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Chapter 36: Diabetes and Pregnancy

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Introduction
  • This chapter discusses pregnancy in both pre-existing diabetes (pregestational diabetes) as well as gestational diabetes (GDM; diabetes diagnosed in pregnancy).
  • These recommendations have been created in collaboration with the Society of Obstetricians and Gynecologists of Canada (SOGC).
Glucose Levels in Pregnancy
  • Elevated glucose levels have adverse effects on the fetus throughout pregnancy.
    • At conception and during the first trimester, hyperglycemia increases the risk of fetal malformations.

    • Later in pregnancy, it increases the risk of macrosomia and metabolic complications at birth.

    • As a result, meticulous glycemic control is required for optimal maternal and fetal outcomes.

Pregestational Diabetes (Type 1 and Type 2)
  • The term “pregestational diabetes” refers to diabetes that was present before pregnancy.
  • Recent large studies of women with pregestational diabetes continue to show higher rates of complications compared to the general population, including perinatal mortality, congenital malformations, hypertension, preterm delivery, large-for-gestational-age (LGA) infants, caesarean delivery and neonatal morbidities.
Preconception care
  • Preconception care for women with pregestational diabetes is associated with better outcomes; however, <50% of women receive such care. Some studies have shown that women with type 2 diabetes are less likely to receive preconception care.
  • Women who are heavier, younger and smokers, and who have a lower socioeconomic status, lower health literacy and a poor relationship with their healthcare provider, are also less likely to receive preconception care.
  • Higher glycated hemoglobin (A1C) levels are associated with poorer outcomes, but maternal obesity may increase the risk of complications, even for women who achieve tight glycemic control (A1C <7.0%).
  • Before attempting to become pregnant, women with type 1 or type 2 diabetes should receive preconception counseling that includes optimal diabetes management and nutrition, preferably in consultation with an interdisciplinary pregnancy team to optimize maternal and neonatal outcomes [Grade C, Level 3].
  • All women of reproductive age with type 1 or type 2 diabetes should receive advice on reliable birth control, the importance of glycemic control prior to pregnancy, the impact of BMI on pregnancy outcomes, the need for folic acid and the need to stop potentially embryopathic drugs prior to pregnancy [Grade D, Level 4].
  • Supplement their diet with multivitamins containing 5 mg folic acid at least 3 months preconception and continuing until at least 12 weeks postconception [Grade D, Level 4]. Supplementation should continue with a multivitamin containing 0.4–1.0 mg folic acid from 12 weeks postconception to 6 weeks postpartum or as long as breastfeeding continues [Grade D, Consensus].
  • Women with type 2 diabetes and irregular menses/PCOS who are started on metformin or a thiazolidinedione should be advised that fertility may improve and be warned about possible pregnancy [Grade D, Consensus].
Assessment and management of complications
  • Women with pre-existing vascular complications are more likely to have poor pregnancy outcomes, and there may be progression in the degree of vascular damage.

Retinopathy

  • Women should undergo an ophthalmological evaluation by an eye care specialist [Grade A, Level 1, for type 1 diabetes; Grade D, Level 4, for type 2 diabetes].
  • The risk of progression of retinopathy is increased with poor glycemic control during pregnancy, and such progression may occur up to 1 year postpartum.
  • Additional risk factors for retinopathy progression include chronic and pregnancy-induced hypertension, preeclampsia and more severe pre-existing retinopathy.
  • Laser photocoagulation for severe nonproliferative or proliferative retinopathy prior to pregnancy reduces the risk of visual impairment in pregnancy.
  • Pregnancy does not affect the long-term outcome of mild-to-moderate retinopathy.

Hypertension

  • The incidence of hypertension complicating pregnancy is 40% to 45% in women with type 1 and 2 diabetes.
  • Type 1 diabetes is more often associated with preeclampsia and type 2 diabetes with chronic hypertension.
  • A number of antihypertensive medications are known to be safe and effective in pregnancy, including calcium channel blockers, labetalol and methyldopa.

Chronic kidney disease

  • Women should be screened for chronic kidney disease prior to pregnancy (see Chronic Kidney Disease chapter, p. S129) [Grade D, Level 4, for type 1 diabetes; Grade D, Consensus, for type 2 diabetes]. Women with microalbuminuria or overt nephropathy are at increased risk for development of hypertension and preeclampsia [Grade A, Level 1] and should be followed closely for these conditions [Grade D, Consensus].
  • Microalbuminuria and overt nephropathy are associated with increased risk of maternal and fetal complications.
  • An estimated glomerular filtration rate (eGFR) should be used prior to pregnancy to determine risk. However, during pregnancy, serum creatinine and not eGFR should be used, as eGFR will underestimate GFR in pregnancy. A random albumin to creatinine ratio and serum creatinine should be measured each trimester.
  • Before attempting to become pregnant, women with type 1 or type 2 diabetes should discontinue medications that are potentially embryopathic, including any from the following classes:
    • ACE inhibitors and ARBs prior to conception or upon detection of pregnancy [Grade C, Level 3]
    • Statins [Grade D, Level 4]
  • Women with type 2 diabetes who are planning a pregnancy should switch from noninsulin antihyperglycemic agents to insulin for glycemic control [Grade D, Consensus].

Cardiovascular disease

  • Although rare, cardiovascular disease (CVD) can occur in women of reproductive age with diabetes.
  • Myocardial infarction in pregnancy is associated with poor maternal and fetal outcomes.
  • Women with known CVD should be evaluated and counseled about the significant risks associated with pregnancy.
Management
  • Care by an interdisciplinary diabetes healthcare (DHC) team composed of diabetes nurse educators, dietitians, obstetricians and diabetologists both prior to conception and during pregnancy, has been shown to minimize maternal and fetal risks in women with diabetes, as well as to optimize care and discuss the need for social support.

Glycemic control

  • Before attempting to become pregnant, women with type 1 or type 2 diabetes should strive to attain a preconception A1C ≤7.0% (or A1C as close to normal as can safely be achieved) to decrease the risk of:
    • Spontaneous abortion [Grade C, Level 3]
    • Congenital anomalies [Grade C, Level 3]
    • Preeclampsia [Grade C, Level 3]
    • Progression of retinopathy in pregnancy [Grade A, Level 1, for type 1 diabetes; Grade D, Consensus, for type 2 diabetes].
  • Pregnant women with type 1 or type 2 diabetes should:
    • Strive for target glucose values:
      • Fasting PG <5.3 mmol/L
      • 1-hour postprandial <7.8 mmol/L
      • 2-hour postprandial <6.7 mmol/L [Grade D, Consensus]
    • Be prepared to raise these targets if needed because of the increased risk of severe hypoglycemia during pregnancy [Grade D, Consensus]
      • Maternal hypoglycemia does not increase the risk of congenital malformations in the offspring or other adverse outcomes, although repeated hypoglycemia and associated loss of glycemic control were associated with macrosomia.
Monitoring
  • Pregnant women with type 1 or type 2 diabetes should perform SMBG, both pre- and postprandially, to achieve glycemic targets and improve pregnancy outcomes [Grade C, Level 3].
  • Frequent self-monitoring of blood glucose (SMBG) in pregnant women with type 1 diabetes is essential during pregnancy in order to obtain the level of glycemic control associated with better outcomes.
  • Preprandial determinations, which are needed to guide the meal-time insulin dose adjustment and, postprandial testing to achieve targets are associated with less macrosomia and preeclampsia.
  • Due to the increased risk of nocturnal hypoglycemia with any intensive insulin therapy, glucose monitoring during the night is often necessary in patients receiving insulin.
  • Monitoring glucose 4 to 7 times per day is also needed in managing type 2 diabetes (i.e. fasting, preprandially and 1 or 2 hours postprandially to achieve good glycemic control).
Pharmacological therapy

Insulin

  • Intensive insulin therapy with basal-bolus therapy or continuous subcutaneous insulin infusion (CSII or the insulin pump) is recommended to achieve glycemic targets prior to pregnancy.
  • Women using CSII should be educated about the increased risk of diabetic ketoacidosis (DKA) in the event of insulin pump failure because DKA is a potentially fatal complication for the fetus.
  • Pregnant women with type 1 or type 2 diabetes should:
    • Receive an individualized insulin regimen and glycemic targets typically using intensive insulin therapy [Grade A, Level 1B, for type 1; Grade A, Level 1, for type 2].
  • Women with pregestational diabetes may use aspart or lispro in pregnancy instead of regular insulin to improve glycemic control and reduce hypoglycemia [Grade C, Level 2, for aspart; Grade C, Level 3, for lispro].
    • Rapid-acting bolus analogues (e.g. aspart, lispro) appear safe for use in pregnancy and show some improvement in postprandial glycemia with reduced hypoglycemia.
    • Lispro does not cross the placenta except at very high doses (>50 units). There is currently no evidence regarding placental transfer of aspart.
  • Detemir [Grade C, Level 2] or glargine [Grade C, Level 3] may be used in women with pregestational diabetes as an alternative to NPH.
    • Glargine does not cross the placenta except at very high doses.
    • There have been no studies looking at detemir placental transfer, but it appears safe in pregnancy.  

CSII

  • Studies have not demonstrated the superiority of CSII over basal-bolus regimen, and, in some studies, there have been more adverse outcomes with CSII.

Oral antihyperglycemic agents and type 2 diabetes

  • A meta-analysis of first-trimester use of either glyburide or metformin and 1 meta-analysis of metformin alone did not show an increased incidence of congenital anomalies. Therefore, women with type 2 diabetes who find themselves on metformin or glyburide when they conceive should continue these agents until insulin is started.
  • In the meantime, the use of oral agents is not recommended for glycemic control in women with type 2 diabetes during pregnancy.

Metformin and polycystic ovary syndrome

  • Higher-level evidence has not shown metformin to be of benefit in women with PCOS in pregnancy.
  • The evidence, therefore, does not support the practice of continuing metformin after conception in women with PCOS and normal glucose tolerance.
  • Women with pregestational diabetes who also have PCOS may continue metformin for ovulation induction [Grade D, Consensus].

Postpartum

  • Women with pregestational diabetes should be carefully monitored postpartum as they have a high risk of hypoglycemia [Grade D, Consensus].
  • Women with type 1 diabetes in pregnancy should be screened for postpartum thyroiditis with a TSH test at 6–8 weeks postpartum [Grade D, Consensus].
  • All women should be encouraged to breastfeed since this may reduce offspring obesity, especially in the setting of maternal obesity [Grade C, Level 3].
  • Metformin and glyburide may be used during breastfeeding [Grade C, Level 3 for metformin; Grade D, Level 4, for glyburide], although further long-term studies are needed to better clarify the safety of these drugs.
  • There are no studies to date looking at thiazolidinedione use, glucagon-like peptide-1 agonist or dipeptidyl peptidase-4 (DPP-4) inhibitor use while breastfeeding; therefore, they should not be taken during breastfeeding.
GDM
Screening and diagnosis

Background

  • Up until the publication of the 2 large-scale RCTs, the benefit of treatment of varying degrees of hyperglycemia in pregnancy was unclear. The results of these 2 trials, despite some methodological differences, show a benefit to treatment over no treatment of diagnosed GDM with regard to select perinatal outcomes. These findings support the need for a screening strategy for GDM, a largely asymptomatic condition, as there appears to be a beneficial intervention for patients with the disease.

TABLE 1

Is there a need to screen for GDM?

  • The utility of screening will vary based on the baseline characteristics of the screened population and the country-specific health economics evaluation. Since there is data confirming that the incidence of adverse perinatal outcomes increases as glucose intolerance increases, the identification of women with hyperglycemia in pregnancy has clinical significance.

What is the optimal method of screening?

  • All pregnant women should be screened for GDM at 24–28 weeks of gestation [Grade C, Level 3].
  • The preferred approach for the screening and diagnosis of GDM is the following [Grade D, Consensus]:
    • Screening for GDM should be conducted using the 50 g GCT administered in the nonfasting state with PG glucose measured 1 hour later [Grade D, Level 4]. PG ≥7.8 mmol/L at 1 hour will be considered a positive screen and will be an indication to proceed to the 75 g OGTT [Grade C, Level 2]. PG ≥11.1 mmol/L can be considered diagnostic of gestational diabetes and does not require a 75 g OGTT for confirmation [Grade C, Level 3].
    • If the GCT screen is positive, a 75 g OGTT should be performed as the diagnostic test for GDM using the following criteria:
      •  ≥1 of the following values:
        • Fasting ≥5.3 mmol/L
        • 1 hour ≥10.6 mmol/L
        • 2 hours ≥9.0 mmol/L [Grade B, Level 1]

FIGURE 1

One-step approach

  • An alternative approach that may be used to screen and diagnose GDM is the 1-step approach [Grade D, Consensus]:
    • A 75 g OGTT should be performed (with no prior screening 50 g GCT) as the diagnostic test for GDM using the following criteria [Grade D, Consensus]:
      • ≥1 of the following values:
        • Fasting ≥5.1 mmol/L
        • 1 hour ≥10.0 mmol/L
        • 2 hours ≥8.5 mmol/L [Grade B, Level 1].

FIGURE 2
What should be the diagnostic threshold for GDM?

  • GDM has classically been in the unusual situation of having no true “gold standard” for its diagnosis. Thus, all of the recent diagnostic thresholds for GDM have been determined by consensus agreement of various national and international professional organizations.

TABLE 2

2013 CDA diagnostic criteria for GDM

  • The  2013 CDA expert committee acknowledges has chosen the preferred approach of sequential screening with a 50 g GCT followed by a 75 g OGTT using the glucose thresholds that result in an OR of 2.00 (fasting ≥5.3 mmol/L, 1 hour ≥10.6 mmol/L, 2 hours ≥9.0 mmol/L).
  • However, it is recognized that the IADPSG consensus group selected a different approach. Therefore, an alternative approach would be 1-step 75 g OGTT using the glucose thresholds that result in an OR of 1.75 (IADPSG recommended criteria).
Management

Lifestyle

  • Women with GDM should receive nutrition counselling from a registered dietitian during pregnancy [Grade C, Level 3] and postpartum [Grade D, Consensus]. Recommendations for weight gain during pregnancy should be based on pregravid BMI [Grade D, Consensus].
  • Meal planning should emphasize moderate carbohydrate restriction and distribution over 3 meals and 3 snacks, one of which should be at bedtime.
  • Hypocaloric diets are not recommended, as they result in weight loss and significant ketosis and are likely inadequate in required nutrients, such as protein and calcium.
  • Prepregnancy body mass is a potent predictor of birth weight and should be considered when making recommendations about energy intake and rate of weight gain.
  • Physical activity should be encouraged unless obstetrical contraindications exist or glycemic control is worsened by the activity.

Glycemic control

  • Women with GDM should:
    • Strive for target glucose values:
      • Fasting PG <5.3 mmol/L [Grade B, Level 2]
      • 1-hour postprandial <7.8 mmol/L [Grade B, Level 2]
      • 2-hour postprandial <6.7 mmol/L [Grade B, Level 2]
    • Perform SMBG, both fasting and postprandially, to achieve glycemic targets and improve pregnancy outcomes [Grade B, Level 2].
  • Avoid ketosis during pregnancy [Grade C, Level 3].

Monitoring

  • Frequent SMBG is essential to guide therapy of GDM. Both fasting and postprandial testing are recommended to guide therapy in order to achieve glycemic targets.
  • Studies support the use of a 1-hour postprandial target, typically 7.8 mmol/L or a 2-hour postprandial target, typically 6.7 mmol/L.
  • Continuous glucose monitoring systems have been useful in picking up previously undetected hyperglycemia, but it is unproven if they are cost effective.
  • Women with GDM, in an effort to control their glucose by diet, may put themselves and their baby at risk for starvation ketosis. It appears prudent to check that urine ketones are negative when focusing on diet therapy for GDM.
Pharmacological therapy

Insulin

  • If women with GDM do not achieve glycemic targets within 2 weeks from nutritional therapy alone, insulin therapy should be initiated [Grade D, Consensus].
  • The use of insulin to achieve glycemic targets has been shown to reduce fetal and maternal morbidity.
  • Insulin therapy in the form of multiple injections should be used [Grade A, Level 1 ].
  • Insulin usually needs to be continuously adjusted to achieve glycemic targets. Rapid-acting bolus analogue insulin may be used over regular insulin for postprandial glucose control, although perinatal outcomes are similar [Grade B, Level 2].
  • A recent analysis reveals that glargine is safe in pregnancy and can be considered an option for pregnant patients. A recent Canadian review of rapid and long-acting basal analogues in GDM for glycemic control and hypoglycemia did not shown superiority.

Oral antihyperglycemic agents

  • For women who are nonadherent to or who refuse insulin, glyburide [Grade B, Level 2] or metformin [Grade B, Level 2] may be used as alternative agents for glycemic control. Use of oral agents in pregnancy is off-label and should be discussed with the patient [Grade D, Consensus].
    • Glyburide is safe and effective in controlling glucose levels in >80% of patients with GDM and does not cross the placenta.
    • Women who are older, are diagnosed earlier than 25 weeks and have higher fasting and postprandial glucose values on their OGTT are less likely to respond to glyburide.
    • While metformin appears to be a safe alternative to insulin therapy with less neonatal hypoglycemia, it does cross the placenta, plus metformin clearance is increased in pregnancy.
Intrapartum glucose management
  • The primary goal of intrapartum management is to prevent neonatal hypoglycemia, which is thought to occur from the fetal hyperinsulinism caused by maternal hyperglycemia.

Neonatal hypoglycemia

  • The Canadian and American Pediatric Associations suggest that plasma glucose <2.6 mmol/L can result in adverse outcomes and, therefore, should be treated in symptomatic infants.
  • Mild neonatal hypoglycemia has been found to be associated with transient abnormalities on physical examination, neurophysiological testing and brain imaging.
  • Longer term follow-up found that infants with neonatal hypoglycemia had increased rates of neurological abnormalities at 18 months and 8 years of age.

Risk of neonatal hypoglycemia is related to maternal glucose levels

  • Maternal hyperglycemia during labour, even when produced for a few hours by intravenous fluids in mothers without diabetes, can cause neonatal hypoglycemia.
  • Women should be closely monitored during labour and delivery, and maternal blood glucose levels should be kept between 4.0 and 7.0 mmol/L in order to minimize the risk of neonatal hypoglycemia [Grade D, Consensus].
  • Some authors advocate less stringent targets as being able to prevent neonatal hypoglycemia if the maternal glucose is kept 4.0 to 8.0 mmol/L.

Intrapartum insulin management

  • Insulin requirements decrease intrapartum, and some patients with type 1 diabetes even do not require exogenous insulin to maintain good glucose control during labour.
  • Women should receive adequate glucose during labour in order to meet their high-energy requirements [Grade D, Consensus].
  • Given the lack of studies, there are no specific protocols that can be recommended to achieve the desired maternal glucose levels during labour.
Postpartum

Breastfeeding

  • Women with GDM should be encouraged to breastfeed immediately after delivery in order to avoid neonatal hypoglycemia [Grade D, Level 4] and to continue for at least 3 months postpartum in order to prevent childhood obesity [Grade C, Level 3] and reduce risk of maternal hyperglycemia [Grade C, Level 3].

Long-term maternal risks

  • With the diagnosis of GDM, there is evidence of impairment of both insulin secretion and action. These defects persist postpartum and increase the risk of impaired fasting glucose, IGT and type 2 diabetes.
  • While elevated FPG during pregnancy and A1C at diagnosis of GDM are strong predictors of early development of diabetes, other predictors include age at diagnosis, use of insulin, especially bedtime insulin or oral agents, and more than 2 pregnancies.
  • Postpartum testing is essential to identify women who continue to have diabetes, those who developed diabetes after temporary normalization and those at risk, including those with IGT. However, many women do not receive adequate postpartum follow-up, and many believe they are not at high risk for diabetes. Only 50% return for postpartum testing. It is essential that the importance of follow-up be explicitly communicated with women and their caregivers who are responsible for postpartum testing.
  • Women should be screened with a 75 g OGTT between 6 weeks and 6 months postpartum to detect prediabetes and diabetes [Grade D, Consensus].

Long-term fetal risks

  • The great majority of studies continue to show an increased risk of obesity and metabolic abnormalities in childhood extending into adolescence and early adulthood for individuals born to mothers who had diabetes during pregnancy.
  • In a detailed study, Chandler-Laney et al were able to show that the relationship between maternal glucose and childhood obesity was independent of a child’s resting energy expenditure, time spent physically active and energy intake.
  • Studies also have found that adequate breastfeeding is associated with a significant decrease in the risk of childhood obesity.
Planning future pregnancies
  • Women with previous GDM should plan future pregnancies in consultation with their healthcare providers.
  • Glucose tolerance should be assessed prior to conception to assure normoglycemia at the time of conception, and any glucose abnormality should be treated.
  • In an effort to reduce the risk of congenital anomalies and optimize pregnancy outcomes, all women should take a folic acid supplement of 0.4 to 1.0 mg.


For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on this topic, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 36.