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!