Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations
Abstract Background Antidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect th...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | BMC Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12916-017-0993-3 |
| _version_ | 1811229100278284288 |
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| author | Daniel R. Morales Jim Slattery Stephen Evans Xavier Kurz |
| author_facet | Daniel R. Morales Jim Slattery Stephen Evans Xavier Kurz |
| author_sort | Daniel R. Morales |
| collection | DOAJ |
| description | Abstract Background Antidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies. Methods A review of MEDLINE and EMBASE identified case–control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups. Results A total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31–1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29–1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08–1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91–1.52) and sibling studies (0.96, 95% CI 0.65–1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13–1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14–1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31–2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77–1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70–1.11 (sibling studies). Conclusions Existing observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data. |
| first_indexed | 2024-04-12T10:08:47Z |
| format | Article |
| id | doaj.art-636402234e73490ca9a39d303dfba7e9 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-12T10:08:47Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-636402234e73490ca9a39d303dfba7e92022-12-22T03:37:22ZengBMCBMC Medicine1741-70152018-01-0116111410.1186/s12916-017-0993-3Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerationsDaniel R. Morales0Jim Slattery1Stephen Evans2Xavier Kurz3Pharmacovigilance and Epidemiology Department, European Medicines Agency, 30 Churchill PlacePharmacovigilance and Epidemiology Department, European Medicines Agency, 30 Churchill PlaceDepartment of Medical Statistics, London School of Hygiene and Tropical Medicine, University of LondonPharmacovigilance and Epidemiology Department, European Medicines Agency, 30 Churchill PlaceAbstract Background Antidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies. Methods A review of MEDLINE and EMBASE identified case–control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups. Results A total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31–1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29–1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08–1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91–1.52) and sibling studies (0.96, 95% CI 0.65–1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13–1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14–1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31–2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77–1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70–1.11 (sibling studies). Conclusions Existing observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.http://link.springer.com/article/10.1186/s12916-017-0993-3AutismAttention Deficit Hyperactivity DisorderPregnancyAntidepressantMeta-analysisEpidemiology |
| spellingShingle | Daniel R. Morales Jim Slattery Stephen Evans Xavier Kurz Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations BMC Medicine Autism Attention Deficit Hyperactivity Disorder Pregnancy Antidepressant Meta-analysis Epidemiology |
| title | Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations |
| title_full | Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations |
| title_fullStr | Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations |
| title_full_unstemmed | Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations |
| title_short | Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations |
| title_sort | antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder systematic review of observational studies and methodological considerations |
| topic | Autism Attention Deficit Hyperactivity Disorder Pregnancy Antidepressant Meta-analysis Epidemiology |
| url | http://link.springer.com/article/10.1186/s12916-017-0993-3 |
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