Advertisement

Maternal Psychiatric Conditions, Treatment With Selective Serotonin Reuptake Inhibitors, and Neurodevelopmental Disorders

Open AccessPublished:April 13, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.04.002

      Abstract

      Background

      This study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitor (SSRI) use during preconception and pregnancy with risk of neurodevelopmental disorders in offspring.

      Methods

      We used data from the Study to Explore Early Development, a multisite case-control study conducted in the United States among children born between 2003 and 2011. Final study group classifications of autism spectrum disorder (ASD) (n = 1367), developmental delays or disorders (DDs) (n = 1750), and general population controls (n = 1671) were determined by an in-person standardized developmental assessment. Maternal psychiatric conditions and SSRI use during pregnancy were ascertained from both self-report and medical records. We used logistic regression to evaluate associations of ASD and DDs (vs. population controls) with maternal psychiatric conditions and SSRI treatment in pregnancy. To reduce confounding by indication, we also examined SSRI associations in analyses restricted to mothers with psychiatric conditions during pregnancy.

      Results

      Psychiatric conditions and SSRI use during pregnancy were significantly more common among mothers of children with either ASD or DDs than among population controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio 1.81, 95% confidence interval 1.44–2.27) as in mothers who did use SSRIs (adjusted odds ratio 2.05, 95% confidence interval 1.50–2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (adjusted odds ratio 1.14, 95% confidence interval 0.80–1.62). Primary findings for DDs exhibited similar relationships to those observed with ASD.

      Conclusions

      Maternal psychiatric conditions but not use of SSRIs during pregnancy were associated with increased risk of neurodevelopmental disorders in offspring.

      Keywords

      Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impairments in social communication, sensory processing, and behavior that begins in childhood and usually persists into adulthood. Over the past 2 decades, ASD prevalence has risen globally (
      • Elsabbagh M.
      • Divan G.
      • Koh Y.J.
      • Kim Y.S.
      • Kauchali S.
      • Marcín C.
      • et al.
      Global prevalence of autism and other pervasive developmental disorders.
      ), including rapid increases in the United States, where the prevalence now stands at 1 in 59 8-year-old children (
      • Baio J.
      • Wiggins L.
      • Christensen D.L.
      • Maenner M.J.
      • Daniels J.
      • Warren Z.
      • et al.
      Prevalence of autism spectrum disorder among children aged 8 years - Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014.
      ). Both genetic and environmental factors appear to shape ASD risk, although the mechanisms of their interplay remain elusive (
      • Lyall K.
      • Croen L.
      • Daniels J.
      • Fallin M.D.
      • Ladd-Acosta C.
      • Lee B.K.
      • et al.
      The changing epidemiology of autism spectrum disorders.
      ). Much research has focused on ASD’s origins during gestation, when the developing brain may be particularly sensitive to environmental perturbations (
      • Lyall K.
      • Croen L.
      • Daniels J.
      • Fallin M.D.
      • Ladd-Acosta C.
      • Lee B.K.
      • et al.
      The changing epidemiology of autism spectrum disorders.
      ).
      Selective serotonin reuptake inhibitors (SSRIs), commonly the first-line treatment for depression in the general adult population (
      American Psychological Association
      Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts, American Psychological Association, Guideline Development Panel for the Treatment of Depressive Disorders..
      ) but approved for a variety of psychiatric indications, are used by an estimated 6% of pregnant women in the United States (
      • Alwan S.
      • Reefhuis J.
      • Rasmussen S.A.
      • Friedman J.M.
      National Birth Defects Prevention Study
      Patterns of antidepressant medication use among pregnant women in a United States population.
      ,
      • Ailes E.C.
      • Simeone R.M.
      • Dawson A.L.
      • Petersen E.E.
      • Gilboa S.M.
      Using insurance claims data to identify and estimate critical periods in pregnancy: An application to antidepressants.
      ,
      • Andrade S.E.
      • Reichman M.E.
      • Mott K.
      • Pitts M.
      • Kieswetter C.
      • Dinatale M.
      • et al.
      Use of selective serotonin reuptake inhibitors (SSRIs) in women delivering liveborn infants and other women of child-bearing age within the U.S. Food and Drug Administration’s Mini-Sentinel program.
      ) and can cross the placenta (
      • Rampono J.
      • Simmer K.
      • Ilett K.F.
      • Hackett L.P.
      • Doherty D.A.
      • Elliot R.
      • et al.
      Placental transfer of SSRI and SNRI antidepressants and effects on the neonate.
      ). Prenatal exposure to SSRIs has been linked to modest increases in the risk of multiple adverse birth outcomes (
      • Alwan S.
      • Friedman J.M.
      • Chambers C.
      Safety of selective serotonin reuptake inhibitors in pregnancy: A review of current evidence.
      ,
      • Yonkers K.A.
      • Wisner K.L.
      • Stewart D.E.
      • Oberlander T.F.
      • Dell D.L.
      • Stotland N.
      • et al.
      The management of depression during pregnancy: A report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists.
      ,
      • Colvin L.
      • Slack-Smith L.
      • Stanley F.J.
      • Bower C.
      Early morbidity and mortality following in utero exposure to selective serotonin reuptake inhibitors: A population-based study in Western Australia.
      ,
      • Tuccori M.
      • Testi A.
      • Antonioli L.
      • Fornai M.
      • Montagnani S.
      • Ghisu N.
      • et al.
      Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: A review.
      ,
      • Reefhuis J.
      • Devine O.
      • Friedman J.M.
      • Louik C.
      • Honein M.A.
      National Birth Defects Prevention Study
      Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports.
      ). Studies in animal models indicate that prenatal SSRI exposure may cause abnormal social-emotional behaviors in offspring (
      • Gemmel M.
      • Bögi E.
      • Ragan C.
      • Hazlett M.
      • Dubovicky M.
      • van den Hove D.L.
      • et al.
      Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome.
      ,
      • Yu W.
      • Yen Y.C.
      • Lee Y.H.
      • Tan S.
      • Xiao Y.
      • Lokman H.
      • et al.
      Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice.
      ), suggesting that neurodevelopment may also be a sensitive end point in humans. Furthermore, the brain’s serotonergic pathways, the target of SSRIs, are often atypical in individuals with ASD; clinical features associated with ASD include abnormal serotonin levels, disrupted biosynthesis and binding of the serotonin transporter protein, and rare variation in serotonin-related genes (
      • Pardo C.A.
      • Eberhart C.G.
      The neurobiology of autism.
      ,
      • Anderson B.M.
      • Schnetz-Boutaud N.C.
      • Bartlett J.
      • Wotawa A.M.
      • Wright H.H.
      • Abramson R.K.
      • et al.
      Examination of association of genes in the serotonin system to autism.
      ). However, whether serotonergic disruption is a cause or correlate of ASD pathophysiology remains an open question.
      To date, epidemiological studies of the potential adverse relationship of prenatal exposure to SSRIs and ASD symptoms have been inconclusive, largely because of the intractable correlation between SSRIs and their psychiatric indications (
      • Morales D.R.
      • Slattery J.
      • Evans S.
      • Kurz X.
      Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: Systematic review of observational studies and methodological considerations.
      ). Several studies have reported adverse relationships between SSRIs and ASD that often diminish or disappear after accounting for the mother’s psychiatric condition (
      • Clements C.C.
      • Castro V.M.
      • Blumenthal S.R.
      • Rosenfield H.R.
      • Murphy S.N.
      • Fava M.
      • et al.
      Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.
      ,
      • Hviid A.
      • Melbye M.
      • Pasternak B.
      Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism.
      ,
      • Malm H.
      • Brown A.S.
      • Gissler M.
      • Gyllenberg D.
      • Hinkka-Yli-Salomäki S.
      • McKeague I.W.
      • et al.
      Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: A national register-based study.
      ,
      • Viktorin A.
      • Uher R.
      • Reichenberg A.
      • Levine S.Z.
      • Sandin S.
      Autism risk following antidepressant medication during pregnancy.
      ) or when comparing siblings discordant on prenatal SSRI exposure (
      • Brown H.K.
      • Ray J.G.
      • Wilton A.S.
      • Lunsky Y.
      • Gomes T.
      • Vigod S.N.
      Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children.
      ,
      • Hagberg K.W.
      • Robijn A.L.
      • Jick S.
      Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.
      ,
      • Sujan A.C.
      • Rickert M.E.
      • Öberg A.S.
      • Quinn P.D.
      • Hernández-Díaz S.
      • Almqvist C.
      • et al.
      Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring.
      ,
      • Sørensen M.J.
      • Grønborg T.K.
      • Christensen J.
      • Parner E.T.
      • Vestergaard M.
      • Schendel D.
      • Pedersen L.H.
      Antidepressant exposure in pregnancy and risk of autism spectrum disorders.
      ). However, some of the largest studies to examine this relationship have found SSRIs to be associated with increased risk of ASD, albeit small, even after applying several bias reduction methods (
      • Liu X.
      • Agerbo E.
      • Ingstrup K.G.
      • Musliner K.
      • Meltzer-Brody S.
      • Bergink V.
      • Munk-Olsen T.
      Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.
      ,
      • Gidaya N.B.
      • Lee B.K.
      • Burstyn I.
      • Yudell M.
      • Mortensen E.L.
      • Newschaffer C.J.
      In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder.
      ,
      • Boukhris T.
      • Sheehy O.
      • Mottron L.
      • Bérard A.
      Antidepressant use during pregnancy and the risk of autism spectrum disorder in children.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Newschaffer C.
      • Lewis G.
      • Magnusson C.
      Antidepressants during pregnancy and autism in offspring: Population based cohort study.
      ,
      • Croen L.A.
      • Grether J.K.
      • Yoshida C.K.
      • Odouli R.
      • Hendrick V.
      Antidepressant use during pregnancy and childhood autism spectrum disorders.
      ,
      • Harrington R.A.
      • Lee L.C.
      • Crum R.M.
      • Zimmerman A.W.
      • Hertz-Picciotto I.
      Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
      ).
      Women being treated for psychiatric symptoms must weigh complex and uncertain risks to themselves and their children when deciding to use SSRIs during pregnancy. More rigorous evidence on whether the treatment itself or the psychiatric disorder that is the indication for treatment is the etiologically relevant factor may improve clinical decision making. The objective of this study was to replicate and extend earlier studies of maternal psychiatric conditions, prenatal SSRI exposure, and ASD risk using more refined data on maternal mental health and child ASD diagnostic profiles. We conducted our analysis using data from a large, geographically and demographically diverse U.S. sample with relatively high SSRI use, reflecting modern trends. In addition, our analyses focused on exposure during vulnerable developmental windows, risk heterogeneity by ASD subtypes, and specificity in comparison with other developmental delays or disorders (DDs).

      Methods and Materials

       Study Population

      The Study to Explore Early Development (SEED) is a multisite, case-control study of ASD and other DDs at six sites across the United States: California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania (
      • Schendel D.E.
      • Diguiseppi C.
      • Croen L.A.
      • Fallin M.D.
      • Reed P.L.
      • Schieve L.A.
      • et al.
      The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network.
      ). Briefly, eligible children were born between 2003 and 2006 (SEED 1) or between 2008 and 2011 (SEED 2) and lived in a site catchment area at birth and study enrollment. The study enrolled three groups: children with ASD (cases), children with other DDs such as language delay or intellectual disability (ID) [DD controls—details summarized in Schendel et al., 2012 (
      • Schendel D.E.
      • Diguiseppi C.
      • Croen L.A.
      • Fallin M.D.
      • Reed P.L.
      • Schieve L.A.
      • et al.
      The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network.
      )], and children from the general population (POP controls). Children with ASD and DDs were recruited from educational and clinical settings that serve children with developmental disorders. Children in the POP group were recruited from randomly sampled state birth records at each study site. The institutional review boards for each site approved the study, and all enrolled participants provided written informed consent for themselves and their children.

       Outcome Assessment

      We sampled a subset of children enrolled in SEED who had completed a multistage process, using gold standard clinical assessments, to determine their final study group classification (ASD, DD, or POP) (
      • Wiggins L.D.
      • Reynolds A.
      • Rice C.E.
      • Moody E.J.
      • Bernal P.
      • Blaskey L.
      • et al.
      Using standardized diagnostic instruments to classify children with autism in the study to explore early development.
      ). First, the primary caregiver (the biological mother for 99.5%) completed the Social Communication Questionnaire (SCQ) (
      • Rutter M.
      • Bailey A.
      • Lord C.
      SCQ: Social Communication Questionnaire.
      ) about the child during the enrollment telephone call. Children who scored ≥11 on the SCQ (
      • Wiggins L.D.
      • Bakeman R.
      • Adamson L.B.
      • Robins D.L.
      The utility of the Social Communication Questionnaire in screening for autism in children referred for early intervention.
      ) or had a prior ASD diagnosis or special education placement regardless of their SCQ score were subsequently administered a comprehensive, in-person assessment that included the Autism Diagnostic Observation Schedule (
      • Lord C.
      • Risi S.
      • Lambrecht L.
      • Cook Jr., E.H.
      • Leventhal B.L.
      • DiLavore P.C.
      • et al.
      The Autism Diagnostic Observation Schedule-Generic: A standard measure of social and communication deficits associated with the spectrum of autism.
      ), the Autism Diagnostic Interview Revised (ADI-R) (
      • 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.
      ,
      • Rutter M.
      • Le Couteur A.
      • Lord C.
      ADI-R: The Autism Diagnostic Interview-Revised.
      ), the Mullen Scales of Early Learning (MSEL) (
      • Mullen E.M.
      Mullen Scales of Early Learning.
      ), and the Vineland Adaptive Behavior Scales-Second Edition (
      • Sparrow S.
      • Cichetti D.
      • Balla D.
      Vineland Adaptive Behavior Scales.
      ). All other children were evaluated with the MSEL, followed by the Vineland Adaptive Behavior Scales-Second Edition if the MSEL standard score was <78. Children in the final ASD group (n = 1429) met ASD diagnostic criteria on the Autism Diagnostic Observation Schedule and either the full ASD diagnostic criteria on the ADI-R or one of three alternative criteria on the ADI-R, as detailed in Wiggins et al. (
      • Wiggins L.D.
      • Reynolds A.
      • Rice C.E.
      • Moody E.J.
      • Bernal P.
      • Blaskey L.
      • et al.
      Using standardized diagnostic instruments to classify children with autism in the study to explore early development.
      ). The ASD group was further subtyped by 1) the presence or absence of co-occurring ID defined by MSEL composite standard scores ≤70; 2) their Autism Diagnostic Observation Schedule calibrated symptom severity score (mild/moderate, severe); 3) their history of developmental regression based on caregiver report of language or social regression on the ADI-R; and 4) having a sibling with ASD (simplex [none] or multiplex [one or more]) based on caregiver report.
      Children with a final classification of DD (n = 1850) were those who were identified from clinical or educational settings as having a neurodevelopmental disorder and who either scored <11 on the SCQ or scored ≥11 but did not meet study criteria for ASD after the in-person assessment. They were further subtyped by the presence or absence of co-occurring ID defined by MSEL composite standard scores ≤70. Children with a final classification of POP (n = 1734) were those enrolled from sampling of birth certificate files who either scored <11 on the SCQ or scored ≥11 but did not meet ASD criteria after the in-person assessment.

       Maternal Psychiatric History and SSRI Use

      Maternal psychiatric disorders and use of SSRIs during pregnancy were ascertained from all participants in three ways: self-report in a telephone interview shortly after study enrollment (SEED Caregiver Interview), self-report on the SEED maternal medical history form, and abstraction from prenatal medical records. During the Caregiver Interview, the mother was queried about the timing, frequency, and names of medications she took, specifically for psychiatric conditions, from 3 months before conception through the end of pregnancy. On the maternal medical history form, the mother was asked to specify whether a doctor had ever diagnosed her with any of the following conditions: attention-deficit/hyperactivity disorder, anxiety disorder, bipolar disorder, depression, eating disorder, obsessive-compulsive disorder, personality disorder, schizophrenia, self-injuring behavior, sleep disorder, suicide attempt, or other condition not listed. For each condition, she was asked regarding the age of onset and whether she had the condition during the pregnancy. Psychiatric diagnoses and the names and timing of medications used during pregnancy were abstracted from her medical records. We coded a mother as having a psychiatric condition and/or as an SSRI user if documented in the Caregiver Interview, maternal medical history, or medical records. Child exposure to maternal psychiatric conditions and SSRIs was examined in five prenatal periods: 3 months preconception, each trimester, and anytime during pregnancy.

       Covariates

      We considered a priori several factors associated with ASD or maternal psychiatric conditions in previous work. We pared down the final adjustment set to covariates associated with child outcomes and not considered intermediates in the pathways of interest; these included maternal race/ethnicity, education level, age at delivery, smoking, and household income during pregnancy.

       Statistical Analyses

      The final analytic sample included children with completed maternal psychiatric and medication information available in all three sources (Caregiver Interview, maternal medical history, and medical record data). We further excluded a small subset of participants (4.5%) with missing sociodemographic information. Using SAS 9.3 (SAS Institute Inc., Cary, NC), we examined crude differences in the distribution of demographic characteristics, maternal psychiatric conditions, and prenatal SSRI use across the child outcome groups using χ2 statistics.
      To disentangle the independent associations of maternal psychiatric condition (“Psy”) and SSRI use with odds of child ASD, our primary analysis evaluated four separate logistic regression models. Using a reference group of children who were never exposed to either factor prenatally (Psy No), the first 3 models examined 1) the association of ASD with prenatal exposure to maternal psychiatric condition, regardless of SSRI exposure (Psy Yes); 2) the association of ASD with prenatal exposure to maternal psychiatric condition but not SSRIs (Psy Yes+SSRI No); and 3) the joint association of ASD with prenatal exposure to both maternal psychiatric condition and SSRIs (Psy Yes+SSRI Yes). In the fourth model, we examined the association of ASD with prenatal exposure to SSRIs in a sample restricted to children of mothers with a psychiatric condition during pregnancy ([Psy Yes+SSRI Yes] vs. [Psy Yes+SSRI No]).
      The above analytical procedures were repeated for DD versus POP comparisons.
      Secondary analyses included stratification by ASD severity, co-occurring ID, a history of developmental regression, and family history of ASD. We did not correct for multiple comparisons.

      Results

      The final analytic sample (N = 4788) comprised 1367 children with ASD, 1750 with DDs, and 1671 POP controls (Table S1). Characteristics of the child, mother, and household, most of which differed between groups, are shown in Table 1.
      Table 1Characteristics of the Study Population, Study to Explore Early Development (SEED), 2003–2006 and 2008–2011 Births (N = 4788)
      VariableASD, n = 1367DD, n = 1750POP, n = 1671ASD vs. POPDD vs. POP
      n (%)p Value
      Child Sex, Male1115 (81.6)1158 (66.2)878 (52.5)<.001<.001
      Gestational Age
       Early preterm, ≤33 weeks83 (6.1)174 (9.9)49 (2.9)<.001<.001
       Preterm, >33 weeks and <37 weeks134 (9.8)222 (12.7)117 (7.0)
       Term, ≥37 weeks1150 (84.1)1354 (77.4)1505 (90.1)
      Cesarean Section Delivery564 (41.3)689 (39.4)544 (32.6)<.001<.001
      Plurality
       Singleton1266 (92.6)1623 (92.7)1598 (95.6)<.001<.001
       Multiple101 (7.4)127 (7.3)73 (4.4)
      Maternal Age, Years
       <25167 (12.2)266 (15.2)173 (10.4).03<.001
       25–29341 (24.9)392 (22.4)392 (23.5)
       30–34484 (35.4)588 (33.6)629 (37.6)
       35–39287 (21.0)398 (22.7)398 (23.8)
       ≥4088 (6.4)106 (6.1)79 (4.7)
      Paternal Age, Years
       <25104 (7.6)167 (9.5)94 (5.6)<.001<.001
       25–29229 (16.8)307 (17.5)284 (17.0)
       30–34393 (28.7)515 (29.4)542 (32.4)
       35–39336 (24.6)426 (24.3)485 (29.0)
       ≥40305 (22.3)335 (19.1)266 (15.9)
      Maternal Race/Ethnicity
       White797 (58.3)1097 (62.7)1239 (74.1)<.001<.001
       Black321 (23.5)389 (22.2)232 (13.9)
       Asian115 (8.4)71 (4.1)90 (5.4)
       Hispanic69 (5.1)91 (5.2)41 (2.5)
       Other65 (4.8)102 (5.8)69 (4.1)
      Maternal Education
       High school or less177 (12.9)308 (17.6)153 (9.2)<.001<.001
       College888 (65.0)1001 (57.2)952 (57.0)
       Graduate school302 (22.1)441 (25.2)566 (33.9)
      Family Income During Pregnancy, USD
       <$50,000549 (40.2)739 (42.2)447 (26.8)<.001<.001
       $50,000–90,000412 (30.1)503 (28.7)559 (33.5)
       >$90,000406 (29.7)508 (29.0)665 (39.8)
      Maternal Smoking During Preconception or Pregnancy
       Yes226 (16.53)246 (14.06)168 (10.1)<.001<.001
       No1141 (83.47)1504 (85.94)1503 (89.9)
      Maternal Hypertension During Pregnancy
       Yes231 (16.90)179 (10.23)186 (11.1)<.001<.001
       No951 (69.57)871 (49.77)1277 (76.4)
       Missing185 (13.53)700 (40.00)208 (12.4)
      Maternal History of Infertility
       Yes267 (19.53)296 (16.91)258 (15.4).009.002
       No1049 (76.74)1355 (77.43)1357 (81.2)
       Missing51 (3.73)99 (5.66)56 (3.4)
      SEED Years
       SEED1628 (45.94)915 (52.29)867 (51.9).001.81
       SEED2739 (54.06)835 (47.71)804 (48.1)
      ASD, autism spectrum disorder; DD, developmental disorder; POP, population controls.
      Approximately one third of mothers in the sample had a psychiatric condition before or during pregnancy (Table 2); 90% of those with a psychiatric condition were diagnosed before the start of pregnancy. Depression was the most prevalent, followed by anxiety, in all study groups. Mothers of children with either ASD or DDs were more likely than mothers of children in the POP group to have two or more psychiatric conditions (19% and 17%, respectively, vs. 11%; p < .001).
      Table 2Frequency of Maternal Psychiatric Conditions and Antidepressant Use During Preconception and/or Pregnancy, Study to Explore Early Development, 2003–2006 and 2008–2011 Births
      ASD, n = 1367DD, n = 1750POP, n = 1671ASD vs. POPDD vs. POP
      n (%)p Value
      Psychiatric Condition500 (36.6)593 (33.9)455 (27.2)<.001<.001
      Specific Conditions
       ADHD52 (3.8)60 (3.4)30 (1.8).001.003
       Anxiety disorder218 (15.9)275 (15.7)170 (10.2)<.001<.001
       Bipolar disorder49 (3.6)64 (3.7)33 (2.0).007.003
       Depression372 (27.2)418 (23.9)321 (19.2)<.001.001
       Eating disorder35 (2.6)44 (2.5)45 (2.7).82.74
       Obsessive-compulsive disorder23 (1.7)32 (1.8)14 (0.8).03.01
       Personality disorder9 (0.7)14 (0.8)6 (0.4).24.09
       Schizophrenia5 (0.4)7 (0.4)2 (0.1).25.11
       Sleep disorder109 (8.0)116 (6.6)68 (4.1)<.001.001
       Self-injuring behavior21 (1.5)20 (1.1)21 (1.3).51.76
       Suicide attempt49 (3.6)60 (3.4)27 (1.6).001.001
      One Psychiatric Condition245 (17.9)294 (16.8)276 (16.5).31.82
      2+ Psychiatric Conditions255 (18.7)299 (17.1)179 (10.7)<.001<.001
      Antidepressant Use
       Any antidepressant148 (10.8)185 (10.6)120 (7.2)<.001.001
       SSRI128 (9.4)171 (9.8)99 (5.9)<.001<.001
      Citalopram16 (1.2)22 (1.3)15 (0.9).46.31
      Escitalopram17 (1.2)20 (1.1)10 (0.6).06.09
      Fluoxetine29 (2.1)36 (2.1)21 (1.3).06.07
      Fluvoxamine1 (0.1)0 (0.0)1 (0.1)>.99.49
      Paroxetine18 (1.3)20 (1.1)8 (0.5).01.03
      Sertraline49 (3.6)77 (4.4)40 (2.4).05.001
      Name unknown20 (1.5)18 (1.0)11 (0.7).03.24
       MAO inhibitor0 (0.0)0 (0.0)0 (0.0)
       TCA3 (0.2)2 (0.1)3 (0.2).81.62
       Serotonin modulator9 (0.7)9 (0.5)5 (0.3).15.32
       Selective serotonin18 (1.3)14 (0.8)23 (1.4).89.10
       Miscellaneous3 (0.2)3 (0.2)0 (0.0).06.25
      ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; DD, developmental disorder; MAO, monoamine oxidase; POP, population controls; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
      The frequencies of any antidepressant use and SSRI use anytime during preconception or pregnancy were higher among mothers of children with ASD or DDs than among mothers of POP controls (Table 2). SSRIs accounted for greater than 85% of antidepressants used, with sertraline and fluoxetine used most often. One quarter of mothers with a psychiatric condition used SSRIs during preconception and/or pregnancy (Table 3). Most SSRI users during pregnancy had initiated SSRI use before the start of pregnancy (77%). Mothers with two or more psychiatric conditions were more likely to use SSRIs than mothers with one condition (Table S2). The most common psychiatric conditions among SSRI users were depression (91%) and anxiety (64%).
      Table 3Frequency of Maternal SSRI Use During Preconception and/or Pregnancy Among Women With Any Psychiatric Disorder, Study to Explore Early Development, 2003–2006 and 2008–2011 Births
      SSRI Use
      Use of antidepressants and diagnoses of psychiatric conditions were independently assessed. The psychiatric condition listed in the table may not be the indication for the mother’s SSRI treatment. This table excludes 9 mothers who used SSRIs during pregnancy but did not have a reported/documented psychiatric condition (4 in DD and 5 in POP).
      ASDDDPOPASD vs. POPDD vs. POP
      n (%
      The proportion of women with each specific psychiatric condition who used SSRIs during pregnancy. The denominators for each psychiatric condition are listed in Table 2.
      )
      p Value
      Any Psychiatric Condition128 (25.6)167 (28.2)94 (20.7).07.005
      ADHD10 (19.2)12 (20.0)4 (13.3).49.44
      Anxiety Disorder83 (38.1)118 (42.9)46 (27.1).02.001
      Bipolar Disorder16 (32.7)26 (40.6)14 (42.4).37.86
      Depression118 (31.7)147 (35.2)88 (27.4).22.02
      Eating Disorder11 (31.4)10 (22.7)5 (11.1).02.14
      OCD8 (34.8)9 (28.1)4 (28.6).70.98
      Personality Disorder1 (11.1)7 (50.0)1 (16.6)>.99.32
      Schizophrenia2 (40.0)6 (85.7)0 (0.0)>.99.08
      Sleep Disorder25 (22.9)30 (25.9)11 (16.2).28.13
      Self-injuring Behavior9 (42.9)6 (30.0)4 (19.0).18.41
      Suicide Attempt14 (28.6)20 (33.3)8 (29.6).92.73
      ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; DD, developmental disorder; OCD, obsessive-compulsive disorder; POP, population controls; SSRI, selective serotonin reuptake inhibitor.
      a Use of antidepressants and diagnoses of psychiatric conditions were independently assessed. The psychiatric condition listed in the table may not be the indication for the mother’s SSRI treatment. This table excludes 9 mothers who used SSRIs during pregnancy but did not have a reported/documented psychiatric condition (4 in DD and 5 in POP).
      b The proportion of women with each specific psychiatric condition who used SSRIs during pregnancy. The denominators for each psychiatric condition are listed in Table 2.
      The adjusted odds of having a child with ASD were nearly twofold higher among mothers with a psychiatric condition during pregnancy, regardless of SSRI use, than among mothers without a psychiatric condition (none of whom used SSRIs, by definition) (Psy Yes vs. Psy No: adjusted odds ratio (aOR) 1.93, 95% confidence interval (CI) 1.59–2.34) (Table 4). Higher odds of ASD were also observed among mothers with psychiatric conditions in stratified analyses considering, separately, mothers who did not use SSRIs during pregnancy ([Psy Yes+SSRI No] vs. [Psy No]: aOR 1.81, 95% CI 1.44–2.27) and mothers who did use SSRIs anytime during pregnancy ([Psy Yes+SSRI Yes] vs. [Psy No]: aOR 2.05, 95% CI 1.50–2.80). When we restricted the analysis to mothers with a psychiatric condition, we found no evidence of association between SSRI use anytime during pregnancy and ASD ([Psy Yes+SSRI Yes] vs. [Psy Yes+SSRI No]: aOR 1.14, 95% CI 0.80–1.62). These relationships were consistent for exposure across the preconception period and all trimesters of pregnancy.
      Table 4Odds of ASD or DD in Offspring Associated With Maternal Psychiatric Conditions and SSRI Use During Preconception and/or Pregnancy, Study to Explore Early Development, 2003–2006 and 2008–2011 Births
      ASD, nexposedDD, nexposedPOP, nexposedASD vs. POP, aOR
      Adjusted ORs were adjusted by the following variables: maternal age (continuous), maternal race, maternal education, family income, and smoking history.
      (95% CI)
      DD vs. POP, aOR
      Adjusted ORs were adjusted by the following variables: maternal age (continuous), maternal race, maternal education, family income, and smoking history.
      (95% CI)
      All Mothers
      Reference group only includes children who were unexposed to both maternal psychiatric condition and SSRIs throughout preconception and pregnancy (ASD, n = 867; DD, n = 1157; POP, n = 1216).
      Maternal Psychiatric Condition (Psy Yes vs. Psy No)
       T04485504161.61 (1.36–1.91)1.41 (1.21–1.65)
       T12933562251.91 (1.55–2.34)1.65 (1.36–2.01)
       T23043482182.04 (1.66–2.50)1.65 (1.36–2.01)
       T33233682411.95 (1.60–2.38)1.59 (1.32–1.92)
       PG3484042641.93 (1.59–2.34)1.60 (1.33–1.92)
      Maternal Psychiatric Condition and No Maternal SSRI Use (Psy Yes+SSRI No vs. Psy No)
       T03293923281.50 (1.25–1.81)1.28 (1.08–1.52)
       T11792121441.78 (1.39–2.28)1.50 (1.19–1.90)
       T21902061401.96 (1.53–2.51)1.47 (1.16–1.87)
       T32062211601.83 (1.45–2.32)1.41 (1.12–1.77)
       PG2232481771.81 (1.44–2.27)1.44 (1.15–1.79)
      Maternal Psychiatric Condition and Maternal SSRI Use (Psy Yes+SSRI Yes vs. Psy No)
       T095137701.98 (1.42–2.77)2.10 (1.54–2.85)
       T186120631.98 (1.39–2.81)2.06 (1.49–2.86)
       T292104642.04 (1.45–2.89)1.80 (1.30–2.51)
       T398109672.18 (1.56–3.05)1.77 (1.28–2.45)
       PG115145812.05 (1.50–2.80)1.92 (1.43–2.57)
      Restricted to Mothers With Psychiatric Condition
      Reference group only includes children of mothers with an active maternal psychiatric condition during the specific time period and no SSRI exposure throughout preconception and pregnancy (ASD, n ranged from 179 to 329; DD, n ranged from 206 to 392; POP, n ranged from 140 to 328). Mothers in the reference group included those who used other forms of psychiatric treatment, including non-SSRI medications and therapy.
      Maternal SSRI Use (Psy Yes+SSRI Yes vs. Psy Yes+SSRI No)
       T095137701.36 (0.96–1.94)1.69 (1.21–2.35)
       T186120631.14 (0.76–1.72)1.46 (0.99–2.15)
       T292104641.06 (0.71–1.57)1.26 (0.85–1.87)
       T398109671.19 (0.81–1.75)1.32 (0.90–1.92)
       PG115145811.14 (0.80–1.62)1.38 (0.98–1.95)
      aOR, adjusted odds ratio; ASD, autism spectrum disorder; CI, confidence interval; DD, developmental disorder; PG, anytime during pregnancy; POP, population controls; SSRI, selective serotonin reuptake inhibitor; T0, 3 months before conception; T, trimester.
      a Adjusted ORs were adjusted by the following variables: maternal age (continuous), maternal race, maternal education, family income, and smoking history.
      b Reference group only includes children who were unexposed to both maternal psychiatric condition and SSRIs throughout preconception and pregnancy (ASD, n = 867; DD, n = 1157; POP, n = 1216).
      c Reference group only includes children of mothers with an active maternal psychiatric condition during the specific time period and no SSRI exposure throughout preconception and pregnancy (ASD, n ranged from 179 to 329; DD, n ranged from 206 to 392; POP, n ranged from 140 to 328). Mothers in the reference group included those who used other forms of psychiatric treatment, including non-SSRI medications and therapy.
      Among mothers with psychiatric conditions, the associations of prenatal SSRI exposure were consistently null in analyses of ASD subtypes defined by autistic symptom severity, ID status, regression history, and family history (Figures S1–S4). However, associations with maternal psychiatric condition suggested risk heterogeneity across some ASD subtypes. Specifically, associations of maternal psychiatric condition both with and without SSRI treatment were strongest among children with ASD without co-occurring ID and in multiplex families (Figures S2 and S4).
      Maternal psychiatric condition and SSRI use generally exhibited similar relationships with DDs as with ASD (Table 4), with some exceptions. Maternal psychiatric conditions during preconception and pregnancy, with and without SSRI use, were associated with DDs, although point estimates were larger for the joint exposure. In analyses restricted to mothers with psychiatric conditions, SSRI use during preconception was associated with higher odds of having a child with DDs (aOR 1.69, 95% CI 1.21–2.35); SSRI use by trimester and anytime during pregnancy also showed modestly higher odds of DDs, although CIs contained the null. In all time windows, maternal psychiatric conditions, particularly when combined with SSRI use, were associated with higher odds of DDs without co-occurring ID but not DDs with co-occurring ID (Figure S5). In models restricted to mothers with psychiatric conditions, SSRI use also trended with higher odds of DDs without co-occurring ID (SSRI use anytime during pregnancy, aOR 1.47, 95% CI 1.03–2.09) but not DDs with co-occurring ID. However, CIs in these secondary analyses of DDs were wide and overlapping.

      Discussion

      Our results, from a large and diverse U.S. sample, suggest that mothers with psychiatric conditions during pregnancy, irrespective of SSRI use, had elevated odds of having a child with ASD or DDs. Maternal psychiatric conditions during pregnancy were most strongly associated with subtypes of ASD and DDs without co-occurring ID. Among mothers with psychiatric conditions during pregnancy, SSRI use was not related to ASD, suggesting that SSRIs may not raise the odds of ASD independently of their psychiatric indications; however, we observed that odds of DDs, particularly DDs without co-occurring ID, were higher in children of mothers who used SSRIs during preconception and pregnancy.
      Our findings of no association between prenatal SSRI exposure and ASD are consistent with the conclusions of several large, population-based studies that specifically address confounding by indication (
      • Clements C.C.
      • Castro V.M.
      • Blumenthal S.R.
      • Rosenfield H.R.
      • Murphy S.N.
      • Fava M.
      • et al.
      Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.
      ,
      • Hviid A.
      • Melbye M.
      • Pasternak B.
      Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism.
      ,
      • Malm H.
      • Brown A.S.
      • Gissler M.
      • Gyllenberg D.
      • Hinkka-Yli-Salomäki S.
      • McKeague I.W.
      • et al.
      Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: A national register-based study.
      ,
      • Viktorin A.
      • Uher R.
      • Reichenberg A.
      • Levine S.Z.
      • Sandin S.
      Autism risk following antidepressant medication during pregnancy.
      ,
      • Brown H.K.
      • Ray J.G.
      • Wilton A.S.
      • Lunsky Y.
      • Gomes T.
      • Vigod S.N.
      Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children.
      ,
      • Hagberg K.W.
      • Robijn A.L.
      • Jick S.
      Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.
      ,
      • Sujan A.C.
      • Rickert M.E.
      • Öberg A.S.
      • Quinn P.D.
      • Hernández-Díaz S.
      • Almqvist C.
      • et al.
      Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring.
      ,
      • Sørensen M.J.
      • Grønborg T.K.
      • Christensen J.
      • Parner E.T.
      • Vestergaard M.
      • Schendel D.
      • Pedersen L.H.
      Antidepressant exposure in pregnancy and risk of autism spectrum disorders.
      ,
      • Castro V.M.
      • Kong S.W.
      • Clements C.C.
      • Brady R.
      • Kaimal A.J.
      • Doyle A.E.
      • et al.
      Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: A replication study.
      ). To strengthen causal inference, four of these studies included sibling analyses, which control for unmeasured or imperfectly measured maternal factors, such as genetics or psychiatric severity (
      • Brown H.K.
      • Ray J.G.
      • Wilton A.S.
      • Lunsky Y.
      • Gomes T.
      • Vigod S.N.
      Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children.
      ,
      • Hagberg K.W.
      • Robijn A.L.
      • Jick S.
      Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.
      ,
      • Sujan A.C.
      • Rickert M.E.
      • Öberg A.S.
      • Quinn P.D.
      • Hernández-Díaz S.
      • Almqvist C.
      • et al.
      Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring.
      ,
      • Sørensen M.J.
      • Grønborg T.K.
      • Christensen J.
      • Parner E.T.
      • Vestergaard M.
      • Schendel D.
      • Pedersen L.H.
      Antidepressant exposure in pregnancy and risk of autism spectrum disorders.
      ). However, reflecting the mixed evidence of this research area, our findings also contradict several other large studies conducted in Sweden (
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Newschaffer C.
      • Lewis G.
      • Magnusson C.
      Antidepressants during pregnancy and autism in offspring: Population based cohort study.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Golding J.
      • Lewis G.
      • Magnusson C.
      Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study.
      ), the Netherlands (
      • El Marroun H.
      • White T.J.
      • van der Knaap N.J.
      • Homberg J.R.
      • Fernández G.
      • Schoemaker N.K.
      • et al.
      Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: Population-based study of young children.
      ), California (
      • Croen L.A.
      • Grether J.K.
      • Yoshida C.K.
      • Odouli R.
      • Hendrick V.
      Antidepressant use during pregnancy and childhood autism spectrum disorders.
      ,
      • Harrington R.A.
      • Lee L.C.
      • Crum R.M.
      • Zimmerman A.W.
      • Hertz-Picciotto I.
      Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
      ), Canada (
      • Boukhris T.
      • Sheehy O.
      • Mottron L.
      • Bérard A.
      Antidepressant use during pregnancy and the risk of autism spectrum disorder in children.
      ), and Denmark (
      • Liu X.
      • Agerbo E.
      • Ingstrup K.G.
      • Musliner K.
      • Meltzer-Brody S.
      • Bergink V.
      • Munk-Olsen T.
      Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.
      ,
      • Gidaya N.B.
      • Lee B.K.
      • Burstyn I.
      • Yudell M.
      • Mortensen E.L.
      • Newschaffer C.J.
      In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder.
      ). These positive findings in other studies persisted even after efforts to reduce confounding by indication through adjustment for maternal psychiatric condition (
      • Boukhris T.
      • Sheehy O.
      • Mottron L.
      • Bérard A.
      Antidepressant use during pregnancy and the risk of autism spectrum disorder in children.
      ,
      • Croen L.A.
      • Grether J.K.
      • Yoshida C.K.
      • Odouli R.
      • Hendrick V.
      Antidepressant use during pregnancy and childhood autism spectrum disorders.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Golding J.
      • Lewis G.
      • Magnusson C.
      Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study.
      ,
      • El Marroun H.
      • White T.J.
      • van der Knaap N.J.
      • Homberg J.R.
      • Fernández G.
      • Schoemaker N.K.
      • et al.
      Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: Population-based study of young children.
      ), restriction to mothers with psychiatric conditions (
      • Liu X.
      • Agerbo E.
      • Ingstrup K.G.
      • Musliner K.
      • Meltzer-Brody S.
      • Bergink V.
      • Munk-Olsen T.
      Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.
      ,
      • Gidaya N.B.
      • Lee B.K.
      • Burstyn I.
      • Yudell M.
      • Mortensen E.L.
      • Newschaffer C.J.
      In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder.
      ,
      • Boukhris T.
      • Sheehy O.
      • Mottron L.
      • Bérard A.
      Antidepressant use during pregnancy and the risk of autism spectrum disorder in children.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Newschaffer C.
      • Lewis G.
      • Magnusson C.
      Antidepressants during pregnancy and autism in offspring: Population based cohort study.
      ,
      • Harrington R.A.
      • Lee L.C.
      • Crum R.M.
      • Zimmerman A.W.
      • Hertz-Picciotto I.
      Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
      ), and propensity weighting methods (
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Newschaffer C.
      • Lewis G.
      • Magnusson C.
      Antidepressants during pregnancy and autism in offspring: Population based cohort study.
      ). In evaluating these methods, a recent systematic review of the literature determined that study designs using SSRI-unexposed mothers with psychiatric conditions (as was done in this study) and/or siblings as comparators afford the most rigorous approaches for circumventing issues of residual confounding by psychiatric indication (
      • Morales D.R.
      • Slattery J.
      • Evans S.
      • Kurz X.
      Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: Systematic review of observational studies and methodological considerations.
      ). The body of evidence produced from these two methods generally supports no association between prenatal SSRI exposure and ASD (
      • Morales D.R.
      • Slattery J.
      • Evans S.
      • Kurz X.
      Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: Systematic review of observational studies and methodological considerations.
      ).
      Associations between ASD and maternal psychiatric conditions preceding or during pregnancy (
      • Hviid A.
      • Melbye M.
      • Pasternak B.
      Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism.
      ,
      • Lauritsen M.B.
      • Pedersen C.B.
      • Mortensen P.B.
      Effects of familial risk factors and place of birth on the risk of autism: A nationwide register-based study.
      ,
      • Wiggins L.D.
      • Rubenstein E.
      • Daniels J.
      • DiGuiseppi C.
      • Yeargin-Allsopp M.
      • Schieve L.A.
      • et al.
      A phenotype of childhood autism is associated with preexisting maternal anxiety and depression.
      ), including depression (
      • Hagberg K.W.
      • Robijn A.L.
      • Jick S.
      Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Golding J.
      • Lewis G.
      • Magnusson C.
      Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study.
      ,
      • El Marroun H.
      • White T.J.
      • van der Knaap N.J.
      • Homberg J.R.
      • Fernández G.
      • Schoemaker N.K.
      • et al.
      Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: Population-based study of young children.
      ,
      • Piven J.
      • Palmer P.
      Psychiatric disorder and the broad autism phenotype: Evidence from a family study of multiple-incidence autism families.
      ), schizophrenia (
      • Daniels J.L.
      • Forssen U.
      • Hultman C.M.
      • Cnattingius S.
      • Savitz D.A.
      • Feychting M.
      • Sparen P.
      Parental psychiatric disorders associated with autism spectrum disorders in the offspring.
      ,
      • Piven J.
      • Chase G.A.
      • Landa R.
      • Wzorek M.
      • Gayle J.
      • Cloud D.
      • Folstein S.
      Psychiatric disorders in the parents of autistic individuals.
      ), anxiety (
      • Duvekot J.
      • van der Ende J.
      • Constantino J.N.
      • Verhulst F.C.
      • Greaves-Lord K.
      Symptoms of autism spectrum disorder and anxiety: Shared familial transmission and cross-assortative mating.
      ), and personality disorders (
      • Daniels J.L.
      • Forssen U.
      • Hultman C.M.
      • Cnattingius S.
      • Savitz D.A.
      • Feychting M.
      • Sparen P.
      Parental psychiatric disorders associated with autism spectrum disorders in the offspring.
      ), are commonly reported in the literature. The prevalence of psychiatric conditions in families of children with ASD is substantially higher than in the general population (
      • Bolton P.F.
      • Pickles A.
      • Murphy M.
      • Rutter M.
      Autism, affective and other psychiatric disorders: Patterns of familial aggregation.
      ,
      • Larsson H.J.
      • Eaton W.W.
      • Madsen K.M.
      • Vestergaard M.
      • Olesen A.V.
      • Agerbo E.
      • et al.
      Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status.
      ). Given the significant genetic overlap between various psychiatric conditions and ASD, heritability likely contributes to these relationships (
      • Solberg B.S.
      • Zayats T.
      • Posserud M.B.
      • Halmøy A.
      • Engeland A.
      • Haavik J.
      • Klungsøyr K.
      Patterns of psychiatric comorbidity and genetic correlations provide new insights into differences between attention-deficit/hyperactivity disorder and autism spectrum disorder.
      ,
      Cross-Disorder Group of the Psychiatric Genomics Consortium
      Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.
      ,
      • Carroll L.S.
      • Owen M.J.
      Genetic overlap between autism, schizophrenia and bipolar disorder.
      ). Shared common genetic risk is also suggested by our finding that maternal psychiatric conditions were more strongly associated with ASD in multiplex families than in simplex families. Future analyses that take into account maternal and child genetic information may be able to determine whether this finding reflects overlap in genetic risk for psychiatric conditions and ASD or heightened psychiatric morbidity associated with raising an earlier-born child with ASD (
      • Zablotsky B.
      • Anderson C.
      • Law P.
      The association between child autism symptomatology, maternal quality of life, and risk for depression.
      ).
      Relationships between DDs and prenatal SSRIs were overall similar to those observed with ASD and in agreement with previous null reports of prenatal SSRI use and attention-deficit/hyperactivity disorder (
      • Malm H.
      • Brown A.S.
      • Gissler M.
      • Gyllenberg D.
      • Hinkka-Yli-Salomäki S.
      • McKeague I.W.
      • et al.
      Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: A national register-based study.
      ,
      • Sujan A.C.
      • Rickert M.E.
      • Öberg A.S.
      • Quinn P.D.
      • Hernández-Díaz S.
      • Almqvist C.
      • et al.
      Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring.
      ,
      • Castro V.M.
      • Kong S.W.
      • Clements C.C.
      • Brady R.
      • Kaimal A.J.
      • Doyle A.E.
      • et al.
      Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: A replication study.
      ), DDs (
      • Harrington R.A.
      • Lee L.C.
      • Crum R.M.
      • Zimmerman A.W.
      • Hertz-Picciotto I.
      Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
      ,
      • Brown A.S.
      • Gyllenberg D.
      • Malm H.
      • McKeague I.W.
      • Hinkka-Yli-Salomäki S.
      • Artama M.
      • et al.
      Association of selective serotonin reuptake inhibitor exposure during pregnancy with speech, scholastic, and motor disorders in offspring.
      ), and ID (
      • Liu X.
      • Agerbo E.
      • Ingstrup K.G.
      • Musliner K.
      • Meltzer-Brody S.
      • Bergink V.
      • Munk-Olsen T.
      Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.
      ,
      • Viktorin A.
      • Uher R.
      • Kolevzon A.
      • Reichenberg A.
      • Levine S.Z.
      • Sandin S.
      Association of antidepressant medication use during pregnancy with intellectual disability in offspring.
      ). While secondary findings suggest that maternal SSRI use may be associated with increased odds of DDs without ID, the CIs for DDs with and without ID overlapped. Because of the large number of tests conducted in secondary analyses, it is also possible that this significant finding is due to chance. Previous studies have observed associations between prenatal SSRI exposure and specific types of DDs, including motor (
      • Harrington R.A.
      • Lee L.C.
      • Crum R.M.
      • Zimmerman A.W.
      • Hertz-Picciotto I.
      Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
      ,
      • Pedersen L.H.
      • Henriksen T.B.
      • Olsen J.
      Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.
      ) and speech/language (
      • Brown A.S.
      • Gyllenberg D.
      • Malm H.
      • McKeague I.W.
      • Hinkka-Yli-Salomäki S.
      • Artama M.
      • et al.
      Association of selective serotonin reuptake inhibitor exposure during pregnancy with speech, scholastic, and motor disorders in offspring.
      ) delays. In our study, the DD group encompassed heterogeneous diagnoses; larger sample sizes of specific DD diagnoses could help clarify these findings. Studies that examine genetic susceptibility for ASD and DDs, as well as genes involved in SSRI metabolism, could also provider further insights and possibly identify genetic subgroups sensitive to prenatal SSRI exposure.
      For both ASD and DD outcomes, associations with maternal psychiatric conditions were stronger for child diagnostic subgroups without co-occurring ID than for those with co-occurring ID. Similar relationships between maternal psychiatric conditions and ASD without co-occurring ID have been noted in other studies (
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Newschaffer C.
      • Lewis G.
      • Magnusson C.
      Antidepressants during pregnancy and autism in offspring: Population based cohort study.
      ,
      • Rai D.
      • Lee B.K.
      • Dalman C.
      • Golding J.
      • Lewis G.
      • Magnusson C.
      Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study.
      ,
      • Wiggins L.D.
      • Rubenstein E.
      • Daniels J.
      • DiGuiseppi C.
      • Yeargin-Allsopp M.
      • Schieve L.A.
      • et al.
      A phenotype of childhood autism is associated with preexisting maternal anxiety and depression.
      ), perhaps indicating a distinct etiologic class compared with conditions with ID, which warrants further research.
      The methodological rigor of this study goes beyond what has been possible in studies making use of national registry data. Our study benefitted from clinically validated diagnoses of neurodevelopmental disorders and detailed data on preconception and pregnancy exposures and potential confounders. Combining both medical records and self-reported data allowed for more accurate characterization of psychiatric history and medication use during pregnancy, overcoming the limitations of ascertaining these exposures exclusively from dispensing data or self-report as done in earlier work. Unlike previous studies focused on maternal depressive disorders, we inspected a wider array of SSRI indications. Including children with DDs further allowed for evaluation of the specificity of impact of SSRI use on non-ASD neurodevelopmental end points. While this study focused specifically on SSRIs, associations with the use of alternative, serotonergically active antidepressants may be a useful topic in future investigations (
      • Sujan A.C.
      • Öberg A.S.
      • Quinn P.D.
      • D’Onofrio B.M.
      Annual research review: Maternal antidepressant use during pregnancy and offspring neurodevelopmental problems - A critical review and recommendations for future research.
      ).
      The SEED population, representing six different geographic locations across the United States, is large and sociodemographically diverse. To enhance generalizability, participants with ASD and DDs were recruited from various settings that provide services to children with disabilities. Nevertheless, as discussed in earlier work, not all invited families enrolled in the study, and response rates differed between cases and controls (
      • Schendel D.E.
      • Diguiseppi C.
      • Croen L.A.
      • Fallin M.D.
      • Reed P.L.
      • Schieve L.A.
      • et al.
      The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network.
      ). However, an analysis that compared characteristics of responders and nonresponders at one site found that although maternal age, education, and race/ethnicity predicted study participation, risk factor analyses adjusted for these sociodemographic variables were generally robust to the impact of nonresponse bias (
      • Schieve L.A.
      • Harris S.
      • Maenner M.J.
      • Alexander A.
      • Dowling N.F.
      Assessment of demographic and perinatal predictors of non-response and impact of non-response on measures of association in a population-based case control study: Findings from the Georgia Study to Explore Early Development.
      ). Furthermore, previous work has demonstrated that completion rates of SEED’s Caregiver Interview and in-person assessment across outcome groups were not associated with sociodemographic factors (
      • DiGuiseppi C.G.
      • Daniels J.L.
      • Fallin D.M.
      • Rosenberg S.A.
      • Schieve L.A.
      • Thomas K.C.
      • et al.
      Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder.
      ). In addition, rates of maternal SSRI use in the SEED sample were comparable with other U.S. estimates (
      • Alwan S.
      • Reefhuis J.
      • Rasmussen S.A.
      • Friedman J.M.
      National Birth Defects Prevention Study
      Patterns of antidepressant medication use among pregnant women in a United States population.
      ,
      • Ailes E.C.
      • Simeone R.M.
      • Dawson A.L.
      • Petersen E.E.
      • Gilboa S.M.
      Using insurance claims data to identify and estimate critical periods in pregnancy: An application to antidepressants.
      ,
      • Andrade S.E.
      • Reichman M.E.
      • Mott K.
      • Pitts M.
      • Kieswetter C.
      • Dinatale M.
      • et al.
      Use of selective serotonin reuptake inhibitors (SSRIs) in women delivering liveborn infants and other women of child-bearing age within the U.S. Food and Drug Administration’s Mini-Sentinel program.
      ), mitigating concerns about selection bias in participation.
      Incorporating data on self-reported maternal psychiatric conditions and SSRI use raises the possibility of exposure misclassification. However, combining these data with information recorded in prenatal medical records reduced bias due to poor recall of exposures before and during pregnancy. Our analytic strategy of examining the impact of prenatal exposure to SSRIs among mothers with psychiatric histories mitigated but did not completely resolve confounding by condition severity. We did not have detailed information on medication dosing or symptoms during pregnancy to parse this bias; however, there was some evidence that mothers of children with ASD and DDs, who were more likely to use SSRIs than mothers of children in the POP group, were also more likely to have multiple psychiatric diagnoses, a crude proxy for condition severity. Power was also limited for trimester-specific analyses among some subgroups. Future planned SEED analyses will examine maternal genetic risk markers of psychiatric conditions to better disentangle the impacts of maternal condition severity and higher propensity for SSRI treatment on ASD and DD outcomes.

       Conclusions

      These results suggest that prenatal exposure to SSRIs is not associated with increased odds of ASD among children of women with a psychiatric indication for treatment. However, in secondary analyses, we noted significant associations between prenatal SSRI exposure and DDs without co-occurring ID, a possible false-positive finding that needs confirmation in future work. Clinical decision making regarding the continuation of SSRI treatment during pregnancy must carefully weigh the potential risk to the baby against the psychiatric risk to the mother. Incorporating maternal and child genetic information into future analyses will further our understanding of the independent and joint effects of maternal psychiatric conditions and their treatments during pregnancy on child neurodevelopmental disorders.

      Acknowledgments and Disclosures

      This study was supported by six cooperative agreements from the Centers for Disease Control and Prevention : Cooperative Agreement Number U10DD000180 , Colorado Department of Public Health ; Cooperative Agreement Number U10DD000181 , Kaiser Foundation Research Institute (California); Cooperative Agreement Number U10DD000182 , University of Pennsylvania; Cooperative Agreement Number U10DD000183, Johns Hopkins University ; Cooperative Agreement Number U10DD000184 , University of North Carolina at Chapel Hill; and Cooperative Agreement Number U10DD000498, Michigan State University, and the National Institutes of Health Grant No. R01HD087915 (to LAC) .
      The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the collaborating institutions.
      We thank the SEED Data Coordinating Center team at the Clinical and Translational Sciences Institute of Michigan State University for their support throughout this study.
      Dr. Pinto-Martin would like to acknowledge her work as an expert witness for Pfizer and Eli Lily related to a case on SSRIs and ASD. All other authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

      References

        • Elsabbagh M.
        • Divan G.
        • Koh Y.J.
        • Kim Y.S.
        • Kauchali S.
        • Marcín C.
        • et al.
        Global prevalence of autism and other pervasive developmental disorders.
        Autism Res. 2012; 5: 160-179
        • Baio J.
        • Wiggins L.
        • Christensen D.L.
        • Maenner M.J.
        • Daniels J.
        • Warren Z.
        • et al.
        Prevalence of autism spectrum disorder among children aged 8 years - Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014.
        MMWR Surveill Summ. 2018; 67: 1-23
        • Lyall K.
        • Croen L.
        • Daniels J.
        • Fallin M.D.
        • Ladd-Acosta C.
        • Lee B.K.
        • et al.
        The changing epidemiology of autism spectrum disorders.
        Annu Rev Public Health. 2017; 38: 81-102
        • American Psychological Association
        Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts, American Psychological Association, Guideline Development Panel for the Treatment of Depressive Disorders..
        (Available at:) (Accessed January 19, 2021)
        • Alwan S.
        • Reefhuis J.
        • Rasmussen S.A.
        • Friedman J.M.
        • National Birth Defects Prevention Study
        Patterns of antidepressant medication use among pregnant women in a United States population.
        J Clin Pharmacol. 2011; 51: 264-270
        • Ailes E.C.
        • Simeone R.M.
        • Dawson A.L.
        • Petersen E.E.
        • Gilboa S.M.
        Using insurance claims data to identify and estimate critical periods in pregnancy: An application to antidepressants.
        Birth Defects Res A Clin Mol Teratol. 2016; 106: 927-934
        • Andrade S.E.
        • Reichman M.E.
        • Mott K.
        • Pitts M.
        • Kieswetter C.
        • Dinatale M.
        • et al.
        Use of selective serotonin reuptake inhibitors (SSRIs) in women delivering liveborn infants and other women of child-bearing age within the U.S. Food and Drug Administration’s Mini-Sentinel program.
        Arch Womens Ment Health. 2016; 19: 969-977
        • Rampono J.
        • Simmer K.
        • Ilett K.F.
        • Hackett L.P.
        • Doherty D.A.
        • Elliot R.
        • et al.
        Placental transfer of SSRI and SNRI antidepressants and effects on the neonate.
        Pharmacopsychiatry. 2009; 42: 95-100
        • Reefhuis J.
        • Devine O.
        • Friedman J.M.
        • Louik C.
        • Honein M.A.
        • National Birth Defects Prevention Study
        Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports.
        BMJ. 2015; 351: h3190
        • Alwan S.
        • Friedman J.M.
        • Chambers C.
        Safety of selective serotonin reuptake inhibitors in pregnancy: A review of current evidence.
        CNS Drugs. 2016; 30: 499-515
        • Yonkers K.A.
        • Wisner K.L.
        • Stewart D.E.
        • Oberlander T.F.
        • Dell D.L.
        • Stotland N.
        • et al.
        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: 403-413
        • Colvin L.
        • Slack-Smith L.
        • Stanley F.J.
        • Bower C.
        Early morbidity and mortality following in utero exposure to selective serotonin reuptake inhibitors: A population-based study in Western Australia.
        CNS Drugs. 2012; 26: e1-e14
        • Tuccori M.
        • Testi A.
        • Antonioli L.
        • Fornai M.
        • Montagnani S.
        • Ghisu N.
        • et al.
        Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: A review.
        Clin Ther. 2009; 31: 1426-1453
        • Gemmel M.
        • Bögi E.
        • Ragan C.
        • Hazlett M.
        • Dubovicky M.
        • van den Hove D.L.
        • et al.
        Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome.
        Neurosci Biobehav Rev. 2018; 85: 102-116
        • Yu W.
        • Yen Y.C.
        • Lee Y.H.
        • Tan S.
        • Xiao Y.
        • Lokman H.
        • et al.
        Prenatal selective serotonin reuptake inhibitor (SSRI) exposure induces working memory and social recognition deficits by disrupting inhibitory synaptic networks in male mice.
        Mol Brain. 2019; 12: 29
        • Pardo C.A.
        • Eberhart C.G.
        The neurobiology of autism.
        Brain Pathol. 2007; 17: 434-447
        • Anderson B.M.
        • Schnetz-Boutaud N.C.
        • Bartlett J.
        • Wotawa A.M.
        • Wright H.H.
        • Abramson R.K.
        • et al.
        Examination of association of genes in the serotonin system to autism.
        Neurogenetics. 2009; 10: 209-216
        • Morales D.R.
        • Slattery J.
        • Evans S.
        • Kurz X.
        Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: Systematic review of observational studies and methodological considerations.
        BMC Med. 2018; 16: 6
        • Clements C.C.
        • Castro V.M.
        • Blumenthal S.R.
        • Rosenfield H.R.
        • Murphy S.N.
        • Fava M.
        • et al.
        Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.
        Mol Psychiatry. 2015; 20: 727-734
        • Hviid A.
        • Melbye M.
        • Pasternak B.
        Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism.
        N Engl J Med. 2013; 369: 2406-2415
        • Malm H.
        • Brown A.S.
        • Gissler M.
        • Gyllenberg D.
        • Hinkka-Yli-Salomäki S.
        • McKeague I.W.
        • et al.
        Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: A national register-based study.
        J Am Acad Child Adolesc Psychiatry. 2016; 55: 359-366
        • Viktorin A.
        • Uher R.
        • Reichenberg A.
        • Levine S.Z.
        • Sandin S.
        Autism risk following antidepressant medication during pregnancy.
        Psychol Med. 2017; 47: 2787-2796
        • Brown H.K.
        • Ray J.G.
        • Wilton A.S.
        • Lunsky Y.
        • Gomes T.
        • Vigod S.N.
        Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children.
        JAMA. 2017; 317: 1544-1552
        • Hagberg K.W.
        • Robijn A.L.
        • Jick S.
        Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring.
        Clin Epidemiol. 2018; 10: 1599-1612
        • Sujan A.C.
        • Rickert M.E.
        • Öberg A.S.
        • Quinn P.D.
        • Hernández-Díaz S.
        • Almqvist C.
        • et al.
        Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring.
        JAMA. 2017; 317: 1553-1562
        • Sørensen M.J.
        • Grønborg T.K.
        • Christensen J.
        • Parner E.T.
        • Vestergaard M.
        • Schendel D.
        • Pedersen L.H.
        Antidepressant exposure in pregnancy and risk of autism spectrum disorders.
        Clin Epidemiol. 2013; 5: 449-459
        • Liu X.
        • Agerbo E.
        • Ingstrup K.G.
        • Musliner K.
        • Meltzer-Brody S.
        • Bergink V.
        • Munk-Olsen T.
        Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study.
        BMJ. 2017; 358: j3668
        • Gidaya N.B.
        • Lee B.K.
        • Burstyn I.
        • Yudell M.
        • Mortensen E.L.
        • Newschaffer C.J.
        In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder.
        J Autism Dev Disord. 2014; 44: 2558-2567
        • Boukhris T.
        • Sheehy O.
        • Mottron L.
        • Bérard A.
        Antidepressant use during pregnancy and the risk of autism spectrum disorder in children.
        JAMA Pediatr. 2016; 170: 117-124
        • Rai D.
        • Lee B.K.
        • Dalman C.
        • Newschaffer C.
        • Lewis G.
        • Magnusson C.
        Antidepressants during pregnancy and autism in offspring: Population based cohort study.
        BMJ. 2017; 358: j2811
        • Croen L.A.
        • Grether J.K.
        • Yoshida C.K.
        • Odouli R.
        • Hendrick V.
        Antidepressant use during pregnancy and childhood autism spectrum disorders.
        Arch Gen Psychiatry. 2011; 68: 1104-1112
        • Harrington R.A.
        • Lee L.C.
        • Crum R.M.
        • Zimmerman A.W.
        • Hertz-Picciotto I.
        Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
        Pediatrics. 2014; 133: e1241-e1248
        • Schendel D.E.
        • Diguiseppi C.
        • Croen L.A.
        • Fallin M.D.
        • Reed P.L.
        • Schieve L.A.
        • et al.
        The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network.
        J Autism Dev Disord. 2012; 42: 2121-2140
        • Wiggins L.D.
        • Reynolds A.
        • Rice C.E.
        • Moody E.J.
        • Bernal P.
        • Blaskey L.
        • et al.
        Using standardized diagnostic instruments to classify children with autism in the study to explore early development.
        J Autism Dev Disord. 2015; 45: 1271-1280
        • Rutter M.
        • Bailey A.
        • Lord C.
        SCQ: Social Communication Questionnaire.
        Western Psychological Services, Los Angeles, CA2003
        • Wiggins L.D.
        • Bakeman R.
        • Adamson L.B.
        • Robins D.L.
        The utility of the Social Communication Questionnaire in screening for autism in children referred for early intervention.
        Focus Autism Dev Disabil. 2007; 22: 33-38
        • Lord C.
        • Risi S.
        • Lambrecht L.
        • Cook Jr., E.H.
        • Leventhal B.L.
        • DiLavore P.C.
        • et al.
        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: 205-223
        • 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: 659-685
        • Rutter M.
        • Le Couteur A.
        • Lord C.
        ADI-R: The Autism Diagnostic Interview-Revised.
        Western Psychological Services, Los Angeles, CA2003
        • Mullen E.M.
        Mullen Scales of Early Learning.
        American Guidance Service, Inc, Circle Pines, MN1995
        • Sparrow S.
        • Cichetti D.
        • Balla D.
        Vineland Adaptive Behavior Scales.
        2nd ed. American Guidance Service, Inc, Circle Pines, MN2005
        • Castro V.M.
        • Kong S.W.
        • Clements C.C.
        • Brady R.
        • Kaimal A.J.
        • Doyle A.E.
        • et al.
        Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: A replication study.
        Transl Psychiatry. 2016; 6e708
        • Rai D.
        • Lee B.K.
        • Dalman C.
        • Golding J.
        • Lewis G.
        • Magnusson C.
        Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study.
        BMJ. 2013; 346: f2059
        • El Marroun H.
        • White T.J.
        • van der Knaap N.J.
        • Homberg J.R.
        • Fernández G.
        • Schoemaker N.K.
        • et al.
        Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: Population-based study of young children.
        Br J Psychiatry. 2014; 205: 95-102
        • Lauritsen M.B.
        • Pedersen C.B.
        • Mortensen P.B.
        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: 963-971
        • Wiggins L.D.
        • Rubenstein E.
        • Daniels J.
        • DiGuiseppi C.
        • Yeargin-Allsopp M.
        • Schieve L.A.
        • et al.
        A phenotype of childhood autism is associated with preexisting maternal anxiety and depression.
        J Abnorm Child Psychol. 2019; 47: 731-740
        • 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: 557-563
        • Daniels J.L.
        • Forssen U.
        • Hultman C.M.
        • Cnattingius S.
        • Savitz D.A.
        • Feychting M.
        • Sparen P.
        Parental psychiatric disorders associated with autism spectrum disorders in the offspring.
        Pediatrics. 2008; 121: e1357-e1362
        • Piven J.
        • Chase G.A.
        • Landa R.
        • Wzorek M.
        • Gayle J.
        • Cloud D.
        • Folstein S.
        Psychiatric disorders in the parents of autistic individuals.
        J Am Acad Child Adolesc Psychiatry. 1991; 30: 471-478
        • Duvekot J.
        • van der Ende J.
        • Constantino J.N.
        • Verhulst F.C.
        • Greaves-Lord K.
        Symptoms of autism spectrum disorder and anxiety: Shared familial transmission and cross-assortative mating.
        J Child Psychol Psychiatry. 2016; 57: 759-769
        • Bolton P.F.
        • Pickles A.
        • Murphy M.
        • Rutter M.
        Autism, affective and other psychiatric disorders: Patterns of familial aggregation.
        Psychol Med. 1998; 28: 385-395
        • Larsson H.J.
        • Eaton W.W.
        • Madsen K.M.
        • Vestergaard M.
        • Olesen A.V.
        • Agerbo E.
        • et al.
        Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status.
        Am J Epidemiol. 2005; 161 (discussion 926–928): 916-925
        • Solberg B.S.
        • Zayats T.
        • Posserud M.B.
        • Halmøy A.
        • Engeland A.
        • Haavik J.
        • Klungsøyr K.
        Patterns of psychiatric comorbidity and genetic correlations provide new insights into differences between attention-deficit/hyperactivity disorder and autism spectrum disorder.
        Biol Psychiatry. 2019; 86: 587-598
        • Cross-Disorder Group of the Psychiatric Genomics Consortium
        Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.
        Lancet. 2013; 381: 1371-1379
        • Carroll L.S.
        • Owen M.J.
        Genetic overlap between autism, schizophrenia and bipolar disorder.
        Genome Med. 2009; 1: 102
        • Zablotsky B.
        • Anderson C.
        • Law P.
        The association between child autism symptomatology, maternal quality of life, and risk for depression.
        J Autism Dev Disord. 2013; 43: 1946-1955
        • Brown A.S.
        • Gyllenberg D.
        • Malm H.
        • McKeague I.W.
        • Hinkka-Yli-Salomäki S.
        • Artama M.
        • et al.
        Association of selective serotonin reuptake inhibitor exposure during pregnancy with speech, scholastic, and motor disorders in offspring.
        JAMA Psychiatry. 2016; 73: 1163-1170
        • Viktorin A.
        • Uher R.
        • Kolevzon A.
        • Reichenberg A.
        • Levine S.Z.
        • Sandin S.
        Association of antidepressant medication use during pregnancy with intellectual disability in offspring.
        JAMA Psychiatry. 2017; 74: 1031-1038
        • Pedersen L.H.
        • Henriksen T.B.
        • Olsen J.
        Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.
        Pediatrics. 2010; 125: e600-e608
        • Sujan A.C.
        • Öberg A.S.
        • Quinn P.D.
        • D’Onofrio B.M.
        Annual research review: Maternal antidepressant use during pregnancy and offspring neurodevelopmental problems - A critical review and recommendations for future research.
        J Child Psychol Psychiatry. 2019; 60: 356-376
        • Schieve L.A.
        • Harris S.
        • Maenner M.J.
        • Alexander A.
        • Dowling N.F.
        Assessment of demographic and perinatal predictors of non-response and impact of non-response on measures of association in a population-based case control study: Findings from the Georgia Study to Explore Early Development.
        Emerg Themes Epidemiol. 2018; 15: 12
        • DiGuiseppi C.G.
        • Daniels J.L.
        • Fallin D.M.
        • Rosenberg S.A.
        • Schieve L.A.
        • Thomas K.C.
        • et al.
        Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder.
        Disabil Health J. 2016; 9: 544-551