diabetes research and clinical practice 107 (2015) 290–299
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rna l hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country. A randomized control trial Jahanara Ainuddin a,*, Nasim Karim b, Anjum Ara Hasan c, Sanower Ali Naqvi d a
Dow University of Health Sciences, Karachi, Pakistan Bahria University, Medical and Dental College, Karachi, Pakistan c Hamdard University Hospital, 4, Karachi, Pakistan d Hamdard College of Medicine and Dentistry, Hamdard University, Karachi, Pakistan b
article info
abstract
Article history:
Aim: To compare treatment with metformin alone, metformin plus insulin and insulin
Received 20 January 2014
alone in women with gestational diabetes (GDM).
Received in revised form
Method: A total of 150 gestational diabetic patients who fulfilled the eligibility criteria were
2 October 2014
included in this prospective randomized control open labeled study. A risk factor based
Accepted 19 October 2014
screening was done followed by a GCT and then local GTT criteria from antenatal clinics.
Available online 31 October 2014
They were initially divided into two groups with odd numbers assigned to metformin treatment and even numbers to insulin treatment. Metformin and/or insulin treatment
Keywords:
was given and target blood sugar levels aimed at FBS 100 mg/dl and postprandial levels
Gestational diabetes
126 mg/dl. Supplemental insulin was added to metformin treatment group to maintain the
Pregnancy
glycemic targets if required. Patients were followed until delivery and maternal fetal out-
Metformin
comes and pharmacotherapeutic characteristics were recorded on a performa.
Insulin
Results: Less maternal weight gain was found in the metformin treated groups (9.8 1.5 kg [metformin alone] vs. 9.8 1.4 kg [metformin plus insulin] vs. 12.5 1.1 kg [insulin alone] P < 0.000). Preeclampsia was significantly less in metformin treated groups. There were no perinatal deaths in the study. Mean birth weight was significantly less in metformin treated groups (3.4 0.4 kg vs. 3.3 0.5 kg vs. 3.7 0.5 kg P < 0.01). Less neonatal morbidity was observed in metformin groups. 42.7% of patients required supplemental insulin (mean dose of 13.6 2 units) in the metformin group. Mean gestational age at which insulin was added was 31.8 5.9 weeks. Conclusion: Metformin is an effective and cheap treatment option for women with gestational diabetes with or without supplemental insulin. # 2014 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +92 301 2530961. E-mail addresses: [email protected], [email protected] (J. Ainuddin), [email protected] (N. Karim), [email protected] (A.A. Hasan), [email protected] (S.A. Naqvi). http://dx.doi.org/10.1016/j.diabres.2014.10.001 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice 107 (2015) 290–299
1.
Introducion
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition in pregnancy[1]. Gestational diabetes complicates about 3–6% of pregnancies with prevalence varying widely in different racial groups [2]. The prevalence of diabetes complicating pregnancy is increasing especially in South Asian countries like Pakistan [3], where the prevalence is estimated to be about 3.5% [4]. GDM is a potential cause of maternal morbidity and perinatal morbidity and mortality. These risks can potentially be reduced if glycemic control is maintained during pregnancy. Studies have shown that effective treatment of hyperglycemia in women with GDM can reduce adverse perinatal outcomes [5]. For years insulin therapy remained the mainstay of treatment for gestational diabetes not controlled by dietary modification. Guidance, vigilance and finances are required for safe self administration of insulin therapy to avoid hypoglycemia and maintaining tight glycemic control at the same time. A logical alternative would be a safe and effective oral therapy that should be more acceptable and cheaper for women with GDM. Metformin, an oral bigaunide that lowers glucose levels with a low risk of hypoglycemia, appears to be a good alternative to insulin in women with GDM. Metformin acts by reducing insulin resistance, improving insulin sensitivity probably by activation of AMP kinase and decreasing ATP concentration of hepatocytes [6]. It improves insulin sensitivity and hyperglycemia by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake and utilization. It also reduces markers of endothelial activation which are closely associated with insulin resistance [7,8]. Metformin crosses the placenta and acts as an insulin sensitizer and therefore will not cause neonatal hypoglycemia [9]. Metformin is a FDA class B drug in pregnancy with no reported teratogenic effects in animal models and human studies done in polycystic ovarian pregnancies [10–15]. Pakistan is projected to become the 8th most prevalent country for diabetes mellitus by 2035 [16]. This population has specific challenges in terms of marked insulin resistance, low socioeconomic status, poor compliance, follow up and affordability of insulin. The current study was designed to assess the effect of metformin treatment in women with GDM with or without supplemental insulin and to compare it with conventional insulin treatment. We hypothesized that in women with GDM in pregnancy metformin treatment compared with insulin will result in better perinatal and maternal outcomes and improved treatment acceptability with low or no additional insulin requirement.
2.
Methods
2.1.
Study design and participants
This trial was a prospective randomized open labeled clinical study with parallel assignment of patients comparing metformin with or without supplemental insulin treatment
291
with insulin alone treatment in GDM. The study was approved by the ethics review board of Dow University of Health Sciences and all participants of the study gave informed written consent. The patients were selected from those attending the antenatal clinics of Lyari General Hospital Karachi and Mamji Hospital Karachi. They belonged to all five major ethnic groups living in urban and rural areas of four provinces in Pakistan. These pregnant women were screened for presence of high risk factors including BMI above 25 kg/m2, previous history of macrosomic baby with weight 4 kg and above, previous history of GDM, family history of diabetes in first degree relatives, previous history of poor obstetric outcome (abortion, congenital anomalies, intrauterine fetal death, neonatal death), presence of polyhydramnios, pregnancy induced hypertension in present pregnancy and history of polycystic ovarian syndrome and presence of glycosuria in the present pregnancy. A 50 g oral glucose challenge test (GCT) was performed as an initial screening test irrespective of the fasting status and a blood sugar level 140 mg/dl (7.8 mmol/l) was considered a positive GCT. These women then had a 2 h 75 g oral glucose tolerance test (OGTT) after an overnight fast of 8–10 h. Diagnosis of GDM was made with at least two out of three elevated plasma glucose levels—fasting glucose >95 mg/dl (5.3 mmol/l), 1 h 180 mg/dl (10 mmol/l) and 2 h 155 mg/dl (8.6 mmol/l). Women who screened negative at first antenatal visit had repeat screening at 28, 32 and 36 weeks of pregnancy (Fig. 1). Women included in the study were between 20 to 46 years of age and had GDM diagnosed with a singleton pregnancy between 20 and 36 weeks of gestation. The exclusion criteria were women who have contraindications for metformin intake, a recognized fetal anomaly on ultrasound examination or ruptured membranes at study entry, presence of any other medical disorder (including type 1 and type 2 diabetes), a positive OGTT before 26–28 weeks of pregnancy consistent with diagnosis of overt diabetes in pregnancy and fetal growth restriction (birth weight 90th centile for gestational age or birth weight >4 kg), SGA (birth weight 30 and had higher blood sugar levels on the OGTT and needed pharmacological treatment for GDM at an earlier gestational age compared to women who maintained euglycemia with metformin alone in our study. Study limitations included a relatively small sample size, long individual study period and a high drop-out rate. The trial was open labeled and blinding was not possible due to different route of administration of the treatments. Long term follow up of infants whose mothers received metformin is continuing. The trial took place in routine clinical practice in a country with high prevalence of diabetes. In summary metformin treatment in gestational diabetes had advantages of less maternal weight gain, no risk of maternal hypoglycemia, cost effective oral therapy with good compliance and acceptability of treatment. There were fewer
neonatal complications with less hypoglycemia and NICU admissions. These findings are important for designing future multicenter studies with bigger sample size as metformin is not yet licensed for use in pregnancy.
Trial registration The trial is registered at Clinical trails.gov identifier number NCT 018557631 where the full protocol can be viewed.
Funding The study was entirely non profitable and received no grants. It was funded by researchers and by administration of Government hospital under Dow University of Health Sciences and by patients themselves at private obstetric clinics of Mamji hospital.
Conflict of interest statement The study was done as part of requirement of Ph.D. in clinical health Sciences at Dow University of Health Sciences, Karachi, Pakistan. The authors have no conflicts of interest regarding publication of this article.
Authors contribution JA designed and conducted the study and wrote the manuscript, NK and AA collected the data and edited and helped in
diabetes research and clinical practice 107 (2015) 290–299
manuscript writing, SSA reviewed the manuscript and helped in statistical analysis.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.diabres.2014.10.001.
references
[1] American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2003;26(Suppl. 1):S103–5. [2] Beischer NA, Oats JN, Henry OA, Sheedy MT. Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia. Diabetes 1991;40(Suppl. 2):35–8. [3] Shera AS, Jawad F, Maqsood A. Prevalence of diabetes in Pakistan. Diabetes Res Clin Pract 2007;70(2):219–22. [4] Jawad F, Irshaduddin P. Prevelance of GDM and pregnancy outcome in Pakistan. East Mediterr Health J 1996;2(2):268–73. [5] Crowther CA, Hiller JE, Moss JR. Effect of treatment of gestational mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. [6] Voillet Benoit, Gulgas Bruno, Garcia NS, Leclarc J, Mforetz F. Andreilli cellular and molecular mechanisms of metformin and overview. Clin Sci 2012;122(6):253–70. [7] Casallero AE, Delgado A, Aguilar-Salinas CA, Herrera AN, Castello JL, Labrera T, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo controlled, randomized clinical trial. J Clin Endocrinol Metab 2004;89:3943–8. [8] Hundal RS, Inzucchi SE. Metformin new understanding new uses. Drug 2003;63:1879–94. [9] Ellioti BD, Langer O, Schussling BA. Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin. Am J Obstet Gynecol 1997;176:527–30. [10] Glueck CJ, Philips H, Cameron D. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75:46–52. [11] Jakubowicz DJ, Iuorno MJ, Jakubowicz S. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524–9. [12] Haq F, Rizvi J. continuation of metformin reduces early pregnancy loss in obese Pakistani women with PCOS. Gynecol Obstet Invest 2010;69:184–9. [13] Briggs G, Freman R, Faffe S. Drugs in pregnancy and lactation. seventh ed. Philadelphia: Lippincott; 2005: 1017–20. [14] Coetzee EJ, Jackson WP. Pregnancy in established noninsulin dependent diabetes. A five and a half year study at Groote Schuur Hospital. S Afr Med J 1980;58:795–802. [15] Hughes RCE, Rowan JA. Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome. Diabetic Med 2006;23:318–22 (Diabetes UK).
299
[16] Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence in adults for 2013 and projections for 2035 for the IDF Diabetes Atlas. Diabetes Res Clin Pract 2014;103(2):137–49. [17] Rowan JA, Hogue WM, Gao W. Metformin versus insulin for the treatment of gestational diabetes. N Eng J Med 2008;19(358):2003–15. [18] Rai L, Meenakshi D, Asha. K. Metformin—a convenient alternative to insulin for Indian women with diabetes in pregnancy. Indian J Med Sci 2009;63(11):491–7. [19] Mathur R. Insulin resistance and the use of metformin: effect on body weight. Bariatric Times 2011;8(1):10–2. [20] Basit A, Shera AS. Prevalence of metabolic syndrome in Pakistan. Metab Syndr Relat Disord 2008;6:171–5. [21] Hyer L, Balani J, Johson A. Metformin treatment for gestational diabetes. Br J Diabetes Vasc Dis 2009;9:220–5. [22] Moore LE, Brieny GI, Clokey D. Metformin and insulin in the management of gestational diabetes mellitus. J Reprod Med 2007;52:1011–5. [23] Tertti K, Ekblad U, Terovahlberg. Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case control study. Rev Diabet Stud 2008;5:95–101. [24] Balani J, Hyer L, Rodin DA. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case control study. Diabetes Med 2009;26:798–802. [25] Hellmuth E, Damm P, Pedersen LM. Oral hypoglycemic agents in 118 diabetic pregnancies. Diabetes Med 2000;17:507–11. [26] Kaaja R, Tikkanen MJ, Vllnikka L. Serum lipoproteins, insulin and urinary prostanoid metabolites in normal and hypertensive pregnant women. Obstet Gynecol 1995;85:353–6. [27] Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin mechanism of action and tolerability. Pharmacol Res 1994;30:187–228. [28] Goh JEL, Sadler L, Rowan JA. Metformin for gestational diabetes in routine clinical practice. Diabetic Med 2011;28(9):1082–7. [29] Ijas H, Vaarasmaki M, Morinpaunen L. Metformin should be considered in the treatment of gestational diabetes: a prospective randomized study. BJOG 2010. http:// dx.doi.org/10.1111/j.1471-0528-2010. [30] Renda E, Faraci M, Prima F, Valeuti O, Hyseni E, Moate S, et al. Treatment of gestational diabetes: oral hypoglycemic agents or insulin? J Perinat Med 2011;5(3):63–4. [31] Niromanesh S, Alan A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract 2012;98(3):422–9. [32] Nicholson W, Bolen S, Witkop CT. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes. Obstet Gynecol 2009;113(1): 193–205. [33] Dulkotia JS, Ola, Bolarinde, Fraser R. Oral hypoglycemic agents vs. insulin in management of gestational diabetes: a systematic review and metaanalysis. AJOG 2010;9:457–9. [34] Maymone AC, Baillargeon JP, Menard J, Ardilouze JC. Oral hypoglycemic agents for gestational diabetes mellitus? Expert Opin Drug Saf 2011;10(2):227–38. [35] Thung NW. The management of gestational diabetes. Vasc Health Risk Manage 2009;5:153–64.
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rna l hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country. A randomized control trial Jahanara Ainuddin a,*, Nasim Karim b, Anjum Ara Hasan c, Sanower Ali Naqvi d a
Dow University of Health Sciences, Karachi, Pakistan Bahria University, Medical and Dental College, Karachi, Pakistan c Hamdard University Hospital, 4, Karachi, Pakistan d Hamdard College of Medicine and Dentistry, Hamdard University, Karachi, Pakistan b
article info
abstract
Article history:
Aim: To compare treatment with metformin alone, metformin plus insulin and insulin
Received 20 January 2014
alone in women with gestational diabetes (GDM).
Received in revised form
Method: A total of 150 gestational diabetic patients who fulfilled the eligibility criteria were
2 October 2014
included in this prospective randomized control open labeled study. A risk factor based
Accepted 19 October 2014
screening was done followed by a GCT and then local GTT criteria from antenatal clinics.
Available online 31 October 2014
They were initially divided into two groups with odd numbers assigned to metformin treatment and even numbers to insulin treatment. Metformin and/or insulin treatment
Keywords:
was given and target blood sugar levels aimed at FBS 100 mg/dl and postprandial levels
Gestational diabetes
126 mg/dl. Supplemental insulin was added to metformin treatment group to maintain the
Pregnancy
glycemic targets if required. Patients were followed until delivery and maternal fetal out-
Metformin
comes and pharmacotherapeutic characteristics were recorded on a performa.
Insulin
Results: Less maternal weight gain was found in the metformin treated groups (9.8 1.5 kg [metformin alone] vs. 9.8 1.4 kg [metformin plus insulin] vs. 12.5 1.1 kg [insulin alone] P < 0.000). Preeclampsia was significantly less in metformin treated groups. There were no perinatal deaths in the study. Mean birth weight was significantly less in metformin treated groups (3.4 0.4 kg vs. 3.3 0.5 kg vs. 3.7 0.5 kg P < 0.01). Less neonatal morbidity was observed in metformin groups. 42.7% of patients required supplemental insulin (mean dose of 13.6 2 units) in the metformin group. Mean gestational age at which insulin was added was 31.8 5.9 weeks. Conclusion: Metformin is an effective and cheap treatment option for women with gestational diabetes with or without supplemental insulin. # 2014 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +92 301 2530961. E-mail addresses: [email protected], [email protected] (J. Ainuddin), [email protected] (N. Karim), [email protected] (A.A. Hasan), [email protected] (S.A. Naqvi). http://dx.doi.org/10.1016/j.diabres.2014.10.001 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice 107 (2015) 290–299
1.
Introducion
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition in pregnancy[1]. Gestational diabetes complicates about 3–6% of pregnancies with prevalence varying widely in different racial groups [2]. The prevalence of diabetes complicating pregnancy is increasing especially in South Asian countries like Pakistan [3], where the prevalence is estimated to be about 3.5% [4]. GDM is a potential cause of maternal morbidity and perinatal morbidity and mortality. These risks can potentially be reduced if glycemic control is maintained during pregnancy. Studies have shown that effective treatment of hyperglycemia in women with GDM can reduce adverse perinatal outcomes [5]. For years insulin therapy remained the mainstay of treatment for gestational diabetes not controlled by dietary modification. Guidance, vigilance and finances are required for safe self administration of insulin therapy to avoid hypoglycemia and maintaining tight glycemic control at the same time. A logical alternative would be a safe and effective oral therapy that should be more acceptable and cheaper for women with GDM. Metformin, an oral bigaunide that lowers glucose levels with a low risk of hypoglycemia, appears to be a good alternative to insulin in women with GDM. Metformin acts by reducing insulin resistance, improving insulin sensitivity probably by activation of AMP kinase and decreasing ATP concentration of hepatocytes [6]. It improves insulin sensitivity and hyperglycemia by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake and utilization. It also reduces markers of endothelial activation which are closely associated with insulin resistance [7,8]. Metformin crosses the placenta and acts as an insulin sensitizer and therefore will not cause neonatal hypoglycemia [9]. Metformin is a FDA class B drug in pregnancy with no reported teratogenic effects in animal models and human studies done in polycystic ovarian pregnancies [10–15]. Pakistan is projected to become the 8th most prevalent country for diabetes mellitus by 2035 [16]. This population has specific challenges in terms of marked insulin resistance, low socioeconomic status, poor compliance, follow up and affordability of insulin. The current study was designed to assess the effect of metformin treatment in women with GDM with or without supplemental insulin and to compare it with conventional insulin treatment. We hypothesized that in women with GDM in pregnancy metformin treatment compared with insulin will result in better perinatal and maternal outcomes and improved treatment acceptability with low or no additional insulin requirement.
2.
Methods
2.1.
Study design and participants
This trial was a prospective randomized open labeled clinical study with parallel assignment of patients comparing metformin with or without supplemental insulin treatment
291
with insulin alone treatment in GDM. The study was approved by the ethics review board of Dow University of Health Sciences and all participants of the study gave informed written consent. The patients were selected from those attending the antenatal clinics of Lyari General Hospital Karachi and Mamji Hospital Karachi. They belonged to all five major ethnic groups living in urban and rural areas of four provinces in Pakistan. These pregnant women were screened for presence of high risk factors including BMI above 25 kg/m2, previous history of macrosomic baby with weight 4 kg and above, previous history of GDM, family history of diabetes in first degree relatives, previous history of poor obstetric outcome (abortion, congenital anomalies, intrauterine fetal death, neonatal death), presence of polyhydramnios, pregnancy induced hypertension in present pregnancy and history of polycystic ovarian syndrome and presence of glycosuria in the present pregnancy. A 50 g oral glucose challenge test (GCT) was performed as an initial screening test irrespective of the fasting status and a blood sugar level 140 mg/dl (7.8 mmol/l) was considered a positive GCT. These women then had a 2 h 75 g oral glucose tolerance test (OGTT) after an overnight fast of 8–10 h. Diagnosis of GDM was made with at least two out of three elevated plasma glucose levels—fasting glucose >95 mg/dl (5.3 mmol/l), 1 h 180 mg/dl (10 mmol/l) and 2 h 155 mg/dl (8.6 mmol/l). Women who screened negative at first antenatal visit had repeat screening at 28, 32 and 36 weeks of pregnancy (Fig. 1). Women included in the study were between 20 to 46 years of age and had GDM diagnosed with a singleton pregnancy between 20 and 36 weeks of gestation. The exclusion criteria were women who have contraindications for metformin intake, a recognized fetal anomaly on ultrasound examination or ruptured membranes at study entry, presence of any other medical disorder (including type 1 and type 2 diabetes), a positive OGTT before 26–28 weeks of pregnancy consistent with diagnosis of overt diabetes in pregnancy and fetal growth restriction (birth weight 90th centile for gestational age or birth weight >4 kg), SGA (birth weight 30 and had higher blood sugar levels on the OGTT and needed pharmacological treatment for GDM at an earlier gestational age compared to women who maintained euglycemia with metformin alone in our study. Study limitations included a relatively small sample size, long individual study period and a high drop-out rate. The trial was open labeled and blinding was not possible due to different route of administration of the treatments. Long term follow up of infants whose mothers received metformin is continuing. The trial took place in routine clinical practice in a country with high prevalence of diabetes. In summary metformin treatment in gestational diabetes had advantages of less maternal weight gain, no risk of maternal hypoglycemia, cost effective oral therapy with good compliance and acceptability of treatment. There were fewer
neonatal complications with less hypoglycemia and NICU admissions. These findings are important for designing future multicenter studies with bigger sample size as metformin is not yet licensed for use in pregnancy.
Trial registration The trial is registered at Clinical trails.gov identifier number NCT 018557631 where the full protocol can be viewed.
Funding The study was entirely non profitable and received no grants. It was funded by researchers and by administration of Government hospital under Dow University of Health Sciences and by patients themselves at private obstetric clinics of Mamji hospital.
Conflict of interest statement The study was done as part of requirement of Ph.D. in clinical health Sciences at Dow University of Health Sciences, Karachi, Pakistan. The authors have no conflicts of interest regarding publication of this article.
Authors contribution JA designed and conducted the study and wrote the manuscript, NK and AA collected the data and edited and helped in
diabetes research and clinical practice 107 (2015) 290–299
manuscript writing, SSA reviewed the manuscript and helped in statistical analysis.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.diabres.2014.10.001.
references
[1] American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2003;26(Suppl. 1):S103–5. [2] Beischer NA, Oats JN, Henry OA, Sheedy MT. Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia. Diabetes 1991;40(Suppl. 2):35–8. [3] Shera AS, Jawad F, Maqsood A. Prevalence of diabetes in Pakistan. Diabetes Res Clin Pract 2007;70(2):219–22. [4] Jawad F, Irshaduddin P. Prevelance of GDM and pregnancy outcome in Pakistan. East Mediterr Health J 1996;2(2):268–73. [5] Crowther CA, Hiller JE, Moss JR. Effect of treatment of gestational mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–86. [6] Voillet Benoit, Gulgas Bruno, Garcia NS, Leclarc J, Mforetz F. Andreilli cellular and molecular mechanisms of metformin and overview. Clin Sci 2012;122(6):253–70. [7] Casallero AE, Delgado A, Aguilar-Salinas CA, Herrera AN, Castello JL, Labrera T, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo controlled, randomized clinical trial. J Clin Endocrinol Metab 2004;89:3943–8. [8] Hundal RS, Inzucchi SE. Metformin new understanding new uses. Drug 2003;63:1879–94. [9] Ellioti BD, Langer O, Schussling BA. Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin. Am J Obstet Gynecol 1997;176:527–30. [10] Glueck CJ, Philips H, Cameron D. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75:46–52. [11] Jakubowicz DJ, Iuorno MJ, Jakubowicz S. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524–9. [12] Haq F, Rizvi J. continuation of metformin reduces early pregnancy loss in obese Pakistani women with PCOS. Gynecol Obstet Invest 2010;69:184–9. [13] Briggs G, Freman R, Faffe S. Drugs in pregnancy and lactation. seventh ed. Philadelphia: Lippincott; 2005: 1017–20. [14] Coetzee EJ, Jackson WP. Pregnancy in established noninsulin dependent diabetes. A five and a half year study at Groote Schuur Hospital. S Afr Med J 1980;58:795–802. [15] Hughes RCE, Rowan JA. Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome. Diabetic Med 2006;23:318–22 (Diabetes UK).
299
[16] Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence in adults for 2013 and projections for 2035 for the IDF Diabetes Atlas. Diabetes Res Clin Pract 2014;103(2):137–49. [17] Rowan JA, Hogue WM, Gao W. Metformin versus insulin for the treatment of gestational diabetes. N Eng J Med 2008;19(358):2003–15. [18] Rai L, Meenakshi D, Asha. K. Metformin—a convenient alternative to insulin for Indian women with diabetes in pregnancy. Indian J Med Sci 2009;63(11):491–7. [19] Mathur R. Insulin resistance and the use of metformin: effect on body weight. Bariatric Times 2011;8(1):10–2. [20] Basit A, Shera AS. Prevalence of metabolic syndrome in Pakistan. Metab Syndr Relat Disord 2008;6:171–5. [21] Hyer L, Balani J, Johson A. Metformin treatment for gestational diabetes. Br J Diabetes Vasc Dis 2009;9:220–5. [22] Moore LE, Brieny GI, Clokey D. Metformin and insulin in the management of gestational diabetes mellitus. J Reprod Med 2007;52:1011–5. [23] Tertti K, Ekblad U, Terovahlberg. Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case control study. Rev Diabet Stud 2008;5:95–101. [24] Balani J, Hyer L, Rodin DA. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case control study. Diabetes Med 2009;26:798–802. [25] Hellmuth E, Damm P, Pedersen LM. Oral hypoglycemic agents in 118 diabetic pregnancies. Diabetes Med 2000;17:507–11. [26] Kaaja R, Tikkanen MJ, Vllnikka L. Serum lipoproteins, insulin and urinary prostanoid metabolites in normal and hypertensive pregnant women. Obstet Gynecol 1995;85:353–6. [27] Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin mechanism of action and tolerability. Pharmacol Res 1994;30:187–228. [28] Goh JEL, Sadler L, Rowan JA. Metformin for gestational diabetes in routine clinical practice. Diabetic Med 2011;28(9):1082–7. [29] Ijas H, Vaarasmaki M, Morinpaunen L. Metformin should be considered in the treatment of gestational diabetes: a prospective randomized study. BJOG 2010. http:// dx.doi.org/10.1111/j.1471-0528-2010. [30] Renda E, Faraci M, Prima F, Valeuti O, Hyseni E, Moate S, et al. Treatment of gestational diabetes: oral hypoglycemic agents or insulin? J Perinat Med 2011;5(3):63–4. [31] Niromanesh S, Alan A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. Diabetes Res Clin Pract 2012;98(3):422–9. [32] Nicholson W, Bolen S, Witkop CT. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes. Obstet Gynecol 2009;113(1): 193–205. [33] Dulkotia JS, Ola, Bolarinde, Fraser R. Oral hypoglycemic agents vs. insulin in management of gestational diabetes: a systematic review and metaanalysis. AJOG 2010;9:457–9. [34] Maymone AC, Baillargeon JP, Menard J, Ardilouze JC. Oral hypoglycemic agents for gestational diabetes mellitus? Expert Opin Drug Saf 2011;10(2):227–38. [35] Thung NW. The management of gestational diabetes. Vasc Health Risk Manage 2009;5:153–64.
