Maternal Selective Serotonin Reuptake Inhibitors Use Research Articles

Sertraline-Induced 5-HT Dysregulation in Mouse Cardiomyocytes and the Impact on Calcium Handling.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 15% of pregnancies in the United States for depression. Maternal use of SSRIs has been linked to an increased risk of congenital heart defects, but the exact mechanism of pathogenesis is unknown. SSRIs, including sertraline, are permeable to the placenta and can produce direct fetal exposure. Previously, we have shown decreased cardiomyocyte proliferation, left ventricle size, and cardiac expression of the serotonin receptor 5-HT2B in offspring of mice exposed to the SSRI sertraline relative to offspring of saline-exposed mice. Using a mouse model of in utero plus neonatal sertraline exposure, we observed lengthened peak-to-peak time of calcium oscillation (saline 784 ±76 ms; sertraline 1121 ± 130 ms, p<0.001) and decreased expression of critical genes in calcium regulation. We also observed significant up-regulation of specific miRNAs that modulate serotonin signaling in neonatal cardiac tissues (Slc6a4: miR-223-5p, miR-92a-2-5p, miR-182-5p; Htr2a: miR-34b-5p, miR-182-5p; Htr2b: miR-223-5p, miR-92a-2-5p, miR-337-5p) (p<0.05) with corresponding levels of the target mRNAs down-regulated (Slc6a4 0.73 ± 0.05; Htr2a 0.67 ± 0.04; Htr2b 0.72 ± 0.03; all p< 0.01), resulting in decreased production of the cognate proteins. Adult mice at 10 weeks showed altered cardiac parameters including decreased heart rates in males (saline 683 ± 8 vs sertraline 666 ± 6 beats per minute, p< 0.05) and ejection fraction in females (saline 83.9 ± 0.6% vs sertraline 80.6 ± 1.1%, p<0.05). These findings raise the question if sertraline exposure during development may increase the potential risk for cardiac disease when subjected to stress.

Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH.

Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation is associated with the effects of EtOH exposure on the development of fetal serotonergic (5-HT) and/or dopaminergic (DA) pathways, i.e., pathways that in postnatal life are believed to regulate mood. Many women who use alcohol (ethanol, EtOH) during pregnancy suffer from depression and take selective serotonin reuptake inhibitors (SSRIs), which might influence these monoaminergic pathways in the fetus. Alternatively, monoaminergic pathway abnormalities might reflect a direct effect of EtOH on the fetal brain. To distinguish between these possibilities, we measured their expressions in fetal brains and in fetal brain-derived exosomes (FB-Es) isolated from the mothers' blood. We hypothesized that maternal use of EtOH and/or SSRIs during pregnancy would be associated with impaired fetal neural development, detectable as abnormal levels of monoaminergic and apoptotic biomarkers in FB-Es. Fetal brain tissues and maternal blood were collected at 9-23 weeks of pregnancy. EtOH groups were compared with unexposed controls matched for gestational age (GA). The expression of 84 genes associated with the DA and 5-HT pathways was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on microarrays. FB-Es also were assayed for serotonin transporter protein (SERT) and brain-derived neurotrophic factor (BDNF) by enzyme-linked immunosorbent assay (ELISA). Six EtOH-exposed human fetal brain samples were compared to SSRI- or polydrug-exposed samples and to unexposed controls. EtOH exposure was associated with significant upregulation of DA receptor D3 and 5-HT receptor HTR2C, while HTR3A was downregulated. Monoamine oxidase A (MAOA), MAOB, the serine/threonine kinase AKT3, and caspase-3 were upregulated, while mitogen-activated protein kinase 1 (MAPK1) and AKT2 were downregulated. ETOH was associated with significant upregulation of the DA transporter gene, while SERT was downregulated. There were significant correlations between EtOH exposure and (a) caspase-3 activation, (b) reduced SERT protein levels, and (c) reduced BDNF levels. SSRI exposure independently increased caspase-3 activity and downregulated SERT and BDNF. Early exposure to EtOH and SSRI together was associated synergistically with a significant upregulation of caspase-3 and a significant downregulation of SERT and BDNF. Reduced SERT and BDNF levels were strongly correlated with a reduction in eye diameter, a somatic manifestation of FASD. Maternal use of EtOH and SSRI during pregnancy each was associated with changes in fetal brain monoamine pathways, consistent with potential mechanisms for the affective dysregulation associated with FASD.

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.

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 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.

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.

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.

Depletion of Cranial Suture Stem Cells by Pharmacological Exposures May Precipitate Premature Suture Fusion

The CDC National Birth Defects Prevention Study has published data suggesting that “environmental” exposures including maternal thyroid diseases, use of selective serotonin reuptake inhibitors (SSRIs), and maternal nicotine use may increase the incidence and or severity of craniofacial anomalies including craniosynostosis. Craniosynostosis is defined as the premature fusion of the suture(s) of the skull occurring in 1:1800–2500 births. A proposed mechanism of craniosynostosis is the disruption of proliferation and differentiation of stem cells in the perisutural area. Here, we hypothesize that the aforementioned teratogenic exposures can cause a depletion of stem cells within the suture resulting in premature suture fusion. To determine if in utero pharmacological exposures deplete stem cells within the calvarial sutures, we exposed pregnant wild‐type mice to levothyroxine, citalopram (SSRI), and nicotine and investigated suture fusion and the presence of stem cell markers ex vivo. Additionally, we exposed primary calvarial suture derived cells to clinically relevant doses levothyroxine, citalopram, and nicotine in vitro and assessed the presence of stem markers via flow cytometry. Micro‐CT assessment of coronal and posterior interfrontal suture fusion revealed that in utero exposure to nicotine and citalopram increased the risk of premature posterior interfrontal suture fusion and exposure to citalopram resulted in an increased likelihood for coronal suture fusion at post‐natal day 15. Further, we confirmed a reduction in Gli1+ cells ex vivo in correlation with in utero teratogen exposure. Our in vitro analysis also indicates a depletion of stem cell populations with teratogen exposure via flow cytometry. Teratogenic exposures including maternal thyroid disorder, maternal use of SSRIs and maternal nicotine use may target calvarial stem cell populations for depletion precipitating an increased risk for craniosynostosis. Investigating the newly defined stem cell niche of the calvarial sutures and its relationship to suture maintenance will provide insight into future manipulation of these cells for therapeutic benefit.Support or Funding InformationNational Institute of Dental and Craniofacial Research [F31DE026684 to ELD; R03DE023350A and R03DE02619‐01A to JC; 5T32DE017551 to MUSC]Cleft Palate Foundation Cleft/Craniofacial Anomalies Grant Award to JCPlastic Surgery Education Foundation Pilot Award to JCNational Institute on Aging (NIA) 1P01AG036675 (Augusta University)National Institutes of Health National Institute of General Medicine [P30GM103331]South Carolina Clinical and Translational Research Institute (NIH/NCATS NIH/NCATS UL1TR000062)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

SSRI Use During Pregnancy May Increase Risk of Language Delays in Offspring

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessSSRI Use During Pregnancy May Increase Risk of Language Delays in OffspringVabren WattsVabren WattsSearch for more papers by this authorPublished Online:12 Dec 2016https://doi.org/10.1176/appi.pn.2016.12a5AbstractThe association was present only among mothers who had made more than one SSRI purchase during pregnancy.Children of women who took selective serotonin reuptake inhibitors (SSRIs) during pregnancy may be at an elevated risk of speech and language disorders, according to a study published in JAMA Psychiatry in October. While experts say the study raises important questions, more research is needed to determine whether exposure to SSRIs confers greater risk than untreated depression during pregnancy over the long term.Alan S. Brown, M.D., M.P.H., says environmental and genetic factors must be taken into account before prenatal exposure to SSRIs can be linked to speech/language disorders.Columbia University Medical CenterAlan S. Brown, M.D., M.P.H., director of the Unit in Birth Cohort Studies at the New York State Psychiatric Institute, and colleagues tracked the incidence of speech/language, scholastic, and motor disorders from birth to 14 years in 56,000 children born in Finland between 1996 and 2010. The offspring were divided into three groups: 15,596 were in the SSRI-exposed group (mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy); 9,537 were in the unmedicated group (mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy); and 31,207 were in the unexposed group (mothers without a psychiatric diagnosis or a history of purchasing SSRIs). Over the study period, there was a total of 829, 187, and 285 instances of speech/language, scholastic, and motor disorders, respectively, in the three groups. The authors found that children in the SSRI-exposed group and the unmedicated group were at a significantly increased risk of speech/language disorders compared with those in the unexposed group.Additional analysis revealed that children of mothers who purchased SSRIs at least twice during pregnancy had a 37 percent increased risk of speech/language disorders compared with offspring in the unmedicated group and a 63 percent increased risk compared with children in the unexposed group. There were no significant differences in the risk of the other disorders between offspring in the SSRI-exposed group and the unmedicated group.“Overall the study is reassuring because there were no scholastic or motor associations, and the risk of language delay, if real, is very small,” Jennifer L. Payne, M.D., the director of the Women’s Mood Disorders Center at Johns Hopkins School of Medicine, told Psychiatric News. Payne, who is also an associate professor of psychiatry and behavioral sciences, was not involved in the study.However, she noted that because the study did not control for severity of depression or postpartum depression, there is no way of knowing whether antidepressant exposure is actually associated with speech and language delays.“Postpartum depression has long been known to affect language development and IQ in children,” she said.In an accompanying editorial in JAMA Psychiatry, Lee Cohen, M.D., and Ruta Nonacs, M.D., Ph.D., of Massachusetts General Hospital wrote of the unknowns that remain regarding maternal use of SSRIs. “Brown et al. have identified a very important research question, … sbut the current report does not answer whether exposure to SSRIs or untreated depression during pregnancy is in equipoise with respect to neurodevelopmental toxicity or if, over the long term, one confers greater risk,” they wrote.“Given the extent to which depression during pregnancy predicts risk for postpartum depression with its attendant morbidity, and in light of the robust data describing the adverse effects of maternal psychiatric morbidity on long-term child development, clinicians will need to broaden the conceptual framework used to evaluate relative risk of SSRI use during pregnancy as they navigate this clinical arena with patients making individual decisions to match patient wishes,” Cohen and Nonacs concluded. The study was funded by the National Institutes of Health. ■An abstract of “Association of Selective Ser-otonin Reuptake Inhibitor Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring” can be accessed here. ISSUES NewArchived

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.

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...

Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy--an epidemiological study using validated EUROCAT data.

BackgroundPrevious studies suggest a possible association between maternal use of selective serotonin-reuptake inhibitors (SSRIs) during early pregnancy and congenital heart defects (CHD). The purpose of this study was to verify this association by using validated data from the Danish EUROCAT Register, and secondary, to investigate whether the risk differs between various socioeconomic groups.MethodsWe conducted a cohort study based on Danish administrative register data linked with the Danish EUROCAT Register, which includes all CHD diagnosed in live births, fetal deaths and in pregnancies terminated due to congenital anomalies. The study population consisted of all registered pregnancies (n = 72,280) in Funen, Denmark in the period 1995–2008. SSRI-use was assessed using The Danish National Prescription Registry, information on marital status, maternal educational level, income, and country of origin from Statistics Denmark was used as indicators of socioeconomic situation, and the CHD were studied in subgroups defined by EUROCAT. Logistic Regression was used to investigate the association between redeemed prescriptions for SSRIs and CHD.ResultsThe risk of severe CHD in the offspring of the 845 pregnant women who used SSRIs during first trimester increased four times (AOR 4.03 (95% CI 1.75-9.26)). We found no increased risk of septal defects. Socioeconomic position did not modify the association between maternal SSRI-use during pregnancy and severe CHD.ConclusionThis study, which is based on data with high case ascertainment, suggests that maternal use of SSRIs during first trimester increases the risk of severe CHD, but does not support findings from previous studies, based on administrative register data, regarding an increased risk of septal defects. The study was unable to document an interaction between socioeconomic status and maternal SSRI-use on the risk of severe CHD.

Use of Selective Serotonin Reuptake Inhibitors During Pregnancy and Risk for Autism

Selective serotonin reuptake inhibitors (SSRIs) are used as first-line treatment of depression/anxiety disorders because of their efficacy and safety. Because SSRIs cross the placenta, cognitive and behavioral development in the child is a concern. Autism spectrum disorders (ASDs) have been linked to maternal use of SSRIs during pregnancy. In this study, data from Danish health registries were used to assess a nationwide cohort for SSRI use during pregnancy and the risk for ASDs in the offspring. The cohort comprised all singleton live births in Denmark from 1996 to 2005 and included information on SSRI prescriptions filled by women in the cohort. Follow-up and diagnoses of autism were aggregated according to maternal use or nonuse of SSRIs during pregnancy. Poisson regression was used to compare the rates of ASD among offspring of women exposed or not exposed to SSRIs. The use of SSRIs was defined as use during the period 4 weeks before the beginning of the pregnancy until delivery. To evaluate the potential for confounding by indication, use of SSRIs was also examined from 2 years until 6 months before the beginning of the pregnancy. This allowed classification of women as those who used SSRIs during that period but not during pregnancy, those who used SSRIs before and during the pregnancy, and those who did not use SSRIs before pregnancy but did use them during pregnancy. From 658,755 live births, the final cohort included 626,875 children (51.3% were boys); 6068 mothers (1.0%) used SSRIs during pregnancy. During 5,057,282 person-years of follow-up, 3892 cases of ASD were identified, including 1603 cases of autistic disorder and 2289 cases of other ASDs, for an incidence rate of 77.0 per 100,000 person-years. The median age at ASD diagnosis was 5.6 years (interquartile range, 4.1–7.5). Strong associations were found between ASDs and maternal psychiatric diagnoses and use of drugs other than SSRIs during pregnancy. The associations suggested possible confounding by indication, especially because mothers with psychiatric diagnoses were also more likely to use SSRIs during pregnancy. During 42,400 person-years of follow-up, 52 cases of ASD were noted among offspring of women exposed to SSRIs during pregnancy (incidence rate, 122.6/100,000 person-years). Compared with no SSRI use before or during pregnancy, this rate corresponded to a crude rate ratio (RR) of 1.62 (95% confidence interval [CI], 1.23–2.13). In a fully adjusted analysis, the use of SSRIs before and during pregnancy or only during pregnancy was not associated with a significantly increased risk for ASDs in the offspring (RR, 1.20; 95% CI, 0.90–1.61). The fully adjusted RRs associated with SSRI use in the first trimester, during pregnancy but not before, and before pregnancy but not during were 1.35 (95% CI, 0.97–1.87), 1.40 (95% CI, 0.92–2.13), and 1.46 (95% CI, 1.17–1.81), respectively. In 574,020 pregnancies that had complete information, the fully adjusted RR was 1.15 (95% CI, 0.85–1.56). In this study, the use of SSRIs during pregnancy was not associated with a significantly increased risk for ASD in the offspring. The increased risk associated with SSRI use before but not during pregnancy suggests that any risk associated with the use of SSRIs during pregnancy may be related to the indications for their use rather than an effect of the drugs. The potential effect of confounding by indication must be considered in future study designs.

Use of Selective Serotonin Reuptake Inhibitors during Pregnancy and Risk of Autism

BackgroundStudies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring.MethodsWe conducted a cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009. Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders. We used a survival analysis of the time to diagnosis in the offspring with Poisson regression to estimate rate ratios of autism spectrum disorders according to maternal use of SSRIs.ResultsDuring 5,057,282 person-years of follow-up, we identified 3892 cases of autism spectrum disorder (incidence rate, 77.0 per 100,000 person-years). A total of 52 cases during 42,400 person-years of follow-up involved offspring of women who were exposed to SSRIs during their pregnancy (incidence rate, 122.6 per 100,000 person-years). As compared with no use of SSRIs both before and during pregnancy, use during pregnancy was not associated with a significantly increased risk of autism spectrum disorders (fully adjusted rate ratio, 1.20; 95% confidence interval [CI], 0.90 to 1.61). Among women who received SSRIs before pregnancy but not during pregnancy, the corresponding fully adjusted rate ratio was 1.46 (95% CI, 1.17 to 1.81).ConclusionsWe did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring. On the basis of the upper boundary of the confidence interval, our study could not rule out a relative risk up to 1.61, and therefore the association warrants further study. (Funded by the Danish Health and Medicines Authority.)

Selective Serotonin Reuptake Inhibitors During Pregnancy and Risk of Stillbirth and Infant Mortality

Maternal psychiatric disease is associated with adverse pregnancy outcomes. Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with congenital anomalies, neonatal withdrawal syndrome, and persistent pulmonary hypertension of the newborn. However, the risk of stillbirth and infant mortality when accounting for previous maternal psychiatric disease remains unknown. To study risk of stillbirth and infant mortality associated with use of SSRIs during pregnancy. Population-based cohort study from all Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) at different periods from 1996 through 2007. The study included women with singleton births. We obtained information on maternal use of SSRIs from prescription registries. Maternal characteristics, pregnancy, and neonatal outcomes were obtained from patient and medical birth registries. We used logistic regression to estimate relative risks of stillbirth, neonatal death, and postneonatal death associated with SSRI use during pregnancy taking into account maternal characteristics and previous psychiatric hospitalization. Among 1,633,877 singleton births in the study, 6054 were stillbirths; 3609, neonatal deaths; and 1578, postneonatal deaths. A total of 29,228 (1.79%) of mothers had filled a prescription for an SSRI during pregnancy. Women exposed to an SSRI presented with higher rates of stillbirth (4.62 vs 3.69 per 1000, P = .01) and postneonatal death (1.38 vs 0.96 per 1000, P = .03) than those who did not. The rate of neonatal death was similar between groups (2.54 vs 2.21 per 1000, P = .24). Yet in multivariable models, SSRI use was not associated with stillbirth (adjusted odds ratio [OR], 1.17; 95% CI, 0.96-1.41; P = .12), neonatal death (adjusted OR, 1.23; 95% CI, 0.96-1.57; P = .11), or postneonatal death (adjusted OR, 1.34; 95% CI, 0.97-1.86; P = .08). Estimates were further attenuated when stratified by previous hospitalization for psychiatric disease. The adjusted OR for stillbirth in women with a previous hospitalization for psychiatric disease was 0.92 (95% CI, 0.66-1.28; P = .62) and was 1.07 (95% CI, 0.84-1.36; P = .59) for those who had not been previously hospitalized. The corresponding ORs for neonatal death were 0.89 (95% CI, 0.58-1.39; P = .62) for women who were hospitalized and 1.14 (95% CI, 0.84-1.56; P = .39) for women who were not. For postneonatal death, the ORs were 1.02 (95% CI, 0.61-1.69; P = .95) for women who were hospitalized and 1.10 (95% CI, 0.71-1.72; P = .66) for women who were not. Among women with singleton births in Nordic countries, no significant association was found between use of SSRIs during pregnancy and risk of stillbirth, neonatal mortality, or postneonatal mortality. However, decisions about use of SSRIs during pregnancy must take into account other perinatal outcomes and the risks associated with maternal mental illness.

Psychological distress and SSRI use predict variation in inflammatory cytokines during pregnancy

Evidence supports the premise that maternal psychological distress adversely affects pregnancy outcomes and that inflammatory markers and placentally-produced corticotrophin-releasing hormone (pCRH) are likely mediating factors. The primary aim of the study was to explore the associations between maternal psychological distress, use of selective serotonin re-uptake inhibitors, pCRH, and maternal plasma inflammatory markers during pregnancy. Measures of maternal plasma pCRH, Interleukins-1, 6, & 10, C-Reactive Protein, Macrophage Migration Inhibitory Factor, and Tumor Necrosis Factor-α were completed in 100 pregnant women. Measures of depression, anxiety, and perceived stress were completed, as well as collection of demographic/behavioral data, e.g. use of selective serotonin re-uptake inhibitors (SSRIs). Significant correlations were found at 14-20 weeks gestation between IL-6 & 10, and depression, anxiety, and perceived stress. Also at 14 - 20 weeks gestation, IL10 levels were significantly lower in women with 4th quartile pCRH levels and IL1β, IL6, and IL10 were significantly lower among women who took an SSRI during pregnancy. After controlling for maternal age, BMI, pCRH level, and SSRI use, psychological distress remained to explain variation in maternal inflammatory markers. These results might suggest that future research should focus on whether depression and anxiety are effectively being treated during pregnancy, and how such a scenario might contribute to an immune system pathway to poor pregnancy outcome.

Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication

To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

1292 Differences in Postpartum Policy After Maternal Use of Selective Serotonin-Reuptake Inhibitors During Pregnancy

Background and Aim±10% of women has a depression during pregnancy and selective serotonin reuptake inhibitors (SSRI) are frequently used. After the use of SSRI’s approximately 30% of neonates show adverse...