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CHAPTERGestational Diabetes Mellitus: An Update
Vinay Kumar Meena, Nazim Hussain, Rajani Nawal
ABSTRACT
Gestational diabetes mellitus (GDM) is the most common medical complication during pregnancy. It happens when the body cannot meet the increased insulin demand during pregnancy. It has been associated with increased risk of maternal and fetal adverse outcomes and its early diagnosis and management are found to have favorable results. Diagnosis is invariably based on two-step test, three-step test and/or glycated hemoglobin (HbA1c) levels as recommended by various societies. Now GDM diagnosed before 24 weeks of gestation has also been given importance as it has been associated with variable pregnancy outcomes and its diagnosis and treatment are potential research areas. Management consists of self-blood glucose monitoring, medical nutritional therapy, and drugs therapy. Insulin is preferred over oral hypoglycemic agents (OHAs) and regular insulin is the drug of choice. Metformin is the preferred agent if OHA has to be used, while there are concerns regarding long-term consequences as it has transplacental passage. After delivery, postpartum screening should be done and those having negative results should be followed up further for development of diabetes.
INTRODUCTION
Insulin sensitivity declines during pregnancy due to estrogen, progesterone and human placental lactogen, it is the body’s adaptation to meet increased fetal glucose demands, in response there is increased levels of insulin secretion in the mother. Gestational diabetes mellitus (GDM) occurs when the body cannot keep up with the increased insulin demand during pregnancy. It is defined as carbohydrate intolerance of different severity that begins or is observed for the first-time during pregnancy. The term GDM is intended to indicate the need for additional monitoring during pregnancy and to facilitate further diagnosis after delivery.
A more traditional definition used by the American Diabetes Association (ADA) is “diabetes diagnosed in the second or third trimester but not clearly seen before pregnancy”. This definition does not include patients diagnosed in the first trimester as they may have previously undiagnosed type 2 diabetes mellitus (T2DM). The term “overt diabetes” is sometimes used to describe diabetes during pregnancy in these individuals. Type 2 diabetes mellitus is diagnosed when it is diagnosed in a nonpregnant state.
The American College of Obstetricians and Gynecologists (ACOG) continues to define GDM as “a condition of carbohydrate intolerance that occurs during pregnancy.” GDM is usually diagnosed between weeks 24 and 28 of pregnancy.
Diagnosis of diabetes early in pregnancy (sometimes called overt diabetes) is more consistent with previously undiagnosed T2DM.
Early GDM includes those “pregnant females who are not reaching threshold for overt diabetes but fulfills criteria for conventional GDM before 24 weeks of gestation”.
The most important perinatal effect of GDM is fetal overgrowth, which can harm both mother and child. The incidence of fetal death in well-treated GDM is not different from that of the general population. “Women with GDM carry 60% lifetime risk of developing T2DM”. In addition, emerging evidence shows that their offspring suffer from long-term health problems including obesity and diabetes.
Why are We Concerned?
Gestational diabetes mellitus has been associated with increased risks of various adverse outcomes. Treatment of GDM is found to reduce the risk of some short-term outcomes like preeclampsia, macrosomia, while a favorable effect on long-term outcomes is not clear.
Short-term Adverse Effects
- Polyhydramnios, macrosomia, preeclampsia, gestational hypertension, preterm delivery, fetal/neonatal cardiomyopathy, and operative/assisted delivery
- Shoulder dystocia, maternal and/or newborn birth trauma, metabolic complications (e.g., hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperviscosity syndrome), neonatal respiratory problems, and stillbirth
“The risks of these adverse outcomes increase with the fasting and postprandial glucose concentration along the whole glucose distribution in a linear manner.” This effect has been seen to show a continuum over the range of blood glucose; however, no clear threshold has been defined that tell us about the increased risk of adverse pregnancy outcomes. “The small increase in congenital anomalies observed in some population-based studies of GDM is likely related to undiagnosed preexisting T2DM or maternal obesity”.
Long-term Adverse Effects
• Adolescent and adult offspring: Children born to GDM females are prone to obesity, abnormal glucose tolerance, hypertension, and metabolic syndrome. There is an increased risk of adverse neurodevelopmental outcomes in these children, some of them are also attributed to environmental and genetic factors; hence, further studies are required in this area.
• Maternal: Females having GDM are prone to development of diabetes mellitus (mainly T2DM), metabolic syndrome, and cardiovascular diseases later in life.
CRITERIA FOR DIAGNOSIS
Diabetes in pregnancy can be pregestational (overt) (which might have not been diagnosed earlier) or GDM.
• Both ADA and ACOG suggest early pregnancy testing (at the first antenatal visit) for undiagnosed T2DM (overt) in women with risk factors.
Current studies on early GDM suggest that this group represents a high-risk population and an important class of GDM to classify. There are substantial differences of opinion to whether they favor early diagnosis and treatment; these approaches are largely extrapolated from studies on diabetes at 24–28 weeks. Hence, there is a lack of consensus toward a standard approach to early GDM. More research is needed in this domain in order to determine the optimal test and diagnostic criteria/glycemic thresholds to provide best possible accuracy to define early GDM.• There is no consensus on the type of test to administer for GDM (to be administered at 24–28 weeks), opinions include:
○ One-step test [2-hour, 75-g oral glucose tolerance test (OGTT)]—recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), ADA, World Health Organization (WHO) and is widely accepted internationally.
○ Two-hour oral glucose tolerance test:
■ Fasting: 92 mg/dL (5.1 mmol/L)
OR■ 1 hour: 180 mg/dL (10 mmol/L)
OR■ 2 hours: 153 mg/dL (8.5 mmol/L)
A single value above threshold is diagnostic.○ Two-step test (1-hour, 50 g GTT without regard to time of day/previous meals; screen-positive patients go on to have a 3-hour 100 g OGTT)—preferred by ACOG and ADA.
– Step 1:
i. 50-g oral glucose is given without regard to time of day.
- Preconceptional management: For people with preexisting diabetes, HbA1c lower than 6.5% is ideal but difficult to achieve, so it is good to improve HbA1c before pregnancy.
- The benefits of treating GDM diagnosed before 24 weeks of gestation have not been proven. In a study comparing treatment initiation at 24–28 weeks versus early immediate treatment of patients if diagnostic criteria are met, early immediate treatment did not reduce the incidence of macrosomia in term infants or preeclampsia in pregnant women. These findings prompted researchers to reconsider the early diabetes screening process. Although treatment is recommended for overt diabetes diagnosed during early pregnancy.
Although other studies have shown that immediate treatment of GDM before 24 weeks of gestation slightly reduces the incidence of adverse pregnancy outcomes compared to no immediate treatment. No significant differences were found in pregnancy-related blood pressure changes or neonatal lean body mass. However, further studies are needed in order to frame proper guidelines for defining, diagnosing, and treating early GDM
ii. Blood glucose concentration at 1 hour after administration is measured.
iii. Glucose ≥135 mg/dL (7.5 mmol/L) or ≥140 mg/dL (7.8 mmol/L) is elevated; this requires a 100-g OGTT.
Note:*Choosing a lower threshold leads to more false-positives, so it should be considered in populations with high prevalence of GDM (some experts also use criteria of 130 mg/dL)
– Step 2:
i. Measure fasting blood glucose concentration
ii. Give 100-g oral glucose
iii. Measure blood glucose concentration at 1, 2, and 3 hours after administration.
iv. A positive test is generally defined by elevated glucose concentrations at two or more readings out of four above thresholds [either Carpenter and Coustan thresholds or National Diabetes Data Group (NDDG) thresholds can be used (Table 1)].
HBA1c only; a diagnosis of overt diabetes is made when Hb A1c is ≥6.5% (≥48 mmol/mol)
ADA prefers a two-step approach while single-step approach is also recommended.
| TABLE 1: Carpenter and Coustan thresholds or National Diabetes Data Group thresholds and their values. | ||
Carpenter/Coustan plasma or serum: mg/dL (mmol/L) |
National Diabetes Data Group Plasma: mg/dL (mmol/L) |
|
Fasting |
95 (5.3) |
105 (5.8) |
1 hour |
180 (10) |
190 (10.6) |
2 hours |
155 (8.6) |
165 (9.2) |
3 hours |
140 (7.8) |
145 (8) |
Both ADA and ACOG suggest early pregnancy testing for undiagnosed T2DM in women with risk factors. Some clinicians screen all women by obtaining an A1c with the routine prenatal laboratory tests. By contrast, a USPSTF (US Preventive Services Task Force) guideline concluded available evidence was insufficient to assess the balance of benefits and harms of screening asymptomatic pregnant patients for glucose intolerance before 24 weeks of gestation.
Role of HbA1c is not established in diagnosing GDM. In pregnancy, HbA1c levels drop due to physiological changes, therefore pregnancy-specific cut-offs need to be recognized for monitoring of overt diabetes mellitus.
MANAGEMENT
○ Treatment of GDM:
– Blood glucose monitoring: Test blood glucose several times a day, self-blood glucose monitoring is advised. The monitoring period should be before breakfast and 1–2 hours after the meal.
– Mild GDM: Here frequency of glucose monitoring can be reduced.
It is defined as blood glucose levels elevation within 5–10 points of target, without evidence of fetal overgrowth [defined as abdominal circumference (AC) >75th centile or estimated fetal weight (EFW) ≥ 90th centile] and normal amniotic fluid volume (i.e., no polyhydramnios).
Blood glucose target levels (based on ADA and ACOG recommendations):
– Fasting blood glucose level: <95 mg/dL (5.3 mmol/L)
– One-hour postprandial blood glucose level:<140 mg/dL (7.8 mmol/L)
– Two-hour postprandial blood glucose level: <120 mg/dL (6.7 mmol/L)
A combination of nutrition therapy, self-monitoring of blood glucose, and drug therapy is essential for a good perinatal outcome. It has led to significant reduction in pregnancy related complications, viz., large for gestational age baby, shoulder dystocia, and pregnancy-related hypertensive disorder.
Medical Nutrition Therapy
Nutrition therapy is the first method, where low glycemic index, high fiber, DASH (Dietary Approaches to Stop Hypertension) diet, and low carbohydrate diet are recommended.
The caloric needs of GDM patients are the same as those of non-GDM patients. For patients with a healthy prepregnancy body mass index (BMI), caloric needs are the same as before in the first trimester, with an increase of 340 calories per day in the second trimester and 452 calories per day in the third trimester. The calories here are usually split between three small to medium meals and 2–4 snacks a day, and has about 40% carbohydrates, 20% protein, and 40% fat. Meal plans are adjusted based on self-monitoring of blood sugar, exercise levels, and weight gain patterns.
Drugs
It is used in patients whose blood sugar cannot be controlled by diet and exercise alone (when at least 30% of blood glucose readings are higher than the target glucose in a week).
Drug therapy is also recommended in patients with indirect evidence of fetal hyperinsulinemia (based on parameters such as AC >75th percentile or EFW ≥90th percentile on early third trimester ultrasound), regardless of maternal blood glucose readings.
Insulin
Recommendations favor the use of insulin instead of noninsulin oral hypoglycemic agents. Insulin is administered according to multiple blood glucose readings taken throughout the day, while complex regimens are required if this fails to maintain target blood glucose levels.
Regular human insulin is the drug of first choice and rapid-acting drugs (insulin lispro and insulin aspart) are safe during pregnancy.
Among long-acting insulins, neutral protamine Hagedorn (NPH) has always been considered safe, detemir has been evaluated in many trials and is safe, insulin glargine can be used if required, and other newer analogs have not been well tested during pregnancy.
Oral Hypoglycemic Drugs
Metformin and glyburide are two drugs that can be used in patients who do not comply with or refuse to take insulin. They are passed transplacentally to the fetus, while knowledge regarding long-term consequences is lacking. “The ADA recommends that metformin be avoided in patients at risk of hypertension, preeclampsia, or intrauterine growth restriction due to potential growth restriction or acidosis in the setting of placental insufficiency.” However, human studies have not shown such an effect, so this is not supported by the ACOG and the Society for Maternal Fetal Medicine. When comparing the two (metformin and glyburide), metformin resulted in a similar rate of perinatal mortality, hypertensive disorder of pregnancy, lower mean birth weight, lesser macrosomia, and lower pregnancy weight gain.
Intrapartum Management
Target blood sugar while labor is in-between 90 mg/dL and 125 mg/dL.
Insulin infusion is started when the labor progresses to the active phase or when patient is held nil by mouth, and when blood glucose level falls below the desired level, dextrose-containing fluids are started and they are titrated as per the blood glucose level.
Postpartum Care of Mother
At 4–12 weeks postpartum, a 75-g oral glucose tolerance test is recommended to rule out the possibility of development of T2DM or impaired fasting glucose. ADA and ACOG recommend repeating tests every 1–3 years for women who developed GDM and had normal postpartum screening results.
CONCLUSION
Gestational diabetes mellitus is the most common complication of pregnancy and its prevalence is increasing globally. Despite knowing the potential benefits of its early diagnosis and management, still there is no consensus on a single standard approach. The mortality and morbidity are shown to have linear relation with glycemic control while no separate risk groups are defined. This highlights the difficulty of defining absolute glycemic thresholds at a single point in pregnancy for GDM diagnosis.
A precise medical approach that defines GDM subtypes and their variations is required. More understanding into genetics and novel biomarkers is required.
Early GDM (before 24 weeks) has also been supposed to be associated with adverse outcomes; hence, more understanding of its development and management is needed.
Evaluation of dietary intervention for establishing optimal carbohydrate threshold in GDM is required. Further understanding of long-term effects of metformin on fetus is to be understood. Efficacy of preconceptional and early pregnancy glycemic control should be clarified.
It should be noted that increased prevalence of GDM reflects increasing metabolic disease burden including prediabetes and obesity in females of child bearing age. So early postnatal screening of mother and long-term follow-up is stressed to prevent progression from GDM to T2DM.
SUGGESTED READINGS
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7. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64.
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