First Trimester Maternal Cortisol Signatures in Small-for-gestational Age

Background: Abnormal maternal hypothalamus-pituitary-adrenal axis is associated with fetal growth, and we hypothesized that the alteration in metabolic signatures of cortisol might be detectable during early pregnancy. The objective of this study was to identify predictable maternal serum signatures of cortisol metabolism during the first trimester of women who are expected to deliver small-for-gestational age (SGA) neonates. Methods: : This prospective cohort study included 112 pregnant women (with and without SGA, n = 56 each). Maternal serum samples were collected at 10~14 gestational weeks to quantify the levels of cortisol and its precursors and metabolites by liquid chromatography-mass spectrometry. Results: : Increased maternal serum levels of tetrahydrocortisol (THF, 11.82 ± 8.16 ng/mL vs. 7.51 ± 2.90 ng/mL, P < 0.005) and decreased 21-deoxycortisol (21-deoxyF, 2.98 ± 1.36 ng/mL vs. 4.33 ± 2.06 ng/mL, P < 0.0001) were observed in pregnant women carrying SGA fetus. In conjunction with individual steroid levels, metabolic ratios corresponding to the activity of related enzymes were calculated. In addition to increased THF/cortisol ratio ( P < 0.006), the SGA group showed a significant increase in the two metabolic ratios including cortisol/11-deoxycortisol (F/11-deoxyF; P < 0.03) and cortisol/21-deoxycortisol (F/21-deoxyF; P < 0.0003) indicating cortisol biosynthesis. The ROC curve generated in combination with three variables of 21-deoxyF concentration and two metabolic ratios of F/21-deoxyF and THF/F resulted in AUC = 0.824 (95% confidence interval, 0.713 ~ 0.918). Conclusions: : A significant decrease in maternal serum levels of 21-deoxyF and an increase in two metabolic ratios of F/21-deoxyF and THF/F, indicating cortisol biosynthetic rate, represent a reliable biomarker for the prediction of SGA in the first trimester.