options, new questions have been raised regarding the use of these medications during pregnancy. These questions are not quickly or easily answered for two reasons: preclinical reproductive toxicity studies in animal models are not completely predictive of human risk and randomized clinical trials of psychotropics cannot be conducted ethically among pregnant patients. Even if a randomized trial of a psychotropic medication compared with placebo could be performed in pregnant women, the characteristics of women who would be likely to agree to such a study would seriously compromise the generalizability of the results.

Therefore, in the postmarketing arena, data regarding pregnancy exposures and outcomes are typically gathered from observational studies. Currently, there is no systematic method for producing these kinds of reproductive outcome studies routinely, so there is often a prolonged delay in gaining adequate information about new drugs and their use during pregnancy. Furthermore, as pregnancy data begin to emerge, interpretation of results is hampered by the difficulties inherent in studying rare outcomes, such as birth defects, and the challenges in appropriately controlling for potential confounding data in observational studies [5]. This scenario creates a continuously evolving dilemma for clinicians and their patients who must base decisions for the treatment of pregnant or potentially pregnant patients on incomplete or no data at all [6]. In the last 2 years, these issues have been particularly high profile with a flurry of studies addressing the risks of the selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Although several small human studies published in the 1990s did not suggest an overall increased risk for birth defects with first-trimester exposure to any one of these medications [7,8], sample sizes in these studies were insufficient to rule out low-to-moderate increased risks for even the more commonly occurring specific birth defects, such as heart defects, neural tube defects and oral clefts.

More recently, some studies with larger samples sizes have suggested an approximate doubling of risk for heart defects with first-trimester exposure to SSRIs, particularly paroxetine [9–11,101], while others have not [12]. In addition, several studies have examined risks for a variety of other adverse pregnancy outcomes associated with late pregnancy exposure to SSRIs. These studies have been inconsistent with respect to the finding of an increased risk for mild prematurity [13,14] and reduced birth weight [13]. However, they have consistently confirmed an increased risk for a neonatal withdrawal or toxicity syndrome, usually self limited, occurring in approximately 20–30% of exposed infants [7,15]. Furthermore, one study has suggested that late pregnancy exposure to SSRIs is linked to an approximately sixfold increased risk for a rare neonatal respiratory complication, persistent pulmonary hypertension of the newborn [16].

With respect to neurobehavioral development, some studies of children with prenatal SSRI exposure have found no medication-related effects on long-term cognitive or behavioral outcomes [17,18]; whereas, ongoing maternal depression after delivery has been noted to pose a risk for neurobehavioral impairment in children [19,20]. However, some smaller studies have reported decreased performance in motor skills among toddlers and alterations in infant response to pain following prenatal exposure to SSRIs [21,22]. The validity of each of these findings, both positive and negative, will be confirmed or refuted by additional studies conducted by other investigators using differing methodologies. A composite picture of the effects of SSRI medications during pregnancy as well as the effects of the underlying psychiatric illness will continue to be constructed as these newer data become available. In particular, studies that consider the contribution of maternal depression to adverse pregnancy outcomes are required, since untreated depression during pregnancy has been linked to an increased risk of preterm birth, fetal growth restriction, pre-eclampsia, newborn behavioral effects and impaired maternal psychosocial function [23]. Studies are also needed to evaluate variability in risks associated with specific drugs within the class of SSRIs, and to determine whether there is a dose for any specific SSRI below which excess risks are not seen (i.e., a no-effect exposure level). Furthermore, investigations are required to determine whether a temporary discontinuation of SSRIs during specific gestational time periods would reduce the risk of associated adverse outcomes. However, the real-world situation is that the clinician and patient must make decisions based on incomplete data that are available at the moment, often in situations where no equally effective alternative medication or other treatment is available. These decisions must take into consideration the possible negative consequences for the mother and the developing embryo or fetus if the mother discontinues medication, switches to a less effective medication or is undertreated [24]. Thus, the evaluation of factors in making an individual risk assessment is a complex task with many unknowns that must be assigned ‘weights’ in the decision-making process. No less challenging for the clinician is the communication of that risk assessment to a woman (who is or who may become pregnant) in a manner that allows her to consider the issues carefully. While perceived small risks for uncertain outcomes may not be likely to alter behavior under normal circumstances, any perceived risk to the baby, no matter how small, may be unacceptable to a pregnant woman, her partner or her physician [25,26]. The woman may view the benefit for herself as an unacceptable competing interest relative to the perceived risk to her infant. This may be framed by a ‘good for me, but bad for the baby’ choice – a false dichotomy since the fetus is fully dependent upon the mother [27].

All of these factors must be considered in communicating risks and benefits to a patient within the context of recognizing that a baseline risk for birth defects of approximately 3% exists in every pregnancy, and that some adverse outcomes associated with the use of SSRIs are more easily manageable than others (e.g., self-limited and relatively mild neonatal complications). SSRIs represent one example of a widely prescribed class of medications used by pregnant or potentially pregnant women for which less than adequate pregnancy data have been available since the first drug in this class was marketed nearly 20 years ago. Many other medications commonly used by women in their childbearing years present the same clinical decision-making challenges that have prompted these considerations [6]. Moving forward, a national, mandatory and systematic surveillance system for all newly marketed drugs used by women of childbearing age would substantially shorten the length of time required to develop such information, while providing observational study data of a high standard. Such a system would help alleviate many of the lingering uncertainties regarding drug prescribing for childbearing women when insufficient information is available [5]. In the meantime, the Organization of Teratology Information Specialists (OTIS) is one resource that can help the clinician and patient gather the most current data and navigate through the various issues related to optimal management of pregnancy [102]. Opportunities for participation in observational research studies can also be found at the US FDA Office of Women’s Health pregnancy registry webpage [103].

Acknowledgements

Christina Chambers receives grant funding for research projects not involving depression or antidepressants from Abbott Laboratories, Amgen, Apotex, Barr Laboratories, Bristol Myers Squibb, Par Laboratories, Sandoz Pharmaceuticals, Sanofi Aventis, Sanofi Pasteur and Teva Pharmaceuticals, and has served as a consultant for Cephalon Pharmaceuticals and Regeneron Pharmaceuticals. Eydie Moses-Kolko has no disclosures. Katherine Wisner receives grant funding from NIH, the Stanley Medical Research Foundation, Pfizer, the American Society for Bariatric Surgery, NYMAC and the State of Pennsylvania to study issues related to depression and/or antidepressants and to develop patient and provider educational tools. Katherine Wisner has pending grant funding from Wyeth for a study on the treatment of postpartum depression, and is a member of the GlaxoSmithKline Speakers’ Bureau.