Abstract
Background:
The present study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitors (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 2003–2011. Final study group classifications of ASD (n=1367), DD (n= 1750), and general population controls (POP)(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 DD (vs. POP) with maternal psychiatric condition 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 DD than POP controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio (aOR)=1.81, 95% confidence interval (CI) 1.44–2.27) as in mothers who did use SSRIs (aOR=2.05, 95% CI 1.50–2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (aOR=1.14, 95% CI 0.8–1.62). Primary findings for DD 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, SSRIs, antidepressants, psychiatric conditions, perinatal, developmental disorders, Antidepressants, Autism, Neurodevelopmental Disorders, Perinatal Exposure, Psychiatric Conditions, SSRIs
INTRODUCTION
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 last two decades, ASD prevalence has risen globally (1), including rapid increases in the United States where the prevalence now stands at 1 in 59 8-year-olds (2). Both genetic and environmental factors appear to shape ASD risk, though the mechanisms of their interplay remain elusive (3). Much research has focused on ASD’s origins during gestation, when the developing brain may be particularly sensitive to environmental perturbations (3).
Selective serotonin reuptake inhibitors (SSRIs), commonly the first-line treatment for depression in the general adult population (4) but approved for a variety of psychiatric indications, are used by an estimated 6% of pregnant women in the United States (5–7) and can cross the placenta (8). Prenatal exposure to SSRIs has been linked to modest increases in risk of multiple adverse birth outcomes (9–13). Studies in animal models indicate that prenatal SSRI exposure may cause abnormal social-emotional behaviors in offspring (14, 15), suggesting that neurodevelopment may also be a sensitive endpoint 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 (16, 17). 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 due to the intractable correlation between SSRIs and their psychiatric indications (18). Several studies have reported adverse relationships between SSRIs and ASD that often diminish or disappear after accounting for the mother’s psychiatric condition (19–22) or when comparing siblings discordant on prenatal SSRI exposure (23–26). 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 (27–32).
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 US sample with relatively high SSRI use, reflecting modern trends. Additionally, our analyses focused on exposure during vulnerable developmental windows, risk heterogeneity by ASD subtypes, and specificity in comparison to other developmental delays and disorders (DD).
METHODS AND MATERIALS
Study Population
The Study to Explore Early Development (SEED) is a multi-site, case-control study of ASD and other DD in six sites across the United States: California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania (33). Briefly, eligible children were born between 2003–2006 (SEED 1) or 2008–2011 (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 DD such as language delay or intellectual disability (DD controls – details summarized in Schendel et al., 2012 (33)), and children from the general population (POP controls). Children with ASD and DD 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 multi-stage process, using gold standard clinical assessments, to determine their final study group classification (ASD, DD, or POP) (34). First, the primary caregiver (the biological mother for 99.5%) completed the Social Communication Questionnaire (SCQ) (35) about the child during the enrollment telephone call. Children who scored >=11 on the SCQ (36) 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 (ADOS) (37), the Autism Diagnostic Interview Revised (ADI-R) (38, 39), the Mullen Scales of Early Learning (MSEL) (40), and the Vineland Adaptive Behavior Scales-Second Edition (VABS-II) (41). All other children were evaluated with the MSEL, followed by the VABS-II if the MSEL standard score was <78. Children in the final ASD group (n=1429) met ASD diagnostic criteria on the ADOS and either the full ASD diagnostic criteria on the ADI-R or one of three alternate criteria on the ADI-R, as detailed in Wiggins et al. (34) The ASD group was further subtyped by 1) the presence or absence of co-occurring intellectual disability (ID) defined by MSEL composite standard scores <=70; 2) their ADOS 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 who 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 of 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 (ADHD), 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 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 5 prenatal periods: 3 months pre-conception, 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, and 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, we examined crude differences in the distribution of demographic characteristics, maternal psychiatric conditions, and prenatal SSRI use across the child outcome groups using chi-square 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 three 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 vs. 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 1,367 children with ASD, 1,750 with DD, and 1,671 POP controls (Supplementary eTable 1). Characteristics of the child, mother and household, most of which differed between groups, are shown in Table 1.
Table 1.
Characteristics of the Study Population, Study to Explore Early Development (SEED), 2002–2006 and 2008–2011 Births (N=4788).
| ASD (N=1367) | DD (N=1750) | POP (N=1671) | ASD vs POP | DD vs POP | ||
|---|---|---|---|---|---|---|
|
|
||||||
| Variable | n (%) | n (%) | n (%) | p-value | p-value | |
|
| ||||||
| Child Sex (Male) | 1115 (81.6) | 1158 (66.2) | 878 (52.5) | <0.001 | <0.001 | |
| Gestational Age | ||||||
| Early Preterm (<=33wks) | 83 (6.1) | 174 (9.9) | 49 (2.9) | <0.001 | <0.001 | |
| Preterm (>33wks & <37wks) | 134 (9.8) | 222 (12.7) | 117 (7.0) | |||
| Term (>=37wks) | 1150 (84.1) | 1354 (77.4) | 1505 (90.1) | |||
| Cesarean-Section Delivery | 564 (41.3) | 689 (39.4) | 544 (32.6) | <0.001 | <0.001 | |
| Plurality | ||||||
| Singleton | 1266 (92.6) | 1623 (92.7) | 1598 (95.6) | <0.001 | <0.001 | |
| Multiple | 101 (7.4) | 127 (7.3) | 73 (4.4) | |||
| Maternal Age (years) | ||||||
| < 25 | 167 (12.2) | 266 (15.2) | 173 (10.4) | 0.03 | <0.001 | |
| 25–29 | 341 (24.9) | 392 (22.4) | 392 (23.5) | |||
| 30–34 | 484 (35.4) | 588 (33.6) | 629 (37.6) | |||
| 35–39 | 287 (21.0) | 398 (22.7) | 398 (23.8) | |||
| >=40 | 88 (6.4) | 106 (6.1) | 79 (4.7) | |||
| Paternal Age (years) | ||||||
| < 25 | 104 (7.6) | 167 (9.5) | 94 (5.6) | <0.001 | <0.001 | |
| 25–29 | 229 (16.8) | 307 (17.5) | 284 (17.0) | |||
| 30–34 | 393 (28.7) | 515 (29.4) | 542 (32.4) | |||
| 35–39 | 336 (24.6) | 426 (24.3) | 485 (29.0) | |||
| >=40 | 305 (22.3) | 335 (19.1) | 266 (15.9) | |||
| Maternal Race | ||||||
| White | 797 (58.3) | 1097 (62.7) | 1239 (74.1) | <0.001 | <0.001 | |
| Black | 321 (23.5) | 389 (22.2) | 232 (13.9) | |||
| Asian | 115 (8.4) | 71 (4.1) | 90 (5.4) | |||
| Hispanic | 69 (5.1) | 91 (5.2) | 41 (2.5) | |||
| Other | 65 (4.8) | 102 (5.8) | 69 (4.1) | |||
| Maternal Education | ||||||
| High School & Less | 177 (12.9) | 308 (17.6) | 153 (9.2) | <0.001 | <0.001 | |
| College | 888 (65.0) | 1001 (57.2) | 952 (57.0) | |||
| Graduate School | 302 (22.1) | 441 (25.2) | 566 (33.9) | |||
| Family Income (During Pregnancy) | ||||||
| <50K | 549 (40.2) | 739 (42.2) | 447 (26.8) | <0.001 | <0.001 | |
| 50–90K | 412 (30.1) | 503 (28.7) | 559 (33.5) | |||
| >90K | 406 (29.7) | 508 (29.0) | 665 (39.8) | |||
| Maternal Smoking (During Preconception + Pregnancy) | ||||||
| Yes | 226 (16.53) | 246 (14.06) | 168 (10.1) | <0.001 | <0.001 | |
| No | 1141 (83.47) | 1504 (85.94) | 1503 (89.9) | |||
| Maternal Hypertension (During Pregnancy) | ||||||
| Yes | 231 (16.90) | 179 (10.23) | 186 (11.1) | <0.001 | <0.001 | |
| No | 951 (69.57) | 871 (49.77) | 1277 (76.4) | |||
| Missing | 185 (13.53) | 700 (40.00) | 208 (12.4) | |||
| Maternal History of Infertility | ||||||
| Yes | 267 (19.53) | 296 (16.91) | 258 (15.4) | 0.009 | 0.002 | |
| No | 1049 (76.74) | 1355 (77.43) | 1357 (81.2) | |||
| Missing | 51 (3.73) | 99 (5.66) | 56 (3.4) | |||
| SEED Years | ||||||
| SEED1 | 628 (45.94) | 915 (52.29) | 867 (51.9) | 0.001 | 0.81 | |
| SEED2 | 739 (54.06) | 835 (47.71) | 804 (48.1) | |||
ASD=Autism spectrum disorder; DD=Developmental disorder; n=Number; 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 DD were more likely than mothers of children in the POP group to have 2+ psychiatric conditions (19% and 17%, respectively, vs. 11%; p<0.001).
Table 2.
Frequency of Maternal Psychiatric Conditions and Antidepressant Use During Pre-Conception and/or Pregnancy, Study to Explore Early Development, 2002–2006 and 2008–2011 Births.
| ASD (n=1367) | DD (n=1750) | POP (n=1671) | ASD vs POP | DD vs POP | |
|---|---|---|---|---|---|
|
|
|||||
| n (%) | n (%) | n (%) | p-value | p-value | |
|
| |||||
| Psychiatric Condition | 500 (36.6) | 593 (33.9) | 455 (27.2) | <0.001 | <0.001 |
| ADHD | 52 (3.8) | 60 (3.4) | 30 (1.8) | 0.001 | 0.003 |
| Anxiety Disorder | 218 (15.9) | 275 (15.7) | 170 (10.2) | <0.001 | <0.001 |
| Bipolar Disorder | 49 (3.6) | 64 (3.7) | 33 (2.0) | 0.007 | 0.003 |
| Depression | 372 (27.2) | 418 (23.9) | 321 (19.2) | <0.001 | 0.001 |
| Eating Disorder | 35 (2.6) | 44 (2.5) | 45 (2.7) | 0.82 | 0.74 |
| Obsessive-Compulsive Disorder | 23 (1.7) | 32 (1.8) | 14 (0.8) | 0.03 | 0.01 |
| Personality Disorder | 9 (0.7) | 14 (0.8) | 6 (0.4) | 0.24 | 0.09 |
| Schizophrenia | 5 (0.4) | 7 (0.4) | 2 (0.1) | 0.25 | 0.11 |
| Sleep Disorder | 109 (8.0) | 116 (6.6) | 68 (4.1) | <0.001 | 0.001 |
| Self-Injuring Behavior | 21 (1.5) | 20 (1.1) | 21 (1.3) | 0.51 | 0.76 |
| Suicide Attempt | 49 (3.6) | 60 (3.4) | 27 (1.6) | 0.001 | 0.001 |
| One Psychiatric Condition | 245 (17.9) | 294 (16.8) | 276 (16.5) | 0.31 | 0.82 |
| 2+ Psychiatric Conditions | 255 (18.7) | 299 (17.1) | 179 (10.7) | <0.001 | <0.001 |
| Antidepressant Use | |||||
| Any Antidepressant | 148 (10.8) | 185 (10.6) | 120 (7.2) | <0.001 | 0.001 |
| SSRI | 128 (9.4) | 171 (9.8) | 99 (5.9) | <0.001 | <0.001 |
| Citalopram | 16 (1.2) | 22 (1.3) | 15 (0.9) | 0.46 | 0.31 |
| Escitalopram | 17 (1.2) | 20 (1.1) | 10 (0.6) | 0.06 | 0.09 |
| Fluoxetine | 29 (2.1) | 36 (2.1) | 21 (1.3) | 0.06 | 0.07 |
| Fluvoxamine | 1 (0.1) | 0 (0.0) | 1 (0.1) | 1.00 | 0.49 |
| Paroxetine | 18 (1.3) | 20 (1.1) | 8 (0.5) | 0.01 | 0.03 |
| Sertraline | 49 (3.6) | 77 (4.4) | 40 (2.4) | 0.05 | 0.001 |
| Name Unknown | 20 (1.5) | 18 (1.0) | 11 (0.7) | 0.03 | 0.24 |
| MAO Inhibitor | 0 (0.0) | 0 (0.0) | 0 (0.0) | ||
| TCA | 3 (0.2) | 2 (0.1) | 3 (0.2) | 0.81 | 0.62 |
| Serotonin Modulator | 9 (0.7) | 9 (0.5) | 5 (0.3) | 0.15 | 0.32 |
| Selective Serotonin | 18 (1.3) | 14 (0.8) | 23 (1.4) | 0.89 | 0.10 |
| Miscellaneous | 3 (0.2) | 3 (0.2) | 0 (0.0) | 0.06 | 0.25 |
ADHD=Attention-deficit/hyperactivity disorder; ASD=Autism spectrum disorder; DD=Developmental disorder; MAO=Monoamine oxidase; n=Number; 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 DD 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 pre-conception and/or pregnancy (Table 3). Most SSRI users during pregnancy had initiated SSRI use before the start of pregnancy (77%). Mothers with 2+ psychiatric conditions were more likely to use SSRIs than mothers with one condition (Supplementary eTable 2). The most common psychiatric conditions among SSRI users were depression (91%) and anxiety (64%).
Table 3.
- Frequency of Maternal SSRI Use During Pre-conception and/or Pregnancy among Women with Any Psychiatric Disorder, Study to Explore Early Development, 2002–2006 and 2008–2011 Births.
| SSRI Usea | ASD | DD | POP | ASD vs POP | DD vs POP |
|---|---|---|---|---|---|
|
| |||||
| n (%b) | n (%b) | n (%b) | p-value | p-value | |
|
| |||||
| Any Psychiatric Condition | 128 (25.6) | 167 (28.2) | 94 (20.7) | 0.07 | 0.005 |
| ADHD | 10 (19.2) | 12 (20.0) | 4 (13.3) | 0.49 | 0.44 |
| Anxiety Disorder | 83 (38.1) | 118 (42.9) | 46 (27.1) | 0.02 | 0.001 |
| Bipolar Disorder | 16 (32.7) | 26 (40.6) | 14 (42.4) | 0.37 | 0.86 |
| Depression | 118 (31.7) | 147 (35.2) | 88 (27.4) | 0.22 | 0.02 |
| Eating Disorder | 11 (31.4) | 10 (22.7) | 5 (11.1) | 0.02 | 0.14 |
| OCD | 8 (34.8) | 9 (28.1) | 4 (28.6) | 0.70 | 0.98 |
| Personality Disorder | 1 (11.1) | 7 (50.0) | 1 (16.6) | 1.00 | 0.32 |
| Schizophrenia | 2 (40.0) | 6 (85.7) | 0 (0.0) | 1.00 | 0.08 |
| Sleep Disorder | 25 (22.9) | 30 (25.9) | 11 (16.2) | 0.28 | 0.13 |
| Self-Injuring Behavior | 9 (42.9) | 6 (30.0) | 4 (19.0) | 0.18 | 0.41 |
| Suicide Attempt | 14 (28.6) | 20 (33.3) | 8 (29.6) | 0.92 | 0.73 |
ADHD=Attention-deficit/hyperactivity disorder; ASD=Autism spectrum disorder; DD=Developmental disorder; n=Number; OCD=Obsessive-compulsive disorder; POP=Population controls; SSRI=Selective serotonin reuptake inhibitor
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).
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 2-fold 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 pre-conception period and all trimesters of pregnancy.
Table 4.
Odds of ASD or DD in Offspring Associated with Maternal Psychiatric Conditions and SSRI Use During Pre-conception and/or Pregnancy, Study to Explore Early Development, 2002–2006 and 2008–2011 Births.
| ASD | DD | POP | ASD vs. POP | DD vs. POP | |
|---|---|---|---|---|---|
|
|
|||||
| nexposed | nexposed | nexposed | Adj-ORc (95% CI) | Adj-ORc (95% CI) | |
|
| |||||
| All Mothers a | |||||
| Maternal Psychiatric Condition (Psy Yes vs. Psy No) | |||||
| T0 | 448 | 550 | 416 | 1.61 (1.36 – 1.91) | 1.41 (1.21 – 1.65) |
| T1 | 293 | 356 | 225 | 1.91 (1.55 – 2.34) | 1.65 (1.36 – 2.01) |
| T2 | 304 | 348 | 218 | 2.04 (1.66 – 2.50) | 1.65 (1.36 – 2.01) |
| T3 | 323 | 368 | 241 | 1.95 (1.60 – 2.38) | 1.59 (1.32 – 1.92) |
| PG | 348 | 404 | 264 | 1.93 (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) | |||||
| T0 | 329 | 392 | 328 | 1.50 (1.25 – 1.81) | 1.28 (1.08 – 1.52) |
| T1 | 179 | 212 | 144 | 1.78 (1.39 – 2.28) | 1.50 (1.19 – 1.90) |
| T2 | 190 | 206 | 140 | 1.96 (1.53 – 2.51) | 1.47 (1.16 – 1.87) |
| T3 | 206 | 221 | 160 | 1.83 (1.45 – 2.32) | 1.41 (1.12 – 1.77) |
| PG | 223 | 248 | 177 | 1.81 (1.44 – 2.27) | 1.44 (1.15 – 1.79) |
| Maternal Psychiatric Condition and Maternal SSRI Use (Psy Yes + SSRI Yes vs. Psy No) | |||||
| T0 | 95 | 137 | 70 | 1.98 (1.42 – 2.77) | 2.10 (1.54 – 2.85) |
| T1 | 86 | 120 | 63 | 1.98 (1.39 – 2.81) | 2.06 (1.49 – 2.86) |
| T2 | 92 | 104 | 64 | 2.04 (1.45 – 2.89) | 1.80 (1.30 – 2.51) |
| T3 | 98 | 109 | 67 | 2.18 (1.56 – 3.05) | 1.77 (1.28 – 2.45) |
| PG | 115 | 145 | 81 | 2.05 (1.50 – 2.80) | 1.92 (1.43 – 2.57) |
| Restricted to Mothers with Psychiatric Condition b | |||||
| Maternal SSRI Use (Psy Yes + SSRI Yes vs. Psy Yes + SSRI No) | |||||
| T0 | 95 | 137 | 70 | 1.36 (0.96 – 1.94) | 1.69 (1.21 – 2.35) |
| T1 | 86 | 120 | 63 | 1.14 (0.76 – 1.72) | 1.46 (0.99 – 2.15) |
| T2 | 92 | 104 | 64 | 1.06 (0.71 – 1.57) | 1.26 (0.85 – 1.87) |
| T3 | 98 | 109 | 76 | 1.19 (0.81 – 1.75) | 1.32 (0.90 – 1.92) |
| PG | 115 | 145 | 81 | 1.14 (0.80 – 1.62) | 1.38 (0.98 – 1.95) |
Adj-OR=Adjusted odds ratio; ASD=Autism spectrum disorder; CI=Confidence interval; DD=Developmental disorder; n=Number; OR=Odds ratio; PG=Anytime during pregnancy; POP=Population controls; SSRI=Selective serotonin reuptake inhibitor; T0=3 months before conception; T1=Trimester one; T2=Trimester two;
T3=Trimester three
Reference group only includes children who were unexposed to both maternal psychiatric condition and SSRIs throughout pre-conception and pregnancy (ASD, n=867; DD, n=1157; POP, n=1216).
Reference group only includes children of mothers with an active maternal psychiatric condition during the specific time period and no SSRI exposure throughout pre-conception 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.
Adjusted ORs were adjusted by the following variables: maternal age (continuous), maternal race, maternal education, family income, and smoking history.
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 (Supplementary Figures 1-4). 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 (Supplementary Figures 2 and 4).
Maternal psychiatric condition and SSRI use generally exhibited similar relationships with DD as with ASD (Table 4), with some exceptions. Maternal psychiatric conditions during preconception and pregnancy, with and without SSRI use, were associated with DD, though 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 DD (aOR=1.69, 95% CI 1.21–2.35); SSRI use by trimester and anytime during pregnancy also showed modestly higher odds of DD, though confidence intervals contained the null. In all time windows, maternal psychiatric conditions, particularly when combined with SSRI use, were associated with higher odds of DD without co-occurring ID but not DD with co-occurring ID (Supplementary Figure 5). In models restricted to mothers with psychiatric conditions, SSRI use also trended with higher odds of DD without co-occurring ID (SSRI use anytime during pregnancy, aOR=1.47, 95% CI 1.03–2.09) but not DD with co-occurring ID. However, confidence intervals in these secondary analyses of DD were wide and overlapping.
DISCUSSION
Our results, from a large and diverse US sample, suggest that mothers with psychiatric conditions during pregnancy, irrespective of SSRI use, had elevated odds of having a child with ASD or DD. Maternal psychiatric conditions during pregnancy were most strongly associated with subtypes of ASD and DD without co-occurring ID. Among mothers with psychiatric conditions during pregnancy, SSRI use was not related to ASD, suggesting that SSRIs may not raise odds of ASD independently of their psychiatric indications; however, we observed that odds of DD, particularly DD without co-occurring ID, were higher in children of mothers who used SSRIs during pre-conception 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 (19–26, 42). 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 (23–26). However, reflecting the mixed evidence of this research area, our findings also contradict several other large studies conducted in Sweden,(30, 43) the Netherlands (44), California (31, 32), Canada (29), and Denmark (27, 28). These positive findings in other studies persisted even after efforts to reduce confounding by indication through adjustment for maternal psychiatric condition (29, 31, 43, 44), restriction to mothers with psychiatric conditions (27–30, 32), and propensity weighting methods (30). 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 the present study) and/or siblings as comparators afford the most rigorous approaches for circumventing issues of residual confounding by psychiatric indication (18). The body of evidence produced from these two methods generally support no association between prenatal SSRI exposure and ASD (18).
Associations between ASD and maternal psychiatric conditions preceding or during pregnancy (20, 45, 46), including depression (24, 43, 44, 47), schizophrenia (48, 49), anxiety (50), and personality disorders (48), 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 (51, 52). Given the significant genetic overlap between various psychiatric conditions and ASD, heritability likely contributes to these relationships (53–55). 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 (56).
Relationships between DD and prenatal SSRIs were overall similar to those observed with ASD, and in agreement with previous null reports of prenatal SSRI use and ADHD (21, 25, 42), DD (32, 57), and ID (27, 58). While secondary findings suggest that maternal SSRI use may be associated with increased odds of DD without ID, the confidence intervals for DD with and without ID overlapped. Due to 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 DD, including motor (32, 59) and speech/language delays (57). In our study, the DD group encompassed heterogenous diagnoses; larger sample sizes of specific DD diagnoses could help clarify these findings. Studies that examine genetic susceptibility for ASD and DD, 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 (30, 43, 46), perhaps indicating a distinct etiologic class compared to conditions with ID, which warrants further research.
The methodological rigor of the present 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 pre-conception 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 from exclusively 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 DD further allowed for evaluation of the specificity of impact of SSRI use on non-ASD neurodevelopmental endpoints. While this study focused specifically on SSRIs, associations with the use of alternative, serotogenically-active antidepressants may be a useful topic in future investigations (60).
The SEED population, representing six different geographic locations across the US, is large and sociodemographically diverse. To enhance generalizability, participants with ASD and DD 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 (33). However, an analysis that compared characteristics of responders and non-responders 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 non-response bias (61). Further, 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 (62). Additionally, rates of maternal SSRI use in the SEED sample were comparable to other US estimates (5–7), 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 DD, who were more likely than mothers of children in the POP group to use SSRIs, 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.
CONCLUSION
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 DD 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.
Supplementary Material
ACKNOWLEDGEMENTS
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 (CA); 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 R01HD087915. 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.
Abbreviations:
- ASD
Autism Spectrum Disorder
- DD
Developmental Delay or Disorder
- ID
Intellectual Disability
- POP
General Population
- SEED
Study to Explore Early Development
- SSRI
Selective serotonin reuptake inhibitors
Footnotes
Disclaimer: 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.
AUTHOR DISCLOSURES
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.
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