DIABETES IN PREGNANCYDIABETES IN PREGNANCYJosephine Carlos-Raboca, MD

Chief, Section of Endocrinology,Diabetes and Metabolism

Makati Medical Center

She is a G3P1 (1011) who was referred to Endocrinology service on her 28th 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)

M.E 39 year old femaleM.E 39 year old female

Past Medical HistoryPast Medical HistoryNon diabetic, non hypertensive, non

asthmaticFMHx(+) Diabetes and Hypertension – MotherPSHxNon smoker, non alcoholic beverage drinkerNo regular form of exercise

Physical ExaminationPhysical Examination

BP = 120/70 mmHg, HR = 76 bpm, RR 16 Wt 85 kg, Ht = 5’3” BMI = 33.2Anicteric, pink palpebral conjunctivae, (-)

cervical adenopathy, (-) carotid bruits, Thyroid not enlarged, no pharyngeal congestionEqual chest expansion with clear breath sounds

both lungs, (-) cracklesAdynamic precordium, Normal rate, regular rhythm

with distinct S1, S2, (-) murmur

Physical ExaminationPhysical ExaminationGravid abdomen, normal bowel sounds, (+)

fetal heart tonesFull 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

Fasting 1-h post BF

1-h post Lunch

1-h post dinner

mg/dL 96 148 129 157

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

Fasting 1-h post BF

1-h post lunch

1-h post diner

mg/dL 88 117 112 124

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

OutlineOutline

Gestational Diabetes Definition/Prevalence Pathogenesis Complications Screening and Diagnosis Management

Pregestational Diabetes

Gestational Diabetes Mellitus Gestational Diabetes Mellitus (GDM)(GDM)

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

4th International Workshop-Conference on GDM, 1998.

PrevalencePrevalence of GDMof GDM

1 – 14%USA--- 3-5%MMC (Asian Population)

– Raboca et al 13.4%

PathogenesisPathogenesis

• Pregnancy is a Pregnancy is a diabetogenic state diabetogenic state characterized by insulin characterized by insulin resistance and resistance and hyperinsulinemia hyperinsulinemia

Metabolic Adaptations during Metabolic Adaptations during PregnancyPregnancy

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 Metabolic Adaptations during PregnancyPregnancy

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 with gestational diabetes mellitus. Am J Clin Nutr 2000; 71:1256S.

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 Metabolic Adaptations during PregnancyPregnancy

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 Metabolic Adaptations during PregnancyPregnancy

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 availability of substrates to the fetus. Eur J Clin Nutr 2000; 54 Suppl 1:S47.

Why Screen for GDM?Why Screen for GDM?

Perinatal Complications:Perinatal Complications:MacrosomiaHypoglycemiaRespiratory Distress Syndrome (RDS)HypocalcemiaHyperbilirubinemiaPolycythemia

Congenital MalformationsCongenital Malformations

SkeletalCardiac (septal and outflow tract lesions)CNS and neural tube defectsGastrointestinal DefectsGenitourinary Tract lesions

Other complicationsOther complications

Pre-ecclampsiaOperative deliveryObesity and diabetes later in life

Who do we screen?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 percent)

Who do we screen?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?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

ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol 2001; 98:525.

How to screen for GDMHow to screen for GDMA 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 RecommendationsScreening and Recommendations55thth International Workshop International Workshop

Conference on GDMConference on GDMDiabetes Care Vol 30 Sup 2 July 2007

GDM should be ascertained at first prenatal visit

Low Risk: screening is not Low Risk: screening is not routine if all conditions are metroutine 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 Average risk: screen at 24-28 weeks of gestationweeks of gestation

Two step method 50gm GCT if positive go to diagnostic

testOne step method proceed to diagnostic test

High RiskHigh RiskSevere obesityStrong family history of diabetes mellitus

type 2Previous 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

ScreeningScreeningGlucose Challenge Test

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

2. Measure plasma or serum glucose after 1 hour.3. A glucose level >130 mg/dL (7.8 mmol/l) is

abnormal.4. Proceed with Oral Glucose Tolerance Test

(OGTT)

Plasma or serum glucose levelCarpenter/Coustan

Plasma levelNational Diabetes Data Group

mg/dL mmol/L mg/dL mmol/LFasting 95 5.3 105 5.8One hour 180 10.0 190 10.6

Two hours 155 8.6 165 9.2

Three hours 140 7.8 145 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.

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

American Diabetes AssociationAt least two values that meet or exceed the following 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 >125 mg/dL (7.0 mmol/L)

OR

Two hour >140 mg/dL (7.8 mmol/L)

Management of GDMManagement of GDM

Diet/Medical Nutrition therapy Blood Glucose Monitoring ExerciseMedication

GOALS:GOALS:Normal outcome of index pregnancy.Decrease risk for abnormal glucose and

insulin homeostasis.Mother (before, during, after pregnancy).Infant subsequent generations.

Medical Nutrition TherapyMedical Nutrition TherapyGoals:

1. Achieve normoglycemia2. Prevent ketosis3. Provide adequate weight gain4. Contribute to fetal well-being

Medical Nutrition TherapyMedical Nutrition TherapyCaloric allotment

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

BMI kcal/kg<22 40 kcal

22 – 25 30 kcal26 - 29 24 kcal

30 12 – 15 cal

Medical Nutrition TherapyMedical Nutrition Therapy

Gestational Diabetes mellitus 2004

Carbohydrate

33 – 40%

Proteins 20 %

Fats 40 %

Timing Total Calories

Breakfast 10 %Lunch 30 %Dinner 30 %Snacks 30 %

ADA 2004ADA 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 PregnancyWeight Gain in Pregnancy

BMI weight gain 1st trim 2nd-3rd 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 11th ed L. Kathleen, Mahan and Strump 2004

Self Blood Glucose MonitoringSelf Blood Glucose MonitoringMonitor 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 MonitoringSelf Blood Glucose MonitoringOne hour postprandial monitoring was associated with

the following benefits as compared to preprandial monitoring

1. Better glycemic control (HbA1c 6.5 vs 8.1 percent)2. Lower incidence of large for gestational age infants (12 vs 42

percent)3. 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

InsulinInsulin

When to use?maternal blood glucose levels fetal abdominal circumference at 29-33

weeks amniotic fluid insulin at 28 weeks

Blood glucose levelsBlood glucose levels

FPG > 95mg/dl (90)

1 hour PPBG > 140 mg/dl (120)

2 hppg > 120 mg/dl

( ) Jovanovic

Insulin in pregnancyInsulin 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 TherapyInsulin 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.

A “mixed/split” insulin regimen is generally used

Oral Anti-hyperglycemic AgentsOral Anti-hyperglycemic AgentsCurrenlty the ADA and ACOG do not

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 drugsOral 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 Metformin in Gestational Diabetes (MIG) TrialDiabetes (MIG) Trial

Prospective Randomized controlled trial in women with GDM 20-33 weeks gestation

Randomized to insulin or metforminPrimary outcome – composite of neonatal

morbidityKey trial in assessing potential role of

metformin during pregnancy

ResultsResults

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

ConclusionsConclusions

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

AcarboseAcarboseA 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, 2002Randomized trial in 91 GDM patients failing diet

therapyGlucose control and glycohemoglobin were similar 6% of acarbose treated patientd required insulin

Other AgentsOther AgentsThe use of thiazolidinediones, glitinides,

and GLP-1 is considered experimental

No controlled data available in pregnancyChan, LY, Yeung, JH, Lau, TK. Placental transfer of rosiglitazone in the first trimester of human pregnancy. Fertil Steril 2005; 83:955.

Peripartum ManagementPeripartum ManagementMaternal 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 day after delivery to ensure that the mother no longer has hyperglycemia.

Post partum care/concernsPost partum care/concerns

50-60% risk for DM 2 in 10-15 yearsDM 1 in GAD+75 gm OGTT 6 weeks after for

prognostication (earlier DM2 in 5 years in IGT +)

Pregestational DiabetesPregestational Diabetes

Counseling about risk of malformation with poor control

Use of low dose estrogen progestogencontraceptive till good metabolic control isachieved.

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 What medical problems should you problems should you consider in a diabetic consider in a diabetic pregnant?pregnant?

Acceleration of retinopathy Pregnancy induced hypertension Progression of Nephropathy

retinopathyretinopathy

Stabilize prior to pregnancyPhotocoagulation if necessaryMonitor for progression high risk for biggest drop in a1c due to hypercoagulable state

Coronary artery diseaseCoronary artery disease

Pregnancy increases oxygen consumptionAvoid pregnancy if possibleStatins not usedIf necessary, fibrates and niacin may be

used

BP meds in pregnancyBP meds in pregnancy

MethyldopaHydralazineCalcium antagonistClonidinelabetalol

DM NephropathyDM Nephropathy

Renal function may deteriorate in more sever disease

Prone to pre-eclampsiaBP target <130/80Stop 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

ConclusionsConclusions 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.THANK YOU.