Genetics
Genetic evidence suggests Lp(a) lowering is unlikely to raise pregnancy-complication risk, Mendelian randomisation preprint (medRxiv 2026)
Original title: Using human genetic variation to estimate the effect of lipoprotein(a) lowering on pregnancy outcomes
Preprint drug-target Mendelian randomisation study using LPA-locus genetic variants in UK Biobank to proxy pharmacological Lp(a) lowering, testing effects on 20 adverse pregnancy and perinatal outcomes (APPOs) using summary data from the MR-PREG collaboration (up to 714,899 women). No associations survived false discovery rate correction across the 20 outcomes, with most estimates close to null, including gestational hypertension, gestational diabetes, preeclampsia, miscarriage and neonatal intensive care admission. Some estimates trended toward benefit (longer gestational age, mean difference 0.04 weeks per 210 nmol/L reduction in Lp(a); lower congenital malformation, OR 0.82, 95% CI 0.72-0.94) and some toward harm (higher stillbirth, OR 1.09, 95% CI 1.00-1.19; lower 1-minute Apgar, OR 1.11, 95% CI 0.99-1.24), all with wide confidence intervals. Sensitivity analyses, including fetal-genotype adjustment and LPA loss-of-function carriers, were consistent. The authors conclude substantial Lp(a) lowering is unlikely to meaningfully raise pregnancy-complication risk, though modest effects on rare outcomes cannot be excluded.
Original abstract
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 Method: 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.