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The Evidence Base for Diabetes Care. Edited by R. Williams, W. Herman, A.-L. Kinmonth and N. J.

Wareham Copyright 2002 John Wiley & Sons, Ltd. ISBN: 0-471-98876-6

11 Gestational Diabetes Mellitus: A Commentary


THOMAS A. BUCHANAN
6602 General Hospital, Los Angeles, CA 90033, USA

ANTENATAL AND PERINATAL CONSIDERATIONS


As detailed by Dr McCance, the best (albeit suboptimal) evidence from crosssectional studies indicates that the risk of perinatal complications increases in a gradual, continuous fashion along with increasing glucose concentrations in the maternal circulation in human pregnancies1,2. Thus, there does not appear to be a true biological threshold for maternal glucose that will discriminate efciently between low-risk and high-risk pregnancies. That fact explains much of the controversy about the optimal way to diagnose gestational diabetes mellitus (GDM), as well as many of the observations about the relationship between clinically-dened glucose thresholds and perinatal outcomes that are reviewed by Dr McCance. Basically, women whose glucose levels fall above some threshold, whether on a 50 g glucose screening test, an oral glucose tolerance test or a fasting glucose determination, will have larger babies and, assuming adequate sample size, demonstrably more perinatal complications than women whose glucose levels fall below the threshold. Given this fact, two general types of approaches could be taken to detect pregnancies at risk for complications related to maternal glycemia. The more sensitive approach would set low glucose thresholds for diagnosis, identifying relatively large numbers of women as potentially at risk but including many pregnancies that will not have an adverse perinatal event. The more specic approach would set high glucose thresholds, so that abnormal pregnancies would have high rates of perinatal complications but so would some of the pregnancies identied as normal. No direct comparison of these two approaches has been undertaken, so no evidence-based recommendations can be made regarding the superiority of one approach over the other. The general trend in the eld has been to set

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thresholds lower and lower so as not to miss any at-risk pregnancies3,4. Whether this trend will decrease or increase5 morbid events is not yet clear. The considerations underlying the diagnosis of GDM can impact the approach to treatment once the condition is diagnosed. If diagnostic thresholds are set high, then a majority of women will be at risk and in need of treatment to lower the risk. As an example, if the diagnosis were based on a fasting serum or plasma glucose concentration >105 mg/dl (5.8 mmol/l), the risk of perinatal complications would be high and insulin treatment could reduce that risk6. On the other hand, if the diagnostic threshold is low (e.g. a plasma glucose concentration >140 mg/dl (7.8 mmol/l) one hour after a 50 g glucose challenge) then only a small minority of abnormal women would actually have an adverse event in the absence of treatment. Other methods would be needed to identify a high-risk subset. Frequent measurement of maternal capillary blood glucose concentrations is often recommended for this purpose. Several studies in which that approach has been applied were estimated to be cost-effective in a retrospective analysis7, despite the fact that many no-risk patients are required to perform glucose monitoring and to take insulin. Measurement of the fetal response to the maternal diabetic environment offers an alternative approach that can be combined with more simple measures of maternal glucose measurement to identify the at-risk subgroup of pregnancies8,9. The costeffectiveness of this approach remains to be assessed. Additional questions that await well-designed studies to address them include: (1) What constitutes optimal dietary treatment? (2) What is the role of other non-pharmacological interventions, such as physical exercise? (3) What is the role of oral antidiabetic agents? and (4) What is the optimal management of labor and delivery? All of these questions should be addressed in terms of optimal perinatal outcome, not in terms of the regulation of maternal glucose levels.

POSTPARTUM CONSIDERATIONS
GDM identies mothers and offspring with an increased risk of adverse health outcomes over the long term. Dr McCance highlighted the increased risk of diabetes in women who have had GDM compared to women in the general population. The risks may come from mechanisms traditionally linked to type 1 diabetes (i.e. autoimmunity directed at pancreatic -cells10) in a minority of women. Interventions to prevent diabetes in those women have not been tested. Physiological studies in patients who appear to be at risk for type 2 diabetes11,12 reveal two fundamental defects compared to normal women: (1) reduced tissue sensitivity to insulin and (2) impaired ability of pancreatic cells to compensate for insulin resistance by increasing insulin secretion. Epidemiological studies13 suggest that insulin resistance may accelerate the development of diabetes, perhaps by worsening -cell function. Accordingly,

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strategies to prevent or delay the onset of diabetes by ameliorating insulin resistance are currently being tested in women with a history of GDM. The interventions include diet and exercise, biguanide therapy and thiazolidinedione therapy. Physiological considerations suggest that at least the rst of these be implemented now, pending the results of the clinical trials. However, whether the approaches will actually work remains to be determined. Likewise, the optimally type and frequency of testing for diabetes after GDM remains controversial. Oral glucose tolerance results have been shown to be superior to other clinical measures for predicting the development of diabetes in two studies14,15. The cost effectiveness of such tests as compared to fasting glucose determinations remains to be evaluated. Finally, family planning is logical in women with a history of GDM, to allow assessment of glycemia prior to birth and minimization of the risk of birth defects in any subsequent pregnancies16. Virtually nothing is known about the mechanisms for or prevention of obesity and diabetes in the offspring of women with GDM. As reviewed by Dr McCance, some of the excess risk may be related to exposure to GDM in utero and, theoretically, could be mitigated by excellent metabolic control during pregnancy. However, it is likely that genetic transmission of risks of obesity and diabetes plays an important role as well. In the absence of data regarding how to manage the children, close observation of growth and glycemia seem prudent, along with measures to minimize obesity. Clearly, high-quality mechanistic and interventional research is needed in this area.

SUMMARY
Maternal glucose levels during pregnancy provide clinically useful information regarding the risk of perinatal and long-term complications in mothers and their children. No clear thresholds for abnormal glucose exist. Thus, management strategies that use glucose as a screening test to separate no-risk from atrisk pregnancies should be combined with additional testing (maternal glucose levels and fetal growth during pregnancy, maternal glucose levels and childhood development thereafter) to ne-tune the assessment of risk and to direct interventions to where the risk really is. Considerable investigation is needed to allow true evidence-based recommendations in all of these areas.

REFERENCES
1. Sacks DA, Greenspoon JG, Abu-Fadil S, Herny HM, Wolde-Tsadik G, Yao JFF (1995) Toward universal criteria gestational diabetes: the 75 gram glucose tolerance test in pregnancy. Am. J. Obstet. Gynecol. 172: 607614.

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2. Sermer M, Naylor CD, Gare DJ, Kenshole AB, Ritchie JWK, Farine D, Cohen HR, McArthur K, Holzapfel S, Biringer A, Chen E, Cadesky KI, Greenblatt EM, Leyland NA, Morris HS, Bloom JA, Abells YB (1995) Impact of increasing carbohydrate intolerance on maternal fetal outcomes in 3637 women without gestational diabetes. Am. J. Obstet. Gynecol. 173: 146156. 3. Metzger BE and the Conference Organizing Committee (1995) Summary and recommendations of the third international workshop-conference on gestational diabetes. Diabetes 40 (Suppl 2): 197201. 4. Metzger BE, Coustan DM the Organizing Committee (1998) Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diab. Care 21 (Suppl 2): B161B167. 5. Naylor CD, Sermer M, Chen E, Sykora K (1996) Cesarean delivery in relation to birthweight and gestational glucose tolerance: pathophysiology or practice style? JAMA 265: 11651170. 6. Kalkhoff RK (1985) Therapeutic results of insulin therapy in gestational diabetes mellitus. Diabetes 34 (Suppl 2): 97100. 7. Kitzmiller JL, Elixhauser A, Carr S, Major CA, DeVeciana M, Dang-Kilduff L, Weschler JM (1998) Assessment of costs and benets of management of gestational diabetes mellitus. Diab. Care 21 (Suppl 2): B123B130. 8. Hofmann HMH, Weiss PAM, Purstner P, Haas J, Gmoser G, Tamussino K, Schmon B. Serum fructosamine and amniotic uid insulin levels in patients with gestational diabetes and healthy control subjects. Am. J. Obstet. Gynecol. 162: 11741177. 9. Buchanan TA, Kjos SL, Schaefer U, Peters RK, Xiang A, Byrne J, Berkowitz K, Montoro M (1998) Utility of fetal measurements in the management of gestational diabetes. Diab. Care 21 (Suppl 2): B99B106. 10. Mauricio D, Balsells M, Morales J, Corcoy R, Puig-Domingo M, de Levia A (1996) Islet cell autoimmunity in women with gestational diabetes and risk of progression to insulin-dependent diabetes mellitus. Diab. Metab. Rev. 12: 275285. 11. Buchanan TA, Metzger BE, Freinkel N, Bergman RN (1990) Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am. J. Obstet. Gynecol. 162: 10081014. 12. Catalano OM, Tzyzbir ED, Wolfe RR, Cales J, Roman NM, Amini SB, Sims EAH (1993) Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am. J. Physiol. 264: E6067. 13. Peters RK, Kjos SL, Xiang A, Buchanan TA (1996) Long-term diabetogenic effect of a single pregnancy in women with prior gestational diabetes mellitus. Lancet 347: 22730. 14. Damm P, Kuhl C, Bertelsen A, Molsted-Pedersen L (1992) Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus. Am. J. Obstet. Gynecol. 67: 60716. 15. Kjos SL, Peters RK, Xiang A, Henry OA, Montoro MN, Buchanan TA (1995) Predicting future diabetes in Latino women with gestational diabetes: utility of early postpartum glucose tolerance testing. Diabetes 44: 586591. 16. Kjos SL, Peters RK, Xiang A, Schaefer U, Buchanan TA (1998) Hormonal choices after gestational diabetes. Diab. Care 21 (Suppl 2): B50B57.