Fluoxetine-induced perinatal morbidity in a sheep model

Domingues, Rafael R.; Beard, Adam D.; Connelly, M.K.; Wiltbank, Milo C.; Hernández, Laura

doi:10.3389/fmed.2022.955560

Cited by 3 publications

(16 citation statements)

References 57 publications

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“…These placental alterations in sheep, and likely in women, appear to be due to fluoxetine inhibition of SERT leading to increased circulating serotonin-producing vasoconstriction of uteroplacental vessels and ultimately restricted blood perfusion to the uterus and placenta (Figure 3). Other authors have also suggested a similar mechanism associating SSRI with increased serotonin altering blood perfusion at the uteroplacental unit affecting placental function and pregnancy outcomes [19,59,[63][64][65][84][85][86].…”

Section: Placental Alterationsmentioning

confidence: 89%

“…Although the interpretation of reproductive and neonatal outcomes in animals can be challenging due to differences in the number of offspring per gestation, gestation length, and stage of fetal development at birth, animal models are crucial for understanding the effects of drugs in humans. 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].…”

Section: General Perspectivesmentioning

confidence: 99%

“…Among animal models, rodents have been the most explored. Nevertheless, a few studies are using the ovine model [63,64]. Sheep have been long recognized as a great model for translational pregnancy studies due to similarities to human pregnancy (number of fetuses per gestation, fetal intrauterine development, and stage of fetal organ maturation at birth) in contrast to mice [72][73][74].…”

Section: General Perspectivesmentioning

confidence: 99%

“…Sheep have been long recognized as a great model for translational pregnancy studies due to similarities to human pregnancy (number of fetuses per gestation, fetal intrauterine development, and stage of fetal organ maturation at birth) in contrast to mice [72][73][74]. We recently used sheep to investigate the effects of SSRI on pregnancy and neonatal outcomes [63]. In our study, fluoxetine treatment during late pregnancy recapitulated several findings associated with SSRI exposure during pregnancy in women (decreased placentome [functional unit of placenta in ruminants], shorter gestation length, decreased birthweight, neonatal morbidity).…”

Section: General Perspectivesmentioning

confidence: 99%

“…Only pups exposed to fluoxetine in utero had increased neonatal mortality despite being fostered by control dams, whereas pups from control dams fostered by dams exposed to fluoxetine during gestation had normal survival rates. In sheep, however, a longer pregnancy (152 days) allows a more robust translational implication concerning prematurity [63]. Shorter pregnancy length compared to a control group along with decreased neonatal weight and increased neonatal morbidity in sheep, as observed in premature babies and neonates exposed to SSRI in utero, implicates a role for maternal SSRI treatment during late pregnancy on fetal development and preterm birth [63].…”

Section: Pregnancy Outcomes-focus On Iugr and Preterm Birthmentioning

confidence: 99%

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

Domingues

Wiltbank

Hernández

2023

Biology of Reproduction

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Maternal use of antidepressants has increased throughout the last decades; selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressants. Despite the widespread use of SSRI by women during reproductive age and pregnant women, an increasing amount of research warns of possible detrimental effects of maternal use of SSRI during pregnancy including low birthweight/small for gestational age and preterm birth. In this review we revisited the impact of maternal use of SSRI during pregnancy, its impact on serotonin homeostasis in the maternal and fetal circulation and in the placenta, and its impact on pregnancy outcomes – particularly intrauterine growth restriction and preterm birth. Maternal use of SSRI increases maternal and fetal serotonin. The increase in maternal circulating serotonin and serotonin signaling likely promotes vasoconstriction of the uterine and placental vascular beds decreasing blood perfusion to the uterus and consequently to the placenta and fetus with potential impact on placental function and fetal development. Several adverse pregnancy outcomes are similar between women, sheep, and rodents (decreased placental size, decreased birthweight, shorter gestation length/preterm birth, neonatal morbidity and mortality) highlighting the importance of animal studies to assess the impacts of SSRI. Herein, we address the complex interactions between maternal SSRI use during gestation, circulating serotonin, and the regulation of blood perfusion to the uterus and fetoplacental unit, fetal growth, and pregnancy complications.

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Section: Placental Alterationsmentioning

confidence: 89%

Section: General Perspectivesmentioning

confidence: 99%

Section: General Perspectivesmentioning

confidence: 99%

Section: General Perspectivesmentioning

confidence: 99%

Section: Pregnancy Outcomes-focus On Iugr and Preterm Birthmentioning

confidence: 99%

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

Domingues

Wiltbank

Hernández

2023

Biology of Reproduction

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The antidepressant fluoxetine (Prozac®) modulates serotonin signaling to alter maternal peripartum calcium homeostasis

Domingues,

Teixeira,

Frizzarini

et al. 2023

Sci Rep

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Antidepressant use is two-fold greater in women compared to men; however, most studies have been performed in male subjects. We aimed to understand the impact of selective serotonin reuptake inhibitors (SSRI, most used antidepressants) on calcium homeostasis and steroid metabolism during the peripartum period. Pregnant sheep (n = 10/group) were treated with vehicle or fluoxetine (most common SSRI) during the last month of gestation. Fluoxetine treatment decreased circulating calcium prior to parturition (8.7 ± 0.1 mg/dL vs 8.2 ± 0.1 mg/dL; P = 0.07). In the control group, total calcium decreased after parturition corresponding to the onset of lactogenesis followed by increase in calcium by day 2 postpartum. Interestingly, this normal transient decrease in circulating calcium was absent in fluoxetine-treated ewes. The steroids cortisol and progesterone were not altered by fluoxetine treatment whereas estradiol was decreased after the onset of treatment (12.4 ± 1.3 vs 9.1 ± 1.2 pg/mL, P = 0.05) and prior to parturition (38.1 ± 8.1 vs 22.3 ± 4.2 pg/mL, P = 0.03). Our hypothesis was supported that fluoxetine treatment alters circulating concentrations of calcium in the peripartum period; however, we surprisingly observed a decrease in estradiol concentrations contrary to reports in in vitro studies.

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A Review of Serotonin in the Developing Lung and Neonatal Pulmonary Hypertension

Archambault,

Delaney

2023

Biomedicines

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Serotonin (5-HT) is a bioamine that has been implicated in the pathogenesis of pulmonary hypertension (PH). The lung serves as an important site of 5-HT synthesis, uptake, and metabolism with signaling primarily regulated by tryptophan hydroxylase (TPH), the 5-HT transporter (SERT), and numerous unique 5-HT receptors. The 5-HT hypothesis of PH was first proposed in the 1960s and, since that time, preclinical and clinical studies have worked to elucidate the role of 5-HT in adult PH. Over the past several decades, accumulating evidence from both clinical and preclinical studies has suggested that the 5-HT signaling pathway may play an important role in neonatal cardiopulmonary transition and the development of PH in newborns. The expression of TPH, SERT, and the 5-HT receptors is developmentally regulated, with alterations resulting in pulmonary vasoconstriction and pulmonary vascular remodeling. However, much remains unknown about the role of 5-HT in the developing and newborn lung. The purpose of this review is to discuss the implications of 5-HT on fetal and neonatal pulmonary circulation and summarize the existing preclinical and clinical literature on 5-HT in neonatal PH.

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Fluoxetine-induced perinatal morbidity in a sheep model

Cited by 3 publications

References 57 publications

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

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

The antidepressant fluoxetine (Prozac®) modulates serotonin signaling to alter maternal peripartum calcium homeostasis

A Review of Serotonin in the Developing Lung and Neonatal Pulmonary Hypertension

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