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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, Chennai

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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 GDM

Cut-off value > 130 mg/dl identifies 90%

women with GDM

GCT is elevated, do a diagnostic oral glucose

tolerance test

Screening Test

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Diagnostic Test – OGTT

Timing of measurement

National Diabetes Data Group (1979)

Carpenter and Coustan (CC)

1982

Fasting 105 mg/dl 95 mg/dl

1 hour 190 mg/dl 180 mg/dl

2 hour 165 mg/dl 155 mg/dl

3 hour 145 mg/dl 140 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 criteria

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OGTT –100g –3 hour Test

Test sample timing

Plasma Glucose value

Fasting (mg%) 95

1 hour (mg%) 180

2 hour (mg%) 155

3 hour (mg%) 140

Two abnormal

values are enough

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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/dl

2 hr postprandial blood glucose <120 mg/dl

Hb A1C (for GDM) < 6.0 %These are venous plasma targets, not

glucometer targets

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Glycemic Targets• HbA1C – not ideal for screening of

GDM• May used for screening of T2DM• Patients with excessive fetal growth -

Insulin• Those who don’t achieve targets in

1w- Insulin• Target values

– Hb 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 negative

Diabetes Care 21(2):B161–B167, 1998, Diabetes Care 2010; 33: 676–682

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Freinkel HypothesisUterin

e After Birth

Mate

rnal D

M

Pla

centa

AA, FatCHO

At BirthMacrosomia

Hypoglycemia

Fetus

Insulin

Obesity

Metabolic Syndrome

CVD

IGT/DM

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IUGR & Macrosomia

Optimal Nutrition + Optimal Glycemic Control Results in optimal

birth weight of 3–3.5 kg.

HTN, IGT Type 2

DM

Barker’s Hypothesis

Low birth weight

Pederson’s hypothesisMacrosomia

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Glucose Metabolism in Pregnancy

• First Half of Pregnancy (Anabolic)– Pancreatic beta-cell hyperplasia hyper

insulinemia – Increased uptake and storage of glucose

• Second Half of Pregnancy (Catabolic)– Placental hormones block glucose receptors and

cause insulin resistance• Increased lipolysis• Increased gluconeogenesis• Decreased glycogenesis

– Increased glucose and amino acids for the fetus

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Pathogenesis of GDM

• Pregnancy is Diabetogenic condition• A Wonderful Metabolic Stress Test• Placental Diabetogenic Hormones

– Progesterone, Cortisol, GH– Human Placental Lactogen (HPL),

Prolactin• Insulin Resistance (IR), ↑ cell

stimulation• Reduced Insulin Sensitivity up to 80%• Impaired 1st phase insulin,

Hyperinsulinemia• Islet cell auto antibodies (2 to 25%

cases)• Glucokinase mutation in 5% of cases

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Fundamental Defect in GDM

• The 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 demand• Plasma Glucose in pregnancy hangs on a

delicate balance• If the Mean Plasma Glucose (MPG) is

– Less than 87 mg% - IUGR of fetus– More than 104 mg% - LGA of fetus

• It is important to screen for hypothyroidism

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Questions in GDM

• Does 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)

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Diabetes in PregnancyWhy is it so important?

1

• Poor Pregnancy outcomes and mortality

• High maternal & perinatal morbidity

2

• High risk of future onset of diabetes in mothers

• A good primary prevention opportunity

3

• Metabolic problems in the offspring

• Including high incidence of diabetes

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Look at the impact of GDM

Mean glucose is >150 – PN Mortality is 24%

Mean glucose is 100-150 - PN Mortality is 15%

Mean glucose is <100 – PN Mortality is 4%

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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 conception

Need preconception metabolic care

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Complications & Glycemic Thresholds

ComplicationMean blood glucose

Spontaneous abortion 160 mg%

Congenital anomalies 140 mg%

Still births 140 mg&

Lung maturation 140 mg%

Metabolic complication 110 mg%

Macrosomia or LGA 110 mg%

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Insulin therapy remains the main stay of

treatment and it is being increasingly used.

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Physiological Insulin Profile

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Insulin Release in Normal Persons

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Time Line of Insulins• 1922- Insulin discovery by Banting and

Best• 1923- Commercial insulin with impurities • 1975- Higher quality Bovine and Porcine

Insulin• 1978- Synthetic Human Insulin• 1982- Synthetic human insulin approved • 1983- Synthetic recombinant human

insulin• 1985- Sequencing the human insulin

receptor• 1996- Lispro insulin (Lilly) analogue• 2003- Glargine insulin (Sanofi Aventis)

analogue• 2004- Glulisine (Sanofi Aventis) analogue• 2006- Detemir insulin (Novo Nordisk)

analogue

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Ideal Insulin in Pregnancy

• Mimic physiological control• No adverse effect upon maternal and fetal

outcome.• No interfere with antenatal, perinatal &

post natal care• IgG bound insulin can cross placenta. So

insulin should not induce antibody generation

• Insulin Analogues fulfills all the criteria• Mimic physiological insulin secretion• Does not cross placenta• No mitogenic potential

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Analogue Insulins (rDNA)

Analogue Change in amino acid sequence Type

Lispro 28-29 Proline and Lysine are interchanged Rapid

Aspart Proline at 28 replaced by Aspartic acid Rapid

Glulisine 3 Lysine by Asparagine; 29 Lysine by Glutamine Rapid

Glargine A21 Asparagine by Glycine; 2 Arginine to C terminal B Long

Detemir B 30 Threonine by Myristic acid a C-14 Fatty acid Long

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Analogue Insulins (rDNA)

AnalogueBrand Name Manufacturer FDA

Lispro HUMALOG Eli Lilly B

Aspart NOVOLOG Novo Nordisk B

Glulisine APIDRA Sanofi Aventis C

Glargine LANTUS(R) Sanofi Aventis C

Detemir LEVEMIR Novo Nordisk B

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Advantages of Analogs

• Batch to Batch consistency• No allergy, antibody formation• No immune mediated lipoatrophy• Glucose control is similar in

endogenous insulin production• Pre prandial hypoglycemia and

postprandial hyperglycemia are well controlled.

• Mealtime flexibility is possible with analogues.

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Benefits of Insulin Analogues

Maternal

More physiological profile

Better glycemic control

Minimum hypoglycemia risk

Greater meal time flexibility

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FPG and Insulin Response

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

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Action Profiles of Insulins

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Pharmacokinetics of Insulins

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

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Insulin Regimens

Basal

Basal Plus

Basal Bolus

Spilt Mix

AM+PM

CSII + CGMS

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Dosage of Insulin Therapy

• Two parameters – Weight and Gestational age

• The level of blood sugar is not the criterion• Insulin requirements increase rapidly,

especially from 28 to 32 weeks of gestation– 1st trimester: 0.7-0.8 U/kg/day– 2nd trimester: 0.8-1.0 U/kg/day– 3rd trimester: 0.9-1.2 U/kg/day

• Increase every 3 days by 2 units based on BGM

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Insulin Titration in GDM

Titrate insulin based on SMBG values: • Fasting 60-90• Pre-meal <95• 2 hour post-meal <120• Bedtime <120

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Insulin Regimens

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Basal-Bolus Insulin Rx.

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Multiple Injection Regimen

NICE Clinical Guideline 63 March 2008

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During Delivery

Blood Glucose IV Fluid with or without Insulin

60-90 mg% 5% DNS – 100 ml/hr

90-120 mg% NS or RL – 100 ml/hr

120-140 mg% NS or RL – 100 ml/hr + 4 U R Insulin

140-180 mg% NS or RL – 100 ml/hr + 6 U R Insulin

> 180 mg% NS or RL – 100 ml/hr + 8 U R Insulin

In GDM Insulin requirement precipitously drops after placental expulsion

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Total 24 hour Insulin requirement in 60 kg 1st Trimester

60 x 0.7 = 42 units – 2/3 pre BF = 28 U, 1/3 = 14 U evening

Of 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

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Barriers for Insulin Rx.

• Patient Resistance: (Psychological Insulin Resistance)– Compliance issues, Needle phobia– Fear of scarring, Fear of wrong dosage– Financial, Difficulties in administration

• Physician Resistance (Clinician Inertia)– Lack of resources and knowledge of

Insulins– Lack of time to plan/follow/educate

intensive regimen• Perceived and real adverse effects

– Weight gain; Hypoglycemia– Optimal control requires multiple injections

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GDM Trials

• Crowther et al – Multicenter – 1000 pts.• Langer et all – 1100 GDM, 1100 Normal• HAPO: 28,000 women (Hyperglycemia And Adverse Pregnancy Outcome)• ACHOIS (Australian Carbohydrate Intolerance Study)• MFMU Maternal and Fetal Medicine Unit (NICHD) GDM Trial

Int J Gynecology & Obstetrics. 2002,78, (1);69-77

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Langer et al – Glyburide Study

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

40www.drsarma.in OAD in Pregnancy: The Other Alternative, O. Langer,

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Alg

ori

thm

for

Rx o

f G

DM

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

42www.drsarma.in Current Diabetes Reviews, 2009, 5, 252-258

Glibenclamide – Class B, may be other SUsMetformin – Class B ( No statins, No ACEi, ARB)TZD – Not to be used, AGI – Class BGLP-1, DPP IV Inhibitors – More studies needed

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OADs in Pregnancy

• New 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 choice

• AGIs – weak drugs – GI side effects -local action

• GLP-1 and DPP IV Inhibitors not studied yet

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Selective v/s Universal screeningSingle 50g GCT v/s 100g OGTT

OADs – Poor Women’s Insulin

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AbstractDiabetes 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 • April 2011 • VOL. 59

47www.drsarma.in NICE Clinical Guideline 63 March 2008

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Insulin Pumps

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Continuous Subcutaneous Insulin Infusion (CSII)

• Blood glucose levels monitored continuously

• Pre specified insulin dose is s/c delivered by pump

• This 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 tooth• Hence round the clock blood glucose is

controlled.

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Artificial Sweeteners

When used within ADI• Aspartame (NutraSweet)

– does not cross placenta; – No adverse effects

• Sucralose (Equal) – acceptable• Acesulfame K (Sunnet) – acceptable• Saccharin (Nectra Sweet, Sweet

Twin)

– Crosses placenta; not acceptable• Cyclamate (Sucril) – not acceptable

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Thank you for your attention