Management of Gestational Diabetes Mellitus

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Introduction Sunil Gupta, Nagpur Gestational Diabetes Mellitus (GDM) is classically defined as “Carbohydrate intolerance resulting in hyperglycemia of variable responsible for the difference in diabetes incidence. Since then, severity with onset or first recognition during pregnancy”. (1) It numerous other observational studies have shown that the does not rule out a prior unidentified glucose intolerance, and offspring of diabetic pregnancies have a higher risk of developing in fact studies have found 10% to 15 % of cases of undiagnosed a diabetic phenotype.(13,14) There is also concern that this leads type 2 diabetes mellitus among GDM patient .(2) The incidence of to an intergenerational effect, with GDM promoting diabetes GDM is increasing, in parallel to the increase in type 2 diabetes. in the offspring, with perpetuation of the vicious cycle when GDM affects 5% to 7% of all pregnancies and frequency is rising the offspring herself develops GDM, thereby predisposing the the world over.(3) Data from South Indian population have shown grandchild to the development of diabetes as well. It is unknown mean prevalence of 13.9% [Urban- 17.8%, Semi-Urban-13.8% and however, what degree of hyperglycemia, or indeed if it is related Rural- 9.9%](4) metabolic disturbances, which increases the risk of diabetes to Insulin resistance increases in normal pregnancy due to the offspring. progressively rising levels of feto-placental hormones such as progesterone, cortisol, growth hormone, prolactin and human Why should GDM be treated ? placental lactogen.(5) The pancreas normally compensates by In clinical practice, it is important to understand whether GDM increasing insulin secretion, but when it fails to do so, or when women’s blood glucose be strictly controlled. insulin secretion declines due to a beta-cell function impairment,(6, 7) then GDM develops. Maternal hyperglycemia, which is typical Tufnell et al (15) concluded that there are insufficient data for any of GDM, cause a greater transfer of glucose to the fetus, causing conclusion on the effects of treatment for these conditions on fetal hyperinsulinemia (8) and an overgrowth of insulin-sensitive perinatal outcome. A systematic review for the US preventive (mainly adipose) tissues, with consequent excessive, unbalanced Services Task Force said that, “limited evidence suggests that GDM fetal growth, causing more trauma at birth, shoulder dystocia treatment after 24 weeks improves some maternal and neonatal and perinatal deaths. Hyperinsulinemia can also cause numerous outcomes. Evidence is even more sparse for screening before neonatal metabolic complications, such as hypoglycemia, 24 weeks of gestation” (16) hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia, Contrary to this, Langer et al (17) recently recorded composite respiratory distress syndrome, and a greater long-term risk of adverse fetal outcomes (stillbirth, macrosomia, large for gestational diabetes mellitus and obesity in the child. (9, 10) GDM is related to age, hypoglycemia, erythrocytosis, hyperbilirubinemia) in 59% of maternal complications too, such as hypertension, pre-eclampsia, untreated and 18% of treated GDM women and in 11% of normal greater need for cesarean delivery, (9,10) and a greater risk of controls. developing diabetes mellitus later on. The Australian Carbohydrate Intolerance Study in Pregnant Exposure of the fetus to hyperglycemia may predispose the child Women (ACHOIS)(18) unequivocally demonstrated that treating to a diabetes phenotype in later life. This has been elegantly GDM (as defined by World Health Organization [WHO] criteria) demonstrated by the long – term follow up of the offspring improves maternal and fetal outcome. The rate of severe perinatal of Pima Indian Mothers. (11, 12) Offspring who were born to outcomes in newborn was significantly lower in the treated group mothers who were already diabetic when pregnant had a 45% than in the control group (1% vs 4%, p= 0.01), and quality of life likelihood of type 2 diabetes by the age of 20-24, whereas was improved in the treated group. it was 8.6% amongst those with mothers who only developed diabetes after pregnancy (ie, were prediabetic ). Amongst siblings Glycemic Targets in Pregnancy: discordant for exposure to hyperglycemia, the sibling exposed to hyperglycemia had a considerably higher risk of subsequent The goal of glucose management in GDM is to keep blood diabetes, suggesting that genetic factors were not predominantly glucose values as near normal as possible. The Fifth International Medicine Update 2010  Vol. 20

Table 1 : Glycemic Targets for Control: Table 2 : Guidelines of the ACOG for exercise during ADA3 Parretti Yogev Siegmund (20) ACOG pregnancy 4th IWC 200121 2003 22 2007 23 20 Exercise recommended in Exercise to be avoided in preg- 19 2001 1998 SBGM CGMS CGMS pregnancy nancy FPG (mg/dl) <95 60-90 62 + 4.5 75 +12 77.3 + 9.0 1. walking 1. skiing 1 h PPPG <130- <140 94 + 6 105+ 13 100.0+12.6 2. jogging/running 2. horseback riding (mg/dl) 140 3. aerobic dance 3. ice hockey 2 h PPPG <120 <120 81.4 + 5.7 97 + 11 -- 4. swimming 4. soccer (mg/dl) 5. cycling 5. basketball Mean blood 6. dancing 6. scuba diving glucose (mg/ -- 100 74.7 + 5.2 83.7 + 18 87.2 + 7.2 Intensity of exercise dl) • 60%-90% of maximal heart rate Abbreviations : FPG, fasting plasma glucose;1h PPPG, 1 hour postprandial • 50%-85% of either maximal oxygen uptake or heart rate reserve plasma glucose; 2hPPPG, 2 hour postprandial plasma glucose; SBGM, self Duration and frequency blood glucose monitoring; CGMS, continuous glucose monitoring system. • 30 minutes a day (in absence of either medical or obstetric complications) Workshop Conference (FIWC) on GDM suggests capillary whole blood glucose concentrations below 96 mg/dl before meals and and Adverse Pregnancy Outcome (HAPO) Study (32) Similarly, either below 140 mg/dl, 1 h afterwards or below 120mg/dl , 2 we should also consider daily fluctuations in glycemia, which may h afterwards. The reference plasma glucose levels suggested by contribute to certain neonatal complications (33, 34). Glycemic the American Diabetes Association (ADA) are below 105 mg/dl control can also be evaluated by HbA1c, but the association before meals and either below 155mg/dl, 1 h afterwards, or below between HbA1c levels and pregnancy outcome seem to be weak. 130 mg/dl 2 h afterwards.3 It is worth emphasizing, however, that (35, 36) The HbA1 value for normal pregnant women is lower than these recommendations do not consider glycemic value higher non pregnant state. The standardization of HbA1c is need to be than those normally recorded in pregnancy outcome. (19) done to validate its results in GDM. Data shows that obese pregnant women have significantly lower Dietary Therapy : blood glucose levels at night. Langer et al found that maintaining a good glycemic control in obese women (mean plasma glucose All GDM should receive counseling from a dietician. Diet <100mg/dl) is associated with a favorable fetal outcome in women recommendation should be individualized with the aim to achieve treated with insulin.(24) This might mean that different glycemic normoglycemia, whilst providing required nutrients for normal values are needed in obese GDM women to reduce fetal and fetal growth and maternal health. A secondary aim is to prevent maternal complications, though prospective studies are needed to excessive maternal weight gain specially for overweight/obese clarify this issue before current recommendations can be changed. women. ADA recommends to provide adequate calories and nutrients to achieve the goals (FBG- < 105mg%, 1hr < 155mg% Measuring postprandial blood glucose co-relates better and 2hr.< 130mg% ). For obese women, a 30%-33% calorie with adverse neonatal events eg malformation, macrosomia, restriction to appx. 25 Kcal/kg actual weight/day is recommended. hypoglycemia and shoulder distocia (25, 26) Carbohydrate should be restricted to 35-40% of calories . Langer et al (27, 28) found higher macrosomia rates with mean blood Emphasis is given to spreading the dietary intake over six meals glucose levels higher than 105 mg/dl, whereas the risk of babies daily, with three main meals and three snacks in order to avoid being small for their gestational age was high when the mean large carbohydrate load at any time. Low glycemic Index food blood glucose levels dropped below 87 mg/dl; mean blood glucose is preferred. Except for saccharin, which can cross placenta and values should therefore be kept between 87 mg/dl and 105 mg/dL thus not recommended, other non-caloric sweeteners may be in GDM patients to avoid these fetal complications.(29) used in moderation (37) As for glycemic control and the other GDM-related fetal Physical Activity : complications (hypoglycemia, hypocalcemia, hyperbilirubinemia and respiratory complications), Langer et al postulated earlier If there is no medical or obstetric contraindication, women with that mean blood glucose levels below 100 mg/dl (as in normal GDM should maintain a sensible level of light and moderate pregnant women) reduce the incidence of all these complications. intensity physical activity until the later stages of the pregnancy (30, 31). A more recent paper (17) clearly showed that maternal and eg- walking for 20-30 min per day with antenatal exercise might fetal complication rates were still higher in GDM than in normal help in achieving glycemic control (37) pregnant women, even when strictly treated to achieve the above mentioned plasma glucose levels. The thresholds used in the past Insulin Therapy: may need to be reconsidered in light of recent CGMS data in normal pregnant women (22, 23) and the results of Hyperglycemia

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When treatment targets are not achieved by dietary means, then There is controversy regarding the use of oral hypoglycemic insulin is required. As the level of insulin resistance varies from agents during pregnancy. Most government drug agencies have person to person, insulin dose also need to be individualized. not approved their use in pregnancy. Glibenclemide (glyburide) has revealed only a minimal placental transfer (41) and several GDM women who have only postprandial hyperglycemia with studies (involving almost 1261 GDM cases) showed adequate normal fasting blood glucose should be given two to three times glycemic control in most patients, fewer hypoglycemic episodes regular or rapid acting insulins with each meal. These women with than with insulin treatment, and neonatal outcomes similar to additional fasting hyperglycemia need long acting NPH insulin in those achieved with insulin.(42, 43) On the other hand, a recent study night before dinner. For many years, fast-acting (regular) insulin, on 500 GDM women reported a significantly higher frequency of and intermediate –acting (isophane) insulin have been the preeclampsia and the need for phototherapy in glyburide-treated preferred insulins for the treatment of GDM. Human insulin patients.(44) does not normally cross the placenta, though antibody bound animal insulin has been reported to do so.( 38 ) However, it has Metformin has been shown to cross the placenta, with fetal been shown by (39) Jovanovic that is maternal glucose control, levels becoming about half those of the mother.(45) The recent rather than maternal anti-insulin antibody levels which influence randomized Metformin in Gestational Diabetes (MiG) trial birth weight. (39) assessing the safety and efficacy of metformin in 363 GDM women showed that metformin, alone or with insulin supplementation, At our centre(40) we evaluated Insulin dose, distribution & factors was not associated with more perinatal complications than insulin influencing the requirement of insulin in 781 GDM & DGGT alone, but insulin had to be associated with the metformin in 46% (Decreased Gestational Glucose Tolerance, where any two hr of cases to achieve an adequate metabolic control. (46) OGTT value of blood glucose is >120mg% but fail to meet the standard ADA or WHO criteria for diagnosis of GDM) women. Metformin has been associated with fewer cases of GDM among We observed that : women with polycystic ovary syndrome, (47) and it was responsible for no neonatal complications in terms of malformations, birth • Amongst total 781 subjects, 382(48.9%) women required weight or neonatal complications in terms of malformations, insulin. Out of 493 GDM women 300(60.8%) and of 288 birth weight or neonatal hypoglycemia.(48) Because it crosses the DGGT women 82 (28.4%) needed insulin to achieve glyce- placenta and relatively few cases have been treated so far, it mic targets. would be prudent to await more information before assuming it • 85.6% were on ≤ 40U insulin and 14.3 % were on > 40U is safe to use this drug in pregnancy. insulin/day at delivery. Women requiring < 40IU Insulin/24hr Acarbose might be used if the patient tolerates the related at delivery were further evaluated as below: gastrointestinal discomfort ; a randomized trial on this drug - Insulin requirement in GDM was 16 ± 9.5 U /day & is underway and the results will tell us more about its safety DGGT 10+ 7.2U/day (P0.002) profile. (49) - There was progressive increase in insulin dose from Thiazolinediones (50) cross the placenta and, apart from one or diagnosis to delivery by 1.5 times( P0.01) two case studies, we know nothing about its safety in pregnancy. The same gose for incretin mimtics, which should not be used - GDM women needed 0.25 IU/Kg/day & DGGT women in pregnancy for the time being . (51) needed 0.17 IU/Kg/day insulin - Pre dinner Insulin dose was highest & breakfast was Post Partum Management : lowest in both the group and was statistically signifi- cant [GDM –P 0.01, DGGT- P 0.01 ] The medical management of gestational diabetes should not conclude with the delivery of the fetus. Although hyperglycemia - Insulin dose was positively co-related to FBG (P 0.01), usually resolves with the conclusion of the pregnancy, women Pre pregnancy wt (P 0.01) GHb%(P 0.01)and Pre Preg- who have had GDM are at high risk of developing diabetes later nancy BMI ( P0.01) but couldn’t be co-related to height, in life. A part from the development of diabetes, women who had age & weeks of diagnosis. GDM have an adverse cardiac risk profile, including the metabolic (52, 53) There is now increasing evidence that the newer rapid acting syndrome. A higher prevalence of cardiovascular disease that insulin analogs lispro and aspart are also safe in pregnancy, and occurs at a younger age, independent of the metabolic syndrome (52) indeed, they are commonly used. Data for glulisine is not available and type 2 diabetes has also been demonstrated. In view of the for it’s use in pregnancy Data regarding the long acting insulin above, it is important that the woman who has had GDM receive analogs are less clear than rapid acting analogs. Until their safety counseling and support to reduce her long-term risk of diabetes. in pregnancy can be clearly established the initiation of long-acting Screening for diabetes, at regular intervals, is recommended. insulin analog in pregnancy cannot be recommended. Conclusion :

Oral Antidiabetic Agents in GDM :

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