Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia

Pre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.

Two-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p < 5 × ^-8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p < 0.0083 considered significant evidence and a p within 0.083-0.05 considered suggestive evidence.

Critical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03-1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01-1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.

Our investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose-response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.