Diabetes and Pregnancy

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

David Thompson MD, FRCPC Howard Berger MD Denice Feig MD, MSc, FRCPC Robert Gagnon MD, FRCSC Tina Kader MD, FRCPC Erin Keely MD, FRCPC Sharon Kozak BSN Edmond Ryan MD, FRCPC Mathew Sermer MD, FRCSC Christina Vinokuroff PDt

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

Pregestational Diabetes

  • All women with pre-existing type 1 or type 2 diabetes should receive preconception care to optimize glycemic control, assess complications, review medications and begin folate supplementation.
  • Care by an interdisciplinary diabetes healthcare 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 pre-existing type 1 or type 2 diabetes.

Gestational Diabetes Mellitus

  • The diagnostic criteria for gestational diabetes mellitus (GDM) remain controversial; however, the committee has chosen a preferred approach and an alternate approach. The preferred approach is to begin with a 50 g glucose challenge test and, if appropriate, proceed with a 75 g oral glucose tolerance test, making the diagnosis of GDM if ≥1 value is abnormal (fasting ≥5.3 mmol/L, 1 hour ≥10.6 mmol/L, 2 hours ≥9.0 mmol/L). The alternate approach is a 1-step approach of a 75 g oral glucose tolerance test, making the diagnosis of GDM if ≥1 value is abnormal (fasting ≥5.1 mmol/L, 1 hour ≥10.0 mmol/L, 2 hours ≥8.5 mmol/L).
  • Untreated GDM leads to increased maternal and perinatal morbidity, while treatment is associated with outcomes similar to control populations.

Introduction

This chapter discusses pregnancy in both pre-existing diabetes (pregestational diabetes) as well as gestational diabetes (GDM; diabetes diagnosed in pregnancy). Some of the management principles are common to both types of diabetes. These recommendations have been created in collaboration with the Society of Obstetricians and Gynaecologists 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 (1,2). As a result, meticulous glycemic control is required for optimal maternal and fetal outcomes. Based on a systematic review of reports of glucose levels in non-GDM pregnancies, normal glucose levels during later pregnancy (mean and 1 SD above mean) were fasting 3.9 ± 0.4 mmol/L, 1 hour postprandial 6.1 ± 0.7 mmol/L, and 2 hours postprandial 5.5 ± 0.6 mmol/L with a mean glucose of 4.9 ± 0.6 mmol/L (3). The peak postprandial glucose occurred at 69 ± 24 minutes (3). However, it should be noted that the mean fasting glucose derived from the total of 255 subjects in this report was 0.6 mmol/L lower than that reported in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (4). The HAPO study was the largest prospective study of glycemia in pregnancy and reported a mean fasting glucose of 4.5 ± 0.4 mmol/L, derived from 23 316 pregnant women (4). Finally, glucose levels in obese, nondiabetic pregnant women were slightly higher than their lean counterparts (5).

Pregestational Diabetes (Type 1 and Type 2)

The term “pregestational diabetes” refers to diabetes that was present before pregnancy. The prevalence of pregestational diabetes has increased in the past decade, primarily as a result of the increase in type 2 diabetes (6). 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 (7–9).

Preconception care

Preconception care for women with pregestational diabetes is associated with better outcomes (10,11). Although multidisciplinary clinics improve outcomes, <50% of women receive such 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 less likely to receive preconception care (11–14). Some, but not all, have shown that women with type 2 diabetes are also less likely to receive preconception care (7,15). Higher glycated hemoglobin (A1C) levels are associated with poorer outcomes, but even women who achieve tight glycemic control (A1C <7.0%) have an increased risk of complications, which may be caused, in part, by maternal obesity (16,17). By discussing pregnancy prior to conception, healthcare providers may be able to improve outcomes by educating women about the importance of strict glycemic control, encouraging folic acid supplementation, discontinuing potentially harmful medications and reducing body weight. Although there are no intervention trials to support larger doses of folic acid for women with diabetes, several factors favour recommending a larger dose. Obesity, which is more common in women with type 2 diabetes, is associated with lower serum folate levels for the same intake, lower intake of folate rich foods and increased risk of neural tube defects independent of glucose (18,19,20). Using a mathematical model, a 5 mg intake will be more effective in reducing neural tube defects in this vulnerable population (21).

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 (7).

Retinopathy
Women with type 1 (22,23) and type 2 diabetes (24) should have ophthalmological assessments before conception, during the first trimester, as needed during pregnancy and within the first year postpartum (25,26). The risk of progression of retinopathy is increased with poor glycemic control during pregnancy, and such progression may occur up to 1 year postpartum (23,25). Additional risk factors for retinopathy progression include chronic and pregnancy-induced hypertension, preeclampsia and more severe pre-existing retinopathy (22,27–29). Laser photocoagulation for severe nonproliferative or proliferative retinopathy prior to pregnancy reduces the risk of visual impairment in pregnancy (30). Pregnancy does not affect the long-term outcome of mild-to-moderate retinopathy (25).

Hypertension
The incidence of hypertension complicating pregnancy is 40% to 45% in women with type 1 and type 2 diabetes (29). Type 1 diabetes is more often associated with preeclampsia and type 2 diabetes with chronic hypertension. Other risk factors for hypertension, such as poor glycemic control in early pregnancy, are potentially modifiable. Some (31,32), but not all (33), studies have found that increased urinary protein excretion in early pregnancy raises the risk of developing hypertension. Any type of hypertension is strongly associated with adverse outcomes. A number of antihypertensive medications are known to be safe and effective in pregnancy, including calcium channel blockers, labetalol and methyldopa.

Chronic kidney disease
Prior to conception, women should be screened for chronic kidney disease. Microalbuminuria and overt nephropathy are associated with increased risk of maternal and fetal complications (34–39). An estimated glomerular filtration rate (eGFR) should be used prior to pregnancy to determine risk (40). However, during pregnancy, serum creatinine and not eGFR should be used, as eGFR will underestimate GFR in pregnancy (41,42). A random albumin to creatinine ratio and serum creatinine should be measured each trimester. Proteinuria increases during pregnancy, but, in women with a normal GFR, pregnancy has no adverse effects on long-term renal function as long as blood pressure and blood glucose are well controlled (34–37,43–45). In women with elevated serum creatinine, however, pregnancy can lead to a permanent deterioration in renal function (46).

There is conflicting information on whether first-trimester exposure to angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is associated with an increased risk of congential malformations. Some (47), but not all (48), cohort studies have demonstrated an increased risk of malformations. A meta-analysis, limited by small study size (786 exposed infants), demonstrated a significant risk ratio (relative risk [RR] 1.78, 95% confidence interval [CI] 1.07–2.94) of increased anomalies in infants exposed to first-trimester ACE inhibitors and ARBs compared to the normal population (49). However, when the group exposed to ACE inhibitor/ARB exposed was compared to a group of other antihypertensive pregnancies, there was no statistically significant difference (RR 1.41, 95% confidence interval (CI) 0.66–3.04). Thus, the increased risk of malformations may be more related to the hypertension itself rather than a direct effect of ACE inhibitors and ARBs. Fetal exposure in the second and third trimesters is clearly associated with a fetal renin-angiotensin system blockade syndrome, which includes renal failure, oligohydramnios, hypotension, intrauterine growth restriction and death (50). The decision to discontinue an ACE inhibitor or ARB prior to pregnancy should be discussed with the patient and may depend on the indication for use/availability of an effective alternative medication. Once a woman is pregnant, all ACE inhibitors and ARBs should be discontinued.

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 (51,52). Women with known CVD should be evaluated and counselled 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 (53–56). An early working relationship should be established between the woman and the DHC team to optimize care, facilitate the planning of pregnancy, ensure adequate self-care practices and discuss the need for social support during pregnancy.

Glycemic control
An important first step in achieving good glycemic control is to set target glucose levels (2,54). Older studies confirm that the lower the mean glucose the better the outcome, with some suggesting a target mean glucose <6.7 mmol/L and others a mean <6.9 mmol/L, while a fasting target <5.9 was still associated with a 29% macrosomia rate (54,57,58). A prospective study in pregnant women with type 1 diabetes showed less preeclampsia with glucose targets of fasting <5.1 mmol/L, preprandial <6.0 mmol/L and 1 hour postprandial <7.8 mmol/L (59). In the absence of specific treatment studies addressing this issue, use of the mean plus 2 SD glucose values of nondiabetic pregnant women appears appropriate giving targets of fasting <5.3 mmol/L, I hour postprandial <7.5 and 2 hours postprandial <6.7 mmol/L. Studies in GDM indicate a 1-hour postprandial target <7.8 mmol/L is associated with good outcomes (see below); thus, harmonizing the 1-hour target <7.8 mmol/L is reasonable.

The limiting factor when seeking euglycemia in women with pregestational diabetes is the increased risk of hypoglycemia during pregnancy, particularly in the first trimester (60–64). The risk of severe hypoglycemia ranged from 22% to 71%, with the likely predictors being a history of severe hypoglycemia and hypoglycemic unawareness. The latter may relate, in part, to the loss of counterregulatory hormones reported in women with pregestational diabetes during pregnancy, particularly growth hormone and epinephrine (65–68). This risk of hypoglycemia may be ameliorated if efforts are made to achieve good glycemic control preconception and by the use of analogue insulins (64,69,70). The risk of hypoglycemia is also present in pregnant women with type 2 diabetes (2). Maternal hypoglycemia does not increase the risk of congenital malformations in the offspring (53,71,72) or other adverse outcomes (2). In later pregnancy, maternal hypoglycemia was associated with a nonsignificant increase in fetal movements (73) and had no impact on fetal heart rate (74) and no long-term consequences for the infant (75), although repeated hypoglycemia and associated loss of glycemic control were associated with macrosomia (68).

Monitoring
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 (57). 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 (58,59,76). 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 (77). Continuous glucose monitoring systems may help identify periods of hyper- or hypoglycemia (78,79) and certainly confirm glycemic variability (80). Whether closed loop systems will become practical for use in pregnancy remains to be seen (81). 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 Insulin therapy must be individualized and regularly adapted to the changing needs of pregnancy (82–85). 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 (86).

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), similar to human insulin (87). There is, as yet, no evidence regarding placental transfer of aspart. Cohort studies have shown improved A1C levels and less hypoglycemia in women with pregestational diabetes in pregnancy taking lispro compared with human insulin, while fetal outcomes were similar (88–90). A randomized trial of 322 women with type 1 diabetes, randomized to insulin aspart vs. human insulin, showed a trend toward reduced episodes of major hypoglycemia, with improved postprandial glucose increments but similar overall glycemic control (91). Perinatal outcomes were similar using insulin aspart and human insulin; however, the study was not powered to show differences in these outcomes (91). Insulin antibodies were low in both groups, in both mother and baby (cord blood) (92). There are no published data on the use of glulisine in pregnancy.

Glargine does not cross the placenta except at very high doses (93). There have been no studies looking at detemir placental transfer. A recent meta-analysis of observational studies showed no adverse fetal outcomes in women taking glargine in pregnancy, while maternal outcomes were similar (94). A randomized trial of detemir use compared with NPH in women with type 1 diabetes has recently been completed, with similar maternal and fetal outcomes in both groups (95). Detemir appears safe in pregnancy. Data on glargine are more limited (cohort and case control studies), and theoretical considerations make it less desirable; however, no adverse maternal or fetal effects have been found to date.

CSII While use of CSII may be preferred by some women with type 1 diabetes, studies have not demonstrated superiority over basal-bolus regimen (89,96–99), and, in some studies, there have been more adverse outcomes with CSII (89,99).

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 (100,101). Therefore, women with type 2 diabetes who find themselves on metformin or glyburide when they conceive should continue these agents until insulin is started. One cohort study of women with type 2 diabetes found an increase in perinatal mortality in women taking metformin compared with insulin; however, the circumstances surrounding these deaths suggest other confounding factors played a role (102). In another cohort study, there was an increase in perinatal mortality in women taking sulphonylureas, or sulphonylureas plus metformin compared to insulin, but not in those taking metformin alone (103). The reason for this is not known. Currently, a large randomized trial is underway to see if adding metformin to insulin will benefit mothers with type 2 diabetes and their infants (MiTy trial). 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 Considerable research has been done on the use of metformin in women with polycystic ovary syndrome (PCOS) around the time of conception and during pregnancy. A number of these studies have evaluated metformin for use in ovulation induction and infertility in this population; however, there are conflicting data regarding the benefits of metformin use in this population. Several observational studies have suggested that metformin may decrease the rate of spontaneous abortions in women with PCOS, prompting many to advocate the use of metformin up to the end of the first trimester or throughout pregnancy in these women (104,105). However, in a meta-analysis of 17 randomized controlled trials (RCTs), metformin use, either alone or with other fertility drugs, had no significant effect on the abortion risk when used preconception (106). In each of the trials in this meta-analysis, metformin was discontinued at the time of diagnosis of pregnancy. Other nonrandomized studies have noted benefit in women who used metformin throughout pregnancy (107). Further data are needed to clarify this issue. A recent Cochrane review of randomized trials found that although metformin was effective in improving ovulation rates and pregnancy rates in women with PCOS, both alone and in combination with clomiphene, this did not translate into a significant increase in live births (108). The reason for this is not known. Metformin also has been associated with improvement in other pregnancy outcomes, including prevention of GDM, in observational studies (109). However, in a recent, randomized, placebo-controlled trial of metformin treatment started in the first trimester of pregnancy in women with PCOS, metformin failed to reduce the rates of preeclampsia, GDM, preterm delivery or a composite of the 3 outcomes (110). Only 1 study to date has looked at longer-term outcomes in women with PCOS taking metformin in pregnancy. This small study found no increase in the rate of abnormal growth and motor development in infants at 18 months of age (111).

In summary, 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. However, the considerable data available help to confirm the safety of metformin given during pregnancy.

Postpartum
Few studies have examined breastfeeding and the use of oral agents. Three case series found metformin in the milk and plasma of breastfeeding women who were taking metformin 500 mg bid or tid, but infant exposure was well below the 10% “level of concern” (0.182% to 0.65%) (112–114). A study looking at weight, height and motor-social development up to 6 months of age in children of mothers taking metformin while breastfeeding showed normal development and no difference from formula-fed infants (111). One of the case series that looked at women taking glyburide or glipizide while breastfeeding found neither drug in the breast milk, and the maximum theoretical infant dose again was well below 10% (<1.5%), with no hypoglycemia found in the 3 infants tested (115). 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. In conclusion, metformin and glyburide can be considered for use during breastfeeding, although further long-term studies are needed to better clarify the safety of these drugs.

GDM

Screening and diagnosis

Background
In order to justify mass screening for a medical disorder, a set of criteria needs to be met (Table 1). For GDM, screening programs became widespread despite not meeting many of these traditional criteria and, thus, have led to numerous debates regarding the utility and methodology of GDM screening (116,117). Recent studies and the publication of new guidelines by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) consensus panel have given us the opportunity to revisit the evidence on screening for GDM (118).

Table 1
Criteria for mass screening
 
  1. The condition sought should be a health problem for the individual and community.
  2. There should be an accepted treatment or useful intervention for patients with the disease.
  3. The natural history of the disease should be adequately understood.
  4. There should be a latent or early symptomatic stage.
  5. There should be a suitable and acceptable screening test or examination.
  6. Facilities for diagnosis and treatment should be available.
  7. There should be an agreed policy on whom to treat as patients.
  8. Treatment started at an early stage should be of more benefit than treatment started later.
  9. The cost should be economically balanced in relation to possible expenditure on medical care as a whole.
  10. Case finding should be a continuing process and not a once and for all project.

Up until the publication of the 2 large-scale RCTs, the benefit of treatment of varying degrees of hyperglycemia in pregnancy was unclear (119,120). 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. Worldwide, there is currently no agreement regarding the optimal screening strategy for GDM. Universal and selective (risk factor based) screening are the most common methods used, but only 1 randomized trial has compared these 2 strategies (121). The most common method of screening is with the stepwise 50 g oral glucose challenge test (OGCT) at 24 to 28 weeks of gestation, followed by an oral glucose tolerance test (OGTT) as the diagnostic test if a certain threshold has been surpassed. The diagnostic test is either the 75 g OGTT or the 100 g OGTT, and for each of these tests different thresholds are recommended by different professional organizations (122–125) (see Table 2 ).

The HAPO study, published in 2008, was a prospective observational study designed to determine if hyperglycemia during pregnancy was associated with an increased risk of maternal or fetal complications, and whether a diagnostic threshold value based on adverse perinatal outcomes could be calculated (4). This large study (n=23 316) confirmed the findings from 2 previous large-scale, prospective, observational studies (126,127) that the incidence of select adverse maternal and fetal outcomes increases along a continuum of increasing maternal hyperglycemia. Unfortunately, no outcome-associated glycemic thresholds were identified that could be used to define internationally accepted criteria for the diagnosis of GDM. Despite this, in 2010, the IADPSG consensus panel decided to use the HAPO data to create new diagnostic thresholds for GDM. These recommendations are summarized in Table 2. The thresholds for the 75 g OGTT used were calculated by defining glucose concentrations at which the odds ratio of the 4 HAPO primary outcomes (birthweight >90%, primary caesarean section rate, neonatal hypoglycemia and cord C-peptide levels >90%) reached 1.75. These arbitrary thresholds, when applied to the HAPO cohort, led to a GDM incidence of 17.8%.

Obviously, adopting these recommendations in Canada will profoundly impact the healthcare system, healthcare providers and our pregnant patients. We will address the issue of whether to change the Canadian Diabetes Association (CDA) guidelines by answering the following questions:

  • Is there a need to screen for GDM?
  • What is the optimal method of screening?
  • What should the diagnostic threshold for GDM be?

Is there a need to screen for GDM?
In two large RCTs comparing treatment vs. nontreatment of pregnant women with glucose intolerance that did not meet the criteria for overt diabetes, the incidence of select adverse perinatal outcomes was lower in the treatment group (119,120). In the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) study (119), there was a reduction in the composite outcome of severe perinatal complications (death, shoulder dystocia, bone fracture, nerve palsy; adjusted RR 0.33, 95% CI 0.14 to 0.75), while in the National Institute of Child Health and Human Development (NICHD) study (120), there was no reduction in the composite primary outcome (perinatal mortality, birth trauma and neonatal hypoglycemia, hyperbilirubinemia, or hyperinsulinemia), but reductions were found in fetal overgrowth, shoulder dystocia, caesarean delivery and preeclampsia. One cannot directly infer from these studies that there is utility to screening for GDM as they were not designed to assess screening vs. nonscreening. The utility of screening will vary based on the baseline characteristics of the screened population and the country-specific health economics evaluation. We can, therefore, infer from the results of these management studies, along with the data confirming that the incidence of adverse perinatal outcomes increases as glucose intolerance increases, that identification of women with hyperglycemia in pregnancy has clinical significance. As hyperglycemia in pregnancy is an asymptomatic condition, diagnosis is dependent on some form of screening. Until a large-scale, randomized trial of screening vs. nonscreening for hyperglycemia in pregnancy is performed, the recommendation to perform screening for GDM will remain in place.

Table 2
Screening and diagnosis guidelines from different associations
GCT, Glucose challenge test; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test.
Glycosuria, age >30 years, obesity, family history of diabetes, past history of GDM or glucose intolerance, previous adverse pregnancy outcome and belonging to a high-risk ethnic group.
Body mass index >30 kg/m2, previous macrosomic baby weighing ≥4.5 kg, previous GDM, family history of diabetes (first-degree relative with diabetes), family origin with a high prevalence of diabetes, such as South Asian (specifically women whose country of family origin is India, Pakistan or Bangladesh), black Caribbean, Middle Eastern (specifically women whose country of family origin is Saudi Arabia, United Arab Emirates, Iraq, Jordan, Syria, Oman, Qatar, Kuwait, Lebanon or Egypt).
Older women; obese women; those with previous history of glucose intolerance; any pregnant woman who has elevated fasting, or casual, blood glucose levels; those with a history of GDM; those with a history of large-for-gestational-age babies; women from certain high-risk ethnic groups; strong family history of diabetes mellitus.
Organization Who is screened? Method of screening Screen positive threshold Diagnostic test Diagnostic threshold for GDM
CDA 2013 (Canadian Diabetes Association) All women 50 g GCT (preferred) Alternative = “1-step” 75 g OGTT (see IADPSG below) ≥7.8 mmol/L 75 g OGTT 1. ≥11.1 mmol/L on 50 g GCT 2. 75 g OGTT Fasting ≥5.3 1 hour ≥10.6 2 hours ≥9.0 One abnormal value needed for diagnosis
ADA 2013 (American Diabetes Association) (122) All women “One-step” 75 g OGTT N/A N/A Fasting ≥5.1 1 hour ≥10.0 2 hours ≥8.5 One abnormal value needed for diagnosis
ADIPS 1998 (Australasia) (124) 1. All women 2. Only “high risk” 50 g or 75 g GCT (nonfasting) 1. 50 g GCT: ≥7.8 mmol/L 2. 75 g GCT: ≥8.0 mmol/L 75 g OGTT Fasting ≥5.5 2 hours ≥8.0 One abnormal value needed for diagnosis
IADPSG 2010 (118) All women “One-step” 75 g OGTT N/A N/A Fasting ≥5.1 1 hour ≥10.0 2 hours ≥8.5 One abnormal value needed for diagnosis
NICE 2008 (United Kingdom) (82) Women with risk factors Risk factors N/A 75 g OGTT Fasting ≥7.0 2 hours ≥7.8 One abnormal value needed for diagnosis
WHO 1999(World Health Organization) (125) 1. Women with risk factors 2. All women 1. Risk factors 2. “One-step” with 75 g OGTT N/A 75 g OGTT Fasting ≥7.0 2 hours ≥7.8 One abnormal value needed for diagnosis

What is the optimal method of screening?
Screening can be universal or risk factor based. The goal of risk factor–based screening would be to ideally identify through historical and clinical risk factors those patients who would benefit most from biochemical screening while allowing those at lower risk to avoid the screening process. Unfortunately, traditional risk factor–based screening has low sensitivity and specificity for identification of GDM (128–130), and the presence of risk factors does not necessarily identify those with the highest risk of adverse outcomes (131). In populations that are older and have increased body mass index (BMI), selective screening ultimately leads to a majority of the pregnant population being screened; thus, universal screening is the pragmatic approach accepted in most North American centers. It is possible that future analysis of the HAPO data based on GDM risk factors might allow modification of this recommendation (132).

Assuming universal screening, the method of screening can be either a sequential or a 1-step process. Methods for sequential screening include the use of glycosuria, A1C, fasting plasma glucose (FPG), random plasma glucose and a glucose load. Aside from the glucose load, all the other methods mentioned have not been adopted due to their poor performance as screening tests in most populations (133–138).

The most common glucose test used in sequential screening is the 50 g GCT performed between 24 to 28 weeks of gestation, and it is the screening test recommended by the CDA in the 2008 guidelines. The performance of the GCT as a screening test depends on the cutoff values used, the criteria for diagnosis of GDM and the prevalence of GDM in the screened population.

The best data regarding the GCT as a screening test come from the Toronto Tri-Hospital study. as all participants had both a 50 g GCT and a 100 g OGTT regardless of the GCT results (127). The threshold for the GCT was 7.8 mmol/L, and GDM was diagnosed according to the National Diabetes Data Group criteria. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the GCT in this study were 76.6%, 82.2%, 14.4% and 98.9% respectively. Using the data from this study, we need to understand that, by using the sequential 50 g GCT followed by a glucose tolerance test, some 20% of the population will screen positive, of whom 16% will not have GDM. Due to the low sensitivity, almost one-fourth of the patients with GDM will not be diagnosed using this strategy; specifically, the test will not identify those women whose only abnormality is elevated FPG. The performance of the 50 g GCT can be improved when slightly more complicated strategies are used, such as factoring in certain risk factors, ethnic background or time from last meal (139–141).

An additional question is whether there is a GCT threshold above which GDM can be reliably diagnosed. The 2008 CDA guidelines recommend diagnosing GDM if the glucose level 1 hour after the 50 g GCT is 10.3 mmol/L. This recommendation is based on a retrospective cohort study in 514 women with a positive 50 g GCT who went on to have a 100 g OGTT (142). Using receiver operating curve analysis, the optimal cutoff point for the upper limit of the GCT was found to be 186 mg/dL (10.3 mmol/L). Using a 2.7% prevalence of GDM, this cutoff point had 36.1% sensitivity, 95.9% specificity, 19.6% PPV and 98.2% NPV. Approximately 21% of those with values >10.3 mmol/L had normal GTT results and, thus, would be wrongly classified as having GDM. More recent studies do not support this cutoff value and, in fact, suggested that only cutoff values >12.2 mmol/L can reliably diagnose an abnormal GTT (143–146). As with all aspects of hyperglycemia in pregnancy, there is evidence that along a continuum of GCT results without a diagnosis of GDM, there is an increase in certain adverse perinatal outcomes (146). At this point, there is no evidence supporting a specific cutoff value of the 50 g GCT to diagnose GDM.

One-step approach
Those who subscribe to the notion that all cases of hyperglycemia in pregnancy need to be diagnosed and treated (i.e. increased sensitivity over specificity) will support the use of 1-step screening. The use of the term screening is misleading in this context as this strategy entails performing the diagnostic test on the entire population at risk. The 1-step approach includes a 75 g OGTT performed in the fasting state at 24 to 28 weeks of gestation with plasma glucose measured at fasting and 1 and 2 hours after the glucose load. The IADPSG and the American Diabetes Association (ADA) have supported this option (118,122), while some European guidelines recommend the 75 g OGTT only to women with risk factors but use the IADPSG thresholds for diagnosis of GDM (147–149). In March 2013, the National Institutes of Health (NIH) held a consensus development conference to discuss the diagnosis of GDM. As of March 6, 2013, a draft statement was published online (150). This draft statement stated that, as of that time, the NIH panel did not find sufficient evidence to support adopting a 1-step approach, such as that proposed by IADPSG (150). Since this is only a draft NIH statement, the final statement may differ. As mentioned above, adopting 1-stage “screening” using the IADPSG thresholds will lead to almost 18% of pregnant patients being diagnosed with GDM. There are no data regarding the performance of combinations of risk factor–based screening and a 75 g OGTT or sequential 50 g GCT followed by a 75 g OGTT using the new IADPSG criteria.

Given this lack of evidence, it is possible that the decision regarding the recommended screening method will be determined by the economic implications on the healthcare resources. An excellent review of the literature on cost effectiveness of different screening strategies for GDM can be found in Health Technology Assessment 2010. Canadian economic data from a prospective, randomized trial of 3 different screening strategies offers relevant information for the Canadian population (151). One thousand five hundred ninety four women were randomized to 1 of 3 groups: sequential screening with the 50 g GCT (cutoff 7.8 mmol/L) followed by the 100 g OGTT as the diagnostic test (group 1) or the 75-g OGTT (group 2); group 3 underwent a 1-step 75 g OGTT. The sequential screening strategy was found to be less expensive while having the same diagnostic power as there was no difference in the incidence of GDM in all 3 groups. This, in itself, is surprising as one would expect the incidence of GDM to be higher in the universally tested group. The authors also indicate that these results might not be applicable to higher-risk ethnic populations (151).

There are no economic analyses of the impact of the newly proposed IADPSG guidelines, although the impact on workload is expected to be substantial (152). In summary, most cost analysis evaluations support a sequential screening approach to GDM; thus, our preferred approach is to continue with this strategy.

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 (see Table 2 ).

The original criteria for diagnosis of GDM were defined solely on the basis of their ability to identify a prediabetic state in the mother (153). Ideally, the diagnostic thresholds would be based on their ability to predict clinically relevant perinatal outcomes, such as perinatal mortality, birth trauma or birth asphyxia. The HAPO trial was supposed to provide this missing link (4). Unfortunately, in this study, no single threshold could be identified that predicted the primary outcome. The continuous association between increasing glucose intolerance and the risk of caesarean section, birth weight >90%, neonatal hypoglycemia and cord C-peptide levels did not permit the determination of new diagnostic criteria. The new IADPSG criteria are the result of yet another expert consensus statement (118). Use of these new thresholds without subjecting them to rigorous clinical evaluation will lead to a significant increase in the number of women labeled as having GDM. This might prove to have a clinical benefit, but there is also the possibility of causing harm through unnecessary interventions, increased anxiety and an effect on women’s perceptions of their health.

2013 CDA diagnostic criteria for GDM
Given the controversy that persists in the international community about the diagnosis of gestational diabetes, there is no clear answer as to what is ideal. In the absence of a single threshold to predict adverse outcomes in pregnancy, one can justifiably select thresholds for the 75 g OGTT that result in an odds ratio (OR) of 1.75 for development of the 4 primary outcomes in HAPO (4) or an odds ratio of 2.00 ( Table 3 ). The IADPSG consensus committee selected the thresholds of OR 1.75; however, this may have implications on cost and workload. Therefore, the 2013 CDA expert committee acknowledges the controversy and 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). This represents minimal change from 2008. 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) ( Figures 1 and 2 ).

Management

Lifestyle
During pregnancy, women should be evaluated and followed by a registered dietitian to ensure that nutrition therapy promotes euglycemia, appropriate weight gain and adequate nutritional intake (154–157). 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 (158). Detailed recommendations for nutritional management of GDM are available (157). Physical activity should be encouraged unless obstetrical contraindications exist or glycemic control is worsened by the activity (159,160).

Table 3
Differences between selecting an OR of 1.75 vs. 2.0 for the primary outcome in the HAPO cohort (4,118)
HAPO, Hyperglycemia and Adverse Pregnancy Outcomes; OR, odds ratio.
  OR 1.75 OR 2.0
Threshold glucose levels (mmol/L)    
Fasting 5.1 5.3
1 hour 10.0 10.6
2 hours 8.5 9.0
% of HAPO cohort that met ≥1 glucose threshold 16.1% 8.8%

Glycemic control
For GDM, good outcomes have been reported using targets of fasting <5.3 mmol/L, 1 hour postprandial <7.8 and 2 hours postprandial <6.7 mmol/L (161–164) and are close to the targets of the 2 RCTs showing benefit for the treatment of GDM (119,120). The upper therapeutic target for 1- and 2-hour postprandial, if based on 2 SD above normal, would be 7.5 and 6.7 mmol/L (3), but, as noted above, the veracity of the numbers from this systematic analysis are suspect. Thus, until prospective studies of precise targets are available, using the targets in the Maternal-Fetal-Medicine-Unit Network study that were associated with achieving good glycemic control and outcomes appears reasonable (120).

Monitoring
Frequent SMBG is essential to guide therapy of GDM (165,166). Both fasting and postprandial testing are recommended to guide therapy in order to achieve glycemic targets (164,165). Studies support the use of a 1-hour postprandial target, typically 7.8 mmol/L (164,167–169) or a 2-hour postprandial target, typically 6.7 mmol/L (120,170,171). Although the peak for postprandial glycemia occurs at 69 ± 24 minutes (3) and hence may lend support to a 1-hour target being used, in obesity, this peak appears delayed (172). Continuous glucose monitoring systems have been useful in picking up previously undetected hyperglycemia, but it is unproven if they are cost effective (173–175). Women with GDM, in an effort to control their glucose by diet, may put themselves and their baby at risk for starvation ketosis. Older studies raised the possibility that elevated ketoacids may be detrimental to the baby (75,176). While the clinical significance of these findings are doubtful, 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 (177,178). In some cases, assessment of fetal growth by early third-trimester ultrasound can be used to guide therapy (179,180). The use of insulin to achieve glycemic targets has been shown to reduce fetal and maternal morbidity (178,181). A variety of protocols have been used, with multiple injections being the most effective (182). Insulin usually needs to be continuously adjusted to achieve glycemic targets. Although the rapid-acting bolus analogues aspart and lispro can help achieve postprandial targets without causing severe hypoglycemia (181–183), improvements in fetal outcomes have not been demonstrated with the use of aspart or lispro compared to regular insulin (181,182). A recent analysis reveals that glargine is safe in pregnancy and can be considered an option for pregnant patients (184). A recent Canadian review of rapid and long-acting basal analogues in GDM for glycemic control and hypoglycemia did not shown superiority (185).

Oral antihyperglycemic agents Glyburide is safe and effective in controlling glucose levels in >80% of patients with GDM (186–188) and does not cross the placenta (189). 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 (187,190). Despite the glucose levels, some earlier studies report more adverse outcomes in women treated with glyburide compared to insulin (191,192). More recent studies have shown glyburide to be a safe alternative with no dose-related increment in neonatal hypoglycemia (193).

In 2008, Rowan et al (194) studied 751 women with GDM who were randomly assigned to open treatment with metformin (with supplemental insulin if required) or insulin. Of the women assigned to metformin, 46.3% received supplemental insulin. Metformin (alone or with supplemental insulin) was not associated with increased perinatal complications compared with insulin. There was less severe hypoglycemia in neonates receiving metformin but more spontaneous preterm delivery( i.e. <37 weeks’ gestation). Other studies have confirmed the safety of metformin with less neonatal hypoglycemia (195). While metformin appears to be a safe alternative to insulin therapy, it does cross the placenta, plus metformin clearance is increased in pregnancy (196). Results of the offspring follow-up of the Metformin in Gestational diabetes trial (Mig TOFU), expected in several years, will provide more data on the long-term safety of metformin.

When comparing metformin to glyburide, there is a 2:1 failure of control of patients on metformin vs. glyburide (197). There is less hypoglycemia with metformin and less weight gain with metformin (198). Ongoing safety data show glyburide is safe (199,200). A recent systematic review of the literature has shown glyburide and metformin have similar outcomes when compared to insulin therapy (201).

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 (202).

Neonatal hypoglycemia There has been much disagreement over the definition of neonatal hypoglycemia because of the lack of rigorous scientific studies. However, recognizing that some guidelines must be provided for use in practice, 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 (203,204). Mild neonatal hypoglycemia has been found to be associated with transient abnormalities on physical examination (205), neurophysiological testing (206) and brain imaging (207).

Longer term follow-up found that infants with neonatal hypoglycemia had increased rates of neurological abnormalities at 18 months (208,209) and 8 years of age (210).

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 (205,211). Studies have generally been performed in mothers with pregestational diabetes or insulin-treated GDM. These have been observational with no randomized trials deliberately targeting different levels of maternal glycemia during labour. Most have found that there is a continuous relationship between mean maternal glucose levels during labour and the risk of neonatal hypoglycemia with no obvious threshold. Authors have often chosen 2 levels within the range and shown that there is more hypoglycemia with the higher value, but the studies do not arrive at a common value. For example, Miodovnik et al (212) found the lowest risk if maternal glucose was <5.0 mmol/L, while Andersen et al (213) reported <7.1 mmol/L. Curet et al (214) found there was less hypoglycemia if the mean glucose was 4.6 mmol/L compared to 5.9 mmol/L (and recommended <5.6 mmol/L), while Lean et al (215) found that a mean of 7.6 mmol/L resulted in more hypoglycemia than 4.1 mmol/L, and Feldberg et al (216) found the same result, comparing values of 7.6 mmol/L and 4.8 mmol/L. Stenninger et al (217) reported 7.8 and 5.3 mmol/L, and Balsells et al (218) recommend keeping the level <7.0 mmol/L. 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 (219–221).

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 (219,220). There are very few studies (although many published protocols) as to the best method of managing glycemia during labour (221,222). Rotating intravenous fluids compared with intravenous insulin were no different in controlling maternal glycemia in GDM (223). Adequate glucose must be provided during labour to meet the high glucose requirements. 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 may have more difficulty breastfeeding due to increased operative deliveries and obesity. Women with GDM should be encouraged to breastfeed immediately after delivery and for at least 3 months postpartum, as this may reduce neonatal hypoglycemia and offspring obesity, and prevent the development of metabolic syndrome and type 2 diabetes in the mother (224–230).

Long-term maternal risks With the diagnosis of GDM, there is evidence of impairment of both insulin secretion and action (231,232). These defects persist postpartum and increase the risk of impaired fasting glucose, IGT and type 2 diabetes (233,234). The cumulative risk increases markedly in the first 5 years and more slowly after 10 years (235,236). At 3 to 6 months postpartum, risks of dysglycemia are in the 16% to 20% range. While elevated FPG during pregnancy is a strong predictor of early development of diabetes (237,238), other predictors include age at diagnosis, use of insulin, especially bedtime insulin or oral agents, and more than 2 pregnancies (239,240). A1C at diagnosis of GDM is also a predictor of postpartum diabetes (241). Any degree of dysglycemia is associated with increased risk of postpartum diabetes (242). After 9 years, 20% of women with prior GDM will develop type 2 diabetes (243). Some women with GDM, especially lean women <30 years of age who require insulin during pregnancy, progress to type 1 diabetes (244,245). Women with positive antibodies (anti-glutamic acid decarboxylase (anti-GAD), anti-insulinoma antigen 2 (anti-IA2)) are more likely to have diabetes by 6 months postpartum (246). 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 (247–249). Only 50% return for postpartum testing (249–252). It is essential that the importance of follow-up be explicitly communicated with women and their caregivers who are responsible for postpartum testing. Telephone and e-mail reminders are helpful at increasing follow-up rates (253). Women should be screened postpartum to determine their glucose status. Postnatal fasting blood glucose has been the most consistently found variable in determining women at high risk for early postpartum diabetes (254). FPG alone, however, will miss many women with some degree of abnormal glucose tolerance (255–257) ; therefore, a 75 g OGTT should be done between 6 weeks and 6 months postpartum. Women should be counselled that the recurrence rate of GDM is high, from 30% to 84%, in subsequent pregnancies (258,259). Metabolic syndrome has been shown to be more prevalent in women with GDM (260–262). Given the increased risk of CVD with metabolic syndrome, consideration should be given for screening for all components of metabolic syndrome in the postpartum care of women with GDM, specifically if there is a family history (263,264). High C-reactive protein, high low-density lipoprotein, fibrinogen and uric acid have been described postpartum in women with a history of GDM (265). Education on lifestyle modification to prevent diabetes and CVD should begin in pregnancy and continue postpartum. Awareness of exercise for prevention of diabetes is low (266), and emphasis on targeted strategies that incorporate women’s exercise beliefs may increase participation rates (267).

Long-term fetal risks There is increasing interest in determining how long the adverse effects of diabetes on pregnancy persist. Freinkel (268) extended the original Pedersen hypothesis of fuel-mediated teratogenesis to suggest that abnormal metabolism during pregnancy could have long-term effects on the offspring of diabetic mothers (ODM) (269). Two groups pioneered work in this area with careful prospective studies.

Information has been collected from the Pima Indians since 1965 examining the impact of maternal diabetes on children and adolescents (270). Children whose mothers had diabetes during pregnancy had a significantly higher incidence of obesity and type 2 diabetes that was detectable by age 9 and persisted into adulthood. Northwestern University enrolled women with both GDM and pregestational diabetes from 1977 to 1983 and followed their offspring until adolescence. Most women had good control of their diabetes during pregnancy. They found that aberrant maternal metabolism in the second and third trimesters (most often beta-hydroxbutyrate levels) was associated with reduced intellectual and psychomotor development on a number of tests performed up to age 11. With respect to growth, neonatal macrosomia had resolved by age 1, and weight was not different from controls until age 5. From age 5 through 16, the BMI of ODM (both GDM and pregestational diabetes) was significantly higher than in control subjects (271).

Since that time, the great majority of studies (270) continue to show an increased risk of obesity and metabolic abnormalities in childhood extending into adolescence and early adulthood (273–275). Some suggest GDM carries greater risk than type 1 for obesity in the offspring (276,277). Obesity in adolescence results in an increased risk of metabolic syndrome (277) and coronary artery disease (278).

How are the long-term consequences of maternal diabetes caused and could they be prevented? Genetics, exposure to abnormal intrauterine metabolism or the family environment all could potentially be involved. The issue was addressed in the Pima by studying nuclear families with siblings born within 3 years of each other, before and after the mother developed diabetes. The fact that the risk of the child developing diabetes was significantly higher (OR 3.7) in siblings born after the mother developed diabetes demonstrated that intrauterine exposure per se conveyed the increased risk (279). A similar study was done in Sweden and looked at BMI at age 18 years. After examining multiple factors, they found that increased BMI was mediated through an intrauterine mechanism (280). Studies have looked at factors that potentially could be modified to reduce risk. Elevated maternal prepregnancy weight and excessive weight gain during pregnancy have been found by many studies to be independent risk factors for childhood obesity and metabolic abnormalities (271–283).

LGA infants of diabetic mothers and accelerated third-trimester growth have widely been found to be independent risk factors for offspring obesity and metabolic syndrome (272–283). Similarly, risk has been shown to be related to maternal glucose levels during pregnancy (281,284,285). In a detailed study, Chandler-Laney et al (286) 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 (223,283,287).

Firm conclusions about the benefits of modifying these risk factors are limited by the lack of intervention studies. One study found that treatment of GDM did not affect obesity at age 2 (288) ; however, in view of the study by Silverman et al (271) and other data, this follow-up is too short to draw conclusions about childhood and adolescence. In view of the known benefits of breastfeeding and of preventing maternal obesity and LGA infants, it would not be ethical to conduct randomized trials deliberately exposing 1 group to suboptimal levels of 1 of these risk factors. However, it seems reasonable to assume that our current efforts at tight control of maternal nutrition and diabetes during pregnancy and promoting breastfeeding will provide benefits throughout childhood and adolescence.

Planning future pregnancies

Women with previous GDM should plan future pregnancies in consultation with their healthcare providers (289,290). 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 (291).

Figure 1
Preferred approach for the screening and diagnosis of gestational diabetes.

1hPG, 1-hour plasma glucose; 2hPG, 2-hour plasma glucose; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test; PG, plasma glucose.

Figure 2
Alternative approach for the screening and diagnosis of gestational diabetes.

1hPG, 1-hour plasma glucose; 2hPG, 2-hour plasma glucose; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test; PG, plasma glucose.

Recommendations

Pregestational Diabetes

Preconception care

  1. 1.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 (11)].
  2. 2.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].
  3. 3.Before attempting to become pregnant, women with type 1 or type 2 diabetes should:
    1. a.Receive preconception counselling 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 (10,56)]
    2. b.Strive to attain a preconception A1C ≤7.0% (or A1C as close to normal as can safely be achieved) to decrease the risk of:
      1. Spontaneous abortion [Grade C, Level 3 (292)]
      2. Congenital anomalies [Grade C, Level 3 (56,292–294)]
      3. Preeclampsia [Grade C, Level 3 (295,296)]
      4. Progression of retinopathy in pregnancy [Grade A, Level 1, for type 1 diabetes (23) ; Grade D, Consensus, for type 2 diabetes]
    3. c.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 (291)]. 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].
    4. d.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 (47–49)]
      • Statins [Grade D, Level 4 (297)]
  4. 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]. Women with pregestational diabetes who also have PCOS may continue metformin for ovulation induction [Grade D, Consensus].

Assessment and management of complications

  1. 5.Women should undergo an ophthalmological evaluation by an eye care specialist [Grade A, Level 1, for type 1 (23,298) ; Grade D, Level 4, for type 2 (26)].
  2. 6.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 (39) ; 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 (39,44)] and should be followed closely for these conditions [Grade D, Consensus].

Management in pregnancy

  1. 7.Pregnant women with type 1 or type 2 diabetes should:
    1. a.Receive an individualized insulin regimen and glycemic targets typically using intensive insulin therapy [Grade A, Level 1B, for type 1 (53,85) ; Grade A, Level 1, (85) for type 2]
    2. b.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]
    3. c.Be prepared to raise these targets if needed because of the increased risk of severe hypoglycemia during pregnancy [Grade D, Consensus]
    4. d.Perform SMBG, both pre- and postprandially, to achieve glycemic targets and improve pregnancy outcomes [Grade C, Level 3 (56)]
  2. 8.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 (69) ; Grade C, Level 3, for lispro (89,90)].
  3. 9.Detemir [Grade C, Level 2 (95)] or glargine [Grade C, Level 3 (94)] may be used in women with pregestational diabetes as an alternative to NPH.

Intrapartum glucose management

  1. 10.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].
  2. 11.Women should receive adequate glucose during labour in order to meet their high-energy requirements [Grade D, Consensus].

Postpartum

  1. 12.Women with pregestational diabetes should be carefully monitored postpartum as they have a high risk of hypoglycemia [Grade D, Consensus].
  2. 13.Metformin and glyburide may be used during breastfeeding [Grade C, Level 3 (109) for metformin; Grade D, Level 4, for glyburide (115)].
  3. 14.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].
  4. 15.All women should be encouraged to breastfeed since this may reduce offspring obesity, especially in the setting of maternal obesity [Grade C, Level 3 (224)].

Gestational Diabetes

Diagnosis

  1. 16.All pregnant women should be screened for GDM at 24–28 weeks of gestation [Grade C, Level 3 (121)].
  2. 17.If there is a high risk of GDM based on multiple clinical factors, screening should be offered at any stage in the pregnancy [Grade D, Consensus]. If the initial screening is performed before 24 weeks of gestation and is negative, rescreen between 24 and 28 weeks of gestation. Risk factors include:
    • Previous diagnosis of GDM
    • Prediabetes
    • Member of a high-risk population (Aboriginal, Hispanic, South Asian, Asian, African)
    • Age ≥35 years
    • BMI ≥30 kg/m 2
    • PCOS, acanthosis nigricans
    • Corticosteroid use
    • History of macrosomic infant
    • Current fetal macrosomia or polyhydramnios [Grade D, Consensus]
  3. 18.The preferred approach for the screening and diagnosis of GDM is the following [Grade D, Consensus]:
    • a.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 (299)]. 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 (127)]. 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 (145)].
    • b.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 (4)]
  4. 19.An alternative approach that may be used to screen and diagnose GDM is the 1-step approach [Grade D, Consensus]:
    1. a.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 (4)]

Management during pregnancy

  1. 20.Women with GDM should:
    1. a.Strive for target glucose values:
      1. i.Fasting PG <5.3 mmol/L [Grade B, Level 2 (164)]
      2. ii.1-hour postprandial <7.8 mmol/L [Grade B, Level 2 (163)]
      3. iii.2-hour postprandial <6.7 mmol/L [Grade B, Level 2 (164)]
    2. b.Perform SMBG, both fasting and postprandially, to achieve glycemic targets and improve pregnancy outcomes [Grade B, Level 2 (163)].
    3. c.Avoid ketosis during pregnancy [Grade C, Level 3 (300)].
  2. 21.Receive nutrition counselling from a registered dietitian during pregnancy [Grade C, Level 3 (157)] and postpartum [Grade D, Consensus]. Recommendations for weight gain during pregnancy should be based on pregravid BMI [Grade D, Consensus].
  3. 22.If women with GDM do not achieve glycemic targets within 2 weeks from nutritional therapy alone, insulin therapy should be initiated [Grade D, Consensus].
  4. 23.Insulin therapy in the form of multiple injections should be used [Grade A, Level 1 (85)].
  5. 24.Rapid-acting bolus analogue insulin may be used over regular insulin for postprandial glucose control, although perinatal outcomes are similar [Grade B, Level 2 (181,182)].
  6. 25.For women who are nonadherent to or who refuse insulin, glyburide [Grade B, Level 2 (187–192)] or metformin [Grade B, Level 2 (194)] 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].

Intrapartum glucose management

  1. 26.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].
  2. 27.Women should receive adequate glucose during labour in order to meet their high-energy requirements [Grade D, Consensus].

Postpartum

  1. 28.Women with GDM should be encouraged to breastfeed immediately after delivery in order to avoid neonatal hypoglycemia [Grade D, Level 4 (227)] and to continue for at least 3 months postpartum in order to prevent childhood obesity [Grade C, Level 3 (225)] and reduce risk of maternal hyperglycemia [Grade C, Level 3 (301)].
  2. 29.Women should be screened with a 75 g OGTT between 6 weeks and 6 months postpartum to detect prediabetes and diabetes [Grade D, Consensus].

Abbreviations:
A1C, glycated hemoglobin; ACE, angiotension-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; GCT, glucose challenge test; OGTT,  oral glucose tolerance test; PCOS, polycystic ovarian syndrome; PG, plasma glucose; SMBG, self-monitoring of blood glucose; TSH, thyroid-stimulating syndrome.

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