Placental weight may influence preeclampsia or eclampsia risk through modulating lipid metabolism: a mediation Mendelian randomization analysis.

INTRODUCTION

Preeclampsia/eclampsia (PE/E) is a leading cause of maternal and perinatal morbidity and mortality and is closely linked to placental dysfunction and maternal metabolic disturbance. Although abnormal lipid profiles are consistently observed in PE/E, whether placental growth - proxied by placental weight (PW) - causally influences PE/E risk through lipid metabolism remains unclear.

METHODS

We performed two-sample Mendelian randomization (MR) using summary statistics from a genome-wide association study (GWAS) of PW in term singleton pregnancies (19,861 child-mother-father trios), nuclear magnetic resonance (NMR)-based metabolic biomarkers in UK Biobank (∼120,000 participants of European ancestry), and PE/E GWAS data from FinnGen (9717 cases and 259,181 controls). We assessed (i) PW → PE/E, (ii) PW → 249 metabolic biomarkers, and (iii) biomarker → PE/E. Multiple testing across biomarkers was controlled using false discovery rate (FDR). Candidate mediators were taken forward to mediation analyses using two-step MR (product-of-coefficients) and multivariable MR (MVMR) as a sensitivity analysis to estimate direct effects.

RESULTS

Genetically predicted higher PW (maternal genetic component) was associated with lower PE/E risk (inverse-variance weighted odds ratio (OR) per 1 SD increase in PW = 0.52, p = 0.013). PW was associated with a subset of lipid-related biomarkers after FDR correction, predominantly very large high-density lipoprotein (HDL) lipid components. Mediation analyses were consistent with partial mediation via very large HDL lipids, including total lipids (estimated mediated proportion ∼10.4%), cholesteryl esters (∼3.9%), and phospholipids (∼3.4%).

CONCLUSION

These MR findings support a protective association of higher PW with PE/E risk and are consistent with a partial contribution of very large HDL lipid pathways. Given the assumptions of MR mediation and the possibility of overlapping metabolic pathways, these results should be interpreted as evidence consistent with mediation rather than definitive mechanistic proof.