Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children

Elizabeth A Suarez; Brian T Bateman; Sonia Hernández-Díaz; Loreen Straub; Katherine L Wisner; Kathryn J Gray; Page B Pennell; Barry Lester; Christopher J McDougle; Yanmin Zhu; Helen Mogun; Krista F Huybrechts

doi:10.1001/jamainternmed.2022.4268

. 2022 Oct 3;182(11):1149–1160. doi: 10.1001/jamainternmed.2022.4268

Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children

Elizabeth A Suarez ^1,^✉, Brian T Bateman ², Sonia Hernández-Díaz ³, Loreen Straub ¹, Katherine L Wisner ^4,⁵, Kathryn J Gray ⁶, Page B Pennell ⁷, Barry Lester ⁸, Christopher J McDougle ^9,¹⁰, Yanmin Zhu ¹, Helen Mogun ¹, Krista F Huybrechts ¹

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

²Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California

³Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

⁴Asher Center for the Study and Treatment of Depressive Disorders, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

⁵Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

⁶Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts

⁷Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

⁸Center for the Study of Children at Risk, Departments of Psychiatry and Pediatrics, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island

⁹Lurie Center for Autism, Massachusetts General Hospital, Lexington

¹⁰Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

Accepted for Publication: August 1, 2022.

Published Online: October 3, 2022. doi:10.1001/jamainternmed.2022.4268

^✉

Corresponding Author: Elizabeth A. Suarez, MPH, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont St, Boston, MA 02120 (h4p@bwh.harvard.edu).

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

Concept and design: Suarez, Bateman, Straub, Huybrechts.

Acquisition, analysis, or interpretation of data: Suarez, Bateman, Hernández-Díaz, Wisner, Gray, Pennell, Lester, McDougle, Zhu, Mogun, Huybrechts.

Drafting of the manuscript: Suarez.

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

Statistical analysis: Suarez, Mogun.

Obtained funding: Hernández-Díaz, Lester, Huybrechts.

Administrative, technical, or material support: Suarez, Hernández-Díaz, Straub, Wisner, Zhu, Huybrechts.

Supervision: Bateman, Hernández-Díaz, Gray, Huybrechts.

Conflict of Interest Disclosures: Dr Hernández-Díaz reported grants from the National Institutes of Health during the conduct of the study; grants from Takeda and personal fees from UCB outside the submitted work; and having served as an epidemiologist with the North America AED pregnancy registry, which is funded by multiple companies. Dr Gray reported personal fees from Illumina, BillionToOne, Roche, and Aetion outside the submitted work. Dr Pennell reported grants from the National Institutes of Health during the conduct of the study. Dr McDougle reported personal fees from Precidiag, Sage Therapeutics, Receptor Life Sciences, and Acadia Pharmaceuticals, as well as royalties from Oxford University Press and Springer Publishing outside the submitted work. Dr Zhu reported grants from Takeda outside the submitted work. Dr Huybrechts reported grants from UCB to her institution outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by the US National Institute of Mental Health (No. R01 MH116194).

Role of the Funder/Sponsor: The US National Institute of Mental Health 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.

Meeting Presentation: This work was presented at the 37th International Conference on Pharmacoepidemiology; August 2021; virtual.

^✉

Corresponding author.

PMCID: PMC9531086 PMID: 36190722

This cohort study evaluates the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children.

Key Points

Question

Is antidepressant exposure during pregnancy associated with an increased risk of specific neurodevelopmental disorders in children?

Findings

In this cohort study including 145 702 antidepressant-exposed pregnancies, antidepressant exposure during pregnancy was not associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, specific learning disorders, developmental speech/language disorders, developmental coordination disorders, intellectual disabilities, or behavioral disorders after accounting for confounding through various design and analytic approaches. Results were generally consistent across antidepressant medication classes, commonly used individual drugs, and gestational exposure windows.

Meaning

These findings suggest that antidepressant use in pregnancy does not increase the risk of neurodevelopmental disorders in children.

Abstract

Importance

Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors.

Objective

To evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children.

Design, Setting, and Participants

This cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021.

Exposures

Dispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis.

Main Outcomes and Measures

Neurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses.

Results

Among the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows.

Conclusions and Relevance

The results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

Introduction

Mental health disorders, and in particular depressive disorders, are common among women of reproductive age, including during pregnancy.^1,2,3 Accordingly, antidepressants and other psychiatric medications are frequently prescribed, especially for women with severe illness. In the US, estimates for the prevalence of antidepressant use during pregnancy range from 6% to 8%.^4,5,6,7 Several studies have attempted to clarify whether antidepressant exposure in utero increases the risk of neurodevelopmental disorders (NDDs) in children. Most of this research has focused on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).⁸ Results have largely been conflicting, and whether antidepressant exposure increases the risk of these childhood disorders remains controversial.⁸ It is possible that confounding by indication of antidepressants for severe depression and by genetic and environmental factors associated with NDDs in children can explain the observed associations.⁹ Moreover, few studies have considered other specific diagnosed NDDs outside of small, hospital- or clinic-based settings.¹⁰ Limited data for intellectual disabilities and motor development are largely inconclusive owing to lack of confounding control and inconsistent measurement of outcomes.¹¹

In this cohort study, we used 2 large health care utilization databases to quantify the association between antidepressant use in pregnancy and various NDDs in children. We controlled for confounding by indication, environment, and genetics through various design and analytic approaches. The large sample size allowed for the assessment of antidepressant classes and individual drugs, and of various exposure windows.

Methods

Data Sources and Study Cohorts

We defined pregnancy cohorts nested in the Medicaid Analytic eXtract (MAX), which includes health care utilization data for Medicaid beneficiaries nationwide, from 2000 to 2014 and the MarketScan Commercial Claims Database (MarketScan), which includes private health insurance claims data, from 2003 to 2015. The development of the MAX pregnancy cohort has been previously described,¹² and similar methods were used in the development of the MarketScan cohort. Both data sources include information on demographics, diagnoses, and procedures received during all health care encounters, including all inpatient, outpatient, or emergency department visits, and dispensed outpatient prescription medications. Individuals aged 12 to 55 years with live-birth deliveries linked to infants were required to have insurance coverage from 3 months before the date of the estimated last menstrual period (LMP) to 1 month after delivery.

This study was approved by the institutional review board of Brigham and Women’s Hospital, which waived the need for informed consent. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines were followed for reporting.

Antidepressant Exposure

The primary exposed group included individuals with at least 1 dispensing of an antidepressant from 127 days after LMP (week 19 of gestation) to delivery, the approximate period of synaptogenesis. Antidepressant use was further categorized by class, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. Exposure to individual antidepressant drugs was assessed for the 5 most commonly used drugs (sertraline, fluoxetine, bupropion, citalopram, and escitalopram). The unexposed group was defined as having no antidepressant dispensing from 90 days prior to pregnancy start through the day prior to delivery.

Neurodevelopmental Outcomes

We defined the following outcomes: ASD, ADHD, specific learning disorders, developmental speech/language disorder, developmental coordination disorder, intellectual disability, behavioral disorder, and any NDD (presence of any of the 7 specific disorders). Validated claims-based algorithms with high positive predictive values were used to define each outcome (eTable 1 in the Supplement).

Covariates

Potential confounders included demographics (age of pregnant individual, race and ethnicity [recorded in MAX only and determined based on information submitted to the Centers for Medicare & Medicaid Services by individual states], state, delivery year), indications for antidepressant use (depression, anxiety, bipolar disorder, other mental health disorders, NDDs in the pregnant individual), proxies for severity of mental health conditions (numbers of psychiatric visits, inpatient and emergency visits for mental health diagnoses, mental health diagnoses, dispensings of other psychotropic medications), lifestyle factors (smoking, alcohol, substance abuse), other medications, comorbidities, adequacy of prenatal care, and county-level socioeconomic level indicators (MAX only). There is a very small proportion of missing data for zip code (<1%), which is used to define county-level socioeconomic indicators; therefore, the adjusted analysis is a complete case analysis that excludes pregnancies without zip code data. The full list of covariates and their respective assessment periods is included in eTable 2 in the Supplement.

Statistical Analysis

Main Analysis

Descriptive statistics were compared between exposure groups using standardized differences; covariates with standardized differences less than 10% were considered balanced. Cumulative incidence was calculated for each outcome stratified by data source and exposure status. Children were followed from birth until the time of the outcome or the time of censoring, marked by the end of enrollment, the end of the study period, or death. To control for measured confounding, weighting based on fine stratification of the propensity score (PS) was used with 50 strata after trimming the nonoverlapping regions of the PS distributions.¹³ Cox proportional hazards regression was used to calculate crude and weighted hazard ratios (HRs). The HRs were estimated in MAX and MarketScan separately and were pooled using fixed-effect meta-analysis (results for the publicly and privately insured cohorts separately are presented in eTables 3-12 in the Supplement).

Given the known potential for unmeasured confounding by treatment indication and by environmental and genetic factors, multiple design and analytic approaches to confounding adjustment were implemented. First, we compared pregnant individuals with antidepressant exposure to unexposed individuals and adjusted for nearly 70 measured covariates using fine stratification of the PS (adjusted). Second, we used a high-dimensional PS (HDPS adjusted) approach, including an additional 200 empirically selected covariates.¹⁴

Third, we compared individuals with exposure during late pregnancy to individuals who were unexposed during pregnancy but filled a prescription for an antidepressant prior to pregnancy (discontinuer referent). Discontinuers were defined as having a dispensing for any antidepressant in the window from 90 to 31 days prior to LMP but not during the window of 30 days prior to LMP through delivery. For class and drug-specific analyses, we additionally considered discontinuers to the specific exposure.

Fourth, we completed a sibling analysis to control for shared familial environmental and genetic confounders. Cox proportional hazards models were stratified on individual identifier. We adjusted for potential nonshared confounders, including all covariates included in the PS models except race and ethnicity, state, and county-level socioeconomic status variables; we additionally considered sibling birth order. The publicly and privately insured cohorts were pooled prior to analysis owing to sparse data challenges. We assessed potential carryover effects from the exposure of the first pregnancy to the outcome of the second pregnancy.¹⁵ Details on methods for the sibling analyses can be found in the eMethods in the Supplement. Because of limited study size, sibling analyses were not conducted for medication classes and individual drugs.

Sensitivity Analyses

The timing of the etiologically relevant window in pregnancy is not well established for these outcomes. Therefore, we defined a secondary exposure window during the first half of pregnancy (LMP through 126 days after LMP) and compared with antidepressant-unexposed pregnant individuals. To ensure that similarity in results between early and late exposure windows was not because of pregnancies with exposure in both windows, we additionally defined antidepressant exposure as only in late or only in early pregnancy. The discontinuer referent analysis and sibling analysis were also repeated using the early pregnancy exposure window.

Exposure misclassification is possible if individuals who fill a prescription for an antidepressant do not take it. This is expected to bias results toward the null. To address this, we required 2 dispensings during the exposure window to meet the exposure definition.

Interpretation

In interpretation of the results, we focused on estimating magnitude of associations in preference to dichotomizing the results as statistically significant or not.¹⁶ Specifically, we judged estimates to be similar or different from the reference group by 3 criteria: (1) strength of the adjusted HR (regardless of whether the 95% CI included the null), (2) degree to which the upper bound of the 95% CI indicated low compatibility between the data and strong adverse effects (ie, the upper bound of the 95% CI excludes a large increase in the risk of NDD), and (3) consistency of the estimates across multiple approaches to confounding adjustment.

All analyses were conducted using SAS, version 9.4 (SAS Institute Inc), and R, version 4.0.3 (R Foundation). No adjustments were made for multiple comparisons.

Results

There were 93 069 and 52 633 pregnancies with exposure to antidepressants in late pregnancy and 1 833 927 and 1 198 818 pregnancies unexposed to antidepressants in the MAX and MarketScan cohorts, respectively. Select characteristics of the pregnant individuals are presented in the Table¹⁷ (all characteristics are summarized in eTables 13 and 14 in the Supplement; early pregnancy exposure characteristics are summarized in eTables 15 and 16 in the Supplement). Across both populations, individuals exposed to antidepressants were older and had greater medication use during pregnancy than unexposed individuals. In the MAX population, antidepressant-exposed individuals were also more likely to be White. After PS weighting, all characteristics were balanced between groups (Table and eTables 13 and 14 in the Supplement).

Table. Select Characteristics of the Cohort for Individuals Exposed to Antidepressants During Late Pregnancy and Individuals Unexposed to Antidepressants Throughout Pregnancy by Data Source.

Characteristic	MAX				MarketScan
	No. (%)		Standard difference, %		No. (%)		Standard difference, %
	Exposed (n = 93 069)	Unexposed (n = 1 833 927)	Crude	Weighted	Exposed (n = 52 633)	Unexposed (n = 1 198 818)	Crude	Weighted
Age, mean (SD), y	26.2 (5.7)	24.3 (5.8)	32.7	4.2	32.7 (4.6)	31.9 (4.6)	17.7	0.5
Race and ethnicity^a^,^b
Asian or Other Pacific Islander	883 (0.9)	73 042 (4.0)	−19.7	2.5	NA	NA	NA	NA
Black or African American	13 642 (14.7)	645 600 (35.2)	−48.9	3.6	NA	NA	NA	NA
Hispanic or Latino	5067 (5.4)	279 317 (15.2)	−32.6	3.6	NA	NA	NA	NA
White	67 389 (72.4)	680 748 (37.1)	75.8	−5.7	NA	NA	NA	NA
Unknown or other	6088 (6.5)	155 220 (8.5)	−7.3	1.1	NA	NA	NA	NA
Indications
Depression	43 721 (47.0)	82 232 (4.5)	111.2	5.6	18 305 (34.8)	34 328 (2.7)	90.4	0.6
Anxiety	24 222 (26.0)	55 849 (3.0)	69.0	−0.3	12 349 (23.5)	27 316 (2.3)	66.7	−3.0
Bipolar disorder	11 771 (12.6)	25 178 (1.4)	45.3	−2.1	2119 (4.0)	2756 (0.2)	26.5	−1.0
Schizophrenia	1218 (1.3)	2726 (0.1)	13.7	−0.7	51 (0.1)	93 (<0.1)	3.9	0.3
Psychosis	1305 (1.4)	4061 (0.2)	13.2	−0.1	145 (0.3)	476 (<0.1)	6.0	−0.3
Other mental health disorders^c	3585 (3.9)	16 483 (0.9)	19.5	0.5	1087 (2.1)	6402 (0.5)	13.6	−1.0
Epilepsy/convulsion	2597 (2.8)	17 701 (1.0)	13.5	−1.1	446 (0.8)	4936 (0.4)	5.5	−0.3
ADHD	2934 (3.2)	10 889 (0.6)	19.0	−1.1	1019 (1.9)	4351 (0.4)	14.8	−0.6
Adjustment disorder	1697 (1.8)	13 412 (0.7)	9.7	−0.7	581 (1.1)	3449 (0.3)	9.8	−0.7
Psychiatric visits
0	79 476 (85.4)	1 789 696 (97.6)	−44.8	−0.8	42 389 (80.5)	1 167 770 (97.4)	−55.9	1.9
1	3579 (3.8)	16 535 (0.9)	19.4	−0.2	1791 (3.4)	5769 (0.5)	21.3	−1.0
2-3	3662 (3.9)	11 254 (0.6)	22.4	0.2	2492 (4.7)	7052 (0.6)	26.0	−0.3
≥4	6352 (6.8)	16 442 (0.9)	31.1	1.1	5961 (11.3)	18 227 (1.5)	40.8	−1.6
Mental health diagnoses
0	41 625 (44.7)	1 625 054 (88.6)	−105.2	2.4	29 921 (56.8)	1 137 078 (94.8)	−99.1	2.7
1	18 301 (19.7)	126 831 (6.9)	38.2	−4.5	9763 (18.5)	37 534 (3.1)	51.2	−5.9
2-3	20 981 (22.5)	65 301 (3.6)	58.7	−1.7	9940 (18.9)	21 930 (1.8)	58.3	0.3
≥4	12 162 (13.1)	16 741 (0.9)	49.1	4.0	3009 (5.7)	2276 (0.2)	33.1	4.0
Mental health ER visits
0	85 412 (91.8)	1 803 275 (98.3)	−30.6	−1.0	51 070 (97.0)	1 194 008 (99.6)	−20.1	−0.6
1	5224 (5.6)	25 482 (1.4)	23.1	−0.2	1099 (2.1)	4134 (0.3)	16.0	−0.2
2-3	2084 (2.2)	4819 (0.3)	17.9	1.4	360 (0.7)	592 (<0.1)	10.5	1.2
≥4	349 (0.4)	351 (<0.1)	8.0	1.8	104 (0.2)	84 (<0.1)	6.0	0.9
Mental health hospitalizations
0	87 502 (94.0)	1 816 957 (99.1)	−28.0	−1.8	51 786 (98.4)	1 197 533 (99.9)	−16.3	−1.4
1	2562 (2.8)	11 636 (0.6)	16.5	0.6	410 (0.8)	787 (0.1)	11.0	0.5
2-3	1976 (2.1)	4248 (0.2)	17.6	1.5	319 (0.6)	418 (<0.1)	10.1	1.3
≥4	1029 (1.1)	1086 (0.1)	13.8	1.2	118 (0.2)	80 (<0.1)	6.4	0.8
Other psychiatric medications
0	71 611 (76.9)	1 790 601 (97.6)	−65.4	−2.0	45 778 (87.0)	1 179 946 (98.4)	−45.1	−1.6
1	7183 (7.7)	21 778 (1.2)	32.1	−1.1	2773 (5.3)	9403 (0.8)	26.4	−0.2
2-3	10 354 (11.1)	17 799 (1.0)	43.6	1.5	3383 (6.4)	8688 (0.7)	31.1	1.3
≥4	3921 (4.2)	3749 (0.2)	27.5	3.4	699 (1.3)	781 (0.1)	15.2	2.3
Lifestyle behaviors
Alcohol abuse	3363 (3.6)	13 921 (0.8)	19.6	0.9	304 (0.6)	806 (0.1)	9.0	0.7
Tobacco use	17 583 (18.9)	137 823 (7.5)	34.1	−2.4	1497 (2.8)	12 022 (1.0)	13.4	−1.5
Substance abuse	10 385 (11.2)	52 472 (2.9)	32.9	−0.3	524 (1.0)	1728 (0.1)	11.3	0.1
Obstetric Comorbidity Index score^d
0	38 972 (41.9)	1 027 424 (56.0)	−28.6	0.7	17 755 (33.7)	526 672 (43.9)	−21.0	1.9
1	21 941 (23.6)	411 137 (22.4)	2.8	0	14 585 (27.7)	316 929 (26.4)	2.9	−0.5
2	15 169 (16.3)	209 624 (11.4)	14.1	−0.5	9614 (18.3)	186 353 (15.5)	7.3	−0.4
≥3	16 987 (18.3)	185 742 (10.1)	23.4	−0.4	10 679 (20.3)	168 864 (14.1)	16.5	−1.3
Other prescription medications
Anticonvulsants	10 448 (11.2)	26 298 (1.4)	41.1	0.5	2878 (5.5)	9325 (0.8)	27.2	0.9
Antipsychotics	10 287 (11.1)	10 544 (0.6)	45.9	2.1	1471 (2.8)	956 (0.1)	23.0	3.5
Anxiolytics	3834 (4.1)	4654 (0.3)	26.7	1.0	1225 (2.3)	1618 (0.1)	20.0	0.6
Benzodiazepines	19 269 (20.7)	33 710 (1.8)	62.5	2.4	9220 (17.5)	33 382 (2.8)	50.3	−0.1
Psychostimulants	3650 (3.9)	9315 (0.5)	23.4	0.1	1660 (3.2)	6951 (0.6)	19.1	−0.8
Opioids	52 341 (56.2)	532 059 (29.0)	57.3	−4.1	16 932 (32.2)	199 561 (16.6)	36.7	−3.9
Corticosteroids	27 599 (29.7)	323 243 (17.6)	28.6	−0.6	15 971 (30.3)	229 744 (19.2)	26.1	−2.5
Antidiabetics	3262 (3.5)	31 978 (1.7)	11.0	−0.3	3191 (6.1)	45 342 (3.8)	10.6	−1.2
Antihypertensives	11 952 (12.8)	94 612 (5.2)	27.1	−0.4	6302 (12.0)	66 183 (5.5)	23.0	−2.0

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Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ER, emergency room; MarketScan, MarketScan Commercial Claims Database; MAX, Medicaid Analytic eXtract; NA, not applicable.

^{^a}

Race and ethnicity were determined on the basis of information submitted to the Centers for Medicare & Medicaid Services by individual states, which was based on information that had been collected and coded from Medicaid applications. The category Other or unknown included individuals who were American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Hispanic or Latino, more than 1 race, and unknown; the category Hispanic or Latino included those with missing race information, whereas data under Other or unknown included Hispanic or Latino with 1 or more races.

^{^b}

Information not available in MarketScan.

^{^c}

Other mental health disorders include delirium, dementia, tic disorder, somatoform spectrum disorder, eating disorder, psychotherapy, and self-inflicted injury.

^{^d}

A comorbidity index as defined by Bateman et al.¹⁷

For all NDD outcomes, the cumulative incidence was higher in the MAX cohort than in the MarketScan cohort (Figure 1 and eFigure in the Supplement). Neurodevelopmental disorders were common among children of individuals with antidepressant exposure; by age 12 years, 46.8% of children (95% CI, 45.6%-48.1%) in the MAX cohort and 24.9% (95% CI, 23.0%-26.9%) in the MarketScan cohort with antidepressant exposure had any NDD, compared with 31.4% (95% CI, 31.1%-31.6%) and 15.1% (95% CI, 14.7%-15.4%), respectively, among unexposed individuals. The most common individual outcome assessed was ADHD; cumulative incidence at 12 years was 33.3% (95% CI, 32.2%-34.5%) and 20.3% (95% CI, 20.0%-20.5%) among children of antidepressant exposed and unexposed individuals, respectively, in MAX, and 17.6% (95% CI, 15.8%-19.5%) and 9.6% (95% CI, 9.3%-10.0%), respectively, in MarketScan. Incidence of ASD was similarly higher among antidepressant-exposed children and publicly insured children; cumulative incidence at 12 years was 4.1% (95% CI, 3.5%-4.7%) and 2.1% (95% CI, 2.0%-2.1%) among children of antidepressant-exposed and unexposed individuals, respectively, in MAX, and 2.9% (95% CI, 2.4%-3.6%) and 1.6% (95% CI, 1.4%-1.7%), respectively, in MarketScan.

Crude HRs for all NDD outcomes suggested an increase in risk, with HRs ranging from 1.32 for specific learning disorders to 2.02 for ADHD, among children exposed to antidepressants in utero compared with unexposed children (Figure 2). Adjustment for measured covariates and proxies for unmeasured covariates via HDPS resulted in substantial attenuation of HRs for all NDDs; estimates from the adjusted analysis ranged from 1.01 (specific learning disorders) to 1.20 (ADHD). When comparing with children of individuals who discontinued use of antidepressants prior to pregnancy, HRs were consistent with the adjusted and HDPS results or further attenuated for all NDD outcomes. The sibling analyses indicated no increased risk for any of the outcomes. Sensitivity analyses for the sibling design did not suggest that carryover effects from the exposure in the first pregnancy to the outcome in the second pregnancy were present (eTable 17 in the Supplement). Additional results for the sibling analyses are available in eTables 21 and 22 in the Supplement.

Figure 2. — The exposed cohort is measured by antidepressant dispensing in late pregnancy. For all analyses except the discontinuer referent, the referent is defined as no antidepressant dispensing from 90 days prior to last menstrual period (LMP) through 1 day prior to delivery. For the discontinuer referent analysis, the referent is defined as antidepressant dispensing in the 31 to 90 days prior to LMP but no dispensing from 30 days prior to LMP through the day prior to delivery. The high-dimensional propensity score (HDPS) analysis used an 80% random sample of the unexposed cohort in the Medicaid Analytic eXtract data owing to sample size constraints in the SAS macro (SAS Institute) used for HDPS analysis. Results from the crude and adjusted analysis using the 80% sample of the referent cohort were very similar to the main results. Event counts for all adjusted analyses are based on the cohort after trimming of nonoverlapping regions of the propensity scores. Counts for the sibling analysis are based on families that had discordance on both antidepressant exposure status and outcome timing. ADHD indicates attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder.

Results by antidepressant class and individual drugs are presented in Figure 3 and eTables 5 through 12 in the Supplement (characteristics are summarized in eTables 18 and 19 in the Supplement). Results for the composite outcome of any NDD indicate no meaningful increase in risk for any of the classes or drugs, with the possible exception of escitalopram. Comparison of escitalopram results across all outcomes evaluated revealed adjusted HRs that tended to be slightly higher than estimates for other drugs and classes. The evidence for ASD, ADHD, specific learning disorders, intellectual disability, developmental speech/language disorder, and behavioral disorders suggests no increased risk that is consistent across all analyses for any class or drug (eTables 5-12 in the Supplement). For developmental coordination disorder, point estimates were elevated in the adjusted analysis and in both discontinuer referent analyses for some individual antidepressants considered, but HRs were imprecisely estimated (eTables 9-12 in the Supplement).

When exposure to antidepressants was defined by dispensings in the first half of pregnancy, 129 358 exposed pregnancies in MAX and 69 138 exposed pregnancies in MarketScan were available for analysis. Results were similar to the main analysis (Figure 4). The discontinuer referent and sibling analyses similarly resulted in null estimates for all outcomes. When antidepressant exposure was defined as only in late pregnancy or only in early pregnancy, results were similar to the main results for each exposure window (eTable 20 in the Supplement). Results from analyses requiring 2 fills of an antidepressant to meet the exposure definition were also consistent with those of the main analysis (eTable 3 in the Supplement).

Figure 4. — The exposed cohort is measured by antidepressant dispensing in early pregnancy, and the referent is measured by no antidepressant dispensing from 90 days prior to last menstrual period (LMP) through 1 day prior to delivery. For the discontinuer referent analysis, the referent is defined as antidepressant dispensing in the 31 to 90 days prior to LMP but no dispensing from 30 days prior to LMP through the day prior to delivery. Event counts for all adjusted analyses are based on the cohort after trimming of nonoverlapping regions of the propensity scores. Counts for the sibling analysis are based on families that had discordance on both antidepressant exposure status and outcome timing. ADHD indicates attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder.

Discussion

In this study of 2 large cohorts of publicly and privately insured parent-child pairs, individuals using antidepressants during pregnancy had a higher risk of having a child with an NDD than individuals not using antidepressants. After adjustment for an extensive list of measured potential confounders, elevated crude HRs shifted substantially toward the null. Comparing with antidepressant discontinuers further shifted estimates to the null, and comparison with unexposed siblings resulted in null estimates for all outcomes. These results point to an increased risk of NDDs owing to factors associated with antidepressant use during pregnancy, but not the medication itself.

Autism spectrum disorder is the most widely studied NDD in relation to antidepressant exposure during pregnancy. Studies using population-based registries in Nordic countries and Canadian provinces have reported estimates of a 20% to 80% increase in ASD risk with antidepressant exposure.^{18,19,20,21,22,23,24,25} Sensitivity analyses suggested that uncontrolled confounding by indication and environment may be a likely explanation in some^21,22,23,25 but not all of these studies.^18,20 Using a broad range of confounding variables, we did not observe an association after adjustment.

Prior studies of the risk of ADHD have also been conflicting, suggesting either no association with antidepressant exposure,^26,27 an increase in risk,^28,29,30 or an increase in risk when comparing with unexposed children that was not sustained in sensitivity analyses.^22,23,31,32 Consistent with this latter group of studies,^22,23,31,32 the association we observed after adjustment for measured confounders was no longer present in analyses that targeted residual confounding by using discontinuer referents or sibling analyses.

Previous studies evaluating the risk of other NDDs have tended to be small and hospital, clinic, or classroom based, and often did not adjust for confounders.^10,11 Prenatal exposure to antidepressants has been associated with various neurodevelopmental characteristics at different time points in childhood: in the first year of life as a risk factor for delayed motor development and motor control^33,34,35 and longer-term risks in the domains of intelligence, social problems, anxiety/depression, and internalizing problems.^36,37 However, the outcomes are too diverse and the studies are too heterogeneous to draw clear conclusions.^10,11 The present results suggest no association between antidepressant use and specific learning disorders, developmental speech/language disorders, intellectual disabilities, and behavioral disorders.

While the class and drug-specific results showed some residual associations in the adjusted analyses and discontinuer analyses for developmental coordination disorder, it is unlikely that these associations are causal. The adjusted and discontinuers analysis for antidepressants overall similarly showed an association, but this was no longer present when accounting for shared environmental and genetic factors in the sibling analysis. While sample size was not adequate to repeat sibling analyses for individual drugs, it is likely that drug-specific sibling comparisons would have resulted in a similar shift to the null.

Compared with exposure to other specific antidepressant classes and drugs, exposure to escitalopram resulted in slightly elevated HRs for all outcomes except for ASD. We did not observe clear differences in patient characteristics (eTables 18 and 19 in the Supplement) that might explain these associations, and all measured covariates were balanced after PS weighting. In a Danish study, no association was found between escitalopram users and antidepressant discontinuers for the outcome of any psychiatric disorders in children.¹⁹ In contrast with the present null results for ASD, an analysis of Swedish mother-child pairs reported an association between citalopram and escitalopram use and ASD, but not with other selective serotonin reuptake inhibitors.²⁴ Further investigation of the association with escitalopram may be warranted.

Limitations

Some limitations of the data and design must be noted. Records of antidepressant dispensing are used as a proxy for actual medication use. However, sensitivity analyses that required 2 fills during the exposure window were consistent with the main results. Most children ended follow-up much sooner than the maximum of 14 years because of administrative censoring (Figure 1). Previous analyses of this cohort found no evidence of informative censoring because of loss of insurance enrollment,³⁸ and follow-up did not differ by antidepressant exposure status. Survival analyses properly account for noninformative, right censoring. Outcomes were defined using algorithms with high positive predictive values, which minimizes the potential bias owing to outcome misclassification. However, in the absence of universal screening for these outcomes, it is possible that parental depression status effects the likelihood of diagnosis and results in differential outcome misclassification. We see no evidence in the present data, however, that individuals with depression are less likely to bring their children in for well-child visits where screening would occur (eTables 13-16 in the Supplement). Despite the extensive list of confounders considered, residual confounding by imperfectly measured variables (eg, lifestyle factors, mental health) and unmeasured factors (eg, childhood environment) may be present. Results from the sibling analysis suggested that there is no association between antidepressant use and any neurodevelopmental outcome. Sibling analyses are useful to control residual confounding that is not easily measured in conventional analysis, such as genetic and environmental factors. However, other potential explanations for this result must be acknowledged. Siblings that differ in exposure status are expected to differ strongly on other nonshared confounders, which can lead to more bias than in the full population analysis.³⁹ However, adjustment for all measured covariates in the sibling analysis resulted in little difference in HR estimates from the crude results (eTable 21 in the Supplement). Sibling comparisons are also more susceptible to exposure misclassification owing to the comparison of siblings with nonshared causes of exposure,^39,40 which may bias estimates toward the null. Sibling comparisons control for shared mediators by design and therefore provide an estimate of the direct causal effect, which could result in the attenuation we observed.⁴¹ Finally, while sibling comparisons are vulnerable to carryover effects,¹⁵ such effects are implausible for in utero antidepressant exposure, and the present analyses ruled out the likelihood that exposure in the first pregnancy had consequences on the outcome in the second pregnancy. In summary, the sibling analyses increased our confidence in the conclusion that there is no association between in utero exposure to antidepressants and NDDs in the offspring.

Conclusions

Results of this cohort study suggest that antidepressant use in pregnancy does not increase the risk of NDDs in children. However, elevated crude cumulative incidence estimates for NDDs suggest that antidepressant use by pregnant individuals is a robust marker of NDD risk in children. Therefore, antidepressant exposure during pregnancy could be an important marker for early screening and intervention in children, with the goal of improving outcomes for NDDs.

Supplement.

eMethods. Additional methods and results for the sibling analyses

eTable 1. Outcome definitions for neurodevelopmental disorders

eTable 2. Full list of covariates included in propensity score models and assessment periods

eTable 3. Hazard ratios and 95% confidence intervals for antidepressant use in late pregnancy and neurodevelopmental disorders for the main analysis and sensitivity analyses, by data source

eTable 4. Hazard ratios and 95% confidence intervals for antidepressant use in early pregnancy and neurodevelopmental disorders for the main analysis and sensitivity analyses, by data source

eTable 5. Hazard ratios and 95% confidence intervals for SSRI use in late pregnancy and neurodevelopmental disorders, by data source

eTable 6. Hazard ratios and 95% confidence intervals for SNRI use in late pregnancy and neurodevelopmental disorders, by data source

eTable 7. Hazard ratios and 95% confidence intervals for TCA use in late pregnancy and neurodevelopmental disorders, by data source

eTable 8. Hazard ratios and 95% confidence intervals for sertraline use in late pregnancy and neurodevelopmental disorders, by data source

eTable 9. Hazard ratios and 95% confidence intervals for fluoxetine use in late pregnancy and neurodevelopmental disorders, by data source

eTable 10. Hazard ratios and 95% confidence intervals for bupropion use in late pregnancy and neurodevelopmental disorders, by data source

eTable 11. Hazard ratios and 95% confidence intervals for citalopram use in late pregnancy and neurodevelopmental disorders, by data source

eTable 12. Hazard ratios and 95% confidence intervals for escitalopram use in late pregnancy and neurodevelopmental disorders, by data source

eTable 13. Characteristics of the cohort for individuals exposed to antidepressants during late pregnancy and individuals unexposed to antidepressants throughout pregnancy, in MAX, crude and propensity score weighted results

eTable 14. Characteristics of the cohort for individuals exposed to antidepressants during late pregnancy and individuals unexposed to antidepressants throughout pregnancy, in MarketScan, crude and propensity score weighted results

eTable 15. Characteristics of the cohort for individuals exposed to antidepressants during early pregnancy and individuals unexposed to antidepressants throughout pregnancy, in MAX, crude and propensity score weighted results

eTable 16. Characteristics of the cohort for individuals exposed to antidepressants during early pregnancy and individuals unexposed to antidepressants throughout pregnancy, in MarketScan, crude and propensity score weighted results

eTable 17. Sibling analysis for antidepressant use during late pregnancy and NDDs stratified by exposure status of first sibling, to investigate carry-over effects

eTable 18. Characteristics of the cohort for individuals exposed to specific antidepressant classes or drugs during late pregnancy, in MAX

eTable 19. Characteristics of the cohort for individuals exposed to specific antidepressant classes or drugs during late pregnancy, in MarketScan

eTable 20. Hazard ratios and 95% confidence intervals for antidepressant exposed exclusive to early or late gestational windows and neurodevelopmental disorders, results pooled across data sources

eTable 21. Counts and crude and adjusted HR (95% CI) for sibling analysis for antidepressant use during late and early pregnancy compared to unexposed, pooled MAX and MarketScan data

eTable 22. Crude and adjusted HR (95% CI) within the full sibling population for antidepressant use during late pregnancy compared to unexposed, pooled MAX and MarketScan data

eFigure. Unadjusted cumulative incidence of select neurodevelopment disorders stratified by antidepressant exposure status during pregnancy and data source

Click here for additional data file.^{(980.8KB, pdf)}

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