Abstract
BACKGROUND: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear.
OBJECTIVES: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference.
DESIGN: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis.
SETTING: This took place in UK general practice.
PARTICIPANTS: Participants were pregnant women with depression.
INTERVENTIONS: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation.
MAIN OUTCOME MEASURES: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability.
DATA SOURCES: UK Clinical Practice Research Datalink.
RESULTS: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratio initiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratio continuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratio multivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratio propensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratio multivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratio propensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratio multivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratio propensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratio multivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratio propensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers.
LIMITATIONS: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured.
CONCLUSIONS: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation.
FUTURE WORK: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns.
FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.
| Original language | English |
|---|---|
| Pages (from-to) | 1-83 |
| Number of pages | 83 |
| Journal | Health Technology Assessment |
| Volume | 27 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 24 Oct 2023 |
Bibliographical note
Funding Information:The research reported in this issue of the journal was funded by the HTA programme as project number 15/80/19. The contractual start date was in August 2017. The draft report began editorial review in May 2021 and was accepted for publicaD鸀on in May 2022. The authors have been wholly responsible for all data collecD鸀on, analysis and interpretaD鸀on, and for wriD鸀ng up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their construcD鸀ve comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
Funding Information:
This project was funded by the NaD鸀onal InsD鸀tute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project informaD鸀on.
Funding Information:
This project benefited from valuable paD鸀ent and public involvement (PPI) from the very outset at the applicaD鸀on for funding stage. We received important feedback on the study plan and design at the funding applicaD鸀on stage from leaders of two perinatal mental health chariD鸀es – Mothers for Mothers (Bristol, UK) (Mrs Maria Viner) and Bluebell Care (Bristol, UK) (Mrs Ruth Jackson). Following oject athe pr aw as rMd, Mr riaao-ledc the PPIV isnterr oject athis porrfegtys rClawith Mlong yeorte Sir who has significant experience of PPI in research. A bespoke PAG comprising women who have had lived experience of perinatal depression and had faced decision-making regarding medicaD鸀ons during pregnancy was set up and three meeD鸀ngs were held where our PPI co-leads facilitated a discussion around important issues in relaD鸀on to this project. Our co-leads purposefully recruited women known to the charity who were well and not currently in the decision-making process around medicaD鸀on use during pregnancy to ensure their well-being. The co-leads took parD鸀cular care to ensure that the members of the PAG were supported during and after each group meeD鸀ng in case any distressing issues arose.
Funding Information:
This research was also supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS FoundaD鸀on Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Publisher Copyright:
Copyright © 2023 Heuvelman et al.
Keywords
- Humans
- Child
- Female
- Pregnancy
- Intellectual Disability/drug therapy
- Antidepressive Agents/adverse effects
- Autistic Disorder
- Family
- Technology Assessment, Biomedical
