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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 pa-tient 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, provid-ers of health care during pregnancy face the dilemma of choosing adequate therapies for individual patients. It is the task of the ob-stetrician to balance the need for extra fuel by the fetus with complications associated with excessive maternal blood glucose. Key elements in the management of preg-nancies complicated with diabetes include a balance of diet, exercise, and medications. Important factors in the clinical manage-ment of patients with diabetes include fre-quent contact with the providers, psycho-logic and social support, prenatal diagnosis and counseling, fetal surveillance, and ad-equate postpartum follow-up. Several areas of controversy exist, including when and how to screen populations for diabetes, which glycemic levels reduce fetal compli-cations without affecting maternal compli- ance, and appropriate timing and mode of delivery. Management of patients with diabetes during pregnancy is guided to obtain target plasma glucose concentrations. Most inves-tigators 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 al 1 published that the glucose value 1 hour after a meal is the most predictive of fetal macro-somia. Other investigators have used differ-ent laboratory tools to manage patients with diabetes during pregnancy such as serum he-moglobin A 1 C levels. This test is not rou-tinely 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 pa-tients who are obese or underweight. Distri-bution of calories usually consists of ap-proximately 40–50% carbohydrates, 20% protein, and 30–40% fat. If dietary manipu-lation does not provide adequate metabolic Correspondence: Jose L. Gonzalez, MD, University of New Mexico, 2211 Lomas Blvd. NE, ACC4, Department of Obstetrics and Gynecology, Albuquerque, NM 87131. E-mail: CLINICAL OBSTETRICS ANDGYNECOLOGY Volume 45, Number 1, 165–169 2002, Lippincott Williams & Wilkins, Inc. CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 45 / NUMBER 1 / MARCH 2002 165control, as reflected by abnormally high plasma glucose concentrations, then medi-cal 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 in-sulin 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 pran-dial insulins are used to cover the glucose excursions after meals. Subcutaneous regu-lar insulin has been prescribed most often. Insulin Lispro, a semisynthetic insulin mol-ecule that maintains the activity of regular insulin, offers the advantage of being ab-sorbed more quickly. Initial concerns re-garding development or progression of dia-betic retinopathy with the use of insulin Lis-pro have not been supported by recent studies.2 Intermediate-acting insulins, like neutral Hagedorn, offer an extended release from a subcutaneous site. Long acting insu-lins are used to suppress the hepatic produc-tion 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 pre-pared as 100 U/mL. Being less immuno-genic, human insulin is preferred over bo-vine insulin. Commercially prepared mix-tures of regular and neutral Hagedorn insulin are not routinely used during preg-nancy. 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 recom-mended in the third trimester.3 Postpartum, the patient should be placed on her prepreg-nancy dose or 50% of the last total daily dose before delivery. Insulin therapy during pregnancy usually involves a combination of usually two insu-lin formulations to more closely resemble what the normal human pancreas does. Methods and timing of insulin administra-tion are as important as the insulin dose in avoidance of hyperglycemia. Shown in Fig-ure 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 in-sulin secretion. Advantages to the pump in-clude basal rates of insulin that reduce the risk of hyperglycemia, decrease in the inci-dence of the ‘dawn’ phenomenon (fasting hyperglycemia) by reducing maternal hypo- TABLE 1. Insulin Formulations Onset Peak Duration Lispro 15–20 min 1–2 hrs 4 hrs Regular 30–60 min 2–4 hrs 4–6 hrs NPH 1–2 hrs 5–7 hrs 10–12 hrs Lente 1–2 hrs 10–12 hrs 14–18 hrs Ultralente 1–2 hrs none 20–24 hrs Lantus 1–2 hrs none 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 0.5 D5/Ringer’s lactate 100–140 1.0 D5/Ringer’s lactate 141–180 1.5 Normal saline 181–220 2.0 Normal saline >220 2.5 Normal saline * as 25 U regular insulin in 250 ml normal saline with intrave-nous line flushed before IV administration is started. 166 GONZALEZglycemia, and improved patient compliance since the patient does not constantly have to inject insulin. Other advantages include in-creased contact with health care providers
and greater flexibility with lifestyle. Disad-vantages of the pump include cost of the de-vice, infection at the needle insertion site, and pump malfunction that may produce hy-perglycemia 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 to-tal dose of regular insulin is divided into 60% being given continuously and 40% be-ing 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- FIG. 1. Examples of three individualized programs for administering in-sulin subcutaneously each day. These programs include a combination of regular and neutral Hagedorn insulin (A), Lispro and neutral Hagedorn in-sulin (B), and Lispro and ultralente insulin (C). Management of Diabetes in Pregnancy 167placement of fluids and electrolytes and the infusion of bicarbonate, insulin administra-tion 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 in-travenous 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 re-versed, the insulin dose is decreased to 5 to 10 U every 2 to 4 hours. Once satisfactory control is achieved, only subcutaneous regu-lar insulin is required using a sliding scale dose regimen. When the patient is eating, in-termediate 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 vi-tal, because strict glucose control (less than 100 mg/dL) is desired to avoid maternal hy-perglycemia or hypoglycemia. Uncon-trolled maternal blood glucose levels during the intrepartum period may result in neona-tal hypoglycemia with the potential for tem-porary or permanent neuronal damage.5 In-trapartum 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 ac-tion. Sulfonylurea, biguanide, alpha-glu-cosidase 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 Jackson 6 published in 1986 did not re-veal any adverse perinatal outcomes when patients with gestational diabetes were treated with oral hypoglycemics. Piacqua-dio et al 7 demonstrated an increase in congenital malformations of Mexican-American women treated during early preg-nancy with oral hypoglycemic agents. In 1994, Denno and Sadler 8 found no embryo-toxicity associated with use of these medica-tions 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 pe-ripherally to increase insulin receptor sensi-tivity. A recent randomized study by Langer et al 9 revealed that glucose levels in gesta-tional diabetic patients could also be con-trolled using glyburide. The need to treat with insulin, rather than glyburide, for inad-equate glucose control was observed in only 4% cases. There were no maternal or neona-tal complications. Further investigation at other institutions is necessary. Areas of Ongoing Investigation Several alternative therapies are being ex-plored for the management of patients with diabetes during pregnancy. These include the possibility of pancreatic islet transplan-tation,
10 embryonic stem cells that could dif-ferentiate into insulin producing tissue, and gene therapy. In addition to glyburide, other hypoglyce-mic agents may be considered as alterna-tives for the treatment of patients with ges-tational 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-vorable outcomes with continued use of this drug during pregnancy. Another area of interest is the develop-ment of noninvasive glucose monitoring de-vices as an alternative to performing mul-tiple finger sticks. These noninvasive glu-cose monitor devices could dramatically change the lifestyle of patients with diabetes in pregnancy. Summary Pregnancies complicated with diabetes are best managed using a multidisciplinary team approach to individualize diet and insulin regimens. The combination of rapid and in-termediate acting insulins more closely re-sembles what happens physiologically with the pancreatic secretion of insulin. In pa-tients 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 hypogly-cemic agent is safest and most effective in controlling maternal hyperglycemia. References 1. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. NiHCD Diabetes in early preg-nancy study. Maternal port prandial glucose level and infant birth weight: The diabetes in early pregnancy study. Am J Obstet Gyne-col. 1991;164:103–111. 2. Buchbinder A, Miodounik M, McElvy S, et al. Is insulin Lispro associated with the de-velopment or progression of diabetic retro-pathy during pregnancy? Am J Obstet Gy-necol. 2000;183:1162–1165. 3. Jovanovic L. Role of diet and insulin treat-ment of diabetes in pregnancy. Clin Obstet Gynecol. 2000;43:46–55. 4. Gabbe S. New concepts and applications in the use of insulin pump during pregnancy. J Matern Fetal Med. 2000;9:42–45. 5. Halamek LP, Stevenson DK. Neonatal hy-poglycemia, part II: Pathophysiology and therapy. Clin Ped. 1998:37:11–16. 6. Coetzee EJ, Jackson WPU. The manage-ment of noninsulin dependent diabetes dur-ing pregnancy. Diabetes Res Clin Pract.
1986;1:281–287. 7. Piacquadio K, Hollingsworth DR, Murphey H. Effects of in utero exposure to oral hypo-glycemic drugs. Lancet. 1991;338:866– 869. 8. Denno KM, Sadler TW. Effects of the bi-guanide class of oral hypoglycemic agents on mouse embryo-genesis. Teratology. 1994;49:260–266. 9. 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. 10. 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 diabe-tes. J Matern Fetal Med. 2000;9:46–51. 11. Gluek CJ, Phillips H, Cameron D, et al. Con-tinuing metformin thoughout pregnancy in women with polycystic ovary syndrome ap-plies to safety reduce first trimester sponta-neous abortion: a pilot study. Fertil Steril. 2001;75:46–52. Management of Diabetes in Pregnancy 169 168 GONZALEZ
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