The Relationship of Preconception and Early Pregnancy Isoprostanes with Fecundability and Pregnancy Loss

Background: Although redox stress likely plays an important role in reproductive health, the utility of peripheral biomarkers of oxidative stress, such as isoprostanes, during the periconception period remains underexplored. We evaluated the relationship between isoprostanes during preconception and gestational week 4 and women's reproductive health outcomes. Methods: The Effects of Aspirin in Gestation and Reproduction trial (2007-2011) enrolled 1228 women attempting pregnancy and followed them for up to 6 menstrual cycles and throughout pregnancy if they became pregnant. We measured creatinine-adjusted, logtransformed isoprostanes 8-iso-prostaglandin F-2 alpha (8-iso-PGF2 alpha), its metabolite 2,3-dinor-iPF2 alpha-III, and stereoisomers 5-iso-PGF2 alpha-VI and 8,12-iso-iPF2 alpha-VI in urine during preconception and 4 weeks gestation. We evaluated pregnancy among participants in each menstrual cycle using human chorionic gonadotropin (hCG) and defined pregnancy loss as observed loss following positive hCG. We calculated fecundability odds ratios (FOR) and 95% confidence intervals (CI) using discrete-time Cox proportional hazards models and relative risk of pregnancy loss using adjusted log-binomial models. Results: Higher preconception isoprostane levels were associated with lower fecundability [e.g., FOR = 0.89; 95% CI = 0.81, 0.97 per interquartile range (IQR) increase in 8-iso-PGF2 alpha]. Among 797 pregnancies, isoprostane levels increased from preconception to 4 weeks gestation (e.g., mean difference = 0.12; 95% CI = 0.10, 0.14 ng/mL for 8-iso-PGF2 alpha) and higher isoprostanes at 4 weeks gestation were associated with lower risk of pregnancy loss (e.g., RR = 0.79; 95% CI = 0.62, 1.00 per IQR increase in 8-iso-PGF2 alpha). Conclusions: Preconception urinary isoprostanes may identify redox stress pathways associated with lower fecundability. However, the increase in isoprostanes into gestational week 4 and the associated lower risk of pregnancy loss may suggest confounding by latent factors in early pregnancy.