Association of maternal homocysteine and coagulation–fibrinolysis biomarkers with small-for-gestational-age birth in pregnancies complicated by gestational diabetes mellitus and preeclampsia

To investigate the associations of maternal homocysteine (Hcy) and coagulation–fibrinolysis biomarkers with small-for-gestational-age (SGA) birth in pregnancies complicated by gestational diabetes mellitus (GDM) and preeclampsia (PE). This single-center retrospective cohort study included 760 women with GDM and PE. SGA was defined according to birthweight-for-gestational-age percentiles. Maternal Hcy, thrombin–antithrombin complex (TAT), thrombomodulin (TM), plasmin–α2-plasmin inhibitor complex (PIC), and tissue plasminogen activator–plasminogen activator inhibitor-1 complex (tPAI-C) were measured, and the TAT/PIC ratio was calculated as an exploratory composite measure. Associations with SGA, fetal growth phenotypes, and placental vascular phenotypes were evaluated, with additional subgroup and sensitivity analyses. Among the 760 pregnancies, 167 (22.0%) resulted in SGA births. Maternal Hcy, TAT, TM, PIC, and tPAI-C levels were higher in the SGA group than in the non-SGA group. After adjustment for relevant confounders, higher Hcy, TAT, TM, tPAI-C, and TAT/PIC ratio were associated with increased SGA risk, with adjusted risk ratios of 1.12 (95% confidence interval, 1.08–1.17), 1.13 (1.07–1.19), 1.07 (1.04–1.11), 1.07 (1.04–1.10), and 1.08 (1.04–1.12), respectively, whereas PIC was not significantly associated with SGA in the primary adjusted model. The proportion of SGA increased from 10.5% in the lowest quartile of the TAT/PIC ratio to 33.7% in the highest quartile, with an adjusted risk ratio of 2.27 (95% confidence interval, 1.44–3.58) for the highest versus lowest quartile. Higher Hcy, TAT, TM, tPAI-C, and TAT/PIC ratio were also associated with higher umbilical artery pulsatility index, lower cerebroplacental ratio, and greater risk of fetal growth restriction. The principal associations remained directionally consistent in sensitivity analyses, although those for TM and the TAT/PIC ratio were not statistically significant among women who delivered more than 7 days after sampling and had no fetal growth restriction diagnosed before sampling ( n = 374). In pregnancies complicated by GDM and PE, higher maternal Hcy levels and coagulation–fibrinolysis abnormalities were associated with SGA and Doppler findings consistent with increased placental vascular resistance. The TAT/PIC ratio should be regarded as an exploratory measure requiring validation in prospective studies.