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

Abstract

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 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.

Although SSRI are commonly used by pregnant women, they are associated with detrimental effects on fetal development and pregnancy outcomes likely through increasing maternal circulating serotonin leading to reduced placental vascular perfusion.

Graphical Abstract

Graphical Abstract.

Introduction

Serotonin is a vasoactive hormone with a multitude of actions throughout the body [1, 2]. Despite the most recognized role for serotonin is related to mood and behavior as a neurotransmitter, >98% of serotonin is present in nonneuronal tissues [3, 4]. Serotonin regulates physiological processes including bone and calcium metabolism, energy homeostasis, gastrointestinal motility, brain development, and vascular resistance, among numerous other functions [1, 2, 4–6]. For decades, altered serotonin signaling has been implicated in the pathophysiology of hypertension, preeclampsia, and neurodevelopment disorders in infants [5, 7–14]. Additionally, serotonin’s effects on pregnancy outcomes have been studied for decades; however, more recently, the role of serotonin in processes including embryonic and fetal brain development, placental function, intrauterine growth restriction (IUGR), and neonatal health have been in the spotlight [13, 15–20] given the increasing maternal use of medications that alter serotonin signaling, including selective serotonin reuptake inhibitors (SSRI). The possible detrimental effects of serotonin on pregnancy and neonatal outcomes support the need for a comprehensive understanding of how serotonin and medications that modulate serotonin signaling are associated with the pathophysiology of multiple conditions, such as gestational hypertension, preeclampsia, IUGR, autism spectrum disorder, preterm birth, and sudden infant death syndrome. Of critical importance is the role SSRI may play in reproductive outcomes, placental function, and fetal development.

The SSRI encompass a class of psychotropic medications used to treat several psychological conditions including depression, obsessive-compulsive disorder, and panic disorder in adult and pediatric patients [21]. Fluoxetine, the first SSRI introduced to the market, has been commercially available since the late-1980s. Since then, other SSRI have become available and now eight compounds have been approved by the Food and Drug Administration (FDA) for patient use. Among these, sertraline, fluoxetine, and citalopram are the most commonly prescribed to pregnant women [22]. Because the use of SSRI, particularly by women during reproductive age, has dramatically increased over the last three decades, numerous women are exposed to SSRI during gestation [23, 24]. The frequency of pregnant women taking SSRI during gestation varies from 6% to 13% among studies. Approximately 300 000 women and their infants yearly in the USA are exposed to SSRI during pregnancy, a critical period that is determinant for adequate maternal and fetal/neonatal wellbeing. In a recent report, 92.2% of women that took SSRI during gestation were using SSRI when they became pregnant and only about 38% of women discontinue treatment by week 13 of gestation [22]. Whether these drugs may benefit women under diverse psychological conditions is beyond the scope of this review and has been examined elsewhere [25–27]. Instead, this review will address the impacts of SSRI on serotonin signaling during gestation and its implications on pregnancy outcomes, particularly IUGR and preterm birth, and neonatal health.

Serotonin metabolism during pregnancy

In a nonpregnant state, most of the circulating serotonin is synthesized by gastrointestinal enterochromaffin cells whereas other organs minimally contribute to the nonneuronal pool of serotonin [1, 2]. However, during pregnancy and lactation, other organs secrete serotonin into the bloodstream as the demand for serotonin increases. For example, serotonin is involved in regulating maternal glucose homeostasis during pregnancy. Kim et al. [28] demonstrated increased pancreatic synthesis and secretion of serotonin leading to about a 2-fold increase in circulating concentrations of the hormone compared to nonpregnant mice. This is critical during pregnancy as serotonin promotes beta cell expansion increasing insulin secretory capacity. During lactation, mammary gland-derived serotonin is involved in the regulation of calcium homeostasis and the mammary gland secretes about 50% of circulating serotonin [29].

In the bloodstream, serotonin is primarily transported inside platelets after uptake by the serotonin transporter (SERT) located on the platelet plasma membrane [1, 3, 4]. Platelets do not synthesize serotonin on their own, therefore, all platelet content of serotonin must be taken up through SERT. Thus, platelet SERT is a key regulator of free (plasma) circulating concentrations of serotonin [4, 30]. A technical caveat of measuring circulating concentrations of serotonin is related to the type of blood sample (Figure 1). In whole blood and serum samples, lysis of platelets releases intraplatelet content of serotonin so that total, free, and intraplatelet, serotonin is measured. In plasma samples, anticoagulants prevent platelet lysis so that only free (nonplatelet) concentration of serotonin is measured. Accordingly, concentrations of total serotonin in the blood (free serotonin plus platelet content as measured in total blood and serum samples) are much greater than the free (plasma) amounts of the hormone [4, 10]. Inhibition of platelet SERT by SSRI prevents the uptake of serotonin resulting in increased free (plasma) concentrations of serotonin, even after greater degradation of free serotonin [30]. In contrast, total (whole blood and serum) concentrations of serotonin are decreased due to depleted amounts of the hormone inside platelets [30]. A similar phenomenon occurs in SERT null mice due to a lack of SERT [31].

Figure 1.

Dynamics of circulating serotonin and role of SSRI inhibition of serotonin transporter (SERT) according to blood sample type. In non-treated individuals, circulating serotonin is mostly transported inside platelets. Platelet lysis in serum and whole blood samples releases intraplatelet serotonin content so that total serotonin (intraplatelet + free) is measured. In plasma samples, anticoagulants prevent platelet lysis so only free serotonin is measured resulting in lower concentrations compared to serum or whole blood samples. Inhibition of platelet SERT in SSRI-treated individuals prevents platelet serotonin uptake. Despite the intense degradation of free serotonin, concentrations of the hormone in plasma samples are increased compared to untreated individuals. On the contrary, circulating serotonin is decreased in serum or whole blood samples due to decreased intraplatelet serotonin content. Created with BioRender.com.

Before the development of the placenta, maternal-derived serotonin modulates embryo morphogenesis and development. After placenta development, it becomes an important source of serotonin utilized by the fetus, for example for neuronal development [32]. Bonnin and colleagues [13] demonstrated that infusion of tryptophan to the uterine artery of a live mouse leads to rapid synthesis and transport of serotonin to the fetus and its detection in the umbilical vein. Towards the end of gestation, embryonic capacity for serotonin synthesis increases [13, 33, 34] so that fetal serotonin is transported into the placenta for degradation [16, 33]. Organic cation transporter 3 (OCT3) located on the fetal-facing plasma membrane of syncytiotrophoblasts and cytotrophoblasts, and likely other known transporters, promote the transfer of fetal serotonin into the placenta [16, 33]. Furthermore, fetal platelets in late pregnancy express functional SERT [35] so that both fetal platelet SERT and the placenta regulate free serotonin concentrations in the fetal circulation [16, 33, 36]. Similarly, placental synthesis of serotonin in humans appears to decrease later in pregnancy as demonstrated by the downregulation of the endocrine machinery for the synthesis of serotonin in the third trimester compared to the first trimester [33, 37].

Modulation of serotonin signaling by selective serotonin reuptake inhibitors

S‌SRI inhibition of serotonin transporter

Although the pharmacokinetics of different SSRI vary substantially, all of them inhibit SERT [38]. Inhibition of SERT in the central nervous system prevents serotonin reuptake by the presynaptic neuron resulting in increased serotonin signaling. Additionally, SSRI promote neuroplastic adaptations culminating with their psychotropic actions [39, 40].

In addition to its role in the brain, SSRI also inhibit peripheral SERT modulating serotonin signaling throughout the body [41]. Inhibition of SERT on peripheral tissues prevents serotonin transport into the cell for degradation, thereby, increasing serotonin signaling through its cell surface receptors. Furthermore, inhibition of SERT on platelets prevents the platelets’ ability to uptake free serotonin in the blood [30]. Accordingly, SSRI treatment increases the concentrations of free (plasma) circulating serotonin (Figures 1 and 2). Because of SSRI’s capacity to increase serotonin signaling in the periphery, recent studies have explored the role of SSRI on several tissues (mammary gland, bone, placenta, etc.) under physiologic and pathologic conditions and their role in altering tissue homeostasis [17, 42–44].

Figure 2.

Regulation of serotonin at the maternal–fetal interface. Circulating maternal serotonin in the intervillous space is taken up by the serotonin transporter (SERT) on the apical border of syncytiotrophoblast and degraded by placental monoamine oxidase A (MAOA). During early and mid-pregnancy, placental-derived serotonin is transported to the placental villous core by OCT3 and, in the fetal blood vessels, taken up into platelets through SERT. During late pregnancy, placental synthesis of serotonin diminishes as fetal serotonin synthesis increases so that fetal serotonin is transported into the placenta by OCT3 and degraded by placental MAOA. Created with BioRender.com.

S‌SRI modulation of serotonin signaling at the uteroplacental unit

Placental SERT is located on the apical region of syncytiotrophoblasts, that is, SERT is in direct contact with maternal blood in the intervillous space [16, 17, 33, 36, 45]. Inhibition of syncytiotrophoblast SERT by SSRI prevents the uptake of maternal serotonin into the placenta increasing serotonin concentrations in the intervillous space [16, 36, 45, 46]. Thus, the decreased SERT-mediated removal of serotonin from the maternal circulation at the placenta due to SSRI treatment, in addition to increased plasma serotonin due to inhibition of platelet SERT, leads to increased serotonin signaling associated with increased vascular resistance of placental vascular beds, which compromises blood perfusion to the uteroplacental unit [47]. Interestingly, fluoxetine inhibition of SERT and OCT3 results in increased serotonin on the maternal and fetal sides of the placenta in an ex vivo perfusion system of the human term placenta [46] and rodent placenta [36].

In addition to the inhibition of SERT, most SSRI decreased the capacity of OCT3 to transport serotonin from the fetal circulation into the placenta in an ex vivo model resulting in decreased placental uptake of fetal serotonin [16, 36, 48]. However, the wide variation for in vivo transplacental transfer of each SSRI compound results in different fetal exposure to SSRI [21, 38, 49]. Thereby, the in vivo capacity of each drug to inhibit SERT uptake of fetal serotonin into fetal platelets and to prevent placental uptake of fetal serotonin by OCT3 is not completely defined. Therefore, although all SSRI inhibit SERT on syncytiotrophoblast increasing serotonin concentrations in the intervillous space and generally on the maternal vascular bed, each SSRI may differently affect plasma content of serotonin in the fetus by modulating fetal platelet SERT function and trophoblast OCT3 fetal-placental transport.

Using in vitro and in situ models, Horackova and collaborators [36] recently demonstrated that SSRI increase serotonin concentrations in the placenta and fetus by inhibiting both SERT and OCT3. Importantly, all tested SSRI were effective at concentrations lower than plasma levels of each drug in humans. Paroxetine has the lowest IC50 for inhibition of SERT and OCT3. Notably, paroxetine appears to be the SSRI with the greatest impairment of fetal development [50, 51], perhaps due to its greater potency to inhibit SERT and OCT3 promoting more drastic alterations of maternal, placental, and fetal concentrations of serotonin. Paroxetine was the only SSRI classified as a pregnancy category D in the previous FDA drug classification, which indicated demonstrated risk for adverse fetal reaction. All other SSRI were labeled as category C.

We have recently shown that fluoxetine decreases pregnancy rates and that both fluoxetine and sertraline decrease the number of pups born as well as increase pup mortality despite their differing placental transfer properties and likely different modulation of fetal concentrations of serotonin. Sertraline had the lowest capacity of all SSRI to inhibit OCT3 and had limited placental transfer [23, 24] resulting in low concentrations of sertraline in the fetal circulation likely causing minor effects on OCT3. Conversely, the placental transfer of fluoxetine is about 70% and it effectively inhibits OCT3. Taken together, the effects of fluoxetine on the modulation of fetal serotonin by inhibiting fetal platelet SERT and placental OCT3 are likely greater than that of sertraline. Nevertheless, both fluoxetine and sertraline decrease the number of pups born and increase neonatal mortality [52]. The investigation of how each SSRI drug modulates maternal, fetal, and neonatal concentrations of serotonin will be useful to identify drugs with a more limited impact on pregnancy and neonatal outcomes.

Impact of SSRI use during gestation on pregnancy outcomes and neonatal health

General perspectives

All SSRI inhibit SERT uptake of serotonin throughout the body; however, their pharmacokinetics differ quite markedly [21, 38, 49, 53]. For example, following oral ingestion, the bioavailability of citalopram is about 95%, whereas it is less than 45% for sertraline [49]. Plasma concentrations of sertraline follow linear kinetics (an increased dose promotes a proportional increase in systemic concentrations of the drug) [54]. However, fluoxetine follows nonlinear kinetics resulting in a disproportional increase in systemic concentrations after dose augmentation due to inhibition of its metabolism (inhibition of liver enzymes CYP2D6, CYP2C, and CYP3A4) [38]. Also important, the half-life of fluvoxamine is about 15 h whereas fluoxetine has a half-life of 1–6 days [22]. Furthermore, fluoxetine metabolism produces an active metabolite, norfluoxetine, which has a longer half-life than fluoxetine itself (8–15 days) [38]. The variability in the pharmacokinetics among SSRI, in addition to an individual’s capacity to metabolize drugs [55], results in a tremendous disparity in systemic concentrations of each SSRI in the maternal circulation and subsequent impact circulating concentrations of serotonin, which may partially account for the apparent differential impact of each SSRI on pregnancy outcomes.

Placental transfer among each SSRI also varies considerably. Although variable between studies (for example fetal exposure of fluvoxamine varies from 7% to 78% compared to maternal exposure in humans), it is generally accepted that placental transfer is greater for fluoxetine, intermediate for sertraline, and lower for paroxetine [38, 49, 56]. Therefore, each SSRI may result in different fetal exposure to the drug, which may account for differences in neonatal outcomes. On the contrary, the effect of SSRI may be related to its efficacy to inhibit placental and fetal SERT and placental OCT3. Horackova et al. demonstrated that all SSRI have the potential to inhibit both placental SERT and OCT3 at systemic concentrations in humans; however, paroxetine appears to have greater potency. These conundrums of the different SSRI add complexity to the interpretation of studies that evaluate all SSRI as a single drug category.

Most studies in humans fail to evaluate the effects of each SSRI compound, the dose of exposure, and/or the gestational period of exposure. However, these conditions are relevant to understand the impact of SSRI on pregnancy and neonatal outcomes as each of these may differentially affect pregnancy outcomes and neonatal health [57]. For example, it appears that maternal use of paroxetine and citalopram, but not fluoxetine and sertraline, are associated with increased risk for fetal cranial birth defects [50]. In a recent report, neonatal respiratory distress occurred regardless of maternal treatment dose and whether SSRI treatment was discontinued during pregnancy [22]. However, only moderate and high doses of SSRI taken during entire gestation were related to preterm birth while low doses throughout gestation or dose reduction/discontinuation during the first trimester did not impact pregnancy length. Several studies demonstrated that the risk for autism spectrum disorders and congenital cardiovascular malformations are greater upon maternal exposure to SSRI during the first trimester [58]. Conversely, premature birth, low birth weight, and persistent pulmonary hypertension of the newborn occur more frequently when maternal exposure to SSRI takes place during the second and third trimesters [58]. The limited availability of studies investigating each of these specific aspects of SSRI usage in humans obscures a complete assessment of the impact of SSRI on pregnancy and neonatal outcomes. Larger, more comprehensive studies are critical to addressing the burden of increasing antidepressant use during gestation and its effects on maternal and infant health.

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, 59–62], sheep [63–66], 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. The limited availability of studies on drug pharmacology in pregnant women further supports the use of animal models [71]. Additionally, animal models allow compliance and uniformity in a dose of exposure and interval between treatments in contrast to studies in humans that often rely on data available on prescription drugs and patient adherence to treatment.

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 [72–74]. 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). The similarities between women and sheep treated with SSRI emphasize the power of the ovine model to investigate the mechanistic effects of SSRI on pregnancy and neonatal outcomes. Specifically, our experiment further supports the use of the ovine model in translational pregnancy studies to investigate the impact of SSRI on the regulation of placental function and fetal development and to explore the preclinical implementation of preventive therapies to overcome the adverse effects. Interestingly, the adverse pregnancy outcomes in women, sheep, and rodents (decreased placental size, decreased birthweight, shorter gestation length/preterm birth, neonatal morbidity, and mortality) highlight the conserved pregnancy effects of altered SERT function and serotonin signaling among species.

Placental alterations

Cardiovascular adaptations occur during pregnancy to increase blood flow to the uterus to sustain adequate embryonic/fetal needs for oxygen, nutrients, and waste exchange that increase as pregnancy progresses [75–77]. To provide a continuous increase of blood supply to the uterus and placenta as fetal demand rises throughout gestation, sustained uterine vasodilation is maintained by increased production of endothelial cell vasodilators and altered responsiveness to vasoactive hormones, for example, serotonin, angiotensin II, and epinephrine [75, 76, 78, 79]. For example, increased serotonin promotes vasoconstriction of arterial beds leading to decreased downstream blood perfusion primarily by binding to serotonin receptor 2 subtypes [47, 80]. The effects of serotonin on uterine/placental vascular perfusion have been demonstrated in rodents [81–83] and sheep [47]. Serotonin treatment to pregnant ewes during the third trimester increases uterine artery vascular resistance by 363% reducing uterine blood flow by 71% [47] and, in rats, serotonin reduces uterine blood blow flow by ~50% and the number of live fetuses by ~85% [83]. Two studies in sheep [63, 64] reported SSRI-induced placental alterations consistent with decreased uterine/placental blood perfusion. In third-trimester pregnant sheep, an intravenous bolus of fluoxetine rapidly decreased blood perfusion to the uterus, which was associated with decreased fetal oxygen saturation, partial pressure of oxygen, and blood pH, whereas partial pressure of carbon dioxide and lactate were increased [64]. In another study, pregnant sheep had decreased placentome growth when treated with fluoxetine during the last month of gestation [63]. Similarly, in humans, changes in fetal heart rate and brain blood flow at week 36 of gestation were associated with maternal SSRI use consistent with fetal hypoxia [84] likely due to a reduction in placental blood perfusion. 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, 63–65, 84–86].

Figure 3.

Proposed physiological model for the impact of SSRI on pregnancy outcomes. Free circulating serotonin and serotonin signaling are increased due to SSRI treatment leading to vasoconstriction of uterine and placental blood vessels. The decreased vascular perfusion of the fetoplacental unit is likely associated with the placental alterations observed in SSRI-treated women: increased placental pathology, decreased placental size/weight, and shorter gestation length (preterm birth). These placental alterations are consistent with adverse fetal and neonatal outcomes associated with maternal SSRI use: low birthweight/small for gestational age and increased neonatal morbidity. * Free (plasma) circulating serotonin. Created with BioRender.com.

To fully understand the impact of SSRI on pregnancy and neonatal outcomes, we must understand how the placenta is affected by SSRI treatment as placental dysfunction might be associated with adverse pregnancy outcomes [19, 58, 85–88]. However, to the best of our knowledge, only one study evaluated placental histopathological alterations in women taking SSRI during gestation. Levy et al. [44] reported multiple placental pathologies in women undergoing SSRI treatment during gestation. Placental vascular lesions of maternal malperfusion were increased 7.4-fold, fetal vascular lesions consistent with the fetal thrombo-occlusive disease were increased 3.6-fold, and composite fetal vascular malperfusion lesions were increased 2.4-fold in women taking SSRI during gestation compared to an untreated control group. Importantly, these findings were independent of possible confounders such as maternal age, gestational age (before vs after 37 weeks), smoking status, diabetes, hypertensive disorders, and neonatal birth weight. Limited studies reported placental weight in patients taking SSRI and results are inconsistent. Although Levy et al. [44] reported decreased placental weight in women taking SSRI, placental weight was greater in women taking antidepressants in two other studies, although multiple drugs were combined (SSRI, alpha-2 receptor antagonists, and serotonin-norepinephrine reuptake inhibitors) [86, 87].

There are limited reports about molecular changes in the placenta associated with maternal use of antidepressants. Kaihola et al. [89] reported increased protein expression of neurotrophic growth factor (NGF). Additionally, the downstream effector of NGF, Rho-associated coiled-coil containing protein kinase 2 (ROCK2) was also increased [89, 90]. Olivier et al. [90] suggested that altered ROCK2 expression in the placenta of women taking SSRI could be related to cardiovascular effects on fetal development although no direct causal relationship was established in their study. Placental NGF is implicated in placenta development and pregnancy maintenance and has been associated with miscarriage and preterm birth [91, 92]. In a recent report [93], SSRI decreased enzyme activity of aromatase and cytochrome P4501A1 in the human term placenta. In vivo and intro studies have also indicated that SSRI may modulate steroidogenic enzymes and steroid synthesis with a shift towards increased estrogen synthesis [94–97]. A recent study reported no effect of maternal SSRI exposure on the placental profile of DNA methylation [98]. Although these studies provided useful information concerning maternal exposure to antidepressants, the implications on placental function and clinical outcomes have not been confirmed. Further studies in human and animal models are needed to fully understand the impact of SSRI on placental blood perfusion, homeostasis, pathology, and transport function to aid in understanding the pathophysiology of pregnancy complications associated with the maternal use of SSRIs.

Studies using mutant mouse models with genetic ablation of SERT have shed light on the role of SERT on pregnancy and neonatal outcomes. Hadden and collaborators [31] reported the occurrence of large areas of necrosis, hemorrhage, and fibrosis in the placenta from SERT-null mice on embryonic day 18 (the day before delivery). Additionally, placenta cell death was 49-fold greater in SERT-null mice compared to wild-type although cellular proliferation and DNA repair were unchanged. Similar to animals and humans treated with SSRI, SERT-null mice have increased plasma concentrations of serotonin due to a lack of platelet uptake of serotonin [30, 31]. Therefore, it seems likely that the detrimental effects of altered SERT function, either due to SSRI inhibition or genetic ablation of SERT (SERT-null mice), on placental structural soundness and function, are mediated by the increased serotonin effect on placental blood perfusion as serotonin decreases blood flow to the uterus. 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. 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]. Consistent with the decreased placental vascular perfusion and function, whole transcriptome sequencing data in SERT -null mice suggest abnormal placental uptake and metabolism of nutrients [70]. 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.

Although it seems likely that the effects of SSRI on the placenta are mediated by restricting blood perfusion to the organ, a direct effect of SSRI on trophoblasts has been suggested. Protein expression of serotonin receptor 1A was greater in the placenta of SSRI-treated women [102]. Sertraline, paroxetine, and fluvoxamine decreased BeWo cell (choriocarcinoma cell line) viability and increased lactate dehydrogenase. Additionally, sertraline increased BeWo cell synthesis of reactive oxygen species, caspase 3/7 activity, and apoptosis while decreasing cellular ATP content and mitochondrial membrane potential [103]. Similarly, in JEG-3 and HIPEC cell models of extravillous trophoblasts, fluoxetine, and sertraline were cytotoxic decreasing cell viability at therapeutic levels [104]. In contrast, in another study from the same group, sertraline, and fluoxetine did not affect the viability of BeWo cells nor human placental trophoblast cells in primary culture [105]. Sertraline and fluoxetine also did not alter the expression of biomarkers of syncytialization (chorionic gonadotropin beta and gap junction protein alpha 1) in primary trophoblasts. These contradictory reports emphasize the need for more research in the area to provide more conclusive interpretations of the possible direct effects of SSRI on various placental cell types.

Pregnancy outcomes—focus on IUGR and preterm birth

For decades, SSRI have been associated with adverse pregnancy outcomes in human and animal models. It has been reported that up to 30% of infants may display some clinical manifestation related to maternal SSRI use [106]. We will focus on the adverse pregnancy outcomes that are more frequently associated with maternal SSRI use and may be encountered more often by clinicians (1) decreased birthweight/small for gestational age and (2) preterm birth. Nevertheless, dozens of other pregnancy and neonatal adverse effects have been reported (postpartum hemorrhage, birth defects, persistent pulmonary hypertension of the newborn, neonatal cardiac issues, increased NICU admissions, neonatal abstinence/toxicity, postnatal adaptation syndrome, developmental delays, autism spectrum disorder, neonatal jitteriness, increased hospital admission up to two years of birth, neonatal death, seizures, endocrine disruption, infant obesity, and respiratory distress) [107–118]. Numerous reports have investigated the role of maternal SSRI use on the occurrence of persistent pulmonary hypertension in the newborn as it appears to be one of the main neonatal side effects related to in utero exposure to SSRI [119, 120]. Noteworthy, persistent pulmonary hypertension of the newborn seems to be related to increased pulmonary vascular resistance associated with increased neonatal circulating serotonin. Additionally, some researchers have claimed that what has been previously described as neonatal withdrawal might be serotonin syndrome due to increased neuronal serotonin concentrations and signaling [121–124].

As uterine and umbilical blood flow are closely related to neonatal weight and placenta size [77, 79], experimental reduction of uterine blood perfusion results in decreased placental and fetal growth in multiple animal models [73]. Multiple studies in humans associated the use of SSRI during gestation with a greater risk for low birth weight and/or small for gestational age neonates [57, 107, 125–130] and preterm birth [51, 57, 61, 115, 125–128, 131–136]. Nevertheless, while the increased risk for preterm birth appears to be a consensus among studies, some report no association between SSRI and greater risk for low birth weight and/or small gestational age [51, 128, 135, 136]. Unfortunately, the incidence of concomitant low birthweight/small for gestational age and preterm birth is often not reported. Low birthweight/small for gestational age are the clinical manifestation of IUGR, a condition in which the fetus does not develop to its expected biological potential before birth [73, 74, 137]. In addition, IUGR is an important cause of prematurity. Both conditions, whether or not due to SSRI exposure, are associated with a greater incidence of poor neonatal outcomes, multiple diseases throughout life, and tremendous economic costs [138, 139]. The placental alterations in women and animals treated with SSRI are consistent with decreased fetal growth, likely due to decreased placental blood perfusion, resulting in low birthweight infants. Further studies are needed to confirm a causal relationship between placental alterations due to SSRI, fetal development, and preterm birth.

In animal models, decreased pregnancy rates, shorter gestation length, decreased neonatal weight, and increased neonatal mortality have been reported when dams are treated with SSRI [52, 59–61, 63, 140, 141]. The main adverse pregnancy and neonatal outcomes due to maternal SSRI treatment during gestation are shown in Table 1. Noteworthy, although pregnancy outcomes were reported in several of these studies, they were not the focus of the investigation, but maternal and/or neonatal behavioral changes due to SSRI treatment. The reports of these adverse pregnancy outcomes in different animal models, rodent strains, SSRI drugs, dosage, and period of exposure strengthen the association between maternal SSRI treatment and unfavorable pregnancy outcomes. There are no specific guidelines to determine preterm birth and prematurity in animal models, which challenges comparisons among animal studies and its translational applications to understanding pregnancy complications in women [142]. However, decreased neonatal weight and increased mortality have been used to infer prematurity in rodents [142, 143] which has been associated with SSRI treatment [52, 59–61, 140, 141]. Further support for an in utero, rather than neonatal, exposure effect of SSRI on neonatal wellbeing has been provided by Noorlander and colleagues [60]. They cross-fostered litters between control and fluoxetine-treated dams. 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]. Additionally, the apparent greater impact of SSRI on the occurrence of low birth weight/small for gestational age neonates and preterm birth upon treatment during late pregnancy [22, 58, 63] is consistent with restriction of fetal growth during the period of greater fetal growth, the last trimester of gestation [144].

Table 1.

Effects of SSRI treatment during gestation on pregnancy and neonatal outcomes in animal models

Animal model	Drug	Main pregnancy and neonatal outcomes	Ref.
Mouse	Fluoxetine	Decreased pregnancy rate, decreased maternal weight gain during gestation, decreased litter size, increased neonatal mortality, dystocia	[52]
		Decreased pregnancy rate, decreased litter size	[59]
		Increased neonatal mortality	[60]
		Decreased neonatal weight	[145]
	Sertraline	Increased embryonic resorption, decreased maternal weight gain, decreased birthweight, increased fetal malformations	[141]
		Decreased pregnancy rate, decreased maternal weight gain during gestation, decreased litter size, increased neonatal mortality, dystocia	[52]
Rat	Fluoxetine	Decreased maternal weight gain during gestation, increased estrogen, and progestogen metabolites decreased uterine weight, decreased birthweight, increased neonatal mortality	[61]
		Shorter gestation length decreased birthweight	[140]
		Decreased maternal weight gain during gestation, reduced litter size, decreased birthweight, increased neonatal mortality	[146]
		Decreased birthweight and weight gain before weaning	[147]
		Increased stillbirth, decreased birthweight, increased neonatal mortality, decreased neonatal weight gain	[148]
	Paroxetine	Decreased neonatal weight	[149]
		Shorter gestation length decreased birthweight, increased neonatal mortality	[150]
Sheep	Fluoxetine	Decreased placentome size, shorter pregnancy length, decreased birthweight, neonatal morbidity (acidemia, increased lactate, hypocalcemia)	[63]
		Transient decreased fetal blood pH, partial pressure of oxygen and oxygen saturation, increased partial pressure of carbon dioxide, higher maternal and fetal blood pressure	[64]

Future directions

In this review we addressed the complex interactions among maternal SSRI use during gestation, its modulation of serotonin concentrations and signaling, regulation of blood perfusion to the uterus and fetoplacental unit, fetal growth, and pregnancy complications. The similar pregnancy outcomes in women, rodents, and sheep studies suggest a similar pathophysiological mechanism among these species despite their different placental structures. Nevertheless, in all these species, increased maternal serotonin cause decreased uterine/placental vascular perfusion. The increase in maternal free (plasma) circulating serotonin due to SSRI use is likely associated with decreased blood flow to the uterus, placenta, and fetus. The decreased vascular perfusion limits placental and fetal growth causing placental pathology and increasing the risk for low birth weight/small for gestational age and preterm birth, which are associated with neonatal morbidity.

Despite the numerous studies demonstrating the increased risk for pregnancy complications in women taking SSRI during gestation, more studies investigating the molecular and physiological mechanisms that lead to pregnancy complications are critical to improving pregnancy outcomes in women with diverse psychological conditions. Animal studies are critical in delineating the pathways of SSRI and serotonin-induced vascular changes, placental alterations, and the consequent impact on fetal development and neonatal outcomes. Specifically, sheep appear to be a particularly useful animal model for translational studies as it allows multiple sampling, maternal and fetal instrumentation, a longer period of SSRI exposure similar to humans (in contrast to mice with shorter gestation), and assessment of in utero fetal development.

Understanding the pathophysiology of SSRI-induced adverse pregnancy outcomes is essential to optimize strategies for the treatment of psychiatric conditions. As physicians become more aware of the possible detrimental pregnancy effects of SSRI given the increasing amount of research in the area, we expect that better assessment of risk/benefit will be implemented likely reducing the number of women and infants exposed to SSRI. Alternatively, the development of therapies to mitigate the effects of SSRI could allow women to benefit from their neuronal effects without the off-target effects likely limiting their impact on pregnancy outcomes. Additionally, as alternative therapies become available, other drugs with limited side effects will benefit women and infants. In the meantime, further studies in human and animal models should address the effects of each SSRI compound, periods of exposure, and dose of each SSRI drug to possibly identify an SSRI with less detrimental effects on maternal and fetal/neonatal wellbeing.

Conflict of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Data availability

No new data were generated or analyzed in support of this research.

Author contribution

RRD (Conceptualization, investigation, funding acquisition, writing—original draft preparation, writing—review and editing), MCW (conceptualization, funding acquisition, supervision, writing—review and editing), LLH (conceptualization, funding acquisition, supervision, writing—review and editing). All authors have read and agreed to the published version of the manuscript.