Maintenance of gestation implicates complex function of multiple endocrine mechanisms, and disruptions of the global metabolic environment prompt profound consequences on fetomaternal well-being during pregnancy and postpartum. Polycystic Ovary Syndrome (PCOS) and gestational diabetes mellitus (GDM) are very frequent conditions which increase risk for pregnancy complications, including early pregnancy loss, pregnancy-induced hypertensive disorders, and preterm labor, among many others. Insulin resistance (IR) plays a pivotal role in the pathogenesis of both PCOS and GDM, representing an important therapeutic target, with metformin being the most widely prescribed insulin-sensitizing antidiabetic drug. Although traditional views neglect use of oral antidiabetic agents during pregnancy, increasing evidence of safety during gestation has led to metformin now being recognized as a valuable tool in prevention of IR-related pregnancy complications and management of GDM. Metformin has been demonstrated to reduce rates of early pregnancy loss and onset of GDM in women with PCOS, and it appears to offer better metabolic control than insulin and other oral antidiabetic drugs during pregnancy. This review aims to summarize key aspects of current evidence concerning molecular and epidemiological knowledge on metformin use during pregnancy in the setting of PCOS and GDM. 1. Introduction Infertility currently affects approximately 48.5 million of women aged 20–44 years around the world [1], with severe implications in their physical and mental well-being [2]. Female fertility entails a complex array of endocrine mechanisms surrounding the integrity of the hypothalamus-pituitary-ovary (HPO) axis, which are especially important in maintenance of a healthy pregnancy, particularly due to the demands of the growing fetus [3]. Many conditions may disrupt this environment, and Polycystic Ovary Syndrome (PCOS)—an endocrine-metabolic disease that encompasses multiple hormonal alterations related to female infertility—stands out mainly due to its high prevalence, affecting 6-7% of women aged 12–45 years [4], with a worrisome 70% of women estimated to remain undiagnosed [5]. The hallmarks of this gynecoendocrine disease are disruption of ovarian steroidogenesis, giving rise to hyperandrogenemia and insulin resistance (IR) [6]. A complex IR-hyperinsulinemia-hyperandrogenemia cycle involved in the endocrine disruptions in PCOS [7] leads not only to the typical clinical picture of PCOS—featuring oligoanovulation and hyperandrogenic manifestations—but also to diverse
References
[1]
H. Teede, A. Deeks, and L. Moran, “Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan,” BMC Medicine, vol. 8, article 41, 2010.
[2]
M. T. Sheehan, “Polycystic ovarian syndrome: diagnosis and management,” Clinical Medicine & Research, vol. 2, no. 1, pp. 13–27, 2004.
[3]
C. B. Kallen, “Steroid hormone synthesis in pregnancy,” Obstetrics and Gynecology Clinics of North America, vol. 31, no. 4, pp. 795–816, 2004.
[4]
J. Vrbikova and V. Hainer, “Obesity and polycystic ovary syndrome,” Obesity Facts, vol. 2, no. 1, pp. 26–35, 2009.
[5]
M. N. Mascarenhas, S. R. Flaxman, T. Boerma, S. Vanderpoel, and G. A. Stevens, “National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys,” PLoS Medicine, vol. 9, no. 12, Article ID e1001356, 2012.
[6]
E. Diamanti-Kandarakis, “Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications,” Expert Reviews in Molecular Medicine, vol. 10, p. e3, 2008.
[7]
J. Rojas, M. Chávez, L. Olivar, et al., “Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth,” International Journal of Reproductive Medicine, vol. 2014, Article ID 719050, 17 pages, 2014.
[8]
S. A. Arslanian, V. D. Lewy, and K. Danadian, “Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and β-cell dysfunction and risk of cardiovascular disease,” The Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 1, pp. 66–71, 2001.
[9]
S. Robinson, A. D. Henderson, S. V. Gelding et al., “Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries,” Clinical Endocrinology, vol. 44, no. 3, pp. 277–284, 1996.
[10]
M. W. Elting, T. J. M. Korsen, P. D. Bezemer, and J. Schoemaker, “Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population,” Human Reproduction, vol. 16, no. 3, pp. 556–560, 2001.
[11]
Z. H. Huang, B. Manickam, V. Ryvkin, et al., “PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 1, pp. E17–E24, 2013.
[12]
S. Borruel, E. Fernández-Durán, M. Alpa？és et al., “Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS),” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 3, pp. 1254–1263, 2013.
[13]
R. Shroff, A. Kerchner, M. Maifeld, E. J. R. van Beek, D. Jagasia, and A. Dokras, “Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 12, pp. 4609–4614, 2007.
[14]
A. J. Cussons, B. G. A. Stuckey, and G. F. Watts, “Metabolic syndrome and cardiometabolic risk in PCOS,” Current Diabetes Reports, vol. 7, no. 1, pp. 66–73, 2007.
[15]
M. C. Amato, V. Guarnotta, D. Forti, M. Donatelli, S. Dolcimascolo, and C. Giordano, “Metabolically healthy polycystic ovary syndrome (MH-PCOS) and metabolically unhealthy polycystic ovary syndrome (MU-PCOS): a comparative analysis of four simple methods useful for metabolic assessment,” Human Reproduction, vol. 28, no. 7, pp. 1919–1928, 2013.
[16]
E. Mor, A. Zograbyan, P. Saadat et al., “The insulin resistant subphenotype of polycystic ovary syndrome: clinical parameters and pathogenesis,” The American Journal of Obstetrics and Gynecology, vol. 190, no. 6, pp. 1654–1660, 2004.
[17]
L. B. Craig, R. W. Ke, and W. H. Kutteh, “Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss,” Fertility and Sterility, vol. 78, no. 3, pp. 487–490, 2002.
[18]
A. Huidobro, A. M. Prentice, A. J. C. Fulford, and J. Rozowski, “Antropometría como predictor de diabetes gestacional: estudio de cohorte,” Revista Médica de Chile, vol. 138, pp. 1373–1377, 2010.
[19]
C. M. Clark Jr., C. Qiu, B. Amerman et al., “Gestational diabetes: should it be added to the syndrome of insulin resistance?” Diabetes Care, vol. 20, no. 5, pp. 867–871, 1997.
[20]
C. M. Boomsma, M. J. C. Eijkemans, E. G. Hughes, G. H. A. Visser, B. C. J. M. Fauser, and N. S. Macklon, “A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome,” Human Reproduction Update, vol. 12, no. 6, pp. 673–683, 2006.
[21]
S. Kamalanathan, J. P. Sahoo, and T. Sathyapalan, “Pregnancy in polycystic ovary syndrome,” Indian Journal of Endocrinology and Metabolism, vol. 17, pp. 37–43, 2013.
[22]
J. M. Lord, I. H. Flight, and R. J. Norman, “Insulin-sensitising drugs (metformin, troglitazone , rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome,” Cochrane Database of Systematic Reviews, vol. 3, Article ID CD003053, 2003.
[23]
H. C. Zisser, “Polycystic ovary syndrome and pregnancy: is metformin the magic bullet?” Diabetes Spectrum, vol. 20, no. 2, pp. 85–89, 2007.
[24]
M.-E. Lautatzis, D. G. Goulis, and M. Vrontakis, “Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review,” Metabolism: Clinical and Experimental, vol. 62, no. 11, pp. 1522–1534, 2013.
[25]
D. S. Feig, G. G. Briggs, and G. Koren, “Oral antidiabetic agents in pregnancy and lactation: a paradigm shift?” Annals of Pharmacotherapy, vol. 41, no. 7-8, pp. 1174–1180, 2007.
[26]
Package Insert for Glucophage, http://www.glucophagexr.com/pages/default.aspx.
[27]
C. R. McCartney, C. A. Eagleson, and J. C. Marshall, “Regulation of gonadotropin secretion: implications for polycystic ovary syndrome,” Seminars in Reproductive Medicine, vol. 20, no. 4, pp. 317–325, 2002.
[28]
M. Karoshi and S. O. Okolo, “Commentary: Polycystic ovarian disease (PCOD): a misnomer, looking for a new name,” International Journal of Fertility and Women's Medicine, vol. 49, no. 4, pp. 191–192, 2004.
[29]
D. H. Abbott, D. A. Dumesic, and S. Franks, “Developmental origin of polycystic ovary syndrome—a hypothesis,” Journal of Endocrinology, vol. 174, no. 1, pp. 1–5, 2002.
[30]
D. A. Dumesic, D. H. Abbott, and V. Padmanabhan, “Polycystic ovary syndrome and its developmental origins,” Reviews in Endocrine and Metabolic Disorders, vol. 8, no. 2, pp. 127–141, 2007.
[31]
M. H. Shanik, Y. Xu, J. Skrha, R. Dankner, Y. Zick, and J. Roth, “Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?” Diabetes Care, vol. 31, supplement 2, pp. S262–S268, 2008.
[32]
G. M. Reaven, “Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals,” Endocrinology and Metabolism Clinics of North America, vol. 34, no. 1, pp. 49–62, 2005.
[33]
J. Rojas, V. Bermúdez, E. Leal, et al., “Insulinorresistencia e hiperinsulinemia como factores de riesgo para enfermedad cardiovascular,” AVFT, vol. 27, pp. 29–39, 2008.
[34]
N. Sekar, J. C. Garmey, and J. D. Veldhuis, “Mechanisms underlying the steroidogenic synergy of insulin and luteinizing hormone in porcine granulosa cells: joint amplification of pivotal sterol-regulatory genes encoding the low-density lipoprotein (LDL) receptor, steroidogenic acute regulatory (stAR) protein and cytochrome P450 side-chain cleavage (P450scc) enzyme,” Molecular and Cellular Endocrinology, vol. 159, no. 1-2, pp. 25–35, 2000.
[35]
E. Y. Adashi, A. J. W. Hsueh, and S. S. C. Yen, “Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells,” Endocrinology, vol. 108, no. 4, pp. 1441–1449, 1981.
[36]
R. Salvi, E. Castillo, M.-J. Voirol et al., “Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway,” Endocrinology, vol. 147, no. 2, pp. 816–826, 2006.
[37]
J. W. Hill, J. K. Elmquist, and C. F. Elias, “Hypothalamic pathways linking energy balance and reproduction,” American Journal of Physiology: Endocrinology and Metabolism, vol. 294, no. 5, pp. E827–E832, 2008.
[38]
A. D. Eyvazzadeh, K. P. Pennington, R. Pop-Busui, M. Sowers, J.-K. Zubieta, and Y. R. Smith, “The role of the endogenous opioid system in polycystic ovary syndrome,” Fertility and Sterility, vol. 92, no. 1, pp. 1–12, 2009.
[39]
D. M. Selva, K. N. Hogeveen, S. M. Innis, and G. L. Hammond, “Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene,” Journal of Clinical Investigation, vol. 117, no. 12, pp. 3979–3987, 2007.
[40]
A. Gambineri, C. Pelusi, V. Vicennati, U. Pagotto, and R. Pasquali, “Obesity and the polycystic ovary syndrome,” International Journal of Obesity, vol. 26, no. 7, pp. 883–896, 2002.
[41]
C.-B. Book and A. Dunaif, “Selective insulin resistance in the polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 9, pp. 3110–3116, 1999.
[42]
E. Méndez, N. Montserrat, and J. V. Planas, “Modulation of the steroidogenic activity of luteinizing hormone by insulin and insulin-like growth factor-I through interaction with the cAMP-dependent protein kinase signaling pathway in the trout ovary,” Molecular and Cellular Endocrinology, vol. 229, no. 1-2, pp. 49–56, 2005.
[43]
A. Dunaif, J. Xia, C.-B. Book, E. Schenker, and Z. Tang, “Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome,” Journal of Clinical Investigation, vol. 96, no. 2, pp. 801–810, 1995.
[44]
J. E. Nestler, D. J. Jakubowicz, and M. J. Iuorno, “Role of inositolphosphoglycan mediators of insulin action in the polycystic ovary syndrome,” Journal of Pediatric Endocrinology & Metabolism, vol. 13, supplement 5, pp. 1295–1298, 2000.
[45]
P. Arner, “Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome,” Biochimie, vol. 87, no. 1, pp. 39–43, 2005.
[46]
L. J. Moran, R. Pasquali, H. J. Teede, K. M. Hoeger, and R. J. Norman, “Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society,” Fertility and Sterility, vol. 92, no. 6, pp. 1966–1982, 2009.
[47]
L. Radosh, “Drug treatments for polycystic ovary syndrome,” American Family Physician, vol. 79, no. 8, pp. 671–676, 2009.
[48]
A. D. Genazzani, E. Chierchia, E. Rattighieri et al., “Metformin administration restores allopregnanolone response to adrenocorticotropic hormone (ACTH) stimulation in overweight hyperinsulinemic patients with PCOS,” Gynecological Endocrinology, vol. 26, no. 9, pp. 684–689, 2010.
[49]
E. M. Velazquez, S. Mendoza, T. Hamer, F. Sosa, and C. J. Glueck, “Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy,” Metabolism: Clinical and Experimental, vol. 43, no. 5, pp. 647–654, 1994.
[50]
A. Kriplani and N. Agarwal, “Effects of metformin on clinical and biochemical parameters in polycystic ovary syndrome,” The Journal of Reproductive Medicine, vol. 49, no. 5, pp. 361–367, 2004.
[51]
D. Kocer, F. Bayram, and H. Diri, “The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 30, no. 5, pp. 367–371, 2014.
[52]
E. Diamanti-Kandarakis, T. Paterakis, and H. A. Kandarakis, “Indices of low-grade inflammation in polycystic ovary syndrome,” Annals of the New York Academy of Sciences, vol. 1092, pp. 175–186, 2006.
[53]
S. Tan, S. Hahn, S. Benson et al., “Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance,” European Journal of Endocrinology, vol. 157, no. 5, pp. 669–676, 2007.
[54]
J. Nawrocka and A. Starczewski, “Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance,” Gynecological Endocrinology, vol. 23, no. 4, pp. 231–237, 2007.
[55]
R. Horejsi, R. M？ller, S. Rackl et al., “Android subcutaneous adipose tissue topography in lean and obese women suffering from PCOS: comparison with type 2 diabetic women,” The American Journal of Physical Anthropology, vol. 124, no. 3, pp. 275–281, 2004.
[56]
J. G. Dolfing, C. M. Stassen, P. M. M. Van Haard, B. H. R. Wolffenbuttel, and D. H. Schweitzer, “Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS,” Human Reproduction, vol. 26, no. 6, pp. 1495–1500, 2011.
[57]
J.-P. Baillargeon and A. Carpentier, “Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity,” Fertility and Sterility, vol. 88, no. 4, pp. 886–893, 2007.
[58]
R. Keskin Kurt, A. G. Okyay, A. U. Hakverdi et al., “The effect of obesity on inflammatory markers in patients with PCOS: a BMI-matched case-control study,” Archives of Gynecology and Obstetrics, vol. 290, no. 2, pp. 315–319, 2014.
[59]
C. Celik, E. Bastu, R. Abali et al., “The relationship between copper, homocysteine and early vascular disease in lean women with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 29, no. 5, pp. 488–491, 2013.
[60]
S. A. Blair, T. Kyaw-Tun, I. S. Young, N. A. Phelan, J. Gibney, and J. McEneny, “Oxidative stress and inflammation in lean and obese subjects with polycystic ovary syndrome,” Journal of Reproductive Medicine, vol. 58, no. 3-4, pp. 107–114, 2013.
[61]
D. W. Stovall, A. P. Bailey, and L. M. Pastore, “Assessment of insulin resistance and impaired glucose tolerance in lean women with polycystic ovary syndrome,” Journal of Women's Health, vol. 20, no. 1, pp. 37–43, 2011.
[62]
S. Livadas, A. Kollias, D. Panidis, and E. Diamanti-Kandarakis, “Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: evidence from 1345 women with the syndrome,” European Journal of Endocrinology, vol. 171, no. 3, pp. 301–309, 2014.
[63]
G. ？nalan, U. Goktolga, T. Ceyhan, T. Bagis, R. Onalan, and R. Pabu？cu, “Predictive value of glucose—insulin ratio in PCOS and profile of women who will benefit from metformin therapy: obese, lean, hyper or normoinsulinemic?” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 123, no. 2, pp. 204–211, 2005.
[64]
A. S. Kumari, A. Haq, R. Jayasundaram, L. O. Abdel-Wareth, S. A. al Haija, and M. Alvares, “Metformin monotherapy in lean women with polycystic ovary syndrome,” Reproductive BioMedicine Online, vol. 10, no. 1, pp. 100–104, 2005.
[65]
A. Kruszyńska, J. S？owińska-Srzednicka, W. Jeske, and W. Zgliczyński, “Proinsulin, adiponectin and hsCRP in reproductive age women with polycystic ovary syndrome (PCOS)—the effect of metformin treatment,” Endokrynologia Polska, vol. 65, no. 1, pp. 2–10, 2014.
[66]
Q. Du, Y. J. Wang, S. Yang, B. Wu, P. Han, and Y. Y. Zhao, “A systematic review and meta-analysis of randomized controlled trials comparing pioglitazone versus the treatment of polycystic ovary syndrome,” Current Medical Research and Opinion, vol. 28, pp. 723–730, 2012.
[67]
A. Ziaee, S. Oveisi, A. Abedini, S. Hashemipour, T. Karimzadeh, and A. Ghorbani, “Effect of metformin and pioglitazone treatment on cardiovascular risk profile in polycystic ovary syndrome,” Acta Medica Indonesiana, vol. 44, no. 1, pp. 16–22, 2012.
[68]
V. R. Aroda, T. P. Ciaraldi, P. Burke et al., “Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome: a randomized, placebo-controlled clinical trial,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 2, pp. 469–476, 2009.
[69]
T. P. Ciaraldi, V. Aroda, S. R. Mudaliar, and R. R. Henry, “Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment,” Metabolism: Clinical and Experimental, vol. 62, no. 11, pp. 1587–1596, 2013.
[70]
K. D. Wilson, Z. Li, R. Wagner et al., “Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality,” PLoS ONE, vol. 3, no. 7, Article ID e2609, 2008.
[71]
R. M. Lago, P. P. Singh, and R. W. Nesto, “Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials,” The Lancet, vol. 370, no. 9593, pp. 1129–1136, 2007.
[72]
L. A. Barbour, C. E. McCurdy, T. L. Hernandez, J. P. Kirwan, P. M. Catalano, and J. E. Friedman, “Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes,” Diabetes Care, vol. 30, no. 2, pp. S112–S119, 2007.
[73]
J. Shao, P. M. Catalano, H. Yamashita, et al., “Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM,” Diabetes, vol. 49, no. 4, pp. 603–610, 2000.
[74]
P. M. Catalano, S. E. Nizielski, J. Shao, L. Preston, L. Qiao, and J. E. Friedman, “Downregulated IRS-1 and PPARγ in obese women with gestational diabetes: relationship to FFA during pregnancy,” American Journal of Physiology: Endocrinology and Metabolism, vol. 282, no. 3, pp. E522–E533, 2002.
[75]
S. Okuno, S. Akazawa, I. Yasuhi et al., “Decreased expression of the GLUT4 glucose transporter protein in adipose tissue during pregnancy,” Hormone and Metabolic Research, vol. 27, no. 5, pp. 231–234, 1995.
[76]
E. Sivan and G. Boden, “Free fatty acids, insulin resistance, and pregnancy,” Current Diabetes Reports, vol. 3, no. 4, pp. 319–322, 2003.
[77]
P. M. Catalano, L. Huston, S. B. Amini, and S. C. Kalhan, “Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus,” The American Journal of Obstetrics and Gynecology, vol. 180, no. 4, pp. 903–916, 1999.
[78]
A. Nadal, P. Alonso-Magdalena, S. Soriano, A. B. Ropero, and I. Quesada, “The role of oestrogens in the adaptation of islets to insulin resistance,” The Journal of Physiology, vol. 587, no. 21, pp. 5031–5037, 2009.
[79]
R. Kaaja and T. R？nnemaa, “Gestational diabetes: pathogenesis and consequences to mother and offspring,” Review of Diabetic Studies, vol. 5, no. 4, pp. 194–202, 2008.
[80]
J. L. Weiss, F. D. Malone, D. Emig, et al., “Obesity, obstetric complications and cesarean delivery rate—a population-based screening study,” American Journal of Obstetrics & Gynecology, vol. 190, no. 4, pp. 1091–1097, 2004.
[81]
T. Tzanavari, P. Giannogonas, and K. P. Karalis, “TNF-α and obesity,” Current Directions in Autoimmunity, vol. 11, pp. 145–156, 2010.
[82]
S. E. Shoelson, J. Lee, and A. B. Goldfine, “Inflammation and insulin resistance,” The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1793–1801, 2006.
[83]
D. Rosenbaum, R. S. Haber, and A. Dunaif, “Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 264, no. 2, pp. E197–E202, 1993.
[84]
J. Kawano and R. Arora, “The role of adiponectin in obesity, diabetes, and cardiovascular disease,” Journal of the CardioMetabolic Syndrome, vol. 4, no. 1, pp. 44–49, 2009.
[85]
I. L. M. H. Aye, T. L. Powell, and T. Jansson, “Review: adiponectin—the missing link between maternal adiposity, placental transport and fetal growth?” Placenta, vol. 34, pp. S40–S45, 2013.
[86]
J. Chen, B. Tan, E. Karteris et al., “Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines,” Diabetologia, vol. 49, no. 6, pp. 1292–1302, 2006.
[87]
R. Retnakaran, Y. Qi, P. W. Connelly, M. Sermer, A. J. Hanley, and B. Zinman, “Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia,” Diabetologia, vol. 53, no. 2, pp. 268–276, 2010.
[88]
T. A. Buchanan and A. H. Xiang, “Gestational diabetes mellitus,” The Journal of Clinical Investigation, vol. 115, no. 3, pp. 485–491, 2005.
[89]
E. P. Gunderson, C. P. Quesenberry Jr., D. R. Jacobs Jr., J. Feng, C. E. Lewis, and S. Sidney, “Longitudinal study of prepregnancy cardiometabolic risk factors and subsequent risk of gestational diabetes mellitus,” The American Journal of Epidemiology, vol. 172, no. 10, pp. 1131–1143, 2010.
[90]
D. Williams, “Pregnancy: a stress test for life,” Current Opinion in Obstetrics and Gynecology, vol. 15, no. 6, pp. 465–471, 2003.
[91]
J. Lauenborg, T. Hansen, D. M. Jensen et al., “Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population,” Diabetes Care, vol. 27, no. 5, pp. 1194–1199, 2004.
[92]
I. Mrizak, A. Arfa, M. Fekih, et al., “Inflammation and impaired endothelium-dependant vasodilatation in non obese women with gestational diabetes mellitus: preliminary results,” Lipids in Health and Disease, vol. 12, article 93, 2013.
[93]
R. Retnakaran, Y. Qi, C. Ye et al., “Hepatic insulin resistance is an early determinant of declining β-cell function in the first year postpartum after glucose intolerance in pregnancy,” Diabetes Care, vol. 34, no. 11, pp. 2431–2434, 2011.
[94]
The HAPO Study Cooperative Research Group, B. E. Metzger, L. P. Lowe, et al., “Hyperglycemia and adverse pregnancy outcomes,” The New England Journal of Medicine, vol. 358, pp. 1991–2002, 2008.
[95]
J. M. Perkins, J. P. Dunn, and S. M. Jagasia, “Perspectives in gestational diabetes mellitus: a review of screening, diagnosis, and treatment,” Clinical Diabetes, vol. 25, no. 2, pp. 57–62, 2007.
[96]
HAPO Study Cooperative Research Group, “Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics,” Diabetes, vol. 58, pp. 453–459, 2009.
[97]
W. H. Tam, R. C. W. Ma, X. Yang et al., “Glucose intolerance and cardiometabolic risk in children exposed to maternal gestational diabetes mellitus in utero,” Pediatrics, vol. 122, no. 6, pp. 1229–1234, 2008.
[98]
N. Freinkel, “Of pregnancy and progeny,” Diabetes, vol. 29, no. 12, pp. 1023–1035, 1980.
[99]
J. Jak？i？, F. Mikulandra, M. Peri？a et al., “Effect of insulin and insulin-like growth factor I on fetal macrosomia in healthy women,” Collegium Antropologicum, vol. 25, no. 2, pp. 535–543, 2001.
[100]
C. N. Hales and D. J. P. Barker, “The thrifty phenotype hypothesis,” British Medical Bulletin, vol. 60, pp. 5–20, 2001.
[101]
T. J. Wilkin and L. D. Voss, “Metabolic syndrome: maladaptation to a modern world,” Journal of the Royal Society of Medicine, vol. 97, no. 11, pp. 511–520, 2004.
[102]
A. Yessoufou and K. Moutairou, “Maternal diabetes in pregnancy: early and long-term outcomes on the offspring and the concept of ‘metabolic memory’,” Experimental Diabetes Research, vol. 2011, Article ID 218598, 12 pages, 2011.
[103]
M. Du, X. Yan, J. F. Tong, J. Zhao, and M. J. Zhu, “Maternal obesity, inflammation, and fetal skeletal muscle development,” Biology of Reproduction, vol. 82, no. 1, pp. 4–12, 2010.
[104]
K. Franke, T. Harder, L. Aerts et al., ““Programming” of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats,” Brain Research, vol. 1031, no. 2, pp. 276–283, 2005.
[105]
J. Rojas, N. Arraiz, M. Aguirre, M. Velasco, and V. Bermúdez, “AMPK as target for intervention in childhood and adolescent obesity,” Journal of Obesity, vol. 2011, Article ID 252817, 19 pages, 2011.
[106]
R. W. Brownsey, A. N. Boone, J. E. Elliott, J. E. Kulpa, and W. M. Lee, “Regulation of acetyl-CoA carboxylase,” Biochemical Society Transactions, vol. 34, no. 2, pp. 223–227, 2006.
[107]
L. Al-Khalili, A. V. Chibalin, M. Yu et al., “MEF2 activation in differentiated primary human skeletal muscle cultures requires coordinated involvement of parallel pathways,” The American Journal of Physiology—Cell Physiology, vol. 286, no. 6, pp. C1410–C1416, 2004.
[108]
M. M. Mihaylova and R. J. Shaw, “The AMPK signalling pathway coordinates cell growth, autophagy and metabolism,” Nature Cell Biology, vol. 13, no. 9, pp. 1016–1023, 2011.
[109]
R. Stark, S. E. Ashley, and Z. B. Andrews, “AMPK and the neuroendocrine regulation of appetite and energy expenditure,” Molecular and Cellular Endocrinology, vol. 366, no. 2, pp. 215–223, 2013.
[110]
P. Banerjee, R. R. Bhonde, and R. Pal, “Diverse roles of metformin during peri-implantation development: revisiting novel molecular mechanisms underlying clinical implications,” Stem Cells and Development, vol. 22, no. 22, pp. 2927–2934, 2013.
[111]
N. Desai, A. Roman, B. Rochelson et al., “Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome,” American Journal of Obstetrics and Gynecology, vol. 209, no. 2, pp. 136-e1–136-e9, 2013.
[112]
H.-Y. Lee, D. Wei, and M. R. Loeken, “Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy,” Diabetes/Metabolism Research and Reviews, vol. 30, no. 1, pp. 23–30, 2014.
[113]
G. S. Eng, R. A. Sheridan, A. Wyman, et al., “AMP kinase activation increases glucose uptake, decreases apoptosis, and improves pregnancy outcome in embryos exposed to high IGF-I concentrations,” Diabetes, vol. 56, no. 9, pp. 2228–2234, 2007.
[114]
J. J. Marin, “Plasma membrane transporters in modern liver pharmacology,” Scientifica, vol. 2012, Article ID 428139, 15 pages, 2012.
[115]
L. Gong, S. Goswami, K. M. Giacomini, R. B. Altman, and T. E. Klein, “Metformin pathways: pharmacokinetics and pharmacodynamics,” Pharmacogenetics and Genomics, vol. 22, no. 11, pp. 820–827, 2012.
[116]
J. W. Jonker and A. H. Schinkel, “Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3),” Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 1, pp. 2–9, 2004.
[117]
S. Eyal, T. R. Easterling, D. Carr et al., “Pharmacokinetics of metformin during pregnancy,” Drug Metabolism and Disposition, vol. 38, no. 5, pp. 833–840, 2010.
[118]
J. Saito, T. Hirota, N. Kikunaga, K. Otsubo, and I. Ieiri, “Interindividual differences in placental expression of the SLC22A2 (OCT2) gene: relationship to epigenetic variations in the 5′-upstream regulatory region,” Journal of Pharmaceutical Sciences, vol. 100, no. 9, pp. 3875–3883, 2011.
[119]
M. Kovo, N. Kogman, O. Ovadia, I. Nakash, A. Golan, and A. Hoffman, “Carrier-mediated transport of metformin across the human placenta determined by using the ex vivo perfusion of the placental cotyledon model,” Prenatal Diagnosis, vol. 28, no. 6, pp. 544–548, 2008.
[120]
M. Maliepaard, G. L. Scheffer, I. F. Faneyte et al., “Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues,” Cancer Research, vol. 61, no. 8, pp. 3458–3464, 2001.
[121]
M. V. St.-Pierre, M. A. Serrano, R. I. R. Macias et al., “Expression of members of the multidrug resistance protein family in human term placenta,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 279, no. 4, pp. R1495–R1503, 2000.
[122]
V. Ganapathy, P. D. Prasad, M. E. Ganapathy, and F. H. Leibach, “Placental transporters relevant to drug distribution across the maternal-fetal interface,” Journal of Pharmacology and Experimental Therapeutics, vol. 294, no. 2, pp. 413–420, 2000.
[123]
G. G. Briggs, R. K. Freeman, and S. J. Yaffe, Drugs in Pregnancy and Lactation, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 2002.
[124]
Package Insert: Metformin Hydrochloride, Bristol-Myers Squibb, New York, NY, USA, 2009.
[125]
S. J. Gutzin, E. Kozer, L. A. Magee, D. S. Feig, and G. Koren, “The safety of oral hypoglycemic agents in the first trimester of pregnancy: a meta-analysis,” Canadian Journal of Clinical Pharmacology, vol. 10, no. 4, pp. 179–183, 2003.
[126]
C. Gilbert, M. Valois, and G. Koren, “Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis,” Fertility and Sterility, vol. 86, no. 3, pp. 658–663, 2006.
[127]
G. G. Briggs, P. J. Ambrose, M. P. Nageotte, G. Padilla, and S. Wan, “Excretion of metformin into breast milk and the effect on nursing infants,” Obstetrics and Gynecology, vol. 105, no. 6, pp. 1437–1441, 2005.
[128]
C. J. Glueck and P. Wang, “Metformin before and during pregnancy and lactation in polycystic ovary syndrome,” Expert Opinion on Drug Safety, vol. 6, no. 2, pp. 191–198, 2007.
[129]
S. J. Gardiner, C. M. J. Kirkpatrick, E. J. Begg, M. Zhang, M. Peter Moore, and D. J. Saville, “Transfer of metformin into human milk,” Clinical Pharmacology and Therapeutics, vol. 73, no. 1, pp. 71–77, 2003.
[130]
B. Charles, R. Norris, X. Xiao, and W. Hague, “Population pharmacokinetics of metformin in late pregnancy,” Therapeutic Drug Monitoring, vol. 28, no. 1, pp. 67–72, 2006.
[131]
T. D. R. Vause, A. P. Cheung, S. Sierra et al., “Ovulation induction in polycystic ovary syndrome,” Journal of Obstetrics and Gynaecology Canada, vol. 32, no. 5, pp. 495–502, 2010.
[132]
O. Khorram, J. P. Helliwell, S. Katz, C. M. Bonpane, and L. Jaramillo, “Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 85, no. 5, pp. 1448–1451, 2006.
[133]
S. Palomba, A. Falbo, and G. B. La Sala, “Metformin and gonadotropins for ovulation induction in patients with polycystic ovary syndrome: a systematic review with meta-analysis of randomized controlled trials,” Reproductive Biology and Endocrinology, vol. 12, article 3, 2014.
[134]
R. G. Farquharson, E. Jauniaux, and N. Exalto, “Updated and revised nomenclature for description of early pregnancy events,” Human Reproduction, vol. 20, no. 11, pp. 3008–3011, 2005.
[135]
H. B. Ford and D. J. Schust, “Recurrent pregnancy loss: etiology, diagnosis, and therapy,” Reviews in Obstetrics and Gynecology, vol. 2, pp. 76–83, 2009.
[136]
P. A. Essah, K. I. Cheang, and J. E. Nestler, “The pathophysiology of miscarriage in women with polycystic ovary syndrome. Review and proposed hypothesis of mechanisms involved,” Hormones, vol. 3, pp. 221–227, 2004.
[137]
E. M. Tuckerman, M. A. Okon, T.-C. Li, and S. M. Laird, “Do androgens have a direct effect on endometrial function? An in vitro study,” Fertility and Sterility, vol. 74, no. 4, pp. 771–779, 2000.
[138]
N. C. Douglas, M. H. Thornton, S. K. Nurudeen, M. Bucur, R. A. Lobo, and M. V. Sauer, “Differential expression of serum glycodelin and insulin-like growth factor binding protein 1 in early pregnancy,” Reproductive Sciences, vol. 20, no. 11, pp. 1376–1381, 2013.
[139]
D. J. Jakubowicz, P. A. Essah, M. Sepp？l？, et al., “Reduced serum glycodelin and insulin-like growth factor-binding protein-1 in women with polycystic ovary syndrome during first trimester of pregnancy,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 2, pp. 833–839, 2004.
[140]
K. A. Toulis, D. G. Goulis, G. Mintziori et al., “Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome,” Human Reproduction Update, vol. 17, no. 6, Article ID dmr025, pp. 741–760, 2011.
[141]
J. Zheng, P. F. Shan, and W. Gu, “The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials,” Journal of Endocrinological Investigation, vol. 36, no. 10, pp. 797–802, 2013.
[142]
S. R. Salpeter, N. S. Buckley, J. A. Kahn, and E. E. Salpeter, “Meta-analysis: metformin treatment in persons at risk for diabetes mellitus,” The American Journal of Medicine, vol. 121, no. 2, pp. 149.e2–157.e2, 2008.
[143]
F. H. Nawaz, R. Khalid, T. Naru, and J. Rizvi, “Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?” Journal of Obstetrics and Gynaecology Research, vol. 34, no. 5, pp. 832–837, 2008.
[144]
G. Koren, C. Gilbert, and M. Valois, “Metformin use during the first trimester of pregnancy: is it safe?” Canadian Family Physician, vol. 52, pp. 171–172, 2006.
[145]
E. Vanky, S. Stridsklev, R. Heimstad et al., “Metformin Versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 12, pp. E448–E455, 2010.
[146]
S. Stridsklev, S. M. Carlsen, ？. Salvesen, I. Clemens, and E. Vanky, “Midpregnancy Doppler ultrasound of the uterine artery in metformin- versus placebo-treated PCOS women: a randomized trial,” The Journal of Clinical Endocrinology & Metabolism, vol. 99, pp. 972–977, 2014.
[147]
F. Sharifzadeh, M. Kashanian, and F. Fatemi, “A comparison of serum androgens in pre-eclamptic and normotensive pregnant women during the third trimester of pregnancy,” Gynecological Endocrinology, vol. 28, no. 10, pp. 834–836, 2012.
[148]
T.-Y. Hsu, K.-C. Lan, C.-C. Tsai, et al., “Expression of androgen receptor in human placentas from normal and preeclamptic pregnancies,” Taiwanese Journal of Obstetrics and Gynecology, vol. 48, no. 3, pp. 262–267, 2009.
[149]
J. M. Roberts and H. Gammill, “Insulin resistance in preeclampsia,” Hypertension, vol. 47, no. 3, pp. 341–342, 2006.
[150]
J. Uzan, M. Carbonnel, O. Piconne, R. Asmar, and J.-M. Ayoubi, “Pre-eclampsia: pathophysiology, diagnosis, and management,” Vascular Health and Risk Management, vol. 7, no. 1, pp. 467–474, 2011.
[151]
R. Menon, “Spontaneous preterm birth, a clinical dilemma: etiologic, pathophysiologic and genetic heterogeneities and racial disparity,” Acta Obstetricia et Gynecologica Scandinavica, vol. 87, no. 6, pp. 590–600, 2008.
[152]
L. Lettieri, A. M. Vintzileos, J. F. Rodis, S. M. Albini, and C. M. Salafia, “Does “idiopathic” preterm labor resulting in preterm birth exist?” American Journal of Obstetrics and Gynecology, vol. 168, no. 5, pp. 1480–1485, 1993.
[153]
S. Bolton, B. Cleary, J. Walsh, E. Dempsey, and M. J. Turner, “Continuation of metformin in the first trimester of women with polycystic ovarian syndrome is not associated with increased perinatal morbidity,” European Journal of Pediatrics, vol. 168, no. 2, pp. 203–206, 2009.
[154]
C. J. Glueck, N. Goldenberg, J. Pranicoff, M. Loftspring, L. Sieve, and P. Wang, “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 on and continued metformin through pregnancy,” Human Reproduction, vol. 19, no. 6, pp. 1323–1330, 2004.
[155]
C. J. Glueck, M. Salehi, L. Sieve, and P. Wang, “Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome,” Journal of Pediatrics, vol. 148, no. 5, pp. 628.e2–632.e2, 2006.
[156]
J. A. Rowan and MiG Investigators, “A trial in progress: gestational diabetes. Treatment with metformin compared with insulin (the Metformin in Gestational Diabetes [MiG] trial),” Diabetes Care, vol. 30, supplement 2, pp. S214–S219, 2007.
[157]
J. A. Rowan, W. M. Hague, W. Gao, M. R. Battin, M. P. Moore, and MiG Trial Investigators, “Metformin versus insulin for the treatment of gestational diabetes,” The New England Journal of Medicine, vol. 358, no. 19, pp. 2003–2015, 2008.
[158]
J. C. Silva, D. R. R. N. Fachin, M. L. Coral, and A. M. Bertini, “Perinatal impact of the use of metformin and glyburide for the treatment of gestational diabetes mellitus,” Journal of Perinatal Medicine, vol. 40, no. 3, pp. 225–228, 2012.
[159]
H. L. Barrett, K. L. Gatford, C. M. Houda et al., “Maternal and neonatal circulating markers ofmetabolic and cardiovascular risk in themetformin in gestational diabetes (MiG) trial,” Diabetes Care, vol. 36, no. 3, pp. 529–536, 2013.
[160]
S. Niromanesh, A. Alavi, F. R. Sharbaf, N. Amjadi, S. Moosavi, and S. Akbari, “Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial,” Diabetes Research and Clinical Practice, vol. 98, no. 3, pp. 422–429, 2012.
[161]
J. A. Rowan, W. Gao, W. M. Hague, and H. D. McIntyre, “Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial,” Diabetes Care, vol. 33, no. 1, pp. 9–16, 2010.
[162]
H. Ij？s, M. V？？r？sm？ki, L. Morin-Papunen et al., “Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study,” An International Journal of Obstetrics and Gynaecology, vol. 118, no. 7, pp. 880–885, 2011.
[163]
K. L. Gatford, C. M. Houda, Z. X. Lu et al., “Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment,” Diabetes, Obesity and Metabolism, vol. 15, no. 7, pp. 660–667, 2013.
[164]
R. Obeid, “Metformin causing vitamin b12 deficiency: a guilty verdict without sufficient evidence,” Diabetes Care, vol. 37, no. 2, pp. e22–e23, 2014.
[165]
J. S. Dhulkotia, B. Ola, R. Fraser, and T. Farrell, “Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis,” American Journal of Obstetrics & Gynecology, vol. 203, no. 5, pp. 457.e1–457.e9, 2010.
[166]
J. C. Silva, C. Pacheco, J. Bizato, B. V. De Souza, T. E. Ribeiro, and A. M. Bertini, “Metformin compared with glyburide for the management of gestational diabetes,” International Journal of Gynecology and Obstetrics, vol. 111, no. 1, pp. 37–40, 2010.
[167]
Y. Barak, M. C. Nelson, E. S. Ong et al., “PPARγ is required for placental, cardiac, and adipose tissue development,” Molecular Cell, vol. 4, no. 4, pp. 585–595, 1999.
[168]
J. Sevillano, I. C. López-Pérez, E. Herrera, M. Del Pilar Ramos, and C. Bocos, “Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates,” Biochemical Journal, vol. 389, no. 3, pp. 913–918, 2005.
[169]
P. Froment and P. Touraine, “Thiazolidinediones and fertility in polycystic ovary syndrome (PCOS),” PPAR Research, vol. 2006, Article ID 73986, 8 pages, 2006.
[170]
J. Gui, Q. Liu, and L. Feng, “Metformin vs insulin in the management of gestational diabetes: a meta-analysis,” PLoS ONE, vol. 8, no. 5, Article ID e64585, 2013.
[171]
V. W. Wong and B. Jalaludin, “Gestational diabetes mellitus: who requires insulin therapy?” Australian and New Zealand Journal of Obstetrics and Gynaecology, vol. 51, no. 5, pp. 432–436, 2011.
[172]
A. Sokup, B. Ruszkowska-Ciastek, K. Góralczyk, M. Walentowicz, M. Szymański, and D. Ro？？, “Insulin resistance as estimated by the homeostatic method at diagnosis of gestational diabetes: estimation of disease severity and therapeutic needs in a population-based study,” BMC Endocrine Disorders, vol. 13, article 21, 2013.
[173]
A. Corbould, F. Swinton, A. Radford, J. Campbell, S. McBeath, and A. Dennis, “Fasting blood glucose predicts response to extended-release metformin in gestational diabetes mellitus,” Australian and New Zealand Journal of Obstetrics and Gynaecology, vol. 53, pp. 125–129, 2013.
[174]
C. P. Spaulonci, L. S. Bernardes, T. C. Trindade, M. Zugaib, and R. P. Francisco, “Randomized trial of metformin vs insulin in the management of gestational diabetes,” American Journal of Obstetrics & Gynecology, vol. 209, no. 1, pp. 34.e1–34.e7, 2013.
[175]
K. Tertti, U. Ekblad, P. Koskinen, T. Vahlberg, and T. R？nnemaa, “Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin,” Diabetes, Obesity and Metabolism, vol. 15, no. 3, pp. 246–251, 2013.
[176]
Identifier NCT01587378, Metformin to Prevent Late Miscarriage and Preterm Delivery in Women with Polycystic Ovary Syndrome Trial (PregMet2), ClinicalTrials.gov, Bethesda, Md, USA, National Library of Medicine, 2012, http://clinicaltrials.gov/show/NCT01855763.
[177]
National Library of Medicine, “Metformin treatment in gestational diabetes and noninsulin dependent diabetes in pregnancy in a developing country (migdm&t2dm),” ClinicalTrials.gov NCT01855763, National Library of Medicine, Bethesda, Md, USA, 2013, http://clinicaltrials.gov/show/NCT01855763.
