Several other transporters are also expressed in the human syncytiotrophoblast, including P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP 1) and breast cancer resistance protein (BCRP). The most obvious questions are whether or not metformin should be continued during pregnancy and whether it should be added to insulin therapy. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Salomki H, Vhtalo LH, Laurila K, Jppinen NT, Penttinen AM, Ailanen L, Ilyasizadeh J, Pesonen U, Koulu M. Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood. official website and that any information you provide is encrypted While it has been suggested from short-term follow-up of offspring exposed to metformin that fetal exposure may lead to improved metabolic health [77], there are mechanisms to suggest otherwise, and the issue is far from clear. Overall, neonatal and maternal complications . Moore LE, Clokey D, Rappaport VJ, Curet LB. A lower insulin dose may be required Possible side Effects of Metformin: Some people experience stomach upsets such as nausea, Indigestion, diarrhoea and loss of appetite. Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. This review explores the current place of metformin in the management of gestational diabetes (GDM) and type 2 diabetes during pregnancy and lactation. Comparative efficacy and safety of OADs in management of GDM: network meta-analysis of randomized controlled trials. It may be detected in breast milk, but breastfeeding or chestfeeding. If lifestyle modification alone fails to achieve glucose control, insulin, glyburide and metformin are safe and effective treatment options during second and third trimesters. Wong VW, Jalaludin B. Gestational diabetes mellitus: who requires insulin therapy? Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Most of these studies suggest that metformin does not increase maternal or short-term fetal adverse outcomes and may reduce maternal weight gain during pregnancy and that it has lower risk of neonatal hypoglycemia and large for gestational age (LGA) babies. government site. In the network meta-analysis by Farrar and colleagues, metformin had the highest probability of being the most effective treatment in reducing the risk of neonatal hypoglycemia (probability of benefit 96.3%), macrosomia (94.0%), LGA (92.8%), preeclampsia (84.0%) and admission to NICU (61.2%) [56]. Pros and cons of use of metformin for the management of gestational diabetes. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. OCT2 regulates uptake by renal epithelial cells and MATE1 and 2 regulate excretion into urine. Bethesda, MD 20894, Web Policies Diagnosis of diabetes < 20 weeks of gestation, Need for pharmacological therapy at <30 weeks, GDM not responding to medical nutrition therapy and exercise, if FPG < 110 mg/dL, Poor compliance or refusal to use insulin, Lack of skills and/or resources for self-management of diabetes with insulin. While International Federation of Gynecology and Obstetrics (FIGO), the UK National Institute for Health and Care Excellence (NICE), and the Endocrine Society guidelines consider insulin, glyburide, and metformin as appropriate first-line therapies for GDM [101103], many other practice guidelines, such as the American Congress of Obstetricians and Gynecologists (ACOG), American Diabetes Association (ADA), and International Diabetes Federation (IDF), recognize that there is insufficient evidence at present to encourage routine use of metformin in GDM over insulin [99,100,105]. Mesdaghinia E, Samimi M, Homaei Z, Saberi F, Moosavi SGA, Yaribakht M. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial. This causes a rise in cellular 5-methyl tetrahydrofolate (THF), though the cell is unable to utilize it. Therefore, it is abundantly clear that more research is needed to ascertain if metformin reprograms gene expression and, if it does, is this more favorable or detrimental to the long-term health of the offspring. 159 South Indian women with GDM; metformin. Ashoush S, El-Said M, Fathi H, Abdelnaby M. Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus. What are the benefits of using metformin in pregnancy? Ibrahim and colleagues randomized 90 pregnant women with GDM or T2D between 20 and 34 weeks gestation, who had poor glycemic control at insulin daily dose 1.12 U/kg, into two groups addition of oral metformin versus increase in insulin dose; 36.9% women were able to reach glycemic targets with daily metformin dose of 1500 mg and 39.2% with daily dose of 2000 mg and 23.9% of metformin users needed increase in insulin dose. AMPK also regulates transcription of several factors involved in the response to environmental stress. Use of metformin earlier in pregnancy predicts supplemental insulin therapy in women with gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. Metformin is used if glycemic targets are not attained with lifestyle modification within 12 weeks and insulin is used if metformin is not tolerated or acceptable to patient. Su DF, Wang XY. Metformin is a medication that has been used to treat type 2 diabetes, insulin-resistance in polycystic ovary syndrome (PCOS), and gestational diabetes. The malformation rate of 1.7% in metformin group was actually significantly lower than control group, where it was 7.2% [88]. Rojas J, Chvez-Castillo M, Bermdez V. The role of metformin in metabolic disturbances during pregnancy: polycystic ovary syndrome and gestational diabetes mellitus. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. No difference in birth weight, neonatal or maternal outcomes. Your doctor may increase your dose if needed until your blood sugar is controlled. A detailed search of MEDLINE, EMBASE and Cochrane databases was undertaken to include all relevant research. Ibrahim MI, Hamdy A, Shafik A, Taha S, Anwar M, Faris M. The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Metformin has beenused to treat PCOS, a condition that can make it harder to get pregnant. Reduces insulin resistance, the main pathophysiology in GDM, May fail to achieve adequate glycemic control in presence of insulinopenia, Increased renal clearance need for higher doses, Glycemic control comparable to insulin or glyburide, Failure rate in 1446% women, who require supplemental insulin, Not approved for use in pregnancy category B, use is off-label, Slightly lower gestational age at delivery, No increased risk of teratogenicity in fetuses exposed in first trimester, Increased risk of preterm birth (inconsistent results), No evidence of growth or motor-social development abnormalities May result in more favorable distribution of adipose tissue in offspring (insufficient evidence), Insufficient data of long-term effects of exposure. The earliest reports of the use of metformin during pregnancy were from South Africa in early 1980s, by Coetzee and colleagues, in women with pre-existing non-insulin-dependent diabetes and GDM [46]. Lower rates of gestational hypertension with metformin. Committee on Practice Bulletins Obstetrics. The benefits, however, need to be weighed against the possible increased risk of preterm delivery, though this has not been demonstrated in recent meta-analyses and might be a chance effect. Good blood sugar control is essential to reduce the likelihood of ill-effects caused by diabetes including damage to the blood vessels, nerves, and eyes. These are involved in histone acetylation. Metformin (dimethyl-biguanide) induced DNA damage in mammalian cells. No difference in neonatal respiratory distress and preterm birth or other neonatal outcomes. diabetes, epigenetic programming, gestational diabetes, metformin, oral antidiabetic agents, pregnancy, type 2 diabetes. As a library, NLM provides access to scientific literature. Metformin A typical dosing regimen is to start metformin extended release . Metformin treatment in type 2 diabetes in pregnancy: an active controlled, parallel-group, randomized, open label study in patients with type 2 diabetes in pregnancy. Maternal and fetal outcomes were similar [71]. A diagnosis of GDM at an earlier gestation, higher fasting glucose, higher maternal BMI, past history of GDM and older age of mother predict the need for supplemental insulin. GDM, gestational diabetes; HbA1c, hemoglobin A1c; LGA, large for gestational age; NICU, neonatal intensive care unit; pH, potential hydrogen; PIH, pregnancy-induced hypertension; RR, relative risk. Luciano-Mateo F, Hernandez-Aguilera A, Cabre N, Camps J, Fernandez-Arroyo S, Lopez-Miranda J, Menendez JA, Joven J. Nutrients in energy and one-carbon metabolism: learning from metformin users. Since then, there have been several observational and randomized controlled trials comparing metformin with insulin and glyburide. Metformin for any indication during pregnancy is associated with lower GWG and a modest reduced risk of pre-eclampsia, but increased gastrointestinal side-effects compared to other treatments.. FPG, fasting plasma glucose; GDM, gestational diabetes; OAD, oral antidiabetic drugs. Common metformin side effects may include: low blood sugar; nausea, upset stomach; or. The .gov means its official. 8600 Rockville Pike 11 RCTs comparing oral antidiabetics with placebo or other oral antidiabetics. Tartarin P, Moison D, Guibert E, Dupont J, Habert R, Rouiller-Fabre V, Frydman N, Pozzi S, Frydman R, Lecureuil C, Froment P. Metformin exposure affects human and mouse fetal testicular cells. More research is clearly needed before metformin can be considered as standard of care in the management of diabetes during pregnancy. Metformin (brand names Glucophage, Glucophage XR, Riomet, Fortamet, Glumetza) is a member of a class of medicines known as biguanides. and transmitted securely. Current guideline recommendations for use of metformin in gestational diabetes. The glycemic control was comparable to insulin group but 46.3% patients on metformin required supplemental insulin, indicating a high failure rate. Those subjects took their last metformin dose 10, 60, or 149 h before sample collection. Growth and motor-social development were similar in 61 nursing infants and 50 formula-fed infants born to mothers taking metformin throughout pregnancy and lactation [76]. AMPK mediates several metabolic effects of metformin on glucose and lipid metabolism, including increase in fatty acid beta-oxidation and insulin signaling, decrease in cholesterol, fatty acid and triglyceride biosynthesis and reduced gluconeogenic and lipogenic gene expression, as detailed in Figure 1. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic AMP; ETC, electron transport chain; FBPase, fructose-1,6-bisphosphatase; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide; OCT, organic cation transporter; PKA, protein kinase A; ROS, reactive oxygen species. In case there is any evidence of polyhydramnios, macrosomia, fetal growth restriction, maternal or fetal distress, the patient should be immediately switched to insulin. Silva JC, Fachin DR, Coral ML, Bertini AM. Metformin (n=286) or metformin plus insulin (n=38). Can it make it harder for me to get pregnant? Preliminary human evidence has been reassuring. Hernandez TL, Brand-Miller JC. Liang HL, Ma SJ, Xiao YN, Tan HZ. Randomized controlled trials comparing metformin with insulin or glyburide in women with gestational diabetes. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Moore LE, Briery CM, Clokey D, Martin RW, Williford NJ, Bofill JA, Morrison JC. Metformin was superior to glyburide and insulin in obese GDM women [52]. Abell SK, Nankervis A, Khan KS, Teede HJ. Feig DS, Murphy K, Asztalos E, Tomlinson G, Sanchez J, Zinman B, Ohlsson A, Ryan EA, Fantus IG, Armson AB, Lipscombe LL, Barrett JFR on behalf of fthe MiTy Collabortive Group. Tertti K, Ekblad U, Heikkinen T, Rahi M, Ronnemaa T, Laine K. The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta. Studies to define which category of patients are more likely to respond to metformin and who may need supplemental insulin. Coetzee EJ, Jackson WP. Padmanabhan S, Zen M, Lee V, Cheung NW. 5705185. While there is assurance that it does not have teratogenic potential and there is some evidence of long-term effects in offspring exposed to metformin in utero, there is a need to further assess its role in fetal programming. Metformin continues to dominate as an oral therapeutic agent for type 2 diabetes mellitus (T2DM), both as monotherapy and in combination with other medications. Increased risk of macrosomia and LGA with glyburide (RR 1.94, 95% CI: 1.033.66. Metformin alone (Fortamet): At first, 1000 milligrams (mg) once a day taken with the evening meal. Metformin increases insulin sensitivity, reduces hepatic glucogeneogenesis and enhances peripheral glucose uptake, resulting in lowering of blood glucose with minimal risk of hypoglycemia and weight gain [8]. Similar fasting and postprandial glucose. Lower maternal weight gain with metformin (7.78. Studies to assess the effect of metformin as add-on to other pharmacological therapies such as insulin, especially in women with pre-existing diabetes. (head, abdominal, and chest), and skin thickness. Toggle navigationNavigation Home Mens Jackets/Waistcoats Effect of metformin on fetal programming and long-term outcomes in exposed offspring. In a recent retrospective multicenter cohort study, Gante and colleagues assessed 388 GDM women who were prescribed metformin; 135 required supplemental insulin. Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. 7 The MiTy trial randomised 502, mostly obese insulin-treated women with type 2 diabetes to either metformin or placebo. Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis. Insulin associated with increased risk of hypertensive disorders of pregnancy compared to OADs. 42.7% in metformin group required supplemental insulin. GDM, gestational diabetes; LGA, large for gestational age; NICU, neonatal intensive care unit; OR, odds ratio; PIH, pregnancy-induced hypertension; SGA, small for gestational age. The impact of an earlier exposure during gestation is as yet unknown. Side effects are minimised by taking metformin either with food or just after eating, and beginning at a low dose. The management of non-insulin-dependent diabetes during pregnancy. This led to speculation that metformin is associated with a healthier fat distribution with less visceral and ectopic fat but there is no conclusive evidence for the same. Before In another meta-analysis of eight studies, metformin exposure in first trimester did not increase the risk of fetal malformations. Metformin may, therefore, be considered in milder forms of GDM where glycemic goals are not attained by lifestyle modification. Metformin use in pregnancy: efficacy, safety, and potential benefits Metformin use in pregnancy: efficacy, safety, and potential benefits J Endocrinol Invest. Nutrition Therapy in Gestational Diabetes . This sheet is about exposure to metformin in pregnancy and while breastfeeding. Online Glucophage Pills - Buy Metformin 1000 Mg - 500 Mg Metformin is a first-line treatment for type 2 diabetes, according to current diabetes guidelines. Higher rate of induced labor or planned Caesarian, Greater need of phototherapy for neonatal jaundice, Earlier need for medical treatment for GDM (26, Higher baseline HbA1c or serum fructosamine concentration [, Metformin impairs 1-C pathways that play a role in developmental programming. Because metformin increases AMPK activation, its effects on offspring need to be evaluated. Further, maternal weight gain in excess of the Institute of Medicine (IOM) recommendations has been associated with a higher risk of adverse fetal and maternal outcomes [13]. This results in a state of insulin resistance starting in midpregnancy. Primary outcome (composite of macrosomia, hypoglycemia, need for phototherapy, respiratory distress, stillbirth or neonatal death and birth trauma): 35% in glyburide group and 18.9% in metformin group. 4 UNI | 4.95 per 1UNI. Metformin can lead to epigenetic modifications through decrease in histone acetylation, histone phosphorylation and histone methylation. While there is mostly a beneficial effect on immediate pregnancy outcomes in mother and newborn, there is clearly a lack of long-term safety data in offspring exposed to metformin and further studies are required. Research design and methods This register-based cohort study from Finland included singleton children born 2004-2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). Coetzee EJ, Jackson WP. Tertti K, Ekblad U, Koshinen P, Vahlberg T, Ronnemaa T. Metformin vs. insulin in gestational diabetes. Pharmacokinetics of metformin during pregnancy. George A, Mathews JE, Sam D, Beck M, Benjamin SJ, Abraham A, Antonisamy B, Jana AK, Thomas N. Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide a randomised controlled trial. Balsells M, Garca-Patterson A, Sol I, Roqu M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. Metformin can be initiated in divided doses of 500 mg twice a day and the dose up-titrated at weekly intervals to 2500 mg per day in divided doses. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived and continued metformin through pregnancy. Metformin had lower incidence of neonatal hypoglycemia compared to insulin or glyburide. Gatford KL, Houda CM, Lu ZX, Coat S, Baghurst PA, Owens JA, Sikaris K, Rowan JA, Hague WM. AMPK activation leads to a switch in cell metabolism toward catabolic pathways generating energy and suppression energy consuming processes such as gluconeogenesis. Rena G, Hardie DG, Ewan RP. Seshiah V, Banerjee S, Balaji V, Muruganathan A, Das AK. Global Guideline on pregnancy and diabetes. Metformin can have a significant failure rate in GDM and there is a need to identify which women are more likely to require insulin. Kelley KW, Carroll DG, Meyer A. Hence, patients may require higher doses of metformin for adequate glycemic efficacy. If these problems keep happening the slow-release In several studies, metformin use was rather beneficial and associated with lower maternal weight gain and lower risk of PIH. Some have proposed that metformin may improve fetal insulin sensitivity by altering fetal programming and reduce the long-term risk of obesity and cardiometabolic risk in the offspring. Lower risk of preeclampsia, PIH, induction of labor and instrumental delivery with metformin compared to insulin. Significant increase in preterm births with metformin. Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at http://www.drugsincontext.com/wp-content/uploads/2018/05/dic.212523-COI.pdf. Metformin is, therefore, considered as the first-line drug in the management of type 2 diabetes (T2D) with excellent data of its efficacy, tolerability and safety in nonpregnant individuals. The effect of metformin on short-term fetal outcomes has been largely favorable (Tables 1, ,22 and and3).3). Kalra B, Gupta Y, Singla R, Kalra S. Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. This is particularly so because the predominant mechanism of action of metformin is via increase in 5AMP-activated protein kinase (AMPK) [8]. Higher incidence of preterm birth with metformin (OR 1.74, 95% CI: 1.132.68). Ijs H, Vrsmki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. Lindsay RS, Loeken MR. Metformin in pregnancy: promises and uncertainties. There was no difference in preeclampsia, perinatal mortality or LGA, but the risk of infant hypoglycemia was less with metformin (relative risk [RR] 0.34, 95% CI: 0.180.62). A recent Cochrane meta-analysis compared metformin and insulin in three RCTs with 241 women with pre-existing diabetes or previous GDM. In a mouse model of T2D embryopathy, Yanqing and colleagues demonstrated that metformin ameliorated insulin resistance and hyperglycemia in pregnant mice fed a high-fat diet. Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. There is some evidence metformin and glyburide are safe in pregnancy. Kalra B, Gupta Y. Summary of published meta-analysis comparing metformin with insulin or glyburide in GDM. Kelley and colleagues recently reviewed the current treatment strategies for women with GDM [7]. Refuerzo JS, Gowen R, Pedroza C, Hutchinson M, Blackwell SC, Ramin S. A pilot randomized, controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy. American Diabetes Association, Standards of Care. For all manuscript and submissions enquiries, contact the Editorial office moc.gnihsilbuplecxeoib@lairotide.cid, For all permissions, rights and reprints, contact David Hughes moc.gnihsilbuplecxeoib@sehguh.divad, Peer review comments to author: 9 March 2018, National Library of Medicine 8 RCTs, 1712 GDM women; metformin (n=853). It has been demonstrated that maternal hyperglycemia causes oxidative stress in the embryo and stimulates AMPK and this may drive the embryopathic effects of diabetes. Blumer I, Hadar E, Hadden DR, Jovanovi L, Mestman JH, Murad MH, Yogev Y. Diabetes and pregnancy: an endocrine society clinical practice guideline. 100 women who remained exclusively on metformin were compared with 100 matched women treated with insulin. Metformin use was, however, associated with less maternal weight gain, PIH, neonatal hypoglycemia and NICU stay, but more small-for-date babies [72]. 1446% required additional insulin. Disclosure and potential conflicts of interest: The authors declare no conflicts of interest. Insulin was added to metformin as required; 84.9% metformin users needed add-on insulin at a mean gestational age of 26.583.85 weeks. Tertti K, Toppari J, Virtanen HE, Sadov S, Ronnemaa T. Metformin treatment does not affect testicular size in offspring born to mothers with gestational diabetes. Glueck CJ, Salehi M, Sieve L, Wang P. Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome. Metformin may be considered as monotherapy in mild GDM, where it may result in less maternal weight gain, lower risk of PIH, lower risk of neonatal hypoglycemia and lower incidence of macrosomia. But if you're unable to reach your blood sugar (glucose) goals with diet and exercise alone, medications are often the next step. Ijs H, Vrsmki M, Morin-Papunen L, Keravuo R, Ebeling T, Saarela T, Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. Metformin can result in low levels of serum vitamin B12 and red blood cell folate [83]. Metformin is transported across the cell membrane and mitochondrial membrane by organic cation transporters (OCT). Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Therefore, caution must be exercised when prescribing metformin in pregnant women. There is clearly a need for more clinical trials to assess the effect of combined insulin plus metformin therapy in pregnancy with type 2 diabetes. Metformin is excreted into breast milk, but the amount is clinically insignificant. The HAPO Study Cooperative Research Group. Cialis Together 10mg Tablets - Tadalafil - 4 Tablets. Thus, there exists significant discord among guidelines with regard to the role of metformin and other oral antidiabetic agents in pregnancy with diabetes and there is a need to reach a uniform consensus in the light of recent evidence to avoid confusion. Additionally, there is a paucity of data on long-term effects in offspring exposed to metformin in utero. Metformin monotherapy in women with overt diabetes is highly unlikely to achieve glycemic targets. Kovo M, Kogman N, Ovadia O, Nakash I, Golan A, Hoffman A. Carrier-mediated transport of metformin across the human placenta determined by using the ex vivo perfusion of the placental cotyledon model. WINGS (Women in India with GDM Strategy) guidelines, 2015 [. Benefit should outweigh risk AU TGA pregnancy category: C US FDA pregnancy category: Not assigned Risk Summary: Data are not sufficient to inform a drug-associated risk for major birth defects or miscarriage; published studies have not reported an increased risk. Metformin doses ranging from 500 to 2500 mg/day have been used to treat women with GDM and the impact of doses exceeding 2500 mg/day on maternal, fetal and neonatal safety has not been determined. Additionally, a substantial number of women may be detected to have hyperglycemia during routine screening in pregnancy. Glyburide should not be used [. AMPK associates with chromatin by phosphorylating histone B2 or regulating histone deacetylases. Federal government websites often end in .gov or .mil. Metformin, therefore, seems to be a logical treatment for GDM. These are summarized in Tables 1 and and2.2. FOIA Arshad R, Khanam S, Shaikh F, Karim N. Feto-maternal outcomes and Glycemic control in Metformin versus insulin treated Gestational Diabetics. The role of metformin in T2D with pregnancy is less clear at the moment, but can be considered in women with high insulin dose requirements and rapid weight gain, as has been noted in a recent review [108]. 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