the primary care guide for pregnancy diabetes

For internal use only. This training material is for educational purposes. It is not to be used, shared, or discussed with customers. Proprietary & Confidential ©AstraZeneca 2014

HYPERGLYCEMIA IN PREGNANCY


What is DM?• A metabolic condition

characterized by chronic hyperglycemia as a result of defective insulin secretion, insulin action or both

• Type 1(IDDM)• Type 2(NIDDM)• Gestational diabetes• Others

– genetic defects in insulin processing or action

– Endocrinopathies– Drugs– exocrine pancreatic defects– genetic syndromes associated with

DM

2


Pregnancy predisposes to persistent hyperglycaemia

• Glucose is made available to the fetus– ↑ placental hormones– ↑ plasma cortisol– A state of insulin resistance– Further aggravated by ↑ body weight and ↑ caloric

intake during pregnancy• GDM develops when the pancreas cannot overcome

the effect of these hormones• Pregestational diabetes becomes worse during

pregnancy

3


Diabetes & Pregnancy4

the prevalence of women with preexisting T2DM getting pregnant (diabetic pregnancies) seems to be rising

nowadays, more and more women go into pregnancy with increased body weight and caloric intake

This prevalence is increasing


• Glucose intolerance of variable severity with onset or first identification during the pregnancy

– Generally occurs in the latter half of pregnancy

– Previously, found to constitute 90% of diabetes in pregnancy

• resolving after delivery

5


Important facts• To understand the effects of hyperglycaemia on

the fetus, it should be remembered that glucose crosses the placenta freely but maternal insulin does not

• Thus, maternal hyperglycaemia leads to fetal hyperglycaemia with a consequent rise in fetal insulin secretion

• Pregnancy is a state of insulin resistance, especially towards term

6


WHAT DOES CHRONIC HYPERGLYCAEMIA LEAD TO?


Multiple implications8

MaternalPre-eclampsiaRecurrent infection-vaginal candidiasis,UTIPolyhydramnios—PPROM, discomfortAnomalies & abortionsSudden IUD

Delivery Problems• Increased instrumental

rates• Birth trauma• Operative delivery• Polyhydramnios—

premature membrane rupture, cord prolapse

Postpartum• Increased risk of developing

DM later in life• Past history of GDM increases

the risk of recurrence in subsequent pregnancies

Retnakaran R. Diabetes Care, 31, 1275-1281

Maternal - medical• Retinopathy• Nephropathy• Neuropathy • Micro/macroangiopathy

FetalCongenital anomalies (4 fold) - sacral agenesis, NTD, cardiac and renal anomaliesMacrosomiaMalpresentationShoulder dystociaPrematurityRespiratory distress syndromeHypoglycemia


9

Fetal macrosomiaThe child later

on…..• Obesity

• Diabetes

mellitus

• Reproductive

problems

• Metabolic

syndrome


WHY IS IT IMPORTANT TO DIFFERENTIATE BETWEEN GESTATIONAL & PREGESTATIONAL DM?

because each diagnosis imparts a different clinical significance


future development of T2DM

The significance of GDM

mothers are at risk of

adverse obstetrical outcomes- esp. fetal overgrowth

11


growth restriction

The significance of pregestational DM

12

Most of the risk is to the fetus

complications during organogenesis

+ complications similar to GDM


Pregestational diabetic pregnancies

• carry a graver consequence– should be managed immediately once

identified• Ideally, evaluation for DM should occur

before pregnancy– to prevent complications during organogenesis

(1st trimester)

13


Hyperglycaemia in the 1st trimester• confers a significantly

increased risk of major malformations

14

Type of Diabetes in pregnancy

T1DM(n=221)

T2DM(n=317)

GDM(n=1822)

Risk of Major congenital abnormality(%)

5.9 4.4 1.4

Farrel T 2002


Fetal malformations & Glycaemic control

• HAPO study • a continuum of increasing risk of perinatal

outcomes as glucose levels increase– even within levels that were previously defined as

normal

15

HAPO study. NEJM 2008


Hyperglycaemia later in pregnancy

• High blood glucose increases fetal growth• Postprandial normoglycemia can reduce the rate

of macrosomia

16

HAPO study. NEJM 2008

FBG>5mmol/L, HbA1c>5.3% MACROSOMIA!


Difference between GDM & DM• GDM

– early pregnancy BS normal

– Usually no effect on organogenesis

– less likely to have congenital defects

– diabetes disappears after delivery

– macrosomia more likely

• DM + Pregnancy– elevated BS since before

pregnancy– effect during

organogenesis– more likely to have

congenital fetal defects (up to 8x more than normal pregnancy)

– fetes may be growth restricted

17

overall though, perinatal outcomes are worse whatever the cause of the hyperglycaemia


HOW DO WE DETECT THOSE ASYMPTOMATIC MOTHERS WITH DM?


Issues of concern1. The frequently undiagnosed nature of

T2DM before pregnancy2. Lack of preconception care3. The increase in complications of

pregnancy due to the coexistence of obesity and T2DM

19


Pregnant women with DM are frequently asymptomatic

• They need to be identified before harm can come to the fetus

20


Screening• during antenatal check-ups,

mothers with unknown elevations of blood glucose need to be identified

• this process of looking for asymptomatic diabetics is termed screening

• The benefits and importance of screening for GDM have been proven (ACHOIS & HAPO study)

21

Crowther NEJM 2005

elevations of maternal blood glucose are deemed harmful to the fetus


In Malaysia• we base our screening strategy on

22

screen selectively those considered high risk (1-step

testing)


Who are those considered high risk?Pregnant women should be screened if they have any of the following risk factors:• BMI > 27kg/m2

• Previous macrosomic baby weighing 4kg or above• Previous gestational diabetes mellitus (GDM)• First-degree relative with diabetes• Bad obstetric history• Glycosuria at the first prenatal visit• Current obstetric problems (essential

hypertension, pregnancy induced hypertension, polyhydramnios and current use of steriods)

• Age above 25 1

23

1. ADA Diabetes Care 20092. Retnakaran R. Clin Endocrinol 2007, Lo JC. Diabetes Care, 20063. Kousta E. Clin Endocrinol, 2000

In recent time, this list has been expanded to include factors such as 2

physical inactivitycertain dietary patternspolycystic ovarian syndrome (PCOS)biochemical markers such as adiponectin & C-reactive protein

Ex-GDM mothers investigated for PCOS- a majority of them displayed characteristic polycystic ovarian morphology

3


Pregnant women should be screened if they have any of the following risk factors:BMI > 27kg/m

2

Previous macrosomic baby weighing 4kg or abovePrevious gestational diabetes mellitus (GDM)First-degree relative with diabetesBad obstetric historyGlycosuria at the first prenatal visitCurrent obstetric problems (essential hypertension, pregnancy induced hypertension, polyhydramnios and current use of steriods)Age above 25

1

What is done now• At booking - assess risk• if risk present, do OGTT

24

First Obstetric Visit• check risk status

Risk Factors

AbsentPresent

Consider normal

OGTT performed after 24 weeks gestation

Consider GDM if diagnostic criteria met

Note:OGTT not performed in:Known pre-existing DM cases& Cases with P/H of GDM

Current screening protocol

Risk Factors• Age >= 40 yrs• Unexplained SB• P/H recurrent miscarriages• P/H BW >= 4.0 kg• Weight > 100 kg• P/H oligomenorrhoea• Strong maternal sibling F/H


Schedule for screening• Between 24-28 weeks of gestation • or earlier if there are stronger indications

25


Recent Recommendations• Based on HAPO study data - even the slightest

hypoglycaemia increases pregnancy adversity

• IADPSG formulated recommendations

• In a bid to achieve international consensus

• Try to catch as many patients with pregnancy hyperglycaemia as possible

26

IADPSG. Diabetes Care 2010


IADPSG strategy27

*To be applied to women without known diabetes antedating pregnancy. Postpartum glucose testing should be performed for all women diagnosed with overt diabetes during pregnancy or GDM. + Decision to perform blood testing for evaluation of glycemia on all pregnant women or only on women with characteristics indicating a high risk for diabetes is to be made on the basis of the background frequency of abnormal glucose metabolism in the population and on local circumstances. ǂ The panel concluded that there have been insufficient studies performed to know whether there is a benefit of generalized testing to diagnose and treat GDM before the usual window of 24-28 weeks’ gestation.IADPSG. Diabetes Care 2010

Table 2 – Strategy for the detection and diagnosis of hyperglycemic disorders in pregnancy*

First prenatal visitMeasure FPG, A1C, or random plasma glucose on all or only high-risk women+

• If results indicate overt diabetes as per Table 1– Treatment and follow-up as for preexisting diabetes

• If results not diagnostic of overt diabetes– and fasting plasma glucose ≥ 5.1 mmol/l (92 mg/dl) but < 7.0 mmol/l (126 mg/dl), diagnose as GDM– and fasting plasma glucose < 5.1 mmol/l (92 mg/dl), test for GDM from 24 to 28 weeks’ gestation with a 75-g OGTT ǂ

24-28 weeks’ gestation: diagnosis of GDM2-h 75-g OGTT: perform after overnight fast on all women not previously found to have overt diabetes or GDM during testing earlier in this pregnancy• Overt diabetes if fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl)• GDM if one or more values equals or exceeds thresholds indicated in Table 1• Normal if all values on OGTT less than thresholds indicated in Table 1


IADPSG screen

• 1st phase - early pregnancy– aimed at detecting previously undiagnosed overt diabetes

– HbA1c or plasma glucose (fasting or random) measurements

– carried out on high-risk women (adult non-pregnant criteria)

• 2nd phase - 24-28 weeks• if 1st phase normal

• 2-hour 75 g OGTT

28


2 discrete phases


THE OGTT


OGTT• The first-line diagnostic test• Initially developed to identify the diabetic in the

general population

30

O’Sullivan, Mahan. Diabetes 1964.


Procedure for OGTT31


Table 6 – Screening for and diagnosis of GDMPerform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with overt diabetes.The OGTT should be performed in the morning after an overnight fast of at least 8 h.The diagnosis of GDM is made when any of the following plasma glucose values are exceeded:• Fasting: ≥ 92 mg/dL (5.1 mmol/L)• 1 h: ≥ 180 mg/dL (10.0 mmol/L)• 2 h: ≥ 153 mg/dL (8.5 mmol/L)


Diagnostic Values 32

OGTT Plasma Glucose Values (mmol/L)Category 0-hour 2-hourNormal < 6.1 * < 7.8

IFG 6.1 * – 6.9 -IGT - 7.8 – 11.0DM ≥ 7.0 ≥ 11.1

Table 2: Diagnostic values for Type 2 Diabetes Mellitus/Glucose Intolerance – oral glucose tolerance test (OGTT) [IDF 2005]


More recent diagnostic criteria• Commonly referred to

diagnostic criteria for the 75 gram OGTT include the WHO and the ADA criteria

• More recently, the IADPSG have adopted stringent criteria based on the HAPO study

33


75-gram oGTT values WHO ADA* IADPSGFasting blood glucose mmol/

l≥ 7.0 ≥ 5.3 ≥ 5.1

1-hour blood glucose mmol/l ≥ 10.0 ≥ 10.0

2-hour blood glucose mmol/l ≥ 7.8 ≥ 8.6 ≥ 8.5


Postpartum considerations34

Should be carried out after 2 months postpartum

P/H GDM woman

Postpartum oGTT

Normal GTAbnormal GT

IGT/DM

Diet & exerciseF/U Blood Glucose Manage as

appropriate

Stable glucose Raised glucose

Diet & exerciseF/U Blood Glucose

75g oGTT

Normal GT


IS THERE ANY OTHER WAY TO DIAGNOSE DM IN PREGNANCY?


Yes, but…

• Only in early pregnancy• Glycated haemoglobin (HbA1c) and plasma

glucose (random or fasting)• HbA1c has been validated for the diagnosis of

DM outside of pregnancy (≥6.5%) with many authorities favouring its use in pregnancy as well

36

International Expert Committee. Diabetes Care 2009

HbA1c limitations•costs•unavailability• inaccuracy in anaemia


Plasma glucose

• Fasting or random

• FPG level of ≥7.0 mmol/L is diagnostic of overt diabetes

• RPG of ≥11.1 mmol/L has to be confirmed with either an FPG or A1c value ≥ the threshold

37


HOW DO WE MANAGE HYPERGLYCAEMIA IN PREGNANCY?

p-


Strategy• Rapid normalisation of blood glucose

• Limited weight gain

• Monitoring for anomalies and complications

• Avoiding macrosomia

• Planned delivery

39


Optimization of metabolic control

• BS control dependant upon diet modification, exercise and hypoglycaemic medications

• Lifestyle modification (dietary advice & appropriate exercise) should be the primary interventions considered

• Resort to medications only when these fail to achieve the desired targets

40


WHAT IS THE DIETARY ADVICE FOR DIABETES IN PREGNANCY?


Weight gain• Less weight gain is safe and has

a beneficial effect on perinatal outcomes in obese women

• A dietitian can provide individualised counselling

42

Caloric restriction• A 33% reduction of calories results in

clinically relevant improvement in glycemic parameters

• 30-35 kcal/kg/day = 1200 Kcal/d is safe• 50% of these calories should be from

complex carbs• Base calculations on home blood

glucose levels

Specific TargetsAvoid concentrated sweets and highly processed foods -

soft drinks, ice cream, cakes and sweetsrestrict CHO to those found in vegetables and dairy products like cheese and cottage cheese

Small frequent meals (4 hourly) instead of fewer larger meals

reduces the amount of insulin needed at any one time, resulting in lower glucose excursionsalso reduce hunger and prevent overeating

Hone J. J Clin Endocrinol Metab 2010


Some more targets• Breakfast should be small & low in

carbs because insulin resistance is highest in the morning

• High-fiber and low-GI foods should be substituted wherever possible for simple sugars

• higher fiber/low GI may assist in delaying absorption of food, thus allowing the insulin peak to “catch up”

• Foods rich in antioxidants have a role in reducing the incidence of fetal anomalies

• fruits and vegetables are recommended

43

Folic acid supplementation Proven to reduce the risk of neural tube defectsat least 3 months preconceptionally and through the first trimester Minimum dose of 4 mg daily


WHAT TO DO IF DIETARY INTERVENTION DOES NOT WORK?

Medication is implemented if 2 or

more glucose values are elevated

after 1 wk of lifestyle management


Oral medication?

There is enough data to show that oral

hypoglycaemic agents (OHAs) are safe in

pregnancy

45

Glibenclamide - the 1st OHA to have proven efficacy and safety in pregnancy

At a dose of 2.5 mg daily to a maximum of 20 mg per daySimilar birth outcomes can be achieved when comparing glibenclamide use to insulin initiation in pregnancy

Langer et al. N Eng J Med 2000Rowan et al. N Eng J Med 2008

Metformin - start 500 mg OD & increase to 500 mg tds

Similar outcomes between metformin and insulin initialisationAlthough 46% of mothers on metformin required additional insulin supplementation for blood sugar optimisation

Although both metformin and glibenclamide cross the placenta, there have been no reports of fetal

adversity so far


When to start OHAs?

• When fasting or premeal BS values constantly exceed 5.5 mmol/L

• dose increase every 4-5 days• OHAs should be started without hesitation

whilst encouraging dietary and exercise efforts

46


WHEN DO WE USE INSULIN?

When MNT & OHA fails to achieve

glycemic goals after 1 wk


Summary of insulins48

Type of insulin

Generic name

Onset Peak Duration

Rapid-acting Insulin lispro 15 minutes 30-90 minutes 3-5 hoursInsulin aspart

Short-acting Regular insulin 30-60 minutes 2-4 hours 5-8 hoursIntermediate acting NPH insulin 1-3 hours 8 hours 12-16 hours

Long-actingInsulin glargine

1 hour Peakless 20-26 hoursInsulin detemir

Commonly used insulins and their properties

• Each type of insulin has an onset time, a peak and duration of action

• The onset time delineates how soon the blood glucose lowering action comes into effect and is commonly used to classify this class of medications - either rapid-, short-, intermediate- or long-acting


Development of Insulins49

Insulin Type Description

Regular or Human

1st biosynthetic type short acting, not very effective for postprandial control, tending to cause hypoglycaemia

Insulin analogues (lispro, aspart)

technically not insulins

They act rapidly, peak in about 1 hour with a duration of action between 2-4 hours

NPH insulin intermediate acting may be mixed with shorter acting insulins to complement its actions

Newer insulin analogues

long acting (peakless) 24 hour duration of action - once daily; provide constant glucose lowering effect; less hypoglycaemia & weight gain


HOW DO WE CALCULATE THE AMOUNT OF INSULIN TO USE?


Philosophy behind insulin• Mimic physiologic secretion of insulin as

close as possible• In pregnancy, this entails multiple injections

of various combinations of rapid, short and intermediate-acting insulin

51

A tried and tested insulin combination is a rapid-acting and

NPH one


Starting dose calculation52

Jovanovic. Diab Care 1982Lapolla et al. Diab Med 2009

Time of pregnancy DosePrepregnancy 0.6 U/kg/dayFirst trimester 0.7 U/kg/daySecond trimester 0.8 U/kg/dayThird trimester (29-34 wks) 0.9 U/kg/dayTerm (35-39 wks) 1.0 U/kg/day

• These are only starting values - blood sugar levels must be optimised rapidly to achieve the target values

• Slightly higher starting doses may be used for obese patients


Starting doses• The regimens are based on predicted total daily insulin

requirements - based on current weight and stage of pregnancy

• 50% of the total dose is given as a basal dose using NPH insulin (intermediate-acting)

– at bedtime or bedtime+breakfast time

• the other 50% of the total dose - given as boluses before meals using insulin analogues (rapid-acting)

– before meals (within 15 minutes) in divided doses (1/6 of the total dose per meal)

53


Adjustments• These doses are starting doses only; after

initiating treatment, the insulin doses must be rapidly adjusted to achieve glucose goals

• Insulin dose adjustment is dependant upon home blood glucose monitoring (HBGM) & A1C testing

• Serial sugar testing (SBS) is carried out between 3-7 days after starting insulin & the dosage of insulin adjusted commensurately

54


HOW DO WE KNOW IF THE DIABETES IS UNDER CONTROL?


Target Values

• Lowered risks of - birthweight > 4 kg, prematurity, neonatal hypoglycaemia & preeclampsia

• HbA1c levels to < 6% before & during pregnancy predicated outcomes similar to non-diabetic pregnant mothers

56

Rowan et al. Diab Care 2010Prutsky et al. JCEM 2013Wyatt et al. Diab Med 2005

Fasting Glucose

2 hr postprandial HbA1c

≤4.9 mmol/L 5.9–6.4 mmol/L < 6%


Recommendations -ADA57

ADA. Diabetes Care 2013

Timing Glucose Level

Premeal, bedtime, overnight 3.3–5.4 mmol/L

Postprandial 5.4-7.1 mmol/L

HbA1c 6.0%


Pillar of assessment

Glycaemic adequacy is assessed through regular blood glucose estimationsMost data regarding target values in pregnancy - derived from pregnant T1DM & T2DM patients

58

Crowther et al. N Eng J Med 2005

Adequate BS control is proven beneficial to the pregnancy. Despite this, no clearly established

• Makes sure no maternal symptoms of DM & hypoglycaemia• Fetal & liquor assessment via P/E & Ultrasound scanning• Biochemical assessment - urine, HBGM & HbA1c


Assessment of the pregnancy• The pregnancy must be treated as a whole• Take precise history

- maternal well-being, FM• Examine for complications

- remember; maternal, fetal & placental• Investigations - in order of priority– ultrasound scan, urine, blood tests, CTG

59


Blood glucose Monitoring •Regular blood glucose monitoring - mainstay of objective

optimization of metabolic control–between 3-4 times a day–a prebreakfast and postprandial (2 hours post-lunch

and dinner) and/or night test• Initially, clinic attendance - primarily for patient education

purposes• Subsequently, self-monitoring of blood glucose is the

optimum• Assessment of long-term control and further optimization -

4-6 weekly by measuring HbA1c levels

60


Postprandial blood glucose monitoring

• Glycaemic control has been shown to be improved by limiting postprandial glucose excursions

• Postprandial glucose correlates well with HbA1C

• By measuring and controlling the postprandial and fasting sugars, the occurrence of neonatal hypoglycaemia and macrosomia may be reduced

61

de Veciana M. NEJM 2013

Do This


Do not manage the blood sugar, manage the patient!

62


MANAGING THE DIABETIC PATIENT IN A PRIMARY CARE SETTING


Diabetic Mx in a primary care setting64

The following are required for adequate management


Algorithm for pregnancy Mx65


What to do when a pt screen is positive66


Evidence of poor glycemic control67

Maternal

Biochemical

Fetalglycosuriapolyuriapolydipsianocturia recurrent infections etc

polyhydramniosmacrosomia

hyperglycaemiaelevated HbA1c


When to refer68

When to refer to

specialist care

inadequate facilities

inadequate staff

poor patient compliance

poor glycemic control


You can manage the diabetic if..• You routinely manage antenatal patients• You know how to screen for & diagnose this

condition• You know how to implement & monitor treatment• You know how to monitor for complications

69

Thank you

the primary care guide for pregnancy diabetes

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