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1 J Korean Diabetes 2016;17: Vol.17, No.4, 2016 ISSN ,,,, 동국대학교의과대학의학전문대학원내과학교실 A Pregnant Woman with Type 2 Diabetes Unintentionally Exposed to Metformin and Voglibose until the Second Trimester of Pregnancy: A Case Report Yeo Un Kim, Jae Hoon Kwak, Se Hwan Yeo, Seong Su Moon, Young Sil Lee Department of Internal Medicine, Dongguk University College of Medicine, Gyeongju, Korea Abstract Use of oral hypoglycemic agents during pregnant women with type 2 diabetes is controversial due to safety issues. Recently, randomized controlled trials support short-term safety of glyburide and metformin for the treatment of gestational diabetes mellitus. However, long-term safety data are not available. Moreover, use of oral hypoglycemic agents, except for metformin and glyburide, during pregnancy were limited to a few case reports. We report the case of a pregnant woman with type 2 diabetes unintentionally exposed to metformin and voglibose in addition to lercanidipine and bisoprolol during fetal organogenesis. The patient was continuously exposed to oral agents because we were not aware of her pregnancy until 22 weeks of gestation. After pregnancy was confirmed, we replaced oral hypoglycemic agents with insulin and discontinue betablockers. Delivery occurred without maternal or fetal complications. Keywords: Diabetes mellitus type 2, Hypoglycemic agents, Pregnancy Corresponding author: Young Sil Lee Department of Internal Medicine, Dongguk University College of Medicine, 87 Dongdae-ro, Gyeongju , Korea, ysbae28@hanmail.net Received: Dec. 9, 2015; Revised: Jan. 13, 2016; Accepted: Mar. 23, 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2016 Korean Diabetes Association The Journal of Korean Diabetes 277

2 서론 임신한당뇨병여성에서경구혈당강하제의사용은선천성기형발생등의안전성문제로일반적으로추천되지않고, 임상영양요법으로혈당조절이충분하지않을시인슐린사용을원칙으로하고있다. 최근 glyburide와 metformin이임신성당뇨병환자에서인슐린과동등한임상적효과와안전성을보여준바가있지만, 아직까지장기간의안전성연구가부족한실정이다 1. 그리고 glyburide 와 metformin 이외의다른경구혈당강하제의임신시사용에대해서는일부의증례보고를제외하고는안전성에대해알려진바가없어추천되지않고있다 2. 이러한이유들로제2형당뇨병여성에서임신이확인되면대개임신초기에경구혈당강하제에서인슐린으로전환되므로, 임신시장기간경구혈당강하제를복용한증례보고는많지않은실정이다 3,4. 저자들은임신중기까지임신인지모른채 metformin과 voglibose를복용하던제2형당뇨병환자의정상분만 1예를경험하여이를보고하고자한다. 증례 환자 : 여자, 38세주소 : 무월경현병력 : 5년전부터제2형당뇨병과고혈압으로 metformin 500 mg/ 일, voglibose 0.9 mg/ 일, lercanidipine 10 mg/ 일및 bisoprolol 2.5 mg/ 일을복용중이었다. 15년전에결혼한상태이나슬하에아이는없었으며, 평소월경주기가불규칙하여 2~3개월마다월경을하였는데, 최근 5 개월간월경이없어산부인과진료후임신 22주로진단되어내원하였다. 최근 6개월간 8 kg의체중증가가있었지만, 임신가능성을의심하지못한채, 불규칙한일상생활과운동부족등이체중증가의원인으로생각하고있었다. 과거력및산과력 : 5년전고혈압, 당뇨병진단받음. 15년전한번의유산력있음. 가족력 : 어머니와오빠가당뇨병으로치료중임. 사회력 : 흡연력및음주력없음신체진찰 : 내원당시키 155 cm, 체중 83 kg, 체질량지수 34.5 kg/m 2 였고, 혈압 123/79 mm Hg였다. 그외특이사항은없었다. 검사실소견 : 당화혈색소 6.0%, 공복혈당 104 mg/dl, 혈청인슐린 mu/l, c-펩타이드 3.59 ng/ml, 총콜레스테롤 135 mg/dl, 중성지방 128 mg/dl, 고밀도지단백콜레스테롤 47 mg/dl, 저밀도지단백콜레스테롤 71 mg/ dl, 혈중요소질소 5 mg/dl, 크레아티닌 0.5 mg/dl, AST 13 U/L, ALT 10 U/L, 소변알부민 / 크레아티닌비 7.0 μg/ mgcr ( 정상 0~30 μg/mgcr), free T ng/dll, 갑상샘자극호르몬 4.04 μiu/ml였다. 기타검사 : 입원후시행된산전초음파에서태아의머리와복부둘레및대퇴부길이는임신 22주에준하는소견이었고, 태아기형등은관찰되지않았다. 경과및치료 : 내원전복용중이던경구약제중 voglibose, metformin과 bisoprolol은중단하였고, 항고혈압제인칼슘억제제는유지하였다. 임신기간중혈당조절을위해아침식전 neutral protamine hagedorn (NPH) 인슐린과매식전 insulin lispro를투여하여, 공복혈당 78~89 mg/dl, 식후 2시간혈당 110~120 mg/dl를유지하였다. 고령의초산모로, 난산에대한걱정등으로환자및보호자가원하여임신 38주 6일에제왕절개로분만하였고, 분만전후산과적합병증은없었다. 신생아는분만당시체중이 3,510 g이었고, APGAR 점수가분만 1분및 5분후각각 9점및 10점이었으며, 신생아저혈당, 고빌리루빈혈증및선천성기형등의이상소견은없었다. 출산후 5년간환자는외래추적관찰하면서피임이권고된상태로인슐린대신경구혈당강하제 (metformin 1.0 g/ 일및 gemigliptin 50 mg/ 일 ) 를복용중이며, 아이는 5세인현재까지성장및발달장애없이건강한상태로지내고있다. 278

3 김여운외 고찰 당뇨병이있는여성에서임신은산모와태아에게여러가지부정적인영향을미칠수있는데, 이것은임신기간중의혈당조절정도와깊은관련이있다고알려져있다. 고혈당은유산과선천성기형의위험성을증가시키고, 거대아, 비정상적분만, 신생아저혈당, 황달, 호흡곤란등의주산기합병증을증가시킬뿐만아니라, 태어난아이는이후성장하면서당뇨병과비만의위험성을가지게되는것으로알려져있다 1-2,5. 따라서임신한당뇨병여성은임신기간중엄격한기준으로혈당을정상으로유지해야되며, 목표혈당을달성하기위해식이조절, 운동등의임상영양요법이선행되어야하고, 이로써혈당조절이충분하지않을때는인슐린사용이추천되고있다. 그러나최근보고들에서임신성당뇨병환자에서 glyburide 6 와 metformin 7 투여가인슐린과비교하여산과및신생아합병증, 선천성기형등을증가시키지않는다고하였고, 다낭성난소증후군환자에서임신기간중 metformin의계속적인사용이유산율을감소시키고, 선천성기형을증가시키지않아 [8,9, glyburide와같이태반을통과하지않는일부의설폰요소제와 metformin은임신한당뇨병환자에서사용이가능할것으로제안하고있으나, 아직까지장기간의안전성에대한자료는부족한실정이다 10. 특히임신성당뇨병환자를대상으로한연구들에서는태아의기관이형성되는임신 1기 (first trimester) 를지난시기에경구혈당강하제에노출된경우들이므로, 임신초기부터경구혈당강하제를계속복용하게되는제2 형당뇨병환자에서의경구혈당강하제노출정도와는다를것으로여겨진다. 물론 metformin의경우, 임신초기부터 metformine을복용한다낭성난소증후군환자에서선천성기형발생등에대한단기간의안전성이알려지고는있지만, 아직제2형당뇨병환자를대상으로한임상연구결과및장기간의안전성등에대한자료들은부족한실정이다. 앞에서언급된 glyburide와 metformin을제외한다른경구혈당강하제들은임신시안전성과관련된임상연구결 과가아직없는상태이며, 소수의증례만이보고되어있는실정이다 2. Yaris 등 3 은임신 7주까지 rosiglitazone, gliclazide, acarbose 및 atorvastatin을복용한다낭성난소증후군을동반한제2형당뇨병환자의정상분만 1예를보고하였고, Kolagasi 등 4 은 gliclazide와 ramipril을임신 16주까지복용하고정상분만한당뇨병 1예를보고하였다. 본증례는제2형당뇨병환자에서임신 22주까지 metformin, voglibose 및 bisoprolol을복용한예로, 태아의기관이형성되는임신초기부터중기까지장기간지속적으로경구혈당강하제에노출된이후에도태아및산모의주산기합병증이없었던경우이다. 비록제왕절개를통해분만하였으나, 이는산모가고령의초산모이면서비만한환자로이에따른난산등을고려한결과로, 경구혈당강하제의노출에따른주산기합병증으로보기는힘들다고여겨진다. 본증례에서와같이임신시 voglibose를비롯한알파글루코시다제억제제의사용에대한증례보고는매우드문데, Wilton 등 11 은임신초기에 acarbose에노출된 5명의여성중 2명이유산되었다고보고하였다. 본증례에서임신초기부터 voglibose를비롯한경구혈당강하제에장기간노출되었음에도불구하고, 태아및산모의주산기합병증이없었던가장큰이유는내원당시당화혈색소가 6.0% 로임신을인지하기전까지혈당관리가비교적잘되었고, 임신을인지한이후적극적인인슐린치료등으로혈당을철저하게관리하였기때문이라고여겨진다. Towner 등 12 은산전당뇨병관리가제대로되지않은상태에서임신초기에경구약제 ( 다양한설폰요소제들 ) 의노출유무보다는산모의고혈당이선천성기형발생에더큰영향을미친다고하였다. 본증례에서는항고혈압약제로칼슘차단제인 lecardipine 과베타차단제인 bisoprolol를임신중기까지복용하였는데, 임신이진단된후에베타차단제는중단하고칼슘차단제만을유지하였다. 일반적으로칼슘차단제는임신시비교적안전하게사용할수있는약제로알려져있지만, 일부의베타차단제는임신기간중사용시태아의성장저하와관련성이보고되고있어베타차단제의일차적사용은추천되지 279

4 않고있다 13. 본증례를통해일부경구혈당강하제의장기간노출이임신시안전하다고판단할수는없지만, 경구혈당강하제의노출자체가임신상태를반드시중단할사유가되지는않을수있으며, 임신전후의혈당관리상태가임신과관련된합병증발생에더큰영향을미칠수있다는것이다. 당뇨병환자는실제경구혈당강하제이외에도항고혈압제및지질강하제등다양한약제를함께복용할가능성이있으므로, 가임기의당뇨병여성환자를접할때는피임유무와월경력등에대한잦은병력청취를간과해서는안되며, 임신을원하는경우에는임신하기전에철저한혈당관리및사전약제조절등을통한계획적인임신이이루어질수있도록환자교육이반드시선행되어야할것으로여겨진다. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. American Diabetes Association. Management of diabetes in pregnancy. Diabetes Care 2015;38(Suppl 1):S Holt RI, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med 2014;31: Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod Toxicol 2004;18: Kolagasi O, Sari F, Akar M, Sari R. Normal pregnancy and healthy child after continued exposure to gliclazide and ramipril during pregnancy. Ann Pharmacother 2009;43: HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358: Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343: 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;358: Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod 2004;19: Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, Tinkanen H, Bloigu R, Puukka K, Ruokonen A, Tapanainen JS. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012;97: Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabetes Care 2007;30 Suppl 2:S Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105: Towner D, Kjos SL, Leung B, Montoro MM, Xiang A, 280

5 김여운외 Mestman JH, Buchanan TA. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995;18: Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51:

DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%) aged over 30 years or older had diabetes in 2010. Based on fasting g

DIABETES FACT SHEET IN KOREA 2012 Korean Diabetes Association (KDA) / Korea Centers for Disease Control and Prevention (CDC) DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%)