Diabetes Mellitus in Pregnancy

Diabetes Mellitus in Pregnancy

Carol J. Homko

Julie A. Rosen

Perceval Bahado-Singh

E. Albert Reece


Diabetes mellitus is a heterogeneous disorder characterized by hyperglycemia, which is a result of relative or absolute insulin deficiency. It is estimated that diabetes mellitus affects approximately 5% of women of childbearing age in the United States and is a major cause of congenital anomalies.1 The goal in treating patients with diabetes in pregnancy is not only a reduction in perinatal mortality but also decreases in perinatal and maternal morbidity.

Prior to the introduction of insulin in 1922, diabetes was a disease with a dismal prognosis, and infertility was common in women with diabetes. Although the outcomes of diabetic pregnancies in the post-insulin era have improved markedly, with maternal mortality rates falling from 45% to just over 2% and perinatal deaths declining to approximately 2% to 3% and lower in women with well-controlled disease, unresolved problems remain.2 These gains in maternal and neonatal morbidity and mortality are credited to a better understanding of the metabolism of patients with diabetes, a recognition of the need for stringent glycemic control to achieve glucose levels as close to euglycemia as possible, the improvement in neonatal intensive care units, new techniques for fetal surveillance, and devices for self-monitoring of blood glucose and, potentially, delivery of pharmacologic agents.


Diabetes in pregnancy is still generally classified using the original system proposed by Priscilla White over 70 years ago,3 even when applied to contemporary patient populations.4,5 White classification relates the onset of diabetes, its duration, and the degree of vasculopathy to the outcome of pregnancy. Because there were differences and some confusion in the interpretation of class A diabetes, particularly when the patient required insulin for therapy, a revision made by Hare and White proposed that class A diabetes should include women known to have diabetes before pregnancy and who are treated with diet alone.6 Thus, White class A classification includes only patients with preexisting diabetes and defines gestational diabetes as a completely separate group.

Women with pregnancies complicated by diabetes mellitus may be separated into one of two groups (Table 30.1):

  • Gestational diabetes mellitus (GDM): women diagnosed in the second or third trimester of pregnancy with diabetes that is clearly not type 1 or type 2 diabetes or other forms.

  • Preexisting diabetes: women known to have diabetes before pregnancy. For the purposes of this chapter, we will use the term “preexisting” diabetes to mean type 1 or type 2 diabetes.

In general, type 1 and type 2 can be distinguished from each other using clinical criteria, islet cell antibody (ICA) studies,10 C-peptide levels,11 or a combination thereof (Table 30.2).

The current, widely used definition of GDM is glucose intolerance diagnosed in the second or third trimester of pregnancy that is not clearly preexisting diabetes.12,13,14,15 Although the causes of this glucose intolerance remain unclear, a key feature of GDM is varying degrees of hyperglycemia.


Significant advances in the understanding of genetic features of diabetes mellitus have been achieved in the last 50 years.16,17,18 Because diabetes mellitus is a heterogeneous disorder rather than a single disease, the different types of diabetes are distinguishable
from each other. Currently, the American Diabetes Association (ADA) classifies diabetes into four major categories19:

  • type 1 diabetes mellitus, an immune-mediated disease in which the beta-cells are destroyed by the patient’s immune system, leading to an absolute deficiency in insulin;

  • type 2 diabetes mellitus, a progressive loss of adequate insulin secretion by beta-cells, usually in the context of insulin resistance;

  • GDM, a discrete form specific to pregnancy, which was not overt prior to gestation and resolves shortly after parturition; and

  • specific types of diabetes due to other causes (Table 30.3).

Approximately 463 million adults worldwide have diabetes.20 Type 1 accounts for 5% to 10% of all cases of diabetes in the general population, with type 2 diabetes comprising 90% to 95% of all cases, and other forms of diabetes representing 1% to 2% of cases.21,22 According to the International Diabetes Federation, in 2019, the top 10 countries with the highest prevalence of diabetes in adults were China (116.4 million), India (77 million), the United States (31 million), Pakistan (19.4 million), Brazil (16.8 million), Mexico (12.8 million), Indonesia (10.7 million), Germany (9.5 million), Egypt (8.9 million), and Bangladesh (8.4 million).20
In the United States, approximately 7.3 million people are estimated to have undiagnosed diabetes and 88 million adults are thought to have prediabetes.21 Hyperglycemia during pregnancy is estimated to affect approximately 15.8% of all live births.20

Ninety percent of all pregnant patients with diabetes have GDM, whereas type 1 and type 2 account for the majority of the remaining 10%.20 The focus of this chapter will be these three predominant forms of diabetes in pregnancy as a broader discussion of the rarer manifestations of the disease is beyond the scope of this text.

Genetics of Type 1 Diabetes Mellitus

Almost 50 years ago, it was discovered that type 1 diabetes is a human leukocyte antigen (HLA)-linked

disorder, whereas type 2 is not, and thus they are two different diseases genetically.23 Genome-wide studies have revealed that HLA gene loci account for only 30% to 70% of genetic basis of type 1 diabetes and greater appreciation for non-HLA genes in the etiology of the disease have been revealed over the last decade-plus, with more than 50 loci now having a reported association with the condition.24 The insulin gene (INS) has the next-strongest association with type 1 diabetes, and variations within a specific region of the gene are thought to mediate immune tolerance to insulin.24 Other non-HLA genes with an identified association with type 1 diabetes also play critical roles in T-cell function.24
Although autoimmunity plays a key role in type 1 diabetes and the presence of autoantibodies to beta-cell proteins (eg, insulin, islet antigen 2, and zinc transporter 8, among others) is a hallmark of the condition, it is now appreciated that only those having more than one antibody progress to clinical disease.25

Type 1 diabetes is a heritable disease, with lifetime risk in siblings of 6% to 7% and 30% to 70% in monozygotic twins, 1.3% to 4% in children of women with type 1 diabetes, and 6% to 9% in children whose fathers have the disease.24 The exact mechanism of the inheritance of type 1 diabetes is not known; however, it appears that the disease itself is not inherited but susceptibility to the disease is, and that the progression to overt type 1 diabetes depends on a confluence of factors, including genetics and epigenetics, metabolomics, and the patient’s own microbiome and immune system.25 Research has shown that the HLA-D region is associated with susceptibility to type 1 diabetes and that variants within this region, specifically those within or close to the DR3 and/or DR4 and/or DQ-α or β alleles, are linked to approximately 50% of the heritability of the disease.26

Genetics of Type 2 Diabetes Mellitus

There are clear genetic and immunologic differences between type 1 and type 2 diabetes. Type 2 diabetes is not linked to HLA and does not seem to be an autoimmune or endocrine disease. However, the development of overt type 2 diabetes does, similar to type 1 diabetes, depend on a combination of genetic and epigenetic factors.

Until the mid-2000s, an appreciation for the genetic contributions to type 2 diabetes susceptibility had not been widely held, although the heritability of the disease had been documented for many years in the literature. Early studies reported a risk of type 2 diabetes in monozygotic twins of women with the disease of nearly 100%; more recent work has shown this rate to be between 52% and 72%.27,28 One of the first genes with a reported association with type 2 diabetes was a variant of transcription factor 7-like 2 (TCF7L2) gene, which was implicated in blood glucose homeostasis and identified in multiple studies and in a number of racial/ethnic populations.26 The advent of genome-wide linkage and association studies afforded investigators opportunities to interrogate other potential loci, and currently upward of 113 have been identified,29 although studies remaining lacking as to the actual functional roles—if any—of these genes and type 2 diabetes.

Genetics of Gestational Diabetes Mellitus

Historically, GDM was believed to be a variant of type 2 diabetes; however, available data now support the concept that GDM is a heterogeneous disorder representing, at least in part, patients who are destined to develop either type 1 or type 2 diabetes in later life.30,31 The exact percentage difference of each subgroup is unknown, but it appears that most GDM cases represent a preclinical state of type 2 diabetes. Immunologic studies have shown that in, at most, 10% of GDM cases, the glucose intolerance may stem from the presence of circulating autoantibodies indicative of type 1 diabetes, including glutamic acid decarboxylase autoantibody (GADA), ICA, insulin autoantibody, tyrosine phosphatase-like islet antigen autoantibody, and zinc transporter 8 autoantibody, although the titers of these antibodies is much lower than that of patients with overt type 1 diabetes.32 Several genome association studies have uncovered a number of shared genetic variants between GDM and type 2 diabetes, with one of the more notable being TCF7L2.33,34,35

The heritability of GDM has been difficult to ascertain for several reasons, the major one being that GDM screening and diagnosis differ significantly, rendering large prospective and retrospective studies challenging to interpret or applicable to broad populations.36 Although genome-based studies have provided unique insights into potential genetic causes of GDM, these investigations have also garnered a greater appreciation for previously unrecognized forms of diabetes, such as latent autoimmune diabetes in adults (LADA; discussed below) and maturity-onset diabetes of the young, which share features with both type 1 and type 2 diabetes and manifest as milder hyperglycemia indicative of GDM.26

Latent Autoimmune Diabetes in Adults

LADA represents a heterogeneous form of diabetes sharing clinical and genetic features with both type 1 and type 2 diabetes. It was first described in the literature in the late 1970s but not named until the early 1990s. As of this writing, the only two prospective studies of patients with LADA are the Norwegian Nord-TrØndelag Health (HUNT) Study and the Swedish Epidemiological Study
of Risk Factors for LADA and Type 2 diabetes (ESTRID) Study, although other studies have been conducted in Europe, the United Arab Emirates, China, and the United States. Similar to patients with type 1 diabetes, risk for LADA has been linked to variants in the HLA-D locus; similar to those with type 2 diabetes, risk for LADA has also been associated with variants in TCF7L2.37 As a condition that straddles both type 1 and type 2 diabetes, patients with LADA exhibit autoantibodies to GADA, although to a lesser extent than those with type 1 diabetes; have lower insulin secretion than patients with type 2 diabetes and require insulin therapy sooner; and tend to have higher body mass indices (BMIs) and less physical activity as risk factors, similar to patients who develop type 2 diabetes.38 Evaluation remains challenging, with several reports of patients misdiagnosed initially as having either type 1 or type 2 diabetes although, once diagnosed, treatment with insulin and diet and exercise are effective.39

Metabolic Changes in Diabetic Pregnancies

The metabolic disturbances in pregnant patients with diabetes are expressed in increased concentrations of circulating metabolic fuels, including carbohydrates, proteins, and fats. This increased circulating maternal level can be transferred to the fetus by the placenta. Although a detailed discussion of placental transfer of nutrients appears in Chapter 6, a brief overview of changes in insulin and glucose metabolism in pregnancy is provided here.

Insulin is the major hormonal signal regulating metabolic responses to feeding and tissue use of carbohydrates; it is also the major glucose-lowering hormone. It is produced by the beta-cells of the pancreas and is secreted into the hepatic portal circulation, from which it reaches and acts on the liver and other peripheral tissues (ie, muscle and fat). Insulin suppresses endogenous glucose production by inhibiting hepatic glycogenolysis and gluconeogenesis. On the other hand, it stimulates glucose uptake and fuel storage of glycogen and triglyceride in the liver, muscle, and adipose tissue.40

During normal pregnancy, insulin sensitivity decreases by approximately 50% to 60% as gestation advances.41,42 In the first trimester of pregnancy, insulin action is enhanced by estrogen and progesterone; thus, an increase in peripheral glucose use leads to lower fasting plasma glucose (FPG) levels,43 a decrease that may explain the clinical observation of increased episodes of hypoglycemia experienced by patients with preexisting diabetes in early pregnancy. Late pregnancy is characterized by accelerated growth of the fetoplacental unit, rising plasma concentrations of several diabetogenic hormones, including human placental lactogen and estrogens, and increasing insulin resistance, especially in the periphery (muscle and, in women with obesity, also at the hepatic level).42

Impaired insulin sensitivity appears to underlie a number of alterations in maternal metabolism necessary for fetal development as well as the eventual demands of labor and delivery in normal pregnancy. The concentration of several factors, including circulating free fatty acids, cholesterol, triglycerides, and phospholipids, contribute to changes in glucose metabolism. Although the mechanisms explaining alterations in glucose processing remain unclear, the advent of the field of metabolomics has revealed a number of potential intermediates in the insulin signaling pathway, which may explain these normal adaptations of pregnancy.44,45

The expression of insulin receptors and insulin-like growth factor (IGF) receptors in the placenta has been suggested to mediate to the metabolic aberrations observed in diabetic pregnancies.46,47,48 Over the course of pregnancy, expression of these receptors appears to change location—first favoring maternal-derived insulin and expressed on the maternal-facing side of the placental interface, and later favoring fetal-derived insulin.48 Dysregulation of the insulin/IGF signaling cascades have been reported in pregnancies affected by GDM and type 1 diabetes48 and linked to fetal overgrowth and adiposity, hyperinsulinemia, and hyperlipidemia. Although a detailed discussion of these signaling pathways falls outside the scope of this chapter, some of the major pathways are those involved in cellular proliferation, survival, and programmed cell death (apoptosis).46,47 Of particular note, these same signaling cascades have been identified in animal studies as having causal roles in the mechanisms underlying diabetes-induced birth defects (see below).

During development, the fetus produces very little endogenous glucose and, therefore, relies upon active transport of maternal glucose across the placenta. As of this writing, six glucose transporter (GLUT) proteins have been detected in the
placenta the expression of which vary as pregnancy progresses and in the presence of maternal diabetes.49 Furthermore, expression of GLUT proteins has been associated with IGF.50 Altered placental expression of GLUT-1, 4, and 9 have been reported in pregnancies complicated by preexisting and gestational diabetes, as compared with nondiabetic pregnancies, and a positive correlation between expression of all three GLUT members and fetal overgrowth in women with preexisting diabetes and GLUT-4 expression in women with GDM have also been published.51 However, the role and importance of the GLUT proteins in diabetic pregnancies remains unclear as investigators have reported divergent results50 and still others have postulated that it is the maternal-to-fetal glucose gradient, and not the active transport of glucose across the placenta, which mediates the effects of maternal hyperglycemia on fetal development.52


The incidence of GDM is estimated to occur in 6% to 9% of pregnant women; however, it differs widely depending on population studied and is reported to be as high as 11.1% in certain racial/ethnic groups and nearly 14% in women with class III obesity (BMI ≥ 40 kg/m2).65

The likelihood of developing gestational diabetes is significantly increased in

  • Women with a family history of type 2 diabetes

  • Women with advanced maternal age

  • Women who are overweight or obese

  • Women of non-white ethnicity

Screening and Clinical Assessment

Women are typically tested for GDM during the 24 to 28th week of pregnancy. Currently, there is no universally agreed upon testing method. Screening and diagnosis of GDM can be performed using either a one-step (2-hour, 75-g oral glucose tolerance test; OGTT) or two-step (50 g screen followed by a 3-hour, 100-g diagnostic OGTT) approach (Table 30.4) (Algorithm 30.1).

The one-step approach was developed by a consensus panel of the International Association of Diabetes in Pregnancy Study Groups (IADPSG); is endorsed by several international organizations; and is used throughout Europe, Australia, and Asia.12,14,66 The two-step approach is endorsed by the American College of Obstetricians and Gynecologists (ACOG) and used in the United States.13 The Society of Obstetricians and Gynaecologists of Canada (SOGC) uses a modified version of the ACOG and IADPSG strategies.15 However, many countries have adapted GDM testing guidelines.67

IADPSG Gestational Diabetes Mellitus Criteria

The IADPSG GDM diagnostic strategy was developed in response to the findings of one of the largest clinical trials to date, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, a 7-year study of over 23,000 pregnant women, which examined the relationship between varying degrees of maternal hyperglycemia in pregnancy and pregnancy outcomes, as well as the long-term health of the babies.68 The major findings of the HAPO study were that maternal hyperglycemia is associated with significantly increased risk of adverse antenatal and postnatal outcomes, including macrosomia, cesarean delivery, newborn hypoglycemia, and respiratory distress syndrome. Study investigators also concluded that women with mild hyperglycemia not indicative of overt diabetes faced an increased risk of these complications.

Based on an analysis of the HAPO study findings, the IADPSG published its testing strategy in 2010, recommending that women be tested for GDM using a 75-g OGTT and lowering the thresholds for diagnosis.14 Using this approach, diabetes status is based on the results of glucose levels measured in any one of three venous blood samples: a FPG sample, and a 1-hour and a 2-hour blood sample, both drawn after consumption of a 75-g glucose solution. A diagnosis of GDM is made if levels of glucose meet or exceed the upper limits of normal values in one or more of the samples drawn (Table 30.4).

ACOG GDM Criteria

In the United States, the GDM testing strategy uses a “two-step approach.”13,19,70 The first step is a screening test, the oral glucose challenge test (OGCT), which consists of:

  • A 50-g oral glucose load, followed 1 hour later by a plasma glucose determination.

  • The screen is performed without regard to the time of day or interval since the last meal.

  • Screening is recommended at 24 to 28 weeks’ gestation in average-risk women not known to have diabetes mellitus.

  • Screening is recommended as soon as possible in women deemed to be a high risk for overt diabetes.

A value of plasma venous glucose between 130 and 140 mg/dL has been recommended as a threshold to indicate the need for a full diagnostic OGTT. When the plasma glucose screening test results are >185 mg/dL, patients have GDM and no further testing is required.

The diagnosis of GDM is based on an abnormal result of an OGTT during pregnancy. A minority of cases are diagnosed on the basis of high fasting glucose levels during pregnancy, in which case the OGTT does not have to be performed.

The OGTT is administered under standard conditions:

  • The patient should have at least 3 days of unrestricted diet with more than 150 g of carbohydrates, and should be at rest during the study.

  • 100 g of glucose is given orally in at least 400 mL of water (or given as a 100-g glucose solution) after an overnight fast of 8 to 14 hours.

  • Diagnosis requires that at least two of four glucose levels of the OGTT meet or exceed the upper limits of normal values (Table 30.4).

Continued Controversies in GDM Criteria

In an effort to develop an international standard for GDM testing, the National Institutes of Health (NIH) convened a workshop in 2013 to assess the benefits and risks of the various GDM testing and diagnostic approaches.71 Drawing upon the expertise of a multidisciplinary panel of experts and all known published studies to that date, the NIH issued a consensus statement that concluded that there was a lack of evidence in favor of adopting the one-step approach (IADPSG criteria) over the two-step approach (ACOG criteria) in the United States. The panel of experts raised a number of
concerns about adopting the IADPSG criteria, which included an increase in the frequency of a GDM diagnosis by two- to threefold, unclear benefit for the additional women identified, and substantial increase to healthcare costs that the additional visits and testing might have. However, the panel agreed that the issues surrounding the best testing approaches and diagnostic criteria for GDM should be revisited in the future.

Subsequent to the 2013 consensus conference, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH convened a workshop in 2017 to examine some of the key research gaps in GDM, focusing primarily on early prenatal diagnosis (<20 weeks’ gestation) and pharmacologic treatment strategies. Similar to the expert panel, which met 4 years prior, the NIDDK workshop attendees noted ongoing gaps regarding best diagnostic criteria and effect of early diagnosis.72


Approximately 1% to 2% of pregnancies are affected by type 1 or type 2 diabetes. Preexisting diabetes is a significant health concern because uncontrolled maternal blood glucose prior to and during the first trimester of pregnancy is associated with fetal malformations, perinatal death, and maternal morbidity and mortality.78,79

Screening and Clinical Assessment

As summarized in Table 30.2, the ADA recommends a number of approaches to diagnose preexisting diabetes based on measurement of one of four abnormalities: glycosylated hemoglobin; FPG; 2-hour, 75-g OGTT; and random elevated glucose with symptoms.19 Patients whose blood glucose levels do not fall within the range of diabetes, but have impaired fasting glucose or impaired glucose tolerance, are considered at risk for developing disease. Although the World Health Organization and the International Diabetes Federation define overt disease20,80 similarly to the ADA, there is a difference in the cutoff values for impaired fasting glucose and impaired glucose tolerance. Diagnosis of overt diabetes complicating pregnancy (not GDM) is made based on the criteria used for assessment of nonpregnant patients.19

Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Diabetes Mellitus in Pregnancy

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