Disclosures I have nothing to disclose 1 4/12/2018 Objectives - - PDF document

4/12/2018 1

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-a Free 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 Stillbirth Macrosomia Shoulder Dystocia Delayed Lung Maturation Perinatal metabolic Abnormalities:

• Hyperbilirubinemia
• Hypoglycemia

Increased 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

• f 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 6

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 pregnancies Pre-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 pregnancy Higher rate of fetal anomalies/perinatal mortality Higher 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

Aspart Lispro Glulisine Regular Regular U-500 NPH Glargine Glargine U-300 Detimir Degludec B B C B X B C X B C Preferred (FDA approved) Preferred Second tier but likely safe Not first choice Not studied in pregnancy First choice Basal Insulin in GDM Safe Not studied in pregnancy Safe and FDA approved Not studied in pregnancy Safe, not absorbed through GI tract, Not safe, high risk of error and severe lows Risk of severe lows Antihyperglycemic: Glyburide Glipizide Metformin Incretins SGLT-2i’s B/C C B B C Not used in Type 2 DM, crosses placenta Not studied Crosses placenta, safe? Second line Not recommended Not recommended Risk unclear Safety unknown No long-term data No safety data No safety data Antihypertensive: ACE-I, ARB, Thiazide Methyldopa, Labetolol CCB, Hydralazine C/D B/C C/C Discontinue before conception ! Drug of choice but side effects Considered 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

• ne-step-approach

with 75-gm 2-hr OGTT 2013 Consensus conference: Lack of adequate evidence for

• ne-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

• f 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, 1hr OGCT Plasma 130-140 2) 3-hr OGTT Fasting 95 mg/dl 1-hr 180 mg/dl 2-hr 155 mg/dl 3-hr 140 mg/dl

1 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 Recommended total 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

• ral 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!