Obstetrics and Gynecology

Gestational Diabetes Mellitus

Gestational Diabetes Mellitus

1. What every clinician should know

Clinical features and incidence

Gestational diabetes mellitus (GDM) is carbohydrate intolerance with onset or first diagnosis during pregnancy. During pregnancy all women develop relative insulin resistance. This is most likely related to placental hormones. Most pregnant women increase their insulin production and maintain euglycemia in the face of insulin resistance. Those who cannot adequately increase insulin production, many of whose pregnancy-related insulin resistance is superimposed upon pre-existing insulin resistance and/or a beta cell defect, develop hyperglycemia which is diagnosed as gestational diabetes.

Such individuals are at increased risk for developing diabetes later in life; approximately 50% will have type 2 diabetes within 20 years of the index pregnancy.

Risk factors

  • Overweight or obesity.

  • Family history of type 2 diabetes.

  • Racial/ethnic group with a high prevalence of diabetes.

  • Previous pregnancy with gestational diabetes.

  • Previous large baby.

  • Previous stillbirth.

  • First degree relative with diabetes.

  • Polycystic ovary syndrome (PCOS) or other conditions of insulin resistance.

  • Hypertension.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

The American College of Obstetricians and Gynecologists (ACOG) currently recommends a two-step process for screening and diagnosis, starting with a 50 gram,1-hour glucose challenge and progressing to a 100 gram, 3-hour glucose tolerance test if the challenge is positive (Table I).

Table I.

ACOG two-step process for screening and diagnosis of gestational diabetes.

The American Diabetes Association (ADA) recommends that at the first prenatal visit patients with risk factors be tested for undiagnosed type 2 diabetes. Standard diagnostic criteria are utilized.

The ADA further recommends that pregnant women not known to have diabetes be tested for GDM at 24-28 weeks, using a 75 gram, 2-hour oral glucose tolerance test (Table II) or by the two step process recommended by ACOG.

Table II.

IADPSG recommendations for diagnosis of GDM on a 75 gram, 2-hour oral glucose tolerance test (OGTT).

The World Health Organization (WHO) and the International Federation of Gynecology and Obstetrics (FIGO) recommend the one-step process (Table II) as well as testing for type 2 diabetes at the first prenatal visit for patients with risk factors.

Rationale for the new diagnostic criteria

The new criteria above, endorsed by ADA, the WHO and FIGO, were developed by the International Association of Diabetic Pregnancy Study Groups (IADPSG) with the goal of putting forth diagnostic criteria that would be accepted throughout the world.

  1. They are evidence-based, derived from data of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, which demonstrated a significant, continuous direct relationship between each of the three OGTT values and each of four primary adverse outcomes as well as a number of secondary adverse outcomes.

  2. They use a 75 gram, 2-hour oral glucose tolerance test; this is standard throughout the world for nonpregnant individuals and should decrease confusion on the part of laboratories and caregivers.

  3. Having the same diagnostic criteria throughout the world will make comparisons among populations and outcomes possible.

The proposed criteria will identify an increased proportion of most populations as having gestational diabetes, likely in the range of 16-18% of pregnant women. If adopted, this will signal a major change in obstetric practice, and will require redesign of approaches to counseling, dietary prescription and management paradigms. It is somewhat reassuring that in two randomized trials of diagnosis and management of mild gestational diabetes, only 20% and 8% required treatment beyond dietary instructions.

Nevertheless, identification and management of mild gestational diabetes significantly reduced a number of important adverse outcomes in these pregnancies, including pre-eclampsia and macrosomia, without increasing the cesarean section rate compared to undiagnosed and untreated control patients with similar degrees of GDM.

We are in the midst of an epidemic of obesity and type 2 diabetes. As of 2012 12.3% of adult Americans have diabetes (http://www.cdc.gov/diabetes/pdfs/data/2014-report-estimates-of-diabetes-and-its-burden-in-the-united-states.pdf) and more than 33% have prediabetes (http://www.cdc.gov/diabetes/pubs/statsreport14/prediabetes-infographic.pdf), meaning that nearly half of adult Americans currently have either diabetes or prediabetes. In light of these statistics, diagnosing gestational diabetes in 16-18% of pregnant women does not seem so surprising.

The IADPSG recommendations are currently being considered by professional groups and government agencies around the world. The NIH held a consensus conference in March 2013 to discuss the evidence for and against adopting these new criteria. The recommendation of the panel was to continue using the two-step process, with the 100 gram 30-hour OGTT until more definitive data become available regarding the benefits of diagnosing and treating an increased number of cases of GDM with the IADPSG criteria. The WHO and FIGO have recommended the use of the IADPSG recommendations.

Currently the American Diabetes Association has endorsed either the one step (IADPSG) or two step approach, while ACOG continues to recommend the two step approach.

3. Management

Maintenance of optimal circulating glucose levels

Recommendations for the management of gestational diabetes include prescription of medical nutrition therapy, determination of goals and appropriate timing of self-glucose monitoring, indications for initiation of pharmacologic treatment (either insulin or oral agents) and management of maternal glucose levels in labor.

Goals for glycemic control

Current recommendations from ACOG and ADA are that glucose levels be maintained below the targets in Table III. While these target levels have recently been challenged based on normative data from nondiabetic pregnant women suggesting that lower targets may be more appropriate, data from future randomized trials are needed to determine whether the use of such lower targets will improve outcomes.

Table III.

Current ACOG and ADA recommended targets.

Self-glucose monitoring

Women with gestational diabetes are instructed on daily self-monitoring of blood glucose. Widely available reflectance meters and spring loaded devices for puncturing the skin of the finger or forearm have made obtaining capillary blood samples easy and measurement of glucose concentrations convenient at any time of day.

At one time these meters were quite variable as to whether the results were comparable to plasma or to whole blood glucose testing. Now most meters are designed to provide results from whole blood testing that are pre-converted to equivalent plasma glucose values. However, it should be kept in mind that capillary blood glucose values are somewhat higher than venous plasma values, especially after meals, since they include a mixture of arterial and venous blood.

While the use of reflectance meters is appropriate for metabolic management of patients with gestational diabetes, they are generally neither accurate nor precise enough for diagnostic testing.

Newer technology for continuous glucose measurement is not currently necessary for patients with gestational diabetes.

While many endocrinologists recommend only preprandial glucose testing in patients with diabetes who are not pregnant, there is Level 1 evidence that postprandial glucose testing in pregnant women with gestational diabetes improves fetal outcomes compared to preprandial testing.

While daily testing is commonly recommended, it is likely that women with milder gestational diabetes may be able to test less frequently. Once good metabolic control has been demonstrated on medical nutrition therapy, it may be possible to decrease testing frequency to every other day or possibly even less often. It is expected that when the newer, lower diagnostic thresholds are in common use, studies will be carried out to determine the safety and efficacy of such alternative, less costly, approaches to management.

It is not clear whether 1-hour or 2-hour post meal glucose testing is more effective for improving outcomes; comparative studies have yielded equivocal results. Either approach is acceptable.

Insulin treatment

Insulin is a large, highly charged molecule that usually does not cross the placenta. Antibody bound insulin has been demonstrated to cross the placenta in some studies, but high titers of insulin antibodies are no longer encountered with any frequency since recombinant human insulin has replaced beef and pork insulin for many years. Women with gestational diabetes who have not been previously exposed to exogenous insulin would also be highly unlikely to manifest insulin antibodies. Insulin appears to be safe and effective for managing gestational diabetes and has stood the test of time.

A number of different insulin preparations, with varying absorption, onset and duration of action are available. The human insulin preparations differ primarily by the vehicle in which they are suspended in terms of how they enhance or delay absorption from subcutaneous injection sites. The human insulin analogs differ generally by a single amino acid substitution. Table IV lists the different widely available insulins.

Table IV.

Widely available insulins.

We generally initiate insulin treatment when at least one third of glucose values at a given time of day exceed goals over a week's interval. Various insulin regimens are used for treatment of gestational diabetes. Total doses will vary depending upon factors such as the patient's BMI and gestational age. One approach that we have found helpful, particularly in women whose BMI is below 30, or in more obese women with mild degrees of hyperglycemia, is outlined below:

  • When only postprandial values are elevated an arbitrary starting dose of 30 units before breakfast is divided into 20 units of an intermediate acting insulin such as NPH and 10 units of a short acting insulin such as lispro or aspart. These doses can then be increased as needed, depending upon the time of blood sugar elevations.

  • When post-dinner glucose is elevated, short acting insulin can be prescribed before dinner.

  • When only fasting glucose values are elevated intermediate acting insulin such as NPH can be prescribed either at bed time or before dinner.

  • When fasting and post dinner values are elevated the intermediate acting insulin can be combined with short acting insulin before dinner.

  • When elevated glucose values are encountered after this approach has been initiated, the appropriate component of the insulin regimen can be increased by 10-20%.

A weight-based insulin approach is especially useful in obese patients with GDM, particularly when glucose values are unequivocally elevated:

  • At the usual starting time of 26-36 weeks, multiply the current weight, in kg, by 0.9 units/kg to calculate the total daily dose.

  • Divide the dose as follows:

    • Morning dose (2/3 of the total daily dose) is twice the evening dose (1/3 of the total daily dose).

    • Morning dose is in the proportion of 2:1 (intermediate acting to short acting insulins).

    • Pre-dinner dose is in the proportion of 1:1 (intermediate acting to short acting insulins)

    • Individual components are then varied depending upon the blood glucose levels at the specific times of day.

Example: A 100 kg woman with GDM would start with a total daily dose of 90 units of insulin. She would take 60 units before breakfast and 30 units before dinner. Her morning dose would be 40 units of NPH insulin and 20 units of insulin lispro or insulin aspart. Her pre-dinner dose would be 14 units NPH and 14 units lispro or aspart.

When initiating this regimen, individual components may be omitted if hyperglycemia has not been occurring at the given time. For example, a 100 kg woman with GDM whose fasting and post-breakfast values are the only ones that are elevated may be started on 30 units of short acting insulin before breakfast and 14 units of NPH insulin before dinner or at bed time.

As needed, insulin dose is increased by 10-20%.

Remember that these formulas are only for calculating a starting dose of insulin. Once insulin therapy has been initiated, individual components are varied in response to glucose elevations at particular times of day.

An approach that we have found not to be helpful in most cases of GDM is the use of the sliding scale. This paradigm involves varying the insulin dose each day depending upon the patient's circulating glucose level. The problem is that insulin is best given in anticipation of its need, rather than after the fact. Since even rapid acting insulin takes time to act, responding retrospectively to elevated glucose levels may introduce more variability than would a more consistent regimen.

Thus we respond to today's glucose values tomorrow - if today's post breakfast glucose is above target (and there is no obvious non-recurrent reason such as a dietary indiscretion), we anticipate that the patient's insulin need has risen, and increase tomorrow's pre-breakfast short acting insulin dose. The exception would be markedly elevated glucose levels, such as those exceeding 200 mg/dl, when we would sometimes recommend an extra dose of short acting insulin to bring the value down quickly. This situation rarely arises in patients with GDM; it is more often encountered with preexisting diabetes.

The use of oral antidiabetic agents for GDM

Insulin has been the traditional "drug of choice" when treatment beyond diet is needed. However, insulin has a number of disadvantages:

  1. Insulin must be given as an injection.

  2. Multiple injections throughout the day are often necessary.

  3. Insulin can cause hypoglycemia.

Because of our patients' natural disinclination to inject themselves, much attention has been focused on the use of oral agents.

Glyburide: an insulin secretagogue

Glyburide, a sulfonylurea, binds to sulfonylurea receptors in pancreatic beta cells, stimulating insulin production and release regardless of the blood sugar level. It is only effective in patients with residual beta cell function, and therefore is not appropriate for the treatment of type 1 diabetes. The resultant insulin release lowers hepatic glucose production and enhances post meal insulin levels. Hypoglycemia is a potential side effect.

In a randomized trial glyburide (up to 20 mg/day) was compared to insulin for patients with gestational diabetes whose circulating glucose values were high enough to merit intervention. Outcomes, including macrosomia, neonatal hypoglycemia and reductions in hemoglobin A1c, were similar in the two groups, and only 5% of glyburide treated subjects required insulin. Glyburide was not detected in cord blood samples from exposed pregnancies. Ensuing case series' reported failure to achieve desired blood glucose levels in up to 20% of glyburide treated gravidas.

A subsequent study from the NICHD Obstetric-Fetal Pharmacology Research Units Network found that cord blood glyburide levels were 70% of simultaneously measured maternal levels. Although the absolute levels were low in both compartments, it appears that glyburide can cross to the fetus in significant amounts. A second study confirmed this finding in 2013.

While no adverse effects on the fetus have been demonstrated when glyburide is used during pregnancy, the possibility remains of long term effects, particularly given the data regarding in utero programming of metabolism by various ambient exposures. When glyburide is prescribed for women with GDM, it is important to document that patients have been counseled regarding the lack of long term studies on the offspring.

When glyburide is prescribed for GDM the usual starting dose is 2.5 mg po prior to breakfast or 2.5 mg po bid before breakfast and before dinner. The dose can be increased by 2.5 mg, then by 5 mg increments with the usual maximum dose being 10 mg po bid. However, pharmacokinetic studies have suggested that plasma concentrations are lower after a given dose of glyburide during pregnancy than in non-pregnant individuals, suggesting that higher doses may be needed.

Changes in dosage recommendations await further clinical studies of safety and efficacy. Current recommendations are to switch to insulin when glucose goals are not achieved at a dose of 20 mg glyburide per day. It can be anticipated that the need for insulin will arise in 5-20% of GDMs treated with glyburide.

Metformin: an insulin sensitizer

Metformin, a biguanide, enhances insulin action, stimulating glucose uptake in the liver and periphery, and suppressing hepatic glucose output. It only works when insulin is present, and it does not stimulate insulin secretion and release or cause hypoglycemia. This drug is commonly used to treat polycystic ovary syndrome (PCOS) and other forms of insulin resistance.

In the MiG trial, a randomized prospective trial comparing the use of metformin and insulin among GDMs requiring treatment, pregnancy outcomes were similar between the two groups. Among subjects assigned to metformin, 46% required the addition of insulin because the maximum metformin dose was not sufficient to achieve glucose goals. Subjects randomized to metformin treatment were more likely to express a preference for the same treatment in future pregnancies than were those using insulin.

Metformin has been shown to cross the placenta. In one study cord arterial metformin levels were approximately twice maternal venous levels at the time of delivery. In a 2-year follow up study to the MiG trial, there were no differences between offspring exposed to metformin in utero and those exposed to insulin, other than greater subcutaneous fat in the former. While no adverse (or beneficial) effects of exposure to metformin have been reported, long term human studies have not been conducted and animal data are sparse, such that caution must still be recommended.

The possibility of fetal programming for adult disease, including obesity and metabolic syndrome, is currently under study, suggesting that transgenerational effects of agents that reach the fetus be subjected to investigation. In the meantime, when metformin is prescribed during pregnancy, counseling regarding unknown negative or positive long term effects on the offspring should be documented.

Obstetrical management

Obstetrical management includes antepartum fetal testing, as well as the timing and mode of delivery.

Antepartum testing

While ultrasound estimates of fetal weight have not been shown to be more accurate than clinical estimation, monthly sonography may be a useful approach to assaying diabetic fetopathy. There has been a series of randomized trials that compared the use of U/S measurement of abdominal circumference between 29 and 33 weeks to guide initiation of insulin therapy to glycemia based management.

In GDMs whose fasting plasma glucose levels started at less than 105 mg/dl, similar proportions (40% U/S based management group, 30% glycemia based management) required insulin, and pregnancy outcomes were similar between the two groups. In a pilot study the use of U/S allowed 38% of "severe" GDMs to avoid insulin while outcomes were comparable. The randomized trials suggest that U/S measurement of abdominal circumference may be a useful indicator of evolving diabetic fetopathy.

If detection of evolving fetal macrosomia can allow a significant proportion of GDM patients to avoid insulin, this approach may be applicable to the milder GDMs diagnosed by the IADPSG criteria and may decrease the need for frequent self-glucose monitoring in those whose AC is not above the 70th percentile. Ultrasound estimation of fetal weight may also be useful in guiding decision making as to mode of delivery (see below).

There is no level 1 evidence to guide recommendations for antepartum testing in women with GDM. ACOG notes that "there is insufficient evidence to determine the optimum antepartum testing regimen for women with GDM with relatively normal glucose levels on diet therapy and no other risk factors."

Based on less than compelling evidence, in our center we perform weekly antepartum testing, generally a modified biophysical profile, beginning at 36 weeks in patients with diet treated GDM who are well controlled and have no other risk factors. Patients with GDM whose glucose levels are not well controlled and/or require insulin or oral antidiabetic agents, or who have other risk factors, are monitored by the twice-weekly testing paradigm applied to women with pre-existing diabetes.

Timing of delivery

Gestational diabetes is not necessarily an indication for early delivery, but its complications may be. A 2011workshop sponsored by NICHD and SMFM concluded that early delivery is not indicated when gestational diabetes is well controlled on diet or medication, but that timing of delivery should be individualized in GDMs whose glucose values were poorly controlled.

Amniocentesis was not considered helpful when early delivery is indicated because of poor metabolic control. We recommend that women with GDM not extend their pregnancies beyond the EDC. When dating is well documented and glucose is well controlled, we offer induction of labor (or repeat C/S if appropriate) between 39 completed weeks and the EDC. A population-based study of almost 200,000 GDMs reported that delivery at 39 weeks or 40 weeks was associated with a statistically significant lower risk of stillbirth and infant death than expectant management for another week. When glucose control is poor or undocumented we recommend earlier delivery.

Mode of delivery

Gestational diabetes is not an indication for cesarean section, but its complications may make cesarean section more likely. For example, hypertensive disorders of pregnancy occur with greater frequency in GDMs than in the general population. When such problems occur, early induction of labor may be necessary, which may make cesarean section more likely. Another scenario is fetal macrosomia, which can be associated with shoulder dystocia.

While the evidence is not unequivocal, ACOG recommends considering cesarean section without a trial of labor in diabetic patients when the estimated fetal weight is 4500 grams or more, and individualization based on the patient's history and the progress of labor when the EFW is 4,000-4,500 grams. A decision analysis concluded that, for women with diabetes whose estimated fetal weight is 4.5 kg or greater, it would require 443 cesarean sections at a cost of $930,000 (1996 dollars) to prevent one permanent brachial plexus injury. Projections of cost were similar when the estimated fetal weight was 4 kg or greater.

Management of GDM in labor

If the fetus has been exposed to hyperglycemia in utero, its pancreas may secrete and release insulin more readily in response to elevated glucose. Once delivery has taken place and the umbilical cord has been cut, the fetus is no longer receiving glucose from the mother. If fetal insulin secretion has been stimulated by hyperglycemia during labor, neonatal hypoglycemia is more likely to ensue. For this reason, it is important to maintain maternal euglycemia throughout the course of labor. Our current approach is as follows:

  1. If induction of labor or cesarean section is planned, and the patient has been in acceptable metabolic control, the usual diet and insulin dose (if the patient is insulin treated) is taken on the day prior to planned delivery. The patient is npo after midnight. Breakfast and insulin are withheld on the morning of induction or C/S.

  2. Rapid infusion of large amounts of glucose during labor has been associated with fetal and neonatal acidemia and should be avoided. However, the mother needs calories during the work of labor lest starvation ketosis develop. Therefore, we infuse 5% dextrose (usually in half normal saline) at a rate of 100-125 ml/hour. We monitor glucose levels at the bedside every 2 hours and aim for a glucose level between 80 and 120 mg/dl.

  3. If bedside glucose testing reveals values of 120 mg/dl or greater, we start an IV insulin infusion at 1 unit per hour; it generally takes 2-4 hours for maternal glucose to reach a steady state, so the dosage is adjusted accordingly.

Postpartum management

Once delivery of the placenta has occurred, maternal insulin resistance may be expected to rapidly diminish. Any insulin infusion used during labor should be discontinued. If anything, there is a tendency toward lower circulating glucose levels during the first day or so postpartum. If the patient with gestational diabetes has been treated with insulin or oral antidiabetic drugs during the pregnancy these should not be continued unless persistent diabetes is encountered.

While definitive testing for diabetes or prediabetes is best accomplished at a later date (see below), it is worthwhile to check a fasting glucose level once the patient is taking a normal diet to make certain that diabetes needing treatment has not persisted. At the time of discharge from the hospital the patient should be given an appointment for a 75 gram, two-hour oral glucose tolerance test at 4-8 weeks post-delivery.

Testing for diabetes and prediabetes

The American Diabetes Association recommends testing between 6-12 weeks postpartum, while ACOG suggests testing at around the time of the 6-week checkup. The rationale for waiting is to allow the metabolic effects of pregnancy to completely dissipate. There are no data to determine the ideal interval before testing, and from a practical perspective if the test is delayed until after the postpartum visit there is a diminishing likelihood that the patient will actually undergo testing.

We find it most effective to send the patient home from her delivery with an appointment for her postpartum test scheduled for a date just prior to her postpartum visit so that the results will be available at that time, or testing can be rescheduled if the patient has not followed through.

As noted above, there are a number of different tests recommended to diagnose diabetes or prediabetes. However, women with gestational diabetes are, by definition, in the reproductive age group and are at risk for another pregnancy in the near future unless permanent sterilization has been carried out.

Should they develop diabetes before the next conception, their pregnancy will be at increased risk for congenital malformations and other problems. They will need preconception counseling, including help to achieve reasonable glycemic control prior to pregnancy in order to minimize these risks. Therefore, we recommend that the full 75 gram, 2-hour OGTT be performed. (See Table V for interpretation of this test.)

Table V.

Interpretation of a 75 gram, 2-hour oral glucose tolerance test (OGTT) in nonpregnant individuals

4. Complications

Pathophysiology

Gestational diabetes is characterized by maternal hyperglycemia. Because glucose is a relatively small molecule and crosses the placenta readily by a process of facilitated diffusion, maternal hyperglycemia leads directly to fetal hyperglycemia. The fetal pancreas responds by increasing production and release of insulin. Insulin is a relatively large molecule and does not cross the placenta, so the fetus cannot modify maternal glucose levels. Consequently, the fetus produces large amounts of insulin but remains hyperglycemic as long as the mother is hyperglycemic.

Fetal hyperinsulinemia is the most likely cause of all or most of the fetal and neonatal complications of GDM. Hyperinsulinemia in utero may also be responsible for long term adverse outcomes in the offspring of GDM pregnancies.

Maternal complications

Pre-eclampsia: hypertensive disorders of pregnancy occur with increased frequency in GDMs compared to controls. Chronic hypertension also appears to be more common in GDMs. There is increasing evidence relating hypertension to insulin resistance, so GDM and hypertensive disorders may have predisposing factors in common. The use of low dose aspirin (81 mg/day beginning by 16 weeks gestation) has been shown to be cost effective in preventing preeclampsia in patients at increased risk for this complication. While gestational diabetes confers an increased risk, it is usually not diagnosed until the late second or early third trimester, so the benefits of initiating this preventive measure so late in pregnancy are unknown. Risks and expense of low dose aspirin treatment are miniscule.

Cesarean section: Cesarean section delivery is more common in GDMs than in nondiabetic control patients. A number of contributing factors may be responsible:

  • Macrosomic fetuses are more likely to need delivery by cesarean section.

  • Pregnancy complications such as pre-eclampsia may lead to early induction of labor, which in the presence of an "unripe" cervix makes cesarean section more likely.

  • Antepartum testing commonly prescribed in GDM pregnancies may be positive, either true positive or false positive, leading to intervention.

  • One study has demonstrated that caregivers who are aware of the diagnosis of GDM are more likely to perform cesarean section compared to caregivers blinded to the diagnosis, even when the fetus is not macrosomic, presumably because of concern for possible adverse outcomes of vaginal birth such as shoulder dystocia.

Hydramnios: Excessive amniotic fluid occurs with increased frequency in both pre-existing diabetes and GDM. The common cause is likely fetal hyperglycemia with resultant osmotic diuresis when the diabetes is poorly controlled.

Fetal complications

Macrosomia: Fetal insulin acts as a "growth hormone" for the fetus; macrosomic or large for gestational age neonates are likely to result. There is evidence from randomized trials that treating gestational diabetes with the goal of normalizing circulating glucose levels can reduce the likelihood of macrosomia.

Stillbirth: Studies using hyperinsulinemic models in fetal primates and sheep have demonstrated an increase in stillbirths, possibly due to increased placental lactate production. Fetal death, while fortunately rare, is more likely as term approaches, and many caregivers induce labor at 39-40 weeks if spontaneous labor has not supervened by this time. This approach is supported by a population-based study showing a lower risk of stillbirth and infant death when delivery is accomplished at 39 weeks or 40 weeks.

Shoulder dystocia: In hyperinsulinemic fetuses of diabetic mothers, the shoulders grow disproportionally to the head so that shoulders may get "stuck" in the birth canal, causing injury such as fractured clavicle, and in some cases, brachial plexus injury which can be permanent in a small proportion of cases.

Neonatal complications

Neonatal Complications of GDM are similar to those seen with pre-existing diabetes and relate to exposure to hyperglycemia in utero.

Neonatal hypoglycemia: Most likely this problem is secondary to fetal hyperinsulinemia which is stimulated by long term or intermittent maternal-fetal hyperglycemia. When the umbilical cord is clamped, the fetus is deprived of the maternal glucose supply. Particularly if the mother has been hyperglycemic during labor, the resulting fetal/neonatal hyperinsulinemia may cause neonatal hypoglycemia in the first few hours of life.

Neonatal plethora: Most likely fetal erythropoietin is increased due to chronic fetal hypoxemia. This raises fetal/neonatal hemoglobin levels and may lead to consequences such as neonatal renal vein thrombosis.

Neonatal hyperbilirubinemia: The normal transition from fetal to neonatal life, in which responsibility for oxygen delivery transfers from the placenta to the neonatal lungs, includes a decreased need for hemoglobin as oxygen levels increase. Hemolysis occurs, with the resulting bilirubin disposed of by the neonatal liver. When plethora is present (see above), the immature liver may be incapable of handling the resultant bilirubin load, leading to indirect hyperbilirubinemia and jaundice.

Respiratory distress: RDS is more common in premature infants of mothers with pre-existing diabetes whose metabolic control is poor or undocumented, presumably due to fetal hyperinsulinemia decreasing surfactant production. It would stand to reason that infants of gestational diabetic mothers similarly poorly controlled would be prone to similar problems.

Neonatal hypocalcemia: This is much more common in infants of mothers with poorly controlled preexisting diabetes but remains a theoretic possibility when GDM is not well controlled.

Long term adverse outcomes in the offspring of GDM pregnancies

Obesity: Studies of the Pima population demonstrated that exposure to hyperglycemia in utero is associated with an increased likelihood of obesity into adult life.

Diabetes: Pima offspring were likely to develop diabetes in direct proportion to the height of maternal glucose levels during pregnancy glucose tolerance testing; female offspring who became pregnant were more likely to develop gestational diabetes if their own mothers had high blood glucose levels during pregnancy, even when they were compared to siblings born before their mothers developed hyperglycemia in pregnancy.

5. Prognosis and outcome

Prevention of subsequent diabetes

Gestational diabetes is a powerful predictor of subsequent diabetes, primarily type 2 diabetes but also type1 diabetes and genetically determined forms of diabetes. As noted above, approximately 50% of former GDMs will have diabetes within 20 years of the index pregnancy. While not all GDMs, or individuals with type 2 diabetes, are overweight or obese, much of the increase in diabetes in our population can be attributed to the epidemic of obesity and sedentary lifestyles.

While we generally do not recommend weight reduction during pregnancy, once delivery has occurred attainment of lower BMI can reduce the chance of developing diabetes in the future. Counseling of former GDMs should be initiated during prenatal visits and continued after the pregnancy. Recommendations should include:

  1. Adoption of a healthy lifestyle, including nutritional counseling and regular exercise.

  2. Weight loss if the patient is overweight or obese. Even modest weight reduction of 5-10% of body weight can ameliorate diabetes or prediabetes. In a randomized trial of lifestyle interventions versus metformin therapy versus placebo in patients at high risk for diabetes, weight loss averaging 2-4 kg was associated with a significant reduction in the development of diabetes, with lifestyle intervention being more effective than metformin. In a subanalysis limited to former GDMs metformin and lifestyle interventions were similarly effective, reducing risk of diabetes by approximately 50%.

  3. Patients diagnosed with diabetes should be referred to a caregiver expert in the management of this disorder; those with prediabetes should be referred and entered into a program to lower the risk of conversion to diabetes.

“What if” scenarios

What if the patient with GDM needs lots of insulin to achieve the goals for glucose control? Is there a limit to the amount of insulin that can be administered?

No, prescribe however much insulin is required to overcome the patient's insulin resistance and maintain glucose levels at the predetermined targets. Many patients with GDM, particularly those who are morbidly obese, require very large doses (100s of units per day).

Should metformin be added to reduce insulin resistance and allow lowering of the insulin dose?

This is often mentioned as an alternative. No data are available to address the benefits of such a regimen. Since metformin crosses the placenta and reaches the fetus and fetal effects are not clearly worked out, we prefer not to use this approach, although no harm has been demonstrated to date.

Insulin syringes only hold up to 1 cc (100 units of U-100 insulin). What can we do when this dose is exceeded?

While this phenomenon is much more common in patients with pre-existing type 2 diabetes than with GDM, it is occasionally encountered. One alternative is to have the patient take two injections. This is obviously more uncomfortable for the patient. An approach which we have found useful is the use of U-500 insulin in order to reduce the volume of the injection.

Unfortunately, only regular insulin comes as U-500. So this requires that patients taking short acting insulin analogs switch to regular insulin. U-500 regular insulin also lasts longer, possibly as long as NPH insulin. For example, if a patient is injecting 70 units of short acting insulin and 30 units of NPH insulin in the morning prior to breakfast and it is necessary to increase her dose to 80 units of short acting insulin with 40 units of NPH insulin, the following steps can be taken:

  • Switch from short acting insulin to regular insulin, which requires taking the injection 20-30 minutes before breakfast rather than just before the meal as with insulin lispro or insulin aspart.

  • Prescribe U-500 regular insulin.

  • To take 70 units of regular insulin, the patient draws up 0.14 cc of U-500 (which looks like she is drawing up 14 units) into a U-100 syringe. She then draws up 0.3 cc (30 units) of U-100 NPH insulin into the same syringe, for a total of 0.44 cc (looks like total of 44 "units").

  • Since U-100 1 cc syringes are marked in two unit increments, dosage increases in U-500 insulin must be made in 0.02 cc (10 units, but looks like 2 "units") increments. This is generally not a problem when patients are taking such large doses; a dose increase of 10 units is only 10% of 100 units!

It is critically important to give explicit written instructions and make sure the patient understands the plan lest she self-administer 5 times more insulin than is desired. We write down the dose in units, and then the dose in cc's, and make sure the patient demonstrates her knowledge of the difference.

Recently a concentrated form of the long-acting insulin analog, insulin glargine U-300, has come on the market. While this may be useful for pregnant patients with type 2 diabetes, it is quite expensive relative to other forms of insulin, and we generally do not find it necessary to prescribe long-acting insulin analogs for women with gestational diabetes.

How many elevated glucose measurements does it take before insulin is started or the dose is increased?

Our rule of thumb is that if 1/3 of the previous week's glucose measurements at a given time of day exceed our target we start insulin or increase the appropriate time's dose. We do take into account other factors, such as whether our dietitian believes that more can be accomplished through dietary modifications, particularly when the patient has just been diagnosed and only been on medical nutrition therapy for a week.

However, we bear in mind that the time for intervention with GDM is generally limited and we may ask the patient to come back sooner than a week if dietary modification is tried, or to call in her blood sugar values sooner than would otherwise be planned.

What about the patient who does not perform her self-glucose monitoring as often as is prescribed?

We take the results that are in her meter at face value and act accordingly. For example, if she has only done three post breakfast glucose tests in the previous week, and one 2-hour value is 130 mg/dl while the others are less than 120 mg/dl, we would increase her morning short acting insulin dose. We assume that the blood sugars on the days she did not test have been lower than the values on days she tested. In our experience it is unusual for patients with GDM to become hypoglycemic on insulin unless they take their insulin and then miss a meal.

How much is the insulin dose increased each time?

We increase the insulin dose by 10-20% depending upon the degree of hyperglycemia and the patient's body habitus (which generally reflects the degree of insulin resistance). Such increases are generally safe for patients with GDM and type 2 diabetes, but smaller increases are more appropriate for patients with type 1 diabetes who may be quite sensitive to 1 or 2 unit increments.

6. What is the evidence for specific management and treatment recommendations?

(This paper outlines the rationale for the recommendations for new diagnostic criteria for GDM put forth by the IADPSG.)

(This is the publication of the main results of the Hyperglycemia and Adverse Pregnancy Outcome study, relating OGTT values to a number of adverse outcomes.)

(This is the ACHOIS study, in which Australian patients with mild gestational diabetes were randomized to treatment versus routine care (a control group in which caregivers and patients were blinded to the diagnosis of GDM). The study demonstrated benefit from the diagnosis and treatment of mild GDM.)

(This is the randomized trial conducted by the NICHD Maternal-Fetal Medicine Units Network in the U.S., in which patients with mild GDM were identified and treated and compared to a control group in which the caregivers and patients were blinded to the diagnosis. As in ACHOIS, significant benefit was demonstrated when mild GDM was diagnosed and treated.)

(This is a randomized trial of preprandial versus 1-hour postprandial glucose measurement in GDMs. Treatment based on postprandial measurements was associated with fewer macrosomic and LGA offspring, lower C/S rates and less neonatal hypoglycemia.)

(This is a large randomized trial of glyburide versus insulin in patients whose GDM was severe enough to require treatment. Perinatal outcomes were similar with the two therapeutic regimens.)

(A pharmacokinetic study by the NICHD Obstetric-Fetal Pharmacology Research Units Network in which various aspects of glyburide metabolism in pregnancy are described. A maternal:cord glyburide ratio averaging 0.7 was reported.)

(This is the current ACOG Educational Bulletin regarding GDM.)

(This is the main publication of the results of the MiG trial, comparing insulin and metformin for the treatment of GDM. Perinatal outcomes were similar, although 46% of subjects randomized to metformin also required insulin. Patients preferred metformin to insulin.)

(This is a useful review of the evidence linking the intrauterine environment to subsequent adult disease.)

(This useful paper outlines the recommendations of ACOG and SMFM for the timing of delivery in pregnancies with various complications.)

(ACOG Educational Bulletin on Macrosomia.)

(This is a population based study of stillbirth and infant death with delivery of GDMs sat various gestational ages.)

(This is the report of the 2013 NIH Consensus Development Conference on diagnosing gestational diabetes.)

(This is a cost-benefit analysis of using low dose aspirin to prevent preeclampsia.)

http://www.who.int/diabetes/publications/Hyperglycaemia_In_Pregnancy/en/.

(These are WHO recommendations.)
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