Early pregnancy oxylipin markers of inflammation and oxidative stress are associated with small-for-gestational-age birth and specific phenotypes of fetal growth restriction.

Abstract

Fetal growth restriction places the fetus at risk for stillbirth, perinatal mortality, and severe morbidity, yet the disease remains difficult to diagnose, predict, and treat. Homeostasis of inflammation and oxidative stress is critical to the establishment of a healthy pregnancy, and biomarkers of these processes could contribute to these goals. Oxylipins are derived from polyunsaturated fatty acids and act as key mediators of this homeostasis and thus may be promising tools for understanding the etiology of fetal growth restriction and possible therapeutic targets. Examine the association between early-pregnancy oxylipin biomarkers of inflammation and oxidative stress and small-for-gestational-age anfd large-for-gestational-age birth as well as ultrasound-based phenotypes of fetal growth restriction. In a case-cohort study of small-for-gestational-age and large-for-gestational-age births (N=901), we measured 24 oxylipins in plasma and urine collected at ∼10 weeks' gestation. We examined associations between oxylipins and small-for-gestational-age (n=248) and large-for-gestational-age birth (n=241) as our primary endpoints. As a secondary approach, we explored associations between oxylipins and phenotypes of small-for-gestational-age and large-for-gestational-age births that were characterized based on longitudinal fetal growth measures. A primary urinary metabolite of the proinflammatory thromboxane-A₂ was associated with small-for-gestational-age birth (odds ratio, 1.43; 95% confidence interval, 1.20-1.72). In secondary analyses, the thromboxane metabolite was most strongly associated with a phenotype of late-pregnancy growth restriction. Additionally, the urinary isoprostanes were associated with increased odds of an early-pregnancy growth restriction phenotype. For example, a 5-series isoprostane was associated with higher odds (odds ratio, 2.22; 95% confidence interval, 1.34-3.69) of early-pregnancy growth restriction compared to appropriate for gestational age. For large-for-gestational-age births, associations were not significant after false discovery rate correction. Associations between circulating oxylipins in early pregnancy and small-for-gestational-age birth may reflect disturbances in the balance of inflammation and oxidative stress, processes that are critical to the establishment of pregnancy and healthy fetal growth. These associations differed based on small-for-gestational-age phenotype, that is, early-pregnancy vs late-pregnancy growth restriction, providing possible insights into distinct etiologies. Oxylipins may be useful targets for early prediction and/or intervention on fetal growth restriction.