Pregnancy Outcomes: Effects of Metformin (POEM) study: a protocol for a long-term, multicentre, open-label, randomised controlled trial in gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy with health risks for mother and child during pregnancy, delivery and further lifetime, possibly leading to type 2 diabetes mellitus (T2DM). Current treatment is focused on reducing hyperglycaemia, by dietary and lifestyle intervention and, if glycaemic targets are not reached, insulin. Metformin is an oral blood glucose lowering drug and considered safe during pregnancy. It improves insulin sensitivity and has shown advantages, specifically regarding pregnancy-related outcomes and patient satisfaction, compared with insulin therapy. However, the role of metformin in addition to usual care is inconclusive and long-term outcome of metformin exposure in utero are lacking. The primary aim of this study is to investigate the early addition of metformin on pregnancy and long-term outcomes in GDM. METHODS AND ANALYSIS: The Pregnancy Outcomes: Effects of Metformin study is a multicentre, open-label, randomised, controlled trial. Participants include women with GDM, between 16 and 32 weeks of gestation, who are randomised to either usual care or metformin added to usual care, with insulin rescue in both groups. Metformin is given up to 1 year after delivery. The study consists of three phases (A-C): A-until 6 weeks after delivery; B-until 1 year after delivery; C-observational study until 20 years after delivery. During phase A, the primary outcome is a composite score consisting of: (1) pregnancy-related hypertension, (2) large for gestational age neonate, (3) preterm delivery, (4) instrumental delivery, (5) caesarean delivery, (6) birth trauma, (7) neonatal hypoglycaemia, (8) neonatal intensive care admission. During phase B and C the primary outcome is the incidence of T2DM and (weight) development in mother and child. ETHICS AND DISSEMINATION: The study was approved by the Central Committee on Research Involving Human Subjects in the Netherlands. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02947503.

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

INTRODUCTION: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. METHODS: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. RESULTS: Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. DISCUSSION: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.