Insulin in Pregnancy Prof. Dr. Sarma VSN - PowerPoint Presentation

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Insulin in Pregnancy

Prof. Dr. Sarma VSN

Rachakonda

M.D., M.Sc., (Canada

), FCGP,

FIMSA

,

FRCP

(Glasgow), FCCP (USA)

Visiting Professor of Internal Medicine, SBMC, FLL, iDRF

Consultant Physician and Cardio-metabolic

Specialist, ChennaiSlide2

Glucose

Challenge Test (GCT

)An excellent screening test is to obtain plasma glucose level one hour after a 50 g glucose load administered at any time of the day without regard to the time since the last meal. It is a well validated and widely applied screening procedure for women between 24 -28 weeks of gestation.Cut-off value > 140 mg/dl identifies 80% women with GDMCut-off value > 130 mg/dl identifies 90% women with GDMGCT is elevated, do a diagnostic oral glucose tolerance test

Screening TestSlide3

Diagnostic Test – OGTT

Timing of measurement

National Diabetes Data Group (1979)Carpenter and Coustan (CC) 1982Fasting105 mg/dl95 mg/dl1 hour190 mg/dl

180 mg/dl

2 hour

165 mg/dl155 mg/dl3 hour145 mg/dl140 mg/dl

Diabetes 1979;28:1039–1057; Am J OBG. 1982;144:768-73

2 or more values

must be abnormal; for at least 3 days prior to the test, the patient should have an unrestricted diet and unlimited physical activity. The patient should fast for 8 hours before the test. The CC criteria detects 54% more women with GDM

than NDDG

criteriaSlide4

OGTT –100g –3 hour Test

Test sample timing

Plasma Glucose valueFasting (mg%)951 hour (mg%)1802 hour (mg%)1553 hour (mg%)140Two abnormalvalues are

enoughSlide5

Glycemic

Control TargetsTight glycemic control can reduce fetal risk. But, stringent glycemic control puts the mother at increased risk of hypoglycemic events and the fetus at risk of being small-for-gestational age. American Diabetes Association (ADA) Recommendations:

Fasting whole blood glucose

<95 mg/dl

1 hr postprandial blood glucose<140 mg/dl2 hr postprandial blood glucose<120 mg/dlHb A1C (for GDM)

< 6.0 %These are venous plasma targets, not glucometer targetsSlide6

Glycemic Targets

HbA1C – not ideal for screening of GDM

May used for screening of T2DMPatients with excessive fetal growth - InsulinThose who don’t achieve targets in 1w- InsulinTarget valuesHb A1c < 6%; Pre pregnancy Hb A1c < 7%Fasting – < 95 mg%Post prandial 1 hour – < 120 mg %Post prandial 2 hours – < 140 mg%Urine ketones should be negativeDiabetes Care 21(2):B161–B167, 1998, Diabetes Care 2010; 33: 676–682Slide7

Freinkel Hypothesis

Uterine

After BirthMaternal DM

P

lacenta

AA, FatCHO

At BirthMacrosomia

Hypoglycemia

Fetus



Insulin

Obesity

Metabolic

Syndrome

CVD

IGT/DMSlide8

IUGR & Macrosomia

Optimal

Nutrition + Optimal Glycemic Control Results in optimal birth weight of 3–3.5 kg.Slide9

Glucose Metabolism in Pregnancy

First Half of Pregnancy (Anabolic)

Pancreatic beta-cell hyperplasia  hyper insulinemia Increased uptake and storage of glucoseSecond Half of Pregnancy (Catabolic)Placental hormones block glucose receptors and cause insulin resistanceIncreased lipolysisIncreased gluconeogenesisDecreased glycogenesisIncreased glucose and amino acids for the fetusSlide10

Pathogenesis of GDM

Pregnancy is Diabetogenic condition

A Wonderful Metabolic Stress TestPlacental Diabetogenic HormonesProgesterone, Cortisol, GHHuman Placental Lactogen (HPL), ProlactinInsulin Resistance (IR), ↑  cell stimulationReduced Insulin Sensitivity up to 80%Impaired 1st phase insulin, HyperinsulinemiaIslet cell auto antibodies (2 to 25% cases)Glucokinase mutation in 5% of casesSlide11

Fundamental Defect in GDMThe hormones of pregnancy cause IR

They also cause direct hyperglycemia

But, the basic defect is The maternal pancreatic  cells are unable to compensate for this increased demandPlasma Glucose in pregnancy hangs on a delicate balanceIf the Mean Plasma Glucose (MPG) isLess than 87 mg% - IUGR of fetusMore than 104 mg% - LGA of fetusIt is important to screen for hypothyroidismSlide12

Questions in GDMDoes GDM pose serious risks to offspring?

Does treatment reduce those risks?

Does treatment reduce other risks associated with GDM (obesity/diabetes in offspring)?Does reducing hyperglycemia reduce risks? (macrosomia & cesarean delivery)Slide13

Diabetes in PregnancyWhy is it so important? Slide14

Look at the impact of GDMSlide15

Congenital Anomalies - DM Control

Maternal HbA1c levels

< 7.2 Nil 7.2-9.1 14% 9.2-11.1 23% > 11.2 25%Critical periods - 3-6 weeks post conceptionNeed preconception metabolic careSlide16

Complications & Glycemic Thresholds

Complication

Mean blood glucoseSpontaneous abortion160 mg%Congenital anomalies140 mg%Still births140 mg&Lung maturation140 mg%Metabolic complication110 mg%Macrosomia or LGA110 mg%Slide17

Insulin therapy remains the main stay of treatment and it is being increasingly used.Slide18

Physiological Insulin ProfileSlide19

Insulin Release in Normal PersonsSlide20

Time Line of Insulins1922- Insulin discovery by Banting and Best

1923- Commercial insulin with impurities

1975- Higher quality Bovine and Porcine Insulin1978- Synthetic Human Insulin1982- Synthetic human insulin approved 1983- Synthetic recombinant human insulin1985- Sequencing the human insulin receptor1996- Lispro insulin (Lilly) analogue2003- Glargine insulin (Sanofi Aventis) analogue2004- Glulisine (Sanofi Aventis) analogue2006- Detemir insulin (Novo Nordisk) analogue Slide21

Ideal Insulin in PregnancyMimic physiological control

No adverse effect upon maternal and fetal outcome.

No interfere with antenatal, perinatal & post natal careIgG bound insulin can cross placenta. So insulin should not induce antibody generationInsulin Analogues fulfills all the criteriaMimic physiological insulin secretionDoes not cross placentaNo mitogenic potentialSlide22

Analogue Insulins (rDNA)

Analogue

Change in amino acid sequenceTypeLispro28-29 Proline and Lysine are interchangedRapidAspart Proline at 28 replaced by Aspartic acidRapidGlulisine3 Lysine by Asparagine; 29 Lysine by Glutamine

Rapid

Glargine

A21 Asparagine by Glycine; 2 Arginine to C terminal B LongDetemirB 30 Threonine by Myristic acid a C-14 Fatty acid LongSlide23

Analogue Insulins (rDNA)

Analogue

Brand NameManufacturer FDALisproHUMALOGEli LillyBAspart NOVOLOGNovo Nordisk

B

Glulisine

APIDRASanofi AventisCGlargineLANTUS(R)Sanofi AventisC

DetemirLEVEMIR Novo NordiskBSlide24

Advantages of AnalogsBatch to Batch consistency

No allergy, antibody formation

No immune mediated lipoatrophyGlucose control is similar in endogenous insulin productionPre prandial hypoglycemia and postprandial hyperglycemia are well controlled.Mealtime flexibility is possible with analogues.Slide25

Benefits of Insulin AnaloguesSlide26

FPG and Insulin Response

Brunzell JD et al. J Clin Endocrio Metab. 1976; 42:222-229Slide27

Action Profiles of InsulinsSlide28

Pharmacokinetics of Insulins

Barnett AH, Owens DR, Lancet 1977; 349:97-99 and 1997,101:60-70Slide29

Insulin RegimensSlide30

Dosage of Insulin Therapy

Two parameters – Weight and Gestational age

The level of blood sugar is not the criterionInsulin requirements increase rapidly, especially from 28 to 32 weeks of gestation1st trimester: 0.7-0.8 U/kg/day2nd trimester: 0.8-1.0 U/kg/day3rd trimester: 0.9-1.2 U/kg/dayIncrease every 3 days by 2 units based on BGMSlide31

Insulin Titration in GDM

Titrate insulin based on SMBG values:

Fasting 60-90Pre-meal <952 hour post-meal <120Bedtime <120Slide32

Insulin RegimensSlide33

Basal-Bolus Insulin Rx.Slide34

Multiple Injection Regimen

NICE Clinical Guideline 63 March 2008Slide35

During Delivery

Blood Glucose

IV Fluid with or without Insulin60-90 mg%5% DNS – 100 ml/hr90-120 mg%NS or RL – 100 ml/hr120-140 mg%NS or RL – 100 ml/hr + 4 U R Insulin140-180 mg%NS or RL – 100 ml/hr + 6 U R Insulin> 180 mg%NS or RL – 100 ml/hr + 8 U R InsulinIn GDM Insulin requirement precipitously drops after placental expulsionSlide36

Total 24 hour Insulin requirement in 60 kg 1

st

Trimester60 x 0.7 = 42 units – 2/3 pre BF = 28 U, 1/3 = 14 U eveningOf the 28U – 2/3 NPH and 1/3 Regular = (19 + 9) in one inj.Of the 14U – ½ Regular pre supper (7U) and ½ NPH at bed Slide37

Barriers for Insulin Rx.

Patient Resistance:

(Psychological Insulin Resistance)Compliance issues, Needle phobiaFear of scarring, Fear of wrong dosageFinancial, Difficulties in administrationPhysician Resistance (Clinician Inertia)Lack of resources and knowledge of InsulinsLack of time to plan/follow/educate intensive regimenPerceived and real adverse effectsWeight gain; HypoglycemiaOptimal control requires multiple injectionsSlide38

GDM Trials

Crowther et al – Multicenter – 1000 pts.

Langer et all – 1100 GDM, 1100 NormalHAPO: 28,000 women (Hyperglycemia And Adverse Pregnancy Outcome)ACHOIS (Australian Carbohydrate Intolerance Study)MFMU Maternal and Fetal Medicine Unit (NICHD) GDM TrialInt J Gynecology & Obstetrics. 2002,78, (1);69-77 Slide39

Langer et al – Glyburide Study

Langer et al - NEJM 2000: 1343-1138, Oct 19Slide40

OAD in Pregnancy: The Other Alternative, O. Langer, Slide41

Algorithm for Rx of GDM

OAD in Pregnancy: The Other Alternative, O. Langer, Slide42

Current Diabetes Reviews, 2009, 5, 252-258

Glibenclamide – Class B, may be other SUs

Metformin – Class B ( No statins, No ACEi, ARB)TZD – Not to be used, AGI – Class BGLP-1, DPP IV Inhibitors – More studies neededSlide43

OADs in PregnancyNew generation of oral hypoglycemic agents glyburide does not cross the placenta and may be used to replace insulin between 11-33 wks.

Metformin can be used in P.C.O. patients during the whole pregnancy. It showed that it reduces miscarriages and the incidence of GDM

TZDs not studied in pregnancy – not a choiceAGIs – weak drugs – GI side effects -local actionGLP-1 and DPP IV Inhibitors not studied yetSlide44

Expert Rev. Endocrinol. Metab. 7(2), 165–167 (2012)

Selective v/s Universal screening

Single 50g GCT v/s 100g OGTT OADs – Poor Women’s InsulinSlide45
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Abstract

Diabetes in pregnancy is associated with risks to the woman and to the developing fetus. Miscarriage,

pre-eclampsia, preterm labour and congenital malformations in fetus are more common in women with pre-existing diabetes. Insulin requirement increases with each trimester of pregnancy in diabetic females. Treatment of gestational diabetes consists of medical nutrition therapy but insulin treatment forms the mainstay of the therapy. Monitoring glycemic control is essential in treatment of gestational diabetes. HbA1c level is helpful to differentiate between a pre-GDM and GDM. Majority of pregnant women with diabetes fail to achieve optimum glycemic control, mostly the postprandial plasma glucose with conventional insulin. In them, the best option is to administer ultra-short-acting analogs, insulin Lispro or insulin Aspart. These analogs improve the postprandial glucose control during pregnancy in both type 1 and type 2 diabetes and are considered safe and effective.

Supplement to JAPI •

A

pril 2011 • VOL. 59Slide47

NICE Clinical Guideline 63 March 2008Slide48

Insulin PumpsSlide49

Continuous Subcutaneous Insulin Infusion (CSII)

Blood glucose levels monitored continuously

Pre specified insulin dose is s/c delivered by pumpThis minimized timing and dosing errors. Continuous Glucose Monitoring System (CGMS)Blood glucose is assessed periodically Insulin dose is calculated CGMS is integrated with a delivery device – blue toothHence round the clock blood glucose is controlled. Slide50

Artificial SweetenersWhen used within ADI

Aspartame (NutraSweet)

does not cross placenta; No adverse effectsSucralose (Equal) – acceptableAcesulfame K (Sunnet) – acceptableSaccharin (Nectra Sweet, Sweet Twin) – Crosses placenta; not acceptableCyclamate (Sucril) – not acceptableSlide51

Thank you for your attention