Management of Diabetes in Pregnancy - Springer Link

Curr Diab Rep (2012) 12:33–42 DOI 10.1007/s11892-011-0249-0

DIABETES AND PREGNANCY (CJ HOMKO, SECTION EDITOR)

Management of Diabetes in Pregnancy Jerasimos Ballas & Thomas R. Moore & Gladys A. Ramos

Published online: 3 December 2011 # Springer Science+Business Media, LLC 2011

Abstract The link between diabetes and poor pregnancy outcomes is well established. As in the non-pregnant population, pregnant women with diabetes can experience profound effects on multiple maternal organ systems. In the fetus, morbidities arising from exposure to diabetes in utero include not only increased congenital anomalies, fetal overgrowth, and stillbirth, but metabolic abnormalities that appear to carry on into early life, adolescence, and beyond. This article emphasizes the newest guidelines for diabetes screening in pregnancy while reviewing their potential impact on maternal and neonatal complications that arise in the setting of hyperglycemia in pregnancy. Keywords Diabetes mellitus . Gestational diabetes mellitus . Metformin . Glyburide . Pregnancy; diabetes management

Introduction: Classification of Diabetes in Pregnancy The most recent criteria for diagnosis and classification of diabetes were issued by the American Diabetes Association (ADA) in 2010 [1••]. The classification includes four clinical types: 1. Type 1 diabetes (DM1), formerly referred to as insulindependent or juvenile-onset diabetes. 2. Type 2 diabetes (DM2), formerly referred to as non– insulin-dependent or adult-onset diabetes. 3. Other specific types of diabetes related to a variety of genetic-, drug-, or chemical-induced diabetes 4. Gestational diabetes mellitus (GDM).

Type 1 Diabetes Clinical Trial Acronyms ACHOIS Australian Carbohydrate Intolerance Study in Pregnant Women DCCT Diabetes Control and Complications Trial HAPO Hyperglycemia and Adverse Pregnancy Outcomes MiG Metformin in Gestational Diabetes

J. Ballas : T. R. Moore : G. A. Ramos (*) Reproductive Medicine Department, University of California San Diego, 200 West Arbor Drive, San Diego, CA, USA e-mail: [email protected]

DM1 accounts for approximately 5% to 10% of patients diagnosed with diabetes in the general population. However, DM1 may represent a slightly greater fraction of reproductiveaged women, due to the relatively earlier age of onset compared with DM2. Markers of the immune response responsible for the pancreatic islet cell destruction pathognomonic of DM1 include autoantibodies directed to pancreatic islet cells, insulin, glutamic acid decarboxylase (GAD65), and tyrosine phosphatase IA-2 and IA-2β. One or more of these autoantibodies are usually present in 85% to 90% of individuals with DM1 and elevated fasting glucose. Most evidence indicates a genetic predisposition related to an individual’s HLA associations with linkage to DQA and DQB genes.

34

Type 2 Diabetes DM2 comprises 90% to 95% of those with diabetes and encompasses individuals who have insulin resistance with relative (rather than absolute) insulin deficiency. These patients, upon diagnosis and for most of their lifetime, do not require insulin therapy for survival. The specific etiology of DM2 is not known, but autoimmunity is not implicated as in DM1. Often associated with obesity or an increase in fat deposition in the abdominal region, the hyperglycemia in these patients is gradual and progressive, making ketoacidosis a rare event compared with DM1. Until recently, diagnosis of DM2 during pregnancy has been difficult due to the overlap with GDM. However, in 2008 to 2009, the International Association of Diabetes in Pregnancy Study Groups (IADPSG) and the ADA issued guidelines that state in high-risk women presenting for their first prenatal visit, DM2 may be diagnosed by the same criteria as outside of pregnancy [1••, 2••]. The new guidelines for diagnosing DM2 are as follows: 1. Hemoglobin A1c (HbA1c) >6.5%, performed in a laboratory using a method that is NGSP (National Glycohemoglobin Standardization Program) certified and standardized to the DCCT assay.* OR 2. Fasting plasma glucose of ≥126 mg/dL, with fasting defined as no caloric intake for at least 8 h.* OR 3. 2-hour plasma glucose ≥200 mg/dL during a 75-g oral glucose tolerance test (OGTT) as prescribed by the World Health Organization.* OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL. *In the absence of unequivocal hyperglycemia, criteria 1 to 3 should be confirmed by repeat testing.

Gestational Diabetes Mellitus New Diagnostic Criteria for GDM The HAPO study was a multicenter prospective cohort trial that aimed to correlate newborn outcomes and glucose parameters in “normal” women defined as those who underwent a 75-g OGTT between 28 and 32 weeks and had fasting plasma glucose ≤105 mg/dL and 2-hour plasma glucose level ≤200 mg/dL [3]. When maternal glucose levels were correlated with measures of newborn adiposity and birth weight greater than 90th percentile, the investigators found a linear relationship between increasing

Curr Diab Rep (2012) 12:33–42

glucose levels and elevated umbilical cord C-peptide, increased percent body fat, and neonatal birth weight [3, 4•]. Considering these findings of excess neonatal obesity in women with “normal” OGTT results, the IADPSG recommended new guidelines for the diagnosis of GDM. They selected an increased odds ratio of 1.75 for the outcomes of the 90th percentile for cord C-peptide, birth weight, and percent neonatal body fat. This translated to the following threshold values based on a 75-g 2-hour OGTT: & & &

Fasting plasma glucose of ≥92 mg/dL 1-hour value of ≥180 mg/dL 2-hour value of ≥153 mg/dL

A single abnormal value would be diagnostic of GDM. Applying these new thresholds, a total of 17.8% of the HAPO cohort would be diagnosed with GDM. The committee also agreed with the ADA position recommending screening of all pregnant women at first prenatal visit to identify those with overt DM2. The IADPSG recommended that women with a fasting glucose value greater than 92 mg/dL but less than 126 mg/dL upon first trimester testing would be diagnosed with GDM. All those with normal fasting glucose values at the time of the first prenatal visit would then undergo 75-g 2-hour OGTT at 24 to 28 weeks. If adopted widely, this new protocol represents a new paradigm for diagnosing GDM based on reducing fetal and childhood morbidity rather than maternal disease as formerly. Why Should GDM Be Treated? The US Preventative Services Task Force recently concluded that, based on available evidence, screening or treatment for GDM cannot be justified [5]. However, two recent randomized controlled trials have demonstrated improved outcomes of neonates in GDM pregnancy whose mothers were treated with diet and/or insulin, compared with no treatment. Crowther et al. [6], in the ACHOIS, randomized 1,000 women with GDM to treatment or no therapy between 16 and 30 weeks of gestation. Criteria for entry into the trial were a fasting glucose less than 140 mg/dL, and a 2-hour postprandial level between 140 and 200 mg/dL, therefore excluding people with overt diabetes. Women randomized to the treatment arm monitored glucose four times daily and dietary counseling was provided. Plasma glucose targets were premeal values less than 99 mg/dL and 3-hour postprandial levels less than 126 mg/dL. Approximately 20% in the treatment arm required insulin to achieve glycemic goals. The birth weight in the intervention group was lower (3,335±551 g vs 3,482±660 g; P1 SD) on a 2-hour glucose test and higher rates of macrosomia, cesarean deliveries, and newborn morbidity [3]. Conversely, improved blood glucose monitoring and strict control have been associated with improvement of all of these outcomes [4•, 6, 7••]. Co-existing maternal obesity may serve as strong confounder as well as an independent factor for fetal overgrowth in diabetic pregnancies, particularly in women diagnosed with GDM [53, 54]. Ultrasound evaluation to assess the fetal growth is an important part of the treatment paradigm in diabetic pregnancies. Fetal overgrowth is most reliably identified in the second and third trimesters, with accelerated abdominal circumference growth beginning at approximately 32 weeks being one of the most consistent findings [55]. This correlates with newborn biometric studies that show excess fetal weight tends to be disproportionally deposited along the abdomen and interscapular region, which likely relates clinically to increased risk of shoulder dystocia and labor abnormalities [56]. Because the American College of Obstetricians and Gynecologists recommends offering elective cesarean delivery in diabetic pregnancies with an estimated fetal weight exceeding 4,500 g, typically an ultrasound is performed between 36 and 37 weeks in all diabetic pregnancies to plan for mode of delivery [57]. Although macrosomia is strongly associated with suboptimal glucose control in diabetic

40

pregnancies, the risk of intrauterine growth restriction must always be considered in diabetic patients in whom disease has been long-standing and there is known cardiovascular or renal compromise. If growth restriction is found, close monitoring of interval growth with Doppler assessments of uteroplacental function and vigilant screening for preeclampsia should be implemented. Fetal lung development is delayed in diabetic pregnancies, likely due to elevated fetal insulin interfering with endogenous glucocorticoid-induced pulmonary maturation at the level of the pulmonary fibroblasts [30]. This delayed maturation likely leads to the disproportionate excess of respiratory distress in near-term infants from diabetic pregnancies [58]. Clinically, this may pose a challenge to timing delivery at term. Although 99% of normal infants at 37 weeks were found to have mature lung phospholipid profiles, in diabetic pregnancies such high proportions are not reached until 38.5 weeks, which should be taken into account before induction of labor, and certainly cesarean delivery, is planned prior to 39 weeks [59].

Conclusions Diabetes in pregnancy is a condition associated with significant morbidity for both mother and offspring. Owing to the global rise in obesity, managing pregnancies to minimize these morbidities will be increasingly challenging. Although significant advances have been achieved, improving maternal, fetal, and neonatal morbidity and mortality, our understanding of this ancient disease continues to be challenged. With the growing body of research linking in utero exposure to abnormal glucose levels with the development of childhood and adult metabolic syndrome, aggressive diagnosis and treatment of diabetes during pregnancy appears warranted [60].

Disclosure No potential conflicts of interest relevant to this article were reported.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. •• American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010; 34 (Suppl 1):S62–69. This updates readers on the classification of and possible etiologies of diabetes mellitus.

Curr Diab Rep (2012) 12:33–42 2. •• International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010; 33(3): S76–S82. This is an update on the new recommendations for screening and diagnosing diabetes in pregnancy. It also notes that pregestational diabetes should be diagnosed in the first trimester. 3. The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358 (19):1991–2002. 4. • The HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcomes: associations with neonatal anthropometrics. Diabetes. 2009; 58(2): 453–459. This secondary analysis of the HAPO trial demonstrates the relationship between maternal hyperglycemia and neonatal anthropometric measurements, which adds support to the Pederson hypothesis. 5. Hillier TA, Vesco KK, Pedula KL, Beil TL, Whitlock EP, Pettitt DJ. Screening for gestational diabetes mellitus: a systematic review for the US preventive services task force. Ann Intern Med. 2008;148:766–75. 6. Crowther CA, Jiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Australian Carbohydrate Intolerance Study Group in Pregnant Women (ACHOIS) trial group, effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477–86. 7. •• Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, Wapner RJ, Varner MW, Rouse DJ, Thorp JM, Sciscione A, Catalano P, Harper M, Saade G, Lain KY, Lain KY, Sorokin Y, Peaceman AM, Tolosa JE, Anderson GB. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009; 361(14): 1139–1148. This randomized control trial demonstrates that treatment of gestational diabetes is associated with lower rates of macrosomia and fat mass in the neonates of mothers with gestational diabetes. 8. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birth weight: the diabetes in early pregnancy study. Am J Obstet Gynecol. 1991;164:103–11. 9. de Veciana M, Trail PA, Evans AT, et al. A comparison of oral acarbose and insulin in women with gestational diabetes mellitus. Am J Obstet Gynecol. 2002;99 Suppl 4:S5. 10. Parretti E, Mecacci F, Papini M. Third trimester maternal glucose level from diurnal profiles in nondiabetic pregnancies—correlation with sonographic paramertes of fetal growth. Diabetes Care. 2001;24:1317–23. 11. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, Hod M, Kitzmiller JL, Kjos SL, Oats JN, Pettitt DJ, Sacks DA, Zoupas C. Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes Care. 2007;30:S251–60. 12. Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chlorpropamide therapy. Pediatrics. 1968;42:824–5. 13. Towner D, Kjos SL, Leung B, et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care. 1995;18: 1446–51. 14. Elliott BD, Schenker S, Langer O, et al. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol. 1994;171: 653–60. 15. Langer O, Conway D, Berkus M, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134–8. 16. Chmait R, Dinise T, Daneshmand S, et al. Prospective cohort study to establish predictors of glyburide success in women with

Curr Diab Rep (2012) 12:33–42

17. 18.

19. 20.

21.

22. 23. 24.

25.

26. 27.

28.

29.

30.

31.

32.

33. 34. 35.

36.

gestational diabetes mellitus. Am J Obstet Gynecol. 2001;185: S197. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30:S209–13. Jacobson GF, Ramos GA, Ching JY, et al. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol. 2005;193:118–24. Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabetes Care. 2007;30:S206–8. Hebert MF, Ma X, Naraharesetti SB, Krudys KM, Umans JG, Hankins GDV, Caritis SN, Miodovnik M, et al. Are we optimizing gestational diabetes treatment with Glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009;85 (6):607–14. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Eng J Med. 2007;356:551–66. Coetzee EJ, Jackson WP. Metformin in management of pregnant insulin-independent diabetics. Diabetologia. 1979;16:241–5. Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med. 2000;17:507–11. Hughes RC, Rowan JA. Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome? Diabet Med. 2006;23:318–22. • Rowan J, Hague W, Gao W, Battin M, Moore P. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008; 358(19): 2003–2015. This discusses the first randomized trial of the use of metformin for the treatment of gestational diabetes. Goh JE, Sadler L, Rowan J. Metformin for gestational diabetes in routine clinical practice. Diabet Med. 2011;28(9):1082–7. Gabbe SG, Holing E, Temple P, et al. Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol. 2000;182:1283–91. Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Am J Obstet Gynecol. 2007;197(5):447–56. Moore TR, Catalano P. Diabetes in Pregnancy in Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore TR (Ed.), Creasy and Resnik’s maternal-fetal medicine: principles and practice (6th ed). 2009: 958–967 Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus in Gabbe SG, Niebyl JR, Simpson JL (Ed), Obstetrics, Normal and Problem Pregnancies (4th ed). 2002: 1089–1097. Sibai BM, Caritis S, Hauth J, et al. Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National institute of child health and human development network of maternal-fetal medicine units. Am J Obstet Gynecol. 2000;182:364–9. Sibai BM, Ross MG. Hypertension in gestational diabetes mellitus: pathophysiology and long-term consequences. J Matern-Fetal Neo M. 2010;23(3):229–33. Hawthorne G. Maternal complications in diabetic pregnancy. Best Pract Res CL OB. 2011;25:77–90. American Diabetes Association. Nephropathy in diabetes—position statement. Diabetes Care. 2004;27(Supp 1):S79–83. Kitzmiller JL, Block JM, Brown FM, Catalano PM, et al. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations. Diabetes Care. 2008;31(5):1060–79. Jensen DM, Damm P, Ovesen P, Molsted-Pedersen L, Beck-Nielsen H, Westergaard JG, Moeller M, Mathiesen ER. Microalbuminuria,

41

37.

38. 39. 40. 41.

42.

43. 44. 45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

preeclampsia, and preterm delivery in pregnant women with type 1 diabetes. Diabetes Care. 2010;33(1):90–4. • Nielsen LR, Damm P, Mathiesen ER. Improved pregnancy outcome in type 1 diabetic women with microalbuniuria or diabetic nephropathy – effect of intensified antihypertensive therapy? Diabetes Care. 2009; 32(1): 38–44. This study highlights the importance of meticulous antihypertensive therapy as an adjunct to the treatment of DM1 in pregnancy. Bhatnagar A, Ghauri AJ, Hope-Ross M, Lip PL. Diabetic retinopathy in pregnancy. Curr Diabetes Rev. 2009;5:151–6. Kollias AN, Ulbig MW. Diabetic retinopathy—early diagnosis and effective treatment. Dtsch Artebl Int. 2010;107(5):75–84. Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med. 2005;33:S347–53. Cullen MT, Reece EA, Homko CJ, et al. The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol. 1996;13:449. American College of Obstetricians and Gynecologists (ACOG). Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin no. 60: pregestational diabetes mellitus. Obstet Gynecol. 2005;105:675–85. Ma J, Rayner CK, Jones KL, et al. Diabetic gastroparesis. Drugs. 2009;69:971–86. Camilleri M. Diabetic gastroparesis. N Engl J Med. 2007;356:820. Miller E, Hare JW, Clohert JP, Dunn PJ, Gleason RE, Soeldner JS, Kitzmiller JL. Elevated hemoglobin A1C in early pregnancy and major congenital anomalies in infants with diabetic mothers. N Engl J Med. 1981;304(22):1331–4. Becerra JE, Khoury MJ, Cordero JF, et al. Diabetes mellitus during pregnancy and the risks of specific birth defects: a population-based case–control study. Pediatrics. 1990;85:1–9. Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DM, Reece A. Diabetes mellitus and birth defects. Am J Obstet Gynecol. 2008;237:e1–9. Anderson JL, Waller DM, Canfield MA, Shaw GM, Watkins ML, Werler MM. Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology. 2005;16(1):87–92. Remsberg KE, McKeown RE, McFarland KF, Irwin LS. Diabetes in pregnancy and cesarean delivery. Diabetes Care. 1999;22: 1561–7. Keller JD, Lopez-Zeno JA, Dooley SL, Socol ML. Shoulder dystocia and birth trauma in gestational diabetes: a five-year experience. Am J Obstet Gynecol. 1991;165:928. Mimouni F, Miodovnik M, Rosenn B, et al. Birth trauma in insulin-dependent diabetic pregnancies. Am J Perinatol. 1992;9: 205–8. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol. 1998;179:476. Langer O, Yogev Y, Most O, Xenakis EMJ. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192:989–97. Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol. 2004;191:964–4. Ogata ES, Sabbagha R, Metzger BE, et al. Serial ultrasonography to assess evolving fetal macrosomia: studies in 23 pregnant diabetic women. JAMA. 1980;243:2405. Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol. 2003;189:1698–704. American College of Obstetricians and Gynecologists (ACOG). Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin no. 40: shoulder dystocia. Obstet Gynecol. 2002;100:1045–50.

42 58. Kjos SL, Walther FJ, Montoro M, et al. Prevalence and etiology of respiratory distress in infants of diabetic mothers: predictive value of fetal lung maturation tests. Am J Obstet Gynecol. 1990; 163:898. 59. Moore TR. A comparison of amniotic fluid fetal pulmonary phospholipids in normal and diabetic pregnancy. Am J Obstet Gynecol. 2002;186:641–50.

Curr Diab Rep (2012) 12:33–42 60. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115:e290–6. 61. Parretti E, Mecacci F, Panini M, et al. Third trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care. 2001;24:1317.