Gestational Diabetes

Etiology

Placental hormone release causes marked insulin resistance. Human placental lactogen is the primary hormone associated with increased insulin resistance; however, this hormone also increases insulin secretion and β-cell proliferation to regulate maternal hyperglycemia in normal pregnancies. Conversely, in patients with GDM, conditions or factors are present that cause maternal pancreatic β-cell dysfunction or the delayed response of the β cells, resulting in decreased insulin secretion and ultimately leading to maternal hyperglycemia. Another factor that promotes abnormally increased insulin resistance is maternal obesity early in pregnancy due to higher free fatty acid levels, which inhibits maternal glucose uptake and stimulates hepatic gluconeogenesis.[3]

Evidence of a genetic etiology has also been found in some GDM studies. Though the association between type 2 diabetes and genetic mutations has been the primary focus, a few similar genetic abnormalities have also been identified with GDM. Several studies have found genetic polymorphisms, including MTNR1B, TCF7L2, HKDC1, GCKR, PPP1R3B, and IRS1, involved in functions such as insulin secretion, glucose metabolism, and insulin resistance in patients with type 2 diabetes that were also associated with GDM. These findings suggest a similar underlying etiology.[3]

Additionally, clinicians should be aware of maturity-onset diabetes of the young, an autosomal dominant genetic condition that is often misdiagnosed as GDM. An estimated 5% of patients diagnosed with GDM have maturity-onset diabetes of the young. In patients with findings during an oral glucose tolerance test (OGTT) of a fasting glucose of more than or equal to 5.5 mmol/L and a glucose increment from the fasting to 2-hour OGTT result of less than 4.6 mmol/L with a positive family history of diabetes, maturity-onset diabetes of the young should be suspected. Fasting glucose more than or equal to 100 mg/dL in patients with a body mass index (BMI) less than 25 kg/m² can also be used to help differentiate these conditions.[3] See StatPearls' companion reference, "Maturity Onset Diabetes in the Young," for more information on this condition.

Gestational Diabetes Risk Factors

The following clinical factors are associated with a high risk of developing gestational diabetes:

• Increased body weight (a BMI >25 or >23 in Asian Americans)
• Decreased physical activity
• A first-degree relative with diabetes mellitus
• High-risk ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander)
• Past history of any of the following
  • GDM
  • Newborn birth weight of ≥4000 g
  • Cardiovascular diseases
• Hypertension
• Low HDL <35 mg/dL or a triglyceride level >250 mg/dL
• Polycystic ovarian syndrome
• Hemoglobin A1C >5.7
• Abnormal oral glucose tolerance test
• Any significant marker of insulin resistance (eg, acanthosis nigricans) [1]

Epidemiology

GDM is a common complication in pregnancy. The International Diabetes Federation recently estimated that globally, 1 in 6 live births had a GDM diagnosis.[3] In the United States, approximately 7% of pregnancies were complicated by diabetes of any type, with 86% of those cases being pregnancies complicated by GDM.[1] The estimated prevalence of GDM in Europe is 10.9%.[4]

Pathophysiology

Physiologic increases in circulating placental hormones, including growth hormone, corticotrophin-releasing hormone, human placental lactogen, prolactin, estrogen, and progesterone, increase insulin resistance during a normal pregnancy. Human placental lactogen is a hormone released by the placenta during pregnancy; this hormone has a comparable composition to growth hormone and induces significant metabolic changes during pregnancy to support the maintenance of fetal nutritional status. This hormone is capable of provoking alterations and modifications in the insulin receptors. Molecular variations, including molecular alteration of the beta-subunit insulin receptor, diminished tyrosine kinase phosphorylation, and remodelings in the insulin receptor substrate-1 and phosphatidylinositol 3-kinase, are associated with diminishing glucose uptake at peripheral tissues. Increased maternal insulin resistance causes elevated maternal postprandial glucose levels and free fatty acids, leading to more glucose available for fetal growth. However, normal pregnancies also have a corresponding increase in insulin secretion to maintain maternal euglycemia. These physiologic processes guide recommendations for GDM testing in the second and third trimesters.[3]

The pathophysiology of GDM is similar to type 2 diabetes, caused by increased insulin resistance and a deficiency in insulin hormone. Maternal pancreatic β-cell dysfunction resulting in decreased insulin secretion is the primary mechanism that results in the inability to control maternal insulin resistance and increased glucose levels, which leads to reduced glucose uptake, increased hepatic gluconeogenesis, and maternal hyperglycemia. Experts have also suggested that higher serum triglyceride levels may cause lipotoxic β-cell injury, impairing insulin secretion even more.[3] Elevated maternal serum glucose levels cross the placenta and produce fetal hyperglycemia, stimulating the fetal pancreas. Consequently, insulin anabolic properties induce fetal tissues to grow at an increased rate.[5]

History and Physical

GDM is primarily initially identified by screening tests in pregnancy. Because early screening is indicated by clinical history and assessment, documenting past medical history, obstetric outcomes,  and family history of type 2 diabetes mellitus are essential components of GDM assessment. The clinical features of gestational diabetes mellitus can be varied. The disproportionate weight gain, obesity, and elevated BMI can be suggestive features.[1] 

The American College of Obstetricians and Gynecologists (ACOG) recommends targeted evaluation for type 2 diabetes early in pregnancy with a 75-g or 50-g oral glucose tolerance test at the initial prenatal visit in patients who have a BMI of 30 kg/m² or more and 1 of the following risk factors:

• History of gestational diabetes mellitus 
• Hemoglobin A1C ≥5.7% on previous testing
• Immediate family member with diabetes
• High-risk race (eg, African American, Latin American, Native American, Asian American, Pacific Islander)
• Cardiovascular disease history
• Hypertension 
• High-density lipoprotein (HDL) cholesterol level <35 mg/dL or a triglyceride level >250 mg/dL
• Polycystic ovary syndrome
• Physical inactivity [6][1]

However, studies have demonstrated that the most significant associations for GDM risk were family history, previous GDM, Southeast Asian ethnicity, parity, and high BMI. Therefore, ethnic and racial differences in these risk factors for GDM development should also be considered.[7] Additionally, recent studies have shown that early screening for gestational diabetes does not prevent adverse outcomes and may even lead to worse outcomes in select patients. These findings highlight the complexity of GDM pathogenesis and management. Consequently, the effectiveness of the early gestational diabetes screening recommendation is debatable and requires additional studies.[8][9]

Evaluation

Gestational Diabetes Screening and Diagnostic Testing

Several laboratory and aneuploid screening studies are performed during the second trimester to provide optimal time for potential interventions. ACOG and the United States Preventive Services Task Force (USPSTF), as well as other professional societies, recommend that laboratory studies for gestational diabetes be performed in all pregnant individuals between 24 and 28 weeks gestation. However, the screening method and cut-off thresholds vary among experts.[1] The IADPSG and the American Diabetes Association (ADA) advocate for a 1-step screening approach for GDM using a 2-hour 75-g OGTT. The primary advantage of the 1-step approach is its ability to screen and diagnose GDM in a single visit, which streamlines the process for patients and clinicians. However, it necessitates fasting before the test and a commitment of approximately 2 hours for the entire procedure.[10]

In contrast, the 2-step screening approach, recommended by the ACOG, starts with a nonfasting 1-hour 50-g glucose challenge test. This initial test can be conveniently integrated into routine prenatal visits and is more straightforward to implement. Most women who undergo the 1-hour glucose challenge test do not require further testing, as they do not meet the threshold for abnormal glucose levels. However, approximately 20% of women fail this initial screening and subsequently undergo a 3-hour fasting diagnostic OGTT to confirm GDM diagnosis. This additional step aims to reduce unnecessary testing and intervention for those who do not have GDM. Different cut-off thresholds are used for the 50-g glucose tolerance screening to be considered an abnormal result, including ≥135 mg/dL (7.5 mmol/L), ≥130 mg/dL (7.22 mmol/L), and ≥140 mg/dL (7.8 mmol/L). Because studies have not demonstrated an optimal cut-off threshold, clinicians should determine which cut-off to implement based on the prevalence of community gestational diabetes risk factors and clinical preference for test sensitivity and specificity.[10]

In patients with a positive 50-g glucose screen, a diagnostic test using a 100-g 3-hour OGTT is necessary.[1] The following values are used as parameters for abnormal results for a 3-hour OGTT:

• Fasting: ≥95 mg/dL
• First hour: ≥180 mg/dL
• Second hour: ≥155 mg/dL
• Third hour: ≥140 mg/dL [1]

The presence of ≥2 abnormal results establishes the diagnosis of gestational diabetes.[1]

A key distinction between the 2 approaches lies in their diagnostic cut-offs. The 1-step approach uses stricter criteria, identifying women with milder forms of hyperglycemia as having GDM. This approach aims to capture cases of GDM earlier, potentially enabling earlier intervention and management to improve maternal and perinatal outcomes. However, the lower diagnostic thresholds used in the 1-step approach may lead to a higher prevalence of GDM than the 2-step method. Studies have not shown a significant difference between these methods in perinatal outcomes. Consequently, several methods are acceptable for diagnosing GDM.[10][2]

Postpartum Gestational Diabetes Evaluation

In the postpartum period, 24 to 72 hours after the delivery, glucose monitoring is recommended. After placenta removal, insulin resistance tends to improve; therefore, insulin or hypoglycemic agents can typically be tapered down.[1][11][12] Furthermore, after delivery, GDM often resolves, but up to one-third of women affected may develop diabetes or impaired glucose metabolism later in life. Studies suggest that between 15% and 70% of women with a history of GDM may progress to diabetes, predominantly type 2 diabetes. Notably, women with a prior GDM diagnosis face a significantly higher risk—up to sevenfold—of developing type 2 diabetes compared to those without such a history. Given these risks, guidelines recommend postpartum screening for all women who have GDM, ideally between 4 to 12 weeks after delivery.[1]

Two primary methods for postpartum screening include a fasting plasma glucose test and a 75-g, 2-hour OGTT. While the fasting plasma glucose test is simpler logistically, this method may miss detecting certain forms of abnormal glucose metabolism. Therefore, the OGTT is typically preferred as it can diagnose impaired fasting glucose levels and impaired glucose tolerance, providing a more comprehensive assessment of postpartum glucose status.[1] The following management is recommended for various fasting plasma glucose and 2-hour OGTT results:

• Diabetes
  • >125 mg/dL or 2-hour glucose >199 mg/dL
  • Initiate or refer for diabetes management
• Impaired fasting glucose or impaired glucose tolerance
  • 100 to 125 mg/dL or 2-hour glucose 140 to 199 mg/dL
  • Initiate dietary modifications and increased physical activity for weight loss
  • Refer for nutritional counseling as needed
  • Consider metformin therapy if fasting glucose and glucose tolerance are impaired
  • Screen for diabetes annually using a hemoglobin A1C, fasting plasma glucose, or 75-g OGTT using nonpregnant thresholds [13]
• Normal findings
  • <100 mg/dL or 2-hour glucose <140 mg/dL
  • Screen for diabetes every 1 to 3 years
  • Initiate dietary modifications and increased physical activity to achieve and maintain a BMI within the normal range [1]

Early detection through postpartum screening can benefit women with impaired fasting glucose or impaired glucose tolerance by enabling preventative interventions (eg, lifestyle modifications) and more intensive therapy for those diagnosed with diabetes. Despite these recommendations, compliance with postpartum testing remains suboptimal, with only between 23% and 58% of women undergoing appropriate postpartum evaluation. This disparity between postpartum testing guidelines and clinical implementation underscores the need for improved patient education and clinician engagement.[7][3]

Treatment / Management

Nonpharmacologic Therapies

GDM management begins with nonpharmacologic approaches, including increased physical activity, dietary changes, and glucose monitoring. The amount of exercise recommended in patients with GDM is 30 minutes of moderate-intensity aerobic exercise at least 5 days a week or a minimum of 150 minutes per week. Additionally, postprandial exercise is often recommended as this has been shown to help control glucose levels for up to 3 hours after eating.[2]

Dietary modifications and gestational weight gain

The ADA and ACOG also recommend nutritional counseling by a registered dietitian and the development of a personalized plan based on the patient's BMI to ensure that the patient's caloric demand is met while avoiding excessive weight gain. Clinicians can also advise patients regarding general dietary modifications, including consuming 3 small to moderate-sized meals and 2 to 3 snacks daily comprised of whole-grain carbohydrates, protein, and unsaturated fats with less carbohydrate at breakfast due to increased carbohydrate intolerance during that time. ACOG recommends a diet lower in carbohydrates; however, the optimal ratio of specific macronutrients in patients with GDM has not been determined. Some studies have also found that combining carbohydrates with lean proteins can help reduce postprandial hypoglycemia. To prevent ketosis at night, which can have adverse effects on fetal neurodevelopment, a bedtime snack is often recommended.[2]

Gestational weight gain may also affect pregnancies complicated by GDM. Maternal obesity and excessive weight gain have been associated with an increased risk of fetal macrosomia, gestational diabetes, gestational hypertension, preeclampsia, and Cesarean section.[14][3] Obese women also have an increased risk of antepartum cardiac dysfunction, proteinuria, nonalcoholic fatty liver disease, and sleep apnea, as well as intrapartum complications, including endometritis, labor induction failure, venous thrombosis, and wound dehiscence. Macrosomia, which has a higher incidence in those who are obese, is also associated with maternal complications (eg, protracted or arrest of labor, uterine rupture, genital tract lacerations, and postpartum hemorrhage). Additionally, macrosomic neonates have an increased risk of shoulder dystocia, clavicular fractures, brachial plexus injuries, and nerve palsies. A recent meta-analysis showed the highest risk of adverse outcomes occurred in women with a BMI of over 40 and a high total gestational weight gain.[15] The same meta-analysis recommended the following range for gestational weight gain for each prepregnancy weight class:

• Underweight (BMI <18.5): 14 to <16 kg
• Normal weight (BMI 18.5 to 24.9): 10 to <18 kg
• Overweight (BMI 25 to 29.9): 2 to <16 kg
• Obesity grade 1 (BMI 30 to 34.9): 2 to <6 kg
• Obesity grade 2 (BMI 35 to 39.9): weight loss or gain of 0 to <4 kg
• Obesity grade 3 (BMI ≥40): 0 to <6 kg [15]

These gestational weight gain ranges for patients with obesity grades 1, 2, or 3 were lower than those recommended by the US National Academy of Medicine guidelines, which recommend 5 to 9 kg in this population.[14] Obese individals are more prevalent than underweight patients and continue to increase, with a reported prevalence in the US of approximately 34%.[16] Antepartum weight loss is not recommended due to an associated risk of small for gestational-age infants. Therefore, in obese pregnant women, the primary management involves diet and behavioral modifications and increased exercise.[16] 

Glucose monitoring

Glucose monitoring 4 times a day is generally advised, though evidence supporting the best frequency is lacking. Obtaining a finger stick blood glucose level once fasting and then 1 or 2 hours postprandial at each meal is the most common monitoring schedule used.[3] Some experts recommend glucose monitoring 4 times a day for 2 weeks, and based on these findings, insulin therapy may be initiated in patients with high glucose levels or, in those with normal range results, glucose monitoring can be performed less frequently.[17] The ADA and ACOG suggest a glucose target of less than 95 mg/dL fasting and 140 mg/dL postprandial or less at 1 hour or 120 mg/dL at 2 hours. Clinicians should advise patients to keep glucose reading logs that can be reviewed at weekly prenatal visits or more frequently as needed.[1]

Pharmacologic Therapies

If the patient's glycemic control is not adequate despite optimal adherence to diet and exercise, pharmacologic treatment is recommended. Insulin therapy has traditionally been considered the standard therapy for patients with GDM not controlled by nonpharmacologic treatment. Oral agents are commonly used also, though this is an off-label use.[1]

Insulin therapy

Insulin does not cross the placental barrier and is recommended by the ADA for first-line treatment of GDM.[1] Insulin regimens usually consist of basal and short-acting insulin formulations. Basal dosages target fasting hyperglycemia, while postprandial hyperglycemia is typically treated by adjusting short-acting insulin dosages. Insulin dosages must be individualized based on glucose monitoring; however, the approximate total insulin required when initiating insulin therapy can be calculated using a patient's weight and gestational age (see Table. Calculation of Initial Total Daily Insulin Requirement for Gestational Diabetes). Thereafter, insulin dosage can be adjusted as indicated by glucose logs.[2]

Table. Calculation of Initial Total Daily Insulin Requirement for Gestational Diabetes

The patient should divide the total daily insulin dose in half, with one half given as basal insulin at bedtime and the other half divided between 3 meals and given as rapid-acting or regular insulin before meals.[2][1]

Oral hypoglycemic agents

The most commonly used oral hypoglycemic agents include metformin and glyburide, though studies on their effectiveness have demonstrated mixed results. Glyburide can be initiated at 2.5 mg daily and a maximum dosage of 20 mg. However, recent studies have not shown similar benefits to insulin treatment. Historically, glyburide was thought not to cross the placental barrier, but this is inaccurate according to recent study results. Additionally, glyburide is associated with an increased risk of neonatal intensive care admission, respiratory distress syndrome, hypoglycemia, and birth injury, as well as possible fetal insulin stimulation. Therefore, ACOG has recommended that glyburide should not be considered a first-line therapy.[1]

The initial dosage of metformin is typically 500 mg a day for 1 week, increased to twice a day thereafter to a maximum dosage of 2,500 to 3,000 mg. Metformin is known to cross the placenta and have adverse effects, including preterm birth and maternal abdominal pain and diarrhea. Furthermore, when compared to insulin, outcomes with metformin use, such as macrosomia, neonatal hypoglycemia, or cesarean delivery, were similar. Significant treatment failure was also noted, with 50% of patients requiring insulin therapy. Metformin may be considered as an alternative to insulin in patients who decline or are unable to afford insulin.[1][2]

Obstetric Considerations

Due to obstetrical risks associated with GDM, management varies depending on multiple clinical factors. For instance, fetal growth is typically assessed with serial ultrasound due to the risk of macrosomia and shoulder dystocia. GDM is also an indication of antepartum fetal surveillance due to the increased risk of fetal demise in patients with diabetes. Additionally, delivery timing and mode may vary depending on clinical indicators. ACOG guidelines recommend delivery by 40 6/7 weeks gestation in patients with diet-controlled GDM and 39 0/7 to 39 6/7 weeks gestation in those with medication-controlled GDM. However, in patients with uncontrolled GDM, delivery between 37 0/7 weeks and 38 6/7 weeks gestation is reasonable; for those with uncontrolled diabetes and other abnormal clinical factors (eg, abnormal antenatal fetal surveillance), earlier delivery may be considered. Furthermore, cesarean delivery may be discussed with women with GDM and an estimated fetal weight 4500 g or greater.[1]

Differential Diagnosis

Many women do not receive the appropriate screening for diabetes mellitus before pregnancy, so in some cases, it is challenging to distinguish GDM from preexisting diabetes and maturity-onset diabetes of the young.[18][19]

Prognosis

Proper control of maternal glucose levels significantly reduces GDM risks, including macrosomia and neonatal hypoglycemia. The risk of preeclampsia decreases from 18% to 12% with treatment.[1] If GDM interventions, including dietary modifications or pharmacologic therapy, are implemented early enough, progression to type 2 diabetes in 10 years is reduced by 35% to 40%. Furthermore, even small reductions in BMI can result in a reduced risk for diabetes by 25%.[20]

Complications

Maternal and fetal complications are associated with GDM. The fetal complications include macrosomia, neonatal hypoglycemia, polycythemia, shoulder dystocia, hyperbilirubinemia, neonatal respiratory distress syndrome, increased perinatal mortality, and hypocalcemia. Maternal complications include preeclampsia, increased risk of developing diabetes mellitus, and increased risk of Cesarean delivery.[21][22]