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Original Article |

Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders FREE

Lisa A. Croen, PhD; Judith K. Grether, PhD; Cathleen K. Yoshida, MS; Roxana Odouli, MSPH; Victoria Hendrick, MD
[+] Author Affiliations

Author Affiliations: Division of Research, Kaiser Permanente Northern California, Oakland (Dr Croen and Mss Yoshida and Odouli), Environmental Health Investigations Branch, California Department of Public Health, Richmond (Dr Grether), and Department of Psychiatry, Neuropsychiatric Institute and Hospital, University of California, Los Angeles (Dr Hendrick).


Arch Gen Psychiatry. 2011;68(11):1104-1112. doi:10.1001/archgenpsychiatry.2011.73.
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Published online

Context The prevalence of autism spectrum disorders (ASDs) has increased over recent years. Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD.

Objective To systematically evaluate whether prenatal exposure to antidepressant medications is associated with increased risk of ASD.

Design Population-based case-control study. Medical records were used to ascertain case children and control children and to derive prospectively recorded information on mothers' use of antidepressant medications, mental health history of mothers, and demographic and medical covariates.

Setting The Kaiser Permanente Medical Care Program in Northern California.

Participants A total of 298 case children with ASD (and their mothers) and 1507 randomly selected control children (and their mothers) drawn from the membership of the Kaiser Permanente Medical Care Program in Northern California.

Main Outcome Measures ASDs.

Results Prenatal exposure to antidepressant medications was reported for 20 case children (6.7%) and 50 control children (3.3%). In adjusted logistic regression models, we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery (adjusted odds ratio, 2.2 [95% confidence interval, 1.2-4.3]), with the strongest effect associated with treatment during the first trimester (adjusted odds ratio, 3.8 [95% confidence interval, 1.8-7.8]). No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.

Conclusion Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD. The potential risk associated with exposure must be balanced with the risk to the mother or fetus of untreated mental health disorders. Further studies are needed to replicate and extend these findings.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that are evident in early childhood and characterized by pervasive impairments in social interaction and communication and by restricted and stereotyped patterns of behavior. Data from twin and family studies suggest a strong genetic component in the etiology of autism,14 and results from neuropathology and brain imaging studies provide evidence for dysregulation in normal brain development during the prenatal or early postnatal period.5,6 Since the first epidemiologic survey was conducted in 1966,7 the reported prevalence of autism has increased dramatically, from 4 to 5 cases per 10 000 population in 1966 to approximately 100 cases per 10 000 population (1%) today.8,9 While at least some of this observed increase in prevalence can be attributed to changing diagnostic standards, availability of services, and greater public awareness, there is considerable scientific and public concern about environmental factors that may contribute to autism risk, most likely in interaction with genetic factors.

Among the numerous secular trends that have occurred during the period of the recognized increase in autism prevalence is an increase in the use of antidepressant medications during pregnancy: from a range of approximately 1% to 6% in the early to mid-1990s to as high as 7% to 13% in more recent years.1013 Based on their efficacy and superior safety profile, selective serotonin reuptake inhibitors (SSRIs) have become the first-line treatment for depression and other psychiatric conditions, including anxiety and obsessive-compulsive disorders. Selective serotonin reuptake inhibitors and other antidepressant medications cross the placenta1012 and are secreted in breast milk,12,13 thus raising concerns about adverse effects from fetal and infant exposure. Atypical serotonin patterns in blood specimens obtained from individuals diagnosed with ASD and their family members have been consistently reported from multiple studies,14 but the underlying biologic pathways that may link serotonin in peripheral blood with phenotypic expression of ASD remain to be elucidated. As called for in a recent article by Hadjikhani,15 systematic study of ASD and prenatal exposure to SSRIs and other antidepressant medications is clearly needed. To our knowledge, no prior studies have addressed this important question.

Studies evaluating prenatal antidepressant exposure and other pediatric outcomes, such as major congenital malformations12,1619 and other adverse obstetric or neonatal outcomes, have shown weak and inconsistent associations.16,18,2022 Poor neonatal adaptation has been reported for exposure late in pregnancy.18,23,24 Directly relevant to concerns about a possible association with ASD, very few studies have evaluated the possible effects of prenatal exposure on longer-term outcomes, such as milestone achievement, cognitive skills, and behavioral outcomes. Although the majority of such studies have found no difference between prenatally exposed and unexposed children, some reports indicate possible subtle effects on motor development and control25 and differences in reaching milestones.26 Experimental studies using rodent models indicate that transient inhibition of the serotonin transporter with the SSRI fluoxetine hydrochloride during early brain development has consequences for some measured behaviors later in life.27,28

Evaluation of fetal exposure to SSRIs and other antidepressant medications as a potential risk factor for ASD and other neurodevelopmental conditions is complicated by the difficulty in distinguishing the effects of medication exposure from the effects of the underlying condition that led to treatment. Making this distinction is especially important for the study of autism because a prior history of psychiatric disorders, including depression, has been reported to be more common among mothers of infants later diagnosed with autism than among mothers of unaffected children, suggesting an underlying, preexisting genetic risk.2932 We conducted a large, population-based case-control study with prospective ascertainment of mothers' prescription drug use and history of mental health disorders to investigate the association between antidepressant use by mothers during pregnancy and subsequent diagnoses of ASDs in children.

The study sample was drawn from the Childhood Autism Perinatal Study, a large case-control study of prenatal, perinatal, and neonatal risk factors for ASDs set within the Kaiser Permanente Medical Care Program in Northern California (KPNC), which is a large integrated health care organization that provides care for more than 3.2 million residents and approximately 25% of births in 14 northern California counties. Except for the lowest and highest income earners, the KPNC membership is representative of the total population in the region.33

Details of case and control selection have been described previously.34 Briefly, all infants born at a KPNC facility between January 1995 and June 1999 and who remained health plan members for at least 2 years following birth were eligible for inclusion (n = 88 163). On the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), children with at least 1 diagnosis of autism (ICD-9-CM code 299.0), Asperger syndrome (ICD-9-CM code 299.8), or pervasive developmental disorder not otherwise specified (ICD-9-CM code 299.8) recorded in the KPNC outpatient clinical databases between January 1995 and November 2002 were considered case children (n = 420). Previous studies, which we have conducted within the KPNC health care system, indicate a high level of diagnostic validity for these case ascertainment procedures.

Children without an ASD diagnosis were randomly sampled from the remaining cohort of live births at a ratio of 5 control children per 1 case child. Control children (n = 2100) were frequency matched to case children by sex, birth year, and hospital of birth.

Because we were interested in examining characteristics of the mother in relation to autism risk in the offspring, we restricted the analysis to 1 child per mother, selecting the case child for women with both a case and a control child in the original study sample and randomly sampling 1 child for inclusion for other women with 2 case or control children (13 case mothers and 5 control mothers). We further restricted the sample to children (73% of initial cases and 72% of initial controls) whose mothers were KPNC members with full pharmacy benefits in the year before delivery (ie, 3 months prior to conception and during each trimester of pregnancy), and we excluded 16 controls whose medical records contained an ASD diagnosis recorded after initial control selection. The final analytic file included all remaining cases and controls from the original study sample.

All inpatient and outpatient prescriptions for antidepressants dispensed at a KPNC pharmacy in the 3 months before the last menstrual period (LMP) through the date of delivery of the study child were identified from the Pharmacy Information Management System. Antidepressants were classified as (1) SSRIs (citalopram hydrobromide, fluoxetine, fluvoxamine maleate, paroxetine hydrochloride, and sertraline hydrochloride); (2) dual-action antidepressants (nefazodone hydrochloride, trazodone hydrochloride, and venlafaxine hydrochloride), including serotonin-noradrenergic-reuptake inhibitors, noradrenergic and specific serotoninergic antidepressants, and noradrenaline-reuptake inhibitors; and (3) tricyclic antidepressants (amitriptyline hydrochloride, desipramine hydrochloride, doxepin hydrochloride, imipramine hydrochloride, nortriptyline hydrochloride, and protriptyline hydrochloride).

In the year before delivery, 4 exposure times were defined: preconception (3 months prior to the estimated LMP), first trimester (first 90 days after the LMP), second trimester (91-180 days after the LMP), and third trimester (181 days after the LMP to date of delivery). The date that the prescription was dispensed and the number of days for which the medication was supplied were used to determine exposure status during each time period. Exposure to antidepressants during a given time period was assumed if a prescription was dispensed during that time period or if the number of days for which the medication was supplied overlapped some portion of the time period. Women were considered“unexposed” if they had no dispensed antidepressant prescriptions and no supply overlap during the entire time period from 3 months prior to the LMP through the date of delivery. The estimated LMP was as recorded in the medical records for women with regular menstrual periods and if in 7-day agreement with a first trimester ultrasonography; for other women, the estimated LMP was derived from a first trimester ultrasonography.

To address the analytic concern about treatment vs underlying condition for which the treatment was prescribed, the mothers' psychiatric conditions diagnosed at any time preceding delivery were identified from inpatient and outpatient databases. These included major depressive disorder (ICD-9-CM codes 296.2, 296.3, and 311), anxiety or phobia (ICD-9-CM codes 300.0 and 300.2), bipolar disorder (ICD-9-CM codes 296.4-296.8), obsessive-compulsive disorder (ICD-9-CM code 300.3), adjustment disorder (ICD-9-CM code 309), and schizophrenic disorders (ICD-9-CM code 295). Mental health diagnoses were typically made by psychiatric or internal medical specialists before the index pregnancies and by psychiatric or women's health specialists during pregnancy. Other relevant medical and utilization history data were obtained from health plan files; data on the mothers' demographic characteristics (self-reported age at delivery, race/ethnicity, educational attainment, and parity) and data on infants' characteristics (birth year, sex, birth weight, and gestational age) were obtained from birth certificates.

The characteristics of cases and controls were compared using theχ2 test (for categorical variables), the Fisher exact test (for proportions), or the 2-sample t test (for continuous variables). Unconditional logistic regression analysis was conducted to estimate unadjusted and adjusted relative risks of ASD associated with antidepressant use by the mother during the year before delivery of the study child. Analyses by specific time periods during this 1-year interval compared women with prescriptions for antidepressants during a particular time period with women who were unexposed during the full 1-year interval before delivery of the study child. We considered a covariate to be a possible confounder of the association between antidepressant exposure and autism if it was associated either with the case or control status or with exposure status in this data set (P < .05), if it is a covariate for which we have a priori knowledge of associations with case or control status or with exposure status in the general population, or if it was a matching variable for control selection. With the exception of gestational age (which is highly correlated with birth weight but less reliably recorded in available medical records), all covariates that met 1 or more of these criteria were included as confounders in adjusted models. All variables were entered simultaneously, and all statistical tests were 2-tailed, with P < .05 considered to represent statistical significance. Further models were adjusted only for those covariates associated both with case or control status and with exposure status among control children. Models were also run with the exclusion of observations with missing data for covariates and for term births only.

To evaluate treatment with antidepressant medications independent of potential effects of the underlying condition for which treatment was prescribed, we included mental health history of the mother as a variable in selected logistic models. In addition, within the stratum of mothers with a mental health history (based on the ICD-9-CM codes cited), we evaluated whether antidepressant exposure in the year before delivery was associated with ASD risk in the children. All study procedures were approved by the institutional review board of KPNC and the California State Committee for the Protection of Human Subjects.

The final study population included 298 children with ASD and 1507 control children. The characteristics of the final study population (73% of initial cases and 72% of initial controls) are shown in Table 1. Mothers of children with ASD were slightly older, more often White non-Hispanic, and more highly educated. A higher proportion of case children had a birth weight of less than 2500 g, and more were delivered before 37 weeks of gestation. The proportion of male children, the proportion of children born in each study year, and the distribution of birth facilities were all similar between case children and control children owing to matching on these variables (data not shown).

Table Graphic Jump LocationTable 1. Characteristics of the Study Population From the Kaiser Permanente Medical Care Program in Northern California

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least 1 prescription for an antidepressant in the year prior to the birth of the study child (Table 2). The majority of these case and control mothers were prescribed SSRIs (Table 2). Of the 20 case mothers who were prescribed an antidepressant medication, 13 (65%) were prescribed SSRIs only, 2 (10%) were prescribed an SSRI in combination with another antidepressant, and 5 (25%) were prescribed 1 or more non-SSRI antidepressants only. Of the 50 control mothers who were prescribed an antidepressant medication, 25 (50%) were prescribed SSRIs only, 9 (18%) were prescribed an SSRI in combination with another antidepressant, and 16 (32%) were prescribed 1 or more non-SSRI antidepressants only.

Table Graphic Jump LocationTable 2. Type of Antidepressant Prescribed in the Year Prior to Delivery of Study Children From the Kaiser Permanente Medical Care Program in Northern California, 1995-1999

Among the children with ASD, the median age at ASD diagnosis for those with prenatal SSRI exposure was similar to that for those without prenatal SSRI exposure (3.6 vs 3.8 years of age; P = .61). The median number of ASD diagnoses recorded in electronic medical records was also similar between the 2 groups (5.0 vs 5.0; P = .63). After adjusting for maternal age, race/ethnicity, education, and child's birth weight, sex, birth year, and facility of birth, mothers of children subsequently diagnosed with ASD were twice as likely to have at least 1 antidepressant prescription in the year prior to delivery of the study child (Table 3). When compared with women with no antidepressant prescription during this period, women with a prescription for an SSRI were more than twice as likely to have a child later diagnosed with ASD (any SSRI: adjusted odds ratio [AOR], 2.2 [95% confidence interval {CI}, 1.2-4.3]; SSRI only: AOR, 2.6 [95% CI, 1.3-5.4]); no association was seen for the small group of women who were prescribed a non-SSRI antidepressant only (Table 3).

Table Graphic Jump LocationTable 3. Risk of Autism Spectrum Disorder Associated With Prescription for Antidepressants for Mothers in the Year Prior to Delivery of Study Children in the Kaiser Permanente Medical Care Program in Northern California, 1995-1999

Owing to the small number of women prescribed antidepressants other than SSRIs and the lack of an association of other antidepressants with ASD risk, all remaining analyses were restricted to the presence or absence of treatment with SSRIs (with or without other antidepressants). Unless otherwise noted, women were considered to be“unexposed” if they had no dispensed SSRI and no supply overlap during the year before delivery. In adjusted models with women not exposed to SSRIs as the reference group (Table 4, model 1), risk of ASD was significantly associated with an SSRI prescription during the preconception period, during the first trimester of pregnancy, and anytime during the year. For the second and third trimesters, during which fewer numbers of women were prescribed an SSRI, point estimates were also elevated but did not reach statistical significance (Table 4, model 1). Results were similar when models were adjusted only for maternal race/ethnicity, the only covariate associated with both case or control status and exposure status (data not shown).

Table Graphic Jump LocationTable 4. Risk of Autism Spectrum Disorder Associated with Prescription for Selective Serotonin Reuptake Inhibitors for Mothers in the Year Prior to Delivery of Study Children in the Kaiser Permanente Medical Care Program in Northern California, 1995-1999
TREATMENT VS INDICATION

Of the 298 case mothers, 10 (3.4%) had a diagnosis of depression, and 25 (8.4%) had a history of a mental health disorder in the year prior to delivery (for 11 of these 25 women [44%], the first mental health diagnosis occurred during the index pregnancy). Of the 1507 control mothers, 41 (2.7%) had a diagnosis of depression, and 99 (6.6%) had a diagnosis of a mental health disorder (for 49 of these 99 women [49%], the first mental health diagnosis occurred during the index pregnancy). When logistic models were adjusted for a history of depression during the year prior to delivery (Table 4, model 2) or, more generally, a history of any mental health disorder during the year prior to delivery (Table 4, model 3), SSRI exposure during the first trimester remained significantly associated with risk of ASD, as was a history of SSRI exposure anytime during the year before delivery. In contrast, no association was seen between risk of ASD and the indication for treatment (ie, the mother having a history of depression [model 2] or a history of any mental health disorder [model 3]) for any time period in the year before delivery (Table 4). Results were similar when history of depression or any mental health disorder was expanded to include diagnoses recorded at any time preceding pregnancy (data not shown).

To further evaluate whether the observed association between prenatal SSRI exposure and ASD risk could be attributed to SSRI treatment rather than the indication for treatment, we conducted an analysis restricted to the subgroup of women with a history of a mental health disorder in the year before delivery (25 case mothers and 99 control mothers). Risk of ASD associated with SSRI use anytime during this year was somewhat elevated in this subgroup but did not reach statistical significance (OR, 1.6 [95% CI, 0.6-4.0]) in unadjusted models, perhaps owing to small numbers. The small number of women precluded analyses that were adjusted for covariates or limited to women with a history of depression during this year.

OTHER POSSIBLE CONFOUNDERS

Although we found no association between ASD and a history of depression or a history of any mental health disorder in models that also included a term for SSRI exposure (Table 4, models 2 and 3), it is possible that women who were prescribed SSRIs during the year before delivery had a more severe underlying condition that accounts for our finding of an association between SSRI exposure and risk of ASD. To assess this possibility, we examined selected indicators of severity among case and control mothers who were prescribed an SSRI in the year before delivery (Table 5). Among these women, both the proportion of women with previous psychiatric hospitalizations and the mean number of psychiatric hospitalizations were not significantly different for case mothers compared with control mothers, and neither was the mean number of SSRI prescriptions or the mean number of days' supply of SSRIs recorded in their medical records between January 1994 (when the pharmacy database was initiated) and date of delivery (Table 5) significantly different between case and control mothers.

Table Graphic Jump LocationTable 5. Severity of Mental Health Condition Among Mothers Using Selective Serotonin Reuptake Inhibitors in the Year Before Delivery at the Kaiser Permanente Medical Care Program in Northern California, 1995-1999

We also performed a sensitivity analysis to examine the possibility that the association between a first trimester prescription for an SSRI and increased risk of ASD risk was a consequence of exposure misclassification. For this analysis, women whose last dispensed SSRI prescription predated the LMP (4 case mothers and 16 control mothers) were considered unexposed throughout pregnancy, even if the days' supply overlapped with the LMP. Risk of ASD associated with first trimester SSRI exposure remained elevated after adjustment for all demographic factors and for history of depression during the year before delivery (AOR, 4.5; [95% CI, 1.7-12.0]) or any mental health disorder during the year before delivery (AOR, 3.7 [95% CI, 1.5-9.3]).

In further analyses, we restricted the case group to those from simplex families (ie, only 1 child with ASD in the family; N = 279). Results were similar to those for the full study group (data not shown). Results were also similar to those obtained for the full study group when adjusted models excluded observations with missing data on mothers' education and/or parity (data not shown) and when restricted to term births (264 case children and 1397 control children) (data not shown).

In this population-based study with prospectively collected data and an analytic approach that simultaneously considered both SSRI exposure (treatment) and mental health history of mother (indication), we found an approximately 2-fold increased risk of ASD associated with treatment with SSRIs of the mother during the year before delivery and an approximately 3-fold increased risk associated with treatment during the first trimester, independent of indication. Additionally, we observed no increase in ASD risk associated with a history of mental health disorders after controlling for SSRI use during pregnancy. Despite the significant association, the number of women in this population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to prenatal SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester.

To our knowledge, very few studies have evaluated possible associations between prenatal exposure to SSRIs and outcomes observable beyond the neonatal or early postnatal period, such as milestone achievement, cognitive skills, and behavioral characteristics. In general, studies have been hampered by small numbers of subjects and inadequate control for indication for treatment. Casper et al25 reported possible subtle effects of in utero SSRI exposure on motor development and motor control in children 6 to 40 months of age. Pedersen et al26 found some delays in reaching motor milestones with second or third trimester exposure to antidepressants (compared with children born to women with untreated depression), but delays were within the range of normal development and resolved by 19 months of age. In a recent review of studies to date, Gentile and Galbally35 concluded that, despite the differences in the age of children studied, the measurements used, and the different aspects of neurodevelopment that were assessed, little evidence has emerged indicating differences between exposed and unexposed children.

There are a number of biologically plausible explanations for our finding of an association between prenatal SSRI exposure and ASD. Multiple prior studies have indicated that abnormalities in serotonin levels and serotoninergic pathways may play a role in autism.36 Brain imaging studies have demonstrated atypical development in brain serotonin synthesis capacity in children with ASD37,38 and abnormalities in serotonin receptor 2A binding in the cerebral cortex.39 Other studies have reported elevated levels of serotonin in peripheral blood but low serotonin levels in the brain and decreased serotonin receptor binding in individuals with autism.4045 Abnormalities in serotonin-related genes have also been identified in studies of autism, although results are inconsistent across studies.46,47 Pharmacological interventions with drugs acting on the serotonin receptor 2, including the SSRI fluoxetine, have shown improvements in some autistic behaviors in children4852; other studies have shown that a decreased serotonin level in the central nervous system is associated with increased autistic symptoms.53 A recent Cochrane review54 concluded that there is no evidence that SSRIs are effective as a treatment for children with autism and that there is emerging evidence that they may cause harm.

In rodent models, transient inhibition of the serotonin transporter by the SSRI fluoxetine during early brain development produced abnormal emotional behaviors in adult animals, indicating a critical role for serotonin in the maturation of brain systems.27,28,55,56 The effects of early exposure to SSRIs mimic the behavioral phenotype of mice genetically deficient in serotonin transporter expression.27 During early fetal development when the blood-brain barrier is still incomplete, the main source of serotonin in rodents is of maternal origin, and maternal serotonin production in these animal models is an important determinant of normal development.57 Whether there are parallel relationships in humans is not yet known. Collectively, these studies suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes.

Our finding of a link between prenatal SSRI exposure and childhood ASDs is complicated by the difficulty in distinguishing the effects of medication exposure from the effects of the underlying condition that led to treatment. In other words, childhood ASDs could also be associated with a family history of psychiatric disorders; several population-based studies2932 have reported an association between family history of schizophrenia or affective disorders and ASD, suggesting a likely link through genetic pathways. However, because these studies2932 did not consider maternal treatment with and prenatal exposure to antidepressant medications, caution is warranted in interpreting their findings. In our study, we do not find an association between ASD and a history of depression or other mental health disorders on the part of the mother in the absence of treatment with SSRIs, suggesting that some of the previously reported findings of an association between ASD and family history of psychiatric disorders may be mediated by maternal treatment and fetal exposure.

Finally, physiologic changes related to a mother's stress or depression during pregnancy, in combination with SSRI exposure, may contribute to changes in fetal brain development leading to a later diagnosis of ASD. Maternal stress has been shown to decrease serotonin levels and the density of synapses in the hippocampus of offspring, and these changes in brain development have been linked to alterations in spatial learning, memory, and other changes in prenatally stressed rodents.58,59 A recently reported experimental model demonstrates that the combined effect of maternal serotonin transporter genotype and prenatal stress may contribute to autistic-like behaviors in offspring.60 Whether the combined effects of prenatal SSRI exposure and prenatal stress is etiologically related to ASD in humans remains to be elucidated.

To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers' recall after diagnosis of ASD in the children. Mother-child pairs were not self-selected for our study but represent a population-based series of cases and controls from a large health care organization that serves approximately 30% of the population in a 14-county region of northern California. The frequency of in utero exposure to any antidepressant medication or specifically to SSRIs among control children in our study is very similar to that reported for deliveries during 1996 in a large study using automated administrative data from 7 health maintenance organizations in the United States,61 is somewhat higher than that reported from the Netherlands from this time period,62 and is lower than that reported from a Tennessee Medicaid population.63

Despite these strengths, several limitations need to be considered when interpreting the results of our study. Case or control status for most children in the study sample was not directly validated through clinical evaluations conducted for our study. In a prior study,64 a subset of 50 children who ended up in our study underwent clinical evaluation with the Autism Diagnostic Interview–Revised65 and the Autism Diagnostic Observation Schedule–Generic66; 94% of these children met criteria for ASD on both instruments, and 100% met criteria on at least one. Furthermore, validation studies conducted by the investigators that included a full review of diagnostic information recorded in KPNC medical records have demonstrated that at least 90% of children with an ASD diagnosis recorded in the KPNC electronic databases meet DSM-IV67 criteria for autism.34 Any misclassification with regard to case or control status would likely bias results toward the null, diminishing our ability to detect a true association between antidepressant use by the mothers and ASD in children. Another limitation of our reliance on medical records is that we were unable to validate actual use of antidepressants by the mothers during the time period of interest because we relied on documentation of dispensed prescriptions. Of particular concern is that first trimester exposure may be overestimated, although the sensitivity analysis that we conducted to address this concern did not alter our results. The half-lives of fluoxetine and norfluoxetine are relatively short, approximately 1 to 3 days and 7 to 15 days, respectively,68 but antidepressants may be sequestered in lipophilic fetal tissues such as the brain, prolonging the period of exposure for the developing fetus after ingestion of the medication has been discontinued by the mother. In addition, we were not able to obtain information on any antidepressant medications that may have been obtained through non-KPNC pharmacies or other sources. A recent survey of self-reported behavior among adult members of KPNC indicated that only 2.6% obtained medications from out-of-system pharmacies, 4.5% from friends or family, and 3.3% from free samples. These findings do not represent mutually exclusive outside sources.69

Uncontrolled confounding by variables that we could not measure must also be considered. Of particular concern is that mothers of children with ASD in our study may be more likely to have prior children with ASD and also to have been treated with SSRIs to help them manage the challenges of parenting an affected child. Thus, our measure of SSRI exposure, particularly in mothers of children with ASD, may in part represent unmeasured underlying genetic risk. Interestingly, prenatal exposure to SSRIs remained associated with increased risk of ASD in simplex families. A further concern is that we have no data on breastfeeding, and children exposed in utero may also be those most likely to be exposed postnatally through breast milk. However, our finding of a stronger association with first trimester exposure suggests that substantial confounding by postnatal exposure is unlikely. Our findings may also be a result of detection bias, such that women who were prescribed SSRIs as treatment for anxiety may be more concerned about their child's development and more likely to have their child assessed, leading to more diagnoses of ASD.

For a small number of case and control mothers, the pharmacy records documented that SSRI prescriptions were dispensed in the year prior to delivery, but there was no corresponding mental health diagnosis recorded in the mothers' medical records for that time period (3 case mothers and 4 control mothers). This suggests either that some mental health diagnoses were not recorded in the mothers' medical records and/or that SSRIs were being prescribed for conditions other than the mental health diagnoses included in our study. For this reason, our findings with regard to mental health history adjusted for SSRI exposure should be interpreted with caution.

Our results suggest that prenatal exposure to SSRIs, especially during the first trimester, may modestly increase the risk of ASDs. The fraction of cases of ASD that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD. Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or fetus of untreated mental health disorders. We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASDs in offspring.

Correspondence: Lisa A. Croen, PhD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612 (lisa.a.croen@kp.org).

Submitted for Publication: August 23, 2010; final revision received April 4, 2011; accepted May 10, 2011.

Published Online: July 4, 2011. doi:10.1001/archgenpsychiatry.2011.73

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by Kaiser Permanente Community Benefit Clinician Research Fund and Cooperative Agreement U10/CCU920392 from the Centers for Disease Control and Prevention.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.

Additional Contributions: We thank Bruce Fireman, MA, and Karin Nelson, MD, for their careful review and valuable input regarding earlier versions of this article.

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Kalra S, Born L, Sarkar M, Einarson A. The safety of antidepressant use in pregnancy.  Expert Opin Drug Saf. 2005;4(2):273-284
PubMed   |  Link to Article
Kendall-Tackett K, Hale TW. The use of antidepressants in pregnant and breastfeeding women: a review of recent studies.  J Hum Lact. 2010;26(2):187-195
PubMed   |  Link to Article
De las Cuevas C, Sanz EJ. Safety of selective serotonin reuptake inhibitors in pregnancy.  Curr Drug Saf. 2006;1(1):17-24
PubMed   |  Link to Article
Berle JO, Steen VM, Aamo TO, Breilid H, Zahlsen K, Spigset O. Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes.  J Clin Psychiatry. 2004;65(9):1228-1234
PubMed   |  Link to Article
di Scalea TL, Wisner KL. Pharmacotherapy of postpartum depression.  Expert Opin Pharmacother. 2009;10(16):2593-2607
PubMed   |  Link to Article
Hadjikhani N. Serotonin, pregnancy and increased autism prevalence: is there a link?  Med Hypotheses. 2010;74(5):880-883
PubMed   |  Link to Article
Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE, Smith D, Yood MU, Platt R.HMO Research Network Center for Education, Research in Therapeutics.  Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy.  Pharmacoepidemiol Drug Saf. 2007;16(10):1086-1094
PubMed   |  Link to Article
Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study.  Can J Psychiatry. 2009;54(4):242-246
PubMed
Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, Ramin S, Chaudron L, Lockwood C. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists.  Gen Hosp Psychiatry. 2009;31(5):403-413
PubMed   |  Link to Article
Tuccori M, Testi A, Antonioli L, Fornai M, Montagnani S, Ghisu N, Colucci R, Corona T, Blandizzi C, Del Tacca M. Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review.  Clin Ther. 2009;31(pt 1):1426-1453
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data.  Arch Gen Psychiatry. 2006;63(8):898-906
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study.  Br J Psychiatry. 2008;192(5):338-343
PubMed   |  Link to Article
Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, Brandes M, Hennen J, Cohen LS. Birth outcomes following prenatal exposure to antidepressants.  J Clin Psychiatry. 2007;68(8):1284-1289
PubMed   |  Link to Article
Ruchkin V, Martin A. SSRIs and the developing brain.  Lancet. 2005;365(9458):451-453
PubMed
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis.  Lancet. 2005;365(9458):482-487
PubMed
Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.  J Pediatr. 2003;142(4):402-408
PubMed   |  Link to Article
Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010;125(3):e600-e608
PubMed   |  Link to Article
Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.  Science. 2004;306(5697):879-881
PubMed   |  Link to Article
Oberlander TF, Gingrich JA, Ansorge MS. Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence.  Clin Pharmacol Ther. 2009;86(6):672-677
PubMed   |  Link to Article
Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, Schendel D, Thorsen P, Mortensen PB. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status.  Am J Epidemiol. 2005;161(10):916-925, discussion 926-928
PubMed   |  Link to Article
Lauritsen MB, Pedersen CB, Mortensen PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.  J Child Psychol Psychiatry. 2005;46(9):963-971
PubMed   |  Link to Article
Piven J, Palmer P. Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families.  Am J Psychiatry. 1999;156(4):557-563
PubMed
Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M, Sparen P. Parental psychiatric disorders associated with autism spectrum disorders in the offspring.  Pediatrics. 2008;121(5):e1357-e1362
PubMed   |  Link to Article
Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology.  Am J Public Health. 1992;82(5):703-710
PubMed   |  Link to Article
Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.  Arch Pediatr Adolesc Med. 2005;159(2):151-157
PubMed   |  Link to Article
Gentile S, Galbally M. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review.  J Affect Disord. 2011;128(1-2):1-9
PubMed   |  Link to Article
Pardo CA, Eberhart CG. The neurobiology of autism.  Brain Pathol. 2007;17(4):434-447
PubMed   |  Link to Article
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.  Ann Neurol. 1999;45(3):287-295
PubMed   |  Link to Article
Chandana SR, Behen ME, Juhász C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism.  Int J Dev Neurosci. 2005;23(2-3):171-182
PubMed   |  Link to Article
Murphy DGM, Daly E, Schmitz N, Toal F, Murphy K, Curran S, Erlandsson K, Eersels J, Kerwin R, Ell P, Travis M. Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.  Am J Psychiatry. 2006;163(5):934-936
PubMed   |  Link to Article
Anderson GM, Horne WC, Chatterjee D, Cohen DJ. The hyperserotonemia of autism.  Ann N Y Acad Sci. 1990;600:331-340, discussion 341-342
PubMed   |  Link to Article
Naffah-Mazzacoratti MG, Rosenberg R, Fernandes MJ, Draque CM, Silvestrini W, Calderazzo L, Cavalheiro EA. Serum serotonin levels of normal and autistic children.  Braz J Med Biol Res. 1993;26(3):309-317
PubMed
Connors SL, Matteson KJ, Sega GA, Lozzio CB, Carroll RC, Zimmerman AW. Plasma serotonin in autism.  Pediatr Neurol. 2006;35(3):182-186
PubMed   |  Link to Article
McNamara IM, Borella AW, Bialowas LA, Whitaker-Azmitia PM. Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes.  Brain Res. 2008;1189:203-214
PubMed   |  Link to Article
Hranilović D, Bujas-Petković Z, Tomicić M, Bordukalo-Niksić T, Blazević S, Cicin-Sain L. Hyperserotonemia in autism: activity of 5HT-associated platelet proteins.  J Neural Transm. 2009;116(4):493-501
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Mulder EJ, Anderson GM, Kema IP, de Bildt A, van Lang NDJ, den Boer JA, Minderaa RB. Platelet serotonin levels in pervasive developmental disorders and mental retardation: diagnostic group differences, within-group distribution, and behavioral correlates.  J Am Acad Child Adolesc Psychiatry. 2004;43(4):491-499
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Devlin B, Cook EH Jr, Coon H, Dawson G, Grigorenko EL, McMahon W, Minshew N, Pauls D, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD.CPEA Genetics Network.  Autism and the serotonin transporter: the long and short of it.  Mol Psychiatry. 2005;10(12):1110-1116
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Anderson BM, Schnetz-Boutaud NC, Bartlett J, Wotawa AM, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA, Haines JL. Examination of association of genes in the serotonin system to autism.  Neurogenetics. 2009;10(3):209-216
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Cook EH Jr, Rowlett R, Jaselskis C, Leventhal BL. Fluoxetine treatment of children and adults with autistic disorder and mental retardation.  J Am Acad Child Adolesc Psychiatry. 1992;31(4):739-745
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DeLong GR, Teague LA, McSwain Kamran M. Effects of fluoxetine treatment in young children with idiopathic autism.  Dev Med Child Neurol. 1998;40(8):551-562
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Hollander E, Chaplin W, Phillips A, Sumner J, Soorya L, Anagnostou E, Wasserman S. Oxytocin increases social cognition in autism. Poster presented at: 44th Annual Meeting of the American College of Neuropsychopharmacology (ACNP); December 11-15, 2005; Waikoloa, Hawaii
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Kolevzon A, Mathewson KA, Hollander E. Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability.  J Clin Psychiatry. 2006;67(3):407-414
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Posey DJ, Erickson CA, Stigler KA, McDougle CJ. The use of selective serotonin reuptake inhibitors in autism and related disorders.  J Child Adolesc Psychopharmacol. 2006;16(1-2):181-186
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Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD).  Cochrane Database Syst Rev. 2010;8(8):CD004677
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Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry.  Neuropsychopharmacology. 2006;31(1):47-57
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Ansorge MS, Morelli E, Gingrich JA. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.  J Neurosci. 2008;28(1):199-207
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Côté F, Fligny C, Bayard E, Launay JM, Gershon MD, Mallet J, Vodjdani G. Maternal serotonin is crucial for murine embryonic development.  Proc Natl Acad Sci U S A. 2007;104(1):329-334
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Hayashi A, Nagaoka M, Yamada K, Ichitani Y, Miake Y, Okado N. Maternal stress induces synaptic loss and developmental disabilities of offspring.  Int J Dev Neurosci. 1998;16(3-4):209-216
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Okado N, Narita M, Narita N. A biogenic amine-synapse mechanism for mental retardation and developmental disabilities.  Brain Dev. 2001;23:(suppl 1)  S11-S15
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Jones KL, Smith RM, Edwards KS, Givens B, Beversdorf DQ. Combined effect of maternal serotonin transporter genotype and prenatal stress in modulating offspring social interaction in mice.  Int J Dev Neurosci. 2010;28(6):529-536
PubMed   |  Link to Article
Andrade SE, Raebel MA, Brown J, Lane K, Livingston J, Boudreau D, Rolnick SJ, Roblin D, Smith DH, Willy ME, Staffa JA, Platt R. Use of antidepressant medications during pregnancy: a multisite study.  Am J Obstet Gynecol. 2008;198(2):194.e1-194.e5
PubMed   |  Link to Article
Bakker MK, Kölling P, van den Berg PB, de Walle HEK, de Jong van den Berg LT. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands.  Br J Clin Pharmacol. 2008;65(4):600-606
PubMed   |  Link to Article
Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy.  Am J Obstet Gynecol. 2007;196(6):544.e1-545.e5
PubMed   |  Link to Article
Croen LA, Matevia M, Yoshida CK, Grether JK. Maternal Rh D status, anti-D immune globulin exposure during pregnancy, and risk of autism spectrum disorders.  Am J Obstet Gynecol. 2008;199(3):234.e1-234.e6
PubMed   |  Link to Article
Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.  J Autism Dev Disord. 1994;24(5):659-685
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Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism.  J Autism Dev Disord. 2000;30(3):205-223
PubMed   |  Link to Article
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric Association; 2000
Stokes PE. A primary care perspective on management of acute and long-term depression.  J Clin Psychiatry. 1993;54:(suppl)  74-84, discussion 85-87
PubMed
Reed M, Brand R, Newhouse JP, Selby JV, Hsu J. Coping with prescription drug cost sharing: knowledge, adherence, and financial burden.  Health Serv Res. 2008;43(2):785-797
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Study Population From the Kaiser Permanente Medical Care Program in Northern California
Table Graphic Jump LocationTable 2. Type of Antidepressant Prescribed in the Year Prior to Delivery of Study Children From the Kaiser Permanente Medical Care Program in Northern California, 1995-1999
Table Graphic Jump LocationTable 3. Risk of Autism Spectrum Disorder Associated With Prescription for Antidepressants for Mothers in the Year Prior to Delivery of Study Children in the Kaiser Permanente Medical Care Program in Northern California, 1995-1999
Table Graphic Jump LocationTable 4. Risk of Autism Spectrum Disorder Associated with Prescription for Selective Serotonin Reuptake Inhibitors for Mothers in the Year Prior to Delivery of Study Children in the Kaiser Permanente Medical Care Program in Northern California, 1995-1999
Table Graphic Jump LocationTable 5. Severity of Mental Health Condition Among Mothers Using Selective Serotonin Reuptake Inhibitors in the Year Before Delivery at the Kaiser Permanente Medical Care Program in Northern California, 1995-1999

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PubMed
Kalra S, Born L, Sarkar M, Einarson A. The safety of antidepressant use in pregnancy.  Expert Opin Drug Saf. 2005;4(2):273-284
PubMed   |  Link to Article
Kendall-Tackett K, Hale TW. The use of antidepressants in pregnant and breastfeeding women: a review of recent studies.  J Hum Lact. 2010;26(2):187-195
PubMed   |  Link to Article
De las Cuevas C, Sanz EJ. Safety of selective serotonin reuptake inhibitors in pregnancy.  Curr Drug Saf. 2006;1(1):17-24
PubMed   |  Link to Article
Berle JO, Steen VM, Aamo TO, Breilid H, Zahlsen K, Spigset O. Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome p450 genotypes.  J Clin Psychiatry. 2004;65(9):1228-1234
PubMed   |  Link to Article
di Scalea TL, Wisner KL. Pharmacotherapy of postpartum depression.  Expert Opin Pharmacother. 2009;10(16):2593-2607
PubMed   |  Link to Article
Hadjikhani N. Serotonin, pregnancy and increased autism prevalence: is there a link?  Med Hypotheses. 2010;74(5):880-883
PubMed   |  Link to Article
Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE, Smith D, Yood MU, Platt R.HMO Research Network Center for Education, Research in Therapeutics.  Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy.  Pharmacoepidemiol Drug Saf. 2007;16(10):1086-1094
PubMed   |  Link to Article
Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study.  Can J Psychiatry. 2009;54(4):242-246
PubMed
Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, Ramin S, Chaudron L, Lockwood C. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists.  Gen Hosp Psychiatry. 2009;31(5):403-413
PubMed   |  Link to Article
Tuccori M, Testi A, Antonioli L, Fornai M, Montagnani S, Ghisu N, Colucci R, Corona T, Blandizzi C, Del Tacca M. Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review.  Clin Ther. 2009;31(pt 1):1426-1453
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data.  Arch Gen Psychiatry. 2006;63(8):898-906
PubMed   |  Link to Article
Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study.  Br J Psychiatry. 2008;192(5):338-343
PubMed   |  Link to Article
Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, Brandes M, Hennen J, Cohen LS. Birth outcomes following prenatal exposure to antidepressants.  J Clin Psychiatry. 2007;68(8):1284-1289
PubMed   |  Link to Article
Ruchkin V, Martin A. SSRIs and the developing brain.  Lancet. 2005;365(9458):451-453
PubMed
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis.  Lancet. 2005;365(9458):482-487
PubMed
Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.  J Pediatr. 2003;142(4):402-408
PubMed   |  Link to Article
Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010;125(3):e600-e608
PubMed   |  Link to Article
Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.  Science. 2004;306(5697):879-881
PubMed   |  Link to Article
Oberlander TF, Gingrich JA, Ansorge MS. Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence.  Clin Pharmacol Ther. 2009;86(6):672-677
PubMed   |  Link to Article
Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, Schendel D, Thorsen P, Mortensen PB. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status.  Am J Epidemiol. 2005;161(10):916-925, discussion 926-928
PubMed   |  Link to Article
Lauritsen MB, Pedersen CB, Mortensen PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.  J Child Psychol Psychiatry. 2005;46(9):963-971
PubMed   |  Link to Article
Piven J, Palmer P. Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families.  Am J Psychiatry. 1999;156(4):557-563
PubMed
Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M, Sparen P. Parental psychiatric disorders associated with autism spectrum disorders in the offspring.  Pediatrics. 2008;121(5):e1357-e1362
PubMed   |  Link to Article
Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology.  Am J Public Health. 1992;82(5):703-710
PubMed   |  Link to Article
Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.  Arch Pediatr Adolesc Med. 2005;159(2):151-157
PubMed   |  Link to Article
Gentile S, Galbally M. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review.  J Affect Disord. 2011;128(1-2):1-9
PubMed   |  Link to Article
Pardo CA, Eberhart CG. The neurobiology of autism.  Brain Pathol. 2007;17(4):434-447
PubMed   |  Link to Article
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.  Ann Neurol. 1999;45(3):287-295
PubMed   |  Link to Article
Chandana SR, Behen ME, Juhász C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism.  Int J Dev Neurosci. 2005;23(2-3):171-182
PubMed   |  Link to Article
Murphy DGM, Daly E, Schmitz N, Toal F, Murphy K, Curran S, Erlandsson K, Eersels J, Kerwin R, Ell P, Travis M. Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.  Am J Psychiatry. 2006;163(5):934-936
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Letter to the Editor: Antidepressant use During Pregnancy and Childhood Autism Spectrum Disorders
Posted on October 7, 2011
Eric G Smith, MD, MPH
University of Massachusetts Medical School,
Conflict of Interest: None Declared
Croen et al.1 deserve praise for their valuable initial investigation of antidepressant use during pregnancy and the risk of autism spectrum disorders. Precisely because of the extreme value of their cohort, we would like to request that the authors provide several pieces of additional information:
1) To our reading, Table 2 indicates all case mothers receiving SSRIs (5.0%) received sertraline (5.0%), and furthermore, that many also received trials on paroxetine (4.4%), fluoxetine (3.4%), or fluvoxamine (3.4%) in the year before delivery. This would seem to imply that >80% of the case mothers receiving SSRIs received >1 SSRI during that year. This seems surprising and might suggest greater-than-average depression severity or treatment-refractoriness. Is our interpretation of Table 2 correct?
2) The authors are to be commended for providing a subanalysis comparing case and control mothers with prior mental health diagnoses in the year prior to delivery, a restriction which substantially attenuates but does not eliminate the direction of the association (unadjusted OR decreases from 2.3 to 1.6 and becomes nonsignificant). However, it has been suggested, based in part on animal models,2 that antenatal depression has adverse effects on child mental health and development.3 Human findings are limited, however, in part because of the difficulty of separating the effects of prenatal and postpartum depression (see comment below). Nevertheless, the plausibility of adverse effects from both the treatment (SSRIs) and the condition being treated (prenatal depression) suggests to us that the subanalysis of case and control mothers with depression in the year prior to delivery is extremely relevant. The authors mention that they considered but did not carry out this analysis due to the small numbers of cases (10) and controls (41). However, in our view these small numbers should not preclude their publication. Such an analysis would aid the interpretation of the Croen et al. study (providing both a quantitative estimate of the association observed and the associated uncertainty in that estimate, which will undoubtedly be substantial) and might help facilitate future meta-analyses concerning this important topic. Could the authors provide these results?
3) Substance abuse is often comorbid with depression, and alcohol abuse may4 or may not5 be associated with autism spectrum disorders. Did the authors have any information about substance abuse diagnoses that they could include in their models?
4) The possible contribution of postpartum or ongoing maternal depression to the autism spectrum disorder risk of offspring of mothers receiving SSRIs during pregnancy does not seem to be considered. This effect could be substantial. Although not evaluating autism spectrum disorders per se, studies of ongoing maternal depression6 have reported associations with disruptive behaviors, a potential precursor or analogue to autism spectrum disorders. Could the authors provide any information on what proportion of case mothers continued to carry a depression diagnosis or receive SSRI treatment after delivery?
We wish to thank Croen et al. for their valuable contribution and look forward to whatever additional information they can provide.
References
1. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. Published online July 4, 2011. doi:10.1001/archgenpsychiatry.2011.73
2. Newport DJ, Stowe ZN, Nemeroff CB. Parental depression: animal models of an adverse life event. Am J Psychiatry. 2002 Aug;159(8):1265-83.
3. Marcus SM. Depression during pregnancy: rates, risks and consequences--Motherisk Update 2008. Can J Clin Pharmacol. 2009 Winter;16(1):e15-22.
4. Aronson M, Hagberg B, Gillberg C. Attention deficits and autistic spectrum problems in children exposed to alcohol during gestation: a follow-up study. Dev Med Child Neurol. 1997 Sep;39(9):583-7.
5. Eliasen M, Tolstrup JS, Nybo Andersen AM, Grønbaek M, Olsen J, Strandberg-Larsen K. Prenatal alcohol exposure and autistic spectrum disorders—a population-based prospective study of 80,552 children and their mothers. Int J Epidemiol. 2010 Aug;39(4):1074-81.
6. Pilowsky DJ, Wickramaratne PJ, Rush AJ, Hughes CW, Garber J, Malloy E, King CA, Cerda G, Sood AB, Alpert JE, Wisniewski SR, Trivedi MH, Talati A, Carlson MM, Liu HH, Fava M, Weissman MM. Children of currently depressed mothers: a STAR*D ancillary study. J Clin Psychiatry. 2006 Jan;67(1):126-36.

Conflict of Interest: Dr. Smith reports no current potential conflicts or relevant financial interests in this manuscript, but does report having received investigator-initiated funding over the last 5 years from Forest Research Institute, an affiliate of Forest Labs, which is an SSRI manufacturer. Drs. Terawejicz and Byatt report no potential conflicts or relevant financial interests in this manuscript.
Author Reply to Letter to the Editor (Smith et al.)
Posted on November 17, 2011
Lisa A Croen, PhD
Kaiser Permanente Division of Research,
Conflict of Interest: None Declared
We thank Smith et al1 for raising several interesting and important points which we address here in the same order as in their letter. With regard to their first point about the surprisingly high number of women who received >1 SSRI in the year before delivery, the concern they raised was justified as the data in Table 2 were unfortunately incorrect with regard to the specific SSRI medications received. The correct data are as follows: fluoxetine: 3.4% of cases and 1.1% of controls; paroxetine: 1.3% of cases and 0.7% of controls; sertraline: 1.3% of cases and 0.6% of controls; and fluvoxamine: 0.3% of cases and 0% of controls. Only 3/15 case mothers and 2/34 control mothers in fact received >1 SSRI during the year before delivery.
Second, for the analysis attempting to separate the effects of treatment from indication, we had not focused on the subset of women with a depression diagnosis in the year before delivery for two reasons: the small number of subjects and because we hypothesized that the potential adverse effects on child development would be similar for depression and other maternal mental health diagnoses. Furthermore, among women with depression, there was a high degree of co-morbidity with other mental health diagnoses in both case (8/10) and control (17/41) mothers. Nevertheless, among the subset of women with depression (10 cases and 41 controls), the risk of ASD associated with SSRI use anytime in the year prior to delivery was consistent with the results presented for the larger subset of women with any mental health diagnosis but with wider confidence intervals (OR, 1.4 [95% CI, 0.4-5.8).
Third, we had abstracted data on substance and alcohol abuse during pregnancy from medical records for 296/298 case mothers and 288/289 randomly sampled control mothers. Only 2 case and 5 control mothers had indication of substance abuse, and 6 case and 2 control mothers had indication of alcohol abuse during the study pregnancy. None of these women had a diagnosis of depression or received a prescription for SSRI in the year before delivery.
Fourth, among women with a depression diagnosis in the year before delivery, 50% of case mothers and 32% of control mothers continued to carry that diagnoses in the year after delivery (OR=2.15, 95% CI 0.53- 8.76, P=0.28). Among women who received SSRIs in the year before delivery, 73% of case mothers and 44% of control mothers received SSRIs in the year after delivery (OR=3.5, 95% CI 0.92-13.16, P=0.06). These results may indicate that continued depression or treatment with SSRI in the postpartum period may confer additional ASD risk.
1. Smith et al. Letter to the Editor:Antidepressant use During Pregnancy and Childhood Autism Spectrum Disorders.

Conflict of Interest: None declared
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