Elsevier

Reproductive Toxicology

Volume 22, Issue 4, November 2006, Pages 571-575
Reproductive Toxicology

Review
Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials

https://doi.org/10.1016/j.reprotox.2006.03.019Get rights and content

Abstract

Serotonin reuptake inhibitors (SRIs) are extensively used in management of clinical depression. Reports vary about the risk of these drugs during pregnancy. To determine the risk of exposure to SRIs, we pooled data from multiple clinical studies that investigated obstetrical outcomes in women exposed to this group of drugs during pregnancy. Studies were identified by search of PUBMED, OVID, and SCOPUS databases and the data were derived from 1990 to 2005 (August). Types of outcome investigated were spontaneous abortion, major malformations, cardiovascular malformations, and minor malformations. The criteria for inclusion of studies in this meta-analysis were exposure of women to any therapeutic dosage of SRI (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) during pregnancy.

Our results find that SRIs do not increase the risk of major, cardiovascular and minor malformations but do increase the risk of spontaneous abortion significantly.

Introduction

An estimated 8% to 20% of all women develop clinical symptoms of depression at some time during their lives [1]. Pregnant women are considered to be at higher risk for depressive episodes particularly when there is pre-existing psychiatric illnesses [2]. The prevalence of depression among pregnant women is 10–16% and thus they usually receive antidepressant drugs during pregnancy [3]. Predisposing factors for depression during pregnancy include personal or familial history of depression, a history of anti-depressive medication and oral contraceptives, mood disorders associated with menstruation, major financial problems, medical complications associated with pregnancy, unwanted pregnancy, lack of support from the husband, and poor quality of sexual relationship [4].

Left untreated, depression can affect women in various ways including decreased nutrition, disrupted sleep, difficulties in following medical recommendations, risk of suicide and increased exposure to tobacco, alcohol and drugs. In addition, there are risks of fetal growth retardation, preterm birth, low birth weight, operative delivery, smaller head circumference, lower Apgar scores and altered mother–infant bonding and infant temperament. These outcomes, in turn, have been associated with mortality, increased risk of severe neurologic morbidity, and mental retardation [5], [6], [7], [8], [9], [10]. Although women are generally advised to avoid medications during pregnancy, the decision to interrupt or withhold antidepressant treatment is therefore complex and must balance the risks of untreated depression with the risks of drug exposure to the fetus.

Serotonin reuptake inhibitors (SRIs) are a relatively new group of antidepressants. Since their introduction to clinical practice in 1988, SRIs have become the drugs of choice for treating depression and are becoming the standard of treatment for a wide spectrum of mood and behavioral disorders, including obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, premenstrual dysphoric disorder, and generalized anxiety disorder [11]. SRIs are also widely used to treat antenatal and postpartum depression.

Preclinical animal studies have not attributed teratogenic effects to SRIs [12]. On the other hand, serotonin has multiple functions during early development and mid-gestational craniofacial morphogenesis; therefore, a potential biological activity of SRIs on the developing embryo might be expected to increase the risk of birth defects [13]. Several clinical investigations have evaluated the safety of SRIs used during pregnancy. Whereas some studies found no adverse pregnancy outcomes [14], [15], [16] others reported possible complications such as spontaneous abortion [17], [18], [19], preterm birth [20], low birth weight [14], [20], [21], malformations [19], respiratory difficulties [22], lower Apgar scores [20] and withdrawal syndrome [11]. Thus, psychiatrists commonly face the clinical dilemma of whether to prescribe antidepressant medications during pregnancy for women with active symptoms of depression or as prophylaxis for women with past histories of major depressive disorder.

The objective of the present study was to collect and review all the clinical trials that investigated the rates of spontaneous abortion and malformations due to SRIs treatment during pregnancy in order to determine whether SRIs increase the incidence of adverse pregnancy outcomes, especially spontaneous abortion and congenital malformations.

Section snippets

Methods

PUBMED, OVID, and SCOPUS databases were searched for studies that investigated birth outcome following exposure to SRIs during pregnancy. Data were collected from 1990 to 2005 (ending with August 28). The keywords used to search were: SRIs or serotonin reuptake inhibitors with pregnancy, birth outcome or obstetrical outcome. The reference list from retrieved articles was also reviewed for additional applicable studies. Types of outcomes investigated were spontaneous abortion, major

Results

After careful review those clinical studies ascertaining SRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) treatment outcomes during pregnancy, including major malformations, minor malformations, and spontaneous abortion, were considered for meta-analysis. We excluded studies that did not have a control group [21], [23], [24]. One study was rejected because of low follow-up and the lack of acquisition of outcome information from reliable sources [15]. The nine studies that met

Discussion

Due to concern that antidepressants may harm the fetus women frequently discontinue medications during pregnancy; however, for pregnant women with recurrent major depression who discontinue medication, the risk of relapse is high and untreated maternal mental illness itself may compromise prenatal care, obstetrical outcome, and the postpartum course [5], [6], [7], [8], [9], [10], [27]. The decision for administration of antidepressants during pregnancy is thus complex and evaluation of the

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