Pregnancy and Diabetes EMILY BRENNAN PGY-4 ENDOCRINOLOGY MAY 20 TH, 2015.
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Transcript of Pregnancy and Diabetes EMILY BRENNAN PGY-4 ENDOCRINOLOGY MAY 20 TH, 2015.
Pregnancy and DiabetesEMILY BRENNAN
PGY-4 ENDOCRINOLOGY
MAY 20TH, 2015
Objectives
The objectives of this talk are to:
Explore insulin needs in pregnancy
Address issues of analogue safety
Explain factors behind declining insulin needs early and late in pregnancy
Review the incidence of hypoglycemia unawareness in pregnancy
Case
A 33 year old female is being followed for her perinatal care. She is 30 weeks pregnant. This is her second pregnancy. She is screened for GDM at 28 weeks, and had a positive test.
PMHx: nil
Meds: pre-natal vitamins
FHx: mother and father have DM.
She has seen the nurse and dietician about the diagnosis of gestational diabetes.
Case
She along with her husband come to see you in clinic. They have questions about her new diagnosis.
What is the difference between gestational diabetes and pre-gestational diabetes?
Diabetes in Pregnancy
Diabetes mellitus is the most common medical condition in pregnancy
2-5% of pregnant women
“Pre-gestational” Diabetes refers to diabetes that was present before pregnancy (T1DM and T2DM)
Prevalence has significantly increased over the past decade due to the increase in type 2 DM
Greater risk of complications in pre-gestational diabetes compared to GDM
“Gestational Diabetes” refers to diabetes limited to pregnancy
Case
She asked what are the potential consequences of gestational diabetes for her baby?
Fetal Consequences
Conception and first trimester:
Increased risk of fetal malformation
2nd/3rd trimester:
Increased risk of macrosomia leading to shoulder dystocia, bone fracture, nerve palsy, need for c-section, perinatal asphyxia
Increased risk of metabolic complications at birth (neonatal hypoglycemia)
Increased perinatal mortality
Increased risk of future diabetes mellitus development
Case
She asks what are the potential consequences of gestational diabetes for her pregnancy and her own health?
CEMACH (Confidential Enquiry into Maternal and Child Health)
2002/2003 in 3,800 pregnancies with T2DM or T1DM
36% women were delivered preterm
67% delivered by c-section
HAPO Trial
NEJM 2008
Designed to clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than overt diabetes mellitus
HAPO Trial
Maternal Consequences
Pre-eclampsia
Hypertension
Miscarriage
Macrosomia -> perineal laceration and uterine rupture
Retinopathy
Chronic kidney disease
Acute metabolic decompensation (DKA or hypoglycemia)
Case
She asks you to explain why diabetes occur during pregnancy?
Normal Endocrine Changes in Pregnancy
Early pregnancy:
glucose requirements of the fetus lead to enhanced transport of glucose across the placenta
Normal Endocrine Changes in Pregnancy
As pregnancy progresses, there are increased levels of many hormones:
human placental lactogen, glucocorticoids, progesterone, free fatty acids, and TNF-alpha
leads to insulin resistance found during the last half of pregnancy
Metabolic Adaptations and Pregnancy
Maternal insulin resistance during pregnancy is normal
Begins in second trimester and peaks in the third trimester
Human placental lactogen is the major driver, and peaks at 30 weeks gestations
TNF and human placental growth hormone also contribute
Metabolic Adaptations and Pregnancy
Prolactin and human placental lactogen (placental hormones) cause hyperplasia of the pancreatic beta cells
Mechanism of regulation is not known defined
Insulin levels are higher in both fasting and postprandial states
Fasting glucose concentrations are 10 to 20% lower Increased storage of tissue glycogen
Increased peripheral glucose utilization
Decreased hepatic glucose production
Glucose consumption by the fetus (especially in late pregnancy)
Metabolic Adaptations and Pregnancy
Development of insulin resistance:
Primarily influenced by placental hormones
Affects glucose and lipid metabolism to ensure adequate supply of nutrients for the fetus
Results in a switch from carbohydrate to fat utilization which is facilitated by insulin resistance and increased concentrations of lipolytic hormones
40-60% reduction in insulin-mediated ‘glucose-disposal’
Metabolic Adaptations and Pregnancy
Important in late pregnancy:
highest rate of fetal growth and highest nutrient demand
Placenta readily transfer glucose, amino acids, and ketones bodies to the fetus, but is impermeable to large lipids
Placenta affects maternal-fetal fuel by:
Placental hormones alter maternal carbohydrate and lipid metabolism
Control trans-placental passage of glucose, fat, and protein
Metabolic Adaption and Pregnancy
Skeletal muscle is the principle site for whole-body glucose disposal, along with adipose tissue
These become severely insulin resistant during the later half of pregnancy
Metabolic Adaption and Pregnancy
In normal pregnancy:
50% decrease in the insulin-mediated glucose disposal
200-250% increase in the insulin secretion to maintain euglycemia in the mother
Placental hormones are believed to be the major factor in reprogramming the mother to achieve the insulin resistant state
However, TNF-alpha and the placental hormones do not directly correlate with insulin resistance; ?obesity or other pregnancy related factors
Underlying Mechanism of Insulin Resistance
Friedman et al. (1999) Diabetes
Obtained muscle from obese GDM women during elective c-section and compared to obese non-GDM women
Showed at 40% reduction in insulin-stimulated glucose transport during pregnancy
65% reduction between GDM and non-GDM women
GLUT4 transporter numbers were comparable
Upon insulin binding to insulin receptors, there was significantly less maximal tyrosine phosphorylation of the IR in GDM patients
Suggested that GDM patients carry an intrinsic defect or impairment in insulin receptor tyrosine phosphorylation
Metabolic Adaptations and Pregnancy
Important differences from non-pregnant states:
Transient maternal hyperglycemia after meals due to insulin resistance
Transient hypoglycemia between meals and at night due to continuous fetal draw
Why does this happen?
Allows preferential use of fat for fuel
Preserve much of the available glucose for fetus
Minimizes protein catabolism
Summary of in Normal Pregnancy
Early pregnancy, pancreatic beta cell hyperplasia to increase insulin production; insulin sensitivity unchanged
Human placental lactogen, prolactin, GH, cortisol all contribute to increased insulin resistance
Normal pregnancy – increased insulin production to compensate
Failure to Adapt
Gestational diabetes mellitus occurs when a woman’s pancreatic function is not sufficient to overcome the insulin resistance
This leads to hyperglycemia throughout pregnancy and can have consequences for the fetus
Insulin resistance complicates pregnancies in women who have T1DM or T2DM due to changing insulin
Back to the Case…
She asks, what are the blood glucose targets I am looking for?
CDA 2013 Treatment Guidelines
Women with GDM should have 2 weeks of nutritional therapy/lifestyle management, if unable to meet targets, then, insulin therapy should be initiated:
Targets:
Fasting under 5.3
1 hour blood glucose under 7.8
2 hours blood glucose under 6.7
71 = 3.9 122 = 6.8
109 =6.1 110 = 6.1
99 = 5.5
88 = 4.8
HAPO Study
Largest prospective study of glycemia in pregnancy:
23,316 women, 15 centers, 9 countries
Mean fasting glucose of 4.5 +/- 0.4 mmol/L from 23 316 pregnant women
Case
She asks how will her diabetes be treated?
Treatment Options
Diet/lifestyle
Insulin
?Oral agents
Attractive because relatively inexpensive, easier administration and better acceptance
Insulin Safety
insulin is thought not to cross the placental barrier because of its large molecular size
Beef and pork insulin have been shown to cross the placenta leading to fetal macrosomia despite excellent glycemic control
Concern that insulin analogs could cross placenta and have unknown consequences teratogenicity and immunogenicity due to alternation in IGF-1 receptor affinity
Placental Transfers
Lispro does not cross placenta except at very high dose (>50 units)
No evidence about aspart transfer
Glargine does not cross placenta (except at very high doses)
No studies looking at determir transfer
Objective: to assess the safety of four insulins (aspart, lispro, glargine, and detemir) for the treatment of diabetes in pregnancy
Systematic review and meta-analysis
24 studies, 6 RCTs
Included a total of 3734 subjects
Safety of Lispro
9 studies; 1561 women (both GDM and pre-GDM)
Safety of Lispro
Hod et al: 2008 Am J Obstet Gynecol
322 women with type 1 diabetes; RCT
Objective: compared lispro with human insulin
Results:
Trend towards reduced major hypoglycemia
Improved postprandial glucose
Perinatal outcomes were similar; but study underpowered
Safety of Aspart
6 RCTs, involved 1143 women (both GDM and pre-GDM)
No increased risk of macrosomia, no difference between c-section rate
Safety of Glargine
8 studies; 702 women (both GDM and pre-GDM)
No difference between NPH/regular and glargine for maternal and fetal outcomes
Safety of Detemir
Two studies; one RCT and one case-control
326 women
No increased risk of large gestation for age, neonatal hypoglycemia
Case
She returns after 3 weeks of being in insulin NPH 8 units at bedtime, and lispro 5 units with each meal.
She has concerns about her sugars being too low,
What is the risk of hypoglycemia?
Hypoglycemia
Early pregnancy has associated nausea and vomiting
Highest risk of hypoglycemia
Insulin resistance typically occurs by 2nd trimester
Maternal Hypoglycemia in T1DM
ter Braak et al 2002. Diabetes/Metabolism Research and Reviews
Systematic Review
Examined consequences of severe hypoglycemia for mother and fetus
Animal studies indicate that hypoglycemia is potentially teratogenic during organogenesis
Maternal Hypoglycemia in T1DM
Maternal Aspects
Highest rate of hypoglycemia in the first trimester
One hypoglycemic episode requiring assistance observed in 66% of pregnancies before 20 weeks
6.7 severe hypoglycemic episodes per patient per pregnancy
15x higher than the intervention group in DCCT
No relationship between HbA1c and proneness to severe hypo
Maternal Hypoglycemia in T1DM
Maternal Aspects
Use of MDI improves glycemic control without increased hypoglycemic episodes (seen in the DCCT trial when women were switched from conventional to intervention treatment for pre-conception)
No clear advantage of CSII over MDI during pregnancy
Hypo-unawareness in Pregnancy
Hormone Changes
Nausea and vomiting are common fluctuations in carbohydrate ingestion
Some report of increase insulin sensitivity during the first trimester, leading to hypoglycemia
Oral contraceptives may cause some relative insulin resistance; may related to periconceptional proneness for hypoglycemia
Possible decreased response catecholamines, GH, and endogenous glucose production
Epinephrine response during clamped hypoglycemia were lower than in non-DM non-pregnant women
In women with DM, epinephrine responses were reduced compared to health women, and their responses during pregnancy were lower during than after pregnancy
Hypo-unawareness in Pregnancy
Tight glycemic control and hypoglycemia result in impairment of glucose counterregulation
In pregnancy, the repeated exposure to low BG levels most likely explains at least in part why there is increased risk of severe hypoglycemia in pregnancy
Maternal Hypoglycemia in T1DM
Fetal Consequences
Limited documentation/studies
Thought that between 4.5-6 weeks gestations in most vulnerable
Data from 1964, Impastato et al. treated pregnancy women with insulin coma therapy (similar to ECT), produce daily coma
19 non-diabetic females during 5 hours in early gestations
6 pregnancies had negative fetal consequences
6 of these the hypoglycemia had been induced before 10 weeks
Case
She is approaching her 37 week of pregnancy. She has been taking NPH 15 units at bedtime, and 6 units at meals.
She has been having lows on this regimen, and has reduced her insulin to 7 units of NPH, and only 3 units at meals.
What is the possible meaning for this decrease?
Decreasing Insulin Requirements?
Typically related to:
Placental insufficiency
Indicates a need for closer observation/delivery of fetus
Decreasing Insulin Requirements?
In contrast, in type 1 diabetes a decline in insulin requirements may be seen in the late first trimester
Studied in the DIEP study
Appears to be related to a transient increase in insulin sensitivity in the latter half of the 1st trimester
Case
With the change in her requirements, she ended up being induced. She had no complications with her delivery.
She is now off insulin, and being seen 6 weeks postpartum.
She asks how to prevent gestational diabetes in her next pregnancy?
Prevention of GDM
Cochrane Review 2015
To assess the effect of combined diet and exercise interventions for preventing GDM and associated adverse health consequences for women and their babies
13 RCTs (4983 women and their babies); significant heterogeneity
No clear difference between women who received a combined diet and exercise intervention versus no intervention
Follow-up
Screen for persistent diabetes at 6-12 weeks post partum
Provide lifelong screening of diabetes
Suggest diet and exercise modifications
Encourage breastfeeding
Helps to prevent neonatal hypoglycemia and avoid childhood obesity
Discuss family planning
Take Home
GDM and pre-GDM are common
Increasing in prevalence
Results in higher risk of fetal and maternal consequences compared to baseline population
Insulin is safe – preferred choices are analogs due to trend to improved control
Thank you!