Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: A nested case-control study

Abstract

Background

Inflammation during pregnancy is hypothesized to influence fetal growth. Eicosanoids, an important class of lipid mediators derived from polyunsaturated fatty acids, can act as both direct influences and biomarkers of inflammation through a variety of biological pathways. However, quantifying these distinct inflammatory pathways has proven difficult. We aimed to characterize a comprehensive panel of plasma eicosanoids longitudinally across gestation in pregnant women and to determine whether levels differed by infant size at delivery.

Methods and findings

Our data come from a case–control study of 90 pregnant women nested within the LIFECODES prospective birth cohort study conducted at Brigham and Women’s Hospital in Boston, Massachusetts. This study included 31 women who delivered small for gestational age (SGA) babies (SGA, ≤10th percentile), 28 who delivered large for gestational age (LGA) babies (≥90th percentile), and 31 who delivered appropriate for gestational age (AGA) babies (controls, >10th to <90th percentile). All deliveries occurred between 2010 and 2017. Most participants were in their early 30s (median age: 33 years), of white (60%) or black (20%) race/ethnicity, and of normal pre-pregnancy BMI (median BMI: 23.5 kg/m ²). Women provided non-fasting plasma samples during 3 prenatal study visits (at median 11, 25, and 35 weeks gestation) and were analyzed for a panel of eicosanoids. Eicosanoids were grouped by biosynthetic pathway, defined by (1) the fatty acid precursor, including linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA), and (2) the enzyme group, including cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP). Additionally, the concentrations of the 4 fatty acids (LA, AA, DHA, and EPA) were measured in maternal plasma. Analytes represent lipids from non-esterified plasma. We examined correlations among eicosanoids and trajectories across pregnancy. Differences in longitudinal concentrations between case groups were examined using Bayesian linear mixed effects models, which included participant-specific random intercepts and penalized splines on gestational age. Results showed maternal plasma levels of eicosanoids and fatty acids generally followed U-shaped curve patterns across gestation. Bayesian models showed that associations between eicosanoids and case status varied by biosynthetic pathway. Eicosanoids derived from AA via the CYP and LOX biosynthetic pathways were positively associated with SGA. The adjusted mean concentration of 12-HETE, a LOX pathway product, was 56.2% higher (95% credible interval 6.6%, 119.1%) among SGA cases compared to AGA controls. Eicosanoid associations with LGA were mostly null, but negative associations were observed with eicosanoids derived from AA by LOX enzymes. The fatty acid precursors had estimated mean concentrations 41%–97% higher among SGA cases and 33%–39% lower among LGA cases compared to controls. Primary limitations of the study included the inability to explore the potential periods of susceptibility of eicosanoids on infant size due to limited sample size, along with the use of infant size at delivery instead of longitudinal ultrasound measures to estimate fetal growth.

Conclusions

In this nested case–control study, we found that eicosanoids and fatty acids systematically change in maternal plasma over pregnancy. Eicosanoids from specific inflammation-related pathways were higher in mothers of SGA cases and mostly similar in mothers of LGA cases compared to controls. These findings can provide deeper insight into etiologic mechanisms of abnormal fetal growth outcomes.

Abstract

In a cohort study, Barrett Welch and colleagues investigate associations between infant size for gestational age and plasma eicosanoids in pregnant women.

Author summary

Why was this study done?

• Inflammation during pregnancy is thought to influence fetal growth. Eicosanoids are an important class of lipid molecules derived from polyunsaturated fatty acids that can directly influence inflammation and be used as biomarkers of activity. This study characterized a large selection of these eicosanoids and fatty acids during pregnancy.

• Although some individual eicosanoids have been previously measured in pregnancy, this study provides a novel evaluation of a comprehensive eicosanoid panel for (1) changes over time in pregnant women and (2) associations with infant size for gestational age at delivery.

What did the researchers do and find?

• Compared to mothers with infants of appropriate size for their gestational age (the control group), mothers of infants small for gestational age had higher blood plasma concentrations of eicosanoids related to inflammation. However, levels in mothers of large for gestational age infants were similar to those of the control group.

What do these findings mean?

• This study provides additional evidence that inflammation processes related to lipid metabolism fluctuate over pregnancy. The differences in eicosanoid levels between mothers by infant size at delivery outcomes may provide further insights into mechanisms of disease and possible therapeutic targets.

• Future studies would benefit from a larger number of participants to evaluate differences in how eicosanoid levels change over time during pregnancy in cases compared to controls. Additionally, improving identification of cases and controls (e.g., with repeated ultrasound measurements) could improve assessment of these relationships.