DIABETES IN PREGNANCY

Josephine Carlos-Raboca, MD Chief, Section of Endocrinology,Diabetes and Metabolism Makati Medical Center

M.E 39 year old female

 She is a G3P1 (1011) who was referred to Endocrinology service on her 28 th week of gestation due to findings of elevated blood sugar values in her 75g OGTT. (fasting 107 mg/dL, 1hr 191 mg/dL 2-h 158 mg/dL)

Past Medical History

 Non diabetic, non hypertensive, non asthmatic  FMHx  (+) Diabetes and Hypertension – Mother  PSHx  Non smoker, non alcoholic beverage drinker  No regular form of exercise

Physical Examination

 BP = 120/70 mmHg, HR = 76 bpm, RR 16 Wt 85 kg, Ht = 5’3” BMI = 33.2

Anicteric, pink palpebral conjunctivae, (-) cervical adenopathy, (-) carotid bruits, Thyroid not enlarged, no pharyngeal congestion  Equal chest expansion with clear breath sounds both lungs, (-) crackles  Adynamic precordium, Normal rate, regular rhythm with distinct S1, S2, (-) murmur

Physical Examination

 Gravid abdomen, normal bowel sounds, (+) fetal heart tones  Full and equal pulses, pink nail beds with good turgor, (-) edema, (-) cyanosis, (-) hyperpigmentation

 She was initially started on a diet plan and 4x/day blood sugar monitoring for 1 week

mg/dL Fasting 96 1-h post BF 1-h post Lunch 1-h post dinner 148 129 157

 She was started on 2x/day insulin with a dose of aspartame insulin 6 units (novorapid) pre breakfast and pre dinner

mg/dL Fasting 88 1-h post BF 117 1-h post lunch 112 1-h post diner 124

repeat LSCS 2, breech presentation cord coil  Live baby boy BW 2,863 gm AS 8/9

Outline

 Gestational Diabetes  Definition/Prevalence  Pathogenesis  Complications  Screening and Diagnosis  Management  Pregestational Diabetes

Gestational Diabetes Mellitus (GDM)

 Any degree of glucose in tolerance with onset or first recognition during pregnancy.

 4 th International Workshop-Conference on GDM, 1998.

Prevalence of GDM

 1 – 14%  USA--- 3-5%  MMC (Asian Population) – Raboca et al 13.4%

Pathogenesis

•

Pregnancy is a diabetogenic state characterized by insulin resistance and hyperinsulinemia

Metabolic Adaptations during Pregnancy

 placental hormones affect both glucose and lipid metabolism to ensure ample fetal fuel supply and nutrients always.

 There is a

switch from carbohydrate to fat utilization

that is facilitated by both insulin resistance and increased plasma concentration of lipolytic hormones Butte, NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 2000; 71:1256S.

Metabolic Adaptations during Pregnancy

 The fasted state is one of “

accelerated starvation

”. Alternative fuels are made available for the mother and

glucose is reserved for the fetus

 Maternal Fuels: Free fatty acids, ketones, glycerol  There is hyperplasia of Beta cells, increased insulin secretion and early increase in insulin sensitivity followed by progressive insulin resistance.

Butte, NF. Carbohydrate and lipid metabolism in pregnancy: normal compared

 Maternal insulin resistance results from increased release of diabetogenic hormones such as – Corticotropin Releasing Hormone – Chorionic Somatomammotropin – Progesterone – Tumor necrosis factor-a  A post receptor defect in the skeletal muscle B-subunit and at Insulin receptor substrate-1 may also contribute to the decline in insulin action.

Yamashita, H, Shao, J, Friedman, JE. Physiologic and molecular alterations in carbohydrate metabolism during pregnancy and gestational diabetes mellitus. Clin Obstet Gynecol 2000; 43:87.

Metabolic Adaptations during Pregnancy

 Insulin levels are higher in both the fasting and the postprandial states during pregnancy  The fasting glucose is 10-20% lower in pregnancy due to: – Increased storage of tissue glycogen – Increased peripheral glucose utilization – Decreased hepatic glucose production – Glucose consumption by the fetus

Metabolic Adaptations during Pregnancy

 The placenta readily transfers

glucose, amino acids, and ketone bodies

to the fetus but is impermeable to large lipids.

 Serum triglyceride and cholesterol levels increase during pregnancy by approximately 300 and 50% respectively.

 The large rise in TG is largely due to – Increased hepatic lipase activity – Reduced lipoprotein lipase activity Herrera, E. Metabolic adaptations in pregnancy and their implications for the

Why Screen for GDM?

Perinatal Complications:

 Macrosomia  Hypoglycemia  Respiratory Distress Syndrome (RDS)  Hypocalcemia  Hyperbilirubinemia  Polycythemia

Congenital Malformations

 Skeletal  Cardiac (septal and outflow tract lesions)  CNS and neural tube defects  Gastrointestinal Defects  Genitourinary Tract lesions

Other complications

 Pre-ecclampsia  Operative delivery  Obesity and diabetes later in life

Who do we screen?

 Pregnant women with any of the following: – A family history of diabetes, especially in first degree relatives – Prepregnancy weight 110 percent of ideal body weight or significant weight gain in early adulthood – Age greater than 25 years – Previous delivery of a baby greater than 9 pounds [4.1 kg] – Personal history of abnormal glucose tolerance – Member of an ethnic group with higher than the background rate of type 2 diabetes (in most populations, the background rate is approximately 2

Who do we screen?

 Previous unexplained perinatal loss or birth of a malformed child – Maternal birth weight greater than 9 pounds [4.1 kg] or less than 6 pounds [2.7 kg] – Glycosuria at the first prenatal visit – Polycystic ovary syndrome – Current use of glucocorticoids – Essential hypertension or pregnancy-related hypertension Solomon, CG, Willett, WC, Carey, VJ, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 1997; 278:1078.

When to screen?

 Screening is optimally performed at

24-28 weeks

of gestation.

Jovanovic, L, Peterson, CM. Screening for gestational diabetes. Optimum timing and criteria for retesting. Diabetes 1985; 34 Suppl 2:21.

 It should be

done during the first prenatal visit if

there is high degree of suspicion that the patient has undiagnosed type 2 diabetes Gestational diabetes mellitus. Diabetes Care 2004; 27 Suppl 1:S88.

 Women with a history of GDM have a 33-50% risk of recurrence, and some of these recurrences may represent type 2 DM

How to screen for GDM

 A fasting plasma glucose level

of >126 mg/dL (7.0 mmol/l) or a casual plasma glucose >200mg/dL (11.1 mmol/l)

meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day 

Precludes

the need for any glucose challenge Diabetes care vol 26, jan 2003

Screening and Recommendations 5

th

International Workshop Conference on GDM

 Diabetes Care Vol 30 Sup 2 July 2007  GDM should be ascertained at first prenatal visit

Low Risk: screening is not routine if all conditions are met

 Belongs to an ethnic group with low prevalence of GDM  Negative history of diabetes mellitus type 2 in first degree relative  Less than 25 years old  Normal weight before pregnancy  Normal weight at birth  No history of abnormal glucose metabolism  No history of poor obstetric outcome

Average risk: screen at 24-28 weeks of gestation

 Two step method  test 50gm GCT if positive go to diagnostic  One step method  proceed to diagnostic test 

High Risk

 Severe obesity  Strong family history of diabetes mellitus type 2  Previous history of GDM, impaired glucose metabolism or glucosuria.  If initially negative for GDM, repeat at 24 28 weeks of gestation or anytime with signs and symptoms suggestive of hyperglycemia

Screening

 Glucose Challenge Test 1.

2.

3.

4.

Give 50 g oral glucose load without regard to time of day.

Measure plasma or serum glucose after 1 hour.

A glucose

level >130 mg/dL (7.8 mmol/l) is abnormal.

Proceed with Oral Glucose Tolerance Test (OGTT)

Diagnosis

Fasting One hour Two hours Three hours Plasma or serum glucose level Carpenter/Coust an

mg/dL

95

5.3

Plasma level National Diabetes Data Group

mmol/L mg/dL

105

mmol/L 5.8

180 155 140

10.0

8.6

7.8

190 165 145

10.6

9.2

8.0

100 gram oral glucose load is given to patient who is fasting. Data from: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diab Care 2000; 23(suppl 1):S4.

American Diabetes Association

Diagnosis

glucose concentrations: Fasting

>95

mg/dL (5.3 mmol/L) One hour

>180

mg/dL (10.0 mmol/L) Two hour

>155

mg/dL (8.6 mmol/L)

World Health Organization

Fasting

OR

Two hour

>125

mg/dL (7.0 mmol/L)

>140

mg/dL (7.8 mmol/L)

Criteria for a positive 2 hour 75 g OGTT for the diagnosis of GDM

Management of GDM

 Diet/Medical Nutrition therapy  Blood Glucose Monitoring  Exercise  Medication

GOALS:

 Normal outcome of index pregnancy.

 Decrease risk for abnormal glucose and insulin homeostasis.

 Mother (before, during, after pregnancy).

 Infant subsequent generations.

Medical Nutrition Therapy

 Goals: 1.

2.

3.

4.

Achieve normoglycemia Prevent ketosis Provide adequate weight gain Contribute to fetal well-being

Medical Nutrition Therapy



Caloric allotment

BMI kcal/kg

<22 22 – 25 26 - 29  30 40 kcal 30 kcal 24 kcal 12 – 15 cal

Nutritional management of obese gestational diabetic woman. J Am Coll Nutr 1992;11:246

Medical Nutrition Therapy

Timing

Breakfast Lunch Dinner Snacks

Total Calories

10 % 30 % 30 % 30 %

Carbohydrat e 33 – 40% Proteins Fats 20 % 40 %

Gestational Diabetes mellitus 2004

ADA 2004

Medical Nutrition Therapy  provide adequate calories to sustain maternal and fetal requirements and  to achieve glycemic control  adequate weight gain  Avoid starvation ketosis  Protein 0 .75 g/kg/d + 10 g  Carbohydrate portion 35-40%  Folic acid 400 ug/day

Weight Gain in Pregnancy

 BMI weight gain 1 st trim 2 nd -3 rd trim  <20 28-40 lbs 5lb 1.07lb/wk  21-26 25-35 3.5 .97

 26-29 15-25 2.0 .67

 >29 15  Krause’ Food Nutrition and Diet 11 th ed L. Kathleen, Mahan and Strump 2004

Self Blood Glucose Monitoring

 Monitor Blood Glucose concentration at least 4 times daily.

 Timing: Fasting and 1 hour after the first bite of each meal

Gestational Diabetes Mellitus. Diabetes care 2004

Self Blood Glucose Monitoring



One hour postprandial

monitoring was associated with the following benefits as compared to preprandial monitoring 1.

2.

3.

Better glycemic control (HbA1c 6.5 vs 8.1 percent) Lower incidence of large for gestational age infants (12 vs 42 percent) A lower rate of cesarian delivery for cephalopelvic disproportion (12 vs 36 percent).

Postprandial vs preprandial blood glucose monitoring in women with GDM requiring insulin therapy. N Engl J med 1995; 333:1237

Insulin

 When to use?

 maternal blood glucose levels  fetal abdominal circumference at 29-33 weeks  amniotic fluid insulin at 28 weeks

Blood glucose levels

 FPG > 95mg/dl (90)  1 hour PPBG > 140 mg/dl (120)  2 hppg > 120 mg/dl  ( ) Jovanovic

Insulin in pregnancy

 Human insulin should be used if prescribed  SBMG should guide the doses and timing of insulin regimen  The rapid Insulin analogs lispro and aspart have been found to be clinically effective with minimal transfer across placenta and no evidence of teratogenesis. Level B  Long acting analogs – no study in pregnancy

Insulin Therapy

 ~15% of women with GDM are placed on insulin therapy  The dose of insulin varies in different populations because of varied rates of obesity, ethnic characteristics, and other demographic criteria  Generally 0.5 to 1.4 U/kg (present weight) is required to maintain target glucose levels.

 endorse the use of oral hyperglygemic agents during pregnancy Gestational diabetes mellitus care 2004  Tolbutamide or chlorpropamide – Cross the placenta and can cause fetal hyperinsulinemia which can lead

to macrosomnia and prolonged neonatal hypoglycemia.

Maternal-fetal transport of hyperglycemic drugs. Clin pharmacokinet 2003

Oral diabetic drugs

 Langer NEJM 343(16):1134-38,2000 use of glyburide after 8 weeks of gestation in 201 women on glyburide vs 203 insulin  Conclusion: No difference in neonatal outcomes such as LGA, hypoglycemia anomaly or stillbirth

Metformin in Gestational Diabetes (MIG) Trial

 Prospective Randomized controlled trial in women with GDM 20-33 weeks gestation  Randomized to insulin or metformin  Primary outcome – composite of neonatal morbidity  Key trial in assessing potential role of metformin during pregnancy

Results

 rate of primary outcome  32% (Met) vs 32.2% (insulin)  Acceptability  76.6% vs 27.2%  No difference in secondary outcomes

Conclusions

 Metformin is an effective and safe treatment option in gestational diabetes requiring insulin  Metformin is more acceptable to women than insulin  Long term study needed to establish long term safety

Acarbose



A comparison of oral acarbose and insulin in women with gestational diabetes mellitus

. deVeciana M, Trail PA, Lau TK, Dulaney K;

Obstet Gynecol 99 (Suppl.):5S,

2002  Randomized trial in 91 GDM patients failing diet therapy  Glucose control and glycohemoglobin were similar  6% of acarbose treated patientd required insulin

Other Agents

 The use of

thiazolidinediones, glitinides, and GLP-1

is considered experimental  No controlled data available in pregnancy

Chan, LY, Yeung, JH, Lau, TK. Placental transfer of rosiglitazone in the first trimester of human pregnancy. Fertil Steril 2005; 83:955.

Peripartum Management

 Maternal hyperglycemia should be avoided during labor to prevent fetal hyper insulinemia and subsequent neonatal hypoglycemia.

 Maternal blood glucose concentration should be maintained between 70 and 90 mg/dL  Blood glucose should be monitored on the

Post partum care/concerns

50-60% risk for DM 2 in 10-15 years DM 1 in GAD+ 75 gm OGTT 6 weeks after for prognostication (earlier DM2 in 5 years in IGT +)

Pregestational Diabetes

  Counseling about risk of malformation with poor control Use of low dose estrogen progestogen contraceptive till good metabolic control is achieved.

  

Goals:

HBA is 1% above normal Preprandial CBG 70-110 mg/dl (3.9-5.6mml/L) CPG 80-110 mg/dl (4.4-6.1 mml/L) 2H Postprandial CBG < 140 mg/dl (7.8mml/L) CPG < 155 mg/dl (8.6mml/L)

What medical problems should you consider in a diabetic pregnant?

  

Acceleration of retinopathy Pregnancy induced hypertension Progression of Nephropathy

retinopathy

 Stabilize prior to pregnancy  Photocoagulation if necessary  Monitor for progression  high risk for biggest drop in a1c  due to hypercoagulable state

Coronary artery disease

 Pregnancy increases oxygen consumption  Avoid pregnancy if possible  Statins not used  If necessary, fibrates and niacin may be used

BP meds in pregnancy

 Methyldopa  Hydralazine  Calcium antagonist  Clonidine  labetalol

DM Nephropathy

 Renal function may deteriorate in more sever disease  Prone to pre-eclampsia  BP target <130/80  Stop ACE inhibitors and ARBs  may cause fetal anuria, pulmonary hypoplasia, oligohydramnios

 Preparing for delivery  Target glucose : 120 mg/dl  D5 0.45 NSS at 100-125 ml/hour  CBG every 1-4 hours  Insulin infusion to start at 1unit/hour of regular insulin if CBG > 120 mg/dl

Conclusions

 Pregnancy is a diabetogenic state  Hyperglycemia causes adverse effects in pregnancy for mother and fetus.

 Detection, diagnosis and proper treatment are necessary for good pregnancy outcome.

 Diabetic patients must be prepared and assessed for complications prior to pregnancy.

 Special problems for pregnant diabetics need to be addressed.

THANK YOU.