Gestational diabetes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Gestational diabetes (GDM) is a form of diabetes that is first detected during pregnancy. It usually occurs in the second or third trimester, in women who were not known to be diabetic before pregnancy. There is no known specific cause, but it is believed that the hormones produced during pregnancy reduces receptivity to insulin, resulting in high blood sugar. Gestational diabetes mellitus (GDM) is similar to type 2 diabetes, a combination of relatively inadequate insulin secretion and reduced responsiveness to insulin occurs. Gestational diabetes occurs in approximately 7.5% of all pregnancies in the United States, and there is often improvements/complete resolution after delivery. Untreated gestational diabetes can damage the health of the fetus and the mother. The risks to the baby include macrosomia (high birth weight), lower blood sugar after birth, jaundice, congenital cardiac and central nervous system anomalies, and skeletal muscle malformations and in the future babies are at risk of developing type 2 diabetes. Increased fetal insulin may inhibit fetal surfactant production and cause [[Infant respiratory distress syndrome|respiratory distress syndrome]]. Hyperbilirubinemia may result from red blood cell destruction.

• Diabetes mellitus is an ancient term first found in the Egyptian Eberes papyrus around 1500 BC. Hyperglycemia in pregnancy was first described by Bennewitz, a German physician in 1824. In 1950, the terminology ‘GDM’ was accepted.^[1]
• John B. O’Sullivan, Wilkerson and Remein in 1957 proposed offering a 3-hour oral glucose tolerance test (OGTT) for patients presenting with risk factors for diabetes such as a family history of diabetes, gestational glycosuria and overdeveloped infants at birth.^[2]

Gestational diabetes refers to hyperglycemia during the second or third trimester of pregnancy.^[3]

Insulin sensitivity reduces slightly during the first and second trimesters but it decreases by 40-60% during the third trimester.^[4][5][6] Other changes at the molecular level that may lead to insulin resistance include a reduced ability of insulin to phosphorylate the insulin receptor, decreased expression of insulin receptor substrate 1 (IRS-1), and increased levels of a specific kinase.^[7] Factors affecting insulin sensitivity include estrogens and progesterone,^[8] human chorionic somatomammotropin (hCS) or placental lactogen (HPL), prolactin, placental growth hormone variant (hGH-V), corticotropin-releasing factor (CRF) and corticotropin, leptin,^[9] tumor necrosis factor α (TNF-α),^[10] adiponectin,^[11] resistin, ghrelin, and interleukin-6.

Basal and postprandial levels of glucose, FFAs, triglycerides, and amino acids are higher in GDM than in normal pregnancy.^[12] Maternal hyperglycemia leads to fetal hyperinsulinism, which is responsible for the macrosomia and neonatal morbidity. The development of macrosomia (defined as birth weight >4000g or above the 90th percentile for gestational age), is a frequent occurrence in pregnancies complicated by DM and GDM. Increased adiposity is the primary component of the macrosomia. Infants of diabetic mothers may have up to twice the body fat content of infants of normal mothers.^[13]

GDM must be differentiated from other causes of hyperglycemia during pregnancy such as diabetes type 1 or type 2.

The prevalence of gestational diabetes mellitus varies widely. It may range from 1% to 14% of all pregnancies. The prevalence of GDM showed a 12% increase per year from 1994 to 2002 in one study.^[14] The increasing rate over time is possibly due to increases in mean maternal age and weight. According to another study, the age and race/ethnicity adjusted prevalence of GDM was from 7.5 per 100 in 1999 compared to 7.4 per 100 in 2005.^[15] The ethnical prevalence of GDM was noticed to be higher in Asian/Pacific Islanders (relative risk=1.97), Hispanic (RR=1.69) and African-American(RR=1.26) than for caucasian women after adjustment for the year and maternal age.^[15]

Risk factors for gestational diabetes include:^{[16][17][18][19][20]}

• A family history of diabetes especially in first degree relatives
• Maternal age >25 yrs
• Certain ethnic groups (such as Native American, Hispanic-American, African-American, South or East Asian, Pacific Islander)
• Body mass index greater than 25 kg/m²
• Gestational diabetes or impaired glucose tolerance test in previous pregnancies
• Previous delivery of a baby >9 pounds
• Personal history of impaired glucose tolerance or impared fasting glucose (pre-diabetes)
• Glycosuria at the first prenatal visit
• Certain medical conditions (such as metabolic syndrome, polycystic ovary syndrome (PCOS), current use of glucocorticoids, hypertension)
• Previous history of unexplained miscarriage or stillbirth
• Smoking (doubles the risk for gestational diabetes)
• Multiple gestation
• Genetic predisposition (.e.g. glucokinase mutation)

Screening can be performed during the first prenatal visit, especially in mothers with risk factors for GDM. If the result is negative, or the test was not carried out during the first prenatal visit, screening at 24-28 weeks gestational age is ideal.^[21][22]

• Regardless of the fasting status of mother ,a one hour plasma glucose level is measured following a 50 gram glucose load. Measurements greater than 130 mg/dl are considered positive for GDM. 130 mg/dl threshold has 88% to 99% sensitivity, and 66% to 77% specificity.^[23]
• The next step is to confirm the diagnosis by performing a 100 gram 3 hour Glucose Test.

• Most women with GDM return to their pre pregnancy glycemic status after delivery.
• Women diagnosed with gestational diabetes have an increased risk of developing overt diabetes mellitus in the future. Women requiring insulin to manage gestational diabetes have a 50% risk of developing diabetes within the next five years. ^[24]
• One-third to two-thirds of women will re-experience GDM in subsequent pregnancies.^[25][26]
• Risk factors for recurrence include older age, multiparity, higher maternal weight in the index pregnancy, and weight gain between pregnancies.^[27][26]

• Maternal complications of GDM can be categorized into obstetrical and long term glycemic status related complications. Pre-eclampsia, polyhydramnios, and difficult labor due to fetal macrosomia, are obstetrical complications. Risk of developing prediabetes or even overt diabetes is noticeable in GDM patients.^[28][29][30]

• Poor glycemic control and increased insulin level may result in increased metabolic demands in the fetus, resulting in fetal and neonatal complications. Large for gestational age, prematurity, respiratory distress syndrome, hyperbilirubinemia, polycythemia, and congenital anomalies, are the most common complications in neonates.^[31][32]

There are two method for diagnosing GDM.

• One-step approach: 75-g Oral glucose tolerance test; and
• Two-step approach with a 50-g (non fasting) screen followed by a 100-g OGTT for those who screen positive.

Both methods have good diagnostic yields.^[33]

• Usually there are no symptoms, or the symptoms are mild and not life threatening to the pregnant woman.^[34]

• Symptoms may include:

• Blurred vision
• Fatigue
• Frequent infections, including those of the bladder, vagina, and skin
• Increased thirst
• Increased urination
• Nausea and vomiting
• Weight loss in spite of increased appetite
• Excessive thirst

There is no specific physical examination finding for gestational diabetes. Signs of insulin resistance (i.e. acanthosis nigricans) may be seen on physical examination.

Generally a test for gestational diabetes is carried out between the 24th and 28th week of pregnancy.

If the patient is at risk for gestational diabetes (see risk factors), a screening test should be done earlier in the pregnancy.

After the diagnosis of GDM, treatment should be commenced with medical nutrition therapy, physical activity, and weight management, depending on the pregestational weight.^[35] The aim of treatment is to achieve the following target for the plasma glucose level:

• Fasting <95 mg/dL (5.3 mmol/L)

• One-hour postprandial <140 mg/dL (7.8 mmol/L)

• Two-hour postprandial <120 mg/dL (6.7 mmol/L)

• Many randomized controlled trials suggest that the risk of GDM may be reduced by diet, exercise, and lifestyle counseling.^[36][37]
• All women diagnosed with GDM require nutritional counseling for the appropriate amount of weight gain during pregnancy as well as dietary control. Women with a normal BMI [20-25], can consume about 30kcal/kg/d while those who are obese [BMI >25-34] should restrict their diet to 25 kcal/kg/d, and those with a BMI >34 should consume 20kcal/kg/d or less.
• These patients should restrict fat intake and substitute simple or refined sugars in their diet for more complex carbohydrates.

All exogenous insulins are pregnancy category B except for glargine, glulisine and degludec which are labeled category C. Insulin therapy in patients with GDM is based on the pre-pregnancy BMI.

• In the first trimester, the insulin requirement is approximately 0.7 units per kilogram body weight.
• By the second trimester, the insulin requirement is 0.8 units per kilogram body weight.
• By term, the insulin requirement is 0.9 -1.0 unit per kilogram body weight per day.^[38]

Recent studies showed that sulfonylureas, such as glyburide, may be inferior to insulin and metformin due to increased risk of neonatal hypoglycemia and macrosomia with this class.^[39]

It is associated with a lower risk of hypoglycemia and potential lower weight gain, may be preferable to insulin if it adequately controls hyperglycemia, however, metformin may slightly increase the risk of prematurity.^[39][40][41]

Weight control, dietary control, and life style modification, are the mainstay modalities for preventing GDM.

After delivery, mothers diagnosed with GDM should have close follow up to prevent overt diabetes in future. Testing with 75 g OGTT 6 to 12 weeks after delivery and then every 1-3 years is recommended for early diagnosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Diabetes mellitus is an ancient term first found in the Egyptian Eberes papyrus around 1500 BC. Hyperglycemia in pregnancy was first described by Bennewitz, a German physician in 1824. In 1950, the term ‘GDM’ was accepted.

• Diabetes mellitus was first described in the Egyptian Eberes papyrus around 1500 BC.^[1]
• Hyperglycemia in pregnancy was first described by Bennewitz, a German physician in 1824.^[1]
• Before the discovery of insulin in 1922, infertility was well recognized in women with diabetes.
• In 1856, the presence of physiological glycosuria in pregnancy and lactation was first described.
• Brocard in 1898, demonstrated for the first time that pregnant women were less tolerant to sugar compared to non-pregnant women; he found the presence of glycosuria 2 hours after the ingestion of 50 g of glucose in 50% of pregnant women compared to 11% found in non-pregnant women.
• Skipper in 1933, published a vast review of the literature on the use of insulin in pregnancy and found a dramatic improvement in maternal mortality, and a modest impact on fetal and neonatal outcomes and survival.
• In the 1950s, many risk factors for the development of abnormalities in carbohydrate metabolism during pregnancy were defined and the term gestational diabetes mellitus (GDM) became accepted.^[2][3][4]
• John B. O’Sullivan, Wilkerson and Remein in 1957, proposed offering a 3-hour oral glucose tolerance test (OGTT) for patients presenting with risk factors for diabetes such as a family history of diabetes, gestational glycosuria and overdeveloped infants at birth.^[3]
• For women without known risk factors, they proposed determining a 1-hour blood glucose value after the ingestion of a 50 g glucose load. A value of 130 mg or more was considered abnormal and a 3-hour OGTT should be performed afterwards.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Gestational diabetes refers to hyperglycemia during the second or third trimester of pregnancy.

Gestational diabetes was referred to as any type of hyperglycemia that was not recognized or present prior to pregnancy. This definition is no longer used because of the increased number of females with type 2 diabetes and obesity who became pregnant without awareness of their pre-pregnancy glycemic status.^[1]

The American Diabetes Association (ADA) classifies GDM as diabetes diagnosed in the second or third trimester of pregnancy, that is not clearly either type 1 or type 2 diabetes.^[1]

White classified diabetes in pregnancy in to two groups:^[2]

• Type A1: Controlled by diet and exercise
• Type A2: Requires insulin for treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Insulin insensitivity due to hormonal changes in pregnancy (especially during the second and third trimesters), and changes in maternal metabolism, are the main predisposing factors for acquiring gestational diabetes.

Maternal metabolic changes during pregnancy varies based on the age of the pregnancy, the maternal nutritional status, and the age of the mother.^[1]

Insulin sensitivity reduces slightly during the first and second trimester, but it decreases by 40-60% during the third trimester.^[2][3][4]

Other changes in the molecular level that may lead to insulin resistant include:^[5]

• A reduction in the ability of insulin to phosphorylate the insulin receptor
• Decreased expression of insulin receptor substrate 1 (IRS-1) and increased levels of a specific kinase

Factors affecting insulin sensitivity include: estrogens and progesterone,^[6] human chorionic somatomammotropin (hCS) or placental lactogen (HPL), prolactin, placental growth hormone variant (hGH-V), corticotropin-releasing factor (CRF) and corticotropin, leptin,^[7] tumor necrosis factor α (TNF-α),^[8] adiponectin,^[9] resistin, ghrelin and interleukin-6.

Basal and postprandial levels of glucose, FFAs, triglycerides, and amino acids, are higher in GDM than in normal pregnancy.^[10]

Maternal hyperglycemia leads to fetal hyperinsulinism, which is responsible for macrosomia and neonatal morbidity. The development of macrosomia (defined as birth weight >4000 g or above the 90th percentile for gestational age), is a frequent complication of pregnancies complicated by DM and GDM.
^[11] Increased adiposity is the primary component of the macrosomia. Infants of diabetic mothers may have up to twice the body fat content of infants of normal mothers.^[12]

Shown below is a schematic model of the disease progression and consequences.

It has been found that women diagnosed with gestational diabetes already have insulin resistance at baseline, with a higher level of plasma insulin levels. This state gets further aggravated by the metabolic changes associated with pregnancy. The pancreas is unable to cope with the additional stress of increased insulin resistance. This results in an inadequate release of insulin and elevated blood sugar levels.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

There are no established causes for gestational diabetes, although several risk factors have been implicated.

There are no established causes for gestational diabetes, however, several risk factors may predispose a woman to develop gestational diabetes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

GDM must be differentiated from other causes of hyperglycemia during pregnancy, for example, diabetes type 1 or type 2.

GDM must be differentiated from other causes of hyperglycemia during pregnancy. They include

• Overt diabetes either type 1 or type 2
• Secondary causes of diabetes (e.g. medication induced diabetes)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

The prevalence of GDM varies from 1% to 14% in different studies. It seems to be more common among Hispanics, Asian/Pacific Islanders, and African-Americans, compared to other races.

The prevalence of gestational diabetes mellitus varies widely. It may range from 1% to 14% of all pregnancies.

The prevalence of GDM showed a 12% increment per year between 1994 to 2002 in one study.^[1] The increasing rate over time is possibly due to increases in mean maternal age and weight.^[2]

In another study over a 7 year period, the age and race/ethnicity adjusted prevalence of GDM was 7.5 per 100 in 1999 and 7.4 per 100 in 2005.^[3]

In one study, the ethnical prevalence of GDM was higher in Asian/Pacific Islanders (relative risk=1.97), Hispanic (RR=1.69) and African-American(RR=1.26) than for caucasian women after adjustment for year and maternal age.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

The predisposing risk factors for gestational diabetes include; an age >25 years, BMI >25, positive history of impaired glucose tolerance test or GDM, positive family history of diabetes, certain ethnic groups, certain medical condition, and multiple gestation.

Risk factors for gestational diabetes include:^{[1][2][3][4][5]}

• A family history of diabetes especially in first degree relatives
• Maternal age >25 yrs
• Certain ethnic groups (such as Native American, Hispanic-American, African-American, South or East Asian, Pacific Islander)
• Body mass index greater than 25 kg/m²
• Gestational diabetes or impaired glucose tolerance test in previous pregnancies
• Previous delivery of a baby >9 pounds
• Personal history of impaired glucose tolerance or impared fasting glucose (pre-diabetes)
• Glycosuria at the first prenatal visit
• Certain medical conditions (such as metabolic syndrome, polycystic ovary syndrome (PCOS), current use of glucocorticoids, hypertension)
• Previous history of unexplained miscarriage or stillbirth
• Smoking (doubles the risk of gestational diabetes)
• Multiple gestation
• Genetic predisposition (.e.g. glucokinase mutation)
• Chronic or gestational hypertension

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

The most useful method for GDM screening is to perform the 50 gram glucose test in 24-28 weeks of pregnancy in low risk women. High risk pregnancies should be screened earlier, at the first prenatal visit if possible.

Screening can be performed during the first prenatal visit, especially in women with risk factors for GDM. If the result is negative or the test was not done during the first prenatal visit, screening at 24-28 weeks of gestation is ideal.^[1][2]

• Regardless of the fasting status of the woman, a 50 gram glucose load is given. 1 hour later, plasma glucose level should be measured. A measurement greater than 130 mg/dl is suggestive of GDM (130 mg/dl threshold has 88% to 99% sensitivity, and 66% to 77% specificity).^[3]
• The next step is to confirm the diagnosis by performing a 100 gram 3 hour Glucose Test.

“1. Test for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. (Level of Evidence: B)”

“2. Test for gestational diabetes mellitus at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. (Level of Evidence: A)”

“3. Screen women with gestational diabetes mellitus for persistent diabetes at 6–12 weeks postpartum, using the oral glucose tolerance test and clinically appropriate nonpregnancy diagnostic criteria (Level of Evidence: E)”

“4. Women with a history of gestational diabetes mellitus should have lifelong screening for the development of diabetes or prediabetes at least every 3 years. (Level of Evidence: B)”

“5. Women with a history of gestational diabetes mellitus found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes. (Level of Evidence: A)”

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Most women with GDM will return to their pre-pregnancy glycemic status after delivery, but there is an increased chance of developing overt diabetes or prediabetes during the next 5 years. Recurrent GDM is another subject that physicians should be aware of.

• If GDM is left untreated, serious fetal complications can develop during pregnancy, and progression to overt diabetes can also occur in the long term.

• Most of women with GDM return to their pre pregnancy glycemic status after delivery.
• Women diagnosed with gestational diabetes have an increased risk of developing overt diabetes mellitus in the future. Women requiring insulin to manage gestational diabetes have a 50% risk of developing diabetes within the next five years.^[1]
• One-third to two-thirds of women will re-experience GDM in subsequent pregnancies.^[2][3]
• Risk factors for the recurrence of GDM include older age, multiparity, higher maternal weight in the index pregnancy, and weight gain between pregnancies.^[4][3]

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