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. 2025 Jun;12(2):325-333.
doi: 10.1007/s40801-025-00490-1. Epub 2025 Apr 16.

Evaluation of the Association Between Postpartum Hemorrhage and Antidepressant Use: A Mendelian Randomization Study

Zhenzhen Chen #  1 , Qingqing Lv #  2 , Shiteng Lin  1 , Wanlong Lin  3 , Wei Zhuang  4
Affiliations

Evaluation of the Association Between Postpartum Hemorrhage and Antidepressant Use: A Mendelian Randomization Study

Zhenzhen Chen et al. Drugs Real World Outcomes. 2025 Jun.

Abstract

Background: The relationship between antidepressants, depression, and the incidence of postpartum hemorrhage (PPH) has been reported in observational studies, but the causal link between these factors remains unknown. Clarifying this relationship is important for treating depression during pregnancy and managing PPH.

Objective: We aimed to assess the causal relationship between antidepressants, depression, and PPH using a two-sample Mendelian randomization method.

Methods: Single nucleotide polymorphisms were identified from publicly available genetics summary databases (FinnGen database, access date: 28 December, 2023, version R9, phenocode: ANTIDEPRESSANTS, 195,321 participants; the genome-wide association studies [GWAS] catalog, access date: 3 April, 2024, GWAS ID: ebi-a-GCST90016607; Integrative Epidemiological Unit database, access date: 3 April, 2024, GWAS ID: ieu-a-1187) as alternative exposure factors for antidepressants and depression. Subsequently, inverse variance weighting, Mendelian randomization-Egger regression, weighted median, simple method, and weighted method were employed for Mendelian randomization analyses, and the results were validated for pleiotropy, heterogeneity, and sensitivity.

Results: The analyses employed three sets of genetic tools, comprising two sets of 9 and 32 single nucleotide polymorphisms that are strongly associated with depression and another set of 26 single nucleotide polymorphisms that are associated with antidepressants. The inverse variance weighting indicated that antidepressants are associated with PPH (odds ratio = 1.36, 95% confidence interval 1.10-1.69, p = 0.005). Conversely, none of the five methods of Mendelian randomization analysis identified an effect of depression on PPH.

Conclusions: This Mendelian randomization analysis indicated that antidepressant use is associated with PPH. However, the evidence does not support a causal relationship between depression and PPH.

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Conflict of interest statement

Declarations. Funding: This work was supported by the Young and Middle-aged Talent Cultivation Projects of Fujian Province, China [grant number 2024GGB27], the Young and Middle-aged Talent Cultivation Projects of Xiamen city, China [grant number 2024GZL-GG10], the National Natural Science Foundation of China [grant number 82304629], Fujian Provincial Natural Science Foundation of China [grant number 2024 J08304], and the Natural Science Foundation of Xiamen, China [grant number 3502Z202371048]. Conflict of interest: Zhenzhen Chen, Qingqing Lv, Shiteng Lin, Wanlong Lin, and Wei Zhuang have no conflicts of interest that are directly relevant to the content of this article. Ethics approval: The data utilized in this study are derived from publicly available GWAS summary data. This research has been conducted using publicly available summary statistics. All original studies have been approved by the corresponding ethical review boards, and the participants have provided informed consent. In addition, no individual-level data were used in this study. Therefore, no new ethical review board approval was required. Our study was conducted in accordance with the Declaration of Helsinki. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: The GWAS summary data used in this study are sourced from publicly available online platforms, including the FinnGen database ( https://www.Finngen.fi/access_results ), the GWAS catalog ( https://www.ebi.ac.uk/gwas/ ), and the IEU database ( https://gwas.mrcieu.ac.uk/ ). Code availability: The code is available from the corresponding author. Author contributions: The first draft of the manuscript was written by ZC. Data collection and analysis were performed by QL. SL participated in the data analysis. WZ designed this study and supported this study. WL designed the study and revised the manuscript. All authors commented on previous versions of the manuscript and read and approved the final manuscript.

Figures

Fig. 1
Fig. 1
Scatter plot of the effect of antidepressants on postpartum hemorrhage (PPH). The slope of each line corresponds to the estimated Mendelian randomization (MR) effect from different methods. Each slope represents the estimated MR effect derived from different methods, showing consistency across approaches. SNP single nucleotide polymorphism
Fig. 2
Fig. 2
Forest plot of the effect of antidepressants on postpartum hemorrhage across different methods. Significant associations were observed using inverse variance weighting, while other methods showed similar trends with wider confidence intervals (CIs). OR odds ratio
Fig. 3
Fig. 3
Funnel plot assessing the directional pleiotropy in the Mendelian randomization (MR) analysis of antidepressants on postpartum hemorrhage. The symmetry suggests no substantial pleiotropy or publication bias. 1/SEIV inverse of standard error for instrumental variables, βIV beta coefficient of instrumental variables, PPH postpartum hemorrhage
Fig. 4
Fig. 4
Leave-one-out analysis of single nucleotide polymorphisms (SNPs) in the Mendelian randomization (MR) study of antidepressants on postpartum hemorrhage. Results indicate that no single SNP significantly drives the overall inverse variance weighting estimate, supporting the robustness of the causal inference
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