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Diabetes in Pregnancy

Ingrid Block-Kurbisch, MD,

Associate Clinical Professor of Medicine

Associate Physician, OB/GYN, UCSF

April 12, 2018

Disclosures

I have nothing to disclose

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Objectives

Definitions: GDM, Pre-GDM 1 & 2

Epidemiology

Implications of GDM and PEDM on outcomes

Pre-conception Care

Populations at high risks for adverse outcomes

Screening for GDM

Treatment and questions about oral agents

Monitoring

Delivery planning

Post-conception Care

Definitions

Hyperglycemia first detected in pregnancy:

- Gestational DM (GDM)

- Diabetes in pregnancy (DIP)

Pre-gestational DM (PEDM):

- Type 1

- Type 2

- Other (Monogenic DM, CF, other)

GDM

- A1GDM: diet controlled

- A2GDM: medication + Diet controlled

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Diabetes in Pregnancy

Most common complication of pregnancy in the US

7% of all pregnancies

Prevalence of GDM correlates well with DM2

Global prevalence of total hyperglycemia in

pregnancy 16.9%

Race/Ethnicity:

- Hispanic, NA, AA, Asian or

Pacific Islander

FH of DM2, GDM

BMI> 25 or

> 23 in Asian Americans

HTN,CVD, Dyslipidemia

Pre-diabetes

PCO-S

Acanthosis Nigricans

Prior GDM

Hx of large infant (> 4000 gm)

Sedentary life style

High Risk Populations

Age Related Prevalence Rates of PEDM

and GDM in the US 1993 – 2009

a Preexisting DM (PDM), b Gestational DM ( GDM)

Correa, A., Bardenheimer, B., Elixhauser, A et al. Maternal Child Health J. (2015) 19:635

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Proportion of Diabetes Types

in Pregnancy in the US

GDM

86%

DM1 0.3-0.8%

DM2

8 + %

Other

• Monogenic DM

• Hyperthyroidism

• Glucocorticoids

• Cystic Fibrosis

• Terbutaline

• Pheochromocytoma

• Acromegaly

Contributing Factors to Insulin Resistance

in Pregnancy

Insulin Resistance

Human placental Lactogen (HPL)

(Human Chorionic Somatomammotropin)Prolactin,Cortisol

Leptin,TNF-aFree Fatty Acids, Resistin, Adiponectin

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Physiologic Rise in Insulin

Levels during Pregnancy

0 6 9 12 16 18 24 28 34 36 40

Weeks of Gestation Delivery

Insulin

Level and Resistance

Onset of classic GDM

250% increase

Increased Sensitivity

Maternal Implications of

GDM

Gestational HTN

Preeclampsia/ Eclampsia

Pre-term delivery

Operative delivery

Emotional distress over outcome

Weight retention post-partum

Up to 50% future risk for DM2

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Fetal Implications of GDM

Fetal/Neonatal/Child and Adult:

LGA / Macrosomia

Stillbirth

Shoulder dystocia

Neonatal hypoglycemia ( NICU stay )

Childhood obesity

DM2

GDM in female offspring

Implications of PEDM

Maternal Risks

Severe hypoglycemia (especially first trimester)

Progression of advanced chronic complications

- Proliferative retinopathy

- Proteinuria/CKD

- Gastroparesis

Pregnancy induced HTN

Cardiovascular event if longstanding DM and AMA

Preeclampsia and Eclampsia

Operative delivery

Anxiety and emotional distress over fetal outcomes

AMA: Advanced maternal age

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Implications of PEDM

Fetal Risks

Congenital Anomalies due to - Hyperglycemia- Teratogenic drugs- Lack of folic acid supplementation

SAB and StillbirthMacrosomiaShoulder Dystocia Delayed Lung MaturationPerinatal metabolic Abnormalities:- Hyperbilirubinemia- HypoglycemiaIncreased risk of childhood obesity and DM 2

Postnatal and future Risks

due to GDM and PMD

Macrosomic Neonate•Hypoglycemia

•Hyperbilirubinemia

•Polycythemia

•Respiratory Distress

•Cardiomyopathy

•Brachial Plexus injuries

Long-term Sequelae

•Congenital anomalies (if early GDM)

•Delayed cognitive and motor development

•Increased risk for type 2 DM

•Childhood Obesity

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Congenital Anomalies in Infants

of Diabetic Mothers with PDM

Fetal Anomaly Gestational Age of Occurrence

(weeks after LMP)

Caudal regression

Anencephaly

Spina bifida

5

6

6

Cardiac anomalies 7-8

Anal/Rectal atresia

Renal anomalies

Situs inversus

8

7

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Mary Martin et al; Basic and Clinical Endocrinology, 1994

Preconception Counseling

Awareness Counseling (at every visit)

- Planning and preventing pregnancy

- importance of tight metabolic control

- diabetes/pregnancy risks of complications

- family planning advise

Overview of preconception care

- for women contemplating pregnancy

In-depth assessment and personalized recommendations

- for women actively planning a pregnancy

Glycemic Goals:

ADA: HbA1c < 6.5%, FPG < 95 mg, 1-hr postprandial < 140

ACOG:HbA1c< 6.0%, FPG < 95 mg, 1-hr postprandial < 140

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Goals of Preconception Care

Planned pregnancy

Lowest A1C without excessive hypoglycemia

Effective contraception until stable control

Evaluate for existing DM complications

Discontinue contraindicated drugs

Start pre-natal Vitamin

Optimize Pre-pregnancy weight

Include women with Pre-DM

Observed Common Characteristics of

Planned versus Unplanned Pregnancy

Planned Pregnancy

Positive relationship with health care team

Positive pre-conception advise

More often Type 1 DM

European or white

Higher socio-economic status

Higher level of education

Married or stable relationship

Employed

Older

Non-smoker

Unplanned Pregnancy

Negative relationship with healthcare team

Discouraged from pregnancy

More often Type 2 DM

Ethnic Minority Group

Lower socio-economic status

Lower level of education

Unmarried/unsupportive partner

Unemployed

Younger

Smoker

R. Temple; Preconception care for women with DM; Clin. Obstetrics and Gynecology;

October 25, 2010

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Observations and Concerns in

Women with Type 2 DM

Fewer planned pregnanciesPre-conception counseling in only 25 % Contraception discussion in only 32% Discussion about obstetric and fetal risk is rare Folic Acid not prescribed prior to conception Late entry into pre-natal care Diagnosis of DM 2 often made in pregnancyHigher rate of fetal anomalies/perinatal mortalityHigher rate of maternal complications Teratogenic medications continued post-conception

R. Temple; Preconception care for women with DM; Clin. Obstetrics and Gynecology; October 25, 2010

Congenital Malformations

in Women with or without PCC

PCC = Pre-conception care Wahabi et al, BMC Public Health 2012

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Who to Refer to High Risk OB

for Preconception counseling

Longstanding PEDM

Established micro vascular complications

Chronic HTN

Hypoglycemia unawareness or DKA

Uncontrolled hyperglycemia

Advanced maternal age ( > 35 yrs)

Prior history of preeclampsia or pregnancy complications

History of moderate to severe obesity

Preconception Care

and Planning

DM Self care

Pregnancy planning

Education

PMD

Endocrinologist

Obstetrician

Ophthalmologist

Nephrologist

Cardiologist

CDE

RD

Support at Home

Support at work

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Medication Safety in Pregnancy and Postpartum

Medication Cat Pregnancy (ACOG) Lactation

AspartLisproGlulisineRegular Regular U-500

NPHGlargineGlargine U-300

Detimir Degludec

BBCBX

BCX

BC

Preferred (FDA approved) Preferred Second tier but likely safe Not first choiceNot studied in pregnancy

First choice Basal Insulin in GDMSafe Not studied in pregnancy

Safe and FDA approved Not studied in pregnancy

Safe, not absorbedthrough GI tract,

Not safe, high risk of error and severe lows

Risk of severe lows

Antihyperglycemic:Glyburide GlipizideMetforminIncretins SGLT-2i’s

B/CCBBC

Not used in Type 2 DM, crosses placenta Not studied Crosses placenta, safe? Second lineNot recommended Not recommended

Risk unclearSafety unknownNo long-term dataNo safety data No safety data

Antihypertensive:ACE-I, ARB, Thiazide Methyldopa, LabetololCCB, Hydralazine

C/DB/CC/C

Discontinue before conception !Drug of choice but side effectsConsidered safe drugs to add on

Not safe Probably safe Probably safe

Statin X Discontinue before conception ! Unsafe

Take Home Points

Maternal and Fetal Outcomes can be improved by consistent intervention before conception

Education and counseling in the primary care setting are critical

Referral for counseling by Obstetrician

Contraception counseling

Nutrition counseling and weight management

Smoking cessation

Pre-natal Vitamin (Folic acid )

Discontinuation of teratogenic drugs

Optimal glycemic control:HbA1c 6-6.5%

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What is the best Test for

Diagnosis of GDM ?

Lack of international consensus

Confusion over competing diagnostic criteria

As of 2018 no unifying approach

Variety of regional, institutional diagnostic criteria

High prevalence of GDM with One-step test

Lack of evidence that treatment of mild GDM results in better outcome ( FPG < 95 mg/dl)

Concerns over high cost and harm

GDM Screening and Diagnosis

1973

50-gm 1-hr

GCT +

3-hrOGTT

Selective

screen

at 24 – 28

weeks

two-step

approach

2014 USPSTF

supports

universal screen

2010 IADPSG

recommends

one-step-approach

with 75-gm 2-hr

OGTT

2013

Consensus

conference:

Lack of

adequate

evidence for

one-step,

high cost and

burden

2015

Cochrane Review:

No specific screening

Strategy has been

shown to be optimal

2018

ACOG continues

to support two-step

Approach with

universal screen

2008

HAPO

Study

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Hyperglycemia and Adverse

Pregnancy Outcomes

HAPO

Large study designed to achieve international consensus on diagnosis of GDM

Impact of maternal glycemia less severe than diabetes on pregnancy and neonatal outcomes

Multicenter (15) and multinational (9 countries)

- 25,505 women

- 2-hr 75-OGTT at 24-32 weeks

- unblinded FPG > 105, 2-hr > 200 mg/dl

The HAPO Study Cooperative Research Group; NEJM; May 8, 2008

Frequency of Primary Outcomes across

the Glucose Categories.

The HAPO Study Cooperative Research Group. N Eng J Med 2008;358:1991-2002.

Glucose Categories 1-7

-FG : < 75- 100 or >

-1-hr: >105 -212 or >

-2-hr: < 90 - 178 or >

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Secondary Outcomes

of HAPO Study

Preeclampsia: strongest association with maternal glycemia: OR: 1.21- 1.28

Other positive associations:

Shoulder dystocia or birth injury: OR 1.20

Delivery before 37 weeks

Hyperbilirubinemia

Neonatal ICU stay

Current Screening Modalities

IADPSG /WHO 2013

One Step Screen:

ACOG/ADA

Two Step Screen:

Fasting 92 mg/dl

1-hr 180 mg/dl

2-hr 153 mg/dl

1) 50-gm, 1hrOGCT

Plasma130-140

2) 3-hr OGTT

Fasting 95 mg/dl

1-hr 180 mg/dl

2-hr 155 mg/dl

3-hr 140 mg/dl1 abnormal value = GDM

Increases prevalence to 18%

2 abnormal values on OGGT = GDM

(Carpenter and Coustan criteria)

IADPSG: International Association of Diabetes Study Group, WHO: World Health Organization

ACOG: American College of Obstetrics and Gynecology, ADA: American

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Screening for GDM and

DIP

Universal screening more sensitive than risk factor based

A1c sensitive test to identify undiagnosed DM2

A1c insensitive screen for GDM

Screen with A1C + 1-hr GCT at first visit if high risk

Cut-offs for 1-hr 50 gm GCT based on regional prevalence

Two-step test endorsed by ACOG/ ADA

One-step 2-hr -75-gm:(endorsed by IADPSG,WHO)

- insufficient evidence for better outcomes

- increases prevalence of GDM to 18 %

- increases health cost and burden

- may be appropriate in certain high risk populations

Treatment of GDM

70-85 % of women achieve normoglycemia with MNT

Initiate Insulin therapy for:

FBG > 95, 1-hr post-meal > 140 despite optimal MNT

NPH is the preferred basal insulin in GDM

Weekly review of mailed BG logs

A1GDM: follow up by primary OB/FNP

A2GDM:Monthly face-to-face visit with HROB team

- Antenatal testing at 32 weeks twice/week

- Induced labor depending on glycemic control

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Risk Reduction with

Treatment for GDM

Decreases Preeclampsia risk (3 trials)

Reduces rate of Macrosomia (5 trials)

Reduces Shoulder Dystocia (3 trials)

Medical Nutrition Therapy

MNT

Goals:

Achieve optimal pre and post meal BG’s

FBG < 95 mg/dl

1- hr post prandial < 140 mg/dl

2- hr post prandial < 120 mg/dl

Prevent ketosis

Promote fetal well-being

Individualize caloric intake based on BMI and weight goals ( 12-40 kcal/Kg, 33-40% CHO)

Teach CHO counting

Promote physical activity

Post-partum counseling on weight management

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Medical Nutrition Therapy

Recommended CHO distribution

Breakfast: 30 - 45 gm

Snack: 15 – 30 gm

Lunch: 45 – 60 gm

Snack: 15 – 30 gm

Dinner: 45 – 60 gm

Bedtime Snack: 15 -30 gm

Total minimum CHO intake: 175 gm/ day

Institute of Medicine

Guidelines on Weight Gain

in Pregnancy

Pre-pregnancy Weight Category

BMI Recommendedtotal Weight Gain

Second and third Trimester rates of Weight Gain lbs / week

Underweight < 18.5 28-40 lbs 1-1.3

Normal 18.5-24.9 25-35 lbs 0.8 - 1

Overweight 25-29.9 15-25 lbs 0.5 – 0.7

Obese (all classes) 30 and > 11-20 lbs 0.4 – 0.6

Institute of Medicine, 2009

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Treatment of GDM with

oral Agents

Glyburide:

-Higher rated of Macrosomia and neonatal hypoglycemia:

-Not first line drug

Metformin: Failure rate up to 40 %

- Safe ? Crosses the placenta in significant amounts.

- long term safety data not yet available

MiG-TOFU trial: 2011

- Large RCT (New Zealand National Women’s Health Database)

- Compared Metformin and insulin

- Slightly earlier delivery and less neonatal hypoglycemia in

Metformin group

-Two year follow up in offspring: no difference in total body fat

mass. Awaiting results of 9 yr follow up

If using Metformin must counsel patient !

PEDM

First Trimester:

Confirm viable pregnancy

Assess for chron. complications

A1c, renal fx and Al/Crea

TFT’s in all DM, selected DM2

Retinal exam

Cardiac risk assessment

Second Trimester:

A1c

18-20 wks: Fetal Echo & anatomic survey

Third Trimester:

A1c

28,32,36 wks: Fetal Growth Scan

Post-delivery insulin regimen:

85% of pre-pregnancy dose

First Trimester:

Nutrition Consult for MNT

Assess patient self knowledge

MDI or CSII-Pump

SBGM: before & 60min post-meals & 3AM

CGM in DM1 patients

Treat chronic HTN as indicated

Second Trimester:

12 weeks start ASA 81 mg daily

Third Trimester:

32 weeks: Antenatal Testing twice /wk

Discuss induction and delivery

Meet with RN to review expectations

Visit birth center

Post-partum follow up with PCP and primary

endocrinologist

Weekly review of mailed BG logs

Monthly face – to - face visit with HROB team

Short-term admission for uncontrolled DM or recurrent moderate /severe

hypoglycemic episodes

Evaluation Treatment

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Insulin Dosing during

Pregnancy

Insulin (Units /Kg)

Week 0 - 6: 0.5 - 0.6 0.7 - 0.8

Week 6 - 16 0.6 - 0.7 0.8 - 0.9

Week 18 - 26 0.7 - 0.8 0.9 - 1.0

Week 26 - 36 0.8 - 0.9 1.1 - 1.3

Week 36 - 40 0.9 - 1.0 1.1 - 1.5

1. Use 50:50% Basal: Bolus Ratio

2. Use active metabolic weight for insulin dose calculation

DM 1 DM 2/GDM

Continuous glucose monitoring in pregnant women with

type 1 diabetes (CONCEPTT): a multicentre international

randomised controlled trial

Denice S Feig et all; The Lancet; Volume 390, Issue

10110, Pages 2347-2359; November 2017

Role of Continuous Glucose

Monitoring

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CONCEPTT

Assessed effectiveness of CGM on maternal glucose control and obstetric and neonatal outcomes

31 Hospitals (Canada, Europe, USA)

325 women, 18-40 years old, Type 1 DM

planning pregnancy or

< 13 weeks pregnant

12 month duration

Primary outcome: change in A1c

Secondary outcome: obstetric and neonatal health

Denice S Feig et all; The Lancet; Volume 390, Issue 10110, Pages 2347-2359; November 2017

CONCEPTT

Results:

Increased time in glucose target in CGM group

Comparable hypoglcycemia

Small difference in A1c

Lower incidence of LGA (NNT: 6)

Lower rate of neonatal hypoglycemia (NNT: 8)

Lower admission rate to NICU (NNT: 6)

One day shorter hospital stay

Less significant outcomes in women planning pregnancy

Costeffectiveness will need further study

Denice S Feig et all; The Lancet; Volume 390, Issue 10110, Pages 2347-2359; November 2017

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Postpartum Follow up and

Interconception Care for GDM

75-g 2-hr OGTT at

4-12 weeks

Diabetes Mellitus

Pre-DM Normal

Follow up with

PMD

Screen for DM every 1-3 years &

Before next conception

Exercise, Weight loss

Family Planning

Preconception Counseling and care

Screen for DM annually & Before next conception

Exercise, Diet, Weight loss

Nutrition counseling

Consider Metformin

Family Planning Preconception Care and Counseling

Treat for DM

Nutrition consult

Diabetes Education

Family Planning Preconception Care and Counseling

Endocrine Referral

References

1. Correa, A.,Bardenheimer, B., Elixhauser, A et al. Mat. Child Health J. (2015)

2. ACOG Practice Bulletin, Number 190, February 2018

3. Epidemiology of Diabetes in Pregnancy; David Simmons

A practical Manual of DM in Pregnancy Second Edition. 2018 John Wiley & Sons

4. The HAPO Study Cooperative Research Group. Hyperglycemia and Adverse

Pregnancy Outcome NEJM, May 8, 2008;358:1991-2002

5. F. M. Brown, J. Wyckoff; Application of One-Step IADPSG versus Two-step

6. Diagnostic Criteria for GDM in the Real World: Impact on Health Services, Clinical Care and Outcomes. Curr Diab Rep (2017)17:85, August 2017

7. Hartling L. Dryden et al. Benefits and harms of treating gestational diabetes

mellitus: a systematic review and meta-analysis for the U.S. Preventive Task

Force and the National Institutes of Health Office of Medical Applications of

Research. Ann Intern Med 2013; 159:123

8. J. Rowan et al Metformin in gestational diabetes: The offspring follow-up (MiG-

TOFU): body composition at 2 years of age; Diabetes Care. 2011;34(10); 2279

9. E. Buschur, F. Brown, J. Wyckhoff, Using Oral Agents to manage Gestational Diabetes: What have we learned?, Curr Diab Rep, (2015) 15:4

10. Denise S Feig et al. Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT): A Multicentre Randomised Controlled Trial; The Lancet, 15 September 2017

11. Institute of Medicine Guidelines on Weight Gain in Pregnancy, IOM 2009

12. F. Peterson-Burch et al: Preconception Counseling for Adolescents and Young Adults with Diabetes; 02/15/2018; A literature review of the past 10 years.

Current Diabetes Reports( 2018) 18:11

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Thank you !

Thank you!