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CLINICAL OBSTETRICS AND GYNECOLOGY Volume 45, Number 1, 165–169 © 2002, Lippincott Williams & Wilkins, Inc.

Management of Diabetes in Pregnancy JOSE L. GONZALEZ, MD Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, University of New Mexico, Albuquerque, New Mexico

Management of the diabetic pregnant patient has changed dramatically during the last 80 years. Since 1920 when insulin was discovered until today when researchers are talking about genetic manipulation, stem cells, and pancreatic islet capsules, providers of health care during pregnancy face the dilemma of choosing adequate therapies for individual patients. It is the task of the obstetrician to balance the need for extra fuel by the fetus with complications associated with excessive maternal blood glucose. Key elements in the management of pregnancies complicated with diabetes include a balance of diet, exercise, and medications. Important factors in the clinical management of patients with diabetes include frequent contact with the providers, psychologic and social support, prenatal diagnosis and counseling, fetal surveillance, and adequate postpartum follow-up. Several areas of controversy exist, including when and how to screen populations for diabetes, which glycemic levels reduce fetal complications without affecting maternal compliCorrespondence: Jose L. Gonzalez, MD, University of New Mexico, 2211 Lomas Blvd. NE, ACC4, Department of Obstetrics and Gynecology, Albuquerque, NM 87131. E-mail: [email protected] CLINICAL OBSTETRICS AND GYNECOLOGY

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ance, and appropriate timing and mode of delivery. Management of patients with diabetes during pregnancy is guided to obtain target plasma glucose concentrations. Most investigators agree that fasting plasma glucose concentrations should be kept under 95 mg/dL and postprandial levels under 120 mg/dL. In 1991 Jovanovic-Peterson et al1 published that the glucose value 1 hour after a meal is the most predictive of fetal macrosomia. Other investigators have used different laboratory tools to manage patients with diabetes during pregnancy such as serum hemoglobin A1C levels. This test is not routinely used to follow glucose levels since it only reflects average values without taking into consideration peaks in plasma glucose concentrations after meals. Patients with glucose intolerance during pregnancy need specific diet instructions. A typical diet includes three meals with three snacks during the day. The diet is often based on 30 kcal/kg of actual weight. This recommendation has to be modified in patients who are obese or underweight. Distribution of calories usually consists of approximately 40–50% carbohydrates, 20% protein, and 30–40% fat. If dietary manipulation does not provide adequate metabolic VOLUME 45

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control, as reflected by abnormally high plasma glucose concentrations, then medical therapy with meticulous capillary blood glucose self-monitoring is necessary.

Insulin Therapy FORMULATIONS

Exogenous insulin lowers blood glucose levels in all types of diabetes. Optimal therapy, should approximate physiologic insulin delivery, which may be difficult. There are many insulin formulations (Table 1). These insulin products differ in their onset, peak, and duration of action. Rapid or prandial insulins are used to cover the glucose excursions after meals. Subcutaneous regular insulin has been prescribed most often. Insulin Lispro, a semisynthetic insulin molecule that maintains the activity of regular insulin, offers the advantage of being absorbed more quickly. Initial concerns regarding development or progression of diabetic retinopathy with the use of insulin Lispro have not been supported by recent studies.2 Intermediate-acting insulins, like neutral Hagedorn, offer an extended release from a subcutaneous site. Long acting insulins are used to suppress the hepatic production of glucose. Ultralente is an example of a long acting insulin that produces a nearly constant level of circulating insulin when given subcutaneously once or twice daily. Almost all insulins used in adults are prepared as 100 U/mL. Being less immunogenic, human insulin is preferred over bovine insulin. Commercially prepared mixtures of regular and neutral Hagedorn TABLE 1.

Lispro Regular NPH Lente Ultralente Lantus

Insulin Formulations Onset

Peak

Duration

15–20 min 30–60 min 1–2 hrs 1–2 hrs 1–2 hrs 1–2 hrs

1–2 hrs 2–4 hrs 5–7 hrs 10–12 hrs none none

4 hrs 4–6 hrs 10–12 hrs 14–18 hrs 20–24 hrs 20 hrs

TABLE 2.

Guidelines for Continuous Insulin Infusion During Pregnancy

Blood Glucose (mg/100 mL)

Insulin Dosage (U/hour)*

Fluids (125 mL/hour)

<100 100–140 141–180 181–220 >220

0.5 1.0 1.5 2.0 2.5

D5/Ringer’s lactate D5/Ringer’s lactate Normal saline Normal saline Normal saline

* as 25 U regular insulin in 250 ml normal saline with intravenous line flushed before IV administration is started.

insulin are not routinely used during pregnancy. When two different insulins are drawn into the same syringe, care must be taken to avoid cross-contamination of bottles. MAINTENANCE THERAPY

The actual patient’s body weight is used to calculate the daily insulin dose. During the first trimester the recommendation is 0.5 U/kg. In the second trimester 0.75 U/kg is recommended, while 1.0 U/kg is recommended in the third trimester.3 Postpartum, the patient should be placed on her prepregnancy dose or 50% of the last total daily dose before delivery. Insulin therapy during pregnancy usually involves a combination of usually two insulin formulations to more closely resemble what the normal human pancreas does. Methods and timing of insulin administration are as important as the insulin dose in avoidance of hyperglycemia. Shown in Figure 1 are three examples of individualized programs. None is clearly most preferred. An alternative for patients with type 1 diabetes is the use of insulin pumps.4 These calibrated pumps deliver insulin in a pattern that most closely resembles physiologic insulin secretion. Advantages to the pump include basal rates of insulin that reduce the risk of hyperglycemia, decrease in the incidence of the ‘dawn’ phenomenon (fasting hyperglycemia) by reducing maternal hypo-

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FIG. 1. Examples of three individualized programs for administering insulin subcutaneously each day. These programs include a combination of regular and neutral Hagedorn insulin (A), Lispro and neutral Hagedorn insulin (B), and Lispro and ultralente insulin (C).

glycemia, and improved patient compliance since the patient does not constantly have to inject insulin. Other advantages include increased contact with health care providers and greater flexibility with lifestyle. Disadvantages of the pump include cost of the device, infection at the needle insertion site, and pump malfunction that may produce hyperglycemia and ketoacidosis. These factors make the insulin pump an alternative only for patients who are very compliant with blood glucose self-monitoring. The insulin

pump dose is often calculated based on 80% of the total daily dose requirement. This total dose of regular insulin is divided into 60% being given continuously and 40% being administered in boluses before meals to cover the carbohydrate load. INTRAVENOUS THERAPY

Ketoacidosis is fortunately uncommon in closely regulated type 1 diabetic patients but may result from profound hyperglycemia and ketosis. Along with the appropriate re-

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placement of fluids and electrolytes and the infusion of bicarbonate, insulin administration is necessary. The desired goal is a serum glucose level of less than 300 mg/dL with no urinary ketone bodies. The author usually begins regular insulin as a 10 to 20 U of intravenous bolus plus 0.15 U/kg/h of constant intravenous infusion. The dose is increased hourly if serum glucoses do not fall despite adequate fluid therapy. As acidosis is reversed, the insulin dose is decreased to 5 to 10 U every 2 to 4 hours. Once satisfactory control is achieved, only subcutaneous regular insulin is required using a sliding scale dose regimen. When the patient is eating, intermediate acting insulin may be started. The intrapartum management of diabetes is similar to the management of a woman with diabetes about to undergo surgery. Monitoring of the blood glucose level by finger stick or venipucture every hour is vital, because strict glucose control (less than 100 mg/dL) is desired to avoid maternal hyperglycemia or hypoglycemia. Uncontrolled maternal blood glucose levels during the intrepartum period may result in neonatal hypoglycemia with the potential for temporary or permanent neuronal damage.5 Intrapartum blood glucose control is achieved by using intravenous infusion of dextrose solutions with minimal or no insulin therapy. Continuous intravenous infusion of regular insulin or Lispro is preferred since the rapid onset and short duration of action make them ideal to titrate the therapy. A constant intravenous infusion pump should be used for this.

Oral Hypoglycemic Agents Oral hypoglyemic drugs include agents with differing chemistries and mechanisms of action. Sulfonylurea, biguanide, alpha-glucosidase inhibitors, and thiazolidinedione drugs are indicated in the management of nonpregnant adults with type 2 diabetes. Oral hypoglycemics have been proposed as alternative modalities in the treatment of gestational diabetes. Studies from Coetzee

and Jackson6 published in 1986 did not reveal any adverse perinatal outcomes when patients with gestational diabetes were treated with oral hypoglycemics. Piacquadio et al 7 demonstrated an increase in congenital malformations of MexicanAmerican women treated during early pregnancy with oral hypoglycemic agents. In 1994, Denno and Sadler8 found no embryotoxicity associated with use of these medications in an animal model. Glyburide, a sulfonylurea that does not cross the placenta, is appealing because of its apparent safety to the fetus. Presumed mechanisms of action include an increase in the secretion of insulin and some effect peripherally to increase insulin receptor sensitivity. A recent randomized study by Langer et al9 revealed that glucose levels in gestational diabetic patients could also be controlled using glyburide. The need to treat with insulin, rather than glyburide, for inadequate glucose control was observed in only 4% cases. There were no maternal or neonatal complications. Further investigation at other institutions is necessary.

Areas of Ongoing Investigation Several alternative therapies are being explored for the management of patients with diabetes during pregnancy. These include the possibility of pancreatic islet transplantation,10 embryonic stem cells that could differentiate into insulin producing tissue, and gene therapy. In addition to glyburide, other hypoglycemic agents may be considered as alternatives for the treatment of patients with gestational diabetes. Medications that increase the receptor-sensitivity to insulin may be more appropriate, since this is the main problem in gestational diabetes. Metformin, a biguanide oral hypoglycemic agent, has been used in patients with infertility and polycystic ovaries.11 Preliminary findings in small groups of patients have reported fa-

Management of Diabetes in Pregnancy vorable outcomes with continued use of this drug during pregnancy. Another area of interest is the development of noninvasive glucose monitoring devices as an alternative to performing multiple finger sticks. These noninvasive glucose monitor devices could dramatically change the lifestyle of patients with diabetes in pregnancy.

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Summary Pregnancies complicated with diabetes are best managed using a multidisciplinary team approach to individualize diet and insulin regimens. The combination of rapid and intermediate acting insulins more closely resembles what happens physiologically with the pancreatic secretion of insulin. In patients with type 1 diabetes, the insulin pump is an alternative if she is highly motivated and compliant with frequent monitoring blood glucose levels. In gestational diabetes, oral hypoglycemic agents like glyburide may be alternative therapies. More studies are needed to determine if any oral hypoglycemic agent is safest and most effective in controlling maternal hyperglycemia.

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References 1. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. NiHCD Diabetes in early pregnancy study. Maternal port prandial glucose level and infant birth weight: The diabetes in early pregnancy study. Am J Obstet Gynecol. 1991;164:103–111. 2. Buchbinder A, Miodounik M, McElvy S, et

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al. Is insulin Lispro associated with the development or progression of diabetic retropathy during pregnancy? Am J Obstet Gynecol. 2000;183:1162–1165. Jovanovic L. Role of diet and insulin treatment of diabetes in pregnancy. Clin Obstet Gynecol. 2000;43:46–55. Gabbe S. New concepts and applications in the use of insulin pump during pregnancy. J Matern Fetal Med. 2000;9:42–45. Halamek LP, Stevenson DK. Neonatal hypoglycemia, part II: Pathophysiology and therapy. Clin Ped. 1998:37:11–16. Coetzee EJ, Jackson WPU. The management of noninsulin dependent diabetes during pregnancy. Diabetes Res Clin Pract. 1986;1:281–287. Piacquadio K, Hollingsworth DR, Murphey H. Effects of in utero exposure to oral hypoglycemic drugs. Lancet. 1991;338:866– 869. Denno KM, Sadler TW. Effects of the biguanide class of oral hypoglycemic agents on mouse embryo-genesis. Teratology. 1994;49:260–266. Langer O, Conway DL, Berkus MD, et al. A comparison of glybuide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134–1138. Hunter SK. Present and future perspectives of the use of free or encapsulated pancreatic islet cell trasplantation on a treatment of pregnancy complicated with Type I diabetes. J Matern Fetal Med. 2000;9:46–51. Gluek CJ, Phillips H, Cameron D, et al. Continuing metformin thoughout pregnancy in women with polycystic ovary syndrome applies to safety reduce first trimester spontaneous abortion: a pilot study. Fertil Steril. 2001;75:46–52.