Shyam KalavalapalliMRCP (London), CCST, MRCP (Diabetes & Endocrinology), FRCP (edin.) Consultant Endocrinologist HYDERABAD

Normal: Insulin moves glucose from the blood into your cells

Gestational Diabetes: Insulin resistance and inadequate insulin leads to less glucose entering the cells so blood

glucose levels become higher

Glucose Insulin Body’s Cells Blood Vessel

Compartment Metabolic Effect

Mother

PlacentalHormones

HPLHPGH

CortisolOestrogen

Progesterone

Placenta

Foetus

Insulin resistance

Impaired insulin action

Aberrant Fuel Mixture

Mode oftransport

Glucose Amino acids Cholesterol TG Ketones

FacilitatedDiffusionBy GLUT3 carriers

Active Diffusion

Lipase

DiffusionFFA Glycerol

Diffusion

Aberrant fuel mixture

Hyperinsulinemia

Fuel Mediated Teratogenesis

Maternal Hyperglycemia

Fetal Hyperglycemia

Fetal Hyperinsulinemia

↑Fetal substrate uptake ↑Oxygen uptake Lung Surfactant↓

Respiratory Distress Syndorme

Lipids / Amino acid ↑Hypoxemia

Polycythemia Macrosomia

↑Erythropoietin

↑BMR

Hypotrophy Pancreaticislet & B cells

PATHOGENICEVENTS

conceptionconception

Preexisting type 2Preexisting type 2

Incipient type 2Incipient type 2

type 1type 1

10 20 30 40

True GDMTrue GDMdeliverydelivery

Follow upFollow up

Period ofexposure

Complications Type ofDiabetes

Aberrantfuel mixture

Hyperinsulinaemia

Foetus

delivery

GDM

PGDM

1st trimester

2nd trimester

3rd trimester

Spontaneous abortions(15%)Congenital Anomalies(5-20%)

Macrosomia(x3,15-45%)

Chronic hypoxiaStillbirth

Birth Injury(x2)C-sections (x3)

NICU (x 4)

Birth injury

Macrosomia(15-45%)

Congenital Anomalies

Hypoglycemia(5 folds)

RDS/Jaundice(doubled)

Morbidity Gestational Diabetes

Type 1 Diabetes Type 2 Diabetes

Hyperbilirubinemia 29% 55% 44%

Hypoglycemia 9% 29% 24%

Respiratory distress

3% 8% 4%

Transient tachypnea

2% 3% 4%

Hypocalcemia 1% 4% 1%

Cardiomyopathy 1% 2% 1%

Polycythemia 1% 3% 3%

Centre N Prevalence Rate

Dr Balaji et al North Chennai, Tamil Nadu

891 16.2%

Dr Anjalakshi et al South Chennai, TamilNadu

1002 15%

Dr K. P. Paulose Trivandrum, Kerala 750 15%

Dr Mary John Ludhiana, Punjab 220 17.5%

Dr Prasanna Kumar Bangalore, Karnataka 49 12%

Dr Shyam Mukundan Alwaye, Kerala 200 21%

Dr Aruyerchelvan Erode, Rural TamilNadu 562 18.8%

TOTAL 3674 16.55%

JAPI 2010; 58: 329

24,505 pregnant women, at 15 centres.

Underwent 75g GTT at 24-32 weeks gestation.

Data remained blinded if FPG ≤ 105mg/dl and 2hr PG ≤ 200mg/dl.

Impact on adverse pregnancy outcomes of varying degrees of glycemia (7 glucose categories).

N Engl J Med 2008;358(19):1991-2002

HAPO Study(Hyperglycemia & Adverse Pregnancy Outcomes Study)

Australian Carbohydrate Intolerance Study in Pregnant Women:

RCT, 1000 women with positive 50g GCT at 24-34 wks underwent 75g GTT.

Randomized to treatment (n = 490) (LSM, SMBG and insulin) vs standard pregnancy care (n = 510).

N Engl J Med. 2005;352(24):2477-86.

N Engl J Med. 2005;352(24):2477-86

Composite outcome (death, shoulder dystocia, fracture or nerve palsy) occured in 7 vs 24 pregnancies.

Intensive group babies – significantly less BW (mean 140g). PIH significantly less in intensive group (12% vs 18%). Better QoL, less risk of depression.

More infants in Intensive group required IV Glucose & had RDS. Intensive group had higher rate of induction of labor.

N Engl J Med. 2005;352(24):2477-86

National Birth Defects Prevention Study (1997-2004):

Proper metabolic control maintained preconceptionallyand in 1st TM - significantly reduces this risk.

Low glycemic load diets in overweight and obese pregnant women reduced the risk of birth defects.

Management of obesity in pregnancy can impact risk of birth defects.

Dietary supplementation – with folic acid.

Arch Pediatr Adolesc Med 2007: 161 (8): 745-50Am J Obstet Gynecol. 2012: 206(3):218.e1

Curr Diab Rep (2012) 12:24–32

Women with GDM should perform home blood glucose monitoring.

Frequency of SMBG & targets – individualized.

More frequent monitoring: reduction in rate of CS, macrosomia, shoulder dystocia and neonatal hypoglycemia.

Fasting & 1-2hr postmeal values.

Diabetes in Early Pregnancy Study: Macrosomia was 35% in women with mean PPG 160mg/dl vs 20% in women with mean PPG 120mg/dl.

Treatment to post-prandial targets results in superior pregnancy outcomes compared to pre-prandial targets.

Curr Diab Rep 2012;12:33–42

Preprandial vs Postprandial SMBG schedules in 66 GDM women who required insulin by 30 wks.

Endocr Pract. 2008;14(2) :245

Excess fetal weight tends to be disproportionately deposited along abdomen & interscapular region. Accelerated AC growth can be detected on USG 32 wks onwards.

90% GDM patients are able to achieve targets with LSM alone. Aims of MNT:◦ Achieve normoglycemia◦ Provide adequate nutrients◦ Avoid excessive weight gain.

Specific dietary advice includes preferential intake of:◦ Carbohydrates with low GI◦ Lean proteins◦ Unsaturated fats & PUFA◦ Frequent small meals/ snacks.

Women with pre-pregnancy BMI >27 should restrict caloric intake to 25 kcal/kg/d (30% calorie restriction).

Curr Diabet Rev 2012; 8 (4): 249

Evidence to support low carbohydrate diets & low GI diets.

Low carbohydrate diet: In a non-randomized study –women on diets <42% carbohydrates:◦ Lower PPG◦ Less likely to require insulin◦ Lower incidence of LGA.

Low GI vs high GI diets – low GI diets resulted in lower BG levels & lower BW.

Vasc Health & Risk Manag 2009; 5: 153–164

If there is no medical or obstetric contraindication, women with GDM should engage in moderate intensity physical activity (walking 20-30 mins/d) until the latter stages of the pregnancy.

Regular physical activity – enhances insulin sensitivity, facilitates weight loss and improves glucose control.

Several studies have demonstrated beneficial effects of moderate physical activity.

Insulin – the mainstay of treatment in patients not controlled on LSM alone.

Human insulin does not cross placenta and is considered safe.

Basal-bolus regimen – gives most effective glucose control. Prandial fast-acting insulin and basal insulin are titrated individually.

Biphasic Insulin – not routinely recommended. Recent Indian study – 320 GDM patients, treated with biphasic human insulin

or biphasic aspart. None required switch-over to MSII. Similar glycemic control and fetal outcomes with few hypoglycemic episodes

in both groups. Lower total insulin dose required in aspart group.

Curr Diabet Rev 2012; 8 (4): 249

Recent evidence: Aspart & Lispro safe & at least as effective as regular insulin.

Both are category B drugs now.

Advantages:

◦ Better PPG control.◦ Less hypoglycemia.◦ Meal-time flexibility.

Diabet Metab Res Rev 2012; 28: 50–61

2 unitsNovorapidActrapid

2 unitsNovorapidActrapid

2 unitsNovorapidActrapid

4 unitsbasal insulin

Insulatard

Insu

lin E

ffect

Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker Inc.; 2002:87

Several small studies of use of CSII.

Systematic review of 23 studies (976 pts) comparing CSII with MSII in non-pregnant type 1 diabetics:◦ Better HbA1c reduction ◦ Less severe hypoglycemia◦ Better QoL measures.

CSII is a good option for patients who donot reach adequate glycemic controls, have frequent hypoglycemia, hypoglycemia unawareness or dawn phenomenon.

Best Pract & Res Clin Obstet Gynecol 2011; 25: 65-76Curr Diab Rep 2012;12:53–59

RCT: Glyburide vs Insulin-◦ 404 GDM women, treated with glyburide or insulin.◦ Similar glycemic control in both groups◦ No differences in LGA, macrosomia, neonatal

hypoglycemia, admission to neonatal ICU, or fetal anomalies. ◦ Glyburide not detected in cord blood.

Expert Opin. Drug Saf. 2011;10(2):227Current Diabetes Reviews 2012; 8(4): 249

Meta-analysis:◦ 745 glyburide treated vs 637 insulin treated pregnancies.◦ Glyburide did not increase the risk of macrosomia, LGA, or

neonatal hypoglycemia.◦ Perinatal mortality or congenital anomalies not examined.

Freely crosses through placental barrier.

Studies on women with PCOS – no evidence of adverse effects on fetus.

Use in preconceptional period and continuation in early pregnancy - no risk of malformations.

2009 Cochrane review: similar neonatal outcomes, but increase in CS rate and neonatal hypoglycemia with insulin.

Curr Diabet Rev 2012; 8 (4): 249Expert Opin Drug Saf 2011;10(2):227-238Acta Obstet et Gynecol Scand 2012; 91: 658–678

RCT of 751 women with GDM, bw 20-33wks, randomized to insulin or metformin.

No difference in rate of resp distress, need for phototherapy, birth trauma, low Apgar score or prematurity (32% vs32.2%, p = 0.95).

No difference in serious fetal or neonatal events.

Lower prevalence of hypoglycemia in newborn (3.3 vs 8.1%, p < 0.008).

Lower weight gain in mother (0.4 ± 2.9 vs 2 ± 3.3 kg, p < 0.001).

High failure rate (46.3%). Better patient acceptability.

N Engl J Med 2008; 358: 2003-2015Expert Opin. Drug Saf 2011; 10(2):227-238

Glyburide – will it accentuate β-cell stress and accelerate their decline?

Metformin – reduces IR, would it be beneficial in long-term prevention of T2DM?

Metformin has transplacental passage – Long-term effects? Potential for lactic acidosis in fetal distress? Any beneficial effect on fetus?

Metformin is categorized as class B and Glyburide as class C medication by FDA.

Combination of the 2 not yet studied.

Meta-analysis of 8 studies:

Significant association of vitamin D deficiency and incidence of GDM. Women with GDM have significantly lower vitamin D than women with

NGT.

No association bw Vitamin D levels & GDM found in an Indian population.

No evidence to support role of vitamin D supplementation to optimize GDM management.

Poel et al. Europ J Intern Med 2012; 23: 465Eur J Clin Nutr 2009; 63: 646

Curr Diab Rev 2012; 8(4): 249

Target maternal glucose – 70-140mg/dl.

Neonatal hypoglycemia more frequent with higher maternal glucose in pregnancy.

Intensity of treatment determined by severity & type of diabetes.

2 options:◦ Continuous infusion of insulin and dextrose separately with hourly

BG.◦ Dextrose infusion with a fixed insulin dose added (8-12 U in each

500 ml) with less frequent monitoring.

Endocrinol Metab Clin N Am 2012;41:161–173

PRE GESTATIONAL DIABETES

GESTATIONAL DIABETES

When Diagnosis Test Cut-off for diagnosis

1st prenatal visit Overt DM FPG 126 mg/dL (7.0 mmol/L)

HbA1C ≥ 6.5%

Randoma 200 mg/dL (11.1 mmol/L)

24-28 weeks GDM FPG 92 mg/dL (5.1 mmol/L)

75g OGTT-1 hr 180 mg/dL (10.0 mmol/L)

75g OGTT-2 hr 153 mg/dL / 140 mg/dL

GDM – Glycemic TargetsRecommended values

for Glycemic Targets

Pre-pregnancy Hb A1c 7.00 (if possible 6.00)

Pregnancy values Range

FPG 70 - 95

1 hr PPG 100 – 140

2 hr PPG 90 – 120

Hb A1c 6.00

41

Hypoglycaemia

Common problem in India.

Early diagnosis in pre-gestational & gestational period is must.

Tight glycemic targets for optimal maternal and fetal outcome.

Diet, exercise, education, & insulin are mainstay.

Insulin analogs are also safe.

Glyburide & metformin are effective alternative.

Long term follow up of mother is essential