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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Medicine 1/2018

Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations

Zeitschrift:
BMC Medicine > Ausgabe 1/2018
Autoren:
Daniel R. Morales, Jim Slattery, Stephen Evans, Xavier Kurz
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s12916-017-0993-3) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Table S1. Variation in comparison and reference groups analysed among observational studies measuring the association between antidepressant exposure during pregnancy and risk of ASD and ADHD in offspring. Table S2. Crude and adjusted effect estimates for the different comparator and reference groups in included observational studies measuring the association between antidepressant exposure and risk of ASD (fixed-effect model). Table S3. Pooled crude and adjusted effect estimates for the different comparator and reference groups in included observational studies measuring the association between antidepressant exposure and risk of ADHD (fixed-effect model). Table S4. Effect estimates when analyses were replaced with other studies using data from Denmark and Sweden. Table S5. Adjusted effect estimates for the different comparator groups in included studies measuring the association between antidepressant exposure and risk of ASD and ADHD substituting estimates for SSRI exposure with any antidepressant exposure. Table S6. Adjusted effect estimates for the different comparator groups in included studies measuring the association between antidepressant exposure and risk of ASD, by study design. Table S7. Adjusted effect estimates for the different comparator groups in included studies measuring the association between antidepressant exposure and risk of ADHD, by study design. Table S8. Risk of bias among primary studies measuring the association between maternal antidepressant exposure during pregnancy and risk of ASD in offspring. Table S9. Risk of bias among primary studies measuring the association between maternal antidepressant exposure during pregnancy and risk of ADHD in offspring. (DOCX 36 kb)
12916_2017_993_MOESM1_ESM.docx
Additional file 3: Figure S2. Adjusted effect estimates for the risk of ASD associated with maternal antidepressant exposure during pregnancy compared to unexposed women by trimester. (TIF 304 kb)
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Additional file 4: Figure S3. Adjusted effect estimates for the risk of ADHD associated with maternal antidepressant exposure during pregnancy compared to unexposed women by trimester. (TIF 285 kb)
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Additional file 5: Figure S6. Adjusted effect estimates for the risk of ASD associated with maternal antidepressant exposure during pregnancy compared to unexposed women according to study design. (TIF 274 kb)
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Additional file 6: Figure S7. Adjusted effect estimates for the risk of ADHD associated with maternal antidepressant exposure during pregnancy compared to unexposed women according to study design. (TIF 229 kb)
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Additional file 7: Figure S4. Adjusted effect estimates for the risk of ASD associated with maternal antidepressant exposure during pregnancy compared to unexposed women by trimester (fixed-effect analysis). (TIF 301 kb)
12916_2017_993_MOESM7_ESM.tif
Additional file 8: Figure S5. Adjusted effect estimates for the risk of ADHD associated with maternal antidepressant exposure during pregnancy compared to unexposed women by trimester (fixed-effect analysis). (TIF 281 kb)
12916_2017_993_MOESM8_ESM.tif
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