Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index

Authors: BORKOWSKI, KAMIL - University Of California, Davis; Newman, John; AGHAEEPOUR, NIMA - Stanford University School Of Medicine; MAYO, JONATHAN - Stanford University School Of Medicine; BLAZENOVIC, IVANA - University Of California, Davis; FIEHN, OLIVER - University Of California, Davis; STEVENSON, DAVID - Stanford University School Of Medicine; SHAW, GARY - Stanford University School Of Medicine; CARMICHAEL, SUZAN - Stanford University School Of Medicine

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2020
Publication Date: 11/17/2020
Citation: Borkowski, K., Newman, J.W., Aghaeepour, N., Mayo, J.A., Blazenovic, I., Fiehn, O., Stevenson, D.K., Shaw, G.M., Carmichael, S.L. 2020. Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index. PLoS ONE. 15(11). Article e0239115. https://doi.org/10.1371/journal.pone.0239115.
DOI: https://doi.org/10.1371/journal.pone.0239115

Interpretive Summary: Spontaneous preterm birth (sPTB) is a major cause of infant disease and death. While metabolic changes leading to preterm birth are unknown, several factors including elevated plasma lipids and chronic inflammation have been implicated. Paradoxically having either a body mass index (BMI) that is either below (<20 kg/m²) or above (>30 kg/m²) the normal range is a risk factors for this condition. Using a cohort of underweight, normal weight and obese women experiencing either sPTB or full term deliveries (n =102; n =17/group), the objective of the study was to identify BMI-associated changes in metabolism and to identify small molecules in the serum of women at mid pregnancy that could identify individuals at high risk for sPTB. For this purpose, we used semi-quantitative determinations of broad swaths of polar and non-polar small molecules (i.e. untargeted metabolomics and lipidomics), along with quantitative metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and serum lipids characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of elevated lipids, characterized by phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of specific arachidonic acid metabolites (i.e. 14(15) epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids) and other structurally similar compounds derived from cytochrome P450/epoxide hydrolase metabolism were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated in each BMI group, and were strongest in the normal weight women. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations demonstrate the potential to predict sPTB mid pregnancy using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.

Technical Abstract: Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<20 kg/m²) and high (>30 kg/m²) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-pregnancy serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full term deliveries (n =102; n =17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15) epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations demonstrate the potential to predict sPTB mid pregnancy using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.