Diabetes in Pregnancy

Martin L Gimovsky MD

Division of Maternal Fetal Medicine

Newark Beth Israel Medical Center

Newark, New Jersey

Learning Points

• Importance - 17 million diabetics in US + 6 million undiagnosed, 6 – 8% of population• Pathophysiology - A diabetic has metabolic

changes that adversely affect blood vessels• Pregnancy - Accelerates/predisposes these

metabolic derangements.• Treatment - Seeks to minimize maternal and

fetal/neonatal M&M by correcting/compensating for fluctuations in blood glucose.

Overview: Diabetes

• Hyperglycemic state fasting and/or postprandial

• Due to relative/absolute deficiency of insulin

• Results in significant changes in intermediary metabolism with striking clinical effects

Beta cells Storage granules

Nucleus

Endoplasmic

reticulum

The Islet of a Type 1 Diabetic

Beta Cells (Injured and then) Destroyed

Islet cells and Isle of Langerhans

Alpha cells

in red

Beta cells

in blue

Delta cells

unmarked

Type 2 and GDM

• Tissue becomes insulin resistant• Hyperglycemia

– Inhibits glucose uptake– Results in inadequate insulin response– Disrupts pulsatile insulin release– Enhances lipolysis in visceral fat– Increases FFA, increases insulin resistance

• Impaired glucose tolerance elevated FBS and increases PP hyperglycemia

Diabetes alters intermediary metabolism

Insulin EffectsGlucose, aa glycogen

Glycogen glucose

Protein synthesis

Protein catabolism

Fatty acid synthesis

Fatty acid release

Glucose, amino acid uptake

Inhibits glucose, amino acid uptake

Comparison of Diabetic Types

1=IDDM 2=NIDDM (3=GDM)

Habitus Normal Obese Pathology Chronic

Autoimmune Increased Insulin Resist

Family History

No Yes

HLA assoc Yes No Sulfonylurea No response Responsive Insulin Low, absent Varies

Diabetes in Pregnancy

• Common medical complication

• 2-5% (2.6%) of live births

• 90% are gestational diabetics, White class A1, A2 (GDM & NIDDM)

• 10% are overt diabetics, White class B-H (IDDM)

Diabetes and Pregnancy

• Pregnancy is a “diabetogenic state.”

• Placenta has passive control of glucose to fetus, but is impermeable to insulin.

• Maternal intermediary metabolism is under control of hormonal influences that insure fetal needs for glucose are met.

Pregnancy as a Diabetogenic State

Increasing glucose (&insulin) demand both maternal and fetal

• Increasing insulin resistance hormone driven • Maternal hyperglycemia fetal excess of nutrients

fetal hyperglycemia & insulinemia, neonatal hypoglycemia

• Teratogenesis• Catabolism consumes energy & oxygen and episodic fetal hypoxemia, results in fetal

hypertension, cardiac remodeling, polycythemia, increased blood viscosity, heart failure, stillbirth

Insulin Resistance in Pregnancy

• More insulin demand: Increased basal level and response to blood glucose, increased overall demand for glucose

• Insulin is less efficient (resistance)– HCS, Prolactin, E&P Hyperglycemia

Facilitate a continuous supply of glucose for placental transfer

Effect of Pregnancy Hormones on Maternal Carbohydrate Metabolism

HCS = decreases glucose tolerance

Prolactin = insulin resistance

Glucocorticoids = glycogenolysis, gluconeogenesis

Overview: Recognition

• IDDM, NIDDM (I,II)

• Poly-dipsia, uria, phagia, glycosuria

• Infections• Vascular damage• FBS > 140 mg/dL• Random BS > 200

• GESTATIONAL(III)

• Hyperglycemia first seen in pregnancy

• Screening: – 50 gram 1 hr > 140

• Diagnosis:– 100 gram GTT 2

abnormal values, or a single value > 200

Clinical Preclinical

Classification of Overt Diabetes (IDDM) in Pregnancy

Hare and White, Diabetes Care 3:394 1980

Class Onset Duration Vascular Rx

B >20 <10 None Insulin

C 10-19 10-19 None Insulin

D <10 >20 Benign Ret

Insulin

F - - Renal Insulin

R,H,T - - Pro Ret, Heart, Renal T

Insulin

Effects of Diabetes in Pregnancy• Fetal• Anomalies• Stillbirth• Macrosomia• Neonatal• Resp distress• Hypoglycemia• Hyperbilirubinemia• Hypocalcemia• Hypertrophic

Cardiomyopathy

• Maternal• Infections, DKA, HyperOsm

Vascular damage results in– Retinopathy

• Benign• Neovascularization

– Renal failure• Microalbuminuria <300• Nephropathy >300

– Myocardial infarction– Neuropathy

• Peripheral • Autonomic

Monitoring Blood Sugar

• Blood glucose levels both fasting and postprandial are the key indicators

• AGP ambulatory blood glucose profile

• SMBG self monitored blood glucose

• HbA1c glycosylated hemoglobin 4-6 week intervals

Normal glucose tolerance in pregnancy

Mean BS 85, range 70 - 106120

70

AGP

Relatively flat, narrow limits

IDDM in Third Trimester3 Injection Regimen

Mean 137, Range 100 - 165

Wider limits, increase in mean value

Overview: Management of Diabetes

• Dietary modifications– Caloric content, distribution of food types,

frequency of meals, snacks in context of “Glycemic Index, Load”

• Interventional Exercise

• Insulin

• Oral hypoglycemics

Dietary Modification

Considerations in Diabetic Diet

• Kcal/kg/d (30 kcal/kg/d) • CHO=50%, Protein 25%, Fat 25% (ADA

2002)• Decrease kcal for BMI > 30, increase for

BMI<25 (ADA 2002)• Low glycemic foods (slow absorption) • Avoid nocturnal hypoglycemia• Avoid ketonemia

•Pro: Measures how rapidly BG is elevated in response to eating a specific food.

•Con: Values not necessarily reflective of how foods are really consumed

•Total calories may be more important

Glycemic Index

RCT: diet + exercise > diet aloneBung et al, 1993

Glycemic Response to Exercise: Nonpregnant and Pregnant

Exercise lowers BG further and faster in pregnancy

Pregnant

Nonpregnant

• Insulin preparations vary by time to peak action and total duration of action

• Lispro- 1h/2h• Regular- 2h/4h• NPH- 4h/8h• Ultralente- 8h/20h

Insulin pen

Oral Hypoglycemics

• First generation: Sulfonylureas

(diabinase)-freely crossed placenta

High level in neonateSevere & prolonged

hypoglycemiaSporadic reports of

anomalies

Oral Hypoglycemics

• Second Generation (Pregnancy category B)

– Glyburide, Glipizide, Glimepride – Biguanides Metformin

• Fast Acting Secretagogues, and Sensitizers

Short duration of action

Oral Hypoglycemics

• Glyburide– Rx of adult onset diabetes– Transplacental dose small– No known fetotoxicity, teratogenicity– Effect is mildly hypoglycemic to gravida and

fetus– Dosed by BMI >< 25 2.5mgs, 5 mgs– Similar effect to a 70:30 mix (NPH:Reg)

Control: Insulin vs Glyburide

Insulin

N=203

Glyburide

N=201

Mean glucose

FBS, Pre, Postpr

114,104,104 116,108,107

Hba1c 1T

Hba1c 3T

5.7%

5.4

5.6%

5.5

Dose 85+/ -48 units 9 +/- 6 mgs

Results No difference in neonatal or PN outcome

Langer et al: Comparison of glyburide and insulin in women with GDM. NEJM 2000;343:1134-8.

Glyburide vs InsulinLanger et al 2000

Glyburide Insulin

LGA 12% 13

Anomalous 2 2

> 4 kgs @ delivery

7 4

NN low BS

NICU admit

RDS/pulmonary

9

6

8

6

7

6

Glyburide After ADA Diet Failure Carolinas Medical Center, 2004

• 4/5 gravidas were controlled, 1/5 insulin

– Neonatal Outcome– 23% had hypoglycemic episode– 11% had polycythemia– 38% were LGA (> 90th centile)– 13% were macrosomic (> 4000 gm)– 7% needed (any) respiratory support

Glycemic Control: Fetal OutcomesSummary, multiple studies

Indicator Threshold/Goal

Perinatal Mortality Mean BS < 115 mg/dL

Spontaneous Abortion HgA1c < 7%

Malformations Postprandial < 140

Macrosomia Mean BS < 100

Neonatal Metabolic Problems

Mean neonatal BS > 1 SD below the mean

Malformations

Postprandial BS < 140 mgs/Dl

Perinatal Mortality

Mean BS < 115 mg/Dl

Neonatal Morbidity in Diabetic Pregnancy

GDM (III) Type I Type II

Hyperbilirubin 29% 55 44

Hypoglycemia 9 29 24

RDS 3 8 4

Cardiomyopathy 1 2 1

Polycythemia 1 3 3

Neonatal BG > 1 SD below the mean

Neonatal hypoglycemia =

Maternal Morbidity

Class DM A1, A2 B, C D,F,R

PIH 10% 8 16

Chronic HBP

10% 8 17

DKA 8% 7 9

C/S 12% 44 57

Guidelines for Diabetic Pregnancy

Preconception Optimal glycemic control

Folic acid x 3 months, GC

1st Trimester Fetal Viability CRL

2nd Trimester Fetal Development Level 2 scan

Fetal growth baseline 24 weeks MMS

3rd Trimester Fetal Growth and Well-being

Kick count @ 28wks NST/BPP

36 weeks EFW, Deliver at 37-38.5 with amnio, 38.5-40 without

Maternal medical risks

Fetal and neonatal risks

Obstetric complications

Family/social supports

Economic

Preconception Counseling

Diabetes and Obesity

Fetal surveillance first 28 weeks

• 1st Trimester• Dx: up to 20% GDM• Fetal viabilty• Accurate dates

• 2nd Trimester• Mult marker screen• Level 2 scan, Fetal

cardiac echo • 24 weeks fetal growth• 28 fetal kick counts

Diabetic Ketoacidosis

• Type 1 diabetic, 2nd trimester

• Infections

• Limited prenatal care

• Unrecognized new onset of diabetes

• Inadequate insulin excessive hepatic glucose production

Diabetic Ketoacidosis

Treatment of DKA

• Recognition: hyperventilation, dehydration, hypotension, fruity odor to breathe, elevated BS, + serum ketones 1:4

• Infection, poor compliance, unrecognized onset of DM

• Treatment: Vigorous fluid resuscitation (NS) until base deficit is < -4; anion gap is < 12

• Small bolus (10u) then continuous infusion of low dose insulin 5u/hr; Potassium 20 meq/hr, bicarbonate replacement < 1 amp, pH < 7.2

3rd Trimester

• Fetal growth by 32 week scan,

• Fetus may be IUGR or LGA, EFW

• Fetal Testing: 28-32 wks BPP, NST 2X

• Comorbidity with PIH, Chronic HBP

• Timing of delivery: term or close

• Confirmation of fetal lung maturity

• Increased glucose is catabolized consumes energy & oxygen.

• The greater the fluctuation in BS, the more fetal hyperglycemia & hyperinsulinemia

• Decrease testing intervals in A2 or >, test twice weekly after 30-32 weeks

• Can reduce the risk

Fetal Demise in-Utero

Comorbidity with HypertensionBlood Pressure during Gestation

Fetal Growth Abnormalities in Diabetic Pregnancy by White Class

California Diabetes Project, 1991

GDM Class A,B,C

Class D,F,R

Total

>90th% 22% 31 22 24

<10th% 4 5 5 4

Big Babies

• Macrosomia – > 4500 gms ACOG, >4250 Langer

• Infants of diabetics (IDM) – 15-45% macrosomic• Large for Gestational Age (LGA) > 90th%

30% diabetes in pregnancy, 70% are constitutional

• Hard to predict fetal weight, easy to measure neonatal weight

Traumatic Birth & Shoulder Dystocia

• Risk is > for diabetic fetus/neonate, at any EGA• Suspected macrosomia- size>dates by FH, EFW>

4500 gms (Tech Bull # 30, 2001)• Induction or prophylactic C/S unlikely to reduce

the rate of permanent injury• By ultrasound EFW above 4500, actual bwt for ½

is within 10% of estimate• At EFW 4500 gms, then estimate 333 – 1667 C/S

to prevent a single permanent Erb’s palsy

Respiratory Distress Syndrome

• Abnormal timing of phospholipid production delay in PG+

• Higher levels of myoinositol persistence of PI+

• PG/PI less favorable at same EGA• Effect is magnified with mean plasma

glucose > 110 mgs• < 38.5 wks w/amnio; >38.5 with > 3% PG

Intrapartum Decisions

@ 40 wks with good control @ 38 with PG:PI

Active phase must be adequate• Protracted descent best managed by C/S• Avoid mid-pelvic operative delivery absolutely• Outlet/low pelvic delivery with great care• Liberal use of C/S

Conclusions

• Regulation of blood glucose needs to begin prior to conception for best result.

• Treatment includes diet, exercise, oral hypoglycemics and insulin.

• Comorbidities- Obesity, HBP, CAD

• Fetal growth and well being, timing of delivery require attention in 3rd trimester.