Herbal, Dietary, and Non-Prescription Medication Use and Spontaneous Abortion: A Case–Control Study with Exploratory Analysis of Pineapple-Associated Molecular Targets

Abstract Background Herbal remedies, selected foods, and non-prescription medications are widely used during pregnancy despite limited evidence regarding their safety. This study examined associations between first-trimester consumption of these products and spontaneous abortion among Iranian women. An exploratory transcriptomic extension investigated predicted pineapple-associated targets and MAPK-related patterns in endometrial datasets from women with recurrent pregnancy loss. Methods In this multicenter case-control study (May 2023–March 2024), 377 women aged 18–45 years were recruited from three prenatal clinics in Tehran, including 167 women with physician-confirmed spontaneous abortion and 210 controls with at least one live birth and no history of abortion. Data on demographic, reproductive, and first-trimester exposure to 45 herbal products, foods, and non-prescription medications were collected using a structured questionnaire. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs), with correction for multiple testing using the Benjamini–Hochberg false discovery rate (FDR). To explore underlying mechanisms, predicted pineapple-associated targets were intersected with lists of differentially expressed genes from GEO datasets (GSE165004 and GSE26787), followed by pathway enrichment analysis. These findings were further assessed using decidual single-cell data to evaluate the common-scale MAPK footprint, and branch-expression. Results In total, 29.97% of participants reported consuming at least one of the evaluated herbal or food items during the first trimester. After adjustment for confounders and multiple comparisons, pineapple consumption was associated with a higher odds of spontaneous abortion (aOR 2.95, 95% CI 1.55–5.64; FDR adjusted P = 0.0276). Twenty candidate genes were shared between the lists of abortion-associated and pineapple-related targets, including six MAPK-associated genes. Additionally, single-cell analysis suggested that the pooled MAPK footprint was lower in abortions. Conclusion Pineapple consumption was associated with higher odds of spontaneous abortion. Exploratory molecular analyses suggested MAPK pathways as a candidate pathway for future investigation, although experimental validation is required to confirm these findings.