Pregnancy Complications and Neonatal Mortality in a Serotonin Transporter Null Mouse Model: Insight Into the Use of Selective Serotonin Reuptake Inhibitor During Pregnancy

Abstract

Selective serotonin reuptake inhibitors (SSRI) are widely prescribed to pregnant woman. Although some SSRI compounds are known to cause pregnancy loss and fetal malformations, other SSRI continue to be used by pregnant women. However, several studies have associated the use of SSRI with adverse pregnancy outcomes: intrauterine growth restriction, preterm birth, and neonatal morbidity. Nonetheless, interpretation of studies in humans are typically complicated by the adverse pregnancy outcomes caused by depression itself. Therefore, we used a mutant mouse model with genetic ablation of the serotonin transporter, the target site for SSRI, to unravel the role of the serotonin transporter on pregnancy outcomes. The serotonin transporter null mice had increased pregnancy loss (17.5 vs. 0%), decreased number of pups born (6.6 ± 0.2 vs. 7.5 ± 0.2), and increased neonatal mortality (2.3-fold). Furthermore, preterm birth, dystocia, and fetal malformations were only observed in serotonin transporter null mice. This genetically ablated serotonin transporter mouse recapitulates several adverse pregnancy outcomes similar to those in women undergoing SSRI treatment during gestation. Additionally, neonatal loss in the present study reproduced a sudden infant death phenotype as in humans and mice with altered serotonergic signaling. In conclusion, findings from this study demonstrate a role for serotonin transporter in pregnancy maintenance and neonatal health. Additionally, it suggests that the adverse pregnancy outcomes in women taking SSRI during gestation might be due to altered serotonin transporter function caused by SSRI independent of underlying depression. This is a critical finding, given the number of women prescribed SSRI during pregnancy, and provides the framework for critical research in this area.

Maternal serotonin: implications for the use of selective serotonin reuptake inhibitors during gestation

“…After embryonic day 10.5, mouse embryos become fully dependent on the placenta [100]; therefore, the increased pregnancy loss in SERT-null mice implicates a vital role for a functional SERT in the regulation of placenta function with an impact on embryonic development and maintenance. Taken together, the placental pathology in SERT -null mice reported by Hadden et al [31] are consistent with the pregnancy and neonatal outcomes observed in our study [69].…”

“…Noteworthy, the findings in the placenta of SERT null mice are similar to findings in the placenta of pregnancies complicated by maternal hypertension, that is, with decreased placental vascular perfusion [31,99]. In a recent report, we described pregnancy complications in a SERT-null mouse model: increased pregnancy loss after embryonic day 10.5, shorter gestation, dystocia, decreased litter size, increased neonatal mortality, and fetal malformations [69]. After embryonic day 10.5, mouse embryos become fully dependent on the placenta [100]; therefore, the increased pregnancy loss in SERT-null mice implicates a vital role for a functional SERT in the regulation of placenta function with an impact on embryonic development and maintenance.…”

“…Multiple animal models have been used to investigate the impact of SSRI on pregnancy outcomes and neonatal health: rodents [52,[59][60][61][62], sheep [63][64][65][66], and fish [67,68]. Additionally, mutant mouse models with altered SERT expression and/or function have been useful to shed light on the role of SERT on pregnancy outcomes and neonatal health [12,31,69,70]. The utilization of animal models allows prospective evaluation of the effects of SSRI on pregnancy outcomes, which are limited in humans as most studies in humans are retrospective.…”

“…Abnormal fetal neurodevelopment has also been reported in mice with dysfunctional maternal SERT [12]. Altogether, the altered placental homeostasis observed in women and animal models treated with SSRI [16, 36, 44, 63, 64], and in SERT-null mice [31, 69], are consistent with increased serotonin leading to reduction of placenta blood perfusion resulting in decreased placental growth and efficiency with consequent impairment of fetal development [47, 81, 101]. Further studies are needed to define and confirm these mechanistic pathways from the molecular to whole-body physiological levels.…”

Fluoxetine-induced perinatal morbidity in a sheep model

“…Increased plasma and/or placenta serotonin content are associated with placenta pathology and IUGR in humans and animal models: idiopathic IUGR in humans ( 10 , 11 , 27 ); serotonin or serotonin precursor treatment in rodents ( 28 , 29 ); SSRI treatment in humans ( 4 , 6 , 15 ), mice ( 30 – 32 ), and sheep (present study); SERT null mouse model ( 33 , 34 ). Increased serotonin signaling caused decreased blood perfusion to the placenta ( 13 , 35 ) resulting in abnormal placenta function and growth ( 19 ).…”