Gestational diabetes

Gestational diabetes (or gestational diabetes mellitus, GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. Gestational diabetes affects 3-10% of pregnancies, depending on the population studied.^[1] No specific cause has been identified, but it is believed that the hormones produced during pregnancy reduce a woman's sensitivity to insulin, resulting in high blood sugar levels.

Gestational diabetes generally has few symptoms and it is most commonly diagnosed by screening during pregnancy. Diagnostic tests detect high levels of glucose in blood samples.

Babies born to mothers with gestational diabetes are at increased risk of complications, primarily growth abnormalities and chemical imbalances such as low blood sugar. Gestational diabetes is a reversible condition and women who have adequate control of glucose levels can effectively decrease the associated risks and give birth to healthy babies.

Women with gestational diabetes are at high risk of developing type 2 diabetes mellitus after pregnancy, while their offspring are prone to developing childhood obesity, with type 2 diabetes later in life. Most patients are treated only with diet modification and moderate exercise but some take anti-diabetic drugs, including insulin therapy.

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Definition

Gestational diabetes is formally defined as "any degree of glucose intolerance with onset or first recognition during pregnancy".^[2] This definition acknowledges the possibility that patients may have previously undiagnosed diabetes mellitus, or may have developed diabetes coincidentally with pregnancy. Whether or not symptoms subside after pregnancy is also irrelevant to the diagnosis .^[3]

Epidemiology

The frequency of gestational diabetes varies widely by study depending on the population studied and the study design. It occurs in between 5 and 10% of all pregnancies (between 1-14% in various studies).^[3]

Pathophysiology

  The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway behind the insulin receptor.^[4]. Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5-2.5 times more insulin is produced in a normal pregnancy.^[4]

Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which progresses thereafter to levels seen in non-pregnant patients with type 2 diabetes. It is thought to secure glucose supply to the growing fetus. Women with GDM have an insulin resistance they cannot compensate with increased production in the β-cells of the pancreas. Placental hormones, and to a lesser extent increased fat deposits during pregnancy, seem to mediate insulin resistance during pregnancy. Cortisol and progesterone are the main culprits, but human chorionic somatomammotropin, prolactin and estradiol contribute too.^[4]

How this imbalance between insulin needs and production develops in GDM, remains unclear. Suggested mechanisms are similar to those in type 2 diabetes: autoimmunity, single gene mutations, and other mechanisms.^[5]

Because glucose travels across the placenta (through diffusion facilitated by GLUT3 carriers), the fetus is exposed to higher glucose levels. This leads to increased fetal levels of insulin (insulin itself cannot cross the placenta). The growth-stimulating effects of insulin can lead to excessive growth and a large body (macrosomia). After birth, the high glucose environment disappears, leaving these newborns with ongoing high insulin production and susceptibility to low blood glucose levels (hypoglycemia).^[6]

Risk factors and symptoms

Classical risk factors for developing gestational diabetes are the following:^[7]

• a previous diagnosis of gestational diabetes or prediabetes, impaired glucose tolerance, or impaired fasting glycaemia
• a family history revealing a first degree relative with type 2 diabetes
• maternal age - a woman's risk factor increases the older she is (especially if older than 35 years of age)
• ethnic background (those with higher risk factors include African-Americans, North American native peoples and Hispanics)
• being overweight, obese or severely obese increases the risk by a factor 2.1, 3.6 and 8.6, respectively.^[8]
• a previous pregnancy which resulted in a child with a high birth weight (>90th centile, or >4000 g)
• previous poor obstetric history

In addition to this, statistics show a double risk of GDM in smokers^[9] Polycystic ovarian syndrome is also a risk factor.^[7] Some studies have looked at more controversial potential risk factors, such as short stature.^[10]

Frequently women with gestational diabetes exhibit no symptoms (which is an argument in favour of screening during pregnancy). However, possible symptoms include increased thirst, increased urination, fatigue, nausea and vomiting, bladder infection, yeast infections and blurred vision.

Diagnosis and screening

Because GDM is asymptomatic in most cases, the diagnosis of gestational diabetes is a process that takes into account a clinical assessment of risk factors, screening tests and diagnostic tests. These tests look for high levels of glucose in plasma or serum. This can be done in a stepwise approach where a suspicious result on a screening test is followed by diagnosic test. Alternatively, a more complicated diagnostic test can be used directly at the first antenatal visit in high-risk patients (for example in those with polycystic ovarian syndrome or acanthosis nigricans).^[6]

Non-challenge blood glucose tests involve measuring glucose levels in blood samples without challenging the subject with glucose solutions. A blood glucose levels can be determined when fasting, 2 hours after a meal, or simply at any random time. Both screening glucose challenge tests and oral glucose tolerance tests involve drinking a glucose solution, to check how the body handles this glucose challenge.

The screening glucose challenge test and oral glucose tolerance test involve drinking a standard solution with a high concentration of glucose, which has a very sweet taste some women find unpleasant. Sometimes, artificial flavours are added for this reason. Some women may experience nausea during the test, and more so with higher glucose levels.^[11][12]

Screening pathways

Screening and diagnostic measures are controversial and differ between countries, in part due to differences in population risks, cost-effectiveness considerations, and lack of an evidence base to support large national screening programs.^[13] The most elaborate regime entails a random blood glucose test during a booking visit, a screening glucose challenge test around 24-28 weeks' gestation, followed by an OGTT if the tests are outside normal limits. If there is a high suspicion, women may be tested earlier.^[3]

In the United States, most obstetricians prefer universal screening of all women with a screening glucose tolerance test.^[14] In the United Kingdom, obstetric units often rely on risk factors and a random blood glucose test.^[15][6] The American Diabetes Association and the Society of Obstetricians and Gynecologists of Canada recommend routine screening unless the patient is low risk (this means the woman must be younger than 25 years and have a body mass index less than 27, with no personal, ethnic or family risk factors)^[3][13] The Canadian Diabetes Association and the American College of Obstetricians and Gynecologists recommend universal screening.^[16][17]

Urinary glucose testing

Women with GDM may have high glucose levels in their urine (glucosuria). Although dipstick testing is widely practiced, it performs poorly, and discontinuing routine testing has not been shown to cause underdiagnosis where universal screening is performed.^[18] Increased glomerular filtration rates during pregnancy contribute to some 50% of women having glucose in their urine on dipstick tests at some point during their pregnancy. The sensitivity of glucosuria for GDM in the first 2 trimesters is only around 10% and the positive predictive value is around 20%.^[19][20]

Non-challenge blood glucose tests

When a plasma glucose level is found to be higher than 126 mg/dl (7.0 mmol/l) after fasting, or over 200 mg/dl (11.1 mmol/l) on any occasion, and if this is confirmed on a subsequent day, the diagnosis of GDM is made, and no further testing is required.^[3] These tests are typically performed at the first antenatal visit. They are patient-friendly and inexpensive, but have a lower test performance compared to the other tests, with moderate sensitivity, low specificity and high false positive rates.^[21][22][23]

Screening glucose challenge test

The screening glucose challenge test is performed between 24-28 weeks, and can be seen as a simplified version of the oral glucose tolerance test (OGTT). It involves drinking a solution containing 50 grams of glucose, and measuring blood levels 1 hour later.^[24]

If the cut-off point is set at 140 mg/dl (7.8 mmol/l), 80% of women with GDM will be detected.^[3] If this threshold for further testing is lowered to 130 mg/dl, 90% of GDM cases will be detected, but there will also be more woman who will be subjected to a consequent OGTT unnecessarily.

Oral glucose tolerance test

The oral glucose tolerance test (OGTT)^[25] should be done in the morning after an overnight fast of between 8 and 14 hours. During the three previous days the subject must have an unrestricted diet (containing at least 150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated during the test and should not smoke throughout the test.

The test involves drinking a solution containing a certain amount of glucose, and drawing blood to measure glucose levels at the start and on set time intervals thereafter.

The diagnostic criteria from the National Diabetes Data Group (NDDG) have been used most often, but some centers rely on the Carpenter and Coustan criteria, which set the cutoff for normal at lower values. Compared with the NDDG criteria, the Carpenter and Coustan criteria lead to a diagnosis of gestational diabetes in 54 percent more pregnant women, with an increased cost and no compelling evidence of improved perinatal outcomes.^[26]

The following are the values which the American Diabetes Association considers to be abnormal during the 100 g of glucose OGTT:

• Fasting blood glucose level ≥95 mg/dl (5.33 mmol/L)
• 1 hour blood glucose level ≥180 mg/dl (10 mmol/L)
• 2 hour blood glucose level ≥155 mg/dl (8.6 mmol/L)
• 3 hour blood glucose level ≥140 mg/dl (7.8 mmol/L)

An alternative test uses a 75 g glucose load and measures the blood glucose levels before and after 1 and 2 hours, using the same reference values. This test will identify less women who are at risk, and there is only a weak concordance (agreement rate) between this test and a 3 hour 100 g test.^[27]

The glucose values used to detect gestational diabetes were first determined by O'Sullivan and Mahan (1964) in a retrospective study (using a 100 grams of glucose OGTT) designed to detect risk of developing type 2 diabetes in the future. The values were set using whole blood and required two values reaching or exceeding the value to be positive. ^[28] Subsequent information has led to alteration in O'Sullivan's criteria. When methods for blood glucose determination changed from the use of whole blood to venous plasma samples, the criteria for GDM were also changed.

Complications

GDM poses a risk to mother and child. This risk is largely related to high blood glucose levels and its consequences. Treatment resulting in better control of these levels can reduce some of the risks of GDM considerably.^[29]

The main risks GDM imposes on the baby are growth abnormalities and chemical imbalances after birth, which may require admission to a neonatal special care unit.

Infants born to mothers with GDM are at risk of being both large for gestational age (macrosomic) and small for gestational age. Macrosomia in turn increases the risk of instrumental deliveries (e.g. forceps, ventouse and caesarean section) or problems during vaginal delivery (such as shoulder dystocia). Macrosomia may affect 12% of normal women compared to 20% of patients with GDM.^[6] Labelling a woman as having GDM may in itself increase the risk of having a caesarean section.^[30][31]

Neonates are also at an increased risk of low blood glucose (hypoglycemia), jaundice, high red blood cell mass (polycythemia) and low blood calcium (hypocalcemia) and magnesium (hypomagnesemia).

GDM also interferes with maturation, causing dysmature babies prone to respiratory distress syndrome due to incomplete lung maturation.

Unlike pre-gestational diabetes, gestational diabetes has not been clearly shown to be an independent risk factor for birth defects. Birth defects usually originate sometime during the first trimester (before the 13th week) of pregnancy, whereas GDM gradually develops and is least pronounced during the first trimester. Studies have shown that the offspring of women with GDM are at a higher risk for congenital malformations; this is thought to be due to the inclusion of women with pre-existent type 2 diabetes who were not diagnosed before pregnancy.^[32][33][34]

Because of conflicting studies, it is unclear at the moment whether or not women with GDM have a higher risk of preeclampsia.^[35]

Prognosis

Gestational diabetes generally resolves once the baby is born. Based on different studies, the chances of developing GDM in a second pregnancy are between 30 and 84%, depending on ethnic background. A second pregnancy within 1 year of the previous pregnancy has a high rate of recurrence.^[36]

If a woman develops gestational diabetes, it implies her body processes glucose differently. Women diagnosed with gestational diabetes have an increased risk of developing diabetes mellitus in the future. The risk is highest in women who needed insulin treatment, had antibodies associated with diabetes (such as antibodies against glutamate decarboxylase, islet cell antibodies and/or insulinoma antigen-2), women with more than two previous pregnancies, and women who were obese (in order of importance).^[37][38] Women requiring insulin to manage gestational diabetes have a 50% risk of developing diabetes within the next five years.^[28] Studies in which women with GDM were followed for more than 10 years indicate that the long-term risk is approximately 70%.^[5] In populations with a low risk for type 2 diabetes, in lean subjects and in patients with auto-antibodies, there is a higher rate of women developing type 1 diabetes.^[38]

The child has an increased risk for childhood and adult obesity and an increased risk of glucose intolerance and type 2 diabetes later in life.^[39] This risk relates to increased maternal glucose values.^[40] It is currently unclear how much genetic susceptibility and environmental factors each contribute to this risk, and if treatment of GDM can influence this outcome.^[41]

There are scarce statistical data on the risk of other conditions in women with GDM; in the Jerusalem Perinatal study, 410 out of 37962 patients were reported to have GDM, and there was a tendency towards more breast and pancreatic cancer, but more research is needed.^[42][43]

Classification

The White classification, named after Priscilla White^[44] who pioneered in research on the effect of diabetes types on perinatal outcome, is widely used to assess maternal and fetal risk. It distinguishes between gestational diabetes (type A) and diabetes that existed prior to pregnancy (pregestational diabetes). These two groups are further subdivided according to their associated risks and management.^[45]

There are 2 subtypes of gestational diabetes (diabetes which began during pregnancy):

• Type A1: abnormal oral glucose tolerance test (OGTT) but normal blood glucose levels during fasting and 2 hours after meals; diet modification is sufficient to control glucose levels
• Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is required

The second group of diabetes which existed prior to pregnancy is also split up into several subtypes.

Treatment

The goal of treatment is to reduce the risks of GDM for mother and child. Scientific evidence is beginning to show that controlling glucose levels can result in less serious fetal complications (such as macrosomia) and increased maternal quality of life. Unfortunately, treatment of GDM is also accompanied by more infants admitted to neonatal wards and more inductions of labour, with no proven decrease in cesarean section rates or perinatal mortality.^[46][47] These findings are still recent and controversial.^[48]

Counselling before pregnancy (for example, about preventive folic acid supplements) and multidisciplinary management are important for good pregnancy outcomes.^[49] Most women can be managed with dietary changes and exercise. Self monitoring of blood glucose levels can guide therapy. Some women will need antidiabetic drugs, most commonly insulin therapy.

Any diet needs to provide sufficient calories for pregnancy. The main goal of dietary modifications is to avoid peaks in blood sugar levels. This can be done by spreading carbohydrate intake over meals and snacks throughout the day, and using slow-release carbohydrate sources. Since insulin resistance is highest in mornings, breakfast carbohydrates need to be restricted more.^[7]

Regular moderately intense physical exercise is advised, although there is no consensus on the specific structure of exercise programs for GDM.^[7][50]

  Self monitoring can be accomplished using a handheld capillary glucose dosage system. Compliance with these glucometer systems can be low.^[29][51]

There is some evidence that certain oral glycemic agents such as glyburide^[52] (a second generation sulfonylurea) might be safe in pregnancy, or at least, are significantly less dangerous to the developing fetus than poorly controlled diabetes. However, few studies have been performed as of this time and this is not a generally accepted treatment. These agents may be used in research settings, or if the patient needs intervention but refuses insulin therapy, and is aware of the risks.^[7] Metformin has shown promising results but is less well studied. Treatment of polycystic ovarian syndrome with metformin during pregnancy has been noted to decrease GDM levels.^[53]

Research suggests a possible benefit of breastfeeding to reduce the risk of diabetes and related risks for both mother and child.^[54]

A repeat OGTT should be carried out 2-4 months after delivery, to confirm the diabetes has disappeared. Afterwards, regular screening for type 2 diabetes is advised.^[7]

Controversy

Gestational diabetes is a controversial subject. Some critics question wether or not GDM is a disease in its own right. Labelling women as 'suffering from GDM' seems to predispose them to more interventions for perceived increased risks, while treatment of GDM has not been proven to affect major outcome parameters such as perinatal mortality and cesarian section rates. Lack of reproducebility of glucose tolerance testing is another problem area.^[55]

See also

• Diabetes mellitus and pregnancy

References