The association of risk factors, circulatory biomarkers and antihypertensive medications with preeclampsia: a Mendelian randomisation analysis.

Background: While many risk factors for pre-eclampsia (PE) have been identified, their causal role and the potential preventive effects of specific antihypertensive drug classes remain unclear. Methods: We examined the potential causal effect of 22 risk factors and two genetically proxied antihypertensive drugs (Beta-blockers and Calcium channel blockers) on PE development and its two related conditions, PE-HTP (PE or other maternal hypertension) and PE-SGA (PE or delivery of a small for gestational age neonate). Using summary statistics from published genome-wide association studies, we employed two-sample Mendelian randomization (MR) using Wald ratio or inverse variance weighted. MR Egger, weighted median and MR-PRESSO (Pleiotropy RESidual Sum and Outlier) were applied and Multivariable MR (MVMR) was also used. Results: Maternal body mass index (BMI), systolic blood pressure (SBP) and diastolic BP (DBP) were significantly associated with all PE outcomes. Higher BMI was associated with increased risk of PE (Odds ratio (OR)=1.50, P=1.58×10⁻⁸), PE-HTP (OR=1.72, P=1.04×10⁻¹⁷) and PE-SGA (OR=1.35, P=2.06×10⁻⁵). Elevated SBP showed strong associations with PE (OR=2.74, P=3.90×10⁻²⁶), PE-HTP (OR =3.64, P=4.23×10⁻³⁷) and PE-SGA (OR=2.21, P=5.01×10⁻¹⁸). Increased DBP was significantly linked to PE (OR=2.33, P=7.03×10⁻¹⁷), PE-HTP (OR=3.08, P=9.59×10⁻²⁷) and PE-SGA (OR=2.04, P=8.38 × 10⁻¹⁴). Age at menarche was associated with PE-HTP, but this effect was mediated by BMI. Genetically proxied calcium channel blockers were linked to reduced risk of PE and PE-HTP (OR per DBP mmHg reduction: 0.37, P=0.004 and 0.23, P=1.90×10-4, respectively). Conclusions: The findings validate the significant role of cardiovascular factors in the PE pathogenesis and highlight new therapeutic possibilities. Keywords: Mendelian randomization, pre-eclampsia, maternal hypertension, small for gestational age neonate, cardiovascular factors, antihypertensive drugs