Article

Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay

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Abstract

To examine associations between prenatal use of selective serotonin reuptake inhibitors (SSRIs) and the odds of autism spectrum disorders (ASDs) and other developmental delays (DDs). A total of 966 mother-child pairs were evaluated (492 ASD, 154 DD, 320 typical development [TD]) from the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study, a population-based case-control study. Standardized measures confirmed developmental status. Interviews with biological mothers ascertained prenatal SSRI use, maternal mental health history, and sociodemographic information. Overall, prevalence of prenatal SSRI exposure was lowest in TD children (3.4%) but did not differ significantly from ASD (5.9%) or DD (5.2%) children. Among boys, prenatal SSRI exposure was nearly 3 times as likely in children with ASD relative to TD (adjusted odds ratio [OR]: 2.91; 95% confidence interval [CI]: 1.07-7.93); the strongest association occurred with first-trimester exposure (OR: 3.22; 95% CI: 1.17-8.84). Exposure was also elevated among boys with DD (OR: 3.39; 95% CI: 0.98-11.75) and was strongest in the third trimester (OR: 4.98; 95% CI: 1.20-20.62). Findings were similar among mothers with an anxiety or mood disorder history. In boys, prenatal exposure to SSRIs may increase susceptibility to ASD or DD. Findings from published studies on SSRIs and ASD continues to be inconsistent. Potential recall bias and residual confounding by indication are concerns. Larger samples are needed to replicate DD results. Because maternal depression itself carries risks for the fetus, the benefits of prenatal SSRI use should be carefully weighed against potential harms.

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... In the exposure and outcome domain, quality ratings were better, with all 14 studies fulfilling the 2to 3-star threshold for good quality. However, this favorable finding was tempered by the recognition that in only one of the 14 studies were all children examined by the investigative team, using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule in an effort to minimize misclassification of autism diagnosis (38). Each of the remaining 13 studies operationalized autism diagnosis as the presence of an ICD-9 or ICD-10 diagnostic code for autism spectrum disorder in the source database. ...
... In addition, there was cause for concern even among the nine studies that did document participant ethnicity, because seven reported group disparities in maternal ethnicity. Ethnic minority representation was significantly lower among participants with an autism diagnosis or antidepressant exposure in six of the seven studies (27-29, 31, 39-40) and higher in only one study (38) (Table 1). ...
... Perhaps more importantly, significant differences in ethnicity in half of the studies (27-29, 31, 38-40), coupled with failure to document ethnicity in five more studies (30, 32-33, 37, 41), indicate an additional advantage of the discordant-sibling design. With one exception (38), the specific ethnic differences reported were that the prevalence of autism was significantly lower among children of Hispanic or immigrant mothers (27,40), and the prevalence of antidepressant exposure was significantly lower among immigrant mothers (28-29, 31, 39). Such differences should not be surprising. ...
Article
Objective: Observational studies of prenatal antidepressant safety are hindered by methodological concerns, including susceptibility to surveillance bias. Some studies address potential bias by using alternative strategies to operationalize study comparison groups. In a meta-analysis of the association between prenatal antidepressant exposure and autism risk, the authors examined the utility of comparison group operationalization in reducing surveillance bias. Methods: A systematic search of multiple databases through August 2017 was conducted, selecting controlled observational studies of the association of prenatal antidepressant exposure with autism. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis produced summary effect measures with 95% confidence intervals stratified by comparator group composition, antidepressant class, and trimester of exposure. Results: Fourteen studies were included, with 13 reporting results using a population-based comparison group, five using a psychiatric control group, and four using a discordant-sibling control group. Eight of the 14 studies were rated poor because of inadequate control for prenatal depression and maternal ethnicity. Autism risk estimates after prenatal exposure to any antidepressant were decidedly different for population-based designs (hazard ratio=1.42, 95% CI=1.18, 1.70; odds ratio=1.58, 95% CI=1.25, 1.99) compared with psychiatric control (hazard ratio=1.14, 95% CI=0.84, 1.53; odds ratio=1.24, 95% CI=0.93, 1.66) and discordant-sibling (hazard ratio=0.97, 95% CI=0.68, 1.37; odds ratio=0.85, 95% CI=0.54, 1.35) designs. Findings for prenatal exposure to selective serotonin reuptake inhibitors were similar. Meta-regression of population-based studies demonstrated that despite statistical adjustment, ethnicity differences remained a significant source of study heterogeneity. Conclusions: In this meta-analysis, neither psychiatric control nor discordant-sibling designs supported an association between prenatal antidepressant exposure and autism. Discordant-sibling designs effectively addressed surveillance bias in pharmacovigilance reports derived from national registries and other large databases.
... Although meta-analytic and narrative reviews of the prenatal SRI exposure-ASD relationship tend to support a significant association (Boukhris & Bérard, 2015;Gentile, 2015;Man et al., 2015), a number of published studies fail to replicate this effect, especially when including important covariates (Castro et al., 2016;Clements et al., 2015;Harrington, Lee, Crum, Zimmerman, & Hertz-Picciotto, 2014;Hviid, Melbye, & Pasternak, 2013;Malm et al., 2016;Rai et al., 2013;Sørensen et al., 2013;Sujan et al., 2017). In addition, although the literature now contains a number of studies with substantial sample sizes, primarily because of the availability of medical record and registry databases, methodological weaknesses remain. ...
... These findings suggest that registry diagnoses of ASD, which are commonly used in studies on this topic, may not always accurately reflect child symptomatology or Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria. Only a few prenatal SRI exposure studies in the extant literature have directly assessed children for ASD outcomes using parental reports or clinical observation (Harrington et al., 2014;Johnson, Smith, Stowe, Newport, & Brennan, 2016). The current study uses both of these assessment methods. ...
... Despite this, not all SRI exposure studies have incorporated measures of maternal prenatal depression (e.g., Rai et al., 2013), whereas others have inferred prenatal depression status based on diagnoses from medical records (e.g., historical diagnoses of major depressive disorder), which may not reflect the actual symptomatology that a mother experienced during pregnancy (Brown et al., 2017;Castro et al., 2016;Viktorin et al., 2017). Others have also used maternal retrospective reports of prenatal depression (Harrington et al., 2014), which may underestimate true exposure (Newport et al., 2008). Review of this literature suggests a need for studies that prospectively measure maternal depression severity as well as medication use in pregnancy and directly assess child social behaviors later in childhood to better understand the stability of behavioral effects. ...
Article
Studies examining associations between fetal serotonin reuptake inhibitor (SRI) exposure and child autism spectrum disorder (ASD) diagnoses or delayed language remain mixed and rarely prospectively follow children or employ gold-standard assessments. We prospectively followed a cohort of mother–child dyads from pregnancy through early elementary school ( N = 178), and obtained maternal and alternate–caregiver ratings of behaviors related to ASD ( N = 137), as well as direct, gold-standard assessments of child ASD symptoms and pragmatic language among dyads who experienced prenatal depression and either took SRIs or were medication free during pregnancy ( N = 44). Prenatal SRI exposure was related to maternal ratings of ASD-related behaviors (β = 0.24 95% confidence interval; CI [0.07, 0.48]), and, among boys, alternative caregiver ratings (males-only β = 0.28 95% CI [0.02, 0.55], females-only β = −0.21 95% CI [–0.63, 0.08]). However, results of our direct assessments suggest an association between SRI exposure and reduced pragmatic language scores (β = –0.27, 95% CI [–0.53, –0.01], but not ASD (Autism Diagnostic Observation Schedule β = 0.14 95% CI [–0.15, 0.41]; Social Responsiveness Scale β = 0.08 95% CI [–0.25, 0.40]). These discrepancies point to issues regarding how ASD is assessed, and the possibility that SRIs may be more strongly associated with language or other broader behaviors that coincide with ASD. Larger prospective studies that incorporate thorough, gold-standard assessments of ASD, language, and other ASD-related behaviors are needed.
... Prenatal exposure to SSRIs in utero has an ascribed association with low birth weight, preterm birth [5] and congenital malformation [6] as well as long-term neuropsychological sequelae, such as depression, anxiety and social dysfunction [7] , that persist into adulthood [8][9][10] . There is a growing body of evidence suggesting there may be an association between the use of SSRIs in pregnancy and the risk of autism spectrum disorder (ASD) in children [11][12][13][14][15][16][17] . However, recent systematic reviews have reported that when controlling for maternal psychiatric conditions and other confounding factors (including genetic syndromes and congenital anomalies which are associated with autistic like behavior) there is insufficient evidence for a significant association between SSRI use during pregnancy and ASD in the offspring [18][19][20] . ...
... All pups alive at the time were examined for general physical development, including body weight at PND 1,4,7,10,14,17 and 21, eye opening at PND 14-16, and incisor eruption at PND 11-14 [39] . ...
... At PND 12,14,16,18 and 20, the pups neuromotor function was measured using the suspension test [39] . The forepaws of the rat were placed on a homemade T-type fixed horizontal metal cross bar (0.5 cm D × 30 cm H). ...
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Background Prenatal exposure to selective serotonin reuptake inhibitor (SSRI), such as fluoxetine (FLX) may increase susceptibility to autism spectrum disorder (ASD). However, findings from published studies on SSRI and ASD are inconsistent. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral and ASD-related neurobiological abnormalities in offspring. Methods FLX or normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX=30, NS=27) on gestation day 11 till birth. The resulting offspring were assessed in terms of their physical development and behavior, and underwent in vivo magnetic resonance spectroscopy ( MRS) to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Results The offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety and impaired social interaction. Moreover, down-regulation of 5-HT or SERT expression and up-regulation of TPH levels was observed in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1 H-MRS in the PFC. Finally, a proteomic study revealed sex-dependent differential protein expression. Conclusions These findings may have translational importance suggesting that the use of SSRI medication alone in pregnant mothers may result in developmental delay and autistic-like behavior in their offspring. Our results also help to guide the choice of outcome measures in the identification of molecular and developmental mechanisms that may confer vulnerability in ASD.
... 47 Overall use of SSRI in pregnancy and ASD risk was assessed in five studies, which found aOR of 1.66 (95%CI, 1.23-2.23). [48][49][50][51][52] The aOR of preconceptional SSRI use and ASD was 1.84 (three studies; 95%CI, 1.48-2.28). [48][49][50] This was less than the aOR seen in first-trimester SSRI use (four studies; aOR, 1.90; 95% CI, 1.28-2.83) ...
... and more than that in second-trimester use (four studies; aOR, 1.73; 95%CI, 1.15-2.61). [48][49][50][51] However, evidence for use of SSRI in the third trimester and its association with ASD was inconclusive (four studies; aOR, 1.64; 95%CI, 0.83-3.24). [48][49][50][51] Additionally, use of non-SSRI medications (duloxetine, venlafaxine, mirtazapine, and bupropion) in pregnancy was also associated with a significant amplified risk (three studies; aOR, 2.05; 95%CI, 1.20-3.49). ...
... [48][49][50][51] However, evidence for use of SSRI in the third trimester and its association with ASD was inconclusive (four studies; aOR, 1.64; 95%CI, 0.83-3.24). [48][49][50][51] Additionally, use of non-SSRI medications (duloxetine, venlafaxine, mirtazapine, and bupropion) in pregnancy was also associated with a significant amplified risk (three studies; aOR, 2.05; 95%CI, 1.20-3.49). 48,49,52 However, qualitative reviews of cohort studies have shown somewhat inconsistent results. ...
Article
Autism Spectrum Disorder is a neurodevelopmental condition in which affected individuals have difficulties while interacting and communicating socially, and repetitive behaviors. It has a multi‐factorial etiology. Various risk factors including genetic and environmental influences have been explored while trying to understand its causation. As older evidence was suggestive of a high heritability, a majority of research focused on finding the underlying genetic causes of autism. Due to these efforts, there have been advances in the knowledge of some of the genetic factors associated with autism. But a recent trend also shows an increasing interest in exploration of various potential environmental triggers. These efforts have brought us closer to understanding the elusive disorder more so than ever before. The current paper discusses the recent trends in research exploring the etiopathogenesis of Autism Spectrum Disorders. This article is protected by copyright. All rights reserved.
... Several studies have reported adverse relationships between SSRIs and ASD that often diminish or disappear after accounting for the mother's psychiatric condition (19)(20)(21)(22) or when comparing siblings discordant on prenatal SSRI exposure (23)(24)(25)(26). However, some of the largest studies to examine this relationship have found SSRIs to be associated with increased risk of ASD, albeit small, even after applying several bias reduction methods (27)(28)(29)(30)(31)(32). ...
... To strengthen causal inference, four of these studies included sibling analyses which control for unmeasured or imperfectly measured maternal factors, such as genetics or psychiatric severity (23)(24)(25)(26). However, reflecting the mixed evidence of this research area, our findings also contradict several other large studies conducted in Sweden, (30,43) the Netherlands (44), California (31,32), Canada (29), and Denmark (27,28). ...
... These positive findings in other studies persisted even after efforts to reduce confounding by indication through adjustment for maternal psychiatric condition (29,31,43,44), restriction to mothers with psychiatric conditions (27)(28)(29)(30)32), and propensity weighting methods (30). In evaluating these methods, a recent systematic review of the literature determined that study designs using SSRI-unexposed mothers with psychiatric conditions (as was done in the present study) and/or siblings as comparators afford the most rigorous approaches for circumventing issues of residual confounding by psychiatric indication (18). ...
Article
Full-text available
Background The present study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitors (SSRI) use during preconception and pregnancy with risk of neurodevelopmental disorders in offspring. Methods We used data from the Study to Explore Early Development, a multisite case-control study conducted in the United States among children born between 2003-2011. Final study group classifications of ASD (n=1367), DD (n= 1750), and general population controls (POP)(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 DD (vs. POP) with maternal psychiatric condition 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. Results Psychiatric conditions and SSRI use during pregnancy were significantly more common among mothers of children with either ASD or DD than POP controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio (aOR)=1.81, 95% confidence interval (CI) 1.44-2.27) as in mothers who did use SSRIs (aOR=2.05, 95% CI 1.50-2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (aOR=1.14, 95% CI 0.8-1.62). Primary findings for DD exhibited similar relationships to those observed with ASD. Conclusions Maternal psychiatric conditions, but not use of SSRIs during pregnancy, were associated with increased risk of neurodevelopmental disorders in offspring.
... Recent studies reported an association between exposure to SSRIs and SNRIs during pregnancy and ASD and ADHD in Offspring [1,[9][10][11][12][13]. However, other studies did not find these associations [2,[14][15][16][17][18][19][20][21][22][23][24]. ...
... The remaining seven studies included in the meta-analysis did not refer to the family history of ASD/ADHD. Assessment of exposure during pregnancy was carried out by interviews in 1 study [11], by prescription dispensing and database linkage in 13 studies [1,2,9,10,[13][14][15][16][17][20][21][22][23][24] or by both these sources in 3 studies [12,18,19]. Seventeen studies [1,2,[9][10][11][12][13][14][15][16][17][18][20][21][22][23][24] reported on SSRI or SNRI exposure during all pregnancy (some of them were separated into three different trimesters), and 1 study reported on exposure during only the first trimester [19]. ...
... Assessment of exposure during pregnancy was carried out by interviews in 1 study [11], by prescription dispensing and database linkage in 13 studies [1,2,9,10,[13][14][15][16][17][20][21][22][23][24] or by both these sources in 3 studies [12,18,19]. Seventeen studies [1,2,[9][10][11][12][13][14][15][16][17][18][20][21][22][23][24] reported on SSRI or SNRI exposure during all pregnancy (some of them were separated into three different trimesters), and 1 study reported on exposure during only the first trimester [19]. Fourteen studies reached Table 1a. ...
Article
Background and objective: An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis. Methods: Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study. Results: Eighteen studies were included in the meta-analysis. We found an association between SSRIs/SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23-1.65, I2=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I2=0%) in the Offspring, although they were not exposed to those medications in utero. Conclusions: Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.
... Autism spectrum disorders.-We identified 7 studies-1 case-control study, 50 2 health record analyses, 40,41 and 4 register-based cohort studies 34,37,57,67 -that reported on the association between in utero antidepressant exposure and autism spectrum disorders (ASDs) ( Table 4). All 4 register-based cohort studies 34,37,57,67 reported a significant association between in-utero antidepressant exposure and risk for ASDs, with relative risks (RRs) ranging from 1.23 to 4.39. ...
... Three studies 39,41,50 did not find a significant association. All, except 1 study, 50 The case-control study 50 compared children with ASD (n = 492) to typically developing controls (n = 320) on self-reported maternal SSRI use during pregnancy. Children with ASDs were not more likely to have been exposed to SSRIs during pregnancy (5.9%) than typically developing children (3.4%). ...
Article
Objective: Reviews on child outcomes following in utero antidepressant exposure have focused on short-term outcomes. However, several recent individual studies reported on adverse physical, neurodevelopmental, and psychiatric outcomes beyond infancy and early childhood. The objective of this systematic review was to establish the long-term effects of prenatal antidepressant exposure on physical, neurodevelopmental, and psychiatric outcomes in individuals aged 4 years and older. Data sources: Embase, MEDLINE Ovid, Web of Science, Cochrane Central, and Google Scholar were systematically searched for all relevant articles, written in English and published prior to November 8, 2018, using terms describing antidepressants, pregnancy, and developmental outcomes. Study selection: All original research articles on long-term outcomes of prenatal antidepressant exposure were eligible for inclusion. After screening and removal of duplicates, a total of 34 studies were identified. Data extraction: Included articles were qualitatively analyzed to determine inconsistency, indirectness, imprecision, and study bias. Results: The identified studies demonstrated statistically significant associations between prenatal antidepressant exposure and a range of physical, neurodevelopmental, and psychiatric outcomes. Yet, the risk of confounding by indication was high. When controlling for confounders, 5 studies investigating physical outcomes (asthma, cancer, body mass index [BMI], epilepsy) found no association except conflicting outcomes for BMI. Eighteen studies examining neurodevelopmental outcomes (cognition, behavior, IQ, motor development, speech, language, and scholastic outcomes) found no consistent associations with antidepressant exposure after taking confounders into account. Eleven studies investigated psychiatric outcomes. After adjusting for confounders, prenatal antidepressant exposure was associated with affective disorders but not with childhood psychiatric outcomes (eg, autism spectrum disorders, attention-deficit/hyperactivity disorder). Conclusions: Reported associations between in utero exposure to antidepressants and physical, neurodevelopmental, and psychiatric outcomes, in large part, seem to be driven by the underlying maternal disorder. When limiting confounding by indication, prenatal exposure to antidepressants was significantly associated only with offspring BMI and affective disorders.
... SSRIs have been shown to disrupt normal cognitive function in rodents and may induce deficiencies in social behaviors similar to those displayed by individuals with autism [12,13]. In humans, epidemiological studies have found that in utero SSRI exposure increases the risk of developing an autism spectrum disorder, particularly when exposure occurs during the second or third trimester [14][15][16]. Notably, this period coincides with synapse formation. However more recent studies accounting for the cofounding factor of maternal psychiatric illness have found no association between SSRIs and the development of autism in offspring [17,18]. ...
... However, fluoxetine also regulates neural physiology independent of serotonin, by inhibiting Wnt [28] and the potassium channel, Kv2.1 [27]. Similar to what is observed in autism, fluoxetine has previously been shown to increase dendritic spine formation [14][15][16][17].To test the hypothesis that fluoxetine alters fetal synapse formation, we developed human cortical spheroids that recapitulate the second trimester fetal brain, when synapses form [3,52]. However, neither acute nor chronic fluoxetine treatment significantly altered excitatory synapse formation, and only acute but not chronic fluoxetine exposure altered inhibitory synapse formation, suggesting that compensatory mechanisms restore normal synapse formation in the presence of chronic fluoxetine administration. ...
Article
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The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation increases the risk of neurodevelopmental abnormalities. However, there is a lack of research into how specific environmental factors directly impact the developing neural circuitry of the human brain. For example, selective serotonin reuptake inhibitors are commonly used throughout pregnancy to treat depression, yet their impact on the developing fetal brain remains unclear. Recently, human brain models have provided unprecedented access to the critical window of prenatal brain development. In the present study, we used human neurons and cortical spheroids to determine whether the selective serotonin reuptake inhibitor fluoxetine alters neurite and synapse formation and the development of spontaneous activity within neural circuits. We demonstrate that cortical spheroids express serotonin transporter, thus recapitulating the early developmental expression of serotonin transporter associated with cortical pyramidal neurons. Cortical spheroids also appropriately express serotonin receptors, such as synaptic 5-HT2A and glial 5-HT5A. To determine whether fluoxetine can affect developing neural circuits independent of serotonergic innervation from the dorsal and medial raphe nuclei, we treated cortical neurons and spheroids with fluoxetine. Fluoxetine alters neurite formation in a dose-dependent fashion. Intriguingly, in cortical spheroids, neither acute nor chronic fluoxetine significantly altered excitatory synapse formation. However, only acute, but not chronic fluoxetine exposure altered inhibitory synaptogenesis. Finally, fluoxetine reversibly suppresses neuronal activity in a dose-dependent manner. These results demonstrate that fluoxetine can acutely alter synaptic function in developing neural circuits, but the effects were not long-lasting. This work provides a foundation for future studies to combine serotonergic innervation with cortical spheroids and assess the contributions of fluoxetine-induced alterations in serotonin levels to brain development.
... These include, inter alia, autism spectrum disorder, schizophrenia, depression, attention-deficit/hyperactivity disorder [10][11][12][13][14][15][16][17] disturbance of the hypothalamic-pituitary axis [5,18], preeclampsia [19,20], metabolic and cardiovascular diseases [21], and pulmonary hypertension [22]. Interestingly, male offspring have higher susceptibility to autism and developmental delays after exposure to SSRIs than female offspring, indicating that fetal sex influences risks for adverse effects of prenatal antidepressants [23]. Additionally, while direct teratogenic effects of antidepressants are disputed, increased risks of lung, heart, and neuronal malformations have been described in the literature [24][25][26][27]. ...
... Therefore, here we considered fetal sex as a factor and found that male placentas are more sensitive to the inhibitory effect of SRIs. This may, at least partly, explain the fetal sex-dependent variation observed in studies of behavioral effects of prenatal treatment with antidepressant drugs [65] and higher risks of neurodevelopmental disorders after prenatal use of antidepressants observed in males [23,66]. ...
Article
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Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal-and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT-and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC 50) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy.
... Recently, an ongoing debate started about whether children whose mothers were treated with SSRIs during pregnancy have an increased risk to develop autism spectrum disorder (ASD). Some studies show a clear correlation between SSRI treatment and increased odds for ASD in the offspring [13][14][15][16][17], whereas others do not find this link or suggest that this increased risk is caused by the depression itself rather than the SSRIs [18,19]. The mothers who do take antidepressants during pregnancy most likely suffer from a more severe depression, and untreated depression during pregnancy may also have negative impact on the offspring [18,[20][21][22][23]. ...
... Videos were recorded using Media recorder 2.5 by direct connection to a computer allowing the data to be stored immediately on an external hard drive. Every 24 hours, the recording was 13 stopped manually and restarted to create recordings with a length of 24h. This was done to assure that if a recording error would occur, data from only one day would be lost. ...
Article
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SSRIs are commonly used to treat pregnant women with depression. However, SSRIs can cross the placenta and affect the development of the fetus. The effects of perinatal SSRI exposure, and especially the effects on social behavior, are still incompletely documented. This study first aims to investigate whether rats show prosocial behavior in the form of consolation behavior. Secondly, it aims to investigate whether perinatal SSRI exposure affects this prosocial behavior. At last, we investigate whether the behavior changed after the rats had been exposed to an additional white-noise stressor. Rat dams received 10 mg/kg/d fluoxetine (FLX) or vehicle (CTR) via oral gavage from gestational day 1 until postnatal day 21. At adulthood, the rat offspring were housed in four cohorts of 4 females and 4 males in a seminatural environment. As prosocial behaviors are more prominent after stressful situations, we investigated the behavioral response of rats immediately after natural aggressive encounters (fights). Additionally, we studied whether a stressful white-noise exposure would alter this response to the aggressive encounters. Our study indicates that CTR-female rats are able to show third party prosocial behavior in response to witnessing aggressive encounters between conspecifics in a seminatural environment. In addition, we showed that perinatal FLX exposure impairs the display of prosocial behavior in female rats. Moreover, we found no signs of prosocial behavior in CTR- and FLX-males after natural aggressive encounters. After white-noise exposure the effects in third party prosocial behavior of CTR-females ceased to exist. We conclude that female rats are able to show prosocial behavior, possibly in the form of consolation behavior. In addition, the negative effects of perinatal fluoxetine exposure on prosocial behavior could provide additional evidence that SSRI treatment during pregnancy could contribute to the risk for social impairments in the offspring.
... Some of these associations are modulated by offspring sex 17,18 . For example, an increased risk for autism spectrum disorder was only found for boys 19 . ...
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Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
... Additionally, paracetamol (acetaminophen) induces oxidative stress and immune dysregulation in humans (103). Furthermore, positive correlation between antidepressant medications and autism has been demonstrated in many studies (104)(105)(106). Other medications display increased susceptibility to autism such as thalidomide, a painkiller, (107), misoprostol, a prostaglandin analog drug for the prevention and treatment of gastric ulcers (108) in the first trimester, and β2-adrenergic agonists like terbutaline to treat asthma (109,110). ...
Article
The prevalence rate of Autism Spectrum Disorder (ASD) has reached over 1% world-wide prompting governments, health providers and schools to develop programs and policies to address this challenging disorder. Here, we review the cause(s), as well as environmental factors, genetic mutations, and neural pathways that are implicated in ASD. We also discuss the criteria that are commonly used for the diagnosis of ASD and future clinical genetic testing that can aid in the diagnosis of this disorder. Finally, we provide practical steps that can be used to reduce the incidence and severity of ASD, as well as prognosis and treatment of autism.
... 1,2 Some epidemiological studies suggest an association between in utero SSRI exposure and increased risks for adverse outcomes for offspring, including the development of autism spectrum disorder (ASD), attention-deficit hyperactivity disorder, depression and anxiety disorders, and other sequelae that span broad developmental domains. [3][4][5][6][7][8][9][10][11] Other studies find no increased risk for offspring associated with maternal SSRI treatment. 8,[11][12][13] Forgoing treatment to avoid potential risks associated with fetal SSRI exposure places offspring at risk for the well-documented effects of maternal depressive and anxiety disorders, which include developmental delays and increased propensity for psychiatric disorders later in life. ...
Article
Human epidemiological and animal-model studies suggest that exposure to stress, but also serotonin-selective reuptake inhibitor (SSRI) antidepressants during pregnancy increase risks for neurodevelopmental disorders in offspring. Yet, little is known about the combined effects of maternal stress and SSRIs with regard to brain development in utero. We found that the placenta is highly permeable to the commonly prescribed SSRI (±) citalopram (CIT) in humans and mice, allowing rapid exposure of the fetal brain to this drug. We investigated the effects of maternal chronic unpredictable stress in mice, with or without maternal oral administration of CIT, from embryonic day (E)8 to E17. We assessed fetal brain development using magnetic resonance imaging and quantified changes in serotonergic, thalamocortical, and cortical development. In utero exposure to maternal stress did not affect overall fetal brain growth. However, serotonin tissue content in the fetal forebrain was increased in association with maternal stress; this increase was reversed by maternal CIT. In utero exposure to stress increased the numbers of deep-layer neurons in specific cortical regions, whereas CIT increased overall cell numbers without changing the proportions of layer-specific neurons to offset the effects of stress on deep-layer cortical development. These findings suggest that stress and SSRI exposure in utero differentially impact serotonin-dependent fetal neurodevelopment such that CIT reverses key effects of maternal gestational stress on offspring brain development.
... Le premier constat concerne la complexité de la situation des personnes présentant des TOC sévères. À ce propos, Harrington et al. (2014) décrivent la diversité des symptômes et les difficultés éprouvées par ces personnes pour s'engager dans une démarche de suivi thérapeutique. indiquent que les TOC affectent toutes les dimensions de la qualité de vie, surtout celles qui obtiennent un score YBOCS supérieur à 20 (correspond à une situation de détresse). ...
Thesis
Full-text available
En raison des rituels compulsifs et des pensées obsédantes, les personnes présentant des TOC sont préoccupées par leur niveau de fonctionnement dans toutes les sphères de la vie. Une impression de déséquilibre occupationnel et une altération de la qualité de vie peuvent apparaître chez ces personnes lorsque leur routine est perçue comme insatisfaisante. Cette thèse vise trois objectifs principaux, soit : (1) déterminer les situations de déséquilibre occupationnel des personnes présentant des TOC, (2) identifier les stratégies d'adaptation utilisées à domicile et (3) développer et documenter l'utilisation de dispositifs techniques/technologiques pour maintenir un équilibre de vie à travers la promotion des occupations. Une étude de la portée (scoping review) a été menée dans un premier temps pour déterminer les données existantes dans les écrits scientifiques internationaux en lien avec les indicateurs de la qualité de vie des personnes présentant des TOC (chapitre 1). Les objectifs sont : (1) explorer les composantes de la qualité de vie des personnes qui présentent des Troubles Obsessionnels Compulsifs (TOC) ; (2) identifier les variables qui modifient leur qualité de vie ; (3) analyser les retombées des TOC sur les activités de la vie quotidienne. Le second chapitre présente une approche innovante et a fait l'objet un article publié dans un ouvrage collectif. Celui-ci porte sur la description du devis de recherche du projet Analyse du Handicap Associé aux Troubles Obsessionnels Compulsifs [AHATOC] (Morgiève et Briffault, 2015). Ce projet est une recherche clinique participative qui a pour objectif d'identifier les facteurs environnementaux liés aux TOC et de concevoir des dispositifs techniques et technologiques de compensation des situations de handicap. L'article propose également deux outils d'évaluation environnementaux : (1) un chrono-ergomètre est un disque circadien permettant de cartographier dans le temps les routines quotidiennes ; (2) une méthodologie a été développée pour cartographier en 2D et en 3D des TOC. Le troisième chapitre concerne une étude qui identifie les stratégies d'adaptation utilisées par les personnes présentant des TOC (chapitre 3) et documente les dimensions altérées de l'équilibre de vie (chapitre 4). Pour cela, des entretiens semi-dirigés ont été réalisés au domicile de huit participants présentant des TOC pour explorer les retombées des obsessions et des compulsions dans les activités de la vie quotidienne. En outre, un questionnaire intitulé inventaire de l'équilibre de vie [IEV] (Larivière et Levasseur, 2016, Matuska, 2012 ) a permis de documenter les atteintes ou perturbation des occupations quotidiennes. Les entretiens ont mis en évidence un degré d'insatisfaction des répondants vis-à-vis du temps passé à réaliser leurs occupations (équivalence). Les données de l'IEV ont révélé une évolution favorable de l'équilibre de vie, bien que le niveau de déséquilibre reste important pour l'ensemble des activités de la vie quotidienne des participants. Le chapitre 5 aborde une étude de cas qui a été menée auprès de deux participantes présentant des TOC. L'étude de cas a analysé les occupations perturbées par les manifestations des TOC et leur évolution sur une période de 30 mois. Trois outils ont été utilisés pour documenter ces deux situations, soit : (1) des entretiens semi-dirigés à partir de la matrice SWOT (Strengths Weaknesses Opportunities and Threats) ; (2) l'Inventaire de l'Équilibre de Vie ; (3) la cartographie des TOC dans le temps. Selon les observations faites, les occupations des deux participantes ont évolué favorablement grâce à l'utilisation des dispositifs techniques et technologiques de compensation. De plus, leur participation active dans la mise en place de ces dispositifs a été un élément favorable à leur acceptation et à leur intégration.
... Human epidemiology studies have suggested that maternal autoimmune disorders and situational environmental exposures are associated with the development of ASD [Atladottir, Henriksen, Schendel, & Parner, 2012;Atladottir et al., 2009;Keil et al., 2010;Stevens, Nash, Koren, & Rovet, 2013;Xiang et al., 2015]. Additionally, associations between exposures to anti-seizure medications [Christensen et al., 2013] and antidepressants [Harrington, Lee, Crum, Zimmerman, & Hertz-Picciotto, 2014] to a future ASD diagnosis have been found. A common thread in the aforementioned exposure studies is the ability to increase neuroinflammation in the fetal brain. ...
Article
Full-text available
Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood–brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood–brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti‐ and pro‐inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age‐matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro‐inflammatory gene, HLA‐DR, were significantly reduced in gray matter and expression levels of the anti‐inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro‐inflammatory (CD68, IL1β) and anti‐inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro‐ or anti‐inflammatory state in ASD. However, altered expression of pro‐ and anti‐inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Lay Summary The anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
... No increase in risk of ASD was evident, however, when unexposed offspring was compared with offspring of pregnant women who received AD for disorders other than depression 43 . Six cohort and case-control (nested in population-based cohorts) investigations, on the other hand, found a modest association of antenatal AD with ASD 44,45,46 , ASD in boys 47 , and ASD without intellectual disability 48,49 . One of the reviewed studies evaluated whether antenatal exposure to SSRI was associated with higher scores for autistic traits in children 50 . ...
Article
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This study investigated whether antenatal exposure to antidepressants (ADs) increases the risks of autism spectrum disorders (ASD), attention deficit/hyperactivity disorders (ADHD), schizophrenia and other mental illnesses, and cognitive and developmental deficits in infants or preschool children. PubMed, EMBASE, BIREME/BVS databases were searched to identify studies examining associations of ADs in pregnancy with neurodevelopmental and psychiatric disorders. Twenty studies addressed ASD and/or ADHD risks while 30 focused on developmental and cognitive deficits in infants or preschool children. Most studies detected no association of antenatal AD with ASD after adjustment of risk ratios for maternal depression or psychiatric disorders. Some studies showed that maternal depression, regardless of whether it is treated or untreated, increased ASD risks. Seven out of 8 studies found no increase in ADHD risk associated with antenatal exposure to selective serotonin reuptake inhibitors, the most commonly used AD. No consistent evidence was found linking AD in pregnancy to neurocognitive developmental deficits in infants or preschool children. A residual confounding by indication (depression severity) remained in almost all studies. This systematic review found no consistent evidence suggesting that ADs in pregnancy increase risks of ASD, ADHD, and neurocognitive development deficits. Some studies, however, found evidence that maternal depression increases ASD risks.
... Another proposed source of the protective factor is the X chromosome, with a protective gene expressed on the paternal X chromosome for females, which increases the threshold for autism expression relatives to males (Skuse 2000); however, no specific protective gene has been identified here. Environmental factors such as in vitro exposure to medications seem to increase autism likelihood in males more than females (Harrington et al. 2014). These factors may interact with genetic risks to further increase autism likelihood in males, and hence increase relative autism protection in females. ...
Article
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Autism is more commonly diagnosed in males than females. One explanation is the ‘female protective effect’: there is something inherent in being female which reduces the likelihood of developing autism. However, evidence suggests that the condition is underdiagnosed in females, perhaps because females express their autism in ways which do not meet current diagnostic criteria. This review explores evidence for a female-typical autism presentation, the Female Autism Phenotype (FAP) and the component of camouflaging (compensating for and masking autistic characteristics) in particular. The evidence so far supports the existence of a female-typical autism presentation, although further examination of the characteristics and their impact across all genders and ages is needed.
... Selective serotonin reuptake inhibitors (SSRIs) during pregnancy cross the placenta and are secreted in breast milk [21], exposing both the fetus and infant. Reports of elevated blood serotonin levels in patients with ASD suggest a possible association between prenatal SSRI exposure and ASD [77], although studies differ on which trimester shows the strongest association [78][79][80][81][82]. Two systematic reviews and meta-analyses concluded that prenatal SSRI exposure is associated with increased risk of ASD, though maternal psychiatric condition as a confounding factor could not be ruled out [76,83,84]. ...
Article
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Background: Current understanding of the etiology of autism is based on the interaction of multiple genes with each other and with environmental factors, leading to a neurodevelopmental process that results in the expression of autism spectrum disorder (ASD) in the child. This suggests that it might be possible to strengthen resilience to environmental stressors during the perinatal period to improve outcomes and possibly prevent the development of ASD. Methods: We searched the MEDLINE database for multiple perinatal factors associated with the development of ASD published between January 1, 2005 and July 1, 2018. The search terms used were "autism" crossed with either "perinatal," "prenatal," "gestational," or "pregnancy," and crossed again with each perinatal risk factor highlighted in this review including topics on parental health, infections, medications, and environmental stressors. We then searched interventions that may improve neurodevelopmental outcome before and during pregnancy, including supplements, breastfeeding, and postpartum stress reduction. We identified recent or unique metanalyses and systematic reviews of the identified focus and on randomized controlled trials and summarized these using the most recent and comprehensive reviews. Results: Folate, omega-3, vitamin D3, environmental toxin avoidance, correcting deficiencies, immune boosting, and prolonged breast feeding are all reported to be linked to the possible reduction of adverse pregnancy outcomes including ASD. Conclusions: Studies of individual components for improving pregnancy outcomes and several uncontrolled preconception to infancy medical practices suggest that multiple interventions might improve the outcomes of pregnancies where there is risk for developing ASD.
... Harrington et al. [95] studied possible associations of ASD and prenatal SRI in 492 ASD children compared to 154 children with neurodevelopmental delay and 320 normal children, and reported a significant association in boys, especially if exposed during the third trimester of pregnancy. ...
Article
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Serotonin has important roles in the development of the brain and other organs. Manipulations of synaptic serotonin by drugs such as serotonin reuptake inhibitors (SRI) or serotonin norepinephrine reuptake inhibitors (SNRI) might alter their development and function. Of interest, most studies on the outcome of prenatal exposure to SRI in human have not found significant embryonic or fetal damage, except for a possible, slight increase in cardiac malformations. In up to a third of newborns exposed to SRI, exposure may induce transient neonatal behavioral changes (poor neonatal adaptation) and increased rate of persistent pulmonary hypertension. Prenatal SRI may also cause slight motor delay and language impairment but these are transient. The data on the possible association of prenatal SRIs with autism spectrum disorder (ASD) are inconsistent, and seem to be related to pre-pregnancy treatment or to maternal depression. Prenatal SRIs also appear to affect the hypothalamic hypophyseal adrenal (HPA) axis inducing epigenetic changes, but the long-term consequences of these effects on humans are as yet unknown. SRIs are metabolized in the liver by several cytochrome P450 (CYP) enzymes. Faster metabolism of most SRIs in late pregnancy leads to lower maternal concentrations, and thus potentially to decreased efficacy which is more prominent in women that are rapid metabolizers. Studies suggest that the serotonin transporter SLC6A4 promoter is associated with adverse neonatal outcomes after SRI exposure. Since maternal depression may adversely affect the child’s development, one has to consider the risk of SRI discontinuation on the fetus and the child. As with any drug treatment in pregnancy, the benefits to the mother should be considered versus the possible hazards to the developing embryo/fetus.
... The full list is found in Electronic Supplementary Material 2. Of the 111 studies, twenty-five (23%) were casecontrol studies and eighty-six (77%) were cohort studies (1,6,7,, although five of the cohort studies did not include an unexposed group as control for comparison (73)(74)(75)(76)92). Sixty-one (55%) were carried out in European countries (21, 23, 24, 28, 29, 32-34, 36, 38, 39, 42, 43, 46, 48, 49, 52, 54-56, 59, 60, 62, 64, 68-72, 77, 79-81, 83, 85, 87-89, 91-94, 97, 99, 101, 103, 105-107, 110, 116-123, 125, 126, 128), twenty (18%) in the United States (1,6,22,25,26,30,31,40,41,45,47,57,61,65,67,75,76,78,86,100), nine (8%) in Canada (7,51,53,63,82,96,100,102,124), seven (6%) in Australia (44,(111)(112)(113)(114)(115)127), and the remaining studies were in Japan, India, Hong Kong, Israel and Egypt (23,35,37,50,58,66,73,74,84,90,95,98,104,108,109). In addition, the types of CNS outcomes being investigated included neurodevelopmental disorders, convulsions and congenital anomalies of CNS such as neural tube defects, spina bifida, anencephaly and microcephaly. ...
Article
INTRODUCTION: Studies have used various epidemiological approaches to study associations between central nervous system (CNS) drug use in pregnancy and CNS outcomes in children. Studies have generally focused on clinical adverse effects, whereas variations in methodologies have not received sufficient attention. OBJECTIVE: Our objective was to review the methodological characteristics of existing studies to identify any limitations and recommend further research. METHODS: A systematic literature search was conducted on observational studies listed in PubMed from 1 January 1946 to 21 September 2017. Following independent screening and data extraction, we conducted a review addressing the trends of relevant studies, differences between various data sources, and methods used to address bias and confounders; we also conducted statistical analyses. RESULTS: In total, 111 observational studies, 25 case–control studies, and 86 cohort studies were included in the review. Publications dating from 1978 to 2006 mainly focused on antiepileptic drugs, but research on antidepressants increased from 2007 onwards. Only one study focused on antipsychotic use during pregnancy. A total of 46 studies obtained data from an administrative database/registry, 20 from ad hoc disease registries, and 41 from ad hoc clinical samples. Most studies (58%) adjusted the confounding factors using general adjustment, whereas only a few studies used advanced methods such as sibling-matched models and propensity score methods; 42 articles used univariate analyses and 69 conducted multivariable regression analyses. CONCLUSION: Multiple factors, including different study designs and data sources, have led to inconsistent findings in associations between CNS drug use in pregnancy and CNS outcomes in children. Researchers should allow for study designs with clearly defined exposure periods, at the very least in trimesters, and use advanced confounding adjustment methodology to increase the accuracy of the findings.
... Recently, an ongoing debate started about whether children whose mothers were treated with SSRIs during pregnancy have an increased risk to develop autism spectrum disorder (ASD). Some studies show a clear correlation between SSRI treatment and increased odds for ASD in the offspring [13][14][15][16][17], whereas others did not find this link or suggest that this increased risk is caused by the depression itself rather than the SSRIs [18,19]. The mothers who do take antidepressants during pregnancy most likely suffer from a more severe depression, and untreated depression during pregnancy may also have negative impact on the offspring [18,[20][21][22][23]. ...
Preprint
SSRIs are commonly used to treat pregnant women with depression. However, SSRIs can cross the placenta and affect the development of the fetus. The effects of perinatal SSRI exposure, and especially the effects on social behavior, are still incompletely documented. This study first aims to investigate whether rats show prosocial behavior in the form of consolation behavior. Secondly, it aims to investigate whether perinatal SSRI exposure affects this prosocial behavior. At last, we investigate whether the behavior changed after the rats had been exposed to an additional white-noise stressor. Rat dams received 10 mg/kg/d fluoxetine (FLX) or vehicle (CTR) via oral gavage from gestational day 1 until postnatal day 21. At adulthood, the rat offspring were housed in four cohorts of 4 females and 4 males in a seminatural environment. As prosocial behaviors are more prominent after stressful situations, we investigated the behavioral response of rats immediately after natural aggressive encounters (fights). Additionally, we studied whether a stressful white-noise exposure would alter this response to the aggressive encounters. Our study indicates that CTR-female rats are able to show third party prosocial behavior in response to witnessing aggressive encounters between conspecifics in a seminatural environment. In addition, we showed that perinatal FLX exposure impairs the display of prosocial behavior in female rats. Moreover, we found no signs of prosocial behavior in CTR- and FLX-males after natural aggressive encounters. After white-noise exposure the effects in third party prosocial behavior of CTR-females ceased to exist. We conclude that female rats are able to show prosocial behavior, possibly in the form of consolation behavior. In addition, the negative effects of perinatal fluoxetine exposure on prosocial behavior could provide additional evidence that SSRI treatment during pregnancy could contribute to the risk for social impairments in the offspring.
... [14], 1,3-butadiene , meta/para-xylene , other aromatic solvents, lead , perchloroethylene, and formaldehyde [15], Diethyl phthalate , Di-butylphthalate and di-(2-ethylhexyl) phthalate metabolites ((5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate) [16,17]. Heavy smoking [18], or the use of certain drugs during pregnancy, including alcohol and cocaine [18,19], methamphetamine (case report [20]) , acetaminophen [21,22], valproate [23] as well as thalidomide [24], or selective serotonin uptake inhibitors (SSRI's) (fluoxetine, sertraline, paroxetine, citalopram, and escitalopram) [25] have also been linked to the development of autism in the offspring, as has the use of pharmaceutical agents for the induction or delay of labour (oxytocin, prostaglandins [26], dexamethasone [27] or terbutaline [28]). Smoking, cannabis use, nicotine and alcohol have also been linked to autistic behaviour in young adults [29]. ...
Preprint
The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism genes (ASG’s) to interrogate ~1 million chemical/gene interactions in the comparative toxicogenomics database. Bias towards ASG’s was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI’s, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG’s, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other endocrine disruptors selectively targeted ASG’s including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms are known to influence sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. The close gene/environment relationships, for multiple suspect pollutants, suggest that the rising incidence of autism might be chemically driven by numerous environmental contaminants in a gene dependent manner. The protective dappled camouflage of the peppered moth was rendered invalid by industrial soot covering the trees, a situation reversed by clean air acts. The rising tide of neurodevelopmental and other childhood disorders linked to multiple pollutants may need a similar solution.
... 4) Although the etiology of ASD is not fully understood, the role of heritability as well as some gestational environmental risk factors, including gestational age, infection, micronutrient insufficiency, fetal hypoxia, and stress, has been somewhat confirmed through various studies. [5][6][7][8][9] However, for variables whose effects on ASD remain unclear, meta-analyses remain the gold standard. ...
Article
Background: The results differ among published studies regarding exposure to meconium and the risk of developing autism spectrum disorders (ASDs). Purpose: The present study pooled all of the epidemiologic studies retrieved from broader databases on the association between meconium exposure and risk of developing ASD in children. Methods: The Web of Science, PubMed, Scopus, and Google Scholar databases were searched without language restrictions for articles published between their inception to February 20, 2020, using relevant keywords. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated as random-effect estimates of the associations among studies. A subgroup analysis was conducted to explore any potential sources of heterogeneity among studies. Results: The pooled estimate of OR reported a weakly significant association between meconium exposure and ASD development in children (OR, 1.13; 95% CI, 1.03-1.24). There was low heterogeneity among the articles reporting risk for ASD among children (I2=19.3%; P=0.259). The results of subgroup analysis based on meconium exposure showed a significant association between a meconium-stained neonate and ASD development (OR, 1.18; 95% CI, 1.11-1.24). Conclusion: Meconium exposure was weakly associated with an increased risk of ASD. However, more evidence based on large prospective cohort studies is required to provide conclusive evidence about whether meconium exposure is associated with an increased risk of ASD development.
... Developmental timing is likely to be important in SSRI exposure. While some work has suggested that in humans, any chronic exposure in the year prior to birth results in heightened risk (Croen et al., 2011), others have found that either the first or third trimester are the periods of greatest risk (Oberlander et al., 2008;Croen et al., 2011;Harrington et al., 2014). In order to address the effects of exposure timing, we evaluated behavior in three different gross exposure cohorts spanning prenatal and postnatal development. ...
Article
Full-text available
Developmental exposure to selective serotonin reuptake inhibitor (SSRI) increases the risk of Autism Spectrum Disorder (ASD), however, the underlying neurobiology of this effect is not fully understood. Here we used the socially monogamous prairie vole as a translational model of developmental SSRI exposure. Paired female prairie voles (n = 20) were treated with 5 mg/kg subcutaneous fluoxetine (FLX) or saline (SAL) daily from birth of the second litter until the day of birth of the 4th litter. This design created three cohorts of FLX exposure: postnatal exposure in litter 2, both prenatal and postnatal exposure in litter 3, and prenatal exposure in litter 4. Post-weaning, subjects underwent behavioral testing to detect changes in sociality, repetitive behavior, pair-bond formation, and anxiety-like behavior. Quantitative receptor autoradiography was performed for oxytocin, vasopressin 1a, and serotonin 1a receptor density in a subset of brains. We observed increased anxiety-like behavior and reduced sociality in developmentally FLX exposed adults. FLX exposure decreased oxytocin receptor binding in the nucleus accumbens core and central amygdala, and vasopressin 1a receptor binding in the medial amygdala. FLX exposure did not affect serotonin 1A receptor binding in any areas examined. Changes to oxytocin and vasopressin receptors may underlie the behavioral changes observed and have translational implications for the mechanism of the increased risk of ASD subsequent to prenatal SSRI exposure.
... Among childhood neuropsychiatric disorders, ASD has been associated with prenatal SSRIs exposure (32). Figure 1 shows that over the last decade observational studies have formed an aggregate of positive findings, with little, if any variety in their effect estimates (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). One meta analysis suggested a pooled odds ratio of 1.82, with a 95% Confidence Interval (CI) = 1.59-2.10 ...
Article
Full-text available
Use of antidepressants (ADs) in general, and in pregnant notwithstanding, has been increasing globally in recent decades. Associations with a wide range of adverse perinatal and childhood outcomes following prenatal ADs exposure have been observed in registry-based studies, with Autism Spectrum Disorders (ASD) frequently reported. Studies using animal models, sibling analyses, and negative control approaches, have linked dysfunctional serotonin metabolism with ASD, but did not convincingly tease apart the role of maternal mental health from that of ADs. As work to decipher the nature of the AD-ASD association continues, this review raises some public health concerns pertinent to a hypothetical conclusion that this association is causal, including the need to identify specific gestation periods with higher risk, the importance of precise assessment of the ASD potential prevention that might be attributed to AD discontinuation, and the estimation of risks associated with prenatal exposure to untreated depression.
... Many authors identified an increased risk of ASD among children exposed intrauterus to SSRIs [49][50][51][52] . The risk was independent on depressive symptoms 52 . ...
Article
Full-text available
Autism spectrum disorders (ASD) are characterized by disconnectivity due to disordered neuronal migration, and by neuronal mitochondrial dysfunction. Different pathways involved in neuronal migration are affected by intrauterine hyperglycemia and hyperinsulinemia, while prolonged neonatal hypoglycemia may cause mitochondrial dysfunction. Our hypothesis was that conditions leading to intrauterine hyperglycemia or neonatal hypoglycemia would influence ASD pathogenesis. In this study, we identified risk factors for ASD by searching PubMed with the MeSH terms "autism spectrum disorder" and "risk factors". We then analyzed the relationship between the risk factors and glucose abnormalities in the mother and the offspring. The relationship between glucose abnormalities and risk factors such as obesity, excessive maternal weight gain, or diabetes mellitus is evident. For risk factors such as malformations or exposure to selective serotonin reuptake inhibitors, the relationship is speculative. In rodents, for example, intrauterine hyperglycemia is associated with malformations, independent of maternal diabetes. In their turn, selective serotonin reuptake inhibitors reduce the signs of neonatal hypoglycemia. Going undetected, prolonged hypoglycemia may harm the neonatal brain. Importantly, our group demonstrated that either high-carbohydrate diets or physical inactivity the day before delivery may influence neonatal glycemia. In that study, of 158 neonates selected to be screened according to maternal lifestyle risk factors, 48 had hypoglycemia. Of note, five of them had not been identified with current screening programs. Controlled studies are needed to clarify whether maternal interventions aiming at maintaining glycemic control, together with screening programs for neonatal hypoglycemia based on maternal lifestyle risk factors and on exposure to specific prenatal medications can reduce the prevalence of ASD.
... Accumulating clinical evidence indicates that perinatal exposure to SSRIs could have a detrimental impact on infant's neurodevelopment, with long-lasting consequences on cognitive and emotional capabilities [19][20][21][22][23][24][25][26] . In addition, other lines of evidence indicate that early exposure to SSRIs during pregnancy could increase the risk of Autism Spectrum Disorders (ASD) [27][28][29][30][31][32] , which in turn present a robust comorbidity with other psychiatric disorders including anxiety and depression 33,34 . However, there is a general agreement that adverse consequences observed after antenatal SSRI treatments should be always contrasted against the highly detrimental consequences of the unmedicated maternal mental illness. ...
Article
Full-text available
Mental disorders including depression and anxiety are continuously rising their prevalence across the globe. Early-life experience of individuals emerges as a main risk factor contributing to the developmental vulnerability to psychiatric disorders. That is, perturbing environmental conditions during neurodevelopmental stages can have detrimental effects on adult mood and emotional responses. However, the possible maladaptive neural mechanisms contributing to such psychopathological phenomenon still remain poorly understood. In this review, we explore preclinical rodent models of developmental vulnerability to psychiatric disorders, focusing on the impact of early-life environmental perturbations on behavioral aspects relevant to stress-related and psychiatric disorders. We limit our analysis to well-established models in which alterations in the serotonin (5-HT) system appear to have a crucial role in the pathophysiological mechanisms. We analyze long-term behavioral outcomes produced by early-life exposures to stress and psychotropic drugs such as the selective 5-HT reuptake inhibitor (SSRI) antidepressants or the anticonvulsant valproic acid (VPA). We perform a comparative analysis, identifying differences and commonalities in the behavioral effects produced in these models. Furthermore, this review discusses recent advances on neurodevelopmental substrates engaged in these behavioral effects, emphasizing the possible existence of maladaptive mechanisms that could be shared by the different models.
... Several studies point to the importance of serotonin for social function, cognitive flexibility, stereotypic behavior and sensory development, modulation of the processing of facial expressions of emotion, sleep-wake rhythm, and locomotion, phenomena that significantly differ in ASD patients compared with healthy control individuals [57][58][59]. Moreover, the CHARGE study showed that in boys, prenatal exposure to selective serotonin reuptake inhibitors (SSRI) such as fluoxetine, especially during the first trimesters, may be associated with an increased risk of ASD [60]. There is evidence suggesting that a number of environmental pollutants (BPA, pesticides, traffic-related air pollution, phthalates, . . . ) contribute to ASD pathogenesis [61]. ...
Article
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Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumor cells, including glioma cells, in vitro. The developing CNS of fetus and newborn is particularly susceptible to the deleterious effects of neurotoxic substances in our environment, and perinatal exposure could result in the later development of diseases, a hypothesis known as the developmental origin of health and disease. Some of these substances affect the serotoninergic system and could therefore be the source of a silent pandemic of neurodevelopmental toxicity. This review presents the available data that are contributing to the appreciation of the effects of the exposome on the serotoninergic system and their potential link with brain pathologies (neurodevelopmental, neurodegenerative, neurobehavioral disorders, and glioblastoma).
... Exposure of the developing fetus to SSRIs, drugs that impact the serotonergic system, very likely also impacts neurodevelopment (Malm, 2012). Prenatal exposure to SSRIs in humans has been suggested as a possible environmental risk factor contributing to increasing rates of autism spectrum disorder (ASD) (Andalib et al., 2017;Croen et al., 2011;El Marroun et al., 2014;Harrington et al., 2014;Hviid et al., 2013;Malm, 2012;Man et al., 2015;Ostuzzi and Barbui, 2014;Rai et al., 2013). While results are not all consistent (Sorensen et al., 2013;Viktorin et al., 2017), reviews and meta-analyses of the prevailing data largely suggest higher risk of ASD after prenatal SSRI exposure. ...
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Evidence demonstrates that psychiatric disorders during pregnancy are detrimental to the offspring. Many disorders are treated with SSRIs and increasing numbers of pregnant women now receive these drugs during gestation. The long-term neurobehavioral consequences of prenatal SSRI exposure require further evaluation. This study examined the effects of prenatal fluoxetine exposure in mice in an extensive battery of behaviors related to neurodevelopment, mood, social, and repetitive behaviors. C57BL/6J dams were administered fluoxetine at a low (0.6 mg/kg/day) or high (6 mg/kg/day) dose or saline from embryonic days 8 to 18. Juvenile mice were tested for changes in ultrasonic vocalizations and neuromotor development. In adulthood, offspring were tested for changes in behaviors related to anxiety, depression, social, and repetitive behaviors. Prenatal exposure to fluoxetine impaired surface righting reflex at P5, and sex-dependently reduced the frequency of ultrasonic vocalizations in juvenile males but not females. In adulthood, both males and females prenatally exposed to high, but not low, doses of fluoxetine exhibited an increase in repetitive behaviors in the marble burying task and a decrease in sucrose preference. Males, but not females, exposed to fluoxetine exhibited increased anxiety-related behaviors in the elevated plus maze. Prenatal fluoxetine exposure did not affect other adult behaviors including social preference, self-grooming, passive avoidance and open field activity. These findings suggest males are more sensitive than females to disruptions in serotonin balance during prenatal development and highlight the need for additional systematic and mechanistic studies to evaluate the impact of fluoxetine exposure during other periods of gestation.
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Perinatal antidepressant drug exposure increases risk for autism spectrum disorder, yet the molecular and neurobehavioral effects of maternal antidepressant drug use on offspring remain poorly understood. In this study, we administered the selective serotonin reuptake inhibitor (SSRI) fluoxetine non-invasively to female mice throughout gestation and early lactation, and then examined social interaction behaviors in offspring. In addition, we measured whole brain gene expression levels of monoamine oxidase A (MAOA), the primary metabolizing enzyme for serotonin. We found deficits in sociability and social novelty-seeking behavior in the juvenile offspring of SSRI-treated mice, and these behaviors persisted into young adulthood. Furthermore, we found decreased MAOA expression in the brains of offspring of SSRI-treated mice. Our findings suggest that exposure to antidepressants during the prenatal and early postnatal period may negatively affect social development. Moreover, reduced MAOA expression may play a role in the mechanistic pathway linking SSRI exposure and behavioral deficits symptomatic of autism.
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In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or "other". We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child's daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies. Review registration number: CRD42018086101 in the PROSPERO database.
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With approximately 10% of pregnant women prescribed antidepressant drugs for the treatment of depressive disorders, there is growing concern regarding the potential long-term effects of this exposure on offspring. Research is needed in clinically relevant models to determine the effects on offspring behaviour and associated neurobiological systems. The aim of this study was to determine the effects of maternal fluoxetine treatment on anxiety-like and depressive-like behaviours in adolescent offspring as well as associated glutamatergic markers, using a clinically relevant rodent model of depression. Wistar-Kyoto (model of innate depression) and Sprague-Dawley rats were treated with fluoxetine (10 mg/kg) from gestational day 0 to postnatal day 14. Male offspring underwent behavioural testing (open field, elevated plus maze, forced swim test) at adolescence followed by quantitative immuno-detection of glutamatergic markers in the prefrontal cortex and ventral hippocampus. Perinatal fluoxetine exposure exacerbated the anxiety-like and depressive-like phenotype in Wistar-Kyoto offspring and induced an anxiety-like and depressive-like phenotype in Sprague-Dawley offspring. Wistar-Kyoto offspring showed reductions in NMDA receptor NR1, NR2A and NR2B subunits, as well as post-synaptic density 95 (PSD-95) and metabotropic glutamate receptor subtype 1 (mGluR1) in the prefrontal cortex; perinatal fluoxetine exposure further reduced NR1, NR2A, PSD-95 and mGluR1 expression in Wistar-Kyoto as well as Sprague-Dawley offspring. In the ventral hippocampus perinatal fluoxetine exposure reduced PSD-95 and increased metabotropic glutamate receptor subtype 5 (mGluR5) and Homer1b/c in both Sprague-Dawley and Wistar-Kyoto strains. These findings suggest that maternal fluoxetine treatment exacerbates effects of underlying maternal depression on offspring behaviour, which may be mediated through alterations in the glutamatergic system. Further research investigating how to minimise these effects, whilst ensuring optimal treatment for mothers, is essential to move the field forward.
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Background: Environmental phenols and parabens are endocrine disrupting chemicals (EDCs) with the potential to affect child neurodevelopment including autism spectrum disorders (ASD). Our aim was to assess whether exposure to environmental phenols and parabens during pregnancy was associated with an increased risk of clinical ASD or other nontypical development (non-TD). Methods: This study included mother-child pairs (N = 207) from the Markers of Autism Risks in Babies - Learning Early Signs (MARBLES) Cohort Study with urinary phenol and paraben metabolites analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from repeated pregnancy urine samples. Because family recurrence risks in siblings are about 20%, MARBLES enrolls pregnant women who already had a child with ASD. Children were clinically assessed at 3 years of age and classified into 3 outcome categories: ASD, non-TD, or typically developing (TD). Single analyte analyses were conducted with trinomial logistic regression and weighted quantile sum (WQS) regression was used to test for mixture effects. Results: Regression models were adjusted for pre-pregnancy body mass index, prenatal vitamin use (yes/no), homeowner status (yes/no), birth year, and child's sex. In single chemical analyses phenol exposures were not significantly associated with child's diagnosis. Mixture analyses using trinomial WQS regression showed a significantly increased risk of non-TD compared to TD (OR = 1.58, 95% CI: 1.04, 2.04) with overall greater prenatal phenol and paraben metabolites mixture. Results for ASD also showed an increased risk, but it was not significant. Discussion: This is the first study to provide evidence that pregnancy environmental phenol exposures may increase the risk for non-TD in a high-risk population.
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Maternal depression and treatment with selective serotonin reuptake inhibitors (SSRIs), the most common form of pharmaceutical intervention, can both have an impact on infant development. As such, it is difficult for healthcare providers to recommend a course of treatment to expectant mothers suffering from depression, or to women on antidepressant medication prior to pregnancy. This review will discuss the existing research on the developmental impacts of maternal depression and its treatment with SSRIs, with a particular focus on contributing factors that complicate our attempt to disentangle the consequences of maternal depression and its treatment such as the timing or severity of the depression. We will explore avenues for translational animal models to help address the question of “Trick or Treat”, i.e.: which is worse for offspring development: exposure to maternal depression, or the SSRI treatment? Further, we will explore sex-dependent outcomes for the offspring in human and animal studies as male and female offspring may react differently to the presence of maternal depression or antidepressant treatment. Without more clinical and preclinical data, it remains difficult for women to make an informed decision regarding their depression treatment before, during, and after their pregnancy.
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Objective Several studies have investigated whether in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental‐ or behavioral disorders. The aim of this study was to perform a systematic review and meta‐analysis based on this literature. Methods A systematic search of eligible literature in PubMed, Embase and PsycINFO and subsequent meta‐analysis was conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guideline. Results A total of 20 studies were included in the review and results from 18 of these were meta‐analyzed. We found a statistically significant positive association between in utero exposure to SSRIs and mental‐ or behavioral disorders such as autism spectrum disorder (Hazard Ratio (HR)=1.27; 95% Confidence interval (CI)=1.10‐1.47), attention‐deficit/hyperactivity disorder (HR=1.33; 95%CI=1.06‐1.66) and mental retardation (HR=1.41; 95%CI=1.03‐1.91). Confounding by indication was identified in five of seven studies investigating this aspect. Conclusion Exposure to SSRIs in utero is associated with increased risk of developing mental‐ or behavioral disorders. However, these associations do not necessarily reflect a causal relationship since the results included in this meta‐analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association. This article is protected by copyright. All rights reserved.
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It is well established that exercise can improve depressive symptoms in the general population; however, it is not clear if these benefits are also seen in pregnancy. This review aimed to synthesize the evidence that examines whether exercise during pregnancy impacts depressive and associated symptoms (e.g. anxiety) during the perinatal period. The review was conducted in accordance with PRISMA guidelines and reporting criteria; literature was searched using PubMed, Scopus and Web of Science database engines. Clinical trials published in English evaluating the effects of a defined exercise protocol during pregnancy on depressive and/or anxiety symptoms during the perinatal period were included. Studies without a control group were excluded. Risk of bias was conducted by Cochrane assessment to appraise the quality of the included studies. Twenty-seven articles, between 1994 and 2019, were included. Of these, only 5 specifically recruited women with depression (n = 334), which all assessed a yoga-based intervention; 4 of these studies showed a statistically significant improvement in depressive and/or anxiety symptoms in the intervention group compared to baseline; however, 2 of these studies also showed an improvement in the control group. The remaining 22 studies used various exercise interventions in pregnant women (n = 4808) with 20 studies reporting that exercise during pregnancy has the ability to improve depressive and/or anxiety measures in the perinatal period compared to either baseline or control. The evidence suggests that exercise of various types in pregnancy can reduce depressive and/or anxiety symptoms in the perinatal period in otherwise healthy women. Specifically in women with antenatal depression, the incorporation of yoga in pregnancy can improve depressive/anxiety symptoms in the perinatal period; however, this is based on a small number of studies, and it is not clear whether this is superior to non-exercise controls. Further studies are needed to determine the potential therapeutic effects of exercise of various types during pregnancy on symptoms of antenatal depression.
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Autism spectrum disorder (ASD) is a rapidly growing global pandemic that affects an estimated 1 in 59–68 children. It is a complex disease with both genetic and environmental etiologies. Due to the rapid increase in the incidence of ASD, environmental causes for ASD are gaining attention. Efforts to probe several environmental exposures that could contribute to causing ASD are underway. In this regard, this chapter is directed towards understanding prenatal exposure to key environmental factors i.e., drugs and dietary nutrients that may act via the same molecular pathway - epigenetics as a potential etiological factor for ASD. Epigenetic regulation is a molecular mechanism known to be a significant contributor to neurodevelopmental disorders. It also offers a means to explain how environmental exposures can impact genetics. We discuss the impact of maternal exposures to certain drugs, and dietary intake, on the developing fetus during pregnancy. Maternal Exposure to some drugs during gestation are associated with a higher risk of ASD, while exposure to other dietary compounds may offer promise to rescue epigenetic regulatory insults related to ASD. However, more work in this important area is still required, nevertheless preliminary research already has important implications in the understanding, prevention and treatment of ASD.
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Sertraline hydrochloride is a commonly prescribed antidepressant medication that acts by amplifying serotonin signaling. Numerous studies have suggested that children of women taking sertraline during pregnancy have an increased risk of developmental defects. Resolving the degree of risk for human fetuses requires comprehensive knowledge of the pathways affected by this drug. We utilized a Drosophila melanogaster model system to assess the effects of sertraline throughout development. Ingestion of sertraline by females did not affect their fecundity or embryogenesis in their progeny. However, larvae that consumed sertraline experienced delayed developmental progression and reduced survival at all stages of development. Genetic experiments showed that these effects were mostly independent of aberrant extracellular serotonin levels. Using an ex vivo imaginal disc culture system, we showed that mitotically active sertraline-treated tissues accumulate DNA double-strand breaks and undergo apoptosis at increased frequencies. Remarkably, the sertraline-induced genotoxicity was partially rescued by co-incubation with ascorbic acid, suggesting that sertraline induces oxidative DNA damage. These findings may have implications for the biomedicine of sertraline-induced birth defects.
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В последние годы наблюдается отрицательная тенденция к увеличению частоты возникновения расстройств аутистического спектра у детей, при этом сопутствующей проблемой является неполное понимание причин и механизмов развития этого патологического состояния. Несмотря на большое количество исследований, до сих пор нет единой общепринятой точки зрения на патогенетические механизмы возникновения и прогрессирования этого расстройства, что затрудняет разработку эффективной диагностической и лечебной тактики, а также профилактики расстройств аутистического спектра.Цель. Проанализировать данные современной научной литературы относительно факторов риска расстройств аутистического спектра.Материалы и методы. С помощью методов обзорного, системного и контент-анализа проанализировали доступные научные источники, посвященные изучению факторов риска расстройств аутистического спектра. Приведены данные мировой научной литературы и проанализированы результаты современных исследований.Выводы. В результате проведенного анализа литературных источников установлено, что в последние годы растет число пациентов с расстройствами аутистического спектра и активно изучаются причины и факторы риска этого патологического состояния. Доказано, что генетический фактор является основным в возникновении аутизма, однако в подавляющем большинстве случаев он сочетается с другими внешними факторами: возраст матери и/или отца старше 30 лет на момент зачатия; экстракорпоральное оплодотворение, прием женщинами за год до зачатия и в период беременности антидепрессантов, наличие одного или нескольких неблагоприятных факторов в акушерском анамнезе (тяжелая гемолитическая болезнь, задержка дыхания минимум на пять минут после рождения, судороги новорожденного, низкий вес при рождении, патологически узкая пуповина и т. д.), влияние прогестерона, вирусная и бактериальная инфекции матери в период беременности, экологические факторы (загрязнение воздуха, влияние табака, тяжелых металлов, пестицидов и т. д.). In recent years, there has been a negative trend towards the increase of the incidence of autism spectrum disorders in children. A related problem is incomplete understanding of the causes and development mechanisms of this pathological condition. Despite a large number of studies, there is still no single generally accepted point of view on the pathogenetic mechanisms of the onset and progression of this disorder. This fact makes it difficult to develop effective management and prevention of autism spectrum disorders.Purpose. To analyze the data of modern scientific literature regarding risk factors of autism spectrum disorders.Materials and methods. Using the review, system and content analysis, the authors analyzed available scientific sources dedicated to the study of the risk factors of autism spectrum disorders. The data of the world scientific literature are presented and the results of modern research are analyzed.Conclusion. As a result of the analysis of literature, it was found that in recent years the number of patients with autism spectrum disorders has increased, and the causes and risk factors of this pathological condition are being actively studied. It is proved that the genetic factor is fundamental in the onset of autism, but in the vast majority of cases, it is combined with other external factors: the age of mother and/or father is older than 30 years at the time of conception, in vitro fertilization, taking antidepressants one year before conception and during pregnancy, the presence of one or more unfavorable factors in the obstetric history (severe hemolytic disease, breath holding for at least five minutes after birth, newborn cramps, low birth weight, pathologically narrow umbilical cord, etc.), the effects of progesterone, maternal viral and bacterial infections during pregnancy, environmental factors (air pollution, effects of tobacco, heavy metals, pesticides, etc.).
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Autism spectrum disorder (ASD) is an increasingly common neurodevelopmental disorder that has a wide variety of etiologies. Patients with autism have deficits in social communication and restricted and repetitive behaviors and interests. Cognitive abilities are variable ranging from profound intellectual disability to above average intellectual capabilities. In addition, medical comorbidities such as gastrointestinal dysfunction, sleep disorders, and seizures are frequently diagnosed. Though there is no cure for autism, on-going research in genetic etiologies and novel therapeutic applications are being studied. ASD is a lifelong condition that has varied clinical presentations across the life span of an individual and requires a multifaceted and diverse team of providers to manage the differing challenges that arise as patients grow and develop.
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This paper reviews and synthesizes key areas of research related to the etiology, development, and maintenance of internalizing symptoms in children, adolescents, and adults with autism spectrum disorder (ASD). In developing an integrated conceptual model, we draw from current conceptual models of internalizing symptoms in ASD and extend the model to include factors related to internalizing within other populations (e.g., children that have experienced early life stress, children with other neurodevelopmental conditions, typically developing children) that have not been systematically examined in ASD. Our review highlights the need for more research to understand the developmental course of internalizing symptoms, potential moderators, and the interplay between early risk and protective factors. Longitudinal studies incorporating multiple methods and both environmental and biological factors will be important in order to elucidate these mechanisms.
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Since the historical scandal of thalidomide in the 1960s, practitioners and future mothers are fearful of drugs during pregnancy. In-uterine exposure to drugs can induce major malformation of the fetus or even intrauterine fetal death. Prescribing drugs to a pregnant woman requires particular attention, and it is necessary to consider both the maternal needs and the proven and potential fetal risks. In this chapter, we review the mechanisms for medication transfer from mother to fetus, fetal risk according to pregnancy timeline, and the main dangerous drugs during pregnancy. We also focus on three prescription debates, which are relevant for neurodevelopmental disorder, because they each point to a paradigmatic situation-diethylstilbestrol, which shows transgenerational adversary effects; valproate, which impacts neurodevelopment as a whole; and antidepressants for which the adverse impact on neurodevelopment is still controversial given the impact of depression itself. Finally, we consider the implications for practice and toxicologic research to promote risk prevention.
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Maternal exposure to the valproate short-chain fatty acid (SCFA) during pregnancy is known to possibly induce autism spectrum disorders (ASDs) in the offspring. By contrast, case studies have evidenced positive outcomes of this anticonvulsant drug in children with severe autism. Interestingly, the same paradoxical pattern applies to the IL-17a inflammatory cytokine involved in the immune system regulation. Such joint apparent contradictions can be overcome by pointing out that, among their respective signaling pathways, valproate and IL-17a share an enhancement of the “type A monoamine oxidase” (MAOA) enzyme carried by the X chromosome. In the Guided Propagation (GP) model of autism, such enzymatic rise triggers a prenatal epigenetic downregulation, which, without possible X-inactivation, and when coinciding with genetic expression variants of other brain enzymes, results in the delayed onset of autistic symptoms. The underlying imbalance of synaptic monoamines, serotonin in the first place, would reflect a mismatch between the environment to which the brain metabolism was prepared during gestation and the postnatal actual surroundings. Following a prenatal exposure to molecules that significantly elicit the MAOA gene expression, a daily treatment with the same metabolic impact would tend to recreate the fetal environment and contribute to rebalance monoamines, thus allowing proper neural circuits to gradually develop, provided behavioral re-education. Given the multifaceted other players than MAOA that are involved in the regulation of serotonin levels, potential compensatory effects are surveyed, which may underlie the autism heterogeneity. This explanatory framework opens up prospects regarding autism prevention and treatment, strikingly in line with current advances along the gut microbiome–brain axis.
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Preclinical studies suggest that stress-related disorders even prior gestation can cause long-term changes at the level of neurobehavioral adaptations. Therefore, it is critical to consider undergoing antidepressant therapy which could reverse the negative consequences in the offspring. Venlafaxine is widely used in clinical practice; however insufficient amount of well-controlled studies verified the safety of venlafaxine therapy during gestation and lactation. The aim of this work was to investigate the effects of perinatal venlafaxine therapy on selected neurobehavioral variables in mothers and their female offspring using a model of maternal adversity. Pre-gestational stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle during pregnancy and lactation. We have shown that pre-gestational stress decreased the number of pups with a significant reduction in the number of males but not females. Furthermore, we found that offspring of stressed and treated mothers exhibited anxiogenic behavior in juvenile and adolescent age. However, during adulthood pre-gestational stress significantly increased anxiety-like behavior of female, with venlafaxine treatment normalizing the state to control levels. Additionally, we found that even maternal stress prior gestation can have long-term impact on adult number of hippocampal immature neurons of the female offspring. A number of questions related to the best treatment options for maternal depression still remains, however present data may provide greater insight into the possible outcomes associated with perinatal venlafaxine therapy.
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Heritability estimates indicate that genetic susceptibility does not fully explain Autism Spectrum Disorder (ASD) risk variance, and that environmental factors may play a role in this disease. To explore the impact of the environment in ASD etiology, we performed a systematic review of the literature on xenobiotics implicated in the disease, and their interactions with gene variants. We compiled 72 studies reporting associations between ASD and xenobiotic exposure, including air pollutants, persistent and non-persistent organic pollutants, heavy metals, pesticides, pharmaceutical drugs and nutrients. Additionally, 9 studies reported that interactions between some of these chemicals (eg. NO 2 , particulate matter, manganese, folic acid and vitamin D) and genetic risk factors (eg. variants in the CYP2R1, GSTM1, GSTP1, MET, MTHFR and VDR genes) modulate ASD risk. The chemicals highlighted in this review induce neuropathological mechanisms previously implicated in ASD, including oxidative stress and hypoxia, dysregulation of signaling pathways and endocrine disruption. Exposure to xenobiotics may be harmful during critical windows of neurodevelopment, particularly for individuals with variants in genes involved in xenobiotic metabolization or in widespread signaling pathways. We emphasize the importance of leveraging multilevel data collections and integrative approaches grounded on artificial intelligence to address gene-environment interactions and understand ASD etiology, towards prevention and treatment strategies.
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Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may influence white matter (WM) development, as previous studies report widespread microstructural alterations and reduced interhemispheric connectivity in SSRI‐exposed infants. In rodents, perinatal SSRIs had sex‐specific disruptions in corpus callosum (CC) axon architecture and connectivity; yet it is unknown whether SSRI‐related brain outcomes in humans are sex specific. In this study, the neonate CC was selected as a region‐of‐interest to investigate whether prenatal SSRI exposure has sex‐specific effects on early WM microstructure. On postnatal day 7, diffusion tensor imaging was used to assess WM microstructure in SSRI‐exposed (n = 24; 12 male) and nonexposed (n = 48; 28 male) term‐born neonates. Fractional anisotropy was extracted from CC voxels and a multivariate discriminant analysis was used to identify latent patterns differing between neonates grouped by SSRI‐exposure and sex. Analysis revealed localized variations in CC fractional anisotropy that significantly discriminated neonate groups and correctly predicted group membership with an 82% accuracy. Such effects were identified across three dimensions, representing sex differences in SSRI‐exposed neonates (genu, splenium), SSRI‐related effects independent of sex (genu‐to‐rostral body), and sex differences in nonexposed neonates (isthmus‐splenium, posterior midbody). Our findings suggest that CC microstructure may have a sex‐specific, localized, developmental sensitivity to prenatal SSRI exposure.
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Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
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At least one in ten women is exposed to a psychotropic medication in the perinatal period, and the rate has increased tremendously over the past two decades. Pregnancy is a period of extreme vulnerability to the onset of depression and other mental illnesses, and the use of pharmacological treatment has become highly concerning to patients and their healthcare providers with limited data available to assess their effectiveness to the pregnant woman and safety to her developing fetus. This has been demonstrated by the high rates of discontinuation of many psychotropic medications upon recognition of pregnancy, thereby posing a risk of relapse of the underlying condition in women with severe form of psychiatric disease, which may have adverse effects on the pregnancy and possibly on the health of the fetus as well. Antidepressants account for the majority of prescribed psychotropic medications for women in the perinatal period and are indicated for a variety of conditions, other than depression. Other commonly reported psychotropic medications among perinatal women include anxiety medications and atypical antipsychotics. Both geographical and temporal factors are important in understanding prescription trends of these medications over the perinatal period.
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In addition to its role in the pathophysiology of numerous psychiatric disorders, increasing evidence points to serotonin (5-HT) as a crucial molecule for the modulation of neurodevelopmental processes. Recent evidence indicates that the placenta is involved in the synthesis of 5-HT from maternally derived tryptophan (TRP). This gives rise to the possibility that genetic and environmental perturbations directly affecting placental TRP metabolism may lead to abnormal brain circuit wiring in the developing embryo, and therefore contribute to the developmental origin of psychiatric disorders. In this review, we discuss how perturbations of the placental TRP metabolic pathway may lead to abnormal brain development and function throughout life. Of particular interest is prenatal exposure to maternal depression and antidepressants, both known to alter fetal development. We review existing evidence on how antidepressants can alter placental physiology in its key function of maintaining fetal homeostasis and have long-term effects on fetal forebrain development.
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To study the association between parental depression and maternal antidepressant use during pregnancy with autism spectrum disorders in offspring. Population based nested case-control study. Stockholm County, Sweden, 2001-07. 4429 cases of autism spectrum disorder (1828 with and 2601 without intellectual disability) and 43 277 age and sex matched controls in the full sample (1679 cases of autism spectrum disorder and 16 845 controls with data on maternal antidepressant use nested within a cohort (n=589 114) of young people aged 0-17 years. A diagnosis of autism spectrum disorder, with or without intellectual disability. EXPOSURES: Parental depression and other characteristics prospectively recorded in administrative registers before the birth of the child. Maternal antidepressant use, recorded at the first antenatal interview, was available for children born from 1995 onwards. A history of maternal (adjusted odds ratio 1.49, 95% confidence interval 1.08 to 2.08) but not paternal depression was associated with an increased risk of autism spectrum disorders in offspring. In the subsample with available data on drugs, this association was confined to women reporting antidepressant use during pregnancy (3.34, 1.50 to 7.47, P=0.003), irrespective of whether selective serotonin reuptake inhibitors (SSRIs) or non-selective monoamine reuptake inhibitors were reported. All associations were higher in cases of autism without intellectual disability, there being no evidence of an increased risk of autism with intellectual disability. Assuming an unconfounded, causal association, antidepressant use during pregnancy explained 0.6% of the cases of autism spectrum disorder. In utero exposure to both SSRIs and non-selective monoamine reuptake inhibitors (tricyclic antidepressants) was associated with an increased risk of autism spectrum disorders, particularly without intellectual disability. Whether this association is causal or reflects the risk of autism with severe depression during pregnancy requires further research. However, assuming causality, antidepressant use during pregnancy is unlikely to have contributed significantly towards the dramatic increase in observed prevalence of autism spectrum disorders as it explained less than 1% of cases.
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Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.
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We investigated placental transfer and neurobehavioural effects in neonates exposed to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline (SSRI's), or to venlafaxine (an SNRI). Women receiving antidepressants during pregnancy and their neonates were studied. Cord and maternal drug concentrations were measured at birth and in the neonates plasma on day 3. Neonates were also assessed using a range of neurobehavioral tests and compared to controls. Median cord/maternal distribution ratio was 0.7-0.86 (range) for SSRIs, 0.72 for the SNRI venlafaxine and 1.08 for the O-desmethyl metabolite. Neonatal abstinence scores were significantly higher (p<0.05) in exposed infants than controls on day 1. Brazelton scores for habituation, social-interactive, motor and autonomic clusters, and serotonin scores were significantly greater (p<0.05) in exposed infants. Transfer of SSRIs and SNRIs across the placenta was substantial. Neonates developed mild behavioral symptoms in the early perinatal period but these were self-limiting and similar for both SSRIs and the SNRI venlafaxine.
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To compare the structural growth and developmental outcome of children born to mothers diagnosed with major depressive disorder during pregnancy who were exposed or not exposed to selective serotonin reuptake inhibitors (SSRIs) in utero. Children whose mothers were diagnosed with major depressive disorder in pregnancy and elected not to take medication (n = 13) were compared with children of depressed mothers treated with SSRIs (n = 31) on birth outcomes and postnatal neurodevelopmental functioning between ages 6 and 40 months. Children underwent blinded standardized pediatric and dysmorphology examinations and evaluations of their mental and psychomotor development with the use of the Bayley Scales of Infant Development (BSID II). The Bayley mental developmental indexes were similar in both groups. Children exposed to SSRIs during pregnancy had lower APGAR scores and scored lower on the Bayley psychomotor development indexes and the motor quality factor of the Bayley Behavioral Rating Scale than unexposed children. The findings that SSRIs during fetal development might have subtle effects on motor development and motor control are consistent with the pharmacologic properties of the drugs.
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Causes and contributing factors for autism are poorly understood. Evidence suggests that prevalence is rising, but the extent to which diagnostic changes and improvements in ascertainment contribute to this increase is unclear. Both genetic and environmental factors are likely to contribute etiologically. Evidence from twin, family, and genetic studies supports a role for an inherited predisposition to the development of autism. Nonetheless, clinical, neuroanatomic, neurophysiologic, and epidemiologic studies suggest that gene penetrance and expression may be influenced, in some cases strongly, by the prenatal and early postnatal environmental milieu. Sporadic studies link autism to xenobiotic chemicals and/or viruses, but few methodologically rigorous investigations have been undertaken. In light of major gaps in understanding of autism, a large case-control investigation of underlying environmental and genetic causes for autism and triggers of regression has been launched. The CHARGE (Childhood Autism Risks from Genetics and Environment) study will address a wide spectrum of chemical and biologic exposures, susceptibility factors, and their interactions. Phenotypic variation among children with autism will be explored, as will similarities and differences with developmental delay. The CHARGE study infrastructure includes detailed developmental assessments, medical information, questionnaire data, and biologic specimens. The CHARGE study is linked to University of California-Davis Center for Children's Environmental Health laboratories in immunology, xenobiotic measurement, cell signaling, genomics, and proteomics. The goals, study design, and data collection protocols are described, as well as preliminary demographic data on study participants and on diagnoses of those recruited through the California Department of Developmental Services Regional Center System.
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This study analyzed 2002 MarketScan data from a convenience sample of enrollees with private health insurance from the largest U.S. firms to examine utilization, expenditures, and factors associated with antidepressant prescriptions. Of enrollees, 11% received at least one antidepressant prescription during the year with average expenditures per enrollee of $51.55. Antidepressant prescriptions were more frequently used than any form of other mental health care and for 42% of users was not associated with any clearly identified mental health or "off-label" indication. In logistical regression analyses, health plan type, prescription days supply, gender, region, age, employment status, and subscriber status were associated with unexplained antidepressant prescription use.
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Fluoxetine (FLX) has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. This study evaluated the effects of developmental FLX exposure on anxiety, depression, aggressivity and pain sensitivity of male and female mice pups. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Pups were submitted to open-field, forced swimming, elevated plus-maze, intruder-resident and hot plate tests at adolescence and adulthood. In male pups, exposure to FLX decreased ambulation at postnatal day (PND) 40 and tended (p=0.07) to increase the latency to the first attack in the intruder-resident test at PND 70, suggesting decreased impulsivity. In female pups, FLX exposure increased immobility time in the forced swimming test at both PND 30 and 70, which is interpreted as depressive-like behavior. In conclusion, our results suggest that maternal exposure to FLX during pregnancy and lactation results in enduring behavioral alterations in male and female pups throughout life.
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Objective: To address the maternal and neonatal risks of both depression and antidepressant exposure and develop algorithms for periconceptional and antenatal management. Method: Representatives from the American Psychiatric Association, the American College of Obstetricians and Gynecologists and a consulting developmental pediatrician collaborated to review English language articles on fetal and neonatal outcomes associated with depression and antidepressant treatment during childbearing. Articles were obtained from Medline searches and bibliographies. Search keywords included pregnancy, pregnancy complications, pregnancy outcomes, depressive disorder, depressive disorder/dt, abnormalities/drug-induced/epidemiology, abnormalities/drug-induced/et. Iterative draft manuscripts were reviewed until consensus was achieved. Results: Both depressive symptoms and antidepressant exposure are associated with fetal growth changes and shorter gestations, but the majority of studies that evaluated antidepressant risks were unable to control for the possible effects of a depressive disorder. Short-term neonatal irritability and neurobehavioral changes are also linked with maternal depression and antidepressant treatment. Several studies report fetal malformations in association with first trimester antidepressant exposure but there is no specific pattern of defects for individual medications or class of agents. The association between paroxetine and cardiac defects is more often found in studies that included all malformations rather than clinically significant malformations. Late gestational use of selective serotonin reuptake inhibitor antidepressants is associated with transitory neonatal signs and a low risk for persistent pulmonary hypertension in the newborn. Psychotherapy alone is an appropriate treatment for some pregnant women; however, others prefer pharmacotherapy or may require pharmacological treatment. Conclusions: Antidepressant use in pregnancy is well studied, but available research has not yet adequately controlled for other factors that may influence birth outcomes including maternal illness or problematic health behaviors that can adversely affect pregnancy.
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Problem/Condition: Autism spectrum disorders (ASDs) are a group of developmental disabilities characterized by impairments in social interaction and communication and by restricted, repetitive, and stereotyped patterns of behavior. Symptoms typically are apparent before age 3 years. The complex nature of these disorders, coupled with a lack of biologic markers for diagnosis and changes in clinical definitions over time, creates challenges in monitoring the prevalence of ASDs. Accurate reporting of data is essential to understand the prevalence of ASDs in the population and can help direct research. Period Covered: 2008. Description of System: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that estimates the prevalence of ASDs and describes other characteristics among children aged 8 years whose parents or guardians reside within 14 ADDM sites in the United States. ADDM does not rely on professional or family reporting of an existing ASD diagnosis or classification to ascertain case status. Instead, information is obtained from children's evaluation records to determine the presence of ASD symptoms at any time from birth through the end of the year when the child reaches age 8 years. ADDM focuses on children aged 8 years because a baseline study conducted by CDC demonstrated that this is the age of identified peak prevalence. A child is included as meeting the surveillance case definition for an ASD if he or she displays behaviors (as described on a comprehensive evaluation completed by a qualified professional) consistent with the American Psychiatric Association's Diagnostic and Statistical Manual-IV, Text Revision (DSM-IV-TR) diagnostic criteria for any of the following conditions: Autistic Disorder; Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS, including Atypical Autism); or Asperger Disorder. The first phase of the ADDM methodology involves screening and abstraction of comprehensive evaluations completed by professional providers at multiple data sources in the community. Multiple data sources are included, ranging from general pediatric health clinics to specialized programs for children with developmental disabilities. In addition, many ADDM sites also review and abstract records of children receiving special education services in public schools. In the second phase of the study, all abstracted evaluations are reviewed by trained clinicians to determine ASD case status. Because the case definition and surveillance methods have remained consistent across all ADDM surveillance years to date, comparisons to results for earlier surveillance years can be made. This report provides updated ASD prevalence estimates from the 2008 surveillance year, representing 14 ADDM areas in the United States. In addition to prevalence estimates, characteristics of the population of children with ASDs are described, as well as detailed comparisons of the 2008 surveillance year findings with those for the 2002 and 2006 surveillance years. Results: For 2008, the overall estimated prevalence of ASDs among the 14 ADDM sites was 11.3 per 1,000 (one in 88) children aged 8 years who were living in these communities during 2008. Overall ASD prevalence estimates varied widely across all sites (range: 4.8-21.2 per 1,000 children aged 8 years). ASD prevalence estimates also varied widely by sex and by racial/ethnic group. Approximately one in 54 boys and one in 252 girls living in the ADDM Network communities were identified as having ASDs. Comparison of 2008 findings with those for earlier surveillance years indicated an increase in estimated ASD prevalence of 23% when the 2008 data were compared with the data for 2006 (from 9.0 per 1,000 children aged 8 years in 2006 to 11.0 in 2008 for the 11 sites that provided data for both surveillance years) and an estimated increase of 78% when the 2008 data were compared with the data for 2002 (from 6.4 per 1,000 children aged 8 years in 2002 to 11.4 in 2008 for the 13 sites that provided data for both surveillance years). Because the ADDM Network sites do not make up a nationally representative sample, these combined prevalence estimates should not be generalized to the United States as a whole. Interpretation: These data confirm that the estimated prevalence of ASDs identified in the ADDM network surveillance populations continues to increase. The extent to which these increases reflect better case ascertainment as a result of increases in awareness and access to services or true increases in prevalence of ASD symptoms is not known. ASDs continue to be an important public health concern in the United States, underscoring the need for continued resources to identify potential risk factors and to provide essential supports for persons with ASDs and their families. Public Health Action: Given substantial increases in ASD prevalence estimates over a relatively short period, overall and within various subgroups of the population, continued monitoring is needed to quantify and understand these patterns. With 5 biennial surveillance years completed in the past decade, the ADDM Network continues to monitor prevalence and characteristics of ASDs and other developmental disabilities for the 2010 surveillance year. Further work is needed to evaluate multiple factors contributing to increases in estimated ASD prevalence over time. ADDM Network investigators continue to explore these factors, with a focus on understanding disparities in the identification of ASDs among certain subgroups and on how these disparities have contributed to changes in the estimated prevalence of ASDs. CDC is partnering with other federal and private partners in a coordinated response to identify risk factors for ASDs and to meet the needs of persons with ASDs and their families.
Conference Paper
Background: Diagnostic instruments such as the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) are intended to be used together, and researchers have made a systematic attempt to evaluate how information from those two instruments should be combined together (Risi et al., 2006). However, the ADI-R algorithm used in the previous study was a “2 years to 3 years and 11 months algorithm” and previous studies have shown that this algorithm resulted in relatively poor sensitivity and specificity for the comparison between toddlers and preschoolers with Autism Spectrum Disorders (ASD) and those with nonspectrum disorders (NS) (Lord, Storoschuk, Rutter, & Pickles, 1993; Ventola et al., 2006). Thus, in this study, we used newly developed ADI-R algorithms that have shown better predictive validity than the preexisting algorithm (Kim & Lord, in prep). Objectives: The purpose of this study is to propose standard criteria for the combined use of the ADI-R and ADOS to diagnose cases of ASD for toddlers from 12 to 47 months of age. Methods: Analyses were conducted using a dataset of the ADI-R and ADOS psychometric scores for 731 children aged from 12 to 47 months (515 cases with ASD; 142 with NS; 74 from children with typical development). Since the new algorithms were developed separately for different groups of children divided by their chronological age and language level, the cases were divided into three groups to examine different standard criteria using information from the ADI-R and/or ADOS. The three groups were: all children from 12 to 20 months of age and nonverbal children from 21 to 47 months; children with single words from 21 to 47 months; and children with phrase speech from 21 to 47 months. The criteria tested in this study were: meeting the cutoff scores for ASD on 1) both the ADOS and ADI-R; 2) either the ADOS or ADI-R; 3) the ADOS alone; 4) the ADI-R alone. Results: For all three groups of children, the first criteria of meeting the cutoffs for both the ADOS and ADI-R resulted in well balanced, high sensitivity and specificity (ranging from 71-88% sensitivity and 70-92% specificity by developmental cells). When the second criteria (meeting the cutoffs on either the ADOS or ADI-R) was used, sensitivity was very high (ranging from 96-98%) but specificity was relatively poor (48-73%). Similarly, when the ADOS was used alone, sensitivity was very high (ranging from 94-98%) but specificity was poor (59-79%). When the ADI-R was used alone, sensitivity and specificity were well balanced but both were lower than those of the first criteria. Conclusions: ASD diagnostic criteria using combined information from both the ADI-R and ADOS better reflect clinical judgments of ASD than any single instrument for toddlers under 4 years of age.
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Background and aims: Medical and public health authorities recommend daily school physical education (PE) as a way to combat childhood obesity. Many schools in low-income communities, such as the Bronx, NY lack PE facilities. We developed a CHAM JAM intervention and assessed its impact on increasing PA levels of students.
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Studies 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. We 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. During 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). We 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.).
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Serotonin, a neurotransmitter found throughout the brain and body, has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led some to believe that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure to substances that manipulate serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs). This review examines evidence regarding the serotonin system and autism spectrum disorders (ASD), as well as what the literature has reported thus far on developmental effects of prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus during pregnancy and clinical implications are also discussed. Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes. The only published study that focused on prenatal SSRI exposure and ASD found an increased risk with exposure to SSRIs, especially during the first trimester. Obstacles that will be faced in future research are isolating medication effects from maternal depression and, given the infrequent occurrence of exposure and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic factor in ASD, and what it points to as a marker for subgrouping, remains unclear. Understanding how the development of ASD might be affected by prenatal factors that influence serotonin levels, such as SSRIs, could identify modifiable targets for prevention. Autism Res 2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.
Chapter
The validity of a study of humans is often separated into two components: the validity of the inferences as they pertain to members of the source population (internal validity), and the validity of the inferences as they pertain to people outside that population (external validity). Scientific generalization extends beyond statistical generalization of study results to the formulation of abstract concepts relating the study factors. Internal validity is a prerequisite for the study to contribute usefully to this process of abstraction, but the generalization process is otherwise separate from the concerns of internal validity and the mechanics of the study design. Keywords: internal validity; external validity; generalization; scientific inference; bias; confounding; misclassification
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Serotonin is known to play a role in brain development prior to the time it assumes its role as a neurotransmitter in the mature brain. Serotonin regulates both the development of serotonergic neurons (termed autoregulation of development) and the development of target tissues. In both cases, the astroglial-derived protein, S-100β plays a role. Disruption of serotonergic development can leave permanent alterations in brain function and behavior. This may be the case in such human developmental illnesses as autism and Down Syndrome.
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This column reviews why signal detection in psychiatric research has been problematic, how the use of biomarkers can help, how and why fixed dose studies are done, and how these studies differ from what clinicians do in practice. The fixed dose studies done with selective serotonin reuptake inhibitors (SSRIs) are used to illustrate general points about clinical trial research methodology relevant to clinical practice. Studies with SSRIs have yielded flat dose-response curves with regard to efficacy but ascending dose-response curves with regard to discontinuation due to adverse effects. These clinical trial findings are explained by studies using serotonin transporter inhibition or occupancy as a surrogate marker for SSRI efficacy and tolerability. Initially, these studies were conducted ex vivo using human platelets as the model system; however, they have now been extended to in vivo measurement of serotonin transporter occupancy in patients using positron emission tomography. The conclusion from this work is that the usually effective, minimum dose of each marketed SSRI produces 70%-80% inhibition or occupancy (depending on the methodology used) of the serotonin transporter; higher rates of inhibition or occupancy do not on average increase efficacy but instead increase early discontinuation rates due to adverse effects. These increased discontinuation rates offset any gain in efficacy when the results are analyzed using the last-observation-carried-forward approach. An understanding of these principles also provides an explanation for what initially may appear to be a conundrum: why some patients can benefit from a dose increase even though, in fixed dose clinical trials, the drug had a flat dose-efficacy curve.