Gestational diabetes mellitus Dr. Kanakamani Madhivanan, M.D., D.M. (Endocrinology), Assistant Professor Department of Endocrinology, Diabetes, Metabolism Christian Medical College, Vellore

Plan of presentation Introduction Physiology of fuel metabolism in normal pregnancy Pathophysiology of GDM Epidemiology of GDM Screening and diagnosis Maternal and fetal risks Management of GDM Obstetric management

Introduction

Introduction Global increase in prevalence of DM Individual importance - Hyperglycemia in pregnancy has adverse effects on both mother and fetus Public health importance – rising epidemic of DM in part attributed to the diabetic pregnancies Prevention of type 2 DM should start intrauterine and continue throughout life

Introduction Gestational diabetes (GDM) is defined as any degree of impaired glucose tolerance of with onset or first recognition during pregnancy . Many are denovo pregnancy induced Some are type 2 ( 35-40%) 10% have antibodies

Introduction Difficult to distinguish pregestational Type 2 DM and denovo GDM Fasting hyperglycemia blood glucose greater than 180 mg/dL on OGT acanthosis nicgrans HbA1C > 5.3% a systolic BP > 110 mm Hg BMI > 30 kg/m2 Fetal anomalies Clues for Type 1 Lean DKA during pregnancy Severe hyperglycemia with large doses of insulin

Fuel metabolism in pregnancy

Fuel metabolism in pregnancy Goal is uninterrupted nutrient supply to fetus The metabolic goals of pregnancy are 1) in early pregnancy to develop anabolic stores to meet metabolic demands in late pregnancy 2) in late pregnancy to provide fuels for fetal growth and energy needs.

Glucose metabolism in pregnancy Early pregnancy E2/PRL stimulates b cells –Insulin sensitivity same and peripheral glucose utilisation – 10% fall in BG levels Late pregnancy Fetoplacental unit extracts glucose and aminoacids, fat is used mainly for fuel metabolism Insulin sensitivity decreases progressively upto 50-80% during the third trimester variety of hormones secreted by the placenta, especially hPL and placental growth hormone variant, cortisol, PRL,E2 and Prog

Glucose metabolism in pregnancy FASTING accelerated starvation and esxaggerated ketosis (maternal hypoglycemia, hypoinsulinemia, hyperlipidemia, and hyperketonemia) FED hyperglycemia, hyperinsulinemia, hyperlipidemia, and reduced tissue sensitivity to insulin Fat Hyperinsulinemia Insulin resistance Glucose Aminoacids Fetus

24-hour insulin requirement before conception is approximately 0 24-hour insulin requirement before conception is approximately 0.8 units / kg. In the first trimester, the insulin requirement rises to 0.7units / kg of the pregnant weight – more unstable glycemia with a tendency to low fasting plasma glucose and high postprandial excursions and the occurrence of nocturnal hypoglycemia By the second trimester, the insulin requirement is 0.8 units per kilogram. From 24th month onwards steady increase in insulin requirement and glycemia stabilises By third trimester the insulin requirement is 0.9 - 1.0 unit /kg pregnant weight per day Last month – may be a decrease in insulin and hypoglycemias esp. nocturnal

EPIdemiology AND Risk factors

Magnitude of problem: Global Prevalence of GDM varies worldwide and among different racial and ethnic groups within a country America – white women (3.9%) and Asian (8.7%) Europe – 0.6% to 3.6% Australia – 3.6% to 4.7% (Indian women – 17.7%) China – 2.3%; Japan – 2.9% Variability is partly because of the different criteria and screening regimens

Magnitude of the problem - India Chennai, hospital based, universal screening – 18.9% had FPG ≥ 126 and PPPG ≥ 140. Trivandrum – 15% Bangalore – 12% Erode – 18.8% Chennai, community based, universal screning, 17.8% in urban, 13.8% in semi urban and 9.9% in rural areas. Chennai : 0.56% Mysore Parthenon Study: 6% Maharashtra, hospital based, selective screening – 7.7% had GDM; 13.9% had IGGT.  

Risk factors A family history of diabetes, especially in first degree relatives Prepregnancy weight ≥110% of ideal body weight or body mass index over 30 kg/m2 or significant weight gain in early adulthood, between pregnancies, or in early pregnancy Age greater than 25 years Previous delivery of a baby greater than 4.1 kg Personal history of abnormal glucose tolerance Member of an ethnic group with higher than the background rate of type 2 diabetes (in most populations, the background rate is approximately 2 percent) Previous unexplained perinatal loss or birth of a malformed child Maternal birthweight greater than 4.1 kg or less than 6 pounds 2.7 kg Glycosuria at the first prenatal visit Polycystic ovary syndrome Current use of glucocorticoids Essential hypertension or pregnancy-related hypertension

Maternal and Fetal risks

Maternal complications Worsening retinopathy – 10% new DR, 20% mild NPDR and 55% mod-severe NPDR progresses Worsening proteinuria. GFR decline depends on preconception creatinine and proteinuria Hypertension and Cardiovascular disease Neuropathy – No worsening (gastroparesis, nausea, orthostatic dizziness can be worsened) Infection

Maternofetal complications Macrosomia: 63 percent Cesarean delivery: 56 percent Preterm delivery: 42 percent Preeclampsia: 18 percent Respiratory distress syndrome: 17 percent Congenital malformations: 5 percent Perinatal mortality: 3 percent Spontaneous abortion, third trimester fetal deaths, Polyhydramnios, preterm birth, ?adverse neurodevelopmental outcome Risk for type 2 DM

Neonatal complications Morbidity associated with preterm birth Macrosomia ± birth injury (shouldeer dystocia, brachial plexus injury) Polycythemia and hyperviscosity Hyperbilirubinemia Cardiomyopathy Hypoglycemia and other metabolic abnormalities (hypocalcemia, hypomagnesemia) Respiratory problems Congenital anomalies

Congenital anomalies 2/3rd CVS or CNS,– 13-20 times common Cardiac( including great vessel anomalies) : most common Central nervous system (spina bifida/anencephaly) : 7.2% Skeletal: cleft lip/palate, caudal regression syndrome Genitourinary tract: ureteric duplication Gastrointestinal : anorectal atresia

Skeletal and central nervous system Caudal regression syndrome Neural tube defects excluding anencephaly Anencephaly with or without herniation of neural elements Microcephaly Cardiac Transposition of the great vessels with or without ventricular Ventricular septal defects Coarctation of the aorta with or without ventricular septal defects or patent ductus arteriosus Atrial septal defects Cardiomegaly Renal anomalies Hydronephrosis Renal agenesis Ureteral duplication Gastrointestinal Duodenal atresia Anorectal atresia Small left colon syndrome

Caudal regression syndrome

Caudal regression syndrome

SCREENING AND DIAGNOSIS

Whom to screen ? No consensus recommended screening ranges from selective screening of average- and high-risk individuals to universal diagnostic testing of the entire population dependent on the risk of diabetes in the population. Risk stratification based on certain variables Low risk : no screening Average risk: at 24-28 weeks High risk : as soon as possible

Low risk for GDM To satisfy all these criteria Age <25 years Not a member of an ethnic group with high prevalence of GDM (not Hispanic, Native American/Alaskan, Asian/Pacific Islander, African American) Normal prepregnancy body weight (not 20% or more over desired body weight or BMI 27 kg/m2 or more) No family history of diabetes in first-degree relatives. No history of abnormal glucose tolerance No history of poor obstetric outcome

High risk Marked obesity Prior GDM (30-50% risk for recurrence) Glycosuria Strong family history

When and how to screen? 24-28 weeks High risk First prenatal visit 50 g glucose loading test High risk women – 3 hr GTT with 100 g glucose

50 g GTT A 50-g oral glucose load is given without regard to the time elapsed since the last meal and plasma or serum glucose is measured one hour later A value ≥130 mg/dL is considered abnormal ; we use ≥130 mg/dL as the threshold for our patients. Capillary blood should not be used for screening unless the precision of the glucose meter is known, it has been correlated with simultaneously drawn venous plasma samples, and has met federal standards for laboratory testing.

100 g GTT Oral glucose tolerance test ( OGTT) with 100 gm glucose Overnight fast of at least 8 hours At least 3 days of unrestricted diet and unlimited physical activity > 2 values must be abnormal Fasting > 95 mg/dl 1-h > 180 mg/dl 2-h > 155 mg/dl 3-h > 140 mg/dl

75 g GTT ADA WHO Fasting > 95 mg/dl 1-h > 180 mg/dl 2-h OR 2-h > 140 mg/dl

Whom and when to screen? Indian Scenario -The DIPSI Guidelines 75 gm GCT with single PG at 2 hrs – ≥ 140 mg/dL is GDM ≥ 120 mg/dL is DGGT Universal screening First trimester, if negative at 24 – 28 weeks and then at 32 – 34 weeks

Management of gdm

MANAGEMENT ISSUES Patient education Medical Nutrition therapy Pharmacological therapy Glycemic monitoring: SMBG and targets Fetal monitoring: ultrasound Planning on delivery

Medical nutrition therapy Goals Achieve normoglycemia Prevent ketosis Provide adequate weight gain Contribute to fetal well-being Nutritional plan Calorie allotment Calorie distribution CH2O intake

Calorie allotment 30 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 morbidly obese pregnant women (BMI >30). 40 kcal per kg current weight per day in pregnant women who are less than BMI 22.

Carb intake Postprandial blood glucose concentrations can be blunted if the diet is carbohydrate restricted. Complex carbohydrates, such as those in starches and vegetables, are more nutrient dense and raise postprandial blood glucose concentrations less than simple sugars. Carbohydrate intake is restricted to 33-40% of calories, with the remainder divided between protein (about 20%) and fat (about 40%). With this calorie distribution, 75 to 80 percent of women with GDM will achieve normoglycemia.

Calorie distribution Variable opinion Most programs suggest three meals and three snacks; however, in overweight and obese women the snacks are often eliminated Breakfast — The breakfast meal should be small (approximately 10%of total calories) to help maintain postprandial euglycemia. Carbohydrate intake at breakfast is also limited since insulin resistance is greatest in the morning. Lunch — 30% of total calories Dinner — 30% of total calories Snacks — Leftover calories (approximately 30% of total calories) are distributed, as needed, as snacks.

Monitoring BG Atleast 4 times Pre vs postprandial monitoring Fasting and 3 one hr postprandial Pre vs postprandial monitoring Better glycemic control (HbA1c value 6.5 versus 8.1 percent) A lower incidence of large-for-gestational age infants (12 versus 42 percent) A lower rate of cesarean delivery for cephalopelvic disproportion (12 versus 36 percent)

Monitoring BG Home monitoring Maintain log book Use a memory meter Calibrate the glucometer frequently HbA1C Ancillary test for feedback to the patient Lower values when compared to nonpregnant state – lower BG and increase in red cell mass and slight decrease in life span – measured every 2-4 weeks Target < 5.1%

Studies report no to moderate correlations between HbA1 and different components of the glucose profile when an HbA1 result of 4% to 5% includes a capillary blood glucose range of 50 to 160 mg/dL. Levels of HbA1c are related to the rate of congenital anomalies and spontaneous early abortions in pre-existing diabetes, but the use of this measure, which retrospectively reflects glycemic profile in the last 10 weeks, for treatment evaluation in GDM is questionable. In addition, the association between glycosylated hemoglobin and pregnancy outcome in GDM or prediction of macrosomia is poor Glycosylated protein and fructosamine widely variable and not yet established

Glycemic targets (ACOG) Fasting venous plasma ≤ 95 mg/dl 1 hour postprandial ≤ 140 mg/dl 2 hour postprandial ≤ 120 mg/dl Pre-meal ≤ 100 mg/dl A1C ≤ 6% ADA premeal 80-110 2 hr postmeal not more than 155 These are venous plasma targets, not glucometer targets

PHARMACOLOGICAL INTERVENTION If the FPG at diagnosis is ≥ 120, can consider immediate therapy. Otherwise, MNT for 2 weeks If majority FPG (4/7) > 95 or PP > 120 then to start on insulin.

Insulin ≈ 15% need insulin Total dose varies. ≈ 0.7 to 2 units per kilogram (present pregnant weight) FBG high – Night NPH ≈ 0.2 units/kg PPBG high – bolus ≈ 1.5 units/10 gm CH2O for breakfast and ≈ 1 unit /10 gm CH2O for lunch and dinner If both pre and postprandial BG high or if the woman's postprandial glucose levels can only be blunted if starvation ketosis occurs - four injection/day regimen. Total 0.7 unit/kg up to week 18 0.8 unit/kg for weeks 18 to 26 0.9 unit/kg for weeks 26 to 36 1. unit/kg for weeks 36 to term. In a morbidly obese woman, the initial doses of insulin may need to be increased to 1.5 to 2. units/kg to overcome the combined insulin resistance of pregnancy and obesity.

OHA in pregnancy Systematic review by John Hopkins University maternal glucose levels did not differ substantially between gravidae treated with insulin versus those treated with oral glucose-lowering agents there was no consistent evidence of an increase in any adverse maternal or neonatal outcome with use of glyburide, acarbose, or metformin compared with use of insulin Inconsistent data. ADA, ACOG, USFDA do not endorse.

OHA in pregnancy Tolbutamide and chlorpropamide Glibenclamide Cross placenta. Fetal hperinsulinemia. Prolonged fetal hypoglycemia Glibenclamide Minimal transplacental transport Observational studies – no excess anomalies or hypoglycemia Only RCT – 404 women. Glib vs insulin. No difference

second-generation sulfonylureas especially glyburide, do not significantly cross the diabetic or nondiabetic placenta. Fetal concentrations reached no more than 1% to 2% of maternal concentrations. tolbutamide diffused across the placenta most freely, followed by chlorpropamide, then glipizide, with glyburide crossing the least. Metformin crosses placenta – not teratogenic in rat models

OHA in pregnancy Metformin Acarbose Thiazolidinediones and GLP-1 Category B No adverse outcome after first trimester Second, third trimester safe and effective Vs. insulin – no serious adverse effects No studies vs. glibenclamide Acarbose Two prelim studies Thiazolidinediones and GLP-1 Not studied

Obstetric management

Fetal monitoring Baseline ultrasound : fetal size At 18-22 weeks: major malformations fetal echocardiogram 26 weeks onwards: growth and liquor volume III trimester: frequent USG for accelerated growth ( abdominal: head circumference)

Timing of delivery Small risk of late IUD even with good control Delivery at 38 weeks – to avoid late still birth and fetal growth leading to shoulder dystocia Vaginal delivery: preferred Caesarian section only for routine obstetric indication just GDM is not an indication ! Unfavorable condition of the cervix is a problem 4500 grams, cesarean delivery may reduce the likelihood of brachial plexus injury in the infant (ACOG). Assessing fetal weight accurately is a problem

Management of labor and delivery Maternal hyperglycemia in labor: fetal hyperinsulinemia, worsen fetal acidosis and neonatal hypoglycemia Insulin requirements come down Maintain sugars: 70-90 mg/dl Routine GDM diet Maintain basal glucose requirements Monitor sugars 1-4 hrly intervals during labour Give insulin as infusion only if sugars more than 120 mg/dl

Glycemic management during labour Later stages of labour: start dextrose to maintain basal nutritional requirements: 150-200 ml/hr of 5% dextrose Elective LSCS: check FBS, if in target no insulin, start dextrose drip Continue hourly SMBG Post delivery keep patients on dextrose-normal saline till fed No insulin unless sugars more than normal nonpregnant levels

Post partum follow up Check BG before discharge Breast feeding: helps in weight loss. Insulin, tolbutamide compatible. Chlropropamide secreted small amounts – watch for hypoglycemia in infant. Glyburide and glipizide not secreted Metformin secreted - no adverse effects Lifestyle modification: exercise, weight reduction OGTT at 6-12 weeks postpartum: classify patients into normal/impaired glucose tolerance and diabetes Contraception – low dose EP can be used. Progestin only pills shown to increase risk of T2DM in GDM Preconception counseling for next pregnancy

Immediate management of neonate Hypoglycemia : 50 % of macrosomic infants 5–15 % optimally controlled GDM Starts when the cord is clamped Exaggerated insulin release secondary to pancreatic ß-cell hyperplasia Increased risk : blood glucose during labor and delivery exceeds 90 mg/dl Anticipate and treat hypoglycemia in the infant

Management of neonate Hypoglycemia <40 mg/dl Encourage early breast feeding If symptomatic give a bolus of 2- 4 ml/kg, IV 10% dextrose Check after 30 minutes, start feeds IV dextrose : 6-8 mg/kg/min infusion Check for calcium, if seizure/irritability/RDS Examine infant for other congenital abnormalities

Future risks in mother and child

Future risks - Mother Atleast 6 weeks post delivery, 75 g OGTT for all GDM ≥ 90% normoglycemic Recurrence of GDM – 30-60% Older Multipara Weight gain interpregnancy Higher infant BW in index pregnancy IGT and T2DM 20% IGT postpartum 3.7% @ 6m , 4.9% @ 15m and 18.9% @ 9 y

Who will progress to DM? WC and BMI – stronset predictors Autoantibodies DM at earlier gestational age Gestational requirement of insulin Higher FBG Higher BG on OGTT Neonatal hypoglycemia Recurrent GDM

Preconception counselling Diabetic mother : glycemic control with insulin/SMBG Target: HbA1c < 7% Folic acid supplementation: 5 mg/day Ensure no transmissible diseases: HBsAg, HIV, rubella Try and achieve normal body weight: diet/exercise Stop drugs : oral hypoglycemic drugs, ACE inhibitors, beta blockers

Risk of developing DM in offspring Type 1 - Father - 1 in 17 risk Mother - 1 in 25 risk if, at the time of pregnancy, the mother is < 25 years of age but a 1 in 100 risk if the mother is 25 years of age or older. These risks are doubled if the affected parent developed diabetes before age 11. Both parents have type 1 diabetes - 1 in 10 - 1 in 4. Type 2 polyglandular autoimmune syndrome – 50% Type 2 Single parent - 1 in 7 if the parent was diagnosed before age 50 and 1 in 13 if the parent was diagnosed after age 50. There is some evidence that the offspring's risk is greater when the parent with type 2 diabetes is the mother. I Both parents - 1 in 2.

Conclusion Gestational diabetes is a common problem in India Risk stratification and screening is essential in all Indian pregnant women Tight glycemic targets are required for optimal maternal and fetal outcome Patient education is essential to meet these targets Long term follow up of the mother and baby is essential

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