Position paper of the Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), and the Italian Study Group of Diabetes in pregnancy: Metformin use in pregnancy

Acta Diabetologica (2023) 60:1421–1437 https://doi.org/10.1007/s00592-023-02137-5 POSITION STATEMENT Position paper of the Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), and the Italian Study Group of Diabetes in pregnancy: Metformin use in pregnancy Laura Sciacca1,2 · Cristina Bianchi1,3 · Silvia Burlina1,4 · Gloria Formoso1,5 Maria Angela Sculli1,7 · Veronica Resi8 · Elisa Manicardi1,6 · Received: 10 April 2023 / Accepted: 12 June 2023 / Published online: 4 July 2023 © The Author(s) 2023 Abstract Objective This document purpose is to create an evidence-based position statement on the role of metformin therapy in pregnancy complicated by obesity, gestational diabetes (GDM), type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and in women undergoing assisted reproductive technology (ART). Methods A comprehensive review of international diabetes guidelines and a search of medical literature was performed to identify studies presenting data on the use of metformin in pregnancy. The document was approved by the councils of the two scientific societies. Results In condition affecting the fertility, as PCOS, metformin use in pre-conception or early in pregnancy may be beneficial for clinical pregnancy, even in ART treatment, and in obese-PCOS women may reduce preterm delivery. In obese women, even in the presence of GDM or T2DM, metformin use in pregnancy is associated with a lower gestational weight gain. In pregnancy complicated by diabetes (GDM or T2DM), metformin improves maternal glycemic control and may reduce insulin dose. Neonatal and infant outcomes related to metformin exposure in utero are lacking. Metformin use in women with GDM or T2DM is associated with lower birth weight. However, an increased tendency to overweight–obesity has been observed in children, later in life. Conclusions Metformin may represent a therapeutic option in selected women with obesity, PCOS, GDM, T2DM, and in women undergoing ART. However, more research is required specifically on the long-term effects of in utero exposition to metformin. Keywords Gestational diabetes · Type 2 diabetes · Obesity · Polycystic ovary syndrome · Placenta · Neonatal outcomes The Italian Society of Gynecology and Obstetrics (SIGO) and the Italian Society of PerinatalMedicine (SIMP) have reviewed the content of the manuscript and agreed with it. This article belongs to the topical collection Pregnancy and Diabetes, managed byAntonio Secchi and Marina Scavini. * Laura Sciacca 1 Interassociative Diabetes and Pregnancy Study Group, Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Rome, Italy 2 Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania, Catania, Italy 3 Metabolic Diseases and Diabetes Unit, University Hospital of Pisa, Pisa, Italy 4 Department of Medicine, DIMED, University of Padova, Padova, Italy 5 Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology (CAST, Ex CeSIMet) G. d’Annunzio University Chieti-Pescara, Chieti, Italy 6 Diabetes Unit, Primary Health Care, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy 7 Endocrinology and Diabetes, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy 8 Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 13 Vol.:(0123456789) 1422 Acta Diabetologica (2023) 60:1421–1437 Introduction Mechanism of action of metformin Treatment of hyperglycemia in pregnancy is mandatory to reduce the risk of adverse maternal and fetal/neonatal outcomes. Metformin use in pregnancy is still a controversial topic. It is well known that metformin improves maternal glycemic control, and it is associated with reduced gestational weight gain in women with T2DM [1]. However, there are relatively a few data about the long-term effects of metformin on offspring of mother with hyperglycemia in pregnancy. It has been reported that neonates born to metformin-treated mothers had lower weight compared to those whose mothers were treated with insulin during pregnancy; however, childhood body mass index (BMI) was significantly higher in the metformin-exposed group [2]. Recently, the Italian Medicines Agency (AIFA) has modified the therapeutic indication (summary of product characteristics [SmPC]) for metformin hydrochloride tablets both immediated release and extended release relatively the use in pregnancy and in the periconceptional period. The SmPC indicates that "if clinically appropriate, the use of metformin may be considered during pregnancy and in the periconceptional period in addition or as an alternative to insulin therapy"[3–6]. The purpose of this document is to review the evidence-based literature regarding the use and the short- and long-term effects of metformin in pregnancies complicated by obesity, GDM, T2DM, PCOS and in women undergoing ART to create an evidence-based position statement on the role of metformin therapy in pregnancy. In particular, the impact of the use of metformin during pregnancy on maternal, fetal, and neonatal outcomes as well as the long-term effects on offspring was evaluated. An Italian Editorial Board composed of experts involved in the clinical management of hyperglycemia in pregnancy was enlisted to review the published data, draw up supporting assertions and conclusions, and make clinical recommendations on the use of metformin in pregnancy. For this position statement, a comprehensive review of international consensus was conducted, and a search of the medical literature was performed to identify studies presenting data on the use of metformin in pregnancy. Priority was given to randomized controlled trials (RCTs) as well as to systematic reviews and meta-analyses of such trials and Cochrane reviews. The references list provided is not exhaustive as a systematic literature review; the position statement provides pertinent publications relevant to the topic. Further updates will be considered periodically according to the developments in evidence-based literature. Metformin is a synthetic analogue of guanidine belonging to the biguanide family. It is the most prescribed oral hypoglycemic agent for type 2 diabetes worldwide, due its efficacy on glycemic control alone or in combination with many other antidiabetic drugs [7]. Metformin belongs to the class of insulin sensitizers and exerts its glucoselowering effect primarily by decreasing hepatic glucose production through suppression of gluconeogenesis, and a modest effect to increase insulin-stimulated peripheral glucose uptake in the other target tissues of insulin action [8, 9]. The hepatic effect of metformin causes a decrease in hepatic glucose production which results in a reduction of blood glucose levels, in particular the fasting plasma glucose (FPG), associated with a marked decline of hyperinsulinemia. Furthermore, metformin incre (...truncated)