Maternal Selective Serotonin Reuptake Inhibitors Research Articles

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants

Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs. Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups. Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age.

Selective serotonin reuptake inhibitors during pregnancy Do not increase the risk of Hirschsprung disease

PurposeHirschsprung disease (HSCR) is a multifactorial disease. Maternal intake of selective serotonin reuptake inhibitors (SSRI) during early pregnancy has previously been associated with increased risk for HSCR. The aim of this study was to assess the risk for HSCR in newborns after maternal intake of SSRI in a population-based Swedish cohort. MethodsThis was a Swedish nationwide, population-based, case–control cohort study containing all children born in Sweden between 1/12006 and 31/122012. The cases were identified in the Swedish National Patient Register and the controls (five age- and sex-matched controls per case) were randomly selected among children without HSCR in the cohort. Data on maternal SSRI use during pregnancy were collected from the Swedish Prescribed Drug Register. ResultsOut of 775,024 born children during the study period, 150 cases of HSCR (112 males) and 750 controls (560 males) were included. Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). The mean age was similar in mothers who had used SSRI compared to those who had not (30.9 (SD +/− 5.1) versus 30.6 (SD +/− 5.0), p = 0.81). ConclusionsThere was no increased risk of HSCR owing to maternal intake of SSRI in this cohort.Level of evidence: Level I.

M53 - EPIGENETIC DIFFERENCES IN CORD BLOOD OF NEWBORNS EXPOSED TO ANTIDEPRESSANT MEDICATION DURING PREGNANCY – A STUDY IN THE AARHUS BIRTH COHORT

Background Depression is common during pregnancy and increasing numbers of women are being prescribed antidepressant medications during pregnancy - especially Selective Serotonin Reuptake Inhibitors (SSRIs). There is emerging evidence suggesting that maternal use of SSRIs may be associated with an increased risk of congenital defects and adverse neurodevelopmental outcomes. One suggestion is that prenatal exposure to maternal depression or SSRIs might influence offspring health through a mechanism involving DNA methylation. The aim of this study was to investigate the association between SSRI exposure during pregnancy and methylation changes in the cord blood of the newborn. Methods We measured DNA methylation at over 850,000 CpG sites in cord blood from 176 newborns in the Aarhus Birth Cohort, selected according to maternal depression or SSRI use status. We carried out epigenome-wide association studies to compare DNA methylation between three groups: (1) SSRI use during pregnancy (n=88); (2) non-medicated depression during pregnancy (n=44); (3) unexposed=no depression or SSRI use during pregnancy (n=44). We performed a single-site regression analysis and a regional analysis adjusting the results for the following covariates: Maternal smoking, parity, maternal age at delivery, the use of other types of medication and Socio-Economic Status (SES), batch effects, and estimated cell composition. Results We found 99 unique Differentially Methylated Regions (DMRs) when comparing the three exposure groups. 18 DMRs were specific to the SSRI exposed compared to the unexposed, and 53 DMRs were specific to the depressed, non-medicated group vs. the unexposed. 27 DMRs were specific to the SSRI exposed compared to the non-medicated, depressed group. Finally, 1 DMR was found in both the SSRI exposed group and the depressed, non-medicated group. Discussion Prenatal exposure to untreated depression was associated with more DNA methylation differences in the newborn than prenatal exposure to SSRIs. Further research is warranted to confirm these findings and investigate causality.

Selective Serotonin Reuptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn: An Update Meta-Analysis.

Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition associated with substantial mortality and morbidity. Previous studies have suggested a possible link between maternal selective serotonin reuptake inhibitor (SSRI) use and the risk of PPHN. This study aimed to provide an up-to-date review and meta-analysis of the topic. Using the search terms [SSRI OR SSRIs OR selective serotonin reuptake inhibitors OR antidepressant OR Prozac OR fluoxetine OR Lexapro OR escitalopram] AND [pregnancy OR maternal OR newborn OR persistent pulmonary hypertension OR PPHN OR neonat* OR fet*], a preliminary search on the PubMed, Medline, EMBASE, Web of Science, and Google Scholar database yielded 7327 articles published in English between January 1, 1960 and October 1, 2017. A total of 9 cohort and case-control studies, with a total of 7,540,265 subjects were systematically reviewed. Random-effects meta-analysis of eight studies revealed a significantly increased risk of PPHN with maternal SSRI use during pregnancy, with a pooled OR of 1.516 (95% confidence interval: 1.035-1.997, p < 0.001). Overall, the absolute increase in risk of PPHN with SSRI use appears small, with an absolute risk difference of 0.619 per 1000 livebirths and a number needed to harm of 1615 women. Current evidence suggests that there were significantly greater odds of PPHN with SSRI use during pregnancy. However, the clinical significance of this association remains modest and likely outweighed by the potential benefits of treatment of perinatal depression. The risk of PPHN associated with SSRI therapy might not warrant the recommendation to withdraw antidepressant therapy, as evidence from other studies show that untreated perinatal depression presents additional adverse maternal and fetal outcomes. Given the increasing prevalence of maternal depression and consequent use of antidepressant medications, further research with robust longitudinal or randomized, controlled studies and mechanistic investigations are needed.

Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure.

Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6+/- mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy.

Maternal SSRI discontinuation, use, psychiatric disorder and the risk of autism in children: a meta-analysis of cohort studies.

We undertook an exclusive meta-analysis of cohort studies investigating the possible link between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autism spectrum disorders (ASD) in children to further investigate our previous suggestion of confounding by indication. The point estimates regarding the following cohorts were extracted and pooled: (1) pregnant women who discontinued SSRI until 3 months before pregnancy; (2) pregnant women who were exposed to SSRI during pregnancy; and (3) pregnant women with maternal psychiatric disorder but no exposure to SSRI during pregnancy. Although the pooled point estimate of the first cohort showed a trend for increase, it did not reach significance. The pooled point estimates of the latter cohorts showed a significant association with ASD which strengthens our previous suggestion of confounding by indication. Future studies should be adequately designed to differentiate whether the previously suggested association is a result of maternal psychiatric disorder or SSRI exposure or both.

Maternal selective serotonin reuptake inhibitor discontinuation, use, psychiatric disorder and the risk of autism in children: A meta-analysis of cohort studies

Linear ubiquitylation, in which ubiquitin units are covalently linked through N- and C-terminal amino acids, is a unique cellular signaling mechanism. This process is controlled by a single E3 ubiquitin ligase, the linear ubiquitin chain assembly complex (LUBAC), which is composed of three proteins – HOIL-1L, HOIP and SHARPIN. LUBAC is involved in the activation of the canonical NF-κB pathway and has been linked to NF-κB dependent malignancies. In this work, we present HOIP-based stapled alpha-helical peptides designed to inhibit LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex. We find our HOIP peptides to be active LUBAC ubiquitylation inhibitors in vitro, though through interaction with HOIP rather than HOIL. Active peptides were shown to have inhibitory effects on cell viability, reduced NF-κB activity and decreased production of NF-κB related gene products. This work further demonstrates the potential of LUBAC as a therapeutic target and of the use of stapled peptides as inhibitors of protein-protein interactions.

Variations in Neurodevelopmental Outcomes in Children with Prenatal SSRI Antidepressant Exposure.

Mood disorders and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy are common and both pose neurodevelopmental risks. This often makes the decision to treat prenatal depression with pharmacotherapy (i.e., antidepressants) challenging for clinicians and mothers. SSRIs block the reuptake of the neurotransmitter serotonin (5HT) and given its developmental role, it is not inconceivable that early changes in 5HT signaling could have an impact on early brain development. Identifying long-term neurodevelopmental effects of prenatal SSRI exposure is challenging in humans due to difficulties in distinguishing the effect of the drug from mother's mood during pregnancy and everyday environment in which the child lives, all of which contribute to shaping emotional, cognitive, and social development long after birth. In this review, we focus on the long-term neurobehavioral effects in childhood illustrating wide variations in outcomes revealing that some, but not all children appear to be affected by prenatal SSRI exposure. Emerging research reports findings that are beginning to distinguish the impact of genetic factors and the environment from prenatal medication exposure. Future research is needed to identify genetic, maternal, and environmental factors that put some children at developmental risk and others who may even benefit from maternal SSRI treatment. Birth Defects Research 109:909-923, 2017.© 2017 Wiley Periodicals, Inc.

Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors

Purpose: Associations have been made between maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy and altered behavior in offspring, including an increased risk of autism. Given the important role serotonin plays in behavior, we hypothesized SSRI exposure in the perinatal period would alter central serotonin receptor expression and program adult behaviors in mice.Methods: Female mice were injected with sertraline or saline throughout pregnancy. Offspring continued to receive injections on postnatal days 1–14, a time period in mice similar to the third trimester in human pregnancy. Adult offspring underwent behavioral testing, and serotonin receptor mRNA levels were quantified.Results: Compared to controls, SSRI exposed mice did not have a reduction in social interactions, spatial learning, or exploratory behavior. As adults, sertraline exposed mice had significantly increased mRNA levels of multiple 5-HT receptors, serotonin transporter (5-HTT), and tryptophan hydroxylase isoform 2 in the cerebral cortex.Conclusion: Although no behavioral phenotype was observed, SSRI exposure in the perinatal period permanently alters cerebral receptor mRNA levels. We speculate these shifts in mRNA expression provide important compensation during SSRI exposure. Further pre-clinical and clinical investigation into additional serotonin-regulated phenotypes is necessary to further assess the long-term implications of perinatal SSRI exposure.

Effect of Maternal ±Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain.

Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates p11 (s100a10) expression and alters neurogenesis. The protein p11 indirectly regulates 5-HT signaling through 5-HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether p11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal p11 expression and neurogenesis. The SSRI ± citalopram was administered to pregnant mice from gestational day 8 to 17. Results show that p11 is expressed in fetal thalamic neurons and thalamocortical axons. Furthermore, p11 protein expression is significantly decreased in the fetal thalamus after in utero ±citalopram exposure compared to untreated controls, and neurogenesis is significantly decreased in specific fetal brain regions. These findings reveal differential regulation of p11 expression and altered neurogenesis in the fetal brain as a result of maternal SSRI exposure.

Pharmacology Review: Maternal Selective Serotonin Reuptake Inhibitor Use and Neurologic Effects on the Neonate

The management of depression during pregnancy is complicated by the risks to the mother and the fetus by both the disease state itself as well as the medications used to treat it. Serotonin reuptake inhibitors, which include the selective serotonin reuptake inhibitors (SSRIs), are commonly used medications for the treatment of depression and other mood disorders. SSRIs readily cross the placenta and can affect fetal 5-hydroxytryptamine levels. Research into the effects of SSRIs on neonates has shown conflicting results, likely confounded by the fact that maternal depression itself may also lead to adverse outcomes for the neonate. This review aims to discuss the link between markers of fetal central nervous damage and maternal SSRI use, evaluate the literature reporting various short- and long-term neurologic effects in neonates after maternal use of SSRIs, and develop recommendations for the management of and parental counseling about various adverse neurologic outcomes of SSRI use during pregnancy.

Effect of prenatal selective serotonin reuptake inhibitor (SSRI) exposure on birthweight and gestational age: a sibling-controlled cohort study.

Up to 10% of women are exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Information on their effect on birthweight and gestational age remains conflicting. The aim of this sibling-controlled prospective cohort study is to address shared geneticand family-level confounding to investigate the effects of prenatal SSRI exposure and maternal depression on birthweight and gestational age. We used the Norwegian Mother and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). Our study population consisted of 27756 siblings; 194 were prenatally exposed to SSRIs and 27500 were unexposed to any antidepressant medication. Random and fixed effects analysis with propensity score adjustment was used to evaluate the effectson birthweight and gestational age. SSRI exposure during two or more trimesters was associated with a decrease in birthweight of 205 g [95% confidence interval (CI) -372 to - 38] and a decrease in gestational length of 4.9 days (95% CI - 9.1 to - 1.4). Neither maternal SSRI use in one trimester, lifetime history of major depression nor depressive symptoms during pregnancy were associated with these pregnancy outcomes (for non-pharmacologically treated depression in two periods in pregnancy, +5 g (95% CI - 56 to + 67) and +4.9 days (95% CI - 4.7 to + 14.7), respectively). Prenatal exposure to SSRIs during two or more trimesters may decrease birthweight and gestational length. Our results indicate that neither maternal depression nor shared genetics and family environment fully explain this association.

Maternal Use of Selective Serotonin Reuptake Inhibitors and Lengthening of the Umbilical Cord: Indirect Evidence of Increased Foetal Activity-A Retrospective Cohort Study.

BackgroundAntenatal depression affects up to 19% of pregnant women. Some of these women are also in need of antidepressant treatment. Nevertheless, the impact of maternal antidepressant treatment and prenatal depression on the course of pregnancy, foetal development and delivery outcomes is not fully understood.MethodsWe analysed data from 24 818 women who gave birth at Kuopio University Hospital between 2002–2012. Logistic regression analysis was used to estimate associations between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and the progression of pregnancy, development of the foetus and delivery outcomes.ResultsAltogether, 369 (1.5%) women used SSRIs. A regression model adjusted for age, overweight, nulliparity, prior termination, miscarriages, smoking, maternal alcohol consumption, chronic illness and polyhydramnion showed that pregnant women exposed to SSRI medication had significantly lower Apgar scores at 1 minute (p < 0.0001) and 5 minutes (p < 0.0001) and more admissions to the neonatal intensive care unit (p < 0.0001) than unexposed pregnant women. In addition, exposed newborns had longer umbilical cords (p < 0.0001) than non-exposed newborns.ConclusionIn addition to the previously known associates with maternal SSRI exposure, such as lowered Apgar scores, SSRI exposure appeared to be associated with increased umbilical cord length. The observation related to increased umbilical cord length may be explained by an SSRI-induced increase in the movements of the developing foetus.

Citalopram and sertraline exposure compromises embryonic bone development.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports

Objective To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects...

SSRI Use During Pregnancy and Autism: Is It a Real Threat?

Autism spectrum disorders (ASDs) are thought to be a result of numerous nonmodifiable risk factors, including advanced parental age, gestational diabetes, birth order, low birth weight, and hypoxia. Recent clinical findings related to the hyperserotonergic theory of ASDs have prompted debate regarding the developmental relationship between maternal selective serotonin reuptake inhibitor (SSRI) use and the manifestation of ASDs in their children, as it may be a potentially controllable prenatal risk factor. This article examines the recent studies that attempt to explore the link between SSRIs and ASDs for the purpose of clinical decision-making. In many studies, SSRIs were associated with possible neurodevelopmental delay and a small but statistically significant link to ASDs after controlling for other risk factors, but no conclusive evidence has been seen in any study. Ultimately, ASDs are the result of interacting genetic and environmental variables, of which SSRIs potentially remain one modifiable contributor, although further research is required to understand their association more thoroughly. [ Psychiatr Ann . 2015;45(2):83–88.]

Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy

Despite the high prevalence of depression, anxiety, and use of antidepressant medications during pregnancy, there is much uncertainty around the impact of high levels of distress or antidepressant medications on the developing fetus. These intrauterine exposures may lead to epigenetic alterations to the DNA during this vulnerable time of fetal development, which may have important lifetime health consequences. In this study we investigated patterns of genome-wide DNA methylation using the Illumina Infinium Human Methylation450 BeadChip in the umbilical cord blood of neonates exposed to non-medicated maternal depression or anxiety (n = 13), or selective serotonin reuptake inhibitors (SSRIs) during pregnancy (n = 22), relative to unexposed neonates (n = 23). We identified 42 CpG sites with significantly different DNA methylation levels in neonates exposed to non-medicated depression or anxiety relative to controls. CpG site methylation was not significantly different in neonates exposed to SSRIs relative to the controls, after adjusting for multiple comparisons. In neonates exposed either to non-medicated maternal depression or SSRIs, the vast majority of CpG sites displayed lower DNA methylation relative to the controls, but differences were very small. A gene ontology analysis suggests significant clustering of the top genes associated with non-medicated maternal depression/anxiety, related to regulation of transcription, translation, and cell division processes (e.g., negative regulation of translation in response to oxidative stress, regulation of mRNA export from the nucleus, regulation of stem cell division). While the functional consequences of these findings are yet to be determined, these small DNA methylation differences may suggest a possible role for epigenetic processes in the development of neonates exposed to non-medicated maternal depression/anxiety.

Perinatal maternal stress and serotonin signaling: Effects on pain sensitivity in offspring

It has been estimated that 20% of pregnant women are facing perinatal stress and depression. Perinatal maternal stress has been shown to increase pain sensitivity in offspring. For the treatment of their depressive symptoms, pregnant women are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). Since the descending pain inhibitory circuit matures perinatally, perinatal SSRI exposure has been shown to affect pain sensitivity in offspring. In the present review, we summarize experimental and clinical evidence for the effect of perinatal maternal stress and SSRI exposure on pain sensitivity in offspring. Both experimental and clinical studies show the effect of perinatal maternal stress on regulation of the hypothalamic-pituitary-adrenal (HPA) system and the serotonin pain inhibitory system. Alterations in these two systems likely underlie long-term alterations in the development of pain sensitivity. This review sheds light on the effect of perinatal maternal stress and treatment with SSRIs on offspring pain sensitivity, in relation to the developing HPA system and 5-HT signaling.

Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity‐score matched cohort in CPRD

Research on the association of maternal selective serotonin reuptake inhibitor (SSRI) use and cardiac malformations in the offspring has yielded conflicting findings. We therefore sought to further investigate the association using data from a large population-based cohort in the UK. The study population consisted of 149 464 pregnancies ending in a live birth between January/1996 and November/2010 from the Clinical Practice Research Datalink's Mother Baby Link. We created propensity-score matched cohorts of first-trimester SSRI users who did not use other antidepressants in the same gestational period ('SSRI users', n=3046) and non-antidepressant users (no use from the 3 months before pregnancy through the second trimester of pregnancy, 'non-users'; n=8991). Weighted logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cardiac malformations overall and septal defects diagnosed in the first year of life, or in the first 6 years of life. Sixteen infants with cardiac malformations were identified among SSRI users; 10 of them were septal defects. Among non-users, there were 48 infants with cardiac malformations, 26 of whom had septal defects. The OR (95% CI) for cardiac malformations was 1.00 (0.50; 2.00), and for septal defects was 1.15 (0.46; 2.87). Results were similar for cardiac malformations diagnosed in the first 6 years of life, and in several sensitivity analyses that were also implemented. The results of this study are most compatible with no association between maternal use of SSRIs in early pregnancy and cardiac malformations or septal defects in the offspring. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring.

Early life events can significantly alter the development of the nociceptive circuit. In fact, clinical work has shown that maternal adversity, in the form of depression, and concomitant selective serotonin reuptake inhibitor (SSRI) treatment influence nociception in infants. The combined effects of maternal adversity and SSRI exposure on offspring nociception may be due to their effects on the developing hypothalamic-pituitary-adrenal (HPA) system. Therefore, the present study investigated long-term effects of maternal adversity and/or SSRI medication use on nociception of adult Sprague-Dawley rat offspring, taking into account involvement of the HPA system. Dams were subject to stress during gestation and were treated with fluoxetine (2×/5 mg/kg/day) prior to parturition and throughout lactation. Four groups of adult male offspring were used: 1. Control+Vehicle, 2. Control+Fluoxetine, 3. Prenatal Stress+Vehicle, 4. Prenatal Stress+Fluoxetine. Results show that post-operative pain, measured as hypersensitivity to mechanical stimuli after hind paw incision, was decreased in adult offspring subject to prenatal stress alone and increased in offspring developmentally exposed to fluoxetine alone. Moreover, post-operative pain was normalized in prenatally stressed offspring exposed to fluoxetine. This was paralleled by a decrease in corticosteroid binding globulin (CBG) levels in prenatally stressed offspring and a normalization of serum CBG levels in prenatally stressed offspring developmentally exposed to fluoxetine. Thus, developmental fluoxetine exposure normalizes the long-term effects of maternal adversity on post-operative pain in offspring and these effects may be due, in part, to the involvement of the HPA system.