2Maternal Diabetes Two lives.. Twice as special An oppurtunity for primary prevention-Maternal health-Child health
3DefinitionGDM is defined as carbohydrate in tolerance of variable severity with onset or first recognition during pregnancy. The definition is applicable regardless of whether insulin is used to treat the disease or if the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy
4IntroductionIncidence of GDM is variable from 17% to 29% of all pregnanciesAssociated with maternal and perinatal complications.90% of all Diabetics are GDM and 10% are due to pregestational diabetes.4 million pregnancies in India are complicated by GDMThis may contribute a part of MMR in India
7GDM prevalence linked to background IGT rates 2%Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-901980s7.6%Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-48.2%Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1990s16.6%V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52:70714.5%Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V,Das AK, Rao PV, Yajnik CS, Prasanna Kumar KM, Nair JD.For the Diabetes Epidemiology Study Group in India (DESI).Diabetologia 2001;44:2000s7
8Significance of Diabetes and Pregnancy Malformation rate in 94/1000 Vs 9.7/1000 in general populationStill birth is 15 times higher 25/1000 Vs 5/1000PNM is 3 times higher 19.9/1000 Vs 6.8/1000Recent concept of adult diseases having their origin inutero insults has been established.1989 WHO/IDF discussed the problem of hyperglycemia in pregnant women. They wanted to achieve pregnancy outcome in diabetic women same as in non diabetic women.
9FREINKEL HYPOTHESIS Uterine At Birth After Birth placenta Macrosomia ObesityHypoglycemiaMaternal DMMetabolic syndromeA InsulinIGT/DMA.AFatCHOFetusCVD
10Diabetes and Pregnancy – Why it is relevant? Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality and poor pregnancy outcomeDiagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary preventionMaternal hyperglycaemia is associated with development of metabolic problems including type 2 diabetes in the offspring
11IUGR & Macrosomia Pederson’s hypothesis Macrosomia Predicts development of HTN, Type 2 DM & IGTBarker’s Hypothesis Low birth weightPederson’s hypothesis MacrosomiaSolution Optimal nutrition+ Optimal glycemic control=Optimal birth weight – 3500 g.
15ADA recommendationScreening ProcedureCriteriaPerform a 75-g OGTT , with plasma glucose measurement fasting and at 1 and 2 h, at weeks of gestation in women not previously diagnosed with overt diabetesThe OGTT should be performed in the morning after an overnight fast of at least 8 hrs.The diagnosis of GDM is made when any of the following plasma glucose values are exceededFasting >= 92mg/dL(5.1mmol/L)1 hr >=180mg/dL(10.0 mmol/L)2 hr>=153 mg/dL (8.5mmol/L)
17GLYCEMIC THRESHOLDS FOR PREVENTION OF DIABETIC COMPLICATION
18Comparison of the Foetal Outcome in a NGT & GDM NormalAbortionsStill birthDied after birthCongenital anomaliesPremature deliveriesSick babiesBig baby ( 3.5 kg)NGT (n = 851)80463189 / 8312278GDM (n =211)122511 / 1481090P value<--0.070.010.230.0020.157
19GDM increases the risk of offspring DM Offspring's of women with GDM, have a 4 to 8 fold increased risk of diabetes.Clausen TD et al., Diabetes Care 2008
20How to reduce this Early screening for GDM Monitoring frequently Proper uses of diet plan , exercise and insulin.Future concepts of CSII, CGMS, telemedicine,e-health, will revolutionize the management of GDM
22Calorie allotment30 kcal per kg current weight per day in pregnant women who are BMI 22 to 25.24 kcal per kg current weight per day in overweight pregnant women (BMI 26 to 29).12 to 15 kcal per kg current weight per day for severely obese pregnant women (BMI >30).40 kcal per kg current weight per day in pregnant women who are less than BMI 22.Jovanovic-Peterson L, Peterson, CM. Nutritional management of the obese gestational diabetic woman. J Am Coll Nutr 1992; 11:246.
23How long MNT?Consensus and hard data are lacking regarding how long diet therapy should be maintained before initiating pharmacologic treatment.70% of the subjects with initial fasting plasma glucose less than 95 mg/dL achieved targeted levels of glycemia within 2 weeks of dietary management, but no significant improvement occurred thereafterMcFarland et al obstet gynecol 1999
24Exercise Prescription Can continue prepregnancy activityKeeping physically active is essential for good glycemic controlUpperbody ergometric exercise usefulDo not start new vigorous exercise for glucose controlUterine contractions,fetal tachy, maternal heart rate to be monitored
25ORAL AGENTS IN PREGNANCY Glyburide study:Randomized trial glyburide vs insulin404 GDMs FPG >95 but <140 mg/dl or 2- hr pp >120 on dietSimilar success of glucose control in both groupsLanger et al: NEJM 200:343:1134
27Animal insulin Insulin Analogues 1920- Introduction of insulin revolutionized Diabetes ManagementIntroduced insulin had impurities and batch to batch variation1980- higher quality insulin from bovine and porcine sources . Then came recombinant Insulin
28IDEAL AGENT SHOULD FULFILL Mimic physiological controlNo adverse effect upon maternal and fetal outcome.Should not interfere with antenatal , perinatal and post natal careInsulin Analogues fulfills all the criteria when given in right doses in right manner.
29ADVANTAGES Batch to Batch consistency No allergy, antibody formation No immune mediated lipoatrophyGlucose control is similar in endogenous insulin productionPreprandial hypoglycemia and postprandial hyperglycemia are well controlled.Mealtime flexibility is possible with analogues.
30Safety issues with Insulin Analogues Ideal insulinMimic physiological insulin secretionDoes not cross placentaNo mitogenic potentialSince IgG bound insulin can cross placenta, therapeutic agent should not induce antibody generation
31STRUCTURAL MODIFICATION OF INSULIN ANALOGUE Insulin Lispro28-29 Proline and Lysine are interchangedInsulin AspartProline at 28 replaced by aspartic acid. (decreases hexamer formation )Insulin glulisinePosition 3 of Lysine with Asparagine ; Lysine at 29 replaced by glutamineInsulin glargineAsparagine at A2 1 is replaced by glycine. 2 arginine added to C terminal of Beta chainInsulin detemirBinds with albumin. Threonine omitted at position 30th of Beta chain and replaced by myristic acid at C 14 FA chain. (delays’ absorption by albumin binding)
33RECEPTOR BINDING, METABOLIC AND MITOGENIC POTENCY OF IA
34HAPO: Hyperglycemia And Adverse Pregnancy Outcome 9 countries, 25 centers, 23,325 patients7 year studyWomen were screened between 24-32weeks with fasting glucose, 1 hour and 2 hour post 75 gm glucose .Medical caregivers were blinded to results except that exceeded pre defined cut offs[ 5.8 fasting, 11.1 post 75 gm glucose] and were then removed from the study.Birth weight, maternal complications, operative delivery, insulin levels in newborn were studied.Int J,Gynecology & Obstetrics. 2002,78, (1);69-77
36GLYCEMIC STATUS IN GDMFASTING HYPOGLYCEMIA POSTPRANDIAL HYPERGLYCEMIA Normalisation of this is possible by Insulin Analogues.
37Insulin aspart qualifies for use in GDM Insulin analogues does not cross the placenta but placental concentration is higher than in maternal blood.
38Insulin Aspart in pregnancy status compared with Human Insulin Moshe Hod et al.,Studied insulin aspart in Type I diabetic patientRandomized parallel group open labelMultinational studyDecreased hypoglycemic spellsIncreased fetal outcome
39Insulin Aspart in pregnancy status compared with Human Insulin Primary objective – Hypoglycemic attacksSecondary objective – Analyze maternal/fetal outcome- HbA1c- 8 point glucose profile- Number of mild hypoglycemia- cord blood insulin AB
50INSULIN TACTICS Twice-daily Split-mixed Regimens RegularNPHInsulin EffectSlide 6-23INSULIN TACTICSTwice-daily Split-mixed RegimensTwice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times.Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:BLSHSB6-23
54Continuous Subcutaneous Insulin Infusion (CSII) Blood glucose levels monitored continuouslyPre specified insulin dose is subcutaneously delivered by pumpThis minimized timing and dosing errors.
55Continuous Glucose Monitoring System (CGMS) Blood glucose is assessed periodicallyInsulin dose is calculatedCGMS integrated monitoring system with a delivery deviceHence round the clock blood glucose is controlled.
56e-health systemPatient has her data in USB device which can be analyzed and seek guidance from internet.
57CSII & CGMSParadigm device connects CGMS and delivery device through bluetooth. This early trial is about to be started in USA.