Diabetes in Pregnancy Mark Alanis, MD, MSCR Assistant Clinical - - PDF document
2/4/2016 Diabetes in Pregnancy Mark Alanis, MD, MSCR Assistant Clinical Professor Maternal-Fetal Medicine University of Colorado Health Memorial Hospital, Colorado Springs, CO disclosures I have no relevant financial conflicts of interest
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Mark Alanis, MD, MSCR Assistant Clinical Professor Maternal-Fetal Medicine University of Colorado Health Memorial Hospital, Colorado Springs, CO
I have no relevant financial conflicts of interest with any commercial entity to disclose. I will discuss the off-label use of insulin and insulin pumps for use in pregnancy. I will not discuss the off label use of any other pharmaceutical agent or medical device during this lecture.
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At the end of this lecture, you will be better prepared to: Counsel patients on the risks of gestationald and pregestational diabetes Sort through the confusion about gestational diabetes testing paradigms Reduce diabetes-related adverse outcomes through achieving maternal euglycemia
Frederick Banting
Born 1891, died 1941 Canadian physician scientist Discovery of insulin, 1922 Nobel prize, 1923
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Pricilla White
Born 1900, died 1989 Mentored by Elliot P. Joslin Among first to show importance
pregnancy White’s Classification in 1949 Banting Medal recipient
Description Class Fetal Growth Gestational Diabetes, no insulin A1 No vascular disease High Risk for Macrosomia Gestational Diabetes, insulin A2 Age of onset, ≥ 20 y B1 Duration < 10 y, no vascular lesions B2 Age of onset, 10-19 y C1 Duration 10-19 y, no vascular lesions C2 Age of onset, < 10 y D1 Duration, ≥ 20 y D2 Benign (non-proliferative) retinopathy D3 Vascular disease High Risk for IUGR Calcified arteries of the legs D4 Calcified arteries of the pelvis E Nephropathy F Many failures G Cardiac disease H Proliferating retinopathy R Renal transplant T
Pridjian G. Obstet Gynecol Clin N Am 2010;37:143, adapted from: White P. Am J Obstet Gynecol 1978;130:228
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Diabetes Type Findings Phenotype Type 1 Autoimmune destruction of β-cells; 33% concordance among mono- zygotic twins; Absolute insulinopenia Onset in childhood or adolescence; Thin; Ketoacidosis Type 2 Progressive insulin secretory defect; insulin resistance; 58-100% concordance among mono-zygotic twins Adult-onset, obese, metabolic syndrome, hyperosmolar coma Gestational Same as type 2 diabetes Onset during pregnancy, resolves in postpartum; Rare, other Pancreatic damage or insufficiency, genetic defects in insulin action Cystic fibrosis
American Diabetes Association, Standards of Medical Care in Diabetes – 2013. Diabetes Care 2013;36, Suppl 1: S11
85% 15% Gestational DM Pregestational DM
Albrecht SS, et al. Diabetes Care 2010;33:768
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Percent of Deliveries (%) Type N 1994 1999 2004 % change All diabetes 1,863,746 3.49 4.04 5.47 56.3 GDM 1,578,703 2.95 3.42 4.61 56.2 Type 1 130,300 0.24 0.31 0.33 33.2 Type 2 87,477 0.09 0.16 0.42 366.7
Hospital Discharge Data 1994-2004 of 43+ million delivery discharges
Albrecht SS, et al. Diabetes Care 2010;33:768
U.S. Adults Aged 18 Years or older
1994 1994 2000 2000
No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
2010 2010
DIABETES OBESITY
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Rate (per 100,000 per year)
Youths 10-19 years of age
Type 2 Type 1
40
CDC, 2011 National Diabetes Fact Sheet, data from SEARCH for Diabetes in Youth Study:
Acute onset Childhood or adolescence Islet cell autoimmune antibodies β-cell destruction Absolute insulinopenia Lifelong requirement for insulin Threat of diabetic ketoacidosis High rate of vascular disease High rate of pregnancy complications
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Insidious onset Asymptomatic Relative insulin deficiency Decreased insulin sensitivity in skeletal muscle Decreased insulin response on hepatic glucose production Inadequate β-cell response for given glucose level Typically older, overweight or obese, family history Most pregnant patients are White’s Class B High rate of pregnancy complications
Onset in late second trimester Asymptomatic Relative insulin deficiency Decreased insulin sensitivity in skeletal muscle Decreased insulin response on hepatic glucose production Inadequate β-cell response for given glucose level Typically older, overweight or obese, family history Lower rate of pregnancy complications
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lots of risks… how do you communicate it all?
Counseling the pregestational diabetic patient
Which diabetic patient has the highest risk for pregnancy complications?
a) Type 1 diabetes b) Type 2 diabetes c) Gestational diabetes d) No difference between the 3 types
ARS
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Pregnancy affects retinopathy in what way?
a) It occurs de novo due to pregnancy b) If already present at conception, it worsens during pregnancy, then returns to baseline c) If already present at conception, it worsens during pregnancy, permanently d) It is not affected by pregnancy
ARS
The most common cause of perinatal mortality in diabetic pregnancies is:
a) Stillbirth b) Congenital anomaly c) Respiratory distress d) Preterm birth ARS
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What is the incidence of brachial plexus injury with shoulder dystocia?
a) 5% b) 15% c) 25% d) 35%
ARS
a) Fasting glucose increases
b) Insulin sensitivity increases in first trimester c) Postprandial glucose increases over gestation d) All of the above
ARS
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Type 1
after diagnosis of GDM
Type 2
diagnosis of GDM
Gestational
Two-Step versus One Step
parameters
individual versus public health benefit
Two Step 1-hour 50 g glucose load 3-hour 100 g glucose load GDM Yes or No When should you do it? What cutoff to use? Should you fast? High false negative and positive rates Very inconvenient What cutoffs to use? Arbitrary diagnosis Risk versus harm with diagnosis
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One Step 2-hour 75 g glucose load GDM Yes or No Moderately inconvenient 3-fold increase in prevalence Arbitrary diagnosis 1979 - 2009 2010 2008 2011 2012 2013 2014
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Hyperglycemia and Adverse Pregnancy Outcomes
HAPO Study Group N Engl J Med 2008;358:1991
Study Features
results
GDM diagnostic testing cutoffs based on
wasn’t the case IADPSG had two goals: 1. Use HAPO to develop cutoffs discretely linked to GDM-related morbidities 2. Develop international standard diagnostic guidelines Cutoffs later arbitrarily defined based Odds Ratios
International Association of Diabetes in Pregnancy Study Group
HAPO Study Group N Engl J Med 2008;358:1991 IADPSG Diabetes Care 2010;33:676
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More GDM Diagnostic Dilemmas
Should you try to differeniate type 1 from type 2 diabetes in unclear situations? What do you call a patient whom you diagnose early in pregnancy: pregestational or gestational? Should the hemoglobin A1c be used to diagnose diabetes mellitus in pregnancy?
It’s not important
ADA/IADPSG:
ACOG: undiagnosed type 2 DM
It can, but it shouldn’t be the only test you order
EVEN More Diagnostic Dilemmas
Should early screening be performed? Should you use NDDG or Carpenter- Coustan criteria for the diagnosis in Two- Step screening? Should the One-Step paradigm be used for the diagnosis of GDM?
ACOG: either
No! (ACOG and NIH) Yes! (ADA, IADSPG, WHO)
Yes!
(ADA and ACOG)
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USPSTF Systematic Review Ann Intern Med 2013;159:115
A 1-hour, 50 g glucose cutoff of 140 mg has 15% false negative rate (CC criteria)
Criteria Year Fasting mg/dL 1-hour mg/dl 2-hour mg/dL 3-hour mg/dL Two-Step (100 g load) C-C 1982 95 180 155 140 NDDG 1979 105 190 165 145 CDA 2008 95 191 160 One-Step (75 g load) WHO 1985 126 140 IADPSG 2010 92 180 153
NIH Consensus Development Conference Statement Vol. 29, Number 1. March 4-6, 2013
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Data Group for 3-hour cutoffs
2013 Practice Bulletin No. 137 Maternal and Obstetric Fetal and Neonatal
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late stages
10 20 30 40 50 60 None Mild Mod-Severe %
Progression by baseline status
Associated with
2-5 years after pregnancy
resolve
Chew EY, et al. Diabetes Care 1995;18:631 Diabetes Control and Complications Trial Group. Diabetes Care 2000;23:1084
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Definition
Microalbuminuria
Number 1 cause of end stage renal disease
Abnormal renal arteriolar dilation Cannot handle hyperfiltration Alteration in renin-angiotensin Transient, mild worsening in pregnancy for mild disease Possibly permanent worsening if severe disease Preeclampsia, preterm birth, IUGR, stillbirth Worst outcomes in: Baseline proteinuria > 3 g in 24 hours (heavy proteinuria) or baseline serum creatinine ≥ 1.5 g/dL (severe renal disease)
Peripheral dilation 5 weeks’ 50% increase in renal blood flow 12 weeks’ 50% increase in GRF 8 weeks’
Physiology Diabetes Outcomes
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Microalbuminuria Nephropathy Renal Insufficiency End Stage Renal Disease
87% 3% 5% 3% 2%
Normal (< 30mg/24h) DM1 micro UA DM2 micro UA DM1 nephropathy DM2 nephropathy
Damm JA, et al. Diabetes Care, in press
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5 10 15 20 25 30 35 40 45 Preeclampsia PTB < 34 wk PTB < 37 wk % Normal UA Micro UA
Jensen DM, et al. Diabetes Care 2010;33:90
Kitzmiller Grenfel Reece Gordon Rosenn Year 1991 1986 1988 1996 1997 Subjects 26 20 31 45 61 Preeclampsia (%) 15 55 35 53 51 IUGR (%) 21
11 11 Delivery < 34 wk (%) 31 27 23 16 25 Perinatal mortality (%) 11 7 6
Gabbe Obstetrics: Normal and Problem Pregnancies, 6th Ed., 2012. Chapter 39: Diabetes Mellitus Complicating Pregnancy pp. 887-921
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1. Diabetic kidney disease is a progression from microalbuminuria to overt nephropathy to impaired creatinine clearance to end stage renal disease 2. Microalbuminuria and nephropathy both strongly increase risk of preeclampsia 3. Good glucose control in pregnancy strongly reduces risk of preterm birth < 34 weeks in setting of microalbuminuria 4. Overt nephropathy strongly increases risk of IUGR and preterm birth < 34 weeks of gestation
Rare (24 case reports in literature between 1953-2007) Mortality:
Relative contraindication to pregnancy if untreated
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serum glucose < 200 mg/dL
For prevention of maternal complications
Preconception consultation Health maintenance screening:
Laser photocoagulation if retinopathy 24-hour urine albumin, total protein, creatinine clearance Aggressive management of blood pressure, <135/85 Strict diet, exercise, and tight glucose control
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MOST can be negated by early and aggressive glucose control
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“big babies are so cute!”
1. Hypertrophic cardiomyopathy 2. Increased perinatal mortality 3. Shoulder dystocia 4. Brachial plexus injury 5. Respiratory distress syndrome 6. Hypoglycemia 7. Hyperbilirubinemia 8. Polycythemia 9. Epigenetic alterations to vascular tree
diabetes
Is birth weight best indicator for fetal overgrowth?
Catalano PM and Hauguel-De Mouzon S. Am J Obstet Gynecol 2011;204:479
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Maternal hyperglycemia Fetal hyperglycemia Fetal hyperinsulinemia Increased accretion of fat Macrosomia Altered anthropometry
Strong Association Cardiac Defects most (septal and outflow defects) Neural tube defects anencephaly Moderate Association Renal bilateral agenesis Anogenital hypospadias Almost pathognomonic Caudal regression Sirenomelia, sacral agenesis
Correa A, et al (National Birth Defects Prevention Study) Am J Obstet Gynecol 2008;199:237 Garne E, et al. Birth Defects Res A Clin Mol Teratol 2012;94:134
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1 2 3 4 5 No Folic Acid Folic Acid No diabetes Diabetes
Parker SE, et al. Am J Obstet Gynecol 2013:209:239
Gabbe Obstetrics: Normal and Problem Pregnancies, 6th Ed., 2012. Chapter 39: Diabetes Mellitus Complicating Pregnancy pp. 887-921
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Death Rates per 1000 deliveries Type Diabete s No Diabetes Odds Ratio 95% CI Stillbirth 9.7 4.0 2.5 1.02-5.9 Perinatal Mortality 17.4 5.9 3.0 1.6-5.9 Infant Mortality 15.5 2.8 8.9 5.2-15.3
Yang J, et al. Obstet Gynecol 2006;108:644
Type 1 vs. Type 2 Diabetes Mellitus
Balsells M, et al. J Clin Endocrinol Metab 2009;94:4284
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10 20 30 40 50 60 %
Type 2 Type 1
Clausen TD, et al. Diabetes Care 2005;28:323
5 10 15 20 25 4000-4250 4250-4500 4500-4750 4750-5000
% Unassisted SVD Birth Weight Non-Diabetic Diabetic
Nesbitt TS, et al. Am J Obstet Gynecol 1998;179:476
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Be aggressive! Time is of the essence!
Oral agents have no place in the management
Preconception is the best opportunity to switch from oral agents to insulin in order to achieve glucose control No matter what type of diabtes, the goal is normal blood glucose levels
Corner stone of management is diet and hypoglycemic therapy to achieve euglycemia
Managing Preexisting Diabetes in Pregnancy: American Diabetes Association Consensus Recommendations. Diabetes Care 2008;31-1060
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12 studies
diabetic women
Period Plasma Glucose Fasting 71 ± 8 1-hour post- prandial 109 ± 13 2-hour post- prandial 99 ± 10 24-hour average 88 ± 10
Hernandez et al. Diabetes Care 2011;34:1660 Fifth International Workshop-Conference on Gestational Diabetes. Diabetes Care 2007;30:S251
ACOG/ADA 95* 140 120 110*
* Not included in 2013 Practice Bulletin
Insulin needs in early pregnancy in type 1 diabetes
Gabbe Obstetrics: Normal and Problem Pregnancies, 6th Ed., 2012. Chapter 39: Diabetes Mellitus Complicating Pregnancy pp. 887-921
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Fasting glucose over gestation
Riskin-Mashiah S, et al. J Perinat Med 2011;39:209
Time Glucose (mg/dL) Early AM, fast ≤ 95 Pre-prandial ≤ 100 1h post-prandial ≤ 140 2h post-prandial ≤ 120 2-6 AM > 60
1- or 2-hour postprandial)
for pregestational DM
pregnancy, and further increases with tighter monitoring than these targets without known benefit Frequent self monitoring of blood glucose and tight adherence to recommended targets (ACOG)
ACOG Practice Bulletin No. 60. 2005 ACOG Practice Bulletin No. 137. 2013
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conversion to plasma standard
value 95% of the time when > 75 mg/dL
95% of the time when < 75 mg/dL
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Continuous glucose monitoring
Small RCT (n = 71) showed benefits
Follow-up RCT (n = 154) showed no benefit
Secher AL, et al. Diabetes Care 2013;36:1877 Murphy HR, et al. BMJ 2008;337:a1680
Early referral to nutritionist Caloric intake extremely important
gain, increasing further risks for preeclampsia, preterm birth, and macrosomia
Total gestational weight gain per IOM guidelines Balanced: 50% carbohydrate, 20% protein, 30% fat
Gabbe Obstetrics: Normal and Problem Pregnancies, 6th Ed., 2012. Chapter 39: Diabetes Mellitus Complicating Pregnancy pp. 887-921
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sulfa allergy
intention-to-treat studies*
unpredictable in pregnancy
glucose
skeletal muscle
intention-to-treat trial**
* Very high rates of switching back to insulin during trials: 20-40% for glyburide, 50% for metformin
Glyburide Metformin
Brand Onset (h) Peak (h) Duration (h) Short-acting Regular (Lilly) Humulin-R 0.5 2-4 5-7 Regular (Novo Nordisk) Novolin-R 0.5 2.5-5 6-8 Lispro Humalog 0.25 0.5-1.5 4-5 Aspart NovoLog 0.25 1-3 3-5 Intermediate-acting Lente insulin (Lilly) Humulin L 1-3 6-12 18-24 Lente insulin (Novo Nordisk) Novolin L 2.5 7-15 22 NPH (Lilly) Humulin-N 1-2 6-12 18-24 NPH (Novo Nordisk) Novolin N 1.5 4-20 24 Long-acting insulin Ultralente (Lilly) Humulin Ultralente 4-6 8-20 >36 Glargine Lantus 1 none 24 Detemir Levemir 1-2 none 24
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Analogues (lispro or aspart) preferred over regular insulin
meals
Multiple-shot regimen vs. continuous infusion necessary Glargine and detemir cannot be combined with other insulins in single shot like NPH can Pregnant women often have differing basal insulin needs depending on time of day, making NPH easier to tailor to individual needs Do not combine with oral hypoglycemic agents
Meta-analysis of lispro vs. regular insulin: numerous retrospective & prospective studies, improved postprandial glucose, lower insulin requirements, possibly increased rates
One RCT of aspart vs. regular insulin (n = 322): no differences in outcomes), trend for lower hypoglycemia with aspart One RCT of detemir vs. NPH (n = 310)
Mathiesen ER, et al. Diabetes Care 2012;35:2012 Murphy HR, et al. BMJ 2008;337:a1680
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New Start
U/kg/d
60% as basal insulin and 40-50% as rapid acting insulin For example:
mg/dL
Total insulin = 0.8 U x 100 kg = 80 units/day
48 units
32 units (e.g. 12/8/12)
demands increase, on average, 3-fold over gestation
50% overall
increase 400% overall
lower first trimester demands
Roeder HA, et al. Am J Obstet Gynecol 2012;207:324
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Antepartum Assessment
28 weeks’
NST or BPP at 32 weeks of gestation
Delivery at term if no complications
Follow a standard management plan in third trimester, delivery at 39 weeks’
ACOG Practice Bulletin No. 60. 2005
Ultrasound
mid-gestation
weeks for fetal growth and fluid
For patients with preexisting
American Diabetes Association guidelines
For preexisting HTN:
based on maternal longterm health and decreased heart and renal disease and incidence of stroke
For diabetic kidney disease:
preeclampsia, and preterm birth
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ACOG GDM Recommendations
NIH Recommendations
Very high rate of cesarean (75% in several studies for pregestational diabetic patients) and glucose control does not appear to affect A1c ≥ 6.4% associated with abnormal fetal testing at term and prompt cesarean delivery Use delayed cord clamping with caution
Miailhe G, et al. Obstet Gynecol 2013;121:983 Lepercq J, et al. Obstet Gynecol 2010;115:1014 Spong CY, et al. Obstet Gynecol 2011;118:323