Use Of Metformin In Pregnancy Research Articles

Initiation of metformin in early pregnancy results in fetal bioaccumulation, growth restriction, and renal dysmorphology in a primate model

BackgroundIn recent years, pragmatic metformin use in pregnancy has stretched to include prediabetes, type 2 diabetes, gestational diabetes and (most recently) pre-eclampsia. With its expanded use, however, concerns of unintended harm have been raised. ObjectiveWe developed an experimental primate model and applied triple-quadruple pole LC mass spectrometry (UHPLC-QQQ) for direct quantitation of maternal and fetal tissue metformin levels with detailed fetal biometry and histopathology. Study designWithin 30 days of confirmed conception (defined as early pregnancy), n=13 time-bred (TMB) Rhesus dams with gestations designated for fetal necropsy were initiated on twice daily human dose-equivalent 10 mg/kg metformin or vehicle control. Pregnant dams were maintained as pairs and fed either a control chow or 36% fat Western-style diet (WSD). Metformin or placebo vehicle control were delivered in a variety of treats while animals were separated via a slide. A Cesarean was performed at G145, and amniotic fluid and blood were collected and the fetus and placenta were delivered. The fetus was immediately necropsied by trained primate center personnel. All fetal organs were dissected, measured, sectioned, and processed per clinical standards. Fluid and tissue metformin levels were assayed using validated UHPLC-QQQ in SRM against standard curves. ResultsAmong the n=13 G145 pregnancies with fetal necropsy, n=1 dam and its fetal tissues had detectable metformin levels despite being allocated to the vehicle control group (>1 μM metformin/kg maternal weight or fetal/placental tissue), while a second fetus allocated to the vehicle control group had severe fetal growth restriction (birthweight 248.32 g, <1%) and was suspected of having a fetal congenital condition. After excluding these two fetal gestations from further analyses, 11 fetuses from dams initiated on either vehicle control (n=4, 3 female, 1 male fetuses) or 10 mg/kg metformin (n=7, 5 female, 2 male fetuses) were available for analyses. Among dams initiated on metformin by G30 (regardless of maternal diet), we observed significant bioaccumulation within the fetal kidney (0.78-6.06 μmol/kg, mean 2.48 μmol/kg) , liver (0.16-0.73 μmol/kg, mean 0.38 μmol/kg), fetal gut (0.28-1.22 μmol/kg, mean 0.70 μmol/kg), amniotic fluid (0.43-3.33 μmol/L, mean 1.88 μmol/L), placenta (0.16-1.0 μmol/kg , mean 0.50 μmol/kg) and fetal serum (0 -0.66 μmol/L , mean 0.23 μmol/L ), and fetal urine (4.1-174.1 μmol/L mean 38.5 μmol/L ), with fetal levels near biomolar equivalent to maternal levels (maternal serum 0.18-0.86 μmol/L , mean 0.46 μmol/L; maternal urine 42.6-254.0 μmol/L , mean 149.3 μmol/L). WSD feeding neither accelerated nor reduced metformin bioaccumulations in maternal or fetal serum, urine, amniotic fluid, placenta nor fetal tissues. In these 11 animals, fetal bioaccumulation of metformin was associated with less fetal skeletal muscle (57% lower cross-sectional area of gastrocnemius) and decreased liver, heart, and retroperitoneal fat masses (p<0.05), collectively driving lower delivery weight (p<0.0001) without changing the crown-rump length. Sagittal sections of fetal kidneys demonstrated delayed maturation, with disorganized glomerular generations and increased cortical thickness; this renal dysmorphology was not accompanied by structural nor functional changes indicative of renal insufficiency. ConclusionsWe demonstrate fetal bioaccumulation of metformin with associated fetal growth restriction and renal dysmorphology following maternal initiation of the drug within 30 days of conception in primates. Given these results and the prevalence of metformin use during pregnancy, additional investigation of any potential immediate and enduring effects of prenatal metformin use is warranted.

Metformin use in pregnancy: What about long-term effects in offspring?

Metformin use in pregnancy is increasing worldwide. Unlike insulin, metformin crosses the placenta. Consequently, maternal and fetal concentrations are comparable. Teratogenic effects are not reported, nor are adverse pregnancy outcomes. Reduced risk of hypertensive disorders, hypoglycemia, and macrosomia are potential benefits, together with lower gestational weight gain. Although metformin has been prescribed for pregnant women during the last 40 years, long-term data regarding offspring outcomes are still lacking. Independent of maternal glycemic control, recent meta-analyses report lower birthweight but accelerated postnatal growth and higher body mass index in metformin-exposed children. The longest follow-up study of placebo-controlled metformin exposure in utero found an increased prevalence of central adiposity and obesity among children 5-10 years old. Recently, a Danish study reported a threefold increased risk of genital anomalies in boys, whose fathers used metformin around the time of conception. This commentary addresses the current controversies on metformin use in pregnancy.

Indicazioni cliniche sull’uso della metformina in gravidanza e nel periodo periconcezionale

The aim of this editorial is to give some practical guidance drawn from the evidence-based literature on the use of metformin in pregnancy and in the periconceptional period for different health conditions, such as overweight and obesity, gestational diabetes, type 2 diabetes mellitus, polycystic ovary syndrome and in women undergoing assisted reproductive technology. Metformin use in pregnancy is still a controversial topic particularly because it can cross the human placenta. Therefore, caution is needed since many long-term effects on the offspring of mothers treated with metformin during pregnancy are not yet fully known.

The metabolic response of human trophoblasts derived from term placentas to metformin

Aims/hypothesisMetformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta.MethodsA cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated {dot{V}mathrm{O}}_{2}. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively.ResultsComplex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups.Conclusions/interpretationIn primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.Graphical

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

ObjectiveThis 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).MethodsA 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.ResultsIn 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.ConclusionsMetformin 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.

Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond.

During pregnancy, the complex hormonal changes lead to a progressive decrease of insulin sensitivity that can drive the onset of gestational diabetes (GDM) or worsen an already-known condition of insulin resistance like type 2 diabetes, polycystic ovarian syndrome (PCOS), and obesity, with complications for the mother and the fetus. Metformin during pregnancy is proving to be safe in a growing number of studies, although it freely crosses the placenta, leading to a fetal level similar to maternal concentration. The aim of this literature review is to analyze the main available evidence on the use of metformin during, throughout, and beyond pregnancy, including fertilization, lactation, and medium-term effects on offspring. Analyzed studies support the safety and efficacy of metformin during pregnancy. In pregnant women with GDM and type 2 diabetes, metformin improves obstetric and perinatal outcomes. There is no evidence that it prevents GDM in women with pregestational insulin resistance or improves lipid profile and risk of GDM in pregnant women with PCOS or obesity. Metformin could have a role in reducing the risk of preeclampsia in pregnant women with severe obesity, the risk of late miscarriages and preterm delivery in women with PCOS, and the risk of ovarian hyperstimulation syndrome, increasing the clinical pregnancy rate in women with PCOS undergoing in vitro fertilization (IVF/FIVET). Offspring of mothers with GDM exposed to metformin have no significant differences in body composition compared with insulin treatment, while it appears to be protective for metabolic and cardiovascular risk.

Metformin use in pregnancy: efficacy, safety, and potential benefits

Metformin use in pregnancy: efficacy, safety, and potential benefits

A Review on the Use of Metformin in Pregnancy and Its Associated Fetal Outcomes.

A commonly used first-line anti-diabetic medication, metformin, has been used in pregnancy. The drug is known to have specific effects on different organs around the body. One of these organs includes the ovaries. Therefore, for more than 40 years, it has often been prescribed for maternal obesity along with gestational diabetes mellitus. Untreated pregnancies like these frequently result in complications for both the mother and the fetus, like macrosomia, pregnancy-induced hypertension, obstructed labor, stillbirths, and perinatal deaths. In addition, there is also evidence that these mothers tend to develop type II diabetes mellitus during their pregnancy and even a few years post-delivery. These complications can be controlled or even reduced with the help of metformin, sometimes combining it with insulin or clomiphene citrate if required. There is still a need to cautiously prescribe the drug by outweighing its benefits against the risk associated with it. The current research on the subject leans more towards the benefits offered to the mother during pregnancy. Only a few randomized, controlled trials have been conducted on the fetal condition after the mother has been administered metformin. Furthermore, these studies lack the appropriate sample size and long-term follow-up on these metformin-exposed offspring. As a result, there are no reliable data available to clinicians and physicians about the drug. Owing to its benefits in certain pregnancies, it is less likely that the drug will cease to be prescribed. Therefore, it becomes increasingly imperative to conduct more research on this topic to ensure the drug is safe for the mother and the offspring.

Controversies in metformin use in pregnancy and the role of triglycerides in fetal overgrowth

Controversies in metformin use in pregnancy and the role of triglycerides in fetal overgrowth

Metformin for pregnancy and beyond: the pros and cons.

Metformin has been used in pregnancy since the 1970s. It is cheap, widely available and is acceptable to women. Despite its increasing use, controversy remains surrounding its benefits and risks. Metformin effectively reduces hyperglycaemia for the mother during pregnancy and it reduces rates of macrosomia and neonatal hypoglycaemia. However, concern exists surrounding an increase in the rate of SGA births and obesity in childhood. We aim to review the evidence and expert opinion behind metformin in pregnancy through to the post-partum period. We performed a literature review of relevant studies from online databases using a combination of keywords. We also searched the references of retrieved articles for pertinent studies. There is strong evidence that metformin is safe in early pregnancy with no risk of congenital malformations. If used throughout pregnancy, it is likely to lead to reduced maternal weight gain and reduced insulin dose in women with type 2 diabetes. In infants, metformin reduces hypoglycaemia and macrosomia but may increase the rate of infants born SGA. There is some evidence of an increased risk of obesity and altered fat distribution in offspring. Metformin appears well tolerated in pregnancy and is more acceptable to women than insulin therapy. Due to increasing rates of maternal obesity, GDM and type 2 diabetes, metformin use in pregnancy is increasing. Overall, it appears safe and effective but further research is needed to examine mechanisms linking metformin to obesity reported during childhood in some follow-up studies.

Metformin in Pregnancy for Women with Type 2 Diabetes: a Review.

To review the current evidence for the use of metformin in pregnancy for women with type 2 diabetes. A large, multicenter, double-blind randomized controlled trial found that women with type 2 diabetes in pregnancy treated with metformin as an adjunct to insulin therapy had less gestational weight gain, insulin requirements, caesarian sections, macrosomia, and neonatal adiposity, but more neonates were small for gestational age (SGA) compared with insulin alone. It is unclear if the higher number of SGA infants are a direct result of metformin exposure or mediated through other effects such as less gestational weight gain and improved glycemic control. Additional follow-up studies of offspring exposed to metformin in utero are required. Metformin may be a useful adjunctive treatment for women with type 2 diabetes in pregnancy to help meet glycemic targets if there are no concerns for or indications of SGA.

The efficacy and safety of metformin alone or as an add-on therapy to insulin in pregnancy with GDM or T2DM: A systematic review and meta-analysis of 21 randomized controlled trials.

Pregnant women are increasingly being exposed to metformin for conditions including gestational diabetes mellitus and type 2 diabetes mellitus. Metformin has been found to exhibit maternal to foetal transfer, and the long-term influence is uncertain. We conducted a meta-analysis to compare the efficacy and safety of metformin alone or as add-on therapy to insulin and insulin in pregnancy with gestational diabetes mellitus or type 2 diabetes mellitus. We performed a comprehensive literature search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov for randomized controlled trials (RCTs) that compared metformin to insulin in pregnancy. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to synthesize the results. Two authors independently extracted the data, evaluated study quality and calculated pooled estimates. Twenty-one studies involving 4,545 patients were included in this meta-analysis. Compared with insulin, metformin significantly reduced the risks of maternal weight gain [MD -1.51kg, 95%CI (-1.90kg, -1.12kg), P<0.00001], gestational age at birth [MD -0.12week, 95%CI (-0.21week, -0.02week), P=0.02], gestational hypertension [RR 0.63, 95%CI (0.48, 0.82), P=0.0006], maternal hypoglycaemia [RR 0.33, 95%CI (0.15, 0.73), P=0.006], birthweight [MD -0.13kg, 95%CI (-0.20kg, -0.07kg), P<0.0001], neonatal hypoglycaemia [RR 0.56, 95%CI (0.49, 0.64), P<0.00001], neonatal intensive care unit admission [RR 0.73, 95%CI (0.64, 0.83), P<0.00001], birthweight ≥4000g [RR 0.70, 95%CI (0.59, 0.83), P<0.0001], and large for gestational age [RR 0.83, 95%CI (0.72, 0.97), P=0.02] and significantly increased the risk of small for gestational age [RR 1.43, 95%CI (1.08, 1.89), P=0.01] in pregnancy. Metformin may have potential benefits for pregnant women and newborns in terms of maternal and foetal outcomes. More studies with long-term follow-up of offspring exposed to metformin in utero are needed to provide evidence for the future use of metformin in pregnancy.

Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis

IntroductionGestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use...

Metformin therapy in pregnancy [Zastosowanie metforminy w ciąży

Gestational diabetes mellitus (GDM), i.e. a carbohydrate metabolism disorder at pregnancy, is one of the most common metabolic complications that occur during this period. Pancreatic b-cell dysfunction and insulin resistance during pregnancy are considered the main causes of the condition. It is currently estimated that GDM is confirmed in 1-25% of patients. Diagnosis and appropriate management allow to reduce the risk of complications in newborns and the perinatal mortality rate and also improve the prognosis for mother and offspring. Metformin is taken by many patients before pregnancy due to both previously diagnosed type 2 diabetes and in the treatment of prediabetes, obesity and polycystic ovary syndrome (PCOS) as part of therapy for insulin resistance. The use of metformin in pregnancy has been controversial for many years, particularly in terms of the safety of continuation of drug therapy. Available scientific data indicate both benefits and possible drug-related adverse effects in offspring of metformin-treated patients. This problem is related not only to patients with type 2 diabetes, but also to those with PCOS who are at increased risk of miscarriage, preterm delivery and the diagnosis of GDM in subsequent stages of pregnancy. Conclusive and uniform recommendations for the use of metformin at each stage of pregnancy have not been established yet due to the doubts about the mechanisms of action of the drug, particularly at the cellular level. This review paper presents the current state of knowledge on the use of metformin during pregnancy.

Progress in use of metformin in pregnancy with diabetes

The efficacy as well as short- and long-term safety of metformin in women with gestational diabetes mellitus have been constantly confirmed in recent years. Metformin could decrease the weight gain during pregnancy and the incidence of hypoglycemia compared with insulin, without increasing the incidence of adverse pregnant outcomes. Moreover, no significant adverse outcome has been found in the offspring of women treated with metformin in pregnancy. This article reviews the evidence for efficacy and safety of using metformin during pregnancy, summarizes the latest guidelines and recommendations, and describes the specific medication regimen. Key words: Metformin; Diabetes, gestational; Validation studies; Clinical protocols

Biodistribution of [11C]-Metformin and mRNA Expression of Placentae Metformin Transporters in the Pregnant Chinchilla.

Background While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy. Methods Three chinchillas in the last part of gestation were injected with [11C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae. Results Dynamic PET with [11C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1. Conclusion Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.

Real-world experience of metformin use in pregnancy: Observational data from the Northern Territory Diabetes in Pregnancy Clinical Register.

In Australia's Northern Territory, Indigenous mothers account for 33% of births and have high rates of hyperglycemia in pregnancy. The prevalence of type 2 diabetes (T2D) in pregnancy is up to 10-fold higher in Indigenous than non-Indigenous Australian mothers, and the use of metformin is common. We assessed birth outcomes in relation to metformin use during pregnancy from a clinical register. The study included women with gestational diabetes (GDM), newly diagnosed diabetes in pregnancy (DIP), or pre-existing T2D from 2012 to 2016. Data were analyzed for metformin use in the third trimester. Regression models were adjusted for maternal age, body mass index, parity, and insulin use. Of 1649 pregnancies, 814 (49.4%) were to Indigenous women, of whom 234 (28.7%) had T2D (vs 4.6% non-Indigenous women; P < 0.001). Metformin use was high in Indigenous women (84%-90% T2D, 42%-48% GDM/DIP) and increased over time in non-Indigenous women (43%-100% T2D, 14%-35% GDM/DIP). Among Indigenous women with GDM/DIP, there were no significant differences between groups with and without metformin in cesarean section (51% vs 39%; adjusted odds ratio [aOR] 1.25, 95% confidence interval [CI] 0.87-1.81), large for gestational age (24% vs 13%; aOR 1.5, 95% CI 0.9-2.5), or serious neonatal adverse events (9.4% vs 5.9%; aOR 1.32, 95% CI 0.68-2.57). Metformin use was independently associated with earlier gestational age (37.7 vs 38.5 weeks), but the risk did not remain independently higher after exclusion of women managed with medical nutrition therapy alone, and the increase in births <37 weeks was not significant on multivariate analysis. We found no clear evidence of any adverse outcomes related to the use of metformin for the treatment of hyperglycemia in pregnancy.

Metformin in Pregnancy: Mechanisms and Clinical Applications.

Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin in pregnancy for women with Polycystic Ovarian Syndrome and for nondiabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven, and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials.

Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study

ObjectiveTo investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.DesignPopulation based exploratory case-control study...

Metformin Use in Pregnancy: Promises and Uncertainties

(Abstracted from Diabetologia 2017;60:1612–1619) Metformin has been prescribed in pregnancy for more than 40 years, but it is since its increased use in polycystic ovarian syndrome treatment that exposure of the fetus to metformin in early pregnancy and its safety for both mother and child have been investigated more robustly. This review discusses the history, key trials, and controversies associated with metformin use in pregnancy.