Journal of Affective Disorders 182 (2015) 132–137
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? Salvatore Gentile a,b,n a b
Department of Mental Health ASL Salerno Mental Health Center, n. 63, Piazza Galdi, 841013 Cava de' Tirreni, Salerno, Italy University of Naples, Medical School “Federico II”, Department of Neurosciences – Perinatal Psychiatry, Via S. Pansini, 5, 80131 Naples, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 12 January 2015 Received in revised form 24 April 2015 Accepted 27 April 2015 Available online 6 May 2015
Recent information suggests that antenatal exposure to psychotropics may impair child neurodevelopment. Thus, aim of this review is to examine systematically available literature investigating potential associations between prenatal use of selective serotonin reuptake inhibitors (SSRIs) and the risk of autism spectrum disorders (ASDs). Methods: Medical literature published in English since 1988 identified using MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library. Search terms: antidepressants, autism (spectrum disorders), childhood, children, neurodevelopment, pregnancy, SSRIs. Searches were updated until March 5, 2015. Results: Six out of eight reviewed articles confirm an association between antenatal SSRI exposure and an increased risk of ASDs in children. However, the epidemiologic evidence on the link between prenatal SSRI exposure and ASD risk must still be cautiously interpreted, because of potential biases of analyzed research. Limitations: Main limitations of reviewed studies include: lack of directly validated clinical evaluation, impossibility to identify women who really took the prescribed medications during pregnancy, no assessment of severity and course of symptoms in relation to the pregnancy, lack of information about unhealthy prenatal lifestyle behaviors. Conclusions: Despite such limitations, available data show that some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs. Thus, there is an urgent need for further, large, well-designed research finalized to definitively assess the existence and the magnitude of this severe risk, thus confirming or denying that we are truly looking at “the fall of Gods”, since for many years SSRIs have been considered the first-choice agents for treating antenatal depression (Gentile, 2014; Gentile, 2011a; Gentile, 2005). & 2015 Elsevier B.V. All rights reserved.
Keywords: Antidepressants Autism spectrum disorders Neurodevelopment Pregnancy Safety SSRIs
Contents 1. Introduction . . . . . 2. Methods . . . . . . . . 3. Results . . . . . . . . . 4. Discussion . . . . . . 5. Conclusions . . . . . Conflict of interest. . . . Role of funding source Acknowledgments . . . . References . . . . . . . . . .
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n Correspondence to: Department of Mental Health ASL Salerno Mental Health Center, n. 63, Piazza Galdi, 841013 Cava de' Tirreni, Salerno, Italy. Tel.: þ 39 089 4455439; fax: þ39 089 4455440. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.jad.2015.04.048 0165-0327/& 2015 Elsevier B.V. All rights reserved.
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
1. Introduction Autism is a set of heterogeneous neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. The worldwide population prevalence is about 1%. Autism affects more male than female individuals, and comorbidity is common (470% have concurrent conditions). Patients diagnosed with autism spectrum disorders (ASDs) have both atypical cognitive profiles (such as impaired social cognition and social perception, executive dysfunctions), and atypical perceptual and information processing (Gray et al., 2014; Lai et al., 2014). Magnetic resonance imaging (MRI) studies have attempted to identify morphological changes in brain architecture associated with ASDs. Preliminary neuroimaging findings evidence an increase in total brain volume (and, especially, in frontal lobe volume), increased thickness in temporal/parietal lobes, structural alterations involving corpus callosum, amygdala, and cerebellum, and changes in grey matter in the posterior cingulate cortex, medial prefrontal cortex, and temporal lobes (Brun et al., 2009; Carper et al., 2013; Palmen et al., 2005; Stigler et al., 2011; Uddin et al., 2011). Recent studies have also provided evidence for an altered epigenetic landscape in ASDs and have hypothesized the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs actually encode proteins that are involved in transcriptional regulation and chromatin remodeling (Abrahams and Geschwind, 2008; Rangasamy et al., 2013). Moreover, mitochondrial dysfunctions and changes in porphyrin metabolism have also been reported to occur with higher frequency among ASD patients than in general populations (Rossignol and Frye, 2012; Woods et al., 2010). Identifying biomarkers for ASDs (Voineagu and Yoo, 2013) has been the focus of intense research since the first description of the disease in the early 1940s (Kanner, 1943). Biomarkers of oxidative stress, as a result of impaired antioxidant mechanism and aberrant neuroimmune responses, have been associated with ASDs (Frustaci et al., 2012; Wei et al., 2013). However, one of the main biomarkers of ASDs includes changes in several neurotransmitter levels. Serotonin has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led to the hypothesis that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Increased blood levels of serotonin were observed in a proportion of autistic patients as high as 35%. Serotonin levels are regulated by genetic variants of serotonin receptor genes, such as SLC6A4 and ITGB3 (Abney et al., 2001; Weiss et al., 2005). Thus, it has been theorized that an increase in serotonergic activity during brain development may facilitate the onset of ASDs (Whitaker-Azmitia, 2005). Several data support the hypothesis that somatodendritic 5-HT1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of substances that manipulate serotonin levels (Gardier et al., 1996). Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure selective serotonin reuptake inhibitors [(SSRIs) – Harrington et al., 2013]. A 4-fold increase in the use of antidepressants during pregnancy has been observed during the period 1996–2005, with nearly 8% of pregnant women prescribed antidepressants during the years 2004–2005 (Andrade et al., 2008). Conversely, the rate of use of psychotropic drugs has remained relatively stable between 2006 and 2011. The most commonly used psychotropics during pregnancy are SSRIs (Hanley and Mintzes, 2014; Meunier et al., 2013). Given this background, the aim of this review is to examine available literature investigating potential associations between prenatal antidepressant SSRI exposure and the risk of ASDs in children.
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2. Methods Fig. 1 shows the systematic literature search and results.
3. Results Studies suggest no link between antenatal antidepressant exposure and ASDs (shown in Table 1). A population-based study collected prospectively data considering both SSRI exposure and mental history of mothers (Croen et al., 2011). The study sample was drawn from the Californian Childhood Autism Perinatal Study, a case–control study aiming to investigate potential risks factors for ASDs. In the ASD cases, 15/298 children were exposed to SSRIs (3.4% to fluoxetine (FLX), 4.4% to paroxetine (PAR), 5.0% to sertraline (SER), and 3.4% to fluvoxamine (FVX)). The study found a 2fold increase in the risk of ASDs associated with SSRI treatment during the year before delivery and a 3-fold increased risk associated with first trimester exposure, independent of maternal psychiatric diagnosis. The case–control study by Rai et al. (2013) included all young people aged 0–17 years and residing in Stockholm, Sweden, between 2001 and 2007 (n ¼589,114). The cohort contained prospectively recorded data on the probands and their first degree relatives collected by record linkage with national and regional healthcare, social, and administrative registries. The characteristics of cases and controls with all available data were similar to the 4429 cases and 43,277 controls with complete data used in the main analysis. Approximately 1% (n ¼44) of mothers of the 4429 case children with ASDs were diagnosed with depression recorded before the birth of the index child, compared with 0.6% (n ¼272) of 43,277 control mothers. Maternal history of depression was associated with a higher risk of ASDs in offspring, but there was no evidence of a relation with paternal depression. This association was limited to children of mothers who reported using antidepressants at the first antenatal interview. The increase in the risk of autism seemed to be confined to those forms of ASDs without intellectual disability. Sørensen et al. (2013) identified all children born alive in Denmark 1996–2006 (n¼ 668,468) and their parents in the Danish Civil Registration System. The Authors obtained information on the mother's prescriptions filled during pregnancy from the Danish National Prescription Registry, on diagnosis of ASDs in the children, and on diagnosis of psychiatric disorders in the parents from the Danish Psychiatric Central Register. Exposure window was defined from 30 days before conception to the day of birth. Main study results were that, after controlling for several confounding factors, the association between prenatal maternal SSRI use and later ASDs in the child, albeit statistically significant, was weaker than that reported in other recent epidemiologic studies (Croen et al., 2011; Ray et al., 2013). The association was found for high as well as for low dose levels, and risk estimates were comparable regardless of timing of exposure. To further investigate this association, a recent study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status (Gidaya et al., 2014). An increased risk of ASDs associated with in utero exposure to SSRIs was observed in this large population-based, case–control study. The effect was present for all exposure windows considered (but the strongest effect was found for third trimester exposure) and persisted after adjustment for SSRI indications. A recent population-based case–control study (Harrington et al., 2014) included families enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. This population-based, case–control investigation recruited children
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S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
PubMed
EMBASE
SCOPUS
Cochrane Library
Related articles identified in reference lists of retrieved papers (excluding duplicates).
297 articles
Selected articles N=8 Articles focused on SSRI use for treating ASD symptoms N=88
EXCLUDED
Articles not reporting primary data N=201
Fig. 1. Systematic literature search and results. Medical literature information published in English since 1988 was identified using MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library. Additional references were manually identified from the reference lists of published articles Search terms (variously combined) were: antidepressants, autism (spectrum disorders), childhood, children, neurodevelopment, pregnancy. Searches were updated until March 5, 2015. Table 1 Studies suggesting a link between antenatal SSRI exposure and ASDs. Study/study design/sample size
SSRIs
Croen et al. (2011) Case–control study 289 case FLX children 1507 randomly selected control children FVX PAR SER Rai et al. ( 2013) Case–control study 4429 case FLX CIT children 43,277 control children PAR SER Sørensen et al. (2013) Cohort study 655,615 children of 428,407 mothers Gidaya et al. (2014) Case–control study 5215 case children 52,150 control children
N/A
FLX FVX PAR SER CIT ESC Harrington et al. (2014) Case–control study 492 case FLX children 320 control children PAR SER CIT ESC
El Marroun et al. (2014) Prospective study 69 case children 376 control children exposed to untreated maternal depression 5531 control children born to healthy mothers
Potential confounders explored
Main study results
Increased risk of ASDs for SSRI exposure during the Maternal health history, psychiatric diagnosis, age, first trimester. AOR: 3.5 (1.5–7.9) Increased risk for race/ethnicity, education level, parity, infant sex, birth weight, gestational age, birth year, birth facility ASDs for SSRI exposure during the year before delivery. AOR: 2.6 (1.5–5.4) Increased risk for ASDs of any antidepressant Parental age, family income, education levels, occupational class, maternal region of birth maternal exposure during the first trimester. AOR: 2.54 (1.37–4.68)a smoking, parity, diabetes, hypertension, birth weight, Apgar score at 5 min Parental age and psychiatric history, gestational age, Increased risk of ASDs for SSRI exposure during birth weight, infant sex, congenital malformations, pregnancy AOR: 1.6 (1. 3–2.0) parity Parental age, psychiatric diagnosis, infant sex, family Increased risk o f ASDs for SSRI exposure during income, duration and timing of exposure pregnancy AOR: 2.5 (1.7–3.7)b
Increased risk of ASDs for SSRI exposure during Maternal age, education levels, birth place, birth weight, preterm birth, year of birth, children age and pregnancy. OR: 3.22 (1.17–8.84)a sex, nicotine, alcohol, illicit substances, non-SSRI medication use, serotonergic supplements, maternal obesity, diabetes, hypertension, mother's anxiety/ mood disorder history
Maternal age, educational level, country of origin, PAR FLX SER smoking habit FVX CIT
Increased risk of ASDs for SSRI exposure during pregnancy. Pervasive developmental problems: OR: 1.91 (1.13–3.47)a Autistic traits ß¼ 0.15 (0.08–0.22)
Abbreviations and notes: (95%CI); CIT: citalopram; ESC: escitalopram; FLX: fluoxetine; FVX: fluvoxamine; SER: sertraline; PAR: paroxetine; SSRIs: selective serotonin reuptake inhibitors; ASDs: autism spectrum disorders; AOR: adjusted odds ratio; OR: odds ratio. a b
Also including mothers exposed to non-selective monoamine reuptake inhibitors. Data for third trimester exposure.
with ASDs, with developmental delays other than ASD, and from the general population. CHARGE eligibility criteria included being 2–5 years old, born in California, having a parent who speaks English or Spanish, and living with at least one biological parent and in the study catchment area of specified California Regional Centers, which coordinate services for persons with developmental disabilities. Mothers' reported use of SSRIs during pregnancy
was associated with increased risk of ASDs in boys. Too few girls were exposed for analysis. Results were robust to sensitivity analyses and adjustment for confounders. Trimester-specific analyses in boys showed the greatest association with ASD during first-trimester SSRI exposure. Very recently, El Marroun et al. (2014) enrolled a relative large number of children exposed to SSRIs, exposed to untreated
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
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Table 2 Studies suggesting no link between antenatal SSRI exposure and ASDs. Study/study design/sample size
SSRIs
FLX FVX Hviid et al. (2013) Cohort study 52 cases during 42,400 person-years of follow-up involved offspring of women PAR SER CIT ESC who were exposed to SSRIs during their pregnancy
Clements et al. (2014)
FLX FVX PAR SER CIT ESC
Potential confounders explored
Main study results
Year of the birth, parity, maternal age, country of origin, place of residence at the start of the pregnancy, smoking status, maternal psychiatric conditions, use of drugs other than SSRIs during pregnancy, diagnoses made in a psychiatric hospital or psychiatric unit (inpatient or outpatient), employment status, mother's level of education Sociodemographic variables, maternal clinical features
No statistically significant association between maternal use of SSRIs during pregnancy and ASDs
No statistically significant association between maternal use of SSRIs during pregnancy and ASDsa
Abbreviations FLX: fluoxetine; FVX: fluvoxamine; SER: sertraline; PAR: paroxetine; CIT: citalopram; ESC: escitalopram: OR: odds ratio (95%CI); ASDs: autism spectrum disorders. a
Statistically significant association between maternal use of SSRIs and attention-deficit hyperactivity disorder ADHD [OR: 1.81 (1.22–2.70)].
maternal mood symptoms, and children born to healthy mothers. The study demonstrated an association between SSRI exposure and an increased risk of ASDs, such as pervasive developmental problems and autistic traits. Prenatal depressive symptoms with no SSRI use were also associated with the risk of autistic traits, albeit this link was weaker and less specific. Studies suggest no link between antenatal antidepressant exposure and ASDs (shown in Table 2). A cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009 linked information on maternal use of SSRIs before and during pregnancy, rate of ASDs diagnosed in the offspring, and a range of potential confounders (Hviid et al., 2013). During 5,057,282 person/years of follow-up, the study was able to identify 3892 cases of ASDs (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 increase in the risk of ASDs. In order to investigate the risk of ASDs in children exposed antenatally to SSRIs, 1377 children with ASDs delivered in a large New-England health care system were identified from electronic health records (Clements et al., 2014). The study also identified 2243 children diagnosed with attention-deficit hyperactivity disorder (ADHD). No association was found between antenatal antidepressant exposure and ASDs, whereas antidepressant exposure during pregnancy was linked to increased risks of ADHD.
4. Discussion Reviewed studies show several limitations. For instance, the study sample investigated by Croen et al. (2011) was not directly validated through clinical evaluation. Another limitation, which is however present in nearly all studies on the reproductive safety of antidepressants, is that the study was unable to differentiate women who really took medications during pregnancy from those who received drug prescription but did not start pharmacological treatment. Several limitations of the study by Rai et al. (2013) need also to be acknowledged, the main being that depression was identified using specialist care records and therefore was probably under-ascertained. In fact, most people with depressive symptoms do not seek psychiatric help or are managed in primary care. Moreover, neither the severity nor the course of depressive symptoms in relation to the pregnancy was assessed. It was not possible to establish whether the association between antenatal antidepressant exposure and ASDs might reflect more severe
forms of depression during pregnancy or was a true iatrogenic effect. The same limitations affect the study by Sørensen et al. (2013). Moreover, although a wide range of lifestyle factors is known to influence the intrauterine environment and increase the risk for adverse outcomes, the study was unable to detect information about specific unhealthy maternal lifestyle factors during the gestational period. Although Gidaya et al. (2014) employed several strategies that can be to account for the confounding from maternal depression, such strategies were not devoid of potential biases. For example, regression adjustment and stratified analyses are both problematic in the face of underreporting of maternal depression and would lead to incomplete control for confounding by indication. Other potential study limitations have been highlighted by Harrington et al. (2014). First, residual confounding by indication for SSRI use remains possible because the study was unable to assess the severity of mental health symptoms. Second, lack of data on SSRI dosage precluded dose–response analyses. The recent study by El Marroun et al. (2014) provided no information about potential parental autistic traits. Moreover, the clinical diagnosis of depression was not assessed by diagnostic instruments. Pregnant mothers actually reported psychological symptoms by questionnaire. An exhaustive report of methodological biases affecting the results of all reviewed studies suggesting a causal relationship between in utero exposure to SSRIs and increased risk of developing ASDs is available in Table 3. To further complicate the attempt to differentiate the effects of the underlying maternal psychiatric disorder from the effects of SSRI exposure, studies using prenatal optimality scales (reviewed by Gardener et al., (2009)) provided some evidence suggesting that exposure to pregnancy complications in general may increase the risk of ASDs. Children born prematurely and very-low-birthweight children had 2.3 times and 3.2 times higher odds of ASDs, respectively (Singh et al., 2013). Pregnancy complications have been associated with both untreated maternal depression (Qiu et al., 2009) and SSRI use during pregnancy (Gentile, 2010). Moreover, a study investigating the relationship between reported maternal conditions, perinatal complications, and autism found three predicting factors for ASDs (gestational age, maternal morphology, and intrauterine stress). Finally, three maternal medical conditions were also identified as independent contributors to the onset of ASDs (urinary infection, high temperatures, and, notably, depression – Wilkerson et al., 2002). A potential association between antenatal depression and ASDs in offspring was also hypothesized by Clements et al. (2014). Thus, the increased rates of ASDs reported in mothers who need serotonergic agents during pregnancy may be the consequence of two
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S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
Table 3 Summary of methodological bias affecting reviewed studies suggesting an increased risk of ASDs in children exposed in utero to SSRIs. Study Croen et al. (2011)
Methodological bias
Difficulties in distinguishing the effects of medication exposure from the effects of the underlying mental disorder and potential physiological
changes related to maternal stress or depression during pregnancy Case or control status for most children in the study sample was not directly evaluated through clinical evaluation Risks of diagnostic misclassification Risks of poor maternal adherence to the pharmacological regimen Lack of data on breastfeeding
Rai et al. (2013)
Depression was identified using specialist care records Health services may be more likely to asses and recognize ASDs in children of mothers already known to psychiatric services (Berksonian bias)
Sørensen et al. (2013)
Data were extrapolated from automated database which are unable to ascertain definitively that the women actually used the prescribed
Gidaya et al. (2014)
A simulation-based approach was used to account for confounding by indication
Harrington et al. (2014)
SSRI exposure was determined by mothers' report Severity of maternal symptoms not assessed Lack of data on maternal SSRI dosage
El Marroun et al. (2014)
medication
The Danish Psychiatric Central Register has a high validity for childhood autism, whereas other forms of ASD diagnosis have not been validated
Mothers with mental disorders may overestimate the problems of their children Clinical diagnosis not obtained in all cases No information about potential parental autistic traits Clinical diagnosis of depression was not obtained with specific diagnostic instruments
independent factors which (alone, both, or together with all the other factors suspected to be involved in the onset of ASDs) impair the physiological development of the fetal brain. Last but not least, it should be noted that current case–control or cohort studies using between-patients design cannot completely control the genetic factors. Genetic factors play significant roles in the development of mental disorders, such ASDs. The known single-gene defects and the diagnosed medical conditions account for about 10% of the cases of autism (Chakrabarti and Fombonne, 2001). Between 21% and 50% of the boys with fragile X syndrome are on the autistic spectrum (Moss and Howlin 2009), and 0–6% of the autism populations have fragile X syndrome (Fombonne et al., 1997). Recently, two large datasets have been discovered: heterogeneous de novo copy-number variants collectively affecting several loci and presumably accounting for 5–8% of the cases of simplex forms of ASD (Sanders et al., 2011)
exposed to SSRIs, although the causality remains to be confirmed. However, the analysis did not include the results of two pertinent articles (Clements et al., 2014; El Marroun et al., 2014) Given such considerations, despite recent research having suggested that the increased frequency of diagnosis of ASDs could be caused in part by non-etiologic factors such as changes in diagnosis reporting practices and diagnostic criteria (Hansen et al., 2015). I have to highlight that six out of the eight articles reviewed here (including case–control and prospective studies) confirm an association between SSRI exposure through placenta and ASDs in children. Thus, more than a few safety signals (Trontell, 2004) exist suggesting that antenatal exposure to SSRIs may increase the risk of ASDs. Another study (Clements et al., 2014) failed to find an association between antenatal SSRI exposure and ASDs, but suggested that maternal use of such antidepressants during pregnancy may increase the risk of ADHD. Therefore, there is an urgent need for further, large, well-designed research finalized to
5. Conclusions
1. definitively assess the existence and the magnitude of this serious risk, thus confirming or denying that we are truly looking at “the fall of Gods” (Gothic, 2014), since for many years SSRIs have been considered the first-choice agents for treating antenatal depression (Gentile, 2011a; Gentile, 2005); 2. investigate whether or not exposed in utero to other classes of antidepressants are involved in facilitating the occurrence of ASDs in children.
Maimburg and Vaeth (2006) found a 50% increased risk of ASDs associated with maternal pharmacological treatment in a populationbased case–control study using Danish national registries. Although they observed no significant association for antiepileptics, antihypertensives, cardiovascular drugs, tocolytics, and steroids, a significant 60% increased risk of autism was observed in relation to use of psychoactive drugs. The Authors did not specify what class or classes of psychotropics were associated with the risk of ASDs. Nevertheless, with regards specifically to the effects of intrauterine SSRI exposure on the developing brain, Oberlander et al. (2009) underlined that, in animal models, prenatal changes in serotonin tone my led to molecular, neuroanatomical, and functional alterations that are influenced by the period of exposure (early vs late pregnancy) and the directions of the serotonin tone changes (increased or decreased). Impaired brain development may also be due to exposure to agents which induce autoinhibitory feedback at serotonergic system. Moreover, in a recent meta-analysis, Man et al. (2014) conclude that there may be an increased risk of ASDs in children antenatally
Meanwhile, when choosing between starting or withdrawing SSRI treatment in pregnant mothers, clinicians should balance the hypothesized risk of ASDs against the ascertained risks associated to untreated maternal depression and the consequences of the worsening of depressive symptoms, which may lead to tragic events for the mother-fetus dyad (Gentile, 2011b).
Conflict of interest Dr. Gentile discloses any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, his work.
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137 Role of funding source None.
Acknowledgments None.
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Harrington, R.A., Lee, L.C., Crum, R.M., et al., 2013. Serotonin hypothesis of autism: implications or selective serotonin reuptake inhibitor use during pregnancy. Autism Res. 6, 149–168. Hviid, A., Melbye, M., Pasternak, B., 2013. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N. Engl. J. Med. 369, 2406–2415. Kanner, L., 1943. The original description of autism, with excellent case examples. Nerv. Child 2, 217–250. Lai, M.C., Lombardo, M.V., Baron-Cohen, S., 2014. Autism. Lancet 383, 896–910. Man, K.K., Tong, H.H., Wong, L.Y., et al., 2014. Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorders in children: a systematic review and meta-analysis of observational studies. Neurosci. Biobehav. Rev. 49, 82–89. Maimburg, R.D., Vaeth, M., 2006. Perinatal risk factors and infantile autism. Acta. Psychiatr. Scand. 114, 257–264. Meunier, M.R., Bennett, I.M., Coco, A.S., 2013. Use of antidepressant medication in the United States during pregnancy, 2002—2010. Psychiatr. Serv. 64, 1157–1160. Moss, J., Howlin, P., 2009. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J. Intellect. Disabil. Res. 53, 852–873. Oberlander, T.F., Gingrich, J.A., Ansorge, M.S., 2009. Sustained neurobehavioral effects of exposure to SSRI antidepressant during development: molecular to clinical evidence. Clin. Pharmacol. Ther. 10, 1–6. Palmen, S.J.M.C., Pol, H.E.H., Kemmer, C., et al., 2005. Increased grey-matter volume in medication-naive high functioning children with autism spectrum disorder. Psychol. Med. 35, 561–570. Qiu, C., Williams, M.A., Calderon-Margalit, R., et al., 2009. Preeclampsia risk in relation to maternal mood and anxiety disorders diagnosed before or during early pregnancy. Am. J. Hypertens. 22, 397–402. Rangasamy, S., D’Mello, S.R., Narayanan, V., 2013. Epigenetics, autism spectrum, and neurodevelopmental disorders. Neurotherapeutics 4, 742–756. Rai, D., Lee, B.K., Dalman, C., Golding, J., et al., 2013. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case–control study. Br. Med. J. 346, f2059. Rossignol, D.A., Frye, R.E., 2012. Mitochondrial dysfunctions in autism spectrum disorder: a systematic review and meta-analysis. Mol. Psychiatry 17, 290–301. Sanders, S.J., Ercan-Sencicek, A.G., Hus, V., Luo, R., Murtha, M.T., Moreno-De-Luca, D., et al., 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885. Singh, G.K., Kenney, M.K., Ghandour, R.M., et al., 2013. Mental health outcomes in US children and adolescents born prematurely or with low birthweight. Depress. Res. Treat. 5, 570–574. Sørensen, M.J., Grønborg, T.K., Christensen, J., et al., 2013. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin. Epidemiol. 5, 449–459. Stigler, K.A., McDonald, B.C., Anand, A, et al., 2011. Structural and functional MRI studies of autism spectrum disorder. Brain Res. 1380, 146–161. Trontell, A., 2004. Expecting the unexpected – drug safety, pharmacovigilance, and the prepared mind. N. Engl. J. Med. 351, 1385–1387. Uddin, Q., Menon, V., Young, C.B., et al., 2011. Multivariate searchlight classifications of structural magnetic resonance in children and adolescents with autisms. Biol. Psychiatry 70, 833–841. Voineagu, I., Yoo, H.J., 2013. Current progress and challenges in the search for autism biomarkers. Dis. Markers 35, 55–65. Wei, H., Alberts, I., Li, X., 2013. Brain IL-6 and autism. Neuroscience 12, 320–325. Weiss, L.A., Abney, M., Cook, E.H., et al., 2005. Sex-specific genetic architecture of whole blood serotonin levels. Am. J. Hum. Genet. 76, 33–41. Whitaker-Azmitia, P.M., 2005. Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int. J. Dev. Neurosci. 23, 75–83. Wilkerson, D.S., Volpe, A.G., Dean, R.S., et al., 2002. Perinatal complications as predictors of infantile autism. Int. J. Neurosci. 112, 1085–1098. Woods, J.S., Armel, S.E., Futon, D.I., et al., 2010. Urinary porphyrin excretion in neurotypical and autistic children. Environ. Health Perspect. 10, 1450–1457.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? Salvatore Gentile a,b,n a b
Department of Mental Health ASL Salerno Mental Health Center, n. 63, Piazza Galdi, 841013 Cava de' Tirreni, Salerno, Italy University of Naples, Medical School “Federico II”, Department of Neurosciences – Perinatal Psychiatry, Via S. Pansini, 5, 80131 Naples, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 12 January 2015 Received in revised form 24 April 2015 Accepted 27 April 2015 Available online 6 May 2015
Recent information suggests that antenatal exposure to psychotropics may impair child neurodevelopment. Thus, aim of this review is to examine systematically available literature investigating potential associations between prenatal use of selective serotonin reuptake inhibitors (SSRIs) and the risk of autism spectrum disorders (ASDs). Methods: Medical literature published in English since 1988 identified using MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library. Search terms: antidepressants, autism (spectrum disorders), childhood, children, neurodevelopment, pregnancy, SSRIs. Searches were updated until March 5, 2015. Results: Six out of eight reviewed articles confirm an association between antenatal SSRI exposure and an increased risk of ASDs in children. However, the epidemiologic evidence on the link between prenatal SSRI exposure and ASD risk must still be cautiously interpreted, because of potential biases of analyzed research. Limitations: Main limitations of reviewed studies include: lack of directly validated clinical evaluation, impossibility to identify women who really took the prescribed medications during pregnancy, no assessment of severity and course of symptoms in relation to the pregnancy, lack of information about unhealthy prenatal lifestyle behaviors. Conclusions: Despite such limitations, available data show that some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs. Thus, there is an urgent need for further, large, well-designed research finalized to definitively assess the existence and the magnitude of this severe risk, thus confirming or denying that we are truly looking at “the fall of Gods”, since for many years SSRIs have been considered the first-choice agents for treating antenatal depression (Gentile, 2014; Gentile, 2011a; Gentile, 2005). & 2015 Elsevier B.V. All rights reserved.
Keywords: Antidepressants Autism spectrum disorders Neurodevelopment Pregnancy Safety SSRIs
Contents 1. Introduction . . . . . 2. Methods . . . . . . . . 3. Results . . . . . . . . . 4. Discussion . . . . . . 5. Conclusions . . . . . Conflict of interest. . . . Role of funding source Acknowledgments . . . . References . . . . . . . . . .
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n Correspondence to: Department of Mental Health ASL Salerno Mental Health Center, n. 63, Piazza Galdi, 841013 Cava de' Tirreni, Salerno, Italy. Tel.: þ 39 089 4455439; fax: þ39 089 4455440. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.jad.2015.04.048 0165-0327/& 2015 Elsevier B.V. All rights reserved.
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
1. Introduction Autism is a set of heterogeneous neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. The worldwide population prevalence is about 1%. Autism affects more male than female individuals, and comorbidity is common (470% have concurrent conditions). Patients diagnosed with autism spectrum disorders (ASDs) have both atypical cognitive profiles (such as impaired social cognition and social perception, executive dysfunctions), and atypical perceptual and information processing (Gray et al., 2014; Lai et al., 2014). Magnetic resonance imaging (MRI) studies have attempted to identify morphological changes in brain architecture associated with ASDs. Preliminary neuroimaging findings evidence an increase in total brain volume (and, especially, in frontal lobe volume), increased thickness in temporal/parietal lobes, structural alterations involving corpus callosum, amygdala, and cerebellum, and changes in grey matter in the posterior cingulate cortex, medial prefrontal cortex, and temporal lobes (Brun et al., 2009; Carper et al., 2013; Palmen et al., 2005; Stigler et al., 2011; Uddin et al., 2011). Recent studies have also provided evidence for an altered epigenetic landscape in ASDs and have hypothesized the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs actually encode proteins that are involved in transcriptional regulation and chromatin remodeling (Abrahams and Geschwind, 2008; Rangasamy et al., 2013). Moreover, mitochondrial dysfunctions and changes in porphyrin metabolism have also been reported to occur with higher frequency among ASD patients than in general populations (Rossignol and Frye, 2012; Woods et al., 2010). Identifying biomarkers for ASDs (Voineagu and Yoo, 2013) has been the focus of intense research since the first description of the disease in the early 1940s (Kanner, 1943). Biomarkers of oxidative stress, as a result of impaired antioxidant mechanism and aberrant neuroimmune responses, have been associated with ASDs (Frustaci et al., 2012; Wei et al., 2013). However, one of the main biomarkers of ASDs includes changes in several neurotransmitter levels. Serotonin has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led to the hypothesis that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Increased blood levels of serotonin were observed in a proportion of autistic patients as high as 35%. Serotonin levels are regulated by genetic variants of serotonin receptor genes, such as SLC6A4 and ITGB3 (Abney et al., 2001; Weiss et al., 2005). Thus, it has been theorized that an increase in serotonergic activity during brain development may facilitate the onset of ASDs (Whitaker-Azmitia, 2005). Several data support the hypothesis that somatodendritic 5-HT1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of substances that manipulate serotonin levels (Gardier et al., 1996). Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure selective serotonin reuptake inhibitors [(SSRIs) – Harrington et al., 2013]. A 4-fold increase in the use of antidepressants during pregnancy has been observed during the period 1996–2005, with nearly 8% of pregnant women prescribed antidepressants during the years 2004–2005 (Andrade et al., 2008). Conversely, the rate of use of psychotropic drugs has remained relatively stable between 2006 and 2011. The most commonly used psychotropics during pregnancy are SSRIs (Hanley and Mintzes, 2014; Meunier et al., 2013). Given this background, the aim of this review is to examine available literature investigating potential associations between prenatal antidepressant SSRI exposure and the risk of ASDs in children.
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2. Methods Fig. 1 shows the systematic literature search and results.
3. Results Studies suggest no link between antenatal antidepressant exposure and ASDs (shown in Table 1). A population-based study collected prospectively data considering both SSRI exposure and mental history of mothers (Croen et al., 2011). The study sample was drawn from the Californian Childhood Autism Perinatal Study, a case–control study aiming to investigate potential risks factors for ASDs. In the ASD cases, 15/298 children were exposed to SSRIs (3.4% to fluoxetine (FLX), 4.4% to paroxetine (PAR), 5.0% to sertraline (SER), and 3.4% to fluvoxamine (FVX)). The study found a 2fold increase in the risk of ASDs associated with SSRI treatment during the year before delivery and a 3-fold increased risk associated with first trimester exposure, independent of maternal psychiatric diagnosis. The case–control study by Rai et al. (2013) included all young people aged 0–17 years and residing in Stockholm, Sweden, between 2001 and 2007 (n ¼589,114). The cohort contained prospectively recorded data on the probands and their first degree relatives collected by record linkage with national and regional healthcare, social, and administrative registries. The characteristics of cases and controls with all available data were similar to the 4429 cases and 43,277 controls with complete data used in the main analysis. Approximately 1% (n ¼44) of mothers of the 4429 case children with ASDs were diagnosed with depression recorded before the birth of the index child, compared with 0.6% (n ¼272) of 43,277 control mothers. Maternal history of depression was associated with a higher risk of ASDs in offspring, but there was no evidence of a relation with paternal depression. This association was limited to children of mothers who reported using antidepressants at the first antenatal interview. The increase in the risk of autism seemed to be confined to those forms of ASDs without intellectual disability. Sørensen et al. (2013) identified all children born alive in Denmark 1996–2006 (n¼ 668,468) and their parents in the Danish Civil Registration System. The Authors obtained information on the mother's prescriptions filled during pregnancy from the Danish National Prescription Registry, on diagnosis of ASDs in the children, and on diagnosis of psychiatric disorders in the parents from the Danish Psychiatric Central Register. Exposure window was defined from 30 days before conception to the day of birth. Main study results were that, after controlling for several confounding factors, the association between prenatal maternal SSRI use and later ASDs in the child, albeit statistically significant, was weaker than that reported in other recent epidemiologic studies (Croen et al., 2011; Ray et al., 2013). The association was found for high as well as for low dose levels, and risk estimates were comparable regardless of timing of exposure. To further investigate this association, a recent study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status (Gidaya et al., 2014). An increased risk of ASDs associated with in utero exposure to SSRIs was observed in this large population-based, case–control study. The effect was present for all exposure windows considered (but the strongest effect was found for third trimester exposure) and persisted after adjustment for SSRI indications. A recent population-based case–control study (Harrington et al., 2014) included families enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. This population-based, case–control investigation recruited children
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S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
PubMed
EMBASE
SCOPUS
Cochrane Library
Related articles identified in reference lists of retrieved papers (excluding duplicates).
297 articles
Selected articles N=8 Articles focused on SSRI use for treating ASD symptoms N=88
EXCLUDED
Articles not reporting primary data N=201
Fig. 1. Systematic literature search and results. Medical literature information published in English since 1988 was identified using MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library. Additional references were manually identified from the reference lists of published articles Search terms (variously combined) were: antidepressants, autism (spectrum disorders), childhood, children, neurodevelopment, pregnancy. Searches were updated until March 5, 2015. Table 1 Studies suggesting a link between antenatal SSRI exposure and ASDs. Study/study design/sample size
SSRIs
Croen et al. (2011) Case–control study 289 case FLX children 1507 randomly selected control children FVX PAR SER Rai et al. ( 2013) Case–control study 4429 case FLX CIT children 43,277 control children PAR SER Sørensen et al. (2013) Cohort study 655,615 children of 428,407 mothers Gidaya et al. (2014) Case–control study 5215 case children 52,150 control children
N/A
FLX FVX PAR SER CIT ESC Harrington et al. (2014) Case–control study 492 case FLX children 320 control children PAR SER CIT ESC
El Marroun et al. (2014) Prospective study 69 case children 376 control children exposed to untreated maternal depression 5531 control children born to healthy mothers
Potential confounders explored
Main study results
Increased risk of ASDs for SSRI exposure during the Maternal health history, psychiatric diagnosis, age, first trimester. AOR: 3.5 (1.5–7.9) Increased risk for race/ethnicity, education level, parity, infant sex, birth weight, gestational age, birth year, birth facility ASDs for SSRI exposure during the year before delivery. AOR: 2.6 (1.5–5.4) Increased risk for ASDs of any antidepressant Parental age, family income, education levels, occupational class, maternal region of birth maternal exposure during the first trimester. AOR: 2.54 (1.37–4.68)a smoking, parity, diabetes, hypertension, birth weight, Apgar score at 5 min Parental age and psychiatric history, gestational age, Increased risk of ASDs for SSRI exposure during birth weight, infant sex, congenital malformations, pregnancy AOR: 1.6 (1. 3–2.0) parity Parental age, psychiatric diagnosis, infant sex, family Increased risk o f ASDs for SSRI exposure during income, duration and timing of exposure pregnancy AOR: 2.5 (1.7–3.7)b
Increased risk of ASDs for SSRI exposure during Maternal age, education levels, birth place, birth weight, preterm birth, year of birth, children age and pregnancy. OR: 3.22 (1.17–8.84)a sex, nicotine, alcohol, illicit substances, non-SSRI medication use, serotonergic supplements, maternal obesity, diabetes, hypertension, mother's anxiety/ mood disorder history
Maternal age, educational level, country of origin, PAR FLX SER smoking habit FVX CIT
Increased risk of ASDs for SSRI exposure during pregnancy. Pervasive developmental problems: OR: 1.91 (1.13–3.47)a Autistic traits ß¼ 0.15 (0.08–0.22)
Abbreviations and notes: (95%CI); CIT: citalopram; ESC: escitalopram; FLX: fluoxetine; FVX: fluvoxamine; SER: sertraline; PAR: paroxetine; SSRIs: selective serotonin reuptake inhibitors; ASDs: autism spectrum disorders; AOR: adjusted odds ratio; OR: odds ratio. a b
Also including mothers exposed to non-selective monoamine reuptake inhibitors. Data for third trimester exposure.
with ASDs, with developmental delays other than ASD, and from the general population. CHARGE eligibility criteria included being 2–5 years old, born in California, having a parent who speaks English or Spanish, and living with at least one biological parent and in the study catchment area of specified California Regional Centers, which coordinate services for persons with developmental disabilities. Mothers' reported use of SSRIs during pregnancy
was associated with increased risk of ASDs in boys. Too few girls were exposed for analysis. Results were robust to sensitivity analyses and adjustment for confounders. Trimester-specific analyses in boys showed the greatest association with ASD during first-trimester SSRI exposure. Very recently, El Marroun et al. (2014) enrolled a relative large number of children exposed to SSRIs, exposed to untreated
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137
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Table 2 Studies suggesting no link between antenatal SSRI exposure and ASDs. Study/study design/sample size
SSRIs
FLX FVX Hviid et al. (2013) Cohort study 52 cases during 42,400 person-years of follow-up involved offspring of women PAR SER CIT ESC who were exposed to SSRIs during their pregnancy
Clements et al. (2014)
FLX FVX PAR SER CIT ESC
Potential confounders explored
Main study results
Year of the birth, parity, maternal age, country of origin, place of residence at the start of the pregnancy, smoking status, maternal psychiatric conditions, use of drugs other than SSRIs during pregnancy, diagnoses made in a psychiatric hospital or psychiatric unit (inpatient or outpatient), employment status, mother's level of education Sociodemographic variables, maternal clinical features
No statistically significant association between maternal use of SSRIs during pregnancy and ASDs
No statistically significant association between maternal use of SSRIs during pregnancy and ASDsa
Abbreviations FLX: fluoxetine; FVX: fluvoxamine; SER: sertraline; PAR: paroxetine; CIT: citalopram; ESC: escitalopram: OR: odds ratio (95%CI); ASDs: autism spectrum disorders. a
Statistically significant association between maternal use of SSRIs and attention-deficit hyperactivity disorder ADHD [OR: 1.81 (1.22–2.70)].
maternal mood symptoms, and children born to healthy mothers. The study demonstrated an association between SSRI exposure and an increased risk of ASDs, such as pervasive developmental problems and autistic traits. Prenatal depressive symptoms with no SSRI use were also associated with the risk of autistic traits, albeit this link was weaker and less specific. Studies suggest no link between antenatal antidepressant exposure and ASDs (shown in Table 2). A cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009 linked information on maternal use of SSRIs before and during pregnancy, rate of ASDs diagnosed in the offspring, and a range of potential confounders (Hviid et al., 2013). During 5,057,282 person/years of follow-up, the study was able to identify 3892 cases of ASDs (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 increase in the risk of ASDs. In order to investigate the risk of ASDs in children exposed antenatally to SSRIs, 1377 children with ASDs delivered in a large New-England health care system were identified from electronic health records (Clements et al., 2014). The study also identified 2243 children diagnosed with attention-deficit hyperactivity disorder (ADHD). No association was found between antenatal antidepressant exposure and ASDs, whereas antidepressant exposure during pregnancy was linked to increased risks of ADHD.
4. Discussion Reviewed studies show several limitations. For instance, the study sample investigated by Croen et al. (2011) was not directly validated through clinical evaluation. Another limitation, which is however present in nearly all studies on the reproductive safety of antidepressants, is that the study was unable to differentiate women who really took medications during pregnancy from those who received drug prescription but did not start pharmacological treatment. Several limitations of the study by Rai et al. (2013) need also to be acknowledged, the main being that depression was identified using specialist care records and therefore was probably under-ascertained. In fact, most people with depressive symptoms do not seek psychiatric help or are managed in primary care. Moreover, neither the severity nor the course of depressive symptoms in relation to the pregnancy was assessed. It was not possible to establish whether the association between antenatal antidepressant exposure and ASDs might reflect more severe
forms of depression during pregnancy or was a true iatrogenic effect. The same limitations affect the study by Sørensen et al. (2013). Moreover, although a wide range of lifestyle factors is known to influence the intrauterine environment and increase the risk for adverse outcomes, the study was unable to detect information about specific unhealthy maternal lifestyle factors during the gestational period. Although Gidaya et al. (2014) employed several strategies that can be to account for the confounding from maternal depression, such strategies were not devoid of potential biases. For example, regression adjustment and stratified analyses are both problematic in the face of underreporting of maternal depression and would lead to incomplete control for confounding by indication. Other potential study limitations have been highlighted by Harrington et al. (2014). First, residual confounding by indication for SSRI use remains possible because the study was unable to assess the severity of mental health symptoms. Second, lack of data on SSRI dosage precluded dose–response analyses. The recent study by El Marroun et al. (2014) provided no information about potential parental autistic traits. Moreover, the clinical diagnosis of depression was not assessed by diagnostic instruments. Pregnant mothers actually reported psychological symptoms by questionnaire. An exhaustive report of methodological biases affecting the results of all reviewed studies suggesting a causal relationship between in utero exposure to SSRIs and increased risk of developing ASDs is available in Table 3. To further complicate the attempt to differentiate the effects of the underlying maternal psychiatric disorder from the effects of SSRI exposure, studies using prenatal optimality scales (reviewed by Gardener et al., (2009)) provided some evidence suggesting that exposure to pregnancy complications in general may increase the risk of ASDs. Children born prematurely and very-low-birthweight children had 2.3 times and 3.2 times higher odds of ASDs, respectively (Singh et al., 2013). Pregnancy complications have been associated with both untreated maternal depression (Qiu et al., 2009) and SSRI use during pregnancy (Gentile, 2010). Moreover, a study investigating the relationship between reported maternal conditions, perinatal complications, and autism found three predicting factors for ASDs (gestational age, maternal morphology, and intrauterine stress). Finally, three maternal medical conditions were also identified as independent contributors to the onset of ASDs (urinary infection, high temperatures, and, notably, depression – Wilkerson et al., 2002). A potential association between antenatal depression and ASDs in offspring was also hypothesized by Clements et al. (2014). Thus, the increased rates of ASDs reported in mothers who need serotonergic agents during pregnancy may be the consequence of two
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Table 3 Summary of methodological bias affecting reviewed studies suggesting an increased risk of ASDs in children exposed in utero to SSRIs. Study Croen et al. (2011)
Methodological bias
Difficulties in distinguishing the effects of medication exposure from the effects of the underlying mental disorder and potential physiological
changes related to maternal stress or depression during pregnancy Case or control status for most children in the study sample was not directly evaluated through clinical evaluation Risks of diagnostic misclassification Risks of poor maternal adherence to the pharmacological regimen Lack of data on breastfeeding
Rai et al. (2013)
Depression was identified using specialist care records Health services may be more likely to asses and recognize ASDs in children of mothers already known to psychiatric services (Berksonian bias)
Sørensen et al. (2013)
Data were extrapolated from automated database which are unable to ascertain definitively that the women actually used the prescribed
Gidaya et al. (2014)
A simulation-based approach was used to account for confounding by indication
Harrington et al. (2014)
SSRI exposure was determined by mothers' report Severity of maternal symptoms not assessed Lack of data on maternal SSRI dosage
El Marroun et al. (2014)
medication
The Danish Psychiatric Central Register has a high validity for childhood autism, whereas other forms of ASD diagnosis have not been validated
Mothers with mental disorders may overestimate the problems of their children Clinical diagnosis not obtained in all cases No information about potential parental autistic traits Clinical diagnosis of depression was not obtained with specific diagnostic instruments
independent factors which (alone, both, or together with all the other factors suspected to be involved in the onset of ASDs) impair the physiological development of the fetal brain. Last but not least, it should be noted that current case–control or cohort studies using between-patients design cannot completely control the genetic factors. Genetic factors play significant roles in the development of mental disorders, such ASDs. The known single-gene defects and the diagnosed medical conditions account for about 10% of the cases of autism (Chakrabarti and Fombonne, 2001). Between 21% and 50% of the boys with fragile X syndrome are on the autistic spectrum (Moss and Howlin 2009), and 0–6% of the autism populations have fragile X syndrome (Fombonne et al., 1997). Recently, two large datasets have been discovered: heterogeneous de novo copy-number variants collectively affecting several loci and presumably accounting for 5–8% of the cases of simplex forms of ASD (Sanders et al., 2011)
exposed to SSRIs, although the causality remains to be confirmed. However, the analysis did not include the results of two pertinent articles (Clements et al., 2014; El Marroun et al., 2014) Given such considerations, despite recent research having suggested that the increased frequency of diagnosis of ASDs could be caused in part by non-etiologic factors such as changes in diagnosis reporting practices and diagnostic criteria (Hansen et al., 2015). I have to highlight that six out of the eight articles reviewed here (including case–control and prospective studies) confirm an association between SSRI exposure through placenta and ASDs in children. Thus, more than a few safety signals (Trontell, 2004) exist suggesting that antenatal exposure to SSRIs may increase the risk of ASDs. Another study (Clements et al., 2014) failed to find an association between antenatal SSRI exposure and ASDs, but suggested that maternal use of such antidepressants during pregnancy may increase the risk of ADHD. Therefore, there is an urgent need for further, large, well-designed research finalized to
5. Conclusions
1. definitively assess the existence and the magnitude of this serious risk, thus confirming or denying that we are truly looking at “the fall of Gods” (Gothic, 2014), since for many years SSRIs have been considered the first-choice agents for treating antenatal depression (Gentile, 2011a; Gentile, 2005); 2. investigate whether or not exposed in utero to other classes of antidepressants are involved in facilitating the occurrence of ASDs in children.
Maimburg and Vaeth (2006) found a 50% increased risk of ASDs associated with maternal pharmacological treatment in a populationbased case–control study using Danish national registries. Although they observed no significant association for antiepileptics, antihypertensives, cardiovascular drugs, tocolytics, and steroids, a significant 60% increased risk of autism was observed in relation to use of psychoactive drugs. The Authors did not specify what class or classes of psychotropics were associated with the risk of ASDs. Nevertheless, with regards specifically to the effects of intrauterine SSRI exposure on the developing brain, Oberlander et al. (2009) underlined that, in animal models, prenatal changes in serotonin tone my led to molecular, neuroanatomical, and functional alterations that are influenced by the period of exposure (early vs late pregnancy) and the directions of the serotonin tone changes (increased or decreased). Impaired brain development may also be due to exposure to agents which induce autoinhibitory feedback at serotonergic system. Moreover, in a recent meta-analysis, Man et al. (2014) conclude that there may be an increased risk of ASDs in children antenatally
Meanwhile, when choosing between starting or withdrawing SSRI treatment in pregnant mothers, clinicians should balance the hypothesized risk of ASDs against the ascertained risks associated to untreated maternal depression and the consequences of the worsening of depressive symptoms, which may lead to tragic events for the mother-fetus dyad (Gentile, 2011b).
Conflict of interest Dr. Gentile discloses any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, his work.
S. Gentile / Journal of Affective Disorders 182 (2015) 132–137 Role of funding source None.
Acknowledgments None.
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