Definitions

Gestational_diabetes

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 generally has few symptoms and it is most commonly diagnosed by screening during pregnancy. Diagnostic tests detect high levels of glucose in blood samples. Gestational diabetes affects 3-10% of pregnancies, depending on the population studied. 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.

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 treatable 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 increased 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.

Definition

Gestational diabetes is formally defined as "any degree of glucose intolerance with onset or first recognition during pregnancy". This definition acknowledges the possibility that patients may have previously undiagnosed diabetes mellitus, or may have developed diabetes coincidentally with pregnancy. Whether symptoms subside after pregnancy is also irrelevant to the diagnosis .

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).

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.. 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.

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.

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.

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).

Risk factors and symptoms

Classical risk factors for developing gestational diabetes are the following:

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

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 diagnostic 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).

Tests for gestational diabetes
Non-challenge blood glucose tests
  • Fasting glucose test
  • 2-hour postprandial (after a meal) glucose test
  • Random glucose test

Screening glucose challenge test
Oral glucose tolerance test (OGTT)

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.

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. 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.

In the United States, most obstetricians prefer universal screening of all women with a screening glucose tolerance test. In the United Kingdom, obstetric units often rely on risk factors and a random blood glucose test. 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) The Canadian Diabetes Association and the American College of Obstetricians and Gynecologists recommend universal screening. The U.S. Preventive Services Task Force found that there is insufficient evidence to recommend for or against routine screening.

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 dipstick testing has not been shown to cause underdiagnosis where universal screening is performed. 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%.

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. 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.

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.

If the cut-off point is set at 140 mg/dl (7.8 mmol/l), 80% of women with GDM will be detected. 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 women who will be subjected to a consequent OGTT unnecessarily.

Oral glucose tolerance test

The oral glucose tolerance test (OGTT) 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.

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.

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. Subsequent information led to alterations 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. The risk increases with higher blood glucose levels. Treatment resulting in better control of these levels can reduce some of the risks of GDM considerably.

The two main risks GDM imposes on the baby are growth abnormalities and chemical imbalances after birth, which may require admission to a neonatal intensive 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. However, the evidence for each of these complications is not equally strong; in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study for example, there was an increased risk for babies to be large but not small for gestational age. Research into complications for GDM is difficult because of the many confounding factors (such as obesity). Labelling a woman as having GDM may in itself increase the risk of having a caesarean section.

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 and impaired surfactant synthesis.

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.

Because of conflicting studies, it is unclear at the moment whether women with GDM have a higher risk of preeclampsia. In the HAPO study, the risk of preeclampsia was between 13% and 37% higher, although not all possible confounding factors were corrected.

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.

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). Women requiring insulin to manage gestational diabetes have a 50% risk of developing diabetes within the next five years. Depending on the population studied, the diagnostic criteria and the length of follow-up, the risk can vary enormously. The risk appears to be highest in the first 5 years, reaching a plateau thereafter. One of the longest studies followed a group of women from Boston, Massachusetts; half of them developed diabetes after 6 years, and more than 70% had diabetes after 28 years. In a retrospective study in Navajo women, the risk of diabetes after GDM was estimated to be 50 to 70% after 11 years. Another study found a risk of diabetes after GDM of more than 25% after 15 years. 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.

Children of women with GDM have an increased risk for childhood and adult obesity and an increased risk of glucose intolerance and type 2 diabetes later in life. This risk relates to increased maternal glucose values. 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.

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 to confirm this finding.

Classification

The White classification, named after Priscilla White 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.

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. These findings are still recent and controversial.

Counselling before pregnancy (for example, about preventive folic acid supplements) and multidisciplinary management are important for good pregnancy outcomes. 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.

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

Self monitoring can be accomplished using a handheld capillary glucose dosage system. Compliance with these glucometer systems can be low. Target ranges advised by the Australasian Diabetes in Pregnancy Society are as follows:

  • fasting capillary blood glucose levels <5.5 mmol/L
  • 1 hour postprandial capillary blood glucose levels <8.0 mmol/L
  • 2 hour postprandial blood glucose levels <6.7 mmol/L

Regular blood samples can be used to determine HbA1c levels, which give an idea of glucose control over a longer time period.

If monitoring reveals failing control of glucose levels with these measures, or if there is evidence of complications like excessive fetal growth, treatment with insulin might become necessary. The most common therapeutic regime involves premeal fast-acting insulin to blunt sharp glucose rises after meals. Care needs to be taken to avoid low blood sugar levels (hypoglycemia) due to excessive insulin injections. Insulin therapy can be normal or very thight; more injections can result in better control but requires more effort, and there is no consensus that it has large benefits.

There is some evidence that certain oral glycemic agents 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. Glyburide, a second generation sulfonylurea, has been shown to be an effective alternative to insulin therapy. In one study, 4% of women needed supplemental insulin to reach blood sugar targets.

Metformin has shown promising results. Treatment of polycystic ovarian syndrome with metformin during pregnancy has been noted to decrease GDM levels. A recent randomized controlled trial of metformin versus insulin showed that women preferred metformin tablets to insulin injections, and that metformin is safe and equally effective as insulin. Severe neonatal hypoglycemia was less common in insulin-treated women, but preterm delivery was more common. Almost half of patients did not reach sufficient control with metformin alone and needed supplemental therapy with insulin; compared to those treated with insulin alone, they required less insulin, and they gained less weight. There remains a possibility of long-term complications from metformin therapy, although follow-up at the age of 18 months of children born to women with polycystic ovarian syndrome and treated with metformin revealed no developmental abnormalities.

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

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.

Controversy

Gestational diabetes is a controversial subject. Some critics question whether GDM is a disease in its own right. Labelling women as 'suffering from GDM' seems to predispose them to more interventions (like cesarean sections) for perceived increased risks, while treatment of GDM has not been proven to affect perinatal mortality or caesarean section rates. Lack of reproduceability of glucose tolerance testing is another problematic area.

See also

Footnotes

External links

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