Diabetes In Pregnancy
Dr. Catherine M. Hegarty,
Medical Director, Joslin Diabetic Center affiliated at Mercy Medical Center
The majority of women with pregnancy complicated by diabetes have gestational diabetes (GDM). The American Diabetes Association defines GDM as any degree of glucose intolerance with onset or first recognition during pregnancy. This includes women who may have had diabetes or abnormal glucose tolerance prior to the pregnancy but were undiagnosed. In the U.S., the prevalence of gestational diabetes varies from 1-14% depending on the population studied.
Poorly controlled gestational diabetes increases the risk of fetal macrosomia with risk of shoulder dystocia or other birth injury, C-section, maternal hypertensive disorders, neonatal hypoglycemia, jaundice, hypocalcemia, and polycythemia. Fasting hyperglycemia with blood glucose > 105 mg/dl (5.8 mmol/l) may be associated with an increased risk of intrauterine fetal demise in the last 4-8 weeks of gestation. Since organogenesis is complete by the time that gestational diabetes appears, major congenital anomalies are uncommon.
Long-term risks of gestational diabetes include increased risk of recurrent GDM in subsequent pregnancies, risk of diabetes in the mother, and increased risk of childhood obesity, glucose intolerance and diabetes in the offspring.
Diagnosis of gestational diabetes is typically made on the basis of an oral glucose tolerance test. A lack of consensus exists regarding the optimal testing protocol and threshold to identify women and infants with increased risk of complications. Many recommend universal screening of all pregnant women. Others advocate screening all but low risk women who meet the following characteristics: age < 25, normal pre-pregnancy weight, member of a low-risk ethnic group, no diabetes in first degree relatives, no history of abnormal glucose tolerance, and no history of poor obstetric outcome. Women of average risk are screened during weeks 24-28 of gestation. High risk women, including women with significant obesity, glycosuria, history of GDM or previous infant > 9lbs, or strong family history, should have testing as soon as possible in the pregnancy with re-testing at 24-28 weeks if the initial testing is normal.
Many diagnostic algorithms utilize a two-step approach with an initial screening glucose challenge. A 50-gm glucose load is given at any time of day and blood glucose is measured 1 hour later. If normal (< 140 mg/dl or 7.8 mmol/l), no further testing is done. If abnormal (> 140 mg/dl), a full, 3-hour glucose tolerance test is performed. Using a 100-gm glucose load, blood glucose levels are measured fasting and at 1 hr, 2 hr, and 3 hr. Criteria from the Fourth International Workshop-Conference on Gestational Diabetes define normal blood glucose levels as follows: fasting < 95 mg/dl (5.3 mmol/l), 1 hr < 180 (10 mmol/l), 2 hr < 155 (8.6 mmol/l) and 3 hr < 140 (7.8 mmol/l). Gestational diabetes is diagnosed if two of the four values exceed the normal range.
Following diagnosis, monitoring and treatment are initiated. Women should be instructed in self-monitoring of blood glucose (SMBG), which appears to be superior to intermittent office monitoring. Evidence suggests that post-prandial monitoring is superior to pre-prandial monitoring, but these findings may reflect the targets, which were set for pre- vs. post-prandial monitoring in the studies rather than the timing of monitoring. Urine ketone monitoring may be useful to detect insufficient caloric intake in women treated with caloric restriction.
Ideally, all women should receive nutritional counseling from a registered dietitian. Individualized medical nutrition therapy should include the provision of adequate calories and nutrients to meet the needs of both the mother and fetus. For detailed discussion of dietary recommendations, please refer to "Medical Nutrition Management of Gestational Diabetes" by Sharon Tilbe, MA, RD, LDN, CDE.
Moderate physical activity has been shown to lower maternal glucose concentrations in women with gestational diabetes. Studies have not yet assessed neonatal outcomes with the use of exercise. In the absence of contraindications and after obstetric clearance, women may be encouraged to start or continue a program of regular physical activity to assist in control of GDM.
The majority of women with GDM will achieve adequate glycemic control with dietary therapy alone. If medical nutrition therapy fails to maintain adequate glycemic control, pharmacological therapy is indicated. Insulin is the pharmacological therapy that has been most widely used and best shown to reduce fetal morbidities when added to medical nutrition therapy. A recent unblinded trial showed that use of glyburide begun after the first trimester resulted in similar outcomes as insulin. At this time in the US, glyburide is not FDA approved for use in pregnancy.
The American Diabetes Association recommends target whole blood glucose levels of less than or equal to 95 mg/dl (5.3 mmol/l) fasting, which is equivalent to a plasma reading of less than or equal to 105 mg/dl (5.8mmol/l). Blood glucose levels taken 1-hour post-prandially should be less than or equal to 140 mg/dl (7.8 mmol/l) using whole blood or less than or equal to 155 mg/dl (8.6 mmol/l) using plasma readings. Blood glucose levels taken 2-hours post-prandially, should be less than or equal to 120 mg/dl (6.7 mmol/l) using whole blood measurements or less than or equal to 130 mg/dl (7.2 mmol/l) using plasma readings. It is important for patients and caregivers to be aware of whether their meter provides whole blood or plasma glucose results. Laboratory methods measure plasma glucose, which is 10-15% higher than whole blood levels. Most blood glucose monitors provide readings equivalent to plasma values.
The specific insulin regimen selected depends upon the results of the SMBG readings. If the only abnormality is an elevation in the fasting blood glucose, intermediate-acting insulin, e.g. NPH, can be given at bedtime. If post-prandial readings are elevated, then short or rapid acting insulin, e.g. regular or lispro can be given prior to the meals with elevated post-prandial readings. If readings are elevated throughout the day, a combination of intermediate and short or rapid-acting insulin can be used. A mix of NPH and short or rapid acting insulin can be given prior to breakfast and supper or the evening dose can be split with short or rapid acting insulin given at supper and NPH given at bedtime. A total daily dose of 0.5 - 0.7 mg/kg can be used as a starting point, with 2/3 of the total given in the morning and 1/3 given in the evening. One third of each dose is given as short or rapid acting insulin with the remainder given as NPH. Dosage adjustments can be made on the basis of SMBG results.
A detailed discussion of obstetric surveillance and management is beyond the scope of this article. Close monitoring of maternal blood pressure and urinary protein should be routine. The initiation, frequency and specific techniques for fetal surveillance should be determined based on the cumulative risk of GDM as well as other medical/obstetric conditions present.
The majority of women diagnosed with GDM will have normal glucose tolerance post-partum. Recurrent GDM is common and occurs in up to 2/3 of mothers in subsequent pregnancies. Women with a history of GDM should be tested as early as possible in subsequent pregnancies and if normal, retested at 24-28 weeks. Women with a history of GDM are at high risk of developing Type 2 diabetes, with the risk correlating with the level of glucose tolerance and body weight. Obese women have a 50-75% risk of developing Type 2 diabetes, whereas women who are at or near ideal body weight have a 25% risk of developing Type 2 diabetes.
To assist with risk-stratification, women with GDM should have a 2-hour glucose tolerance test using a 75 gm glucose load at 6-8 weeks postpartum, or shortly after cessation of breast-feeding. If normal, women should be counseled on lifestyle modification to decrease the risk of type 2 diabetes. They should have ongoing periodic monitoring of their glycemic status. Women who are found to have abnormal glucose tolerance should also be counseled that they are at significant risk for diabetes in the near future and should be educated on lifestyle modification, and ideally receive intensive medical nutrition therapy and instruction on an individualized exercise program. They should have repeat testing at least yearly.
Pregnancy Complicated by Pre-existing Diabetes:
Women with Type 1 and Type 2 diabetes face additional challenges with pregnancy. In women with GDM, blood glucose levels are normal prior to conception and in early pregnancy during the period of fetal organogenesis, making congenital malformations rare. In women with pre-existing diabetes, poor control at the time of conception and during early pregnancy significantly increases the risk of miscarriage and congenital malformation. The risk for both spontaneous abortion and congenital anomalies is related to glycemic control and can approach 65% if diabetes is poorly controlled early in pregnancy. In addition, elevated blood glucose levels with advancing pregnancy confer increased risk for fetal macrosomia, neonatal hypoglycemia and other complications. In women with pre-existing diabetes, chances for a successful pregnancy outcome are significantly improved with aggressive control of blood glucose prior to conception. Normalizing blood glucose control before and in early pregnancy reduces the risk of major congenital anomalies and spontaneous abortion to near that of the risks in women without diabetes. All women of childbearing age with diabetes should be counseled regarding the importance of planning their pregnancies and obtaining tight glycemic control prior to becoming pregnant.
Pre-conception evaluation and counseling are crucial in order to evaluate the risks to both the mother and fetus of a potential pregnancy. In addition to educating women about the importance of intensive glycemic control prior to conception to decrease the risks to a developing baby, an assessment of pre-existing diabetes-related complications and other maternal medical problems allows for risk assessment and education about potential maternal risks of a pregnancy.
Certain diabetes-related complications may worsen during pregnancy or significantly increase the risks to the mother or infant. In some women, retinopathy may progress during pregnancy. Women with advanced retinopathy should be treated and stabilized prior to pregnancy. If significant impairment in renal function exists (creatinine > 2 mg/dl or creatinine clearance of < 50 ml/min) there is a significant risk of permanent worsening of renal function with pregnancy. Elevated urinary protein (> 190 mg/day) is associated with an increase in maternal hypertensive disorders. Women with more significant levels of proteinuria (> 400 mg/day) are at increased risk of intrauterine growth retardation later in pregnancy. Untreated ischemic heart disease is also associated with a high risk of maternal mortality and constitutes a contraindication to pregnancy in most women. Lastly, gastroparesis can make glycemic control during pregnancy extremely difficult, due to erratic and unpredictable food absorption and can compromise maternal and fetal nutritional status.
The evaluation of women with diabetes contemplating pregnancy should include assessment of their glycemic control utilizing both results of SMBG results and HbA1c levels. A dilated eye examination by an ophthalmologist should be done with treatment undertaken as appropriate. Clinical evaluation should include evaluation for autonomic neuropathy, including hypoglycemia unawareness, gastroparesis, and orthostatic hypotension. Serum creatinine and 24-h urine for creatinine clearance and excretion of microalbumin and protein should be obtained to evaluate renal function and the presence of and degree of nephropathy. An EKG should be done in women with longstanding (> 10 years) of diabetes or if additional cardiovascular risk factors are present. Further cardiac testing should be done as indicated. Normal thyroid status should also be confirmed, particularly in women with Type 1 diabetes.
Once initial evaluation and counseling are done, women contemplating pregnancy should meet with both a nurse educator to review diabetes self-management skills and with a nutrition educator to develop a meal plan. Women with Type 1 diabetes should initiate an intensive insulin regimen that is adjusted as appropriate to achieve and maintain near-normal blood glucose levels and a HbA1c at or near the upper limit of the normal range (or the lowest level possible without undue risk of maternal hypoglycemia). Achieving this level of control typically requires frequent SMBG and 3-4 injections of insulin daily or use of an insulin pump. Target blood glucose levels prior to conception to achieve a HbA1c level as mentioned include pre-prandial plasma glucose levels of 80-110 mg/dl (4.4-6.1 mmol/l), and 2-hour post-prandial plasma glucose levels of < 155 mg/dl (8.6 mmol/l). Women with Type 2 diabetes are typically managed in the same manner with discontinuation of oral agents and initiation of an intensive insulin regimen to achieve optimal control prior to conception.
Once a woman with diabetes becomes pregnant, aggressive glycemic control throughout gestation is of utmost importance. Target blood glucose levels are essentially the same as those discussed in women with GDM. In women with Type 1 diabetes, glycemic control during the first trimester can be complicated by hypoglycemia, in part due to morning sickness. Women taking insulin must be educated in prevention and appropriate treatment of hypoglycemia. In women with hypoglycemia unawareness, the target blood glucose levels may need to be loosened to prevent severe hypoglycemia.
Insulin requirements in the first trimester typically average 0.7 U/kg/day in women with Type 1 diabetes. As pregnancy progresses past the 18th week, insulin requirements gradually increase up to 1.0 U/kg/day close to term. Women with type 2 diabetes often have a similar insulin requirement as women with Type 1 diabetes early in pregnancy (~0.7-0.8 U/kg). However, insulin requirements increase much more through pregnancy and can reach up to 2.2 U/kg/day close to term. Frequent SMBG and communication with the health care team allow the insulin regimen to be adjusted on a frequent basis to maintain glycemic control throughout pregnancy. HbA1c levels should be done every 1-2 month and ideally be maintained in the normal range.
Controversies in Management:
As mentioned above, there is a lack of consensus regarding the optimal testing strategy and diagnostic threshold. Different organizations (ADA, WHO) advocate different diagnostic tests and thresholds. Whether universal screening or selective screening is more appropriate and cost effective, which screening test should be done (e.g.100 gm, 3 hr glucose tolerance test; 75 gm, 2 hr glucose tolerance test; 50 gm, 1 hr glucose challenge; fasting blood glucose, etc.) and which glycemic thresholds best identify women and fetuses at risk of complications from GDM are all issues which are debated and under study.
Likewise, the optimal timing of post-prandial SMBG readings (1 hr vs. 2 hr) and targets for both the fasting and post-prandial SMBG results are not universally agreed upon. Some authorities advocate lower targets than those recommended by the ADA cited above. The case for lower target blood glucose levels is supported by a recent study that showed that in pregnant women without diabetes, the blood glucose level peaks 1 hr after meals and mean post-prandial glucose levels never exceeded 105.2 mg/dl (5).
And lastly, there is some data on the utility of fetal growth measures to select individuals for insulin therapy. Measurement of the fetal abdominal circumference early in the third trimester may help risk-stratify patients and identify pregnancies at low risk of macrosomia despite mild elevations in maternal blood glucose levels, thereby avoiding insulin therapy without increasing risk to the fetus.
- Clinical Practice Recommendations: "Gestational Diabetes". Diabetes Care (Supplement 1) 25: S94-S96 (2002).
- Clinical Practice Recommendations: "Preconception Care of Women with Diabetes". Diabetes Care (Supplement 1) 25: S82-S84 (2002).
- "Medical Management of Pregnancy Complicated by Diabetes" 3rd edition (2000). American Diabetes Association, Inc. Alexandria, VA.
- Joslin Diabetes Center and Joslin Clinic, Inc. "Guideline for Detection and Management of Diabetes in Pregnancy" (2002).
- Parretti, Elena, et. al. "Third-Trimester Maternal Glucose Levels From Diurnal Profiles in Nondiabetic Pregnancies" Diabetes Care 24:1319-1323 (2001).
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