Diabetes Mellitus And Pregnancy

BY

Mohammed shereif MD of Internal Medicine

Endocrine unit

Faculty of Medicine-Mansoura University

☻ AGENDA: Review On Diabetes Mellitus.

Endocrinology Of Pregnancy.

Diabetes Mellitus And Pregnancy.

Complications of Diabetes on

pregnancy.

Management.

Review On Diabetes Mellitus

DIABETES MELLITUS: DEFINED

Diabetes is a group of metabolic diseases

characterized by hyperglycemia.

Hyperglycemia resulting from defects in insulin

secretion, insulin action, or both.

The chronic hyperglycemia of diabetes is associated

with long-term damage, dysfunction, and failure of

different organs, especially the eyes, kidneys, nerves,

heart, and blood vessels

DIABETES CLASSIFICATION:

♣ Type 1 (IDDM).

♣ Type 2 (NIDDM).

♣ Gestational diabetes.

♣ Other specific types.

Criteria for the diagnosis of diabetes mellitus:

Symptoms of diabetes and rondam plasma glucose ≥ 200 mg/dl (11.1 mmol/l).

OR

FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 hours.

OR

2-h plasma glucose ≥ 200mg/dl (11.1 mmol/l) during an OGTT.

OR

A1C ≥ 7%.

Endocrinology Of Pregnancy

The placenta produces larger quantities of more

hormones than any other human organ.

Placental Diabetogenic Hormones are:

Progesterone, Cortisol, GH

Human Placental Lactogen (HPL), Prolactin

Placental hormones affect glucose and lipid

metabolism to ensure that fetus has ample

supply of nutrients.

Changes in maternal metabolism during normal pregnancy:

♣ Decreased fasting plasma glucose level.♣ Increased post prandial plasma glucose.♣ Increased plasma insulin level and IR.♣ ß- cell hypertrophy and hyperplasia.♣ Increased fat metabolism.♣ Increased ketone production.♣ Decreased circulating amino acids.♣ Decreased glucose production in the liver.♣ renal threshold for glucose glycosuria.

Pregnancy Pathophysiology: Insulin resistance occurs because the hormonal changes

associated with pregnancy partially block the effects of insulin.

Maternal pancreatic beta cells increase insulin secretion almost three fold to compensate for increased insulin resistance.

If the mother’s pancreas is unable to produce sufficient insulin to overcome insulin resistance, maternal glucose levels increase and GDM occurs.

GDM may disappears after pregnancy because the hormonal changes that caused insulin resistance are no longer present.

Diabetes Mellitus And Pregnancy

Diabetes in Pregnancy: Types Gestational Diabetes Mellitus (GDM)

♣ Type A1: abnormal (OGTT) but normal blood glucose levels during fasting and 1-2 hours after meals.

♣ Type A2: abnormal (OGTT) with abnormal glucose levels during fasting and/or after meals.

Pregestational Diabetes Mellitus♣ Type 1: autoimmune process that destroys pancreatic

B cells.♣ Type 2 (“lifestyle diabetes”): acquired insulin

resistance related to obesity.

Criterion White Classification

Gestational diabetes, insulin not required A1

Gestational diabetes, insulin required A2

Onset at age 20 years or older and duration of less than 10 years B

Onset at age 10-19 years or duration of 10-19 years C

Age of onset < 10 years of age D1

Duration >= 20 years D2

Calcification of vessels of the leg (macrovascular disease), formerly called Class E

D3

Benign retinopathy (microvascular disease) or Hypertension (not preeclampsia)

D4

Proliferating retinopathy R

Nephropathy F

Criteria for both classes R and F RF

Many pregnancy failures G

Evidence of arteriosclerotic heart disease H

Renal transplant T

Diabetes in Pregnancy:Diabetes in Pregnancy: ClassificationClassification

Pregestational Diabetes: Types 1 and 2

Gestational Diabetes Mellitus:“Any degree of glucose intolerance with onset

or first recognition during pregnancy.”♣ The definition applied whether insulin or only The definition applied whether insulin or only

diet modification is used for treatment of GDM.diet modification is used for treatment of GDM.♣ It does not exclude the possibility It does not exclude the possibility

that unrecognized glucose intolerance that unrecognized glucose intolerance

may have antedated or begun may have antedated or begun

concomitantly with the pregnancy.concomitantly with the pregnancy.

Risk Risk AssessmentAssessment

Risk factors for developing Risk factors for developing GDM:GDM:

A family history.A family history.

Gestation diabetes in a previous pregnancy.Gestation diabetes in a previous pregnancy.

Obesity and BMI > 30 kg/m2Obesity and BMI > 30 kg/m2

Older maternal age > 30 y.Older maternal age > 30 y.

Previous still birth or spontaneous miscarriage.Previous still birth or spontaneous miscarriage.

A previous delivery of a large baby ( > 9 bounds).A previous delivery of a large baby ( > 9 bounds).

Women of hispanic, or African American.Women of hispanic, or African American.

Low risk for GDM:♣ Age less than 25 years. ♣ Normal weight before pregnancy (BMI less

than 25 kg/m2). ♣ Member of an ethnic group with a low

prevalence of GDM♣ No first degree relative with diabetes mellitus.♣ No history of abnormal glucose tolerance.♣ No history of poor obstetric outcome.

Screening For GDM

SelectiveUniversal

Obesity

Age Age 25 years 25 years

Familial diabetes

Poor obstetric outcome

Abnormal glucose metabolism

based on

Clinics in laboratory medicine, 21.1 March 2001, 173-192

Diabetes Care 23.1, ADA clinical practice recommendation 2000

High GDM prevalence ethnic groups

Performing GCT in all pregnant women

Screening StrategyScreening Strategy

Whom to Screen for GDM ? Low Risk Group

♣ No screening required for GDM

Intermediate Risk Group♣ Screen around 24–28 weeks of gestation

High Risk Group♣ As soon as possible after conception♣ Must - before 24–28 weeks of gestation♣ Better do a full 3 hr OGTT for GDM♣ If negative screening in 2nd & 3rd trimester

Screening strategies for GDM

☻The approach

One-step approach

Two-step approach

☻One step approach:♣ Perform a diagnostic oral glucose

tolerance test (OGTT) without prior

plasma or serum glucose testing.

♣ Cost effective in high risk patients or

population.

☻Two step approach:

Initial screening plasma or serum glucose 1h after

50gm oral glucose load.

Exceeding the Glucose threshold value or the GCT

Diagnostic OGTT

♣ Two step approach glucose threshold

> 140 mg 80% of women with GDM

and the yield is further increased to 90%

by using a cutoff of > 130 mg/dl.

POSITIVE SCREEN DOES NOT

ESTABLISH THE DIAGNOSIS OF

GESTATIONAL DIABETES!!!

50-g oral glucose challenge The screening test for GDM, may be performed

in the fasting or fed state. Sensitivity is improved if the test is performed in the fasting state.

A plasma value above 130 - 140 mg/dl one hour after is commonly used as a threshold for performing a 3-hour OGTT.

If initial screening is negative, repeat testing is performed at 24 to 28 weeks.

Diagnosis Of GDM

3 hour Oral glucose tolerance testPrerequisites:

♣ Normal diet for 3 days before the test.

♣ At least 10 hours fast.

♣ Test is done in the morning at rest.

Giving 75 gm (100 gm by other authors) glucose in 250 ml water orally.

2 or more values greater than or equal to the following cutoffs is diagnostic of GDM.

single abnormal value indicates CHO intolerance.

♣ For ADA criteria 2 or more values from either 100 or 75 g OGTT must be met or exceeded to make the diagnosis of GDM

♣ For WHO criteria, one of the 2 values must be met or exceeded to make the diagnosis of GDM

OGTT GTT 100gr GTT 75gr

Criteria ADA ADA

Sample Plasma

(mg/dl)

Plasma

(mg/dl)

Fasting 95 95

1 h 180 180

2 h 155 155

3 h 140 ---

Diagnostic Criteria for GDMDiagnostic Criteria for GDM

Complications of

Diabetes on pregnancy

NEONATAL COMPLICATIONS:

Congenital anomalies.

Premature delivery.

Perinatal asphyxia.

Macrosomia and Shoulder Dystocia.

Respiratory distress syndrome.

Hyperbilirubinemia. 

Cardiomyopathy.

Polycythemia and hyperviscosity syndrome.

Metabolic complications.

Late effects on the offspring:

Increased risk of IGT.

Future risk of T2DM.

Risk of Obesity.

Macrosomic Newborn (4.2kg)

Shoulder Dystocia

Erb’s palsy

Maternal COMPLICATIONS:♣ Difficult diabetic control (Ketoacidosis).

♣ Repeated infections during pregnancy and

puerperium.

♣ PET and eclampsia: 15-20%.

♣ Operative and difficult deliveries: increased CS

rate.

♣ Postpartum hemorrhage.

♣ Increase incidence of diabetic complications:

nephropathy, neuropathy and retinopathy.

Management

Prepregnancy Evaluation Of Diabetic Women

Complete history and physical examination.

Multidisciplinary team including obstetricians,

endocrinologists, dieticians, & midwives optimize

outcome.

To achieve normoglycemia as far as possible:

♣ FBS < 95 mg/dL.

♣ 1h PP < 140 mg/dL.

♣ 2h PP < 120 mg/dL.

Monitoring:♣ SMBG intermittent office monitoring.

♣ For women treated by insulin 1h post -

prandial monitoring is superior to pre-prandial

monitoring.

♣ Urine glucose not useful in GDM.

♣ Urine ketone be useful in detecting insufficient caloric or carbohydrate intake in women treated with calorie restriction.

Target Blood Glucose Values

Our blood glucose goals in pregnant diabetic

women are:

♣ ACOG:♥ Fasting glucose concentrations ≤ 95 mg/dL (5.3

mmol/L).

♥ Preprandial glucose concentrations no higher than

100 mg/dL (5.6 mmol/L).

♥ One-hour postprandial glucose concentrations no

higher than 140 mg/dL (7.8 mmol/L).

♥ Two-hour postprandial glucose concentrations no

higher than 120 mg/dL (6.7 mmol/L).

♥ Mean capillary glucose 100 mg/dL (5.6 mmol/L)

and glycosylated A1C ≤ 6 percent (ACOG, 2005).

♣ ADA:

♥ Preprandial glucose concentrations 80 to 110 mg/dL

(4.4 to 6.1 mmol/L).

♥ Two-hour postprandial glucose concentrations no

higher than 155 mg/dL (8.6 mmol/L) (ADA, 2004).

Nutritional counseling♣ Registered dietitian.

♣ Individualization of medical nutrition

therapy (MNT).

♣ Adequate calories and nutrients to meet

the needs of pregnancy.

♣ Non caloric sweeteners.

Nutritional RecommendationsDistribution of total calories is:

♣ 35-45 % carbohydrates.♣ 20-25 % protein.♣ 35-40 % fat.

Most programs suggest three meals and three snacks, however, in overweight and obese women the snacks are often eliminated.

Exercise !Moderate regular exercise

such as: walking, cycling

or swimming are excellent

forms of exercise for

pregnant women. Keeping

well-hydrated and

well-nourished is essential

Medical Therapy: If normoglycemia cannot be maintained by

medical nutritional therapy, then anti-

hyperglycemic agents should be initiated.

Insulin.

Oral anti-hyperglycemic agents.

Insulin: Insulin therapy is recommended when MNT fails to

maintain self monitored glucose at the following level (ACOG&ADA):♠ FBG < 95 mg/dl or

♠ 1h PPPG < 130-140mg/dl or

♠ 2h PPPG < 120 mg/dl.

Use of insulin preparations of low antigenicity will minimize the transplacental transport of insulin antibodies: human insulin is the least immunogenic of

the commercially available preparations.

Regular insulin, which is often used in

pregnancy for the treatment of diabetes has

some drawbacks:

It starts its action from 30 to 60 min after

subcutaneous injection and it peaks too late (2-4 h

after injection) to be very effective in postprandial

control.

In addition, it lasts too long (duration of 6-8 h), with

an increased risk of postprandial hypoglycemia.

Insulin molecules clump in hexamers that must

be broken up to dimers and monomers before

absorption, so delaying their effectiveness.

Therefore, in the last few years

insulin analogues started to be used

to optimize glucose control during

pregnancy.

The New Insulin Analogues

Insulin LisproInsulin Lispro

Insulin AspartInsulin Aspart

Insulin GlulisineInsulin Glulisine

Insulin GlargineInsulin Glargine

Insulin DetemirInsulin Detemir

Rapidly Acting Long acting

Insulin Lispro: There are various safety issues to consider:

Immunogenicity,Teratogenicity, Embryotoxicity, and Retinopathy.

The studies reported to date suggest that insulin lispro may be considered a treatment option in patients with GDM.

Insulin Aspart: Aspart insulin is now approved for use in

pregnancy and offers a valuable treatment option.

Insulin Glulisine: At present no reports on glulisine use in

pregnancy are available.

Insulin Detemir: At present there are data on the use of detemir

in pregnancy with no difference from NPH

Insulin Glargine:

At present the use of insulin glargine in

pregnancy is approved:

♣ Concerns have been raised about the high affinity of

glargine for the IGF-1 receptor and the potential

sequelae of macrosomia.

Insulin TitrationThe starting insulin dose can be calculated

on the basis of the patient's weight

♣ The average insulin requirement in pregnant women

is 0.7 units/kg in the first trimester, often increasing to

0.8 U/kg for weeks 13 to 28, 0.9 U/kg for weeks 29 to

34, and 1.0 U/kg for weeks 35 to term.

♣ In a pregnant diabetic patient the rationale for insulin

therapy is based on mimicking the physiology of

insulin secretion.

♣ The basal insulin is supplied by the administration of

NPH, lente, ultralente insulin at bedtime or both before

breakfast and at bedtime.

♣ The meal-related (glucose excursion) insulin includes

the use of insulin lispro or aspart before meals (0-15

min) or regular insulin before meals (30-45 min).

♣ This method characterized the intensified therapy

(multiple injections daily) versus conventional therapy

(one or two injection daily).

Oral Anti Diabetic Drugs

The use of Acarbose, Thiazolidinediones,

Glinides and Glucagon-like peptide 1

agonists is contraindicated during

pregnancy

Sulfonylureas are currently the only

drugs to be studied in GDM women in

randomized controlled trials.

Most data regarding oral antidiabetic

drug safety in pregnancy are

regarding Glyburide.

Metformin Metformin is classified as a category B drug, which

implies that there is no evidence of animal or fetal

toxicity or teratogenicity.

Metformin does not stimulate insulin secretion and

does not cause hypoglycemia.

The concentration of metformin in breast milk is

generally low and mean infant exposure to the drug is

clearly below the 10% level. Therefore, use of

metformin by breast-feeding mothers is safe.

In PCOS, use of Metformin is associated

with a tenfold reduction in gestational

diabetes (from 31 to 3%) and it is safely

associated with spontaneous abortion

reduction (from 73 to 10%).

Although , most current studies demonstrate

that oral hypoglycemic agents, such as

Glyburide and Metformin, are safe to use in

pregnancy with maternal and perinatal

outcomes similar to insulin treatment.

But there is a need for a randomized controlled

trial with long-term follow up of both mothers

and children.

Long-term therapeutic

considerations♫ At least six weeks after delivery, all women with

previous GDM should undergo an oral glucose tolerance test using a two-hour 75 gram oral glucose tolerance test.

♫ Reclassification of maternal glycemic status should be performed at least 6 weeks after delivery and according to the guidelines of the “Report of the Expert Comitte on the Diagnosis and Classification of DM”

Criteria for the diagnosis of diabetes mellitus

Normoglycemia IFG and IGT Diabetes mellitus

FPG <100 mg/dl FPG 100 mg/dl and <126 mg/dl

(IFG) FPG > 126 mg/dl

2-h PG <140 mg/dl 2-h PG 140

mg/dl and <200 mg/dl (IGT)

2-h PG > 200 mg/dl

— —

Symptoms of DM and casual plasma glucose concentration > 200 mg/dl

♣ Women with gestational diabetes rarely require

insulin in the postpartum period and

approximately 15% of those remain glucose

intolerant or demonstrate overt diabetes in the

postpartum state.

♣ If glucose level are normal post-partum,

reassessment of glycemia should be undertaken

at a minimum of 3-years intervals.

♣ Women with IFG or IGT in the postpartum

period should be tested for DM annually.

These patients should receive intensive MNT

and should be placed on an exercise program.

♣ The patients should be educated to seek

medical attention if they develops symptoms

suggestive of hyperglycemia.

Summary

Diabetes in pregnancy may be gestational diabetes or

pregestational diabetes.

pregnancy is diabetogenic as it converts latent to

overt diabetes.

Adequate blood glucose levels during pregnancy,

reduces morbidity of both mother and child

Diet represents the mainstay for glycemic control.

Insulin aspart and lispro has been approved during

pregnancy.

Insulin glargine,and detemir do not show any contraindications during pregnancy.

Insulin glulisine has no data regarding their use in pregnancy.

Glyburide and Metformin, are safe to use in pregnancy with maternal and perinatal outcomes similar to insulin treatment.

The routine use of oral antidiabetic drugs during pregnancy is not recommended because of the necessity of randomized clinical trials with long-term follow-up for both mother and child.