Thyroid disorders and pregnancy loss: a bidirectional mendelian randomization exploration

Thyroid hormones are essential for normal pregnancy and fetal development. The relationship between thyroid disease and the risk of spontaneous abortion (SA) and recurrent spontaneous abortion (RSA) has been reported, but causality is unclear. The purpose of this study was to investigate whether there is a causal association between thyroid disorders and SA/RSA. In this bidirectional mendelian randomization (MR) analysis, the causal effects of genetically predicted hyperthyroidism, hypothyroidism on adverse pregnancy outcome including SA and RSA were explored. Statistics on thyroid disorders-associated genetic variants were obtained from the Sakaue’s genome-wide association studies (GWAS). The SA and RSA GWAS from the Laisk’s study and FinnGen cohort were used as outcome data for discovery and replication analyses, respectively. Results were pooled by meta-analysis. A reverse MR analysis was also conducted by treating SA/RSA as the exposure to further substantiate our results. Genetically predicted hypothyroidism showed a modest positive association with SA (OR: 1.024, 95% CI: 1.005–1.043, P = 0.014), though the effect size was small. No significant associations of hypothyroidism with RSA, hyperthyroidism with SA or RSA were found (all P > 0.05). Reverse MR and sensitivity analyses further confirmed the robustness of the results. This study suggests a potential causal role of hypothyroidism in SA, albeit with a limited effect magnitude. There were no significant causal relationships of hypothyroidism with RSA, hyperthyroidism with SA or RSA and SA/RSA with thyroid disorders. Further studies should validate these findings and elucidate the pathophysiological mechanisms behind them.