Selective serotonin reuptake inhibitors in human pregnancy: On the way to resolving the controversy

Summary

There has been an increase in the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy. However, in the last 10 years, in spite of a vast literature regarding use in pregnancy there seems to be some confusion as to the possible risk of these drugs, especially related to cardiovascular anomalies. In addition, there are data on developmental follow-up studies that raise the question of possible slight developmental and neurobehavioral problems. The purpose of the present review is therefore to critically summarize the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. Although most studies have not shown an increase in the overall risk of major malformations, several have suggested that the use of SSRIs may be associated with a small increased risk for cardiovascular malformations. However, new compelling evidence shows that this apparent increased risk occurs also in women with untreated depression, highlighting the probable ascertainment bias involved in many of these studies. Persistent pulmonary hypertension of the newborn (PPHN) has also been described with an absolute risk of <1%; however, here too, higher rates were described among offspring of women with untreated depression. Poor neonatal adaptation has been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Of the few postnatal developmental follow-up studies, there are no significant developmental problems. The literature on SSRIs in pregnancy is somewhat confusing but when analysing all prospective cohort data there seems to be no demonstrable increase in the rate of major anomalies or developmental disorders. When evaluating the risk/benefit ratio of SSRI treatment in pregnancy, the risk associated with treatment discontinuation – e.g. higher frequency of relapse, increased risk of preterm delivery and postpartum depression – appear to outweigh the potential, unproven risks of treatment. Moreover, maternal depression may negatively affect the child's development, emphasizing the importance of prevention by appropriate treatment during pregnancy with the least minimal effective dose.

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for the treatment of depression, anxiety and other disorders. The prevalence rates of depression during pregnancy have been estimated as 7.4%, 12.8% and 12.0%, for the first, second and third trimesters, respectively, and up to 20% of women may have a depressive episode in the first postpartum year [1], [2]. Indeed, the frequency of the reported use of antidepressants in pregnancy increased from 2.5% in 1998 to >8% in 2006, as reported by the American National Birth Defects Study [2], [3]. One important group of drugs comprises the SSRIs, first introduced for clinical use in the 1980s. They have better tolerability and safety compared with first generation antidepressants, e.g. tricyclic antidepressants, and are safer in overdose exposures. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter which mediates the reuptake of serotonin into the presynaptic terminal. Thus, treatment with an SSRI initially blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission due to an increase in synaptic dopamine concentrations [4], [5]. All SSRIs, including those with an additional effect on norepinephrine reuptake (SNRIs), share a similar mechanism of action despite having different chemical structures. SSRI use in pregnancy has increased over the years and in the USA is ∼6% [4], [5]. SSRIs readily cross the human placenta [6], [7] and are also secreted, although in relatively small amounts, in human milk. SSRIs are the most studied antidepressants in pregnancy with >33 000 pregnancies reported in different studies [4]. Nevertheless there are still conflicting views on the risks of these drugs during pregnancy. When judging the use of these drugs in pregnancy one should consider the possible overall effects on the fetus in relation to risks of untreated depression or anxiety for the mother and offspring.

The purpose of the present review is to summarize and evaluate the risk/benefit analysis of SSRI use during human pregnancy, including neonatal effects and neurodevelopmental outcome with special emphasis on prospective cohort studies.