Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses

Supplementary Material for: A Novel Early Pregnancy Risk Prediction Model for Gestational Diabetes Mellitus

<b><i>Introduction:</i></b> Accurate early risk prediction for gestational diabetes mellitus (GDM) would target intervention and prevention in women at the highest risk. We evaluated novel biomarker predictors to develop a first-trimester risk prediction model in a large multiethnic cohort. <b><i>Methods:</i></b> Maternal clinical, aneuploidy and pre-eclampsia screening markers (PAPP-A, free hCGβ, mean arterial pressure, uterine artery pulsatility index) were measured prospectively at 11–13⁺⁶ weeks’ gestation in 980 women (248 with GDM; 732 controls). Nonfasting glucose, lipids, adiponectin, leptin, lipocalin-2, and plasminogen activator inhibitor-2 were measured on banked serum. The relationship between marker multiples-of-the-median and GDM was examined with multivariate regression. Model predictive performance for early (< 24 weeks’ gestation) and overall GDM diagnosis was evaluated by receiver operating characteristic curves. <b><i>Results:</i></b> Glucose, triglycerides, leptin, and lipocalin-2 were higher, while adiponectin was lower, in GDM (<i>p</i> < 0.05). Lipocalin-2 performed best in Caucasians, and triglycerides in South Asians with GDM. Family history of diabetes, previous GDM, South/East Asian ethnicity, parity, BMI, PAPP-A, triglycerides, and lipocalin-2 were significant independent GDM predictors (all <i>p</i> < 0.01), achieving an area under the curve of 0.91 (95% confidence interval [CI] 0.89–0.94) overall, and 0.93 (95% CI 0.89–0.96) for early GDM, in a combined multivariate prediction model. <b><i>Conclusions:</i></b> A first-trimester risk prediction model, which incorporates novel maternal lipid markers, accurately identifies women at high risk of GDM, including early GDM