US Pharm. 2006;31(11)(Diabetes suppl):31-36.

About 4% of pregnant patients in the United States have diabetes mellitus (DM), making it the most common medical complication of pregnancy. Most pregnant patients with diabetes have gestational diabetes mellitus (GDM), with glucose intolerance developing during pregnancy. The remaining patients have been diagnosed with DM prior to pregnancy (pregestational DM). In pregestational DM, type 2 DM is twice as common as type 1 DM.1

Prior to the introduction of insulin therapy, pregnant women with DM and their babies had higher rates of morbidity and mortality. Although these outcomes have greatly improved over the last 80 years, diabetes in pregnancy is still associated with increased complications, especially when glycemic control is poor. Fortunately, with optimal glycemic control and obstetrical management of the pregnant patient with DM, outcomes comparable to those in the general population are possible. This article introduces the pharmacist to the basic pathophysiology of diabetes during pregnancy, discusses gestational and pregestational DM and its management, and reviews some important counseling points to educate pregnant patients with DM and achieve favorable outcomes.

Pathophysiology of Diabetic Pregnancy
During an uncomplicated pregnancy, significant changes in hormonal regulation of carbohydrate, protein, and lipid metabolism occur. Because maternal and fetal nutritional demands increase during late gestation and lactation, adequate nutritional stores must be present during early gestation. Normal pregnancy has been described as a diabetogenic state because of the progressive increase in postprandial glucose levels and insulin response during late gestation.2 When complicated by diabetes, pregnancy becomes an even more complex disarray of metabolic changes, as reduced insulin activity leads to a metabolically abnormal environment.3

Pregnancy complicated by diabetes increases not only the complexity of management required to produce normoglycemia but also the risk of complications. Early complications associated with hyperglycemia include spontaneous abortion, preterm delivery, and congenital malformations, while late complications, including macrosomia, the need for cesarean delivery, and preeclampsia, are also more common. Additionally, microvascular and macrovascular complications can all affect and be affected by pregnancy. Fetal prognosis and risk factors for fetal compromise can be determined using the White classification, which is based upon the mother's age at onset and duration of diabetes and the presence of vasculopathy.4,5

While it is important for pregnant patients with pregestational type 1 DM to have good glycemic control during early pregnancy to minimize adverse outcomes, tight glycemic control increases the risk for complications associated with hypoglycemia. Although changes in insulin sensitivity in diabetic and nondiabetic women are often not significant until later in gestation, various factors can increase hypoglycemic risk early in gestation in women with diabetes. In fact, in early pregnancy, women who are insulin dependent often require a decrease in their insulin dosage. Other factors thought to put women with DM at risk for complications are decreased food intake secondary to nausea, the fetus acting as a glucose sink, and increased insulin sensitivity.6 A decreased counterregulatory response to hypoglycemia by epinephrine and glucagon may also have a role.7,8 Conversely, the risk for ketoacidosis is increased in pregnant patients with type 1 DM because of their dependence on exogenous insulin and the subtle changes in glucose metabolism and insulin sensitivity that can occur.

Pregnant patients with type 2 DM and those who develop GDM share similar metabolic characteristics. Abnormalities in glucose metabolism, including defects in response to insulin secretion and decreased insulin sensitivity, as well as increased hepatic glucose production, are all major components of the disease pathophysiology. 2 Despite the physiologic similarities of pregestational type 2 DM and GDM, the outcomes in patients with GDM are often better than in those with type 2 DM.4,5 Because GDM develops later in pregnancy, women with the disease are less likely to have infants with congenital anomalies and their risk of microvascular or macrovascular complications during pregnancy is decreased. Regardless, patients who develop GDM are more likely to have macrosomic fetuses and are at higher risk of preeclampsia than are patients without DM. After pregnancy, both the mother and infant have an increased risk of type 2 DM.9,10

Management of Pregestational DM
Nonpharmacologic management, particularly monitoring and lifestyle modifications, is essential in managing all types of DM. In the nonpregnant patient, type 1 DM is managed primarily with insulin therapy, while type 2 DM is managed with oral antihyperglycemic agents and/or insulin. In the pregnant patient with DM, insulin is still preferred for those with type 1 DM and in those with type 2 DM that is not controlled through diet. Oral agents are sometimes used in those who are not insulin dependent, but their use is limited because of uncertainty regarding their safety and efficacy in pregnant patients.

Nonpharmacologic Management
Monitoring: During pregnancy, glucose concentration and hemoglobin A1c (HbA1c) values are lower than those of nonpregnant women; both fall by approximately 20% in nondiabetic pregnant patients. Thus, striving for blood glucose values and HbA1c levels at--or even below--the normal range for nonpregnant individuals is recommended. 11 Exceptionally strict glycemic control (average glucose values <86 mg/dL) is not recommended and should be avoided due to adverse maternal outcomes.12  Blood glucose values recommended for women with pregestational DM by the American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) are shown in Table 1.13,14



Frequent monitoring of blood glucose (i.e., before and after meals and at bedtime) during pregnancy is advised for patients with type 1 or type 2 DM to help prevent and/or treat hypoglycemia and hyperglycemia. As pregnancy may also exaggerate rebound from hypoglycemia, elevated morning blood glucose values may indicate nocturnal hypoglycemia and warrant occasional nighttime blood glucose monitoring. 15,16

HbA1c values can help determine chronic glycemic control. In nonpregnant patients, HbA1c values depict control over the eight to 12 weeks prior to testing. In pregnant women with pregestational DM, monitoring HbA1c is recommended every four to six weeks, as pregnancy shortens the life span of red blood cells. Some studies have shown that an HbA1c value of 7% or lower may not sufficiently reduce the risk of complications in pregnant patients; therefore, a target value less than 6%, along with close monitoring for hypoglycemia, is recommended.14

In pregnant patients with type 1 DM, urine ketones should be monitored during illness or when blood glucose values are greater than 180 mg/dL. In both situations, there is a greater risk of ketoacidosis, which is associated with worsened fetal outcomes.17

Nutritional Therapy and Other Lifestyle Modifications: Diet therapy can help the pregnant diabetic patient achieve glycemic control, manage weight gain, and prevent adverse pregnancy outcomes, although it is not sufficient treatment for most patients with pregestational DM. During pregnancy, caloric requirements are approximately 300 kcal higher than basal daily needs in nonpregnant women. Recommendations are based upon ideal body weight and body mass index (BMI) (Table 2).13 Restricting carbohydrates to 35% to 40% of calories is important to control postprandial blood glucose. Complex carbohydrates are preferred over simple sugars because they are more nutrient dense and cause less of an increase in postprandial blood glucose.18 Daily folate and iron supplementation or a prenatal vitamin is also recommended. Avoiding excessive weight gain and performing moderate low-impact exercise can also improve glycemic control, especially in pregnant patients with type 2 DM who have no contraindications ( Table 3). Patients with type 1 DM and those who are deconditioned or who did not exercise before pregnancy should exercise more judiciously.19



Pharmacologic Management
Intensive insulin therapy is usually considered the best method for achieving desirable glycemic control. Some women with type 2 DM may achieve good glycemic control with diet alone; however, those who do not, and those who took oral antihyperglycemic agents prior to pregnancy should be treated with insulin during pregnancy. Insulin requirements are similar in patients with type 1 or type 2 DM during the first trimester, but as the pregnancy progresses to the third trimester, insulin needs become proportionately greater in women with type 2 DM than in those with type 1 DM.20



Antigenicity of insulin preparations should be carefully considered in order to minimize the transplacental transport of insulin antibodies. Human insulin is the least immunogenic and is the preferred commercially available preparation. Human regular insulin has been the most widely studied in pregnancy and is used as the benchmark for insulin safety and efficacy in pregnant women. Of the rapid-acting insulin analogs (i.e., lispro, aspart, glulisine), only lispro and aspart have been studied in pregnancy and are considered safe with no evidence of teratogenicity. Both have immunogenicity similar to that of human regular insulin and may be advantageous in providing tight glycemic control and lowering the risk of delayed postprandial hypoglycemia.21

The longer-acting insulin analogs (i.e., glargine, detemir) have not been widely used or extensively studied during pregnancy. Human recombinant  insulin (isophane insulin or neutral protamine Hagedorn [NPH]) is the preferred basal insulin, and women taking glargine prior to pregnancy should be switched to NPH because of concerns about the mitogenic potency of glargine. A comparison of various insulin preparations is found in Table 4.21,22



Oral antihyperglycemic agents are commonly used in the management of type 2 DM. However, there are several issues that confound the use of these agents during pregnancy. While some agents, such as glyburide and metformin, may be safe and effective alternatives to insulin therapy, as some studies suggest, these drugs are not FDA approved for use in pregnancy. Drugs which cross the placenta and can cause fetal hyperinsulinemia (e.g., tolbutamide, chlorpropamide) can cause macrosomia and prolonged neonatal hypoglycemia and should be avoided. Few or no data are available for other oral antihyperglycemic agents.23,24 The ADA and ACOG both recommend insulin over other agents for glycemic control in pregnant women with type 1 or type 2 DM.13,14

Intrapartum and Postpartum Management

The type of delivery, either spontaneous or induced, as well as vaginal or cesarean, will determine the proper recommendations for maintaining glycemic control and preventing hypoglycemia. In general, insulin requirements usually decrease during delivery and in the postpartum period. Because maternal hyperglycemia is the major cause of neonatal hypoglycemia, maintenance of maternal euglycemia during the peripartum period is crucial.25 Management of glycemic control is more erratic in lactating diabetic women, and episodes of hypoglycemia may be more frequent in this population. Breast-feeding may also influence which oral antihyperglycemic agents are used in women with type 2 DM. 26

Management of GDM

To reduce the risk of maternal and fetal morbidity, especially macrosomia and related complications such as shoulder dystocia, health care providers should be vigilant about identifying women with GDM. Determining which patients to screen is controversial; some authorities suggest universal screening, while others recommend against screening patients with a low risk of GDM. Regardless, women who test positive during initial screening should undergo a three-hour oral glucose tolerance test (GTT) with a 100-g glucose load for a definitive diagnosis (Table 5 ).26,27 As with pregestational DM, both nonpharmacologic and pharmacologic management are essential to achieve optimal outcomes.



Nonpharmacologic Management
Monitoring: Because glycemic control in patients with GDM is often managed through diet, monitoring serves a slightly different purpose than in those with pregestational DM. Monitoring of fasting and one-hour postprandial blood glucose is performed to determine the degree of hyperglycemia in order to assess fetal risk and helps determine whether and when insulin should be initiated (Table 6).26,28 Once insulin therapy has been initiated, more frequent monitoring may be required to help prevent hypoglycemic complications and to guide therapy as the pregnancy progresses. In patients with GDM, monitoring of HbA1c may be helpful as an ancillary test to confirm that blood glucose monitoring is accurately reflecting maternal glycemic control but has less of a role than it does in pregnant patients with pregestational DM.



Nutritional Therapy and Other Lifestyle Modifications: Nutritional counseling by a registered dietitian is recommended for all patients with GDM. Calorie allotment and carbohydrate-intake limits for patients with GDM are similar to those of women with pregestational DM. 13,18

Exercise appears to improve glycemic control by increasing tissue sensitivity to insulin. Women with GDM who participate in cardiovascular exercise may have reduced fasting and postprandial blood glucose concentrations. In some women, the initiation of insulin may be delayed or obviated completely. The ADA encourages women with GDM who have no contraindications to participate in moderate exercise as part of their treatment plan.26

Pharmacologic Management
Insulin is the only treatment recommended in the U.S. for maintaining normoglycemia in patients with GDM who do not achieve adequate blood glucose control through medical nutritional therapy. Approximately 15% of women with GDM require insulin therapy. This figure includes women who have difficulty maintaining normoglycemia and those at high risk of delivering a macrosomic infant, as verified by ultrasound.26,29

The dose of insulin is patient specific and varies according to degree of obesity, ethnic characteristics, and diet. Most studies report that a total insulin dose ranging from 50 to 90 units/day is required to achieve adequate glucose control.

While oral antihyperglycemic agents are not approved by the FDA for use during pregnancy, data are becoming more widely available on using certain agents for managing GDM. A study of glyburide therapy in 404 women with mild GDM who were randomized to receive either glyburide or insulin showed similar mean blood glucose concentrations during treatment with no differences in the frequency of macrosomia.30 A large study is underway in Australia evaluating the safety and efficacy of metformin in GDM. Until more data on outcomes and the long-term effects on offspring are available, use of glyburide or metformin is not recommended.

Intrapartum and Postpartum Management

As with pregestational DM, avoiding maternal hyperglycemia is important to reduce the risk of neonatal hypoglycemia. For patients with GDM who use insulin, insulin can usually be withheld during delivery, and an infusion of normal saline is often sufficient to maintain euglycemia.31 Blood glucose should be measured on the day after delivery to ensure that the mother is no longer hyperglycemic. A regular diet can usually be resumed after delivery. It is often beneficial for women who experienced GDM to periodically check their blood glucose at home and report any high values to their physician. Although most women with GDM return to normoglycemia after delivery, their risk for overt DM, impaired glucose tolerance, and recurrent GDM is higher than in those with unaffected pregnancies.32

Education--Pharmacist's Role:Preconception counseling is one of the first steps in increasing the likelihood of a healthy pregnancy, especially for patients with type 1 or type 2 DM.14 Glycemic control should be carefully evaluated, and adjustments in diet, lifestyle, and medications should be made to achieve euglycemia even before a woman becomes pregnant. Identifying a history of acute and chronic complications of DM is also important and allows for proper monitoring and management during pregnancy. Information on fetal and maternal complications should be discussed with the patient, highlighting risks applicable to the patient and her fetus.

Pharmacists need to counsel women who take medications to prevent or treat microvascular and macrovascular complications of DM on whether the medications are safe during pregnancy. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for cardiovascular and renal protection and blood pressure control are contraindicated during pregnancy; methyldopa or a long-acting calcium channel blocker may be a safer alternative. Potent LDL cholesterol–lowering therapy, such as statins, is also contraindicated during pregnancy.

Pharmacists are well positioned to make recommendations regarding therapy for a patient's glycemic control and to help manage complications associated with a diabetic pregnancy. With proper education and appropriate management of a pregnant woman's DM, excellent outcomes for both the woman and her baby can be achieved.

References

1. Engelgau MM, Herman WH, Smith PJ, et al. The epidemiology of diabetes and pregnancy in the US, 1988. Diabetes Care. 1995;18:1029-1033.

2. Landon MB, Catalan PM, Gabbe SG. Diabetes mellitus. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 4th Ed. London: Churchill Livingstone; 2001.

3. Buchanan TA, Kitzmiller JL. Metabolic interactions of diabetes and pregnancy. Annu Rev Med. 1994;45:245-260.

4. Diamond MP, Salyer SL, Vaughn WK, et al. Reassessment of White's classification and Pedersen's prognostically bad signs of diabetic pregnancies in insulin-dependent diabetic pregnancies. Am J Obstet Gynecol. 1987;156:599-604.

5. Reece EA, Sivan E, Francis G, Homko CJ. Pregnancy outcomes among women with and without diabetic microvascular disease (White's classes B to FR) versus non-diabetic controls. Am J Perinatol. 1998;15:549-555.

6. Weiss PAM, Hofmann H. Intensified conventional insulin therapy for the pregnant diabetic patient. Obstet Gynecol. 1984;64:629-637.

7. Diamond MP, Reece EA, Caprio S, et al. Impairment of counterregulatory hormone responses to hypoglycemia in pregnant women with insulin-dependent diabetes mellitus. Am J Obstet Gynecol . 1992;166:70-77.

8. Rosenn BM, Miodovnik M, Khoury JC, et al. Counterregulatory hormonal responses to hypoglycemia during pregnancy. Obstet Gynecol. 1996;87:568-574.

9. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192:989.

10. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477.

11. Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr. 2000;71:1256S.

12. ter Braak EW, Evers IM, Willem Erkelens D, Visser GH. Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences. Diabetes Metab Res Rev. 2002;18:96.

13. ACOG. Practice Bulletin #60. Pregestational Diabetes Mellitus. Obstet Gynecol. 2005;105:675.

14. Preconception care of women with diabetes. Diabetes Care. 2004;27(Suppl 1):S76.

15. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med . 1995;333:1237.

16. Manderson JG, Patterson CC, Hadden DR, et al. Preprandial versus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized controlled clinical trial. Am J Obstet Gynecol. 2003;189:507.

17. Rizzo T, Metzger BE, Nurns WJ. Correlations between antepartum maternal metabolism and intelligence of offspring. N Engl J Med. 1991;325:911.

18. The American Diabetes Association. Modern Management of the Pregnant Diabetic Woman. 4th ed. 2001.

19. Jovanovic L. Glycemic control in women with type 1 and type 2 diabetes mellitus during pregnancy. UpToDate. Available at: www.uptodate.com. Accessed September 2006.

20. Langer O, Anyaegbunam A, Brustman L, et al. Pregestational diabetes: insulin requirement throughout pregnancy. Am J Obstet Gynecol. 1988;159:616.

21. Hirsch I. Insulin analogues. N Engl J Med. 2005;352:174.

22. Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes . 2000;49:999.

23. Langer O. Oral hypoglycemic agents and the pregnant diabetic: "from bench to bedside." Semin Perinatol. 2002;26:215.

24. Greene MF. Oral hypoglycemic drugs for gestational diabetes. N Engl J Med. 2000;343:1178.

25. Jovanovic L, Peterson CM. Insulin and glucose requirements during the first stage of labor in insulin-dependent diabetic women. Am J Med. 1983;75:607.

26. Gestational diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S88.

27. Oats JJ. Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 1998 Aug 21 (Suppl 2):B58-B59.

28. ACOG. Practice Bulletin #30: Gestational Diabetes.

29. Bonomo M, Cetin I, Pisoni MP, et al. Flexible treatment of gestational diabetes modulated on ultrasound evaluation of intrauterine growth: a controlled randomized clinical trial. Diabetes Metab. 2004;30:237.

30. Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134.

31. Glueck CJ, Goldenberg N, Pranikoff J, et al. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod. 2004;19:1323.

32. MacNeill S, Dodds L, Hamilton DC, et al. Rates and risk factors for recurrence of gestational diabetes. Diabetes Care. 2001;24:659.

To comment on this article, contact editor@uspharmacist.com.