Maternal Selective Serotonin Reuptake Inhibitors Research Articles

The Effect of SSRI Exposure in Pregnancy on Early Respiratory and Metabolic Adaptation in Infants Born Preterm

Selective serotonin reuptake inhibitors (SSRIs) are increasingly used for maternal depression during pregnancy; however, their use has been linked to adverse effects in newborns. Respiratory and feeding problems, jaundice, metabolic and temperature dysregulation and hypoglycemia have been described in term infants. However, scarce data exists on early neonatal adaptation in exposed infants born prematurely. We aimed to assess the effects of SSRI exposure on early neonatal adaptation measures in infants born prematurely. Data from preterm infants exposed to maternal SSRIs during pregnancy and from matched controls were retrospectively collected. Forty-two infants comprised the final cohort: 21 infants with SSRI exposure and 21 matched controls. 1 min Apgar score was significantly lower in the exposed group compared to the non-exposed group (p = 0.043). No differences were found in 5 min Apgar scores, cord pH, need for delivery room resuscitation, rate of hypoglycemia, hyponatremia, hyperbilirubinemia, need for phototherapy, temperature stability and maximal oxygen requirements. No differences were found in the total time of respiratory support, time to reaching full enteral feeds, length of stay and complications of prematurity. Unlike studies in term infants, no significant differences were found in adaptation and short-term outcomes between preterm infants with and without SSRI exposure in pregnancy.

Associations between maternal depressive symptoms and selective serotonin reuptake inhibitor antidepressant treatment on internalising and anxiety behaviours in children: 12-year longitudinal study

Prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure is associated with increased internalising and anxious behaviours in young children; whether this continues into early adolescence is unknown. Also, it is not well established whether it is the in utero exposure to SSRIs or the underlying maternal mood that contributes more to these associations. To examine associations between maternal depressive symptoms, prenatal SSRI antidepressant treatment and internalising and anxiety behaviours from childhood into pre-adolescence. From a prospective longitudinal cohort, measures of maternal depressive symptoms and SSRI use and child outcomes (n = 191 births) were obtained from the second trimester to 12 years. Maternal reports of internalising and anxiety behaviours in children were obtained at 3, 6 and 12 years. Multilevel mixed-effects models revealed that maternal depressed mood at the third trimester assessment, not prenatal SSRI exposure, was associated with longitudinal patterns of higher levels of internalising and anxiety behaviours across childhood from 3 to 12 years of age. At each age, hierarchical regressions showed that maternal mood at the third trimester, compared with current maternal depression or prenatal SSRI exposure, explained a greater proportion of the variance in internalising and anxiety behaviours. Even with prenatal SSRI treatment, maternal depressed mood during the third trimester still had an enduring effect as it was associated with increased levels of internalising and anxiety behaviours across childhood and into early adolescence. Importantly, we found no evidence of a 'main effect' association between prenatal SSRI exposure and internalising and anxiety behaviours in children.

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood. In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood (“maternally-depressed”), and we further classified cases into SSRI-exposed, maternally-depressed (n = 14); SSRI-exposed, not maternally-depressed (n = 6); SSRI non-exposed, maternally-depressed (n = 20); and SSRI non-exposed, not maternally-depressed (n = 24). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n = 31; males n = 33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.

Prenatal stress and fluoxetine exposure in mice differentially affect repetitive behaviors and synaptic plasticity in adult male and female offspring

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal depression but prenatal SSRI exposure itself may be a risk factor for autism in offspring. The present study investigated in C57BL/6J pregnant mice whether restraint stress (G4–18) and/or treatment with the SSRI fluoxetine (G8–18) affects autism-related behaviors and hippocampal synaptic plasticity in male and female offspring. The findings indicate that restraint stress reduces preference for sucrose reward in pregnant dams that is reversed by fluoxetine. In adult male offspring, combined prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning. In adult female offspring, the prenatal experiences did not affect self-grooming, but restraint stress alone or SSRI exposure alone impaired spatial reversal learning. Prenatal stress reduced anxiety-related behavior in male and female offspring. Further, LTP induced by theta-burst stimulation of Schaffer-commissural afferents in field CA1 was significantly reduced in female offspring exposed to prenatal stress alone or combination with fluoxetine. Together, these findings suggest that exposure to prenatal stress, SSRI treatment or the combination differentially affects male and female offspring in autism-like behaviors and synaptic plasticity.

Hypersensitivity of Zebrafish htr2b Mutant Embryos to Sertraline Indicates a Role for Serotonin Signaling in Cardiac Development.

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants prescribed in 10% of pregnancies in the United States. Maternal use of SSRIs has been linked to an elevated rate of congenital heart defects, but the exact mechanism of pathogenesis is unknown. Previously, we have shown a decrease in cardiomyocyte proliferation, left ventricle size, and reduced cardiac expression of the serotonin receptor 5-HT 2B in offspring of mice exposed to the SSRI sertraline during pregnancy, relative to offspring of untreated mice. These results suggest that disruption of serotonin signaling leads to heart defects. Supporting this conclusion, we show here that zebrafish embryos exposed to sertraline develop with a smaller ventricle, reduced cardiomyocyte number, and lower cardiac expression of htr2b relative to untreated embryos. Moreover, zebrafish embryos homozygous for a nonsense mutation of htr2b ( htr2bsa16649 ) were sensitized to sertraline treatment relative to wild-type embryos. Specifically, the ventricle area was reduced in the homozygous htr2b mutants treated with sertraline compared with wild-type embryos treated with sertraline and homozygous htr2b mutants treated with vehicle control. Whereas long-term effects on left ventricle shortening fraction and stroke volume were observed by echocardiography in adult mice exposed to sertraline in utero, echocardiograms of adult zebrafish exposed to sertraline as embryos were normal. These results implicate the 5-HT 2B receptor functions in heart development and suggest zebrafish are a relevant animal model that can be used to investigate the connection between maternal SSRI use and elevated risk of congenital heart defects.

Severe Pulmonary Stenosis in a Newborn with Antenatal Exposure to Selective Serotonin Reuptake Inhibitor Drug: A Case Report

Depression in pregnancy is being recognized as a major contributor to adverse maternal and fetal outcomes. Recent years have seen significant research focused on the development of safe pharmacological methods to treat depression in pregnancy, resulting in the common use of selective serotonin reuptake inhibitors (SSRIs) as a first line of treatment. There have been a few reports of congenital birth defects associated with the consumption of SSRIs during pregnancy, particularly congenital heart defects. Several studies have attempted to evaluate the relationship between SSRI use and congenital heart defects in neonates, but they were inconclusive. In this report, a case where maternal SSRI intake during two consecutive pregnancies was associated with neonatal pulmonary valve stenosis, raising the possibility of a correlation between the usage of a certain SSRI, and a particular congenital heart defect has been described. Keywords: Congenital heart defects, Depression, Pregnancy, Pulmonary valve stenosis, Serotonin uptake inhibitors

The Relationship Between Maternal Antidepressants and Neonatal Hypoglycemia: A Systematic Review.

The aim of the article is to review systematically current researches investigating the relationship between intrauterine exposure to antidepressants and neonatal hypoglycemia. This paper included studies published in electronic databases from January 2005 to July 2020. The searched keywords were as follows: antidepressants, pregnancy, selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, escitalopram, sertraline, fluvoxamine, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), venlafaxine, tricyclic antidepressants (TCAs), neonatal outcomes, neonatal hypoglycemia, imipramine, clomipramine, amitriptyline, bupropion, trazodone, and mirtazapine. This review examined 10 relevant studies. The odds ratio/risk ratio reported in the studies were 1.33-1.73 for any antidepressant, 1.30-1.35 for SSRI, 1.42-2.11 for SNRI, and 2.07 for TCAs. The risk of neonatal hypoglycemia in infants exposed to maternal TCAs appears to be slightly higher compared to infants exposed to maternal SSRIs. Data from current studies consistently show that exposure to maternal antidepressants during pregnancy may be related to increased risk of neonatal hypoglycemia in infants.

Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood–brain barrier (BBB). TriozanTM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + TriozanTM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Interactions between maternal fluoxetine exposure, the maternal gut microbiome and fetal neurodevelopment in mice

Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.

Maternal Psychiatric Conditions, Treatment With Selective Serotonin Reuptake Inhibitors, and Neurodevelopmental Disorders

BackgroundThis study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitor (SSRI) use during preconception and pregnancy with risk of neurodevelopmental disorders in offspring. MethodsWe used data from the Study to Explore Early Development, a multisite case-control study conducted in the United States among children born between 2003 and 2011. Final study group classifications of autism spectrum disorder (ASD) (n = 1367), developmental delays or disorders (DDs) (n = 1750), and general population controls (n = 1671) were determined by an in-person standardized developmental assessment. Maternal psychiatric conditions and SSRI use during pregnancy were ascertained from both self-report and medical records. We used logistic regression to evaluate associations of ASD and DDs (vs. population controls) with maternal psychiatric conditions and SSRI treatment in pregnancy. To reduce confounding by indication, we also examined SSRI associations in analyses restricted to mothers with psychiatric conditions during pregnancy. ResultsPsychiatric conditions and SSRI use during pregnancy were significantly more common among mothers of children with either ASD or DDs than among population controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio 1.81, 95% confidence interval 1.44–2.27) as in mothers who did use SSRIs (adjusted odds ratio 2.05, 95% confidence interval 1.50–2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (adjusted odds ratio 1.14, 95% confidence interval 0.80–1.62). Primary findings for DDs exhibited similar relationships to those observed with ASD. ConclusionsMaternal psychiatric conditions but not use of SSRIs during pregnancy were associated with increased risk of neurodevelopmental disorders in offspring.

Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.

Acute Delivery Room Resuscitation of Neonates Exposed to Selective Serotonin Reuptake Inhibitors

To determine whether full-term neonates with in utero exposure to selective serotonin reuptake inhibitors (SSRI) require respiratory support in the delivery room, as indicated by the standardized Neonatal Resuscitation Program algorithm, significantly more often than nonexposed neonates. In this retrospective cohort study, we extracted data from medical records of full-term neonates with and without in utero SSRI exposure, defined as documentation of third trimester maternal SSRI treatment. A hospital-based sample was identified at Northwestern Medical Hospital in Chicago, Illinois. Full-term singleton newborns identified in a 6-month period (n=4933) were selected for study. Neonates with a major congenital anomaly were excluded. The primary outcome was initiation of respiratory support in the delivery room, as indicated by the Neonatal Resuscitation Program algorithm. Of the 4933 full-term singleton neonates, 3.3% were exposed to SSRI in utero. Respiratory support was initiated significantly more often in SSRI exposed (12.9%) than unexposed (4.2%) neonates (covariate-adjusted OR, 4.04; 95% CI, 2.40-6.49). In utero SSRI exposure also was associated with a higher rate of neonatal intensive careunit admission (covariate-adjusted OR, 2.19; 95% CI, 1.30-3.50) and 1-minute Apgar score of ≤5 (covariate-adjusted OR, 3.51; 95% CI, 2.07-5.67). In this cohort, in utero SSRI exposure was associated with a significantly greater odds of resuscitation in the delivery room as well as neonatal intensive care unit admission. Although the mechanism underlying these associations have not been determined and causality cannot be assumed, these findings supporta recommendation that third trimester SSRI exposure be considered a risk factor for needing resuscitation.

Semax, synthetic ACTH(4–10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats

Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4–10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1–14, a time period equivalent to 27–40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15–28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development.

Effects of maternal depression and prenatal SSRI exposure on executive functions and susceptibility to household chaos in 6-year-old children: prospective cohort study.

Maternal depressed mood during pregnancy may shape a child's adaptation to their environment and engagement in goal-directed behaviour such as executive functions. Whether everyday household context also alters executive functions in children with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure remains to be determined. To examine the impact of prenatal depressed maternal mood and SSRI exposure on child executive functions and to determine whether these exposures shape a susceptibility to household chaos. A prospective cohort study of mothers and their children (118 mother-children dyads (47 SSRI-exposed, 71 non-exposed)) followed from the second trimester to 6 years. Regression models examined relationships between maternal depressed mood and household chaos on maternal report of child executive functions. Competitive-confirmatory regression models examined whether children were susceptible to household chaos or were positively influenced by less chaos. Prenatal SSRI exposure, third-trimester maternal depressed mood and household chaos in a three-way interaction were associated with executive functions within a model of differential susceptibility. When household chaos was low, children of non-prenatally depressed mothers had better executive function than children of prenatally depressed mothers, regardless of whether the mothers were SSRI-treated. However, when household chaos was high, SSRI-exposed children of mothers who were not depressed during pregnancy had poorer executive functions at 6 years of age compared with SSRI-exposed children whose mothers were symptomatic during pregnancy. The impact of household chaos depended on whether mothers were prenatally depressed and whether mothers were SSRI-treated.

What tomorrow will bring: Expectations for the next day predicting the cortisol awakening response in young adults

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Maternal use of selective serotonin reuptake inhibitors (SSRI) during pregnancy-neonatal outcomes in correlation with placental histopathology.

We investigated the association between prenatal selective serotonin reuptake inhibitors (SSRI) exposure and pregnancy-outcomes with correlation to placental-histopathology. Included were pregnancies with maternal SSRI use throughout pregnancy (SSRI-group) and the control group was matched with pregnancies unexposed to SSRI. Placental lesions were classified according to the "Amsterdam" criteria. Adverse neonatal outcome was defined as ≥1 early neonatal-complications. SSRI group had lower birthweights (p < 0.001), higher rates of meconium (p = 0.009), NICU admissions (p < 0.001), and adverse neonatal-outcome (p < 0.001). SSRI placentas had lower birthweight-to-placental-weight ratio (p = 0.02) and higher rates of fetal vascular malperfusion (FVM) lesions (p = 0.03). Using multivariable analyses: GA < 37 weeks (aOR = 2.1, 95%CI 1.7-4.6) and SSRI (aOR = 1.7, 95%CI 1.3-3.9) were independently associated with adverse neonatal outcome while GA < 37 weeks (aOR = 1.6, 95%CI 1.2-3.4), SSRI (aOR = 1.3, 95%CI 1.1-2.6), and smoking (aOR = 1.2, 95%CI 1.1-4.0) were independently associated with FVM lesions. SSRI use during pregnancy was independently associated with adverse neonatal outcome and placental FVM.

Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression

ABSTRACT Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear. We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively. Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides. Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.

Placental glucocorticoid receptors are not affected by maternal depression or SSRI treatment

Background: Prenatal depression is common, with an estimate that up to one in five pregnant women suffers from depressive symptoms. Maternal depression is associated with poor pregnancy outcomes such as preterm birth and low birth-weight. Such outcomes possibly affect offspring development. Previous studies suggest placental RNA levels of the glucocorticoid receptor are altered by maternal depression or anxiety; this stress may affect the placenta of male and female foetuses differently. However, it is unknown if the protein levels and activity of this receptor are additionally affected in women with depressive symptoms or being pharmacologically treated for depression.Methods: In this study, we investigated whether the glucocorticoid receptor (NR3C1) in the placenta is affected by maternal depression and/or selective serotonin reuptake inhibitor (SSRIs) treatment. Placentas from 45 women with singleton, term pregnancies were analysed by Western blot to determine glucocorticoid receptor levels, and by DNA-binding capacity to measure glucocorticoid receptor activation.Results: There were no differences in levels of the glucocorticoid receptor or activity between groups (control, depressive symptoms, and SSRI treatment; n = 45). Similarly, there was no difference in placental glucocorticoid receptor levels or activity dependent upon foetal sex.Conclusion: Maternal depression and SSRI treatment do not affect the glucocorticoid receptors in the placenta.

332: Maternal use of SSRIs during pregnancy - neonatal outcomes in correlation with placental histopathology

The association between maternal Selective Serotonin Reuptake Inhibitors (SSRIs) exposure during pregnancy and adverse pregnancy outcomes is controversial. We aimed to investigate the association between prenatal SSRIs exposure and pregnancy outcomes with correlation to placental histopathology. The study group included all singleton pregnancies with maternal SSRIs use throughout pregnancy (SSRIs group) that had a full placental histopathology-report. The control group was matched in a 1:1 ratio with unexposed pregnancies matched by year, mode of delivery, gestational-age, and maternal age. Pregnancy and placental reports of both groups were reviewed. Placental lesions were classified according to the current “Amsterdam” criteria. Adverse neonatal outcome was defined as ≥1 early neonatal complications. Multivariable regression analyses were performed to identify independent associations with adverse neonatal outcome and with specific placental lesions. Included were 82 cases of maternal SSRIs use and 82 matched controls. The SSRIs group had higher rates of smoking (p< 0.001), lower birthweights (2948±599 vs. 3331±647 gr, p< 0.001), higher rates of meconium (p=0.009), NICU admissions (p< 0.001), and composite adverse neonatal outcome (32.9% vs. 8.5%, p< 0.001). Placentas from the SSRIs group were characterized by lower birth-weight/placental-weight ratio (p=0.02) and higher rates of fetal vascular malperfusion (FVM) lesions (23.1% vs. 9.7%, p=0.03). Using multivariable regression analysess (table) GA < 37 weeks (aOR=2.1 95% CI 1.7-4.6), and SSRI use (aOR=1.7 95% CI 1.3-3.9) were independently associated with composite adverse neonatal outcome, while GA < 37 weeks (aOR=1.6 95% CI 1.2-3.4), SSRI use (aOR=1.3 95% CI 1.1-2.6), and smoking (aOR= 1.2 95% CI 1.1-4.0) were independently associated with FVM lesions. Maternal SSRIs use during pregnancy was independently associated with adverse neonatal outcome and placental FVM lesions. Prospective studies are needed to further study this association.