Review Article
Experience of metformin use in gestational diabetes:
Contribution to the debate
Krishnan Swaminathan a,b,
2. Aims
To evaluate the maternal and foetal outcomes in women with
gestational diabetes treated with metformin at Victoria...
of treatment due to gastro-intestinal side effects and was able
to manage on diet alone after discontinuation. We, therefo...
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Experience of Metformin Use in Gestational Diabetes: Contribution to the Debate


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Experience of Metformin Use in Gestational Diabetes: Contribution to the Debate

  1. 1. ExperienceofMetforminUseinGestational Diabetes:ContributiontotheDebate
  2. 2. Review Article Experience of metformin use in gestational diabetes: Contribution to the debate Krishnan Swaminathan a,b, * a Consultant Endocrinologist, Apollo Specialty Hospital, Lakeview Road, KK Nagar, Madurai 625 020, India b Formerly Consultant Endocrinologist, Victoria Hospital, Kirkcaldy, United Kingdom a r t i c l e i n f o Article history: Received 8 April 2013 Accepted 8 May 2013 Keywords: Gestational diabetes Metformin Pregnancy a b s t r a c t With the current epidemic of obesity, more women are being diagnosed with gestational diabetes (GDM). Insulin therapy has been the gold standard in diabetic pregnancy as it does not cross the placenta. However, recent data from well designed trials and meta analysis may mark a significant change in practice in terms of using oral agents, especially met- formin in gestational diabetes. The aim of this brief communication is to share our experience of metformin use in gestational diabetes, thus contributing to the debate. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Background Insulin has always been the gold standard in the treatment of hyperglycaemia in gestational diabetes mellitus (GDM). There has always been a great reluctance to use metformin in gesta- tional diabetes due to placental transfer, lack of randomised control studies, doubts over efficacy, fear of congenital anoma- lies and paucity of long-term data on “metformin babies”. This was clearly reflected in the 1998 Australasian Diabetes in Preg- nancy Society guidelines that stated that “oral agents have no place in the treatment of gestational diabetes under normal circumstances”. But there has always been interest in the use of metformin in diabetic pregnancy since the 1960’s with studies mainly from South Africa1e3 which led its authors to conclude that “metformin appears to be safe for use in gestational dia- betes”. There is also some evidence of beneficial effects in women with polycystic ovarian syndrome who continued metformin during the first trimester and throughout preg- nancy.4,5 Reassuringly, these studies have shown that metfor- min was not teratogenic and reduced the otherwise high rate of first trimester abortion in these women. The recently published MiG study (Metformin in gestational diabetes) has gone a long wayinaddressingthisissue.Theauthorsofthisstudyconcluded thatmetformin,onitsownorincombinationwithsupplemental insulin, is a safe and effective option for women with GDM.6 Metformin is easy to use, does not cause hypoglycaemia, in- creases insulin sensitivity and insulin mediated glucose use in peripheral tissues7 which make an attractive option considering the insulin resistance in pregnancy. While metformin use in GDM is still controversial and debatable, we have been using metformin in gestational diabetes since 2006 (Victoria Hospital, Kirkcaldy, United Kingdom) after informed consent and this study is to evaluate our experience with metformin use on maternal and foetal outcomes. * Apollo Specialty Hospital, Lakeview Road, KK Nagar, Madurai 625 020, India. Tel.: þ91 (0) 8526421150; fax: þ91 (0) 452 2580199. E-mail address: k_swaminathan@hotmail.com. Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 3 e1 1 5 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.005
  3. 3. 2. Aims To evaluate the maternal and foetal outcomes in women with gestational diabetes treated with metformin at Victoria Hos- pital, Kirkcaldy, United Kingdom. 3. Methods The study involved retrospective analysis of case notes of all women diagnosed with gestational diabetes and treated with metformin between July 2006 and March 2009 at Forth Park Hospital, Kirkcaldy, United Kingdom. Local Ethics Committee approval was obtained for this study. GDM (Gestational Dia- betes Mellitus) was diagnosed based on SIGN Guidelines (Scottish Intercollegiate Guidelines Network).8 A random plasma glucose was recorded if glycosuria was detected or routinely at 24e28 weeks gestation. A 75 g oral glucose toler- ance test was carried out if the plasma glucose was >5.5 mmol/l (99 mg/dl) 2 h or more after food or >7 mmol/l (126 mg/dl) if within 2 h of food. GDM was diagnosed if the fasting glucose was >5.5 mmol/l (99 mg/dl) or 2 h glucose >9 mmol/l (162 mg/dl) on an oral glucose tolerance test. After a 1e2 week period of intensive dietary intervention, treatment with metformin was offered if the fasting glucose was >6 mmol/l (108 mg/dl) or if the pre-meal blood glucose was >7 mmol/l (126 mg/dl) on 2 occasions. Informed consent was obtained from all women undergoing therapy with metformin as this was an unlicensed indication. Supplemental insulin was considered if the blood glucose targets as listed above were breached on maximal or tolerable dose of metformin. Preeclampsia was defined as a condition characterised by new onset hypertension and proteinuria after 20 weeks gestation in a previously normotensive woman. Eclampsia was defined as occurrence of seizures in a woman with pre- eclampsia in the absence of other neurological syndromes. Stillbirth was defined as delivery of a foetus that had died after 24 weeks gestation. Macrosomia was defined as birth weight 4000 g. Neonatal hypoglycaemia was defined as two or more neonatal glucose values 2.6 mmol/l (47 mg/dl). Neonatal respiratory distress was defined as need for at least 4 h of respiratory support with supplemental oxygen, continuous positive airway pressure, or intermittent positive-pressure ventilation during the first 24 h after delivery. All the data were recorded and analysed using Microsoft excel 2007. 4. Results The cohort consisted of 54 women treated with metformin during the study period. The baseline characteristics are shown in Table 1. The predominant ethnicity was Caucasian (85%) followed by South Asian (11%). The proportion of current smokers was 22% and one-third of women had previous his- tory of gestational diabetes. The mean starting dose of metformin was 620 g and the mean total dose at term or discontinuation was 1305 g. The discontinuation rate of metformin was 7.4%. Approximately 22% of women needed supplemental insulin. There were no significant hypoglycaemic events recorded on any of the women. The mean weight gain during pregnancy (booking to term) was 8.5 kg. Preeclampsia was diagnosed in two women (3.7%) and one of the two had eclampsia as well (1.9%). Premature labour was recorded in two women (3.7%). The mean gestational age at delivery was 38.1 weeks. The predominant type of delivery was spontaneous vaginal delivery (72%) followed by Elective Caesarean section (17%), Emergency Caesarean section (9%) and forceps delivery (2%). The mean birth weight of “metfor- min babies” was 3566 g. Other foetal/neonatal outcomes are listed in Table 2. 5. Discussion Our retrospective study shows that metformin use in gesta- tional diabetes is well tolerated with a low incidence of detrimental outcomes in the mother and foetus. Metformin is a category B drug (no evidence of foetal or animal teratogenicity)9 but there are legitimate concerns of metformin use in pregnancy. Placental transfer of metformin is well recognised10 leading to concern about the possible adverse effects on the foetus. There is also concern regarding the possible effects in the mother. A non-randomised and non blinded study11 showed an increased rate of preeclampsia with metformin in pregnant women with GDM or type 2 dia- betes (32% with metformin vs 10% with insulin, p 0.02). The authors felt that there was an impression of association be- tween metformin and preeclampsia. In contrast, our study showed a preeclampsia rate of 3.7% (n ¼ 2/54). Both the women were obese. One woman with preeclampsia (and eclampsia) had a BMI (Body Mass Index) of 46 at booking and had in fact discontinued metformin four weeks after the start Table 1 e Baseline characteristics of women with GDM treated with metformin {mean (SD)}. Age (Years) 31.9 (5.9) BMI at booking (kg/m2 ) 32.9 (6.5) Random blood glucose (mmol/l) 7.6 (1.8) Fasting glucose on OGTT (mmol/l) 5.6 (0.8) 2-h glucose on OGTT (mmol/l) 9.1 (1.9) Gestational age at diagnosis (weeks) 26.3 (6.6) HbA1c at diagnosis (%) 5.7 (0.4) Gestational age at start of metformin (weeks) 28.6 (7.1) Table 2 e Fetal/neonatal outcomes in “metformin mothers”. Macrosmic babies 10 (18.5%) Stillbirths (%) 1 (1.9%) Neonatal hypoglycaemia (%) 2 (3.7%) Neonatal Respiratory distress (%) 2 (3.7%) Shoulder dystocia (%) 2 (3.7%) Phototherapy (%) 1 (1.9%) Congenital Malformationsa 1 (1.9%) a Ventricular septal defect on a background of Down’s syndrome. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 3 e1 1 5114
  4. 4. of treatment due to gastro-intestinal side effects and was able to manage on diet alone after discontinuation. We, therefore, do not feel that metformin played any part in the occurrence of preeclampsia (and eclampsia) in these women. Obesity it- self is a major risk factor for preeclampsia12 and may explain the reason for preeclampsia in both of our women as well as in the results of a non randomised study,11 in which women on metformin were more obese than their insulin counterparts. There is at least some merit in speculating that metformin reduces endothelial activation and may in fact reduce pre- eclampsia in insulin resistant pregnant women. To give credence to this hypothesis, a retrospective study on pregnant women with type 2 diabetes13 showed no significant differ- ence in preeclampsia rates in metformin treated mothers compared to a control group (comprising sulphonylurea and insulin treated mothers), in spite of more adverse risk factors in the metformin group. Reassuringly, the MiG study (Met- formin in Gestational Diabetes)6 showed no significant dif- ferences in maternal hypertensive complications between the metformin and the insulin treated mothers. In addition, this trial showed that the rate of primary outcome (a composite of neonatal complications: neonatal hypoglycaemia, neonatal respiratory distress, need for phototherapy, birth trauma or premature birth) did not differ significantly between metfor- min and insulin groups. A 38-year-old lady unfortunately had an unexplained stillbirth at 37 weeks gestation in our study. Glycaemic control was excellent throughout pregnancy on a metfor- min dose of 1.5 g daily. Gestational hypertension without preeclampsia was noted on the day preceding the stillbirth. The placental pathology showed villous dysmaturity, retro placental haemorrhage, fibrin encasement and foetal stem artery occlusion. We believe that factors other than gly- caemia, mainly associated with insulin resistance and obesity, cause micro and macro vascular changes in the placenta.14 This, in turn may lead to chronic fetal hypoxia that could explain such stillbirths. Apart from one non- randomised study,11 there has been no evidence of increased risk of stillbirths with metformin in any of the recent studies.6,15 The main drawback of our study is the lack of a comparator group as this was not set up for a case control study. In conclusion, our study adds to the accumulating evi- dence that may shift clinical practice towards using metfor- min in gestational diabetes in women who meet the criteria for insulin initiation. This would be of particular relevance in developing countries where the rates of diabetes are greatly increasing and cost of insulin prohibitive. Conflicts of interest The author has none to declare. Acknowledgements I sincerely thank Professor Ian W. Campbell, Fiona Jamieson, Denise Burns, Claire Henderson, Jeanette Baird, Carol Franks and Jennifer Thomson from the diabetes team at Victoria Hospital, Kirkcaldy, United Kingdom. r e f e r e n c e s 1. Coetzee EJ, Jackson WP. Diabetes newly diagnosed in pregnancy. A 4-year study at Groote Schuur Hospital. S Afr Med J. 1979 Sep 1;56(12):467e475. 2. Coetzee EJ, Jackson WP. Pregnancy in established non- insulin-dependent diabetics. A five-and-a-half year study at Groote Schuur Hospital. S Afr Med J. 1980 Nov 15;58(20):795e802. 3. Coetzee EJ, Jackson WP. The management of non-insulin- dependent diabetes during pregnancy. Diabetes Res Clin Pract. 1985e1986 Feb;1(5):281e287. 4. Glueck CJ, Philips H, Cameron D, et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fert Steril. 2001 Jan;75(1):46e52. 5. Gilbert C, Valois M, Koren G. Pregnancy outcome after first- trimester exposure to metformin: a meta-analysis. Fert Steril. 2006 Sep;86(3):658e663. 6. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. MiG trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003e2015. 7. Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992 Jun;15(6):755e772. 8. SIGN Guidelines 55. Section 8: Management of Diabetes in Pregnancy. 9. Feig D, Briggs G, Koren G. Oral antidiabetic agents in pregnancy and lactation: a paradigm sShift? Ann Pharmacother: 41(7):1174e1180. 10. Charles B, Norris R, Xiao X, et al. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit. 2006;28:67e72. 11. Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabetic Med. Jul 2000;17(7):507e511. 12. Sibai BM, Gordon T, Thom E, et al. Risk factors for pre- eclampsia in healthy nulliparous women: a prospective multicentre study. The National Institute of Child health and human development network of maternal-fetal Units. Am J Obstet Gynecol. 1995;172:642e648. 13. Hughes RCE, Rowan JA. Pregnancy in women with Type 2 diabetes: who takes metformin and what is the outcome? Diabetic Med. Mar 2006;23(3):318e322. 14. Campbell IW, Duncan C, Urquhart R, Evans M. Placental dysfunction and stillbirth in gestational diabetes. Br J Diabetes Vasc Dis. 2009;9:38e40. 15. Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a caseecontrol study. Diabetic Med. August 2009;26(8):798e802. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 3 e1 1 5 115
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