diabetes in pregnancy martin l gimovsky md division of maternal fetal medicine newark beth israel...
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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.