Causal Associations between Pre-Pregnancy Obesity Traits and Hypertensive Disorders of Pregnancy: A Two-Sample Mendelian Randomization Analyses.

Background: While observational studies have established associations between pre-pregnancy obesity and hypertensive disorders of pregnancy, the causal nature of this relationship requires elucidation.

Objective: To investigate potential causal effects of pre-pregnancy obesity traits on hypertensive disorders of pregnancy-gestational hypertension, pre-eclampsia, and eclampsia-using genetic epidemiology approaches.

Methods: We performed a comprehensive two-sample Mendelian randomization (MR) analysis leveraging summary statistics from large-scale genome-wide association studies (GWAS). Eleven adiposity-related exposure traits were evaluated: body mass index (BMI), overweight status, obesity (subclassified into grades 1-3), childhood obesity, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), liver fat percentage, visceral adipose tissue volume, and abdominal subcutaneous adipose tissue volume. Primary causal estimates were derived via inverse-variance weighted (IVW) regression, supplemented by sensitivity analyses using MR-Egger and weighted median methods.

Results: Genetic predisposition to elevated BMI, overweight, obesity, obesity class 1, obesity class 2, childhood obesity, WHR, and abdominal subcutaneous adipose tissue volume were linked to increased risks of gestational hypertension and pre-eclampsia. Obesity class 3 also increased the risk of gestational hypertension. Additionally, obesity class 3 and childhood obesity increased the risk of eclampsia. Consistent results were observed using alternative MR methods in sensitivity analyses.

Conclusions: This genetic evidence substantiates causal effects of multidimensional pre-pregnancy adiposity on hypertensive pregnancy complications. Our findings highlight the importance of life-course weight management strategies beginning in childhood and extending through reproductive planning to mitigate risks of pregnancy-related vascular disorders.