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Figure 1.
Relative Risks (RRs) of Intellectual Disability Attributable to Exposure to Any Antidepressant During Pregnancy
Relative Risks (RRs) of Intellectual Disability Attributable to Exposure to Any Antidepressant During Pregnancy

The full sample consists of 179 007 children born during 2006 and 2007, of whom 873 had been diagnosed with intellectual disability and 3982 were born to a mother with antidepressant treatment during pregnancy. The figure presents the RRs (95% CIs) of intellectual disability among children of mothers with at least 2 dispensations of antidepressant drugs that overlapped the pregnancy compared with unexposed children. There was a clinically relevant subsample of 8021 children, of whom 69 had been diagnosed with intellectual disability and 2372 were born to a mother with antidepressant treatment during pregnancy. All mothers, both medicated and nonmedicated, had at least 1 diagnosis of depression or an anxiety disorder before childbirth (eTable 4 in the Supplement). Therefore, the offspring of mothers with medication use during pregnancy is compared with the offspring of mothers who may share similar underlying factors.

aAnalyses not adjusted for covariates.

bAnalyses adjusted for birth date, maternal and paternal age, the father's psychotropic medication use that overlapped the pregnancy, and maternal and paternal educational levels at childbirth.

cAnalyses adjusted for the factors listed in footnote b and for any maternal diagnosis of depression before childbirth (yes/no) (see eTable 4 in the Supplement for specific diagnosis codes).

dAnalyses adjusted for the factors listed in footnote b and for maternal or paternal diagnoses before childbirth of specific psychiatric disorder subgroups (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, schizophrenia, and other psychiatric diagnosis (see eTable 4 in the Supplement for specific diagnosis codes).

Figure 2.
Relative Risks (RRs) of Intellectual Disability Among Offspring of Mothers Treated With Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants, Non-SSRI Antidepressants, or Nonantidepressant Psychotropic Drugs
Relative Risks (RRs) of Intellectual Disability Among Offspring of Mothers Treated With Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants, Non-SSRI Antidepressants, or Nonantidepressant Psychotropic Drugs

The sample consists of 179 007 children born during 2006 and 2007, of whom 873 had been diagnosed with intellectual disability. There were 3178 children born to mothers treated with SSRIs during pregnancy, 804 children born to mothers treated with non-SSRI antidepressants during pregnancy, and 1626 children born to mothers treated with nonantidepressant psychotropic medications during pregnancy. The figure presents RRs (95% CIs) of intellectual disability among children of mothers with at least 2 dispensations of antidepressants or other psychotropic medications that overlapped the pregnancy compared with unexposed children.

aAnalyses not adjusted for covariates.

bAnalyses adjusted for birth date, maternal and paternal age, the father's psychotropic medication use that overlapped the pregnancy, and maternal and paternal educational levels at childbirth.

cAnalyses adjusted for the factors listed in footnote b and for any maternal diagnosis of depression before childbirth (yes/no) (see eTable 4 in the Supplement for specific diagnosis codes).

dAnalyses adjusted for the factors listed in footnote b and for maternal and paternal diagnoses before childbirth of specific psychiatric disorder subgroups (yes/no), including depression, anxiety disorders, substance use disorder, bipolar disorder, compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, schizophrenia, and other psychiatric diagnosis (see eTable 4 in the Supplement for specific diagnosis codes).

Table.  
Study Participant Characteristics by Antidepressant Medication Use During Pregnancy
Study Participant Characteristics by Antidepressant Medication Use During Pregnancy
Supplement.

eTable 1. List of Medications Considered in the Study

eTable 2. Psychotropic Drugs During Pregnancy

eTable 3. Detailed Information About Parental Education Levels

eTable 4. Psychiatric Diagnosis Codes Included in the Study

eTable 5. Clinical Subsample Subject Characteristics

eFigure 1. Medication Exposure Definition

eFigure 2. Kaplan-Meier Failure Estimate of Intellectual Disability

eFigure 3. Relative Risks of Intellectual Disability in Children of Mothers With a Single Dispensation of Any Antidepressant During Pregnancy

eFigure 4. Relative Risks of Intellectual Disability in Children of Mothers With Any Number of Dispensations of Any Type Antidepressant During Pregnancy

eFigure 5. Plotted Schoenfeldt Residuals for Each Covariate With 4 Degrees of Freedom

eFigure 6. Relative Risks of Mild to Moderate Intellectual Disability

eFigure 7. Relative Risks of Severe Intellectual Disability

eFigure 8. Relative Risks of Intellectual Disability Without Comorbid Autism Spectrum Disorder

eFigure 9. Results From Bootstrapped Analyses

eFigure 10. Sex-Specific and Sex-Combined Relative Risks of Intellectual Disability

eFigure 11. Relative Risks of Intellectual Disability in Children of Mothers Treated With Antidepressants During Pregnancy, Including Gestational Age and Birth Weight

eFigure 12. Trimester-Specific Relative Risks of Intellectual Disability

eFigure 13. Duration-Dose-Response Effect on the Relative Risk of Intellectual Disability

eFigure 14. Effects of Potential Misclassification in Unexposed Children

eFigure 15. Relative Risks of Intellectual Disability Stratified on Maternal Polypharmacy

eFigure 16. Percentage of Mothers With Medication During Pregnancy and a Psychiatric Diagnosis Before Child Birth

eFigure 17. Relative Risks of Intellectual Disability Due to Exposure to Any Antidepressant During Pregnancy, Where All Antidepressant Treated Mothers Were Assumed to Have Suffered Depression

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Original Investigation
October 2017

Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring

Author Affiliations
  • 1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
  • 2The Seaver Autism Center for Research and Treatment, Mount Sinai, New York, New York
  • 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 4Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
  • 5Department of Community Mental Health, University of Haifa, Haifa, Israel
JAMA Psychiatry. 2017;74(10):1031-1038. doi:10.1001/jamapsychiatry.2017.1727
Key Points

Question  Does maternal antidepressant medication use during pregnancy increase the risk of intellectual disability in offspring?

Findings  In this population-based cohort study of 179 007 pregnancies, an association of maternal antidepressant medication use during pregnancy with intellectual disability in offspring was attenuated when parental factors other than medication use were taken into account.

Meaning  An elevated risk of intellectual disability in children born to women who used antidepressant medication during pregnancy is likely attributable to factors underlying the treatment and not to the antidepressant medication itself.

Abstract

Importance  Maternal antidepressant medication use during pregnancy has previously been associated with adverse outcomes in offspring, but to our knowledge, the association with intellectual disability (ID) has not been investigated.

Objectives  To examine the association of maternal antidepressant medication use during pregnancy with ID in offspring and investigate the importance of parental mental illness for such an association.

Design, Setting, and Participants  A population-based cohort study of 179 007 children born from January 1, 2006, through December 31, 2007, with complete parental information from national registers who were followed up from birth throughout 2014.

Main Outcomes and Measures  We estimated relative risks (RRs) and 95% CIs of ID in children exposed during pregnancy to any antidepressant medication or specifically to selective serotonin reuptake inhibitor (SSRI) antidepressants, all other non-SSRI antidepressants, or other nonantidepressant psychotropic medications. Analyses were adjusted for potential confounders. In addition to full population analyses, we used a subsample to compare mothers who used antidepressants during pregnancy with mothers who had at least one diagnosis of depression or anxiety before childbirth but did not use antidepressants during pregnancy.

Results  Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. With adjustment for potential confounders, the RR of ID after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Results from analyses of SSRI antidepressants, non-SSRI antidepressants, and nonantidepressant psychotropic medications and analyses in the clinically relevant subsample did not deviate from the full-sample results.

Conclusions and Relevance  The unadjusted RR of ID was increased in offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to a mechanism integral to other factors, such as parental age and mother’s psychiatric disorder.

Introduction

Intellectual disability (ID) has an estimated lifetime prevalence of 0.7% to 2.0% in the population of western societies,1-4 has immense social effects, and is a leading cause of health care–related societal costs.5 Intellectual disability is commonly diagnosed in childhood, is defined by an IQ below 70 along with adaptive deficits that impair everyday functioning, and can be divided based on severity.6 Genetic and environmental factors are implicated in ID and include chromosomal and hereditary factors, such as trisomy 21 (Down syndrome)7 and fragile X syndrome8; factors that affect fetal development, such as uncontrolled diabetes9; and congenital exposures to infectious agents10,11 or toxic agents.12-14

Adverse outcomes have also been associated with conventional medications used during pregnancy, including the antiepileptic and mood-stabilizing medication sodium valproate, which has been associated with poor cognitive development and lower IQ in exposed offspring.15 In recent decades, use of antidepressant medications, particularly selective serotonin reuptake inhibitors (SSRIs), has increased significantly in general16 and among pregnant women in particular.17,18 Antidepressants pass the placenta,19 and a mouse study20 reported smaller head size in mice prenatally exposed to SSRIs. Moreover, high levels of serotonin in serotonin transporter knockout mice are thought to cause abnormal wiring of the somatosensory cortex and the lateral geniculate nucleus in the brain.21 Human observational studies report associations between prenatal antidepressant exposure and reduced time in gestation,22-25 lower birth weight,23,25 reduced fetal head growth,26 and adverse offspring outcomes, including septal heart defects,27 persistent pulmonary hypertension,28,29 and malformations at birth.30 Furthermore, ID commonly co-occurs with autism spectrum disorder (ASD),31 which has been associated with maternal antidepressant medication during pregnancy in many32-36 but not all studies.37-43 There are also reports of an association of fetal antidepressant exposure with delayed fetal brain development44 but not with behavioral or emotional problems in early childhood.45

In this study, we examine a potential association of maternal antidepressant medication during pregnancy with diagnosed ID in the offspring and assess to what extent maternal and paternal factors confound such an association. In addition to studying treatment with any antidepressant, we study treatment specifically with SSRI antidepressants, all other non-SSRI antidepressants, and nonantidepressant psychotropics.

Methods
Study Population

A birth cohort based on all live-born children conceived from July 1, 2005, and born from January 1, 2006, through December 31, 2007, was established by linkage of Swedish national registers using the unique individual Swedish national registration number.46 Mothers and offspring were identified in the Swedish Medical Birth Register, which covers 99% of all births nationwide since 1973 and provides information on gestational age at birth that was used to calculate the duration of pregnancy.47 In Sweden, 95% of all pregnant women undergo ultrasonography in the early second trimester, which provides the gestational age of the fetus with an error margin of ±7 days.48 The fathers were identified using the Multi-generation Register.49 To be included in the study, children had to have complete information on gestational age at birth and the identity of the father. By Swedish law, informed consent was not necessary because the study used data available from national registries. The register data were linked by the governing bodies and deidentified before provided to the researchers. The study was approved by the regional ethics committee in Stockholm, Sweden.

Medications

The Swedish Prescribed Drug Register contains information on all dispensed prescription medications in Sweden since July 2005 along with medication name, prescription and dispensation dates, and the Anatomical Therapeutic Chemical code.50,51 We identified dispensations of all psychotropic medications prescribed in Sweden (eTable 1 and eTable 2 in the Supplement). Medication periods were calculated beginning at the dispensation date through the last dispensed dose, assuming 1 pill was consumed per day (eFigure 1 in the Supplement). The offspring were classified as unexposed to antidepressants if they were born to mothers without any antidepressant medication periods that overlapped the pregnancy, defined as the period from the estimated conception date until the birth date. Offspring were considered to be exposed if the mother had at least 2 dispensations of antidepressants with medication periods that overlapped the pregnancy. Offspring of mothers with only a single medication dispensation that overlapped the pregnancy were not included as exposed or unexposed but were analyzed separately because of uncertainty of exposure. Antidepressant medication is normally used for longer periods; therefore, a single dispensation with a medication period in pregnancy may represent medication with use halted before conception or not consumed at all because of fear of adverse effects on the fetus.

Ascertainment of ID

A clinically ascertained diagnosis of ID was identified in the Swedish National Patient Register.52 This register includes all inpatient psychiatric admissions since 1973 and all outpatient specialist admissions since 2001 and provides admission dates along with the main and 8 secondary diagnosis codes in accordance with the ICD. Intellectual disability was defined as having at least 1 inpatient or outpatient specialist care admission between birth and the end of follow-up at December 31, 2014, with an ICD-10 code of F70 to F79. Supplemental analyses were conducted for mild to moderate ID using ICD-10 codes of F70, F71, and F74 to F79; severe ID (including profound ID) using ICD-10 codes of F72 to F73; and ID without ASD by excluding children with an ASD ICD-10 code of F84.

Covariates

A previous study53 found an increasing prevalence of childhood psychiatric disorders over time by year of birth. Increase over time was also observed in the current cohort (eFigure 2 in the Supplement). To adjust for potential temporal trends, we included the birth date of the offspring as the number of days from January 1, 2005, to the birth date. Because age was best supported by the available studies,54 maternal and paternal ages at childbirth were categorized into younger than 20 years, 20 through 29 years, 30 through 39 years, and 40 years or older, using 20 through 29 years as the reference. Maternal and paternal educational levels were included, coded from 1 to 7 (1 indicating compulsory school shorter than 9 years; 2, compulsory school for 9 years; 3, upper secondary school up to 2 years; 4, upper secondary school for 3 years; 5, postsecondary education <3 years; 6, university for 3 years; and 7, doctoral education) (eTable 3 in the Supplement) as a measure of socioeconomic status. To adjust for potential confounding by indication, we included maternal and paternal psychiatric disorders diagnosed in the Swedish National Patient Register before childbirth within several psychiatric disorder subgroups (eTable 4 in the Supplement). Paternal psychotropic medication use that overlapped the pregnancy was also included, as well as maternal medication use with psychotropic drugs other than antidepressants that overlapped the pregnancy. Covariates related to the paternal psychiatric disorder were included because paternal psychiatric illness has been hypothesized to affect maternal well-being.55

Sensitivity Analyses

Analyses were also performed separately for offspring born to mothers with only a single antidepressant dispensation and any number of antidepressant dispensations with medication periods that overlapped pregnancy compared with unexposed offspring during pregnancy. The proportional hazards assumption for the Cox proportional hazards regression models was examined using Schoenfeld residuals.56 Analyses were performed separately for mild to moderate ID, severe ID, and ID without ASD. To account for potential within-family correlations in the data attributable to multiple births from the same parents, we used bootstrap techniques.57 Potential sex specificity of associations was tested by analyses of male and female offspring separately. The role of gestational age and birth weight in the causal pathway was examined. Potential trimester-specific and duration-dose-response effects were analyzed. The effect of potential misclassification of unexposed offspring born to mothers with an antidepressant dispensation within 6 months of conception was examined. The role of polypharmacy was also examined.

Statistical Analysis

Relative risks (RRs) of ID and the associated Wald-type, 2-sided 95% CIs were estimated by the hazard ratios from Cox proportional hazards regression models. The age of the child is one of the most important determinants of childhood psychiatric disorder diagnosis,53 which was observed in our sample (eFigure 2 in the Supplement), and Cox proportional hazards regression allows for detailed adjustment for censoring that affects the length of follow-up of each child.58 The Cox proportional hazards regression models were fitted using days since birth as the underlying time scale. Each child was followed up from birth until a diagnosis of ID, death, or end of follow-up on December 31, 2014, whichever came first. In the primary analyses, children of mothers with at least 2 antidepressant dispensations with medication periods that overlapped pregnancy were compared with children of mothers not exposed to antidepressant medication during the pregnancy. Mothers with only a single antidepressant dispensation with a medication period that overlapped pregnancy were analyzed separately (eFigure 3 in the Supplement) and in combination with mothers with at least 2 dispensations (eFigure 4 in the Supplement).

Analyses were conducted for all included children to provide a public health perspective and in a clinically relevant subsample of children born to mothers with at least 1 diagnosis before childbirth of depression or anxiety, the most common diagnoses motivating antidepressant medication. In this subsample, the control group corresponds to offspring born to mothers with a depression or anxiety diagnosis but without any medication dispensation.

First, we examined children of mothers medicated during pregnancy with any type of antidepressant. The RRs of ID were calculated in a sequence of models with increasing degree of adjustment for potential confounding factors according to the model: (1) crude analyses without covariate adjustment; (2) analyses adjusted for confounding by nonpsychiatric parental factors, including offspring birth date, mother's and father's dispenses of other psychotropic medications during pregnancy, maternal and paternal age, and maternal and paternal educational level at childbirth; (3) supplementing model 2 with additional adjustment for any maternal depressive diagnosis before childbirth; and (4) supplementing model 3 with additional adjustment for any diagnosis before childbirth of specific psychiatric disorders in the mother’s and/or father's lifetime. The psychiatric disorders included separate variables for a diagnosis of depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, compulsive disorder, attention-deficit/hyperactivity disorder, ASD, ID, and any other psychiatric diagnosis (eTable 4 in the Supplement).

Second, we calculated the RRs of ID among children of mothers treated specifically with SSRI antidepressants, non-SSRI antidepressants, or nonantidepressant psychotropic medications compared with children of mothers not treated with these medications during pregnancy.

All tests of statistical hypotheses were performed on the 2-sided 5% level of significance. Data management and statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc) and STATA/IC, version 14 (StataCorp), respectively.

Results

Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. The Table presents descriptive statistics for the full population cohort, and eTable 5 in the Supplement presents descriptive statistics for the clinical subsample. Of 180 444 children in the Medical Birth Register conceived from July 1, 2005, and born to December 31, 2007, a total of 179 007 (99.3%) had complete data and were included in the analyses. Intellectual disability was diagnosed in 873 children (0.5%).

Antidepressants and ID

The cohort included 3982 children (2.2%) born to mothers with at least 2 dispensations of antidepressant medication that overlapped the pregnancy, whereas 172 646 (96.4%) were born to mothers with no antidepressant medication dispensations that overlapped the pregnancy. The unadjusted RR (model 1) of ID in the children exposed to maternal antidepressant medication use during pregnancy was estimated at 1.97 (95% CI, 1.42-2.74). After adjustment for potential confounders (model 4), the RR was estimated at 1.33 (95% CI, 0.90-1.98), with comparable estimates in analyses restricted to the clinically relevant subsample (n = 8021) (Figure 1).

Medication Subgroups

Among the 3982 pregnancies exposed to antidepressant medication, 3178 women (79.8%) were treated with SSRI antidepressants and 804 (20.2%) were treated with non-SSRI antidepressants. In an additional 1626 (0.9%) pregnant women not treated with antidepressants, the mother had at least 2 dispensations with other psychotropic medications. In analyses adjusted for all included confounders (model 4), the RR of ID in the offspring was estimated at 1.48 (95% CI, 0.98-2.23) for SSRI antidepressants, 0.81 (95% CI, 0.33-2.00) for non-SSRI antidepressants, and 1.31 (95% CI, 0.75-2.27) for nonantidepressant psychotropic medications (Figure 2).

Sensitivity Analyses

Analyses of children of mothers who used a single antidepressant medication during pregnancy (eFigure 3 in the Supplement) or any number of antidepressant medications during pregnancy (eFigure 4 in the Supplement) revealed lower RRs than the main analysis but similar patterns of gradual attenuation. Inspection of the Schoenfeld residuals did not suggest any violation of the proportional hazards assumption (eFigure 5 in the Supplement). Analyses of mild to moderate ID (eFigure 6 in the Supplement), of severe ID (eFigure 7 in the Supplement), of ID without comorbid ASD (eFigure 8 in the Supplement), using bootstrap techniques (eFigure 9 in the Supplement), of male and female offspring separately (eFigure 10 in the Supplement), of gestational age and birth weight (eFigure 11 in the Supplement), of trimester-specific exposures (eFigure 12 in the Supplement), of duration-dose-response effects (eFigure 13 in the Supplement), of potential misclassification of children classified as unexposed (eFigure 14 in the Supplement), and of polypharmacy (eFigure 15 in the Supplement) revealed results that did not deviate quantitatively and qualitatively from the main findings in Figure 1 and Figure 2.

Discussion

This population-based cohort study was, to our knowledge, the first to directly assess the RR of diagnosed ID in children born to mothers treated with antidepressant medication during pregnancy. We observed a higher RR of ID among offspring born to mothers treated with antidepressants during pregnancy (0.9% of children affected) compared with offspring of mothers not treated with antidepressants during pregnancy (0.5% of children affected) before adjustment for confounding factors. However, with incremental adjustment for maternal and paternal confounding factors, this association was gradually attenuated to a statistically nonsignificant RR estimated at 1.33 (95% CI, 0.90-1.98). Thus, the association between offspring ID and maternal antidepressant medication may, to a large extent, be explained by confounding by the covariates included and adjusted for in the current analyses.

This finding was further supported in analyses confined to the 8021 children born to mothers with at least 1 diagnosis of depression or anxiety before childbirth. In these analyses, all children were born to a mother with a diagnosis of a disorder for which antidepressant treatment may be prescribed and may therefore be more similar with regard to factors other than the antidepressant medication (eg, genetic susceptibility to a psychiatric disorder) or to environmental factors correlated with the psychiatric disorder. Moreover, to further examine potential medication-specific effects, we performed additional analyses of children born to mothers treated during pregnancy specifically with SSRI antidepressants, non-SSRI antidepressants, or nonantidepressant psychotropic medications. The results of these analyses were comparable to the results of the analyses of children exposed to any antidepressant during pregnancy, which further suggests that the underlying condition precipitating the medication is important for the association between ID in the offspring and maternal medication use during pregnancy. This interpretation was additionally supported by sensitivity analyses, which did not reveal a trimester-specific or duration-dose-response effect on the association.

Strengths and Limitations

Strengths of this study include a large, prospectively ascertained, population-based sample of children and their parents with near-complete health care data coverage. Risks of selection bias are limited by the use of data from a health care system with equal access and complete information on all included children and parents. Inclusion of children born during a limited period (2006-2007) reduced the risk of potential time-dependent confounding. Inclusion of the parents’ diagnoses of psychiatric disorder allowed detailed adjustment for confounding. The requirement of at least 2 dispensations overlapping the pregnancy increased the specificity of the exposure. Analyses of medications divided into SSRI antidepressants, non-SSRI antidepressants, and nonantidepressant psychotropic medications revealed similar findings, which support the interpretation that underlying factors confound the association between medication during pregnancy and increased risk of ID among offspring.

These findings should nevertheless be interpreted in light of some limitations. Although medications recorded in the Swedish Prescribed Drug Register have been prescribed and collected, adherence is not known. To address this limitation, we focused on children of mothers with at least 2 dispensations that overlapped the pregnancy and analyzed children of mothers with a single dispensation separately. Moreover, the Swedish National Patient Register does not provide information from primary care; as such, diagnoses confined to primary care go undetected. However, this did not affect the study's ability to detect children with ID because they are referred to a specialist who is covered by the Swedish National Patient Register. The lack of primary care data may, however, have affected the ability to capture parental psychiatric diagnoses and the ability to adjust for potential confounding. A supplemental analysis revealed that almost 40% of the mothers treated with antidepressant medication during pregnancy lacked any psychiatric diagnosis before childbirth in the Swedish National Patient Register (eFigure 16 in the Supplement). In a sensitivity analysis in which all antidepressant-treated mothers were assumed to have a depression diagnosis, the RR of ID was further attenuated (eFigure 17 in the Supplement). Moreover, the study could not adjust for other potential confounding factors, including disorder severity, lifestyle factors, and factors that affect fetal development (eg, exposure to uncontrolled diabetes,9 infectious agents,10,11 or toxic agents).12-14 Expanded covariate adjustment could further attenuate or strengthen the association. Furthermore, other factors related to ID, such as trisomy 21 (Down syndrome)7 and fragile X syndrome,8 were not specifically investigated in the current study.

Last, although the current study included many children and adjusted for many important confounding factors, the outcome was rare and the number of children diagnosed with ID during the follow-up period of the first 7 to 8 years after birth was 873 (0.5%). Although this figure is lower than some previous estimates,2-4 it is comparable to the prevalence of 0.6% in children aged 3 to 10 years in a US survey1 and to prevalence estimates from register-based sources in other Scandinavian cohorts.4 Previous literature suggests increasing prevalence of childhood psychiatric disorders over time,53 which is also supported by our data (eFigure 2 in the Supplement). Because children with ID without clinical care are not captured, the prevalence estimate of ID in the current study may be an underestimate of the true prevalence in the population. In addition, the likelihood diagnosis may differ among groups (eg, through increased medical surveillance of children born to mothers treated with antidepressants during pregnancy). Because ID is relatively uncommon and our prevalence estimates are only slightly lower than expected, the misclassification would likely not significantly change the RRs and would not affect the primary conclusions of our results. However, low prevalence limits the statistical power, particularly in the compound-specific analyses of the study, and prevents more detailed analyses (eg, of specific drugs). Additional research of the association between maternal psychotropic medication use during pregnancy and ID in offspring is therefore warranted.

Conclusions

The unadjusted RR of ID was increased among offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to mechanisms integral to other factors, such as parental age and underlying psychiatric disorder.

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Article Information

Corresponding Author: Alexander Viktorin, PhD, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1230, New York, NY 10029 (alexander.viktorin@ki.se).

Accepted for Publication: May 11, 2017.

Published Online: July 12, 2017. doi:10.1001/jamapsychiatry.2017.1727

Author Contributions: Drs Viktorin and Sandin had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Viktorin, Uher, Reichenberg, Levine, Sandin.

Acquisition, analysis, or interpretation of data: Viktorin, Kolevzon, Reichenberg, Levine, Sandin.

Drafting of the manuscript: Viktorin, Reichenberg, Levine, Sandin.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Viktorin, Uher, Levine, Sandin.

Obtained funding: Viktorin, Reichenberg, Sandin.

Administrative, technical, or material support: Viktorin, Kolevzon, Reichenberg, Sandin.

Study supervision: Viktorin, Reichenberg, Sandin.

Conflict of Interest Disclosures: Dr Kolevzon reported consulting for Vencerx Therapeutics, Genentech, Ovid Therapeutics, and Supernus Pharmaceuticals. Dr Levine reported receiving research support from Shire Pharmaceuticals. No other disclosures were reported.

Funding/Support: This study was supported by grant HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; grant MH097849 from the National Institute of Mental Health; the Beatrice and Samuel A. Seaver Foundation; the Canada Research Chairs Program and the Canadian Institutes of Health Research Foundation program (Dr Uher); the Fredrik and Ingrid Thuring Foundation (Dr Viktorin); and the Swedish Society of Medicine (Dr Viktorin).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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