The Pregnant Diabetic AC Lectures/May 5/1.30 Dra. Ngalo… · rdy LP, et al., Diabetes Care. 1996...

The Pregnant DiabeticQueenie G. Ngalob, MD, FPCPMay 5, 2014

Outline

• Classification of diabetes in pregnancy• Effect of diabetes and pregnancy on

• Conceptus• Mother

• Treatment recommendations for pregnant diabetics

Classification of DM in pregnancy

Gestational Diabetes

PreGestationalDiabetes

(Type 1 or Type 2)Overt Diabetes

PregnancyPreexisting

IADPSG. Diabetes Care. 2010; 33(3): 676-682






• UNITE for Diabetes (Philippines)• Evaluate for risk factors on 1st prenatal visit• 75gm OGTT ASAP if with any risk factor, 24-28th week if none

Unite for Diabetes. www.endo-society.org.ph

Risk factors for GDM• Prior GDM• Glucosuria• Family history of DM• Prior macrosomic (>8lbs) baby• Macrosomia in current pregnancy• Age ≥ 25 years old• PCOS• Overweight or obese• Polyhydramnios in current pregnancy• Intake of drugs affecting carbohydrate metabolism

Unite for Diabetes. www.endo-society.org.ph

Diagnosis – 1st Prenatal Visit

Diagnosis FBS, mg/dl (mmol/l)

RBS, mg/dl (mmol/l)

HBA1C*%

Overt Diabetes**

≥ 126 (≥ 7.0)

≥ 200(≥ 11.1)

≥ 6.5


≥ 92-125 (≥ 5.1 – 6.9)

na na

*NGSP certified & standardized to the DCCT reference assay** repeated on another dayIf criteria not met, repeat testing at 24-28 weeks AOG using 75gm OGTT

ADA 2014,WHO 2013, EndoSoc 2013, IADPSG 2010

Diagnosis FBS, mg/dl (mmol/l)

1st hourmg/dl (mmol/l)

2nd hour mg/dl (mmol/l)

Overt Diabetes**

≥ 126 (≥ 7.0)

na ≥ 200(≥ 11.1)


≥ 92-125 (≥ 5.1 – 6.9)

≥ 180(≥ 10.0)

153-199(8.5-11.0)

ADA 2014,WHO 2013, EndoSoc 2013, IADPSG 2010

Diagnosis – 24th to 28th week AOG using 75 gm OGTT






IADPSG. Diabetes Care. 2010; 33(3): 676-682

Effect DM on the conceptus

Fetal malformation

Perinatal mortality

Spontaneous abortion

Boulot P, et al., Diabetes Care 26:2990–2993, 2003Lapolla A., et al. Nutr Metab Cardiovasc Dis. 2008 May;18(4):291-7

Persson M, et al., Diabetes Care. 2009 Nov;32(11):2005-9Eriksson UJ, et al., . Rev Endocrinol Metabol Dis 2003;4:79–93.

Kousseff BG. Diabetic embryopathy. Curr Opin Pediatr 1999;11:348Bell R., et al., BJOG. 2008 Mar;115(4):445-52.

Fetal Malformations• 1.86-7 fold higher risk

• 3rd to 7th weeks AOG embryogenesis & organogenesis

• Rates similar between Type 1 & 2• Toxic metabolites may be

teratogenic• Pathogenesis is poorly

understood

Congenital malformationsThe poorer the glycemic control periconceptionally

or early in pregnancy, the greater the riskfor congenital anomalies.

Towner D, et al., Diabetes Care 1995;18:1446–51.Langer O, et al., J Mat Fet Med 2000;9:35–41.

Temple R, et al., BMJ 2002;325:1275–6.Schaefer-Graf UM, et al., Am J Obstet Gynecol 2000;182:313–20.

Suhonen L, et al., Diabetologia 2000;43:79–82.

Malformations associated with pre-existing diabetes

OR

CNS All 1.55anencephalus 1.9Encephalocoele 3.27

Head Anotia 4.37GI Omphalocoele 2.32

Urinary Bilateral Renal agenesis 2.43

Musculo-skeletal

All 1.66

Garne E, et al., Birth Defects Research (Part A) 94:134–140, 2012

Malformations associated with pre-existing diabetes

OR

Congenitalheart defects

All 2.07Common arterial truncus 2.59Transposition of great vessels 2.00Single ventricle 2.57Ventricular septal defect 1.43Atrial septal defect 2.15Atrioventricular septal defect 2.21Coarctation of the Aorta 1.84

Garne E, et al., Birth Defects Research (Part A) 94:134–140, 2012

Spontaneous abortions

• 4 fold increased risk

• Risk rises poor glycemic control

Temple R., BMJ. 2002 Nov 30;325(7375):1275-6.

Perinatal mortality

• 2.3 to 6- fold increased risk

• Intrauterine stillbirth (>24 weeks AOG) or neonatal death (within 28 days of life)

Feig, et al., Diabetes Care. 2014 Apr 4. [Epub ahead of print]Boulot P, et al., Diabetes Care 26:2990–2993, 2003Dunne R, et al., Diabet Med. 2003 Sep;20(9):734-8.

Lapolla A., et al. Nutr Metab Cardiovasc Dis. 2008 May;18(4):291-7Persson M, et al., Diabetes Care. 2009 Nov;32(11):2005-9

Pregnancy Loss

Cundy T, et al., Diabetes Care 30:2603–2607, 2007

Perinatal outcomes

MACROSOMIAOR 11.45

(95% CI 10.61 – 12.36)

FETAL DISTRESSOR 11.45

(95% CI 10.61 – 12.36)

PRETERMOR 4.86

(95% CI 4.47-5.28)

RESPIRATORY DISTRESS SYNDROME

OR 4.65(95% CI 2.2-9.84)

Perrson M, et al., Diabetes Care 32:2005–2009, 2009

Effect DM on the conceptus

Pantalone K, et al., Endocr Pract. 2011;17:448-455

Effect of pregnancy on the diabetic mother

DM Complications Obstetric Outcomes

DM retinopathy

DCCT group. Diabetes Care 23:1084–1091, 2000Boulot P, et al., Diabetes Care 26:2990–2993, 2003

D. Thompson et al., Can J Diabetes 37 (2013) S168eS183Chew EY, et al., Diabetes Care. 1995 May;18(5):6

No to mild retinopathySmall risk for progression

Established retinopathy can rapidly progress during and up to 1 year after pregnancy, more so in poorly controlled

(OR 1.63 to 2.48)

Effects of pregnancy on retinopathy eventually diminish

after the first year.

Chew EY, et al., Diabetes Care. 1995 May;18(5):631-7.

Patients with more severe diabetic retinopathy at

baseline were more likely to show progression

(Χ2 trend P<0.001)


Patients with higher levels of HBA1C were at greater risk for progression

DM nephropathy

Rossing K, et al., Diabetologica 2002, 45: 36-41 Miodovnik M, et al., Am J Obstet Gynecol 1996;174:1180-91

Biesenbach, et al., Nephrol. Dial. Transplant. (1992) 7 (2): 105-109Purdy LP, et al., Diabetes Care. 1996 Oct;19(10):1067-74.

Normal creatininealbuminuria and creatinine

clearance is preserved during pregnancy

Microalbuminuriamay worsen but typically

modest and reversible(BP and blood sugar are well-

controlled)

Moderate to severecan significantly deteriorate and

may not be reversible

DM nephropathy & pregnancy outcomes

Sibai BM, et al., Am J Obstet Gynecol. 2000 Feb;182(2):364-9Jensen DM, et al., Diabetes Care 33:90–94, 2010

Ekbomm P, et al, Diabetes Care 24:1739–1744, 2001

Increased risk of preeclampsia, exacerbation of hypertension

(OR 1.75-4.0)

Hypertension leads to increased risk of preterm delivery

Placental dysfunction leads to intrauterine growth restriction

and fetal distress

Obstetric Outcomes

PREECLAMPSIAOR 4.47

(95% CI 3.77 to 5.31)

VACUUM EXTRACTION/FORCEP

SOR 1.41

(95% CI 1.25 TO 1.58)

CESAREAN SECTIONOR 5.31

(95% CI 4.97 TO 5.69)

Perrson M, et al., Diabetes Care 32:2005–2009, 2009

Management of PreGDM

Preconception During Pregnancy Postpartum

• Counseling• Glycemic

control• Weight control • Co-morbidities

Management of PreGDM

Preconception Counseling

Should be provided to all diabetic women of childbearing potential or considering

pregnancy

• Start at puberty or on diagnosis

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013ADA, Diabetes Care. 2014 Jan;37 Suppl 1:S14-80

IDF 2009.


Risk of malformations & adverse outcomes associated with unplanned pregnancy or

poor metabolic control

Use of effective contraception

Need for pregnancy to be planned, sufficient control of glucose & co-morbidities

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013ADA, Diabetes Care. 2014 Jan;37 Suppl 1:S14-80

IDF 2009.

Time, commitment and effort is required


Diabetes Specialist

Diabetes Educator

Dietician Obstetrictian

Patient &

partner

Improved glycemic parameters

Outcome No. of Studies

Mean Difference(95% CI)

Mean HBA1C decrease in the 1st trimester

5 - 1.92%(-2.05, -1.79)

Wahabi et al. BMC Public Health 2012, 12:792

Decreased risk for congenital malformations


OR = 0.25 (0.16, 0.37)

Decreased Perinatal Mortality


OR = 0.34 (0.15, 0.75)

Preconception Glycemic Control

Strive to achieve blood glucose and HBA1C as close to normal as possible when they can be safely achieved without undue hypoglycemia.

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013

• ideal preconception glucose levels not established

Bell R, et al. Diabetologia. 2012 Feb 8.

OR 1.3 (95% CI 1.2, 1.4) for every 1% increase in HBA1C

Strategies : Insulin-treated

• Intensified therapy using subcutaneous insulin

• Provide basal coverage• Human insulin : NPH• Analogs : Glargine, Detemir

• Provide prandial coverage• Human insulin : regular• Analogs : Aspart, Lispro

Kitzmiller JL, et al., Diabetes Care. 2008 May;31(5):1060-79

http://dtc.ucsf.eduJacobs DM Care 20:1279, 1997



Recommend multiple daily doses of insulin or continuous SC insulin infusion

over split-dose, premixed insulin

Changes should be done well before conception or before withdrawing contraception to allow patient to

gain expertise



Suggest rapid acting insulin analog (aspart or lispro) in preference to regular insulin

Basal insulins detemir and glargine : preconceptionally & during pregnancy

Strategies : OHAS-treated

No trials on use of oral hypoglycemics in

pregestational DM Shift to insulin

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013Kitzmiller JL, et al., Diabetes Care. 2008 May;31(5):1060-79

Overweight & Obese

Weight reduction before pregnancy for

overweight and obese diabetic women.

Increased risk for complications during pregnancy


Overweight (25.01-30

kg/m2)n=2882

Obese(30.01-40

kg/m2)n=1679

Morbidly obese (>40 kg/m2)

n-=248

Hypertensive disorders

1.74(1.45-2.15)

3.0(2.4-3.74)

4.87(3.27-7.24)


1.78(1.25-2.52)

2.95(2.05-4.25)

7.44(4.42-12.54)

Caesareansection

1.5(1.36-1.66)

2.02(1.79-2.28)

2.54(1.94-3.32)

OR for maternal outcomes according to antenatal BMI

Callaway LK, et al., Med J Aust 2006; 184 (2): 56-59.

Overweight (25.01-30

kg/m2)n-=2882

Obese(30.01-40

kg/m2)N=1679

Morbidly obese (>40 kg/m2)

n-=248

Birth defects 1.58(1.02-2.46)

3.41(1.67-6.94)

Hypoglycemia 2.57 (1.39-4.78)

7.14(3.04-16.74)

Prematurity (<34 wks)

2.13(1.13-4.01)

Admission to NICU

2.77(1.81-4.25)

OR for neonatal outcomes according to antenatal BMI

Callaway LK, et al., Med J Aust 2006; 184 (2): 56-59.

Ocular careHave a detailed ocular assessment by a suitably-trained and qualified eye care professional in advance of withdrawing

contraception or trying to conceive

If retinopathy is documented, should be appraised of risk of worsening during

pregnancy.


Ocular care

If degree of retinopathy warrants therapy, recommend deferring conception until the

retinopathy has been treated and stabilized.

• The greater the degree of preconception retinopathy, the greater the risk of progression during pregnancy

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013Chew EY, et al., Diabetes Care. 1995 May;18(5):631-7.


Patients in whom retinopathy was most likely to progress had both the poorest control at baseline and largest

improvement during early pregnancy

Renal Function

Have renal function assessed in advance

of withdrawing contraception or

trying to conceive


• Urine albumin-creatinine ratio

• Serum Crea• eGFR

Renal Function

If with significantly reduced GFR, refer to nephrologist before

pregnancy


• baseline renal assessment

• review the woman’s specific risk of worsening renal function in the event of pregnancy

Address Co-morbidities

HYPERTENSIONSatisfactory BP control

(<130/80) preconception

Withdraw ACEI and ARB

DYSLIPIDEMIAWithdraw statins

VASCULAR RISKEvaluate risk factors

screening for CAD treat and counsel



• Counselling• Glycemic


• Targets• SMBG• MNT• Weight

management• Pharmacologic• Peripartum

Glycemic TargetsParameter Goal

mg/dl (mmol/L)

Fasting & Preprandial

≤ 95 (≤ 5.3)≤ 90 (5.0) if can be achieved without

hypoglycemia1 hour PP ≤ 140 (≤7.8)

2 hour PP ≤ 120 ( ≤ 6.7)

HBA1C ≤ 7 % (ideally ≤ 6.5)


Self-monitoring of blood glucose (SMBG)

Recommend SMBG in all DM pregnant

patients


Self-monitoring of blood glucose (SMBG)

Recommend SMBG in all DM pregnant

patients

Frequency• Fasting & Pre-meals• Postprandial - 1 or 2

hours after the start of each meal, choosing when is peak

• bedtime and during the night as indicate.

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013Negrato CA, et al., Diabetol Metab Syndr. 2012 Dec 22;4(1):54.

HBA1C

Perform HBA1C at the initial visit and

monthly until target levels are achieved,

then 2-3 months thereafter.

Targets•EndoSoc : ≤ 7% (6.5% ideal)•ADA : <6%


Medical Nutrition Therapy (MNT)

Recommend MNT to help achieve and

maintain desired glycemic control while providing

essential nutrient requirements


Medical Nutrition Therapy (MNT)

• a carbohydrate-controlled meal plan

• Promotes adequate nutrition and weight gain, normoglycemia and no ketosis

• Individualized, adjusted as pregnancy progresses

• CHO : 35-45% of TCR

• 3 small to moderate-sizedmeals

• 2 to 4 snacks• Including

evening snack


Weight Management

Follow the Institute of Medicine revised

guidelines for weight gain during pregnancy

Excess weight gain associated with macrosomia (OR 3.58)Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013

Kitzmiller JL, et al., Diabetes Care. 2008 May;31(5):1060-79

2009 Institute of Medicine Recommendations for total and rate of weight gain in pregnancy,

by Prepregnancy BMI

Prepregnancy BMI Range(kg)

Rates of weight gain in 2nd & 3rd trimester

Mean (Range), kg/wk

Underweight (<18.5 kg/m2) 12.5-18 0.51 (0.44-0.58)Normal (18.5-24.9 kg/m2) 11.5-16 0.42 (0.35-0.5)Overweight (25-29.9 kg/m2)

7-11.5 0.28 (0.23-0.33)

Obese (≥ 30 kg/m2) 5-9 0.22 (0.17-0.27)


• Provide background/ basal coverage• Human insulin : NPH• Analogs : Glargine, Detemir

• Provide prandial coverage• Match with carbohydrate intake• Human insulin : regular• Analogs : Aspart, Lispro

Pharmacologic Therapy


Strategies

Recommend multiple daily doses of insulin or continuous SC insulin infusion

over split-dose, premixed insulin

Suggest rapid acting insulin analog (aspart or lispro) in preference to regular insulin

Suggest use of basal insulins for pregnancy: Detemiror glargine



Suggest that Detemir be initiated in1. Require basal insulin2. NPH insulin, in appropriate doses, has

previously resulted in, or thought that may result in problematic hypoglycemia

3. Successfully taking detemir before pregnancy.


Mathiesen ER, et al., Diabetes Care 35:2012–2017, 2012

P 310 T1DM womenplanning to be or pregnant at 8-12 weeks AOG, A1C ≤ 8% on confirmation or pregnancy17 countries

I Detemir vs NPH insulin

O Primary: HBA1C at 36 wks AOGSecondary: A1C at 8-12, 14 and 24 wks AOG, # attaining ≤ 6%, FPG, SMBGMaternal : hypoglycemia, deterioration of retinopathy, AE, weight gain

M Open-labelled, randomized trial, noninferiority

Detemir in pregnancy


Parameter at 36 weeks AOG

Detemir(n=152)

NPH(n=158)

significance

HBA1C 6.27% 6.33% -0.06 (95% CI-0.21 to 0.08)

HBA1C ≤ 6% 41% 32% P=0.28

Estimated mean FPG

85.7 mg/dl 97.4 mg/dl P=0.017*

Mean PG from 8-point SMPG

119 mg/dl 123 mg/dl P=0.082

Results – Glycemic outcomes


Parameter at 36 weeks AOG

Detemir(n=152)

NPH(n=158)

significance

Major hypoglycemia

16% 21% P=0.615

Weight gain 11.5kg 11kg NS

Adverse Events (AE)

Reported as same ~90%

Serious AE 40% 31% * To be Reportedin another paper

Results – Maternal tolerability


Outcome Detemirn=152

NPH n=158

Serious Adverse Events 40 % 31 %

Pregnancy, puerperium, perinatal conditions

25.7 % 16.5 %

Infection & infestation 4.6 % 1.3 %

Reproductive system & breast 2.0 % 3.2 %

Nervous system 2.6 % 1.3 %

Metabolism and nutrition disorders 11.2 % 8.2 %

Hypoglycemia unawareness 2 pts 7 pts

Diabetes inadequate control 5 pts 1 pts

DKA 3 pts 0 pts

“Few events were considered by the investigator to be possibly or probably related

to one or both investigational products (between 8-12% of the mothers)”

Results – Maternal tolerability

Detemir in Pregnancy – Perinatal and Obstetric Outcomes

P 310 T1DM womenplanning to be or pregnant at 8-12 weeks AOG, A1C ≤ 8% on confirmation or pregnancy17 countries

I Detemir vs NPH insulin

O Composite pregnancy outcomeGA at delivery, SGA or LGA, birthweight, macrosomia, live births, early fetal death, perinatal mortality and induced abortions, neonatal hypoglycemia, congenital malformations, preterm delivery, preeclampsia, AE (fetal & Maternal

M Open-labelled, randomized trial, noninferiority

Hod M, et al., J Matern Fetal Neonatal Med, 2014; 27(1): 7–13

Sample size computed based on primary outcome (HBA1C at 36 weeks) and NOT to detect perinatal and obstetric outcomes

Results – perinatal & obstetric outcomesParameter- Detemir

(n=152)NPH

(n=158)significance

Composite outcome 62.7% 66.2% OR 0.86 (95% CI 0.53, 1.40)

GA at delivery (wks) 38.2 (SD 1.9) 37.8 (SD 1.5) P=0.012Live births 90.1% 93.8% P=0.284

Preterm delivery 20.3% 26.5% P=0.238

Early fetal death 7.7% 6.2% -

Perinatal death 1.4 0.7 -

Neonatal death 0 0 -

SGA 2.3% 0.7% -

LGA 46.1 53.7 0.228

Macrosomia 18.8 25.7 0.18

Neonatal hypoglyc 11.7 17.6 0.223


Results – Congenital Malformations based on treatment during organogenesis

Parameter Detemir(n=84)

NPH(n=154)

Signifi-cance

Congenitalmalformation

4.8% 7.1% -

Minor malformation 1.2% 5.2% -Major malformation 3.6% 1.9% -


Results – Adverse Events in Children

Parameter Detemir(n=84)

NPH(n=154)

significance

AE 36.8% 34.8% -Serious AE 23.7 20.3 -Severe AE 9.9 7.6 -AE possibly/probably related to basal insulin

0.7 0


“Detemir is well-tolerated…Further reassurance will be provided with the collection of longterm

observational data from a large cohort.”

Glargine

Suggest that pregnant women successfully using glargine before

pregnancy may continue it during

pregnancy


Glargine

• Increased affinity to IGF-1 receptors • mitogenicity• Role of IGF-1 in fetal tissues

• Placenta perfusion study showed that glargine does not cross the placenta

Kurtzhals P, et al., Diabetes 2000; 49: 999–1005Chisalta SI, et al., Am J Physiol Endocrinol Metab 286: E896–E901, 2004.

Pollex E, et al., Diabetes Care 33:29–33, 2010

Glargine – Maternal outcomesOutcome # of

studies

N I2 Effect (OR) 95% CIGl NPH

1st TrimesterHBA1C

4 143 158 79% (Mean Diff)-0.08

-0.64, 0.49

Severe Hypoglycemia

4 155 205 52% 0.84 0.18, 3.79

Preeclampsia 8 331 371 44% 0.55 0.23, 1.32

Gestational/ New Onset HPN

4 155 205 1% 0.49 0.2, 1.2

Lepercq J, et al., Obstet Gynecol Int. 2012;2012:649070

Glargine – Neonatal outcomesOutcome # of

studies

N I2 Effect (OR) 95% CIGl NPH

Neonatal hypoglycemia

7 304 346 6% 0.99 0.63, 1.56

NICU admission 6 274 307 13% 0.79 0.45, 1.38

Congenital malformations

5 237 271 0% 0.78 0.39, 1.59

Macrosomia 4 157 198 0% 1.2 0.71, 2.02


Glargine


Current available data from retrospective studies and one prospective cohort show that glargine does not result in increased risk for the mother and fetus.


NO randomized clinical trials regarding the use

of non-insulin antihyperglycemics in

pregestational diabetes



NO randomized clinical trials regarding the use

of non-insulin antihyperglycemics in

pregestational diabetes

Shift OHAS to insulin once pregnancy

confirmed


Labor & Delivery

Suggested targets during labor & delivery

: 72-126 mg/dl

( 4.0-7.0 mmol/l)

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013ADA 2014 Standards of Care. Diab Care (37) : S14-80, 2014


Labor & Delivery

Hyperglycemia during labor and delivery increases risk of• neonatal

hypoglycemia• fetal distress• birth asphyxia• abnormal heart rate

Method:• No evidence on single

best way of maintaining target BG

• No recommendation and at discretion of practitioner






• Lactation

Lactation

Recommend whenever possible,

women with diabetes should breastfeed

their infants.


Lactation

Oral agents with data on transfer to

breastmilk1. Metformin - <1%2. Glyburide, Glipizide

<1.5%

Blumer I, et al., J Clin Endocrinol Metab 98: 4227–4249, 2013Feig DS, et al., Ann Pharmacother. 2007 Jul;41(7):1174-80

Glueck CJ, et al., J Pediatr. 2006 May;148(5):628-632






• Lactation

Thank you.

The Pregnant Diabetic AC Lectures/May 5/1.30 Dra. Ngalo… · rdy LP, et al., Diabetes Care. 1996...

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