AI Insight
This study used Mendelian randomization, a genetic epidemiology method, to estimate whether pharmacological lowering of lipoprotein(a) could harm pregnancy or perinatal outcomes. Analyzing data from up to 714,899 women across multiple studies, researchers found no statistically significant causal associations between genetically proxied Lp(a) lowering and any of the 20 adverse pregnancy outcomes examined, including preeclampsia, gestational diabetes, and miscarriage. Some point estimates suggested possible effects on stillbirth, congenital malformation, and gestational age, but these were either small in magnitude or accompanied by wide confidence intervals that preclude firm conclusions.
Why it matters
New Lp(a)-lowering therapies are advancing in clinical development, and establishing their safety during pregnancy is critical before they could be considered in women of childbearing age. These findings provide preliminary reassurance that substantial Lp(a) reduction is unlikely to meaningfully increase pregnancy-related risks, though definitive conclusions await clinical trial data.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Lipoprotein(a) (Lp[a]) is a genetically determined causal and independent cardiovascular risk factor and Lp(a) targeted therapies are being developed. However, evidence on the safety of substantial Lp(a) lowering during pregnancy is limited. We evaluated the impact of Lp(a) lowering on adverse pregnancy and perinatal outcomes (APPOs) using human genetic evidence. Material and Methods: We applied a drug-target Mendelian randomization (MR) approach using genetic variants associated with Lp(a) in the UK Biobank at the LPA locus to proxy pharmacological Lp(a) lowering. Summary-level APPO data were obtained from the MR-PREG collaboration, comprising up to 714,899 women across multiple studies. Twenty APPOs were included. Sensitivity analyses included adjustment for fetal genotype, alternative Lp(a) datasets, leave-one-study-out analyses, and exploration of Lp(a) genetic scores and individuals homozygous for LPA loss-of-function variants in the UK Biobank. Results: Across 20 APPOs, MR estimates showed no strong evidence of causal effects, with no associations surviving false discovery rate P-value correction. Most estimates were close to null, including gestational hypertension, gestational diabetes, preeclampsia, miscarriage and neonatal intensive care unit admission. Some associations were slightly larger in magnitude but with wide confidence intervals: gestational age (mean difference 0.04 weeks, 95% CI 0.02-0.06 per 210nmol/L reduction in Lp[a]) and congenital malformation (OR 0.82, 95% CI: 0.72-0.94) in the protective direction of effect, and higher odds of stillbirth (OR 1.09, 95% CI: 1.00-1.19) and low Apgar at 1 minute (OR 1.11, 95% CI: 0.99-1.24). Sensitivity analyses consistently supported the primary findings, with no evidence of increased maternal nor offspring risk in analyses adjusting for maternal-fetal genotype, across alternative exposure datasets, or in leave-one-study-out tests. Individual-level analyses of Lp(a) genetic score and LPA loss-of-function variants showed no associations, although power was limited. Conclusion: These findings suggest that substantial lowering of Lp(a) is unlikely to increase APPO risk, although modest effects, particularly for rare outcomes, cannot be excluded.